CRISPR is typically used to edit disease-causing gene mutations, but is increasingly being tapped for broader applications. The latest? Identifying sequences that activate genes, which could help unravel the causes of autoimmune disease.

While CRISPR shows great promise in the treatment of genetic disease, the genes it cuts outthose that code directly for proteinsonly make up 2% of the human genome. The other 98% consists of regulatory gene sequences, including promoters, which switch on genes next to them, and enhancers, which activate genes that may sit far away from them in the genome.

When the balance of promoters and enhancers is out of whack, it can lead to disease. But its difficult to pinpoint just which regulators have a hand in causing disease, as specific regulators play a role in specific cells, under specific conditions.

Jacob Corn and Alexander Marson at the University of California, San Francisco, focused on T cells and the IL2RA protein, which tells T cells if they should step up or dampen an inflammatory response. If the enhancers that switch on IL2RA are faulty, the T cells dont suppress inflammation, which could cause autoimmune disorders, such as Crohns and inflammatory bowel disease (IBD).

Corn and Marson usedCRISPR activation, or CRISPRa, to homein on the IL2RA gene. This methoduses a guide RNA to target sections of the genome, much like regular CRISPR, but instead of cutting them, it activates those sequences to see how they affect gene expression.

They created 20,000 guide RNAs for use with CRISPRa: "We essentially performed 20,000 experiments in parallel to find all the sequences that turn on this gene," said Marson, an assistant professor of microbiology and immunology at UC San Francisco, in a statement.

The teamturned up several sequences that might be important for ILR2A expression, including a common genetic variant that was already linked to increased IBD riskbut was not well understood. The findings are published in Nature.

"This starts to unlock the fundamental circuitry of immune cell regulation, which will dramatically increase our understanding of disease," Marson said.

The utility of CRISPR is growing by the day. Recently, UC San Diego researchers created a new version of CRISPR that targets RNA rather than DNA, which could be used to treat diseases caused by errant repeats in RNA sequences, including Huntington disease and a type of amyotrophic lateral sclerosis.

And scientists at eGenesis have deployed the gene-editing tool in the organ transplant field. By snipping out a family of viruses in the pig genome, they have overcome one obstacle in xenotransplantation, or using animal organs for human transplant.

The next step forthe UCSF researchers isto modify their method so that it can screen for enhancers of many different genes at once.

"Not only can we now find these regulatory regions, but we can do it so quickly and easily that it's mind-blowing," said Corn, assistant adjunct professor of molecular and cell biology at Berkeley. "It would have taken years to find just one before, but now it takes a single person just a few months to find several."

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'Gentler' CRISPR sheds light on autoimmune disease | FierceBiotech - FierceBiotech

Recommendation and review posted by simmons

The latest research on patient preferences, quality-of-life, ear health, thyroidectomy, and other topics related to the specialty of otolaryngology will be presented in Chicago Sept 10-13, during the AAO-HNSF 2017 Annual Meeting & OTO Experience.

The 2017 Annual Meeting includes hundreds of research presentations. All abstracts to be presented are now available online as a PDF.

Nineteen studies have been selected to be presented during the Best of Orals session on Sunday, Sept 10, at 10 am, CDT, in room E450A of the McCormick Place Convention Center. These studies, identified by the Annual Meeting Program Committee, comprised of physician members, are recognized for outstanding scientific merit and innovation.

What role does the Internet and social media play in patient perception of physicians? This study looks at the physicians age and online/social media presence in relation to positive ratings and comments from patients.

What drives patients decisions, and what are their preferences of care? Where do factors like cost, timely appointments, experience, and thorough physical exam fall in a patients list of priorities?

This study reviewed 906 patient charts to identify significant factors predicting hypocalcemia after total thyroidectomy. After extensive analysis of patient demographics and surgical characteristics, only parathyroid hormone (PTH) was found to have significantly predicted hypocalcemia postoperatively. Further findings suggest that early, standardized supplementation can significantly reduce hypocalcemia-related extended stays and associated costs.

This is the first population-level analysis focusing on quality metrics for parathyroidectomy. The study identified independent, potentially modifiable perioperative factors that may assist in appropriate risk stratification for patients susceptible for readmission and reoperation.

What are the outcomes and complications after rhinoplasty with either autologous rib graft (ARG) or cadaveric rib graft (CRG)? This meta-analysis demonstrates that further research is needed to determine the complication rates and outcomes of ARG versus CRG in rhinoplasty.

Is advanced age an independent risk factor for complications following free flap surgery of the head and neck? Are such patients likely to have a longer hospital stay or be discharged to a skilled nursing facility? This study analyzes the effects of increasing age on outcomes of microvascular reconstructive surgery of the head and neck.

This study assesses the sustainability of clinical benefit with balloon dilation of the Eustachian tube (BDET) using the Eustachian tube balloon catheter (ETBC) in conjunction with medical management at 12 months follow-up in adult patients aged 22 years and older with drug-refractory Eustachian tube dilatory dysfunction (ETDD).

Do ototopical quinolones delay tympanic membrane healing in a drug-specific manner? This study compared the effect of both ciprofloxacin + dexamethasone and ofloxacin on tympanic membrane perforation healing in rats, with reported results.

The study population consisted of 8,281 individuals diagnosed with HNSCC, with 537 (6.4%) surviving to 5 years with the purpose to estimate the prevalence of comorbidity in HNSCC survivors at diagnosis and evaluate changes in prevalence of comorbidity over time.

This review analyzed the effect of adjuvant radiation on survival in pathologic N1 oropharyngeal squamous cell carcinoma (OPSCC) and if these findings apply to HPV+ tumors.

Laryngotracheal stenosis (LTS) is a fibroinflammatory disorder that causes narrowing of the airway. This study analyzed the effects of macrophage polarization on LTS-derived and normal airway fibroblasts (FBs) in vitro.

This study assessed patient decision making in subglottic stenosis treatment with findings that predict that most patients will prefer voice-sparing, low-risk procedures, consistent with an endoscopic approach, even if they require multiple procedures.

Is there a significant difference in postoperative complications in tympanoplasty with or without concurrent therapeutic mastoidectomy? This study addressed this question in the management of chronic ear disease alone.

Is the human middle ear inhabited by more diverse microbial communities than was previously thought? The aim of this prospective multicenter cohort study was to profile and compare the middle ear microbiomes of human individuals with and without chronic otitis media.

Does gender, age, nasal trauma, prior nasal surgery, allergic rhinitis, or additional surgeries (at the time of procedure) affect postoperative Nasal Obstruction Symptom Evaluation (NOSE) scores? This study analyzed disease specific quality-of-life in patients undergoing septoplasty and functional septorhinoplasty.

Is the modified Swallowing Quality of Life instrument a valid measure of dysphagia-specific QOL in children? Does it demonstrate a significant association with videofluoroscopic swallow studies and moderate-to-strong correlations with multiple domains of generic QOL measure?

Is balloon catheter dilation (BCD) an effective treatment for sinus pressure headaches? In this study, participants were recruited who reported sinus pressure headaches, localizing to either unilateral or bilateral maxillary and/or frontal sinuses, and were blinded and randomized to receive either BCD of the affected sinus ostia or a sham procedure.

This study explored whether single-nucleotide polymorphisms (SNPs) in the Thymic Stromal Lymphopoietin gene are associated with chronic rhinosinusitis and can predict TSLP activity.

This study analyzed cranial nerve XII (CNXII) stimulation 5-year outcomes and assessed effects of stimulation and body mass index (BMI). The study found that cranial nerve stimulation demonstrates significant clinical improvements at one year, but was it maintained at 5years?

See the original post here:
Physician Experts Highlight Research Ahead of Otolaryngology's Annual Meeting - Sleep Review

Recommendation and review posted by simmons

When an experiment turns into a tradition in Laughlin, it means there was a show worth taking a chance on at one timethen consistently that same show proved itself time after time to be one audiences didnt want to miss. The Memorial Day Comedy Festival at the Riverside Resort was that show. Experiencing comedy served up as a variety show with veteran comedian Gabe Lopez as the shows producer, performer and emcee was like discovering a hidden gem on the entertainment landscapemore along the lines of one of those underground clubs in Vegas, known only to a lucky few. But now the word is out and the Comedy Festival is coming back to the Riverside Resort over the Labor Day weekend this time.

If you are a local, or a regular visitor to Laughlinespecially if your visits are on holiday weekendsyou are aware that the Avi Resort & Casino doesnt simply wait for the Fourth of July to set off a major fireworks display. Nope. Beginning in 1996, and continuing every year since, they have been filling the skies above the Colorado River with the amped-up creations of Zambelli Internationale Fireworks on Memorial Day weekend, the Fourth of July and Labor Day weekend.

The Colorado Belle is home to a multitude of outdoor festivals that embrace particular themes and for the Labor Day Riverwalk Festival, its a celebration of the end of summer and the cooler temperatures just starting to take hold of the Colorado River regionthink of it as one big neighborhood block party.

Theres a lot to be said for being in the right place at the right time, but could Air Supplys long-time success be the result or a chance meeting or was the cosmos working overtime on a little something called destiny? Maybe, but one thing is for surenone of it would have been possible at all without their hard work and tenacity to make it happen.The two Russells, Graham Russell and Russell Hitchcock, happened to be cast in the same Sydney, Australian production of Jesus Christ Superstar in 1975, and everything changed after that.

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Pneumonia ventolin inhaler - Albuterol aerosol inhaler - Laughlin Entertainer

Recommendation and review posted by sam

As physicians who collectively care for thousands of transgender children, adolescents and adults in Philadelphia, we are deeply troubled by the presidents new policy that bans transgender Americans from joining the military and immediately stops gender-affirming medical care for those in active duty.

The reasoning for such a policy outlined earlier by the president that the military cannot be burdened with the tremendous medical costs and disruption that transgender in the military would entail is not supported by scientific evidence or by our experiences with transgender patients.

This reasoning implies that care to support transgender individuals medical transition is necessarily invasive and expensive. In fact, for our patients, the most common interventions include supporting social transition and prescribing hormones, like estrogen or testosterone, which cost less than $50 per month.

Despite higher costs for procedures like gender reassignment surgery, which only a minority of transgender individuals undergo, a report by the RAND corporation and a recent study published in the New England Journal of Medicine confirm that the overall cost to the military to care for transgender soldiers would be negligible.

Actually, most gender-affirming treatment for transgender individuals will in the end save the health care system money. A report by PolicyLab at Childrens Hospital of Philadelphia (CHOP) details how treatments like puberty blockers and mental health support services for transgender children and adolescents can actually prevent the need for some expensive procedures later in life.

These treatments also lead to better health outcomes as adults by shielding patients from the high costs of mental health conditions or substance abuse that might result from untreated gender dysphoria. Further restricting such treatments as the ban proposes could have unintended consequences.

As stated in our recent qualitative studies published in Journal of Adolescent Health and Transgender Health, we found that many young transgender women described lack of access to gender-affirming hormone therapy as a barrier to receiving other essential preventive and cost-saving care, such as mental health support or HIV Pre-exposure Prophylaxis,a daily pill to prevent HIV infection.

Transgender women are at nearly 50 times the risk for HIV infection compared to the average person.

Beyond this flawed over estimation of health care costs, and underestimation of potential savings, any message of you are not welcome here can cause major harm to the mental and physical well-being of transgender individuals, which make up one percent of the U.S. population. Transgender people have high rates of depression and anxiety, and as many of 40 percent have attempted suicide. These and other physical health problems are not due to their identity, but rather a result of shame, stigma and isolation when ones identity is not affirmed.

When caring for transgender children and adolescents, we talk to them about what they want to be when they grow up. They have the same hopes and dreams as other kids.

Take, for example, one 18-year-old patient who during his first visit to the CHOP Gender and Sexuality Development Clinic disclosed that despite being born assigned female sex at birth, he knew he was a boy since age four. At that young age, he had begun walking around with his shirt off because he felt he was a boy like his dad and couldnt understand why he was being told to put it back on. He also said that he has always wanted to serve our country in the military, just like his father.

But, we cant only be concerned for those who have hopes of serving their country; if enacted, this directive could have particularly grave consequences for the thousands of transgender individuals already serving in the military.

The current U.S. Department of Defense policy states that transgender individuals can serve openly and cannot be discharged solely on the basis of being transgender.

This policy helped a patient, who we are calling Sarah, at Philadelphias Mazzoni Center transition socially and medically while continuing to serve in the military. She was able to start hormones safely under medical supervision, and she had the full support of her fellow service members and her commanding officer. Without this policy, Sarah would have been forced to decide between her duty to her country and hiding her true self.

The policy also allowed a patient, here referred to as Michelle, at the University of Pennsylvania Health System begin to affirm her female gender via hormone therapy while actively serving her country. Michelle was able to seek civilian medical care for gender affirmation in collaboration with her base physicians and supervising officers. Though she enlisted as male, Michelle said that the reception to her transgender identity on the base was overwhelmingly positive, especially among her peers. She considers her status as a member of the U.S. military as integral to her identity as her gender, and has always hoped it would be her lifelong career.

Clearly this policy does not align with the real stories that we, as physicians, confront every day when we talk to patients for whom this is a deeply personal matter. Even if you disregard stories like our patients, there is no evidence to support the idea that allowing transgender individuals to serve in our military would burden us with medical costs, and there could be major negative effects to health and well-being of those currently serving if gender-affirming medical care is restricted. Our patients, and any transgender individuals, who wish to bravely serve their country should continue to be able to do so.

Nadia Dowshen, MD, MSHP is a pediatrician and adolescent medicine specialist who is co-founder of the Childrens Hospital of Philadelphia Gender (CHOP) and Sexuality Development Clinic, a faculty member at PolicyLab at CHOP and assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Allison Myers, MD, MPH is a family medicine physician and clinical assistant professor of family medicine and community health at the University of Pennsylvania where she specializes in the care of LGBTQ patients.

Lin-Fan Wang, MD, MPH is a family medicine physician at Mazzoni Center Family & Community Medicine, which provides comprehensive health care with a primary focus on the needs of lesbian, gay, bisexual, and transgender individuals.

The views expressed by contributors are their own and are not the views of The Hill.

More here:
Military ban will risk the health and well-being of transgender Americans - The Hill (blog)

Recommendation and review posted by sam

Parkinsons stem cell breakthrough

Miodrag Stojkovic/Science Photo Library

By Helen Thomson

MONKEYS with a Parkinsons-like disease have been successfully treated with stem cells that improved their movement for up to two years after transplant. A similar trial is now being prepared for people.

Parkinsons destroys dopamine-producing cells in the brain, leading to tremors and difficulty moving. Previous experiments using stem cells from embryos have shown promise in replacing lost cells, but the use of these is controversial.

Jun Takahashi at Kyoto University, Japan, and colleagues wondered whether they could treat monkeys with a disease like Parkinsons using induced pluripotent stem cells, which are made by coaxing blood or skin cells into becoming stem cells.

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The team generated stem cells from three people with Parkinsons and four without the disease. They then transformed these into dopamine-producing brain cells.

All the monkeys who received injections of these cells showed a 40 to 55 per cent improvement in their movements, matching results from previous experiments with embryonic stem cells. Monkeys who had a control injection minus the cells didnt improve (Nature, DOI: 10.1038/nature23664).

Stem cells from people with and without Parkinsons were equally effective. The monkeys became more active and showed less tremor, says Takahashi. Their movements became smoother.

After the transplant, the monkeys were given immunosuppressive drugs to prevent the new cells from being rejected and observed for up to two years. No serious side effects appeared during this time.

This study shows that the stem cells behave as you would like them to and they appear safe, says Roger Barker of the University of Cambridge. All of which gives one greater confidence in moving to human studies.

This article appeared in print under the headline Parkinsons stem cell breakthrough

More on these topics:

See original here:
Human blood and skin cells used to treat Parkinson's in monkeys - New Scientist

Recommendation and review posted by Bethany Smith

| Marlowe Hood |

PARIS (AFP) Lab monkeys with Parkinsons symptoms regained significant mobility after neurons made from human stem cells were inserted into their brains, researchers reported Wednesday in a study hailed as groundbreaking.

The promising results were presented as the last step before human clinical trials, perhaps as early as next year, the studys senior author, Jun Takahashi, a professor at Kyoto University, told AFP.

Parkinsons is a degenerative disease that erodes motor functions. Typical symptoms include shaking, rigidity and difficulty walking. In advanced stages, depression, anxiety and dementia are also common.

Worldwide, about 10 million people are afflicted with the disease, according to the Parkinsons Disease Foundation.

Earlier experiments had shown improvements in patients treated with stem cells taken from human foetal tissue and likewise coaxed into the dopamine-producing brain cells that are attacked by Parkinsons.

Dopamine is a naturally occurring chemical that plays several key roles in the brain and body.

But the use of foetal tissue is fraught with practical and ethical problems.

So Takahashi and his colleagues, in a medical first, substituted so-called induced pluripotent stem cells (iPSCs), which can be easily made from human skin or blood. Within a year, some monkeys who had could barely stand up gradually recovered mobility.

They became more active, moving more rapidly and more smoothly, Takahashi said by email. Animals that had taken to just sitting start walking around in the cage.

These findings are strong evidence that human iPSC-derived dopaminergic neurons can be clinically applicable to treat Parkinsons patients, he said.

Experts not involved in the research described the results as encouraging.

The treatment, if proven viable, has the potential to reverse Parkinsons by replacing the dopamine cells that have been lost a groundbreaking feat, said David Dexter, deputy research director at Parkinsons UK.

Not only did the new cells survive but they also integrated with the existing neuronal network, he said.

Neurons made from foetal tissue grafted into brains have been known to survive for more than a decade, and the researchers said they expected those derived from iPSCs to last just as long.

Tilo Kunath, Parkinsons Senior Research Fellow at the University of Edinburgh, said the outcome was extremely promising, and highlighted the advantage of avoiding stem cells extracted from human foetal tissue.

It means that this therapy can be used in any country worldwide, including Ireland and most of South America, where medical use of human embryonic stem cells is banned.

The results, reported in the journal Nature, were not the same for the dozen monkeys in the experiment, each of which received donor neurons from a different person.

Some were made with cells from healthy donors, while others were made from Parkinsons disease patients, said lead author Tetsuhiro Kikuchi, also from Kyoto University.

Read the rest here:
Study shows human stem cells restore mobility in Parkinson's monkeys - Borneo Bulletin Online

Recommendation and review posted by simmons

Biol Res 45: 279-287, 2012

RESEARCH ARTICLES

In Osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis

Ana Mara Pino1, Clifford J. Rosen2 and J. Pablo Rodrguez1*

1Laboratorio de Biologa Celular y Molecular, INTA, Universidad de Chile, 2Maine Medical Center Research Institute, Scarborough, Maine, USA.

ABSTRACT

The formation, maintenance, and repair of bone tissue involve close interlinks between two stem cell types housed in the bone marrow: the hematologic stem cell originating osteoclasts and mesenchymal stromal cells (MSCs) generating osteoblasts. In this review, we consider malfunctioning of MSCs as essential for osteoporosis. In osteoporosis, increased bone fragility and susceptibility to fractures result from increased osteoclastogenesis and insufficient osteoblastogenesis.

MSCs are the common precursors for both osteoblasts and adipocytes, among other cell types. MSCs' commitment towards either the osteoblast or adipocyte lineages depends on suitable regulatory factors activating lineage-specific transcriptional regulators. In osteoporosis, the reciprocal balance between the two differentiation pathways is altered, facilitating adipose accretion in bone marrow at the expense of osteoblast formation; suggesting that under this condition MSCs activity and their microenvironment may be disturbed. We summarize research on the properties of MSCs isolated from the bone marrow of control and osteoporotic post-menopausal women. Our observations indicate that intrinsic properties of MSCs are disturbed in osteoporosis. Moreover, we found that the regulatory conditions in the bone marrow fluid of control and osteoporotic patients are significantly different. These conclusions should be relevant for the use of MSCs in therapeutic applications.

Key words: MSCs, osteoporosis, adipogenesis, bone marrow microenvironment

BACKGROUND

The formation, maintenance, and repair of bone tissue depend on fine-tuned interlinks in the activities of cells derived from two stem cell types housed in the bone marrow interstice. A hematologic stem cell originates osteoclasts, whereas osteoblasts derive from mesenchymal stem cells (MSCs). Bone tissue is engaged in an unceasing process of remodelling through the turnover and replacement of the matrix: while osteoblasts deposit new bone matrix, osteoclasts degrade the old one.

Bone marrow provides an environment for maintaining bone homeostasis. The functional relationship among the different cells found in bone marrow generates a distinctive microenvironment via locally produced soluble factors, the extracellular matrix components, and systemic factors (Raisz, 2005; Sambrook and Cooper, 2006), allowing for autocrine, paracrine and endocrine activities. If only the main cellular components of the marrow stroma are considered, the activity of adipocytes, macrophages, fibroblasts, hematopoietic, endothelial and mesenchymal stem cells and their progeny bring about a complex range of signals.

Osteoporosis is a bone disease characterized by both decreased bone quality and mineral density. In postmenopausal osteoporosis, increased bone fragility and susceptibility to fractures result from increased osteoclastogenesis, inadequate osteoblastogenesis and altered bone microarchitecture.

The pathogenesis of the disease is hitherto unknown, hence the interest in basic and clinical research on the mechanisms involved (Raisz, 2005; Sambrook and Cooper, 2006). Cell studies on the origin of postmenopausal osteoporosis initially focused on osteoclastic activity and bone resorption processes; then on osteoblastogenesis, and more recently on the differentiation potential of mesenchymal stem cells (MSCs) (Shoback, 2007). Moreover, distinctive environmental bone marrow conditions appear to provide support for the development and maintenance of unbalanced bone formation and resorption (Nuttall and Gimble, 2004; Tontonoz et al., 1994). In this review, we consider the participation of the differentiation potential of MSCs, the activity of bone marrow adipocytes and the generation of a distinctive bone marrow microenvironment.

MESENCHYMAL STEM CELLS (MSCs)

Bone marrow contains stem-like cells that are precursors of nonhematopoietic tissues. These cells were initially referred to as plastic-adherent cells or colony forming-unit fibroblasts and subsequently as either mesenchymal stem cells or marrow stromal cells (MSCs) (Minguell et al., 2001; Lindnera et al., 2010; Kolf et al., 2007). There is much interest in these cells because of their ability to serve as a feeder layer for the growth of hematopoietic stem cells, their multipotentiality for differentiation, and their possible use for both cell and gene therapy (Minguell et al., 2001; Kolf et al., 2007). Friedenstein et al. (1970) initially isolated MSCs by their adherence to tissue culture surfaces, and essentially the same protocol has been used by other investigators. The isolated cells were shown to be multipotential in their ability to differentiate in culture or after implantation in vivo, giving rise to osteoblasts, chondrocytes, adipocytes, and/or myocytes.

MSCs populations in the bone marrow or those that are isolated and maintained in culture are not homogenous, but rather consist of a mixture of uncommitted, partially committed and committed progenitors exhibiting divergent stemness (Baksh et al., 2004). These heterogeneous precursor cells are morphologically similar to the multipotent mesenchymal stem cells, but differ in their gene transcription range (Baksh et al., 2004). It has been proposed that in such populations, cell proliferation, differentiation and maturation are in principle independent; stem cells divide without maturation, while cells close to functional competence may mature, but do not divide (Song et al., 2006).

Several molecular markers identify committed progenitors and the end-stage phenotypes, but at present there are no reliable cell markers to identify the uncommitted mesenchymal stem cells. Given the difficulty to identify a single marker to evaluate the population of stem cells, various combinations of these markers may be used (Seo et al., 2004; Lin et al., 2008; Xu et al., 2009). Therefore, MSCs are mainly defined in terms of their functional capabilities: self-renewal, multipotential differentiation and transdifferentiation (Baksh et al., 2004).

Hypothetically, the fate of MSCs appears to be determined during very early stages of cell differentiation ("commitment"). During this mostly unknown period, both intrinsic (genetic) and environmental (local and/or systemic) conditions interplay to outline the cell's fate towards one of the possible lineages. Based on microarray assays comparing gene expression at the stem state and throughout differentiation, it has been proposed that MSCs multilineage differentiation involves a selective mode of gene expression (Baksh et al., 2004; Song et al., 2006). It appears that "stemness" is characterized by promiscuous gene expression, where pluripotential differentiation results from the maintenance of thousands of genes at their intermediate expression levels. Upon commitment to one fate, only the few genes that are needed for differentiation towards the target tissue are selected for continuous expression, while the rest are downregulated (Zipori, 2005; Zipori, 2006).

The gene expression profile of undifferentiated human MSCs (h-MSCs) show high expression of several genes (Song et al., 2006; Tremain et al., 2001), but the contribution of such genes in preserving h-MSC properties, such as self-renewal and multilineage differentiation potential, or in regulating essential signalling pathways is largely unknown (Song et al., 2006). Several factors like age (Zhou et al., 2008), culture condition (Kultere et al., 2007), microenvironment (Kuhn and Tuan, 2010), mechanical strain (McBride et al., 2008) and some pathologies (Seebach et al., 2007; Hofer et al., 2010) appear to affect MSCs' intrinsic activity.

MSCs' commitment towards either the osteoblast or adipocyte lineage is determined by a combination of regulatory factors in the cells' microenvironment. The adequate combination leads to the activation of lineage-specific transcriptional regulators, including Runx2, Dlx5, and osterix for osteoblasts, and PPARy2 and a family of CAAT enhancer binding proteins for adipocytes (Murunganandan et al., 2009). Although the appropriate collection of regulatory factors required for suitable differentiation of MSCs is largely unknown, the TGF/BMPs, Wnt and IGF-I signals are briefly considered.

Several components of the BMP family are secreted in the MSCs' microenvironment (Lou et al., 1999, Gori et al., 1999; Gimble et al., 1995); BMP-2/4/6/7 have been identified as mediators for MSCs differentiation into osteoblasts or adipocytes (Muruganadan et al., 2009). The intracellular effects of BMPs are mediated by an interaction with cell surface BMP receptors (BMPRs type I and type II) (Gimble et al., 1995). It seems that differentiation into adipocytes or osteoblasts is highly dependent on the type of receptor I expressed by the cells, so that adipogenic differentiation requires signaling through BMPR IA, while osteogenic differentiation is dependent on BMPR IB activation (Gimble et al., 1995). The active receptors trigger the activation of Smad proteins, which induce specific genes. Under osteogenic differentiation, BMP action promotes osterix formation through Runx2-dependent and Runx2-independent pathways, thereby triggering osteogenic differentiation (Gori et al., 1999; Shapiro, 1999).

In addition to the role of BMPs in bone formation, BMPs also positively mediate the adipogenic differentiation pathways (Haiyan et al., 2009). It has been demonstrated that there is a binding site for Smad proteins in the promoter region of PPARy2 (Lecka-Czernik et al., 1999), and over-expression of Smad2 protein suppresses the expression of Runx2 (Li et al., 1998). These observations suggest that adequate content of osteoblasts and adipocytes in the bone marrow is dependent on balanced signaling through this pathway. Moreover, considering the distinct role assigned to BMPRIA and BMPRIB, the temporal gain or loss of a subtype of BMP receptors by MSCs could be critical for commitment and subsequent differentiation (Gimble et al., 1995144).

Wnt signaling in MSCs is also decisive for the reciprocal relationship among the osteo/adipogenic pathways. Activation of the Wnt/p-catenin pathway directs MSCs differentiation towards osteoblasts instead of adipocytes (Bennett et al., 2005; Ross et al., 2000; Moldes et al., 2003). Animal studies have shown that activation of the Wnt signaling pathway increases bone mass, preventing both hormone-dependent and age-induced bone loss (Bennett et al., 2005). Furthermore, Wnt activation may control cell commitment towards osteoblasts by blocking adipogenesis through the inhibition of the expression of both C/EBP and PPARy adipogenic transcription factors, as demonstrated in vivo in humans (Qiu et al., 2007), in transgenic mice expressing Wnt 10b (Bennett et al., 2005) and in vitro (Rawadi et al., 2003). MSCs' self-renewing and maintenance of the undifferentiated state appear to be dependent on appropriate canonical Wnt signaling, promoting increased proliferation and decreased apoptosis (Boland et al., 2004; Cho et al., 2006). The overexpression of LRP5, an essential co-receptor specifically involved in canonical Wnt signaling, has been reported to increase proliferation of MSCs (Krishnan et al., 2006). In addition, disruption in vivo or in vitro of -catenin signaling promoted spontaneous conversion of various cell types into adipocytes (Bennett et al., 2002). Moreover, the importance of this pathway for bone mineral density has been highlighted by the observation that genetic variations at either the LRP5 or Wnt10b gene locus are associated with osteoporosis (Brixen et al., 2007; Usui et al., 2007).

Also, insulin-like growth factor-I (IGF-I) signalling is clearly an important factor in skeletal development. The IGF regulatory system consists of IGFs (IGF-I and IGF-II), Type I and Type II IGF receptors, and regulatory proteins including IGF-binding proteins (IGFBP-1-6) and the acid-labile subunit (ALS) (Rosen et al., 1994). The ligands in this system (i.e. IGFs) are potent mitogens, and in some circumstances differentiation factors, that are bound in the circulation and interstitial fluid as binary (to IGFBPs) or ternary complexes (IGF-ALS-IGFBP-3 or -5) with little free IGF-I or -II. IGF bio-availability is regulated by the interaction of these molecules at the receptor level; hence changes in any component of the system will have profound effects on the biologic activity of the ligand. The IGFBPs have a particularly important role in regulating IGF-I access to its receptor, since their binding affinity exceeds that of the IGF receptors. The IGF system is unique because the IGFBPs are regulated in a cell-specific manner at the pericellular microenvironment, such that small changes in their concentrations could strongly influence the mitogenic activity of IGF-I (Jones and Clemmons, 1995; Hwa and Rosenfeld, 1999; Firth and Baxter, 2002). IGFs are expressed virtually by all tissues, and circulate in high concentrations. Although nearly 80% of the circulating IGF-I comes from hepatic sources, both bone and fat synthesize IGF-I and these tissues contribute to the total circulating pool. Locally produced IGF-I predominates over circulating IGF-I in maintaining skeletal integrity (Rosen et al., 1994; Kawai and Rosen, 2010), and both ALS and IGFBP-3 participate in regulating bone function. However, the possible autocrine/paracrine roles of IGF-I and IGFBPs in marrow (Liu et al., 1993; Peng et al., 2003) or in osteoblast (Zhao et al., 2000; Zhang et al., 2002; Wang et al., 2007) are practically unknown.

RELATIONSHIP BETWEEN THE OSTEO- / ADIPOGENESIS PROCESSES - THE FAT THEORY FOR OSTEOPOROSIS

Since in the bone marrow MSCs are the common precursor cells for osteoblast and adipocytes, adequate osteoblast formation requires diminished adipogenesis. As pointed out above, MSCs commitment and differentiation into a specific phenotype depends on hormonal and local factors (paracrine/autocrine) regulating the expression and/or activity of master differentiation genes (Nuttall and Gimble, 2004; Muruganadan et al., 2009) (Figure 1). A reciprocal relationship has been postulated to exist between the two differentiation pathways whose alteration would facilitate adipose accretion in the bone marrow, at the expense of osteoblast formation, thus decreasing bone mass (Reviewed in Rosen et, al 2009; Rodrguez et al.. 2008; Rosen and Bouxtein, 2006). Such unbalanced conditions prevail in the bone marrow of osteoporosis patients, upsetting MSC activity and the microenvironment (Nuttall and Gimble, 2004; Moerman et al., 2004; Rosen and Bouxtein, 2006). This proposition is known as the fat theory for osteoporosis. Moreover, this alteration of osteo-/adipogenic processes is also observed in other conditions characterized by bone loss, such as aging, immobilization, microgravity, ovariectomy, diabetes, and glucocorticoid or tiazolidindione treatments, highlighting the harmful consequence of marrow adipogenesis in osteogenic disorders (Wronski et al., 1986; Moerman et al., 2004; Zayzafon et al., 2004; Forsen et al., 1999).

Cell studies comparing the differentiation potential of MSCs derived from osteoporotic patients (o-MSCs) with that of control MSCs (c-MSCs) have shown unbalanced osteogenic/adipogenic processes, including increased adipose cell formation, counterbalanced by reduced production of osteogenic cells (Nuttall and Gimble, 2004; Rodrguez et al., 2008; Rosen and Bouxtein, 2006). Further research on MSC differentiation has shown that activation of PPARy2, a master transcription factor of adipogenic differentiation, positively regulates adipocyte differentiation while acting as a dominant negative regulator of osteogenic differentiation (Lecka-Czernik et al., 1999; Jeon et al., 2003; Khan and Abu-Amer, 2003). In contrast, an increase in bone mass density was observed in a PPARy deficient mice model; even the heterozygous deficient animals showed high bone mass and increased osteoblastogenesis (Cock et al., 2004). On the other hand, Runx2 expression by MSCs inhibits their differentiation into adipocytes, as may be concluded from experiments in Runx2-/- calvarial cells, which spontaneously differentiate into adipocytes (Kobayashi et al., 2000).

In vivo observations further support the fat theory. Early studies observed that osteoporosis was strongly associated with bone marrow adipogenesis. Iliac crest biopsies showed that bone marrow from osteoporotic patients had a considerable accumulation of adipocytes in relation to that of healthy elderly women (Moerman et al., 2004; Meunier et al., 1971). More recently, increased bone marrow adiposity measured by in vivo proton magnetic resonance (1H-MRS) has been associated with decreased bone mineral density in patients with low bone density (Griffith et al., 2005; Yeung et al., 2005; Blake et al., 2008).

In newborn mammals there is no marrow fat; however the number of adipocytes increases with age such that in humans over 30 years of age, most of the femoral cavity is occupied by adipose tissue (Moore and Dawson, 1990). The function of marrow fat is largely unknown; in humans it was first considered to be 'filler' for the void left by trabecular bone during aging or after radiation. Later, these cells have been proposed to have a role as an energy source, or as modulators of adjacent tissue by the production of paracrine, and autocrine factors (reviewed in Rosen et al., 2009). In fact, adipokines, steroids, and cytokines (Lee et al., 2002; Pino et al., 2010; Rosen et al., 2009;) can exert profound effects on neighboring marrow cells, sustaining or suppressing hematopoietic and osteogenic processes (Omatsu et al., 2010; Krings et al., 2012; Rosen et al., 2009; Rodrguez et al., 2008).

Thus, the function of bone marrow adipose tissue may be similar to that of extra medullary fat. As such, it has been well established that unbalanced production of signaling products from subcutaneous or visceral fat modulates several human conditions including obesity, lipodystrophy, atherogenesis, diabetes and inflammation. Recent studies in mice, suggest a complex fat phenotype in the bone marrow, presenting mixed brown and white adipose properties (Lecka-Czernik, 2012). Further work is needed to find out whether differences in the quality or quantity of marrow fat, take part in deregulated bone remodelling in some bone diseases.

STUDIES ON THE ACTIVITY OF OSTEOPOROTIC MSCs

Because of their ability to self-renew, human MSCs can be expanded and differentiated in vitro, offering many perspectives for tissue engineering and regenerative medicine approaches. However, there is scarce information on whether specific diseases affect the properties of MSCs, because of the difficult accessibility to human bone marrow in health and disease (Cipriani et al., 2011; Corey et al., 2007).

Our research has focused on the properties of MSCs isolated from bone marrow of control and osteoporotic post-menopausal women. We grouped our observations on functional characteristics of o-MSCs and c- MSCs in three categories, which are summarized in Table I, as follows:

General activities: h-MSCs isolated from osteoporotic and control donors have similar CFU-F, but different proliferation rates. O-MSCs showed significantly diminished proliferation rate and decreased mitogenic response to IGF-I. The pERK/ERK ratio is increased in o-MSCs, compared with control c-MSCs. In other cell types, activation of the MEK/ERK signalling pathway enhances the activity of adipogenic transcription factors (Prusty et al., 2002). We also observed decreased TGF- production by o-MSCs, as well as decreased capacity to generate and maintain a type I collagen-rich extracellular matrix, both conditions supporting cell differentiation into the adipocyte phenotype. Then, considering that the lineage fate of MSCs is dependent on early activation by specific BMPs, PPARy and Wnt signaling (Ross et al., 2000; Rawadi et al., 2003; Westendorf et al., 2004; Baron and Rawadi, 2007), we compared the expression level of some genes related to these pathways in c- and o- MSCs. Results obtained by RT-PCR showed that in c- and o-MSCs the expression level of mRNA for -catenin, Dkk-1, and BMPRIB was similar; while the level of mRNA for Wnt 3a was undetectable in both types of samples. The expression level of mRNA for GSK-3p, LRP6 and Osx was lower in o-MSCs than in c-MSCs, while the mRNA level for Ror2, Wnt 5a, BMPRIA showed doubtful. To further quantify the expression level of GSK-3P, LRP6, Osx, Ror2, Wnt 5a, BMPRIA real time RT-PCR was performed. As shown in Table I, statistically significant decreased mRNA levels for GSK-3p, LRP6 and Osx (0.64, 0.26 and 0.18 fold, respectively) were observed in o-MSCs, as compared to c-MSCs. In addition, mRNA levels for Ror2, Wnt 5a, and BMPRIA were similar in both types of cell samples.

These data suggest impaired regulation by the BMPs and Wnt pathways in o-MSCs, representing some intrinsic deviation from control cells that might underlie the impaired self-renewal, and adipogenic/osteogenic differentiation potential observed in o-MSCs. mRNA levels for Ror2, Wnt 5a, and BMPRIA were similar in both types of cell samples.

STUDIES ON THE ACTIVITY OF BONE MARROW FLUID OF POST-MENOPAUSAL WOMEN

Distinctive environmental bone marrow conditions appear to support the development and maintenance of the balance between bone resorption and bone formation. Knowledge is scarce about the intramedullar concentration of compounds with recognized regulatory effects on bone formation or resorption and is limited to some pathologic conditions or estimated from measurements in plasma (Wiig et al., 2004; Iversen and Wiig, 2005; Lee et al., 2002; Khosla et al., 1994).

Measurement of soluble molecules found in human bone marrow has been particularly difficult, not only because of tissue seclusion, but also because of the complicated anatomy and blood perfusion of bone. Since it may be expected that concentrations measured in the bone marrow fluid (BMF) more reliably reflect the physiologically relevant levels in the interstitial compartment surrounding the bone cells than values found in blood, we isolated the extracellular bone marrow fluid by directly spinning bone marrow samples for 20 min at 900xg. Considering the complex organization in such a regulatory milieu, we opted for evaluating some molecules recognized as markers of adipocyte, proinflammatory or osteoclastic/osteoblastic activity (Pino et al., 2010).

The concentrations of cytokines or receptors measured in the bone marrow extracellular fluid from control and osteoporotic human donors are indicated in Table II. In addition, the concentrations of IGF-I and its IGFBPs were analyzed, as well as the C-terminal telopeptide cross-links of type I collagen (CTX). Results summarized in Table II indicate significantly different concentrations of regulatory molecules in the extracellular fluid of control versus osteoporotic women; this last group was characterized by higher content of proinflammatory and adipogenic cytokines. Also, osteoporotic samples showed decreased leptin bioavailability, suggesting that insufficient leptin action may characterize the osteoporotic bone marrow (Pino et al., 2010). In addition, bioavailability of IGF-I appears diminished in o-BMF, as shown by the increased IGFBP3/IGF-I ratio.

TABLE II

Regulatory activity in bone marrow fluid of post-menopausal women

Taken together our results and those of other researchers identify significant differences between functional properties of control and osteoporotic MSCs, displayed in vitro, in cells under basal or differentiating conditions. Moreover, it can be concluded that such divergence prevails also in vivo, because the bone marrow fluid of osteoporotic patients characterizes by unfavourable content of several regulatory molecules. Therefore, the properties of both MSCs and bone marrow microenvironment are significantly impaired in osteoporotic patients, negatively affecting bone formation.

CONCLUSIONS

In the pathogenesis of osteoporosis, impairment of both MSCs functionality and microenvironment add to the known detrimental effect of increased osteoclast activity, resulting in decreased bone formation.

O-MSCs are characterized by intrinsic functional alteration leading to poor osteogenic capability and increased adipogenesis. Osteoporotic bone marrow microenvironment differs from the control microenvironment by increased concentration of pro-adipogenic and pro-inflammatory regulatory factors.

The content and/or quality of adipocytes in the bone marrow appear critical to delineate impairing of MSCs; in this sense osteoporosis could be homologated to other age-related diseases such as obesity, atherogenesis and diabetes, which are characterized by extramedullar unbalanced adipocyte formation and signaling.

Currently it is not known how damaged o-MSCs emerge, further work is needed to ascertain the role of the microenvironment, and genetic and epigenetic factors, as proposed for other stem cells-related pathologies.

The conclusion that intrinsic properties of MSCs are altered in osteoporosis should be relevant for the therapeutic use of MSCs, which represent an interesting promise for regenerative medicine for several severe human diseases.

The possibility of reversing o-MSCs impairment opens new perspectives for osteoporosis therapy.

ACKNOWLEDGEMENTS

We thank Dr. Mariana Cifuentes for her critical review of the manuscript and valuable comments. This work was supported by a grant from the Fondo Nacional de Ciencia y Tecnologa (FONDECYT # 1090093)

REFERENCES

ASTUDILLO P, ROS S, PASTENES L, PINO AM, RODRGUEZ JP (2008) Increased adipogenesis of osteoporotic human-msenchymal stem cells (MSCs) characterizes by impaired leptin action. J Cell Biochem 103: 1054-1065[Links]

BAKSH D, SONG L, TUAN RS (2004) Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 8: 301-316. [Links]

BARON R, RAWADI G (2007) Minireview: Targeting the Wnt/-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148:2635-2643. [Links]

BENNETT CN, LONGO KA, WRIGHT WS, SUVA L J, LANE TF, HANKENSON KD, MACDOUGALD OA (2005). Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102: 3324-3329. [Links]

BENNET CN, ROSS SE, LONGO KA, BAJNOK L, HEMATI N, JOHNSON KW, HARRISON SD, MACDOUGALD OA (2002) Regulation of Wnt signaling during adipogenesis. J Biol Chem 277:30998-31004. [Links]

BIANCO P, ROBEY PG (1999) Diseases of bone and stromal cell lineage. J Bone Miner Res 14: 336-41. [Links]

BLAKE GM, GRIFFITH JF, YEUNG DK, LEUNG PC, FOGELMAN I (2008) Effect of increasing vertebral marrow fat content on BMD measurement, T-Score status and fracture risk prediction by DXA. Bone 44: 495-501[Links]

BOLAND GM, PERKINS G, HALL DJ, TUAN RS (2004) Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem 93:1210-1230. [Links]

BRIXEN K, BECKERS S, PEETERS A, PITERS E, BALEMANS W, NIELSEN TL, WRAAE K, BATHUM L, BRASEN C, HAGEN C, ANDERSEN M, VAN HUL W, ABRAHAMSEN B (2007) Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) genes are associated with peak bone mass in non-sedentary Men: results from the Odense Androgen Study. Calcif Tissue Int 81:421-429. [Links]

CHO HH, KIM YJ, KIM SJ, KIM JH, BAE YC, BA B, JUNG JS (2006) Endogenous Wnt signaling promotes proliferation and suppresses osteogenic differentiation in human adipose derived stromal cells. Tissue Eng 12:111-121. [Links]

CIPRIANI P, MARRELLI A, LIAKOULI V, DI BENEDETTO P, GIACOMELLI R (2011) Cellular players in angiogenesis during the course of systemic sclerosis. Autoimmunity Rev 10:641-646. [Links]

COCK TA, BACK J, ELEFTERIOU F, KARSENTY G, KASTNER P, CHAN S, AUWERX J (2004) Enhanced bone formation in lipodystrophic PPARhyp/hyp mice relocates haematopoiesis to the spleen. EMBO reports 5: 1007-1012. [Links]

COREY SJ, MINDEN MD, BARBER DL, KANTARJIAN H, WANG JCY, SCHIMMER AD (2007) Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer 7: 118-129. [Links]

FIRTH SM, BAXTER RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824-854. [Links]

FORSEN L, MEYER HE, MIDTHJELL K, EDNA TH (1999) Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trondelag Health Survey. Diabetologia 42: 920-925. [Links]

FRIEDENSTEIN AJ, CHAILAKHJAN RK, LALYKINA KS (1970). The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393-403[Links]

GIMBLE JM, MORGAN C, KELLY K, WU X, DANDAPANI V, WANG CS, ROSEN V (1995) Bone morphogenetic proteins inhibit adipocyte differentiation by bone marrow stromal cells. J Cell Biochem 58: 393-402. [Links]

GORI F, THOMAS T, HICOK KC, SPELSBERG TC, RIGGS BL (1999) Differentiation of human marrow stromal precursor cells: bone morphogenetic protein-2 increases Osf2/Cbfa1, enhances osteoblast commitment, and inhibits late adipocyte maturation. J Bone Miner Res 14: 1522-1535. [Links]

GRIFFITH JF, YEUNG DK, ANTONIO GE, LEE FK, HONG AW, WONG SY, LAU EM, LEUNG PC (2005) Vertebral bone mineral density, marrow perfusion, and fat content in healthy men and men with osteoporosis: dynamic contrast-enhanced MR imaging and MR spectroscopy. Radiology 236: 945-951. [Links]

HAIYAN H, TAN-JING S, LI X, HU L, HE Q, LIU M, LANE MD, TANG QQ (2009) BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 106:12670-12675. [Links]

HESS R, PINO AM, ROS S, FERNNDEZ M, RODRGUEZ JP (2005) High affinity leptin receptors are present in human mesenchymal stem cells (MSCs) derived from control and osteoporotic donors. J Cell Biochem 94:50-57. [Links]

HOFER EL, LABOVSKY V, LA RUSSA V, VALLONE VF, HONEGGER AE, BELLOC CG, WEN HC, BORDENAVE RH, BULLORSKY EO, FELDMAN L, CHASSEING NA (2010) Mesenchymal stromal cells, colony-forming unit fibroblasts, from bone marrow of untreated advanced breast and lung cancer patients suppress fibroblast colony formation from healthy marrow. Stem Cells Dev 19: 359-370. [Links]

HWA V, OH Y, ROSENFELD RG (1999) The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 20:761-787[Links]

IVERSEN PO, WIIG H (2005) tumor necrosis factor a and adiponectin in bone marrow interstitial fluid from patients with acute myeloid leukemia inhibit normal hematopoiesis. Clin Cancer Res 11:6793-6799. [Links]

JEON MJ, KIM JA, KWON SH, KIM SW, PARK KS, PARK SW, KIM SY, SHIN CS (2003) Activation of peroxisome proliferator-activated receptor-y inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts. J Biol Chem 278: 23270-23277. [Links]

JONES JI, CLEMMONS DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3-34. [Links]

KAWAI M, ROSEN CJ (2010) The IGF-I regulatory system and its impact on skeletal and energy homeostasis. J Cell Biochem 111:14-19. [Links]

KHAN E, ABU-AMER Y (2003) Activation of peroxisome proliferator-activated receptor-y inhibits differentiation of preosteoblasts. J Lab Clin Med 142: 29-34. [Links]

KHOSLA S, PETERSON JM, EGAN K, JONES JD, RIGGS BL (1994) Circulating cytokine levels in osteoporotic and normal women. J Clin Endocrinol Metab 79:707-611. [Links]

KOBAYASHI H, GAO Y, UETA C, YAMAGUCHI A, KOMORI T (2000) Multiline-age differentiation of Cbfa1-deficient calvarial cells in vitro. Biochem Biophys Res Commun 273: 630-636. [Links]

KOLF CM, CHO E, TUAN RS (2007) Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation Arthritis Research & Therapy 9:204 -213. [Links]

KRINGS A, RAHMAN S, HUANG S, LU Y, CZERNIK PJ, LECKA-CZERNIK B (2012) Bone marrow fat has browne adipose tissue characteristics, which are attenuated with aging and diabetes. Bone 50: 546-552. [Links]

KRISHNAN V, BRYANT HU, MACDOUGALD OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116: 1202-1209. [Links]

KUHN NZ, TUAN RS (2010) Regulation of stemness and stem cell niche of mesenchymal stem cells: implications in tumorigenesis and metastasis. J Cell Physiol 222: 268-277. [Links]

KULTERE B, FRIEDL G, JANDROSITZ A, SNCHEZ-CABO F, PROKESCH A, PAAR C, SCHEIDELER M, WINDHAGER R, PREISEGGER KH, TRAJANOSKI Z (2007) Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation. BMC Genomics 8: 70-84. [Links]

LECKA-CZERNK B (2012) Marrow fat metabolism is linked to the systemic energy metabolism. Bone 50: 534-539. [Links]

LECKA-CZERNIK B, GRINNELL SJ, MOERMAN EJ, CAO X, MANOLAGAS SC, OBRIEN CA (1999) Identification of a Smad binding element in the PPARy2 promoter: A potential site of cross-talk between osteoblastogenesis and adipogenesis signaling pathways. J Bone Miner Res 14: Suppl1, S1056. [Links]

LECKA-CZERNIK B, GUBRIJ I, MOERMAN EA, KAJKENOVA O, LIPSCHITZ DA, MANOLAGAS SC, JILKA RL (1999) Inhibition of Osf2/Cbaf1 expression and terminal osteoblast differentiation by PPAR-gamma2. J Cell Biochem 74: 357-371. [Links]

LEE WY, KANG MI, OH ES, HAN JH, CHA BY, LEE KW, SON HY, KANG SK, KIM CC. (2002) The role of cytokines in the changes in bone turnover following bone marrow transplantation. Osteoporos Int 13:62-68. [Links]

LI J, TSUJI K, KOMORI T, MIYAZONO K, WRANA JL, ITO Y, NIFUJI A, NODA M (1998) Smad2 overexpression enhances smad4 gene expression and suppresses Cbfa1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells. J Biol Chem 273: 31009-31015. [Links]

LI X, SHET K, RODRIGUEZ JP, PINO AM, KURHANEWICZ J, SCHWARTZ A, ROSEN CJ (2012) Unsaturation Level Decreased in Bone Marrow Lipids of Postmenopausal Women with Low Bone Density Using High Resolution HRMAS NMR. ASBMR 2012 Annual Meeting American Society of Bone and Mineral Research. October 12-15, 2012, Minneapolis, Minnesota, USA. [Links]

LIN NH, MENICANIN D, MROZIK K, GRONTHOS S, BARTOLD PM (2008) Putative stem cells in regenerating human periodontium. J Periodont Res 43: 514-523. [Links]

LINDNERA U, KRAMERA J, ROHWEDEL J, SCHLENKE P (2010) Mesenchymal stem or stromal cells: toward a better understanding of their biology? Transfus Med Hemother 37:75-83[Links]

LIU JP, BAKER J, PERKINS AS, ROBERTSON EJ, EFSTRATIADIS A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59-72. [Links]

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In Osteoporosis, differentiation of mesenchymal stem cells ...

Recommendation and review posted by simmons

Wed,17 Dec 2003 05:30:00

Bone marrow transplant is a procedure in which healthy bone marrow is transplanted into a patient whose bone marrow is not functioning properly. Problems in bone marrow are often caused by chemotherapy or radiation treatment for cancer. This procedure can also be done to correct hereditary blood diseases. The healthy bone marrow may be taken from the patient prior to chemotherapy or radiation treatment (autograft), or it may be taken from a donor (allograft).

Wed,17 Dec 2003 05:30:00

Bone marrow is the soft, sponge-like material found inside bones. It contains immature cells called stem cells that produce blood cells. There are three types of blood cells: white blood cells, which fight infection; red blood cells, which carry oxygen to and from organs and tissues; and platelets, which enable the blood to clot.

Wed,17 Dec 2003 05:30:00

Alternatively, hereditary or acquired disorders may cause abnormal blood cell production. In these cases, transplantation of healthy bone marrow may save a patient's life. Transplanted bone marrow will restore production of white blood cells, red blood cells, and platelets.

Wed,17 Dec 2003 05:30:00

Donated bone marrow must match the patient's tissue type. It can be taken from the patient, a living relative (usually a brother or a sister), or from an unrelated donor. Donors are matched through special blood tests called HLA tissue typing.

Bone marrow is taken from the donor in the operating room while one is unconscious and pain-free (under general anaesthesia). Some of the donor's bone marrow is removed from the top of the hip bone. The bone marrow is filtered, treated, and transplanted immediately or frozen and stored for later use. Then, transplant material is transfused into the patient through a vein and is naturally transported back into the bone cavities where it grows to replace the old bone marrow.

Alternatively, blood cell precursors, called stem cells, can be induced to move from the bone marrow to the blood stream using special medications. These stem cells can then be taken from the bloodstream through a procedure called leukapheresis.

The patient is prepared for transplantation by administering high doses of chemotherapy or radiation (conditioning). This serves two purposes. First, it destroys the patient's abnormal blood cells or cancer. Second, it inhibits the patient's immune response against the donor bone marrow (graft rejection).

Following conditioning, the patient is ready for bone marrow infusion. After infusion, it takes 10 to 20 days for the bone marrow to establish itself. During this time, the patient requires support with blood cell transfusions.

Wed,17 Dec 2003 05:30:00

Wed,17 Dec 2003 05:30:00

The major problem with bone marrow transplants (when the marrow comes from a donor, not the patient) is graft-versus-host disease. The transplanted healthy bone marrow cells may attack the patient's cells as though they were foreign organisms. In this case, drugs to suppress the immune system must be taken, but this also decreases the body's ability to fight infections.

Other significant problems with a bone marrow transplant are those of all major organ transplants - finding a donor and the cost. The donor is usually a sibling with compatible tissue. The more siblings the patient has, the more chances there are of finding a compatible donor.

Wed,17 Dec 2003 05:30:00

The patient will require attentive follow-up care for 2 to 3 months after discharge from the hospital. It may take 6 months to a year for the immune system to fully recover from this procedure.

See the article here:
Bone marrow transplant - Doctor NDTV

Recommendation and review posted by sam

Scientific pioneer, superstar surgeon, miracle worker thats how Paolo Macchiarini was known for several years. Dressed in a white lab coat or in surgical scrubs, with his broad, handsome face and easy charm, he certainly looked the part. And fooled almost everyone.

Macchiarini shot to prominence back in 2008, when he created a new airway for Claudia Castillo, a young woman from Barcelona. He did this by chemically stripping away the cells of a windpipe taken from a deceased donor; he then seeded the bare scaffold with stem cells taken from Castillos own bone marrow. Castillo was soon back home, chasing after her kids. According to Macchiarini and his colleagues, her artificial organ was well on the way to looking and functioning liked a natural one. And because it was built from Castillos own cells, she didnt need to be on any risky immunosuppressant drugs.

This was Macchiarinis first big success. Countless news stories declared it a medical breakthrough. A life-saver and a game-changer. We now know that wasnt true. However, the serious complications that Castillo suffered were, for a long time, kept very quiet.

Meanwhile, Macchiarinis career soared. By 2011, he was working in Sweden at one of the worlds most prestigious medical universities, the Karolinska Institute, whose professors annually select the winner of the Nobel prize in physiology or medicine. There he reinvented his technique. Instead of stripping the cells from donor windpipes, Macchiarini had plastic scaffolds made to order. The first person to receive one of these was Andemariam Beyene, an Eritrean doctoral student in geology at the University of Iceland. His recovery put Macchiarini on the front page of the New York Times.

Macchiarini was turning the dream of regenerative medicine into a reality. This is how NBCs Meredith Vieira put it in her documentary about Macchiarini, appropriately called A Leap of Faith: Just imagine a world where any injured or diseased organ or body part you have is simply replaced by a new artificial one, literally manmade in the lab, just for you. This marvelous world was now within reach, thanks to Macchiarini.

Last year, however, the dream soured, exposing an ugly reality.

Macchiarini gave his regenerating windpipes to 17 or more patients worldwide. Most, including Andemariam Beyene, are now dead. Those few patients who are still alive including Castillo have survived in spite of the artificial windpipes they received.

In January 2016, Macchiarini received an extraordinary double dose of bad press. The first was a Vanity Fair article about his affair with Benita Alexander, an award-winning producer for NBC News. She met Macchiarini while producing A Leap of Faith and was soon breaking one of the cardinal rules of journalism: dont fall in love with the subject of your story.

By the time the program aired, in mid-2014, the couple were planning their marriage. It would be a star-studded event. Macchiarini had often boasted to Alexander of his famous friends. Now they were on the wedding guest list: the Obamas, the Clintons, Vladimir Putin, Nicolas Sarkozy and other world leaders. Andrea Bocelli was to sing at the ceremony. None other than Pope Francis would officiate, and his papal palace in Castel Gandolfo would serve as the venue. Thats what Macchiarini told his fiancee.

But as the big day approached, Alexander saw these plans unravel, and finally realised that her lover had lied about almost everything. The pope, the palace, the world leaders, the famous tenor they were all fantasies.

Likewise the whole idea of a wedding: Macchiarini was still married to his wife of 30 years.

Macchiarinis deceit was so outlandish, Vanity Fair sought the opinion of the Harvard professor Ronald Schouten, an expert on psychopaths, who gave this diagnosis-at-a-distance: Macchiarini is the extreme form of a con man. Hes clearly bright and has accomplishments, but he cant contain himself. Theres a void in his personality that he seems to want to fill by conning more and more people.

Which left a big, burning question in the air: if Macchiarini was a pathological liar in matters of love, what about his medical research? Was he conning his patients, his colleagues and the scientific community?

The answer came only a couple of weeks later, when Swedish television began broadcasting a three-part expos of Macchiarini and his work.

Called Experimenten (The Experiments), it argued convincingly that Macchiarinis artificial windpipes were not the life-saving wonders wed all been led to believe. On the contrary, they seemed to do more harm than good something that Macchiarini had for years concealed or downplayed in his scientific articles, press releases and interviews.

Faced with this public relations disaster, the Karolinska Institute immediately promised to investigate the allegations but then, within days, suddenly announced that Macchiarinis contract would not be extended.

Macchiarinis fall was swift, but troubling questions remain about why he was allowed to continue his experiments for so long. Some answers have emerged from the official inquiries into the Karolinska Institute and the Karolinska University hospital. They identified many problems with the way the twin organisations handled him.

Macchiarinis fame had won him well-placed backers. These included Harriet Wallberg, who was the vice-chancellor of the Karolinska Institute in 2010, when Macchiarini was recruited. She pushed through his appointment despite the fact that he had some very negative references and dubious claims on his rsum.

This set a dangerous example. It showed department heads and colleagues that they should give Macchiarini special treatment.

He could do pretty much as he pleased. In the first couple of years at Karolinska, he put plastic airways into three patients. Since this was radically new, Macchiarini and his colleagues should have tested it on animals first. They didnt.

Likewise, they didnt undertake a proper risk assessment of the procedure, nor did Macchiarinis team seek government permits for the plastic windpipes, stem cells, and chemical growth factors they used. They didnt even seek the approval of Stockholms ethical review board, which is based at Karolinska.

Though Macchiarini was in the public eye, he was able to sidestep the usual rules and regulations. Or rather, his celebrity status helped him do so. Karolinskas leadership expected big things from their superstar, things that would bring prestige and funding to the institute.

They also cited a loophole known as compassionate use. Macchiarini, they claimed, wasnt really doing clinical research. No, he was just caring for his patients who were, one and all, facing certain death with no other treatment options available and no time to waste. In such dire circumstances, new treatments can be tried as a last resort.

This argument didnt wash with those who later investigated the case. In their view, Macchiarini was certainly engaged in clinical research. Besides which, compassionate concerns dont override the basic principles of patient safety and informed consent. Macchiarini, meanwhile, said he did not accept the findings of the disciplinary board.

As it turned out, Macchiarinis patients werent all at deaths door at the time he treated them. Andemariam Beyene, for instance, had recurrent cancer of the windpipe but, aside from a cough, was still in good health. But even if his days had been numbered, this didnt necessarily justify what Macchiarini put him through.

Beyenes death two and a half years after the operation, caused by the failure of his artificial airway, was a grueling ordeal. According to Pierre Delaere, a professor of respiratory surgery at KU Leuven, Belgium, Macchiarinis experiments were bound to end badly. As he said in Experimenten: If I had the option of a synthetic trachea or a firing squad, Id choose the last option because it would be the least painful form of execution.

Delaere was one of the earliest and harshest critics of Macchiarinis engineered airways. Reports of their success always seemed like hot air to him. He could see no real evidence that the windpipe scaffolds were becoming living, functioning airways in which case, they were destined to fail. The only question was how long it would take weeks, months or a few years.

Delaeres damning criticisms appeared in major medical journals, including the Lancet, but werent taken seriously by Karolinskas leadership. Nor did they impress the institutes ethics council when Delaere lodged a formal complaint.

Support for Macchiarini remained strong, even as his patients began to die. In part, this is because the field of windpipe repair is a niche area. Few people at Karolinska, especially among those in power, knew enough about it to appreciate Delaeres claims. Also, in such a highly competitive environment, people are keen to show allegiance to their superiors and wary of criticising them. The official report into the matter dubbed this the bandwagon effect.

With Macchiarinis exploits endorsed by management and breathlessly reported in the media, it was all too easy to jump on that bandwagon.

And difficult to jump off. In early 2014, four Karolinska doctors defied the reigning culture of silence by complaining about Macchiarini. In their view, he was grossly misrepresenting his results and the health of his patients. An independent investigator agreed. But the vice-chancellor of Karolinska Institute, Anders Hamsten, wasnt bound by this judgement. He officially cleared Macchiarini of scientific misconduct, allowing merely that hed sometimes acted without due care.

For their efforts, the whistleblowers were punished. When Macchiarini accused one of them, Karl-Henrik Grinnemo, of stealing his work in a grant application, Hamsten found him guilty. As Grinnemo recalls, it nearly destroyed his career: I didnt receive any new grants. No one wanted to collaborate with me. We were doing good research, but it didnt matter I thought I was going to lose my lab, my staff everything.

This went on for three years until, just recently, Grinnemo was cleared of all wrongdoing.

The Macchiarini scandal claimed many of his powerful friends. The vice-chancellor, Anders Hamsten, resigned. So did Karolinskas dean of research. Likewise the secretary-general of the Nobel Committee. The university board was dismissed and even Harriet Wallberg, whod moved on to become the chancellor for all Swedish universities, lost her job.

Unfortunately, the scandal is much bigger than Karolinska, which accounts for only three of the patients who have received Macchiarinis regenerating windpipes.

The other patients were treated at hospitals in Barcelona, Florence, London, Moscow, Krasnodar, Chicago and Peoria. None of these institutions have faced the same kind of public scrutiny. None have been forced to hold full and independent inquiries. They should be.

If the sins of Karolinska have been committed elsewhere, it is partly because medical research facilities share a common milieu, which harbours common dangers. One of these is the hype surrounding stem cells.

Stem cell research is a hot field of science and, according to statistics, also a rather scandal-prone one. Articles in this area are retracted 2.4 times more often than the average for biomedicine, and over half of these retractions are due to fraud.

Does the heat of stem cell research the high levels of funding, prestige and media coverage it enjoys somehow encourage fraud? Thats what our experience of medical research leads us to suspect. While there isnt enough data to actually prove this, we do have some key indicators.

We have, for example, a growing list of scientific celebrities who have committed major stem cell fraud. There is South Koreas Hwang Woo-suk who, in 2004, falsely claimed to have created the first human embryonic stem cells by means of cloning. A few years ago, Japans Haruko Obokata pulled a similar con when she announced to the world a new and simple and fake method of turning ordinary body cells into stem cells.

Hwang, Obokata and Macchiarini were all attracted to the hottest regions of stem cell research, where hope for a medical breakthrough was greatest. In Macchiarinis case, the hope was that patients could be treated with stem cells taken from their own bone marrow.

Over the years, this possibility has generated great excitement and a huge amount of research. Yet, for the vast majority of such treatments, there is little solid evidence that they work. (The big exception is blood stem cell transplantation, which has been saving the lives of people with leukemia and other cancers of the blood for decades.)

Its enough to worry officials from the US Food and Drug Administration (FDA). They recently published an article in the New England Journal of Medicine admitting that stem cell research has mostly failed to live up to its therapeutic promise.

An alarmingly wide gap has grown between what we expect from stem cells and what they deliver. Each new scientific discovery brings a flood of stories about how it will revolutionise medicine one day soon. But that day is always postponed.

An unhappy result of this is the rise of pseudo-scientific therapies. Stem cell clinics have sprung up like weeds, offering to treat just about any ailment you can name. In place of clinical data, there are gushing testimonials. There are also plenty of desperate patients who believe because theyve been told countless times that stem cells are the cure, and who cannot wait any longer for mainstream medicine. They and their loved ones fall victim to false hope.

Scientists can also suffer from false hope. To some extent, they believed Macchiarini because he told them what they wanted to hear. You can see this in the speed with which his breakthroughs were accepted. Only four months after Macchiarini operated on Claudia Castillo, his results provisional but very positive were published online by the Lancet. Thereafter it was all over the news.

The popular press also has a lot to answer for. Its love of human interest stories makes it sympathetic to unproven therapies. As studies have shown, the media often casts a positive light on stem cell tourism, suggesting that the treatments are effective and the risks low. It did much the same for Macchiarinis windpipe replacements. A good example is the NBC documentary A Leap of Faith. Its fascinating to rewatch as a lesson on how not to report on medical science.

It is fitting that Macchiarinis career unravelled at the Karolinska Institute. As the home of the Nobel prize in physiology or medicine, one of its ambitions is to create scientific celebrities. Every year, it gives science a show-business makeover, picking out from the mass of medical researchers those individuals deserving of superstardom. The idea is that scientific progress is driven by the genius of a few.

Its a problematic idea with unfortunate side effects. A genius is a revolutionary by definition, a risk-taker and a law-breaker. Wasnt something of this idea behind the special treatment Karolinska gave Macchiarini? Surely, he got away with so much because he was considered an exception to the rules with more than a whiff of the Nobel about him. At any rate, some of his most powerful friends were themselves Nobel judges until, with his fall from grace, they fell too.

If there is a moral to this tale, its that we need to be wary of medical messiahs with their promises of salvation.

Read the rest here:
Dr Con Man: the rise and fall of a celebrity scientist who fooled almost everyone - The Guardian

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On Monday, the U.S. Food and Drug Administration (FDA) announced that the agency is targeting clinics that offer unproven stem cell therapies, calling such offices "unscrupulous clinics" selling "so-called cures." The FDA seized materials from one clinic in California, and sent a warning letter to another in Florida.

The FDA will not allow deceitful actors to take advantage of vulnerable patients by purporting to have treatments or cures for serious diseases without any proof that they actually work," said FDA Commissioner Dr. Scott Gottlieb in a statement.

The agency announced that on Friday, Aug. 25th, U.S. Marshals seized five vials of a vaccine that is intended for people at a high risk for smallpox (for example, people in the military) from StemImmune Inc. in San Diego, California. The FDA says it learned that StemImmune was using the vaccines as well as stem cells from body fat to create an unapproved stem cell therapy. On its website, StemImmune says "The patients own (autologous, adult) stem cells, armed with potent anti-cancer payloads, function like a Trojan Horse, homing to tumors and cancer cells, undetected by the immune system." The stem cell treatment was injected into the tumors of cancer patients at the California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, California.

MORE: Three People Are Nearly Blind After Getting a Stem Cell Treatment

The FDA also sent a warning later to U.S. Stem Cell Clinic in Sunrise, Florida. The company recently came under public scrutiny when a March report revealed that three people had severe damage to their vision one woman went blindafter they were given shots of what the company said were stem cells into their eyes during a study sponsored by the clinic. The FDA says that an inspection of U.S. Stem Cell Clinic revealed that the clinic was using stem cells to treat diseases like Parkinson's, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease and pulmonary fibrosis. According to the FDA, there are currently only a limited number of stem cell therapies approved by the agencyincluding ones involving bone marrow, for bone marrow transplants in cancer care, and cord blood for specific blood-related disorders. There are no approved stem cell treatments for other diseases.

The FDA says U.S. Stem Cell Clinic also attempted to interfere with the FDA's most recent inspection by refusing to allow FDA investigators to enter without an appointment, and denied the agency access to its employees. "Refusing to permit entry or FDA inspection is a violation of federal law," the FDA says.

Action by the FDA on clinics promoting unproven stem cell therapies is "a long time coming," says Sean Morrison, former president of the International Society for Stem Cell Research (ISSCR) and d irector of the Childrens Research Institute at UT Southwestern. "C linics are preying on the hopes of desperate patients claiming they can cure all manner of diseases with stem cells that have not been tested in clinical trials, and in some cases, are flat out impossible."

In the past, medical experts were concerned over Americans traveling to countries with less medical regulation for stem cell therapies, but Morrison says such clinics have been popping up stateside over the last five years. "It's not a few companies in the U.S. making claims about therapies with stem cells," says Morrison. "It's scores of companies. The problem has exploded in the U.S."

Morrison blames the lack of FDA crackdown in the past for the growing problem. "At some point people made the calculation that the FDA didnt seem to be enforcing these laws," he says. "The margins are huge. They charge people tens of thousands of dollars."

Since stem cell therapy is still an active and legitimate area of scientific research, it can be hard for Americans to figure out what is safe and effective and what is not. Even when it comes to clinical trials, the scientific soundness is murky. A July 2017 paper reported that 18 U.S. companies have registered "patient-sponsored" stem cell studies on ClinicalTrials.gov. That means that the patients receiving the treatment paid for them, which isn't the case in more legitimate studies. None of these were gold standard studies: meaning the people were not randomly assigned to receive the treatment or not, so the participants knew they were receiving the therapy that could bias the results. Only seven of the studies disclosed upfront that patients had to pay to join the study, and none revealed that the costs ranged from $5,000 to $15,000 a treatment, Wired reports.

While Morrison says he's glad the FDA has taken action, he says it's not enoughat least not yet. "The FDA has to show that there is really a sustained commitment to enforcement," he says. "When the FDA wasnt bringing actions against these companies, I think people thought this meant that it was a gray area and that they could get away with it."

Undoing that damage could be a long process, and one that Morrison says needs consistent attention by the agency. In a letter released on Monday, FDA commissioner Gottlieb said the agency is stepping up enforcement of stem cell therapies and regenerative medicine. "Ive directed the FDA to launch a new working group to pursue unscrupulous clinics through whatever legally enforceable means are necessary to protect the public health," said Gottlieb. Whether those efforts have an impact remains to be seen.

Originally posted here:
FDA Cracks Down on Stem Cell Clinics But Patients Are Still at Risk - TIME

Recommendation and review posted by simmons

In BriefResearchers have discovered that acute myeloid leukemia causes leaking from the bone marrow that interferes with chemotherapy delivery. If chemotherapy for AML can be used together with drugs to treat this problem, outcomes may improve dramatically.

Researchers have discovered that the most common form of acute leukemia which strikes adults, acute myeloid leukemia (AML), prevents chemotherapy from being delivered properly by causing bone marrow to leak blood. This means that, by using drugs developed to treat blood vessel and heart problems in concert with chemotherapy, AML might be much more treatable. In this study, these drugs reversed bone marrow leaks in tissue from mice and humans, and also boosted chemotherapy effects. Since these drugs are already in clinical trials for other applications, the team hopes that they may be approved for use in the treatment of AML patients soon.

We found that the cancer was damaging the walls of blood vessels responsible for delivering oxygen, nutrients, and chemotherapy. When we used drugs to stop the leaks in mice, we were able to kill the cancer using conventional chemotherapy, Diana Passaro, Francis Crick Institute researcher and first author of the paper,said in a press release.

The team studied the ways in which AML affects bone marrow by injecting healthy mice with bone marrow from AML patients to create AML mice. They then used intravital microscopy to compare the bone marrow of AML mice with healthy mice and observed pre-loaded fluorescent dyes leaking from the bone marrow blood vessels into the AML mice. Next, they discovered that the cells lining the blood vessels in AML mice were oxygen-starved, which led to increases in nitric oxide (NO), a muscle relaxant. They realized this was probably causing the leaking, and provided NO blockers to the AML mice which slowed leukemia progress and extended remission.

The team not only helped chemotherapy drugs to reach their targets more effectively, but they also found that NO blockers increased stem cells in the bone marrow. This might help healthy cells out-compete cancerous cells, and improve treatment outcomes. Finally, the researchers found that an inability to reduce NO levels and chemotherapy failure were related.

With an average lifetime risk of less than half of one percent among the general population, AML is relatively rare. This is in addition to the fact that AML is a disease that primarily affects older people; the average age of AML patients in the US is 67, and the disease is even rarer before the age of 45. Despite this rarity, however, TheAmerican Cancer Society estimates that there will be around 21,380 new cases of AML in the US in 2017, and about 10,590 deaths, almost all in adults.

This high death rate is linked to the character of this form of cancer, which is particularly aggressive. This is in large part due to chemotherapy resistance and relapse, fewer than 25 percent of patients survive longer than five years after diagnosis. However, if this research leads to a new regimen of combined drug therapy, these numbers may change.

The team is optimistic about their findings and hopes to start clinical trials soon. Weve uncovered a biological marker for this type of leukemia as well as a possible drug target, Francis Crick Institute Group Leader and paper senior author Dominique Bonnet said in the press release. The next step will be clinical trials to see if NO blockers can help AML patients as much as our pre-clinical experiments suggest.

More:
Chemo-Boosting Drug Discovered for Leukemia - Futurism - Futurism

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From left to right: Richard Stone, a doctor at Dana-Farber Cancer Institute in Boston, poses with Peter Karalekas (center), 76, and Matthew Churitch, 22. Churitch donated stem cells to Karalekas two years ago, and he visited Dana-Farber with Karalekas earlier this summer. (Courtesy photo)

BOSTON -- After winding his way through Massachusetts, Connecticut, New Hampshire and Maine for 76 years, Peter Karalekas has a proclamation: He's a Southerner now.

He still lives in Kittery, Maine, just about an hour from the Lowell middle school where he taught for 21 years.

He has no plans to move.

Rather, Karalekas considers himself a Southerner because of his stem cells.

He never exactly felt all that sick.

Karalekas worked tirelessly for decades, first as a teacher and coach at the James S. Daley Middle School in Lowell and then as the owner of a half-dozen T-Bones restaurants across New Hampshire.

Even despite the 12-hour days, seven days a week, in the grind of the restaurant industry, Karalekas felt healthy and rarely fell ill.

Peter Karalekas, left, a 76-year-old former Lowellian, smiles during his first meeting with Matthew Churitch, 22, of Nashville, Tennessee, who helped save Karalekas life by donating stem cells. (Courtesy photo)

The two, who do not have children, moved to Kittery 17 years ago.

Everything started to change in 2014.

Karalekas recalls being "short-winded," but he had very few other symptoms when he was diagnosed with myelodysplastic syndrome, a rare type of cancer in which the bone marrow is damaged and cannot produce enough blood cells.

The prognosis was not good.

"They said the only thing that would save me was a stem cell transplant," Karalekas said. "Otherwise, I had a couple of months to live, because my cells were all dropping drastically.

He went onto a registry, hoping for a donor to pop up, but doctors told him it could take from six months to two years to find the right match. Even with a transplant, Karalekas said, his chances of success were "30 to 40 percent."

The call came four weeks later.

Matthew Churitch got his call quickly, too.

He joined the National Marrow Donor Program's Be the Match Registry in 2014, the summer between his freshman and sophomore years at Clemson University. His mother had been on the registry to donate for years. Churitch's decision was simple: When a friend was diagnosed with leukemia, he knew he should sign up, too.

He did the requisite cheek swab, unsure if he would ever even be contacted to donate. By the time he had finished the following semester, he got the call.

A match was found.

Churitch went through several more levels of testing and preparation to donate stem cells to a stranger. He went to Clemson's student health center to have blood drawn.

He returned to his native Nashville, Tennessee, going to a medical center 10 days in a row to receive shots in his stomach that would stimulate his bone marrow and prepare his cells for transplant.

He sat for eight hours, a needle in each arm as his stem cells were filtered out so they could be transferred to Boston.

"Getting the shots isn't fun," he said. "You're pretty sore afterward for a few weeks. But knowing that the person on the other end is in hundreds and hundreds times more pain than any donor would ever go through -- that kind of pushed me through."

Karalekas and Churitch first connected via an anonymous letter, per the transplant registry's rules, updating Churitch on Karalekas's lengthy, isolated recovery. They were able to speak directly after a year.

Churitch dialed Karalekas' number on a lengthy walk to class, took a deep breath and hit the call button. Moments later, both men were crying and laughing.

"That was really awesome, just being able to hear his voice and recognize that there's somebody else on the other end of this," Churitch said. "A lot of people don't get the chance to connect with their recipients or their donors."

Karalekas wanted more. He told his wife early on that he wanted to meet his "angel from heaven," so when Churitch graduated Clemson earlier this year, Karalekas paid to bring the 22-year-old and his mother to New England.

In late June, Karalekas and his wife pulled into a pickup lane at Logan International Airport in Boston.

"I got out of the car, I charged over, and I gave them both a huge hug," Karalekas said.

Karalekas showed Churitch and his mother around for five days.They went on a private tour of Fenway Park; they wandered the historic streets of Portsmouth, New Hampshire; they visited Dana-Farber together to meet the team that treated Karalekas.

Both families quickly bonded. Karalekas recalls his brother George asking Churitch about his portable phone charger, expressing curiosity about how convenient it was. A few weeks later, a brand-new portable charger arrived at George's door, a gift from Churitch.

In January, Karalekas and his wife will vacation in Arizona and will cheer on Churitch's mother -- without Churitch even present -- in the Phoenix Marathon.

Donor and recipient talk every week.

"It's like we're a very, very close-knit family now," Karalekas said. "He's the son we never had."

Churitch is now in his first year at the University of South Carolina School of Medicine Greenville with hopes of becoming a physician. He hopes to use Karalekas's experience as inspiration for any patients facing future hardship, and he hopes that others, especially young people, will see their success and join the registry.

"You never know where that will take you," he said. "You can gain a friend for life, impact somebody and their family in need."

Karalekas said he feels he has a new life: His chances of beating the disease are now 97 percent, he says, up from the 30 percent or 40 percent when he started treatment. Thanks to the transplant from a handsome, athletic college student in Tennessee.

"I said, 'I'm a Southerner now,'" Karalekas said. "My stem cells are 99 percent this gentleman. I'm 99 percent him."

Follow Chris on Twitter @ChrisLisinski.

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For Lowell native, stem cell match becomes a match as friends - Lowell Sun

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AsianScientist (Aug. 30, 2017) - In a study published in Cell Stem Cell, scientists in Japan and Switzerland have found that bacterial infections can stress blood-producing stem cells in the bone marrow and reduce their ability to self-replicate.

When a person becomes infected with a virus or bacteria, immune cells in the blood or lymph react to the infection. Some of these immune cells use sensors on their surfaces, called Toll-like receptors (TLR), to distinguish invading pathogens from molecules that are expressed by the host. By doing so, they can attack and ultimately destroy pathogens thereby protecting the body without attacking host cells.

Bone marrow contains hematopoietic stem cells which create blood cells, such as lymphocytes and erythrocytes, throughout the lifetime of an individual. When infection occurs, a large number of immune cells are activated and consumed. Hence, it is necessary to replenish these immune cells by increasing blood production in bone marrow.

Recent studies have revealed that immune cells are not the only cells that detect the danger signals associated with infection. Hematopoietic stem cells also identify these signals and use them to adjust blood production. However, little was known about how hematopoietic stem cells respond to bacterial infection or how it affected their function.

In this study, researchers from Kumamoto University and the University of Zurich analyzed the role of TLRs in hematopoietic stem cells upon bacterial infection, given that both immune cells and hematopoietic stem cells have TLRs.

To generate a model of bacterial infection, researchers injected one of the key molecules found in the outer membrane of gram negative bacteria and known to cause sepsislipopolysaccharide (LPS)into lab mice. They then analyzed the detailed role of TLRs in hematopoietic stem cell regulation by combining genetically modified animals that do not have TLR and related molecules, or agents that inhibit these molecules.

The results showed that LPS spread throughout the body, with some eventually reaching the bone marrow. This stimulated the TLRs of the hematopoietic stem cells and induced them to proliferate. They also discovered that while LPS promoted stem cell proliferation, it also induced stressed the stem cells, impairing their ability to successfully self-replicate and resulting in diminished blood production. Similar results were obtained after infection with Escherichia coli bacteria.

Fortunately we were able to confirm that this molecular reaction can be inhibited by drugs, said Professor Hitoshi Takizawa of Kumamoto University who led the study. The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria. It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.

The article can be found at: Takizawa et al. (2017) Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness.

Source: Kumamoto University.Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Continued here:
Bacterial Infection Stresses Blood Stem Cells | Asian Scientist ... - Asian Scientist Magazine

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Bone marrow contains hematopoetic stem cells, the precursors to every blood cell type. These cells spring into action following bone marrow transplants, bone marrow injury and during systemic infection, creating new blood cells, including immune cells, in a process known as hematopoiesis.

A new study led by University of Pennsylvania and Technical University of Dresden scientists has identified an important regulator of this process, a protein called Del-1. Targeting it, the researchers noted, could be an effective way to improve stem cell transplants for both donors and recipients. There may also be ways to modulate levels of Del-1 in patients with certain blood cancers to enhance immune cell production. The findings are reported this week in The Journal of Clinical Investigation.

Because the hematopoetic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications, said George Hajishengallis, the Thomas W. Evans Centennial Professor in the Department of Microbiology in Penns School of Dental Medicine and a senior author on the work.

I think that Del-1 represents a major regulator of the hematopoetic stem cell niche, said Triantafyllos Chavakis, co-senior author on the study and a professor at the Technical University of Dresden. It will be worthwhile to study its expression in the context of hematopoetic malignancy.

For Hajishengallis, the route to studying Del-1 in the bone marrow began in his field of dental medicine. Working with Chavakis, he had identified Del-1 as a potential drug target for gum disease after finding that it prevents inflammatory cells from moving into the gums.

Both scientists and their labs had discovered that Del-1 was also expressed in the bone marrow and began following up to see what its function was there.

In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes [white blood cells]from the marrow into the periphery, Hajishengallis said, something analogous to what it was doing in the gingiva. But it turned out it had a much more important and global role than what I had imagined.

The researchers investigations revealed that Del-1 was expressed by at least three cell types in the bone marrow that support hematopoetic stem cells: endothelial cells, CAR cells and osteoblasts. Using mice deficient in Del-1, they found that the protein promotes proliferation and differentiation of hematopoetic stem cells, sending more of these progenitor cells down a path toward becoming myeloid cells, such as macrophages and neutrophils, rather than lymphocytes, such as T cells and B cells.

In bone marrow transplant experiments, the team discovered that the presence of Del-1 in recipient bone marrow is required for the transplanted stem cells to engraft in the recipient and to facilitate the process of myelopoesis, the production of myeloid cells.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to those with normal Del-1 levels.

We saw roles for Del-1 in both steady state and emergency conditions, Hajishengallis said.

Hajishengallis, Chavakis and their colleagues identified the protein on hematopoetic stem cells with which Del-1 interacts, the 3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The scientists see potential applications in bone marrow and stem cell transplants, for both donors and recipients. In donors, blocking the interaction between Del-1 and hematopoetic stem cells could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation. Transplant recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia, associated with low levels of white blood cells, might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

Its easy to think of practical applications for these findings, said Hajishengallis. Now we need to find out whether it works in practice, so our studies continue.

Excerpt from:
Targeting bone marrow protein could be effective way to improve ... - Gears Of Biz

Recommendation and review posted by Bethany Smith

Scientists around the world are researching ways to reverse the aging process. There have been a few scientific breakthroughs in the last years, such as a March 2013, Science report. The report discussed how a team of scientists at the University of New South Wales had successfully reversed the aging process in mice with a NAD+ booster, NMN that stimulated the natural repair processes in cells (1).

In August 2017, a different technique was reported. According to ScienceDaily. its being touted as a possible fountain of youth. The ability to rejuvenate the heart and even reverse aging is the claim of a recent study (2).

The European Heart Journal published the study where researchers injected cardiac stem cells taken from the hearts of newborn lab rats into the hearts of old rats (22 months old, which is considered old for a rat lifespan). The result was a reversal in their aging hearts. The paper claims that the old rats appeared newly invigorated after receiving their injections.

In fact, the researchers noticed a 20% increase in the old rats exercising ability. Certainly, the scientists anticipated that this treatment would improve the old rats hearts, what they didnt expect were other benefits, such as the rat fur (shaved away for the surgery) growing back faster than normal.

In addition, the scientists noticed that the rats telomeres had changed. Instead shrinking, the common effect of aging, the telomers in the treated rats actually lengthened. This was an astounding side-effect of the cardiac stem cell injections.

Telomeres are repetitive nucleotide sequences that are found along the ends of chromosomes and become like protective caps. They prevent the ends of the chromosomes from deteriorating, as well as fusing with other chromosomes. Unfortunately, this protection begins to wear away with age and the length of the telomeres shorten as the body ages (3).To discover that the rats telomeres grew longer along with other systemic rejuvenating effects, the primary investigator on the research and director of the Cedars-Sinai Heart Institute Dr Eduardo Marbn proclaimed that it was like discovering, an unexpected fountain of youth.

Dr Marbns team completed the worlds first cardiac stem cell infusion in 2009. Dr Marbn developed the process of growing cardiac-derived stem cells when he was at John Hopkins University. Hes continued his research at Cedars-Sinai.

Conducting research in various heart-related cell therapy for more than 12 years, some of that research included using cardiosphere-derived cells.

According to Life Map Discovery, Cardiosphere-derived cells are isolated from atrial or ventricular biopsy specimens of patients undergoing heart surgery. The tissues are processed and cultured until a fibroblast-like cell layer forms. In this process, some cells migrate to this layer and techs can use them to further isolate and culture to create cardiospheres (4).

A March 2012 publication by the Journal of the American College of Cardiology (JACC) discussed the injection of cardiosphere-derived cells (CDCs) into infarcted mouse hearts. The injections resulted in superior improvement of cardiac function. (5)

According to Dr Marbn, Our previous lab studies and human clinical trials have shown promise in treating heart failure using cardiac stem cell infusions.

In the teams latest study, they used a specific type of stem cells taken from the newborn rats. Instead of stem cells, anther group received a placebo treatment consisting of saline injections. Each group was then compare to a group of four-month-old rats.

ScienceDaily reported that Dr Marbn stated that the cardiac stem cells secrete, tiny vesicles that are chock-full of signaling molecules such as RNA and proteins. Apparently, its the vesicles found in the young cells that, contain all the needed instructions to turn back the clock.

With these latest results, he said, Now we find that these specialized stem cells could turn out to reverse problems associated with aging of the heart.

The team is underway with more research, such as the ability to recreate the same results by administering the stem cells via IV (Intravenous) or with non-newborn cardiac stem cells. According to co-primary investigator and the first author of the study Lilian Grigorian-Shamagian, MD, PhD, their study didnt measure whether receiving the cardiosphere-derived cells extended lifespans. This will be another area the team plans to investigate.

References & Image Credits:(1) How NASA Anti-aging Drug Works(2) Science Daily(3) Wikipedia(4) LifeMapSC(5) OnlineJACC

Continued here:
Cardiac Stem Cells May Be Fountain of Youth - Top Secret Writers

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TAMPA (FOX 13) - Repairing a damaged heart has become much more than opening clogged arteries in the Cardiac Catheterization Lab at Pepin Heart Hospital in Tampa.

Dr. Charles Lambert and his team are injecting stem cells directly into specific areas in the walls of damaged hearts.

"We know where viable tissue is, what part of the heart is contracting and has live cells there," he explains.

Finding that living tissue begins with creating a color-coded map of the heart identifying areas where blood flow is maximized.

"We go back after mapping with a needle that comes out of the catheter and we do roughly twenty injections in viable tissue area," Lambert says.

It's all part of an experimental clinical trial Shiela Allen hopes will help her failing heart recover. Less than two hours after welcoming her youngest grandchild into this world, her grandson drove her to the emergency room.

"I couldn't breathe," she recalled.

Sheila was shocked when doctors told her that her heart was pumping at less than half of what it should.

"Now that I look back, I can figure out I had all the symptoms but I was just putting it off because I'm busy, I'm old, I'm a little bit overweight," she admits.

Like many women, Sheila ignored warning signs like fatigue, coughing and shortness of breath - especially when lying down.

"The coughing was odd to me because I was not congested, I could not lay flat in bed so I was propped up on four or five pillows," she says.

Similar to a balloon filled with too much water, the cardiac muscle is overstretched, thin, and weak. So weak, it can only pump a fraction of the blood inside its chambers to the rest of the body. That causes fluid to back up into the lungs and other parts of the body like the legs.

For about a decade, cardiologists have tried using stem cells to strengthen the muscle with mixed results. This study is hoping a new twist, will make it more successful.

Along with using the heart map to direct the injections, the stem cells are also different. Instead of taking them from the patient, syringes like these are filled with stem cells from donors.

"These trial cells are taken from healthy volunteers that are actually medical students, not here in town, but actually up in the northeast," he explains.

Another key difference in the study is the product's maker, Mesoblast. It is allowing people like Sheila, who have heart failure from unknown causes, to also enter the study. The clinical trial using the younger cells is now in 50 centers across the world.

"They're preserved so when we randomize a patient we take it off the shelf, treat it, warm it, the cells are perfectly alive and healthy and then administer it to the patients," Lambert says.

Side effects in earlier studies included a drop in blood pressure, bleeding, and fluid accumulation around the heart.

"It was basically like I was having another heart catheterization," Sheila says her side effects were minimal. "Three days after the procedure I was on a plane going on a trip."

She's not sure if she got a placebo or the actual cells, but as she completes her cardiac rehabilitation therapy, she says she is feeling better, "I've had a little more energy I dont know if it's related to that."

Energy allowing her to spend time with her family, and watch her youngest grandchild grow.

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Damaged hearts being repaired with stem cells - FOX 13 News, Tampa Bay

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Stem cells and genome editing offer exciting opportunities within regenerative medicine. However, any clinical application of stem cells requires strict regulation to ensure that the cells are not exposed to animal derived products.

StemFit Basic02 is a xeno-free, defined medium for human pluripotent stem cell (hiPSC) culture that offers an effective solution for regenerative medicine research. This medium has been proven to effectively maintain Induced Pluripotent Stem (iPS) and Embryonic Stem (ES) cells under feeder-free conditions, during the reprogramming, expansion and differentiation phases of stem cell culture.

Specially formulated to enhance single cell expansion in the cloning step of stem cell genome editing, StemFit Basic02 offers superior and stable growth performance, high colony forming efficiency and robust scalable cell expansion. This ensures high karyotype stability over long periods and hence reproducible culture conditions.

StemFit cell culture media has been independently evaluated by CGT Catapult, an independent centre of excellence helping advance the UK cell and gene therapy industry. In these tests, StemFit not only delivered higher cell proliferation, but also showed characteristics such as homogeneity of gene expression compared with iPS cells cultured with 4 other media without any chromosomal abnormalities.

Original post:
Xeno-free Cell Culture Medium for Regenerative Medicine Research - Technology Networks

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Stem cells and genome editing offer exciting opportunities within regenerative medicine.

However, any clinical application of stem cells requires strict regulation to ensure that the cells are not exposed to animal derived products.

Now Amsbio announces the availability of StemFit Basic02 feeder-free stem cell culture media.

StemFit Basic02 is a xeno-free, defined medium for human pluripotent stem cell (hiPSC) culture that offers an effective solution for regenerative medicine research.

This medium has been proven to effectively maintain Induced Pluripotent Stem (iPS) and Embryonic Stem (ES) cells under feeder-free conditions, during the reprogramming, expansion and differentiation phases of stem cell culture.

Specially formulated to enhance single cell expansion in the cloning step of stem cell genome editing, StemFit Basic02 offers superior and stable growth performance, high colony forming efficiency and robust scalable cell expansion.

This ensures high karyotype stability over long periods and hence reproducible culture conditions.

StemFit cell culture media has been independently evaluated by CGT Catapult, an independent centre of excellence helping advance the UK cell and gene therapy industry.

In these tests, StemFit not only delivered higher cell proliferation, but also showed characteristics such as homogeneity of gene expression compared with iPS cells cultured with four other media without any chromosomal abnormalities.

Read more from the original source:
Xeno-free cell culture medium for regenerative medicine research - Scientist Live

Recommendation and review posted by simmons

Photo: supplied

Obesity is a predominantly genetic disease, rather than a lifestyle choice thats the central premise of a new SBS show calledThe Obesity Myth.

The show, which followed doctors and patients at the University of Melbournes Austin Health forsix months, aimsto dispel the stigma attached to obesity.

Austin Healths Weight Control Clinic head professor Joseph Proietto says obese people face constant discrimination.

There is a lot of misunderstanding and misinformation about obesity in the community its an injustice, he says.Gluttony is seen as sinful, and to commit a sin you have to use free will. So the idea has been that people choose to be fat.

The world-renowned obesity management expert says he hopes the program will show obesity is far more complicated than generallythought.

Recent research has revealed how the body regulates weight through the hormones leptin (which decreases appetite) and ghrelin (which increases it). Whenpeople lose weight, their leptin levels decreaseand their ghrelin levels increase.

In 2011, Austin Health discovered levels of otherhormones also change according to weight gain or loss, and that those changes are enduring. Proiettosays this evidence points strongly to weight gain being genetic.

Finding that hormone changes after weight loss are long-lasting showed us that medication needs to be life-long, he says. Obesity is a chronic condition.

In 2014, another of the clinics studies showed the rate of weight loss did not affect how quickly weight was regained, and that more people succeeded in a rapid weight-loss program than a gradual program.

Professor Joseph Proietto. Photo: SBS

To combat obesity in patients, the clinics physicians conduct a thorough history and targeted examination, then offer a partial, very-low-energy diet thatreplaces breakfast and lunch.

After theyve lost all the weight they want to lose, whether it takes three months, six months or a year, then we wean them off the diet and back onto things like carbs and fruit, Proietto says.

A dietician will outlinea balanced, energy-reduced diet, and the clinic will continue to follow the patientsprogress. If theyre struggling to keep weight off because of increased hunger, medication is prescribed.

Proietto hopes the clinics research intoobesity will become common knowledge.

GPs are getting better at treating this condition than they used to be, he says. Hopefully they will continue to educate the public to try to dispel this myth.

If youre struggling with obesity Proietto says not to beat yourself around the head, because its probably genetic. He suggests seeking medical assistance.

Speak to your doctor about it, and see if you can get some help, he says.

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SBS show The Obesity Myth is breaking down stigma - The Weekly Review

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Every woman experiences the menopause differently, but many just aren't prepared for the range of symptoms and emotions this life shift can involve.

Oestrogen is the main hormone that reduces during the menopause. It affects many different areas of your body including your brain, so can cause many symptoms when its levels start to naturally fall. And these signs might occur even if you're still having periods. This time, called the perimenopause, can last for several years. It means many women won't make the connection to their hormones and end up suffering in silence.

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Dr Louise Newson, a GP who specialises in menopause (and runs a regular private menopause clinic at Parkway Hospital in Solihull), is passionate that this needs to change. She says she is often disappointed about how little accurate information there is for women to learn about the menopause. Which seems silly, considering it's something that's going to happen to all of them.

"Ten years ago if I'd had this conversation I would have said "oh, apart from night sweats and hot flushes, there's not that many other symptoms" but now I've seen hundreds and hundreds of women all telling me about all these other symptoms related to their changing hormone levels. And it's 2017 and many women are having rubbish lives because of it. And it doesn't have to be like this," she says.

Dr Newson wants women to know they're not alone. Here she explains the unexpected symptoms the menopause can cause:

It's often the symptoms people can't see that lead to the most difficulties, says Dr Newson.

Feelings of depression and low self-esteem, anxiety and panic attacks are very common symptoms of the menopause, she reveals. She has seen loads of women who have wrongly been prescribed antidepressants. Many also become fearful of everyday scenarios, she explains:

"I hear from a lot of women who find they're too scared to go into their car or they don't like their husband's driving anymore. They'll say they just worry about things they've never really worried about before."

Anxiety and depression symptoms can be debilitating and impact on work and family life. If you're experiencing anything similar, you should see your doctor.

Think the menopause will finally mean you're free from PMS? Not necessarily unfortunately, says Dr Newson. It's not uncommon for mood swings to appear during this time which can have a big impact on relationships.

"People tell me how cross they get - fed up with their children and fed up with their husbands. They often don't want their partner touching them. When women get better they realise how bad-tempered they've been and how hard it's been for their partner to live with them."

GettyThomas Barwick

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It might not be too surprising to learn that sleep becomes harder during perimenopause and menopause. Night sweats are common, of course. But even if you don't experience those, you might be more tired than normal and put it down to an exhausting life perhaps you have a stressful job, or grown up children giving you grief?

Dr Newson says if you can't get through the day without needing a nap, that's a sign you might need some help.

"A lot of people think they're tired because they have a new job or their children are stressing them out. I know myself when I was having symptoms I felt so tired and I just blamed it on work. And now I'm doing more work and I'm less tired! A lot of women tell me they literally come home from work and go straight to bed. Or they have a nap in the afternoon but they've never told anyone because they think it's just what happens when you get a bit older, which is awful," she says.

Falling oestrogen levels affect the joints in numerous ways making movement feel stiffer and more painful for some people. But many women will be misdiagnosed with arthritis when it's likely related to depleting hormones. It also means women are likely to stop exercising, even if they used to enjoy it before, potentially making other symptoms worse, says Dr Newson.

We're not very good at talking about bladders, but if you're going through the menopause or perimenopause, you might find you're getting up more frequently to pee in the night or even experiencing bladder weakness. Dr Newson explains it's because oestrogen affects the pelvic floor and bladder too.

"Often someone just wouldn't think to trouble the doctor because everyone knows your bladder gets a little bit weaker as you get older. And it's embarrassing if you cough and sneeze and get a little bit of wee in your pants. You likely wouldn't talk to your friends about it, even though your friends are probably suffering the same."

Dr Newson's advice is clear, if you're experiencing any of these symptoms, there are a range of treatment options, so make an appointment with your GP.

Dr Louise Newson has been working with Menopause & Me - a new website dedicated to supporting women throughout their menopause journeys.

Excerpt from:
5 unexpected symptoms of the menopause every woman needs to know about - Netdoctor

Recommendation and review posted by simmons

Chandigarh: For the first time, dairy farmers will now have the option of sexed semen for desi cattle breeds like Sahiwal, Gir and Red Sindhi cows and Murrah buffaloes. Sexed genetics, which is used to produce offspring of a desired sex, was not available for these breeds till now. ABS India (ABS), a division of Genus Plc, on Thursday launched 'sexed dairy genetics' in Chandigarh. The technology is designed to deliver more high-value pregnancies to dairy herds countrywide. Priced differently for different genetics, ABS Sexcel will be available to the Indian dairy farmers at approximately 30-40% less than the import price of the sexed semen. At a press conference to announce the launch, British deputy high commissioner, Andrew Ayre said, "It is an important day for the UK and the Indian dairy industry to extend Sexcel benefits to Indian dairy farmers, helping them to double their income by 2022 as targeted by the government." Arvind Gautam, managing director, ABS India said it would give farmers a new option for achieving their desired genetic blueprint and would help them profit through genetic progress. "We have a unique product and trial results are very effective. For the first time, sexed semen of indigenous cattle breeds like Sahiwal, Red Sindhi and Gir cows and Murrah buffaloes is available in India." Rahul Gupta, head (production) of the company added, "Dairy farmers may now breed their cows with the sexed genetics specifically designed to produce more female cows using this new technology. The technology produces female sexed semen through a new, cutting edge, laser-kill technology."

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Dairy farmers can get sexed semen for native cattle breeds within India - Times of India

Recommendation and review posted by Bethany Smith

By Giorgia GuglielmiAug. 31, 2017 , 2:13 PM

The saying you are what you eat is particularly true for female honey bees, which grow up to be either small, sterile workers or large, fertile queens depending on their diet. Previously, many researchers thought that something in the food fed to young queensa secretion called royal jellywas what made the difference. Now, a new study suggests its signaling molecules in the grub of young worker bees that keeps their sexual development in check. That diet, a mixture of pollen and honey called beebread, is shot through with a special kind of microRNA (miRNA), noncoding RNA molecules that help regulate gene expression. To find out whetherthese miRNAs were the culprit, scientists added them to the diet of larvae raised in the lab. These larvae developed more slowly, with smaller bodies and smaller ovaries than larvae fed food without the supplement, the team reports today in PLOS Genetics. The researchers also found that one common, plant-derived miRNA in beebread switches off a gene that helps larvae turn into queens. After being eaten with food, the miRNAs might enter the bees gut and spread throughout the rest of the body, where they could help regulate key genes, the scientists say. Although plant miRNAs alone arent likely to turn queens into workers, queens-to-be probably dont want to eat the commoners bread.

Read the rest here:
Why some baby bees are destined to become workersor queens - Science Magazine

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MANHATTAN, Kan. (AP) Research at the Kansas Wheat Innovation Center could revolutionize farming not just in Kansas but around the world.

Scientists there use advanced breeding techniques to isolate sought-after qualities. Different than genetic modification, breeding selects wheat varieties that need less water, can grow in extreme heat, or are durable against disease and pests in process that can take nearly a decade. Researchers at the Kansas Wheat Innovation Center hope to reduce that time so farmers can grow better wheat, faster, said Aaron Harries, vice president of research and operations.

This year, the wheat streak mosaic virus ravaged wheat crops in western Kansas. A tiny mite that remained active during an unusually warm winter spread the disease over a larger area than before. Within a few years, a variety of wheat resistant to the virus will be in the hands of farmers, Harries said.

But even as researchers develop tougher wheats, Mother Nature catches up. Disease evolves and climates change.

"We're always striving to improve the yield," he said.

This year, a consortium of international geneticists will likely finish sequencing wheat's genome.

Similar to the Human Genome Project that mapped human genetics, the project, which began in part with the center's research, will lay out the fundamentals of the wheat gene so scientists can more easily identify desirable traits.

It's not just farmers that benefit from Kansas Wheat research. Varieties are being developed that are naturally sweeter, so bakers and food companies can use less sugar to sweeten doughs.

The Capital-Journal reports that researchers are also talking to the growing number of people who have celiac disease. Those with the condition are unable to digest gluten, a protein found in wheat, barley and rye. With clues unlocked in the wheat genome, the institute hopes to locate the specific portions of the protein that cause the reaction and breed it out or silence it, Harries said.

"That's the protein that makes bread rise, so we're not trying to make it 'gluten free,'" he said. "We're trying to make it 'celiac safe.'"

To find the wheat qualities farmers and consumers want, researchers not only turn to wheat currently being grown, but they also have a store of ancient grains the wild grass varieties bred together to form modern wheat. Scientists collected the grains from places such as Syria, Iraq and Israel.

"We go treasure hunting for traits from those relatives and cross them into modern bread wheat," Harries said.

With all these different types of wheat on the market, Harries said the Kansas Wheat Innovation Center sees a revolution coming in the way wheat is grown, sold and processed. Currently, farmers growing consumer grain sell it to the elevator at harvest, which turns it over to a company in the food industry.

In future, farmers may contract directly with a certain company to grow a specific type of wheat.

A farmer with 100 acres may grow 50 acres of consumer wheat, 25 acres of sweet wheat and 25 acres of celiac-safe wheat, Harries said.

"Ultimately that will change the way we grow wheat." he said.

These advances in wheat are years away, but they begin in tiny pots in the institute's more than 35,000-square-foot, $11 million facility. That's where Heartland Plant Innovations research associate Tyler Suelter and a team breed new wheat varieties using a doubled haploid technique that can shave years off the breeding process.

Suelter said it sounds complex, but it's really an acceleration of traditional breeding.

The process involves producing plants that have all the same genetics. When a variety is identified, scientists emasculate the plants, leaving only the female reproductive system.

Maize is used to pollinate the plant so an embryo is produced. Since the embryo wasn't pollinated with wheat, it has half the number of chromosomes. Breeders will later double the count, so the plant has two copies of identical chromosomes a process that takes generations with typical breeding.

The research has produced nearly 100,000 doubled haploid variations and reduces the amount of time it takes to breed a new wheat variety.

"The time savings comes from how long it takes to grow the plants out. With (traditional breeding), you grow out several generations, and each takes six months," Suelter said. "With doubled haploid, you basically fix those traits in a single generation."

___

Information from: The Topeka (Kan.) Capital-Journal, http://www.cjonline.com

An AP Member Exchange shared by the Topeka Capital-Journal.

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Kansas researchers looking at new wheat varieties - San Francisco Chronicle

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Women have had to face many challenges within the workforce, particularly in the agriculture sector, which has traditionally been dominated by men. This changing, however, as more women are establishing themselves as forces to be reckoned with within the industry.

Although in different parts of the business, both women are focused on making the company and industry more sustainable. Nkala started her career at McCain South Africa through the company Graduate Trainee Program in 2004. Since then she has been promoted into different positions including being the first ever female production manager at the Springs plant, a position she holds today. Vorster followed her interest and passion for genetics and extension to McCain South Africa, where she is currently the only female Agronomist.

Both women have pioneered different techniques and implemented strategies to help McCain South Africa become more sustainable as a business.

Pumeza Nkala

Educating colleagues and employees on water became incredibly important. By making people aware of the drought and its effect, we were able to ensure that water usage was handled effectively and efficiently, explains Nkala. The water reduction strategy looked at technical elements like water cascading, process refinements and different process technologies. The result of this is that each of the plants now has a dedicated water usage team that reviews water usage results daily and proposes gap closing measures.

Since implementing this strategy there has been a 42% reduction in water wastage at the Springs plant and a 23% reduction at the Delmas facility over the past two years.

Ineke Vorster

As an agronomist, she plays an important role within the business. She looks at how varieties can help to optimise yields on the field and in the factory. This is made possible when crops are planted in the correct place and in the correct way. If the soil isnt perfect or the conditions are not favourable there could be a negative impact on the crops and this, in turn, will affect stock and what consumers will be able to buy. Not only could this affect the business and consumers, but the farmers as well.

Vorster goes above and beyond to ensure that the farms are sustainable and that the landscape can handle the planting in order to preserve and look after the growing crops and farms. I absolutely love everything about my job, the trial work is quite repetitive and you need to constantly look for answers and solutions. By actively being out there in the fields, you pick up on things that can sometimes be missed in theory, says Vorster. She says that it is the interaction with farmers, field officers and trying to find a solution to problems that they are facing that really gives her a thrill.

Both Nkala and Vorster want to encourage young women to follow their dreams and to not let anything stand in their way. We have all faced challenges in our lives but it is how you overcome them and rise above them that really matters. If you love what you do and are following your passion every day it really does make a difference, so dont settle for anything less than what you want, concluded Vorster.

Originally posted here:
Women forces to be reckoned with in agriculture - Bizcommunity.com

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LONDON (Reuters)Scientists have successfully used reprogrammed stem cells to restore functioning brain cells in monkeys, raising hopes the technique could be used in future to help patients with Parkinsons disease.

Since Parkinsons is caused by a lack of dopamine made by brain cells, researchers have long hoped to use stem cells to restore normal production of the neurotransmitter chemical.

Now, for the first time, Japanese researchers have shown that human induced pluripotent stem cells (iPS) can be administered safely and effectively to treat primates with symptoms of the debilitating disease.

So-called iPS cells are made by removing mature cells from an individualoften from the skinand reprogramming them to behave like embryonic stem cells. They can then be coaxed into dopamine-producing brain cells.

The scientists from Kyoto University, a world-leader in iPS technology, said their experiment indicated that this approach could potentially be used for the clinical treatment of human patients with Parkinsons.

In addition to boosting dopamine production, the tests showed improved movement in affected monkeys and no tumors in their brains for at least two years.

The human iPS cells used in the experiment worked whether they came from healthy individuals or Parkinsons disease patients, the Japanese team reported in the journal Nature on Wednesday.

This is extremely promising research demonstrating that a safe and highly effective cell therapy for Parkinsons can be produced in the lab, said Tilo Kunath of the MRC Centre for Regenerative Medicine, University of Edinburgh, who was not involved in the research.

The next step will be to test the treatment in a first-in-human clinical trial, which Jun Takahashi of Kyoto University told Reuters he hoped to start by the end of 2018.

Any widespread use of the new therapy is still many years away, but the research has significantly reduced previous uncertainties about iPS-derived cell grafts.

The fact that this research uses iPS cells rather human embryonic stem cells means the treatment would be acceptable in countries such as Ireland and much of Latin America, where embryonic cells are banned.

Excitement about the promise of stem cells has led to hundreds of medical centers springing up around the world claiming to be able to repair damaged tissue in conditions such as multiple sclerosis and Parkinsons.

While some treatments for cancer and skin grafts have been approved by regulators, many other potential therapies are only in early-stage development, prompting a warning last month by health experts about the dangers of stem-cell tourism.

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Human Stem Cells Fight Parkinson's Disease in Monkeys - Scientific American

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