NIH study describes new method for tracking T cells in HIV patients

Researchers use a naturally occurring HIV variant to trace a T cell lineage for 17 years

WHAT:
A team of researchers has reported a novel method for tracking CD4+ T cells in people infected with HIV. CD4+ T cells are critical for immune defense against an array of pathogens and are a primary target of HIV. In the study, researchers used a unique, replication-incompetent (defective) form of HIV identified in a patient in the early 1990s. The defective virus had integrated into the genome of a single CD4+ T cell. Like a barcode, this "provirus" marked the originally infected CD4+ T cell and its progeny, enabling researchers to track its lineage for 17 years. This new method allows scientists to distinguish dividing cells from dying ones, something that has not been possible with existing labeling techniques, but is essential for studying how immune cells survive HIV infection.
The study, published in the online issue of AIDS, was conducted by Hiromi Imamichi, Ph.D., H. Clifford Lane, M.D., and others in the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The cell lineage is part of a subset of CD4+ T cells called "effector memory" (TEM) cells. This distinction is significant because it is currently believed that TEM cells last for only days or weeks. The NIAID investigators demonstrated that this subpopulation of T cells can persist for at least 17 years.

The researchers also observed in the blood cells of patients a higher frequency of defective HIV proviruses than what has been reported in previous work. Although these defective variants cannot produce an infectious virus, many retain the ability to generate small pieces of HIV, leading the researchers to speculate that these "foreign materials" within CD4+ T cells may play a key role in the ongoing immune activation that is characteristic of HIV infection, including in patients with "undetectable" virus in their blood.

Source:NIH/National Institute of Allergy and Infectious Diseases 

ISMGA urges TN govt to allot more fund to Govt Siddha Medical College at Palayamkottai

The Indian Siddha Medical Graduates Association (ISMGA) has requested the Commissionerate of Indian System of Medicines in Chennai to favourably consider development activities at the 50 years old Government Siddha Medical College at Palayamkottai in Thirunelveli district in Tamil Nadu. The college is celebrating its 50th anniversary this year.
In a telephonic talk with Pharmabiz, Dr Padmaram Chandra, the national secretary of ISMGA said he has submitted a memorandum to the Commissioner of Indian Medicine demanding more funds to the medical college this year because so many developmental projects have been chalked out by the former students of the college, of them a major chunk are their members. He said the government should give priority to develop the infrastructure facilities of the college before initiating future programmes.
Although there have been complaints from students, teachers, former students and well-wishers about the poor situation of the college, the authorities are keeping mum over the issue even on the golden jubilee time.  Miffed over the apathetic attitude of the state government, the Chennai based Centre for Traditional Medicines and Research (CTMR) last week met the state health secretary and briefed him of the deplorable condition of the Siddha medical college and wanted his intervention in the matter. Due to lack of space, the consulting rooms of the hospitals are invariably overcrowded and often creates inconveniences to the patients visiting the hospital.
“In general both the two Siddha medical colleges in the government sector are lacking infrastructural facilities and the students are facing serious problems. The situation of the private Siddha medical colleges is also not better.  If the Central Council of Indian Medicine (CCIM) follows strict rules during their inspection, no college in Chennai would be able to run the courses and all of them have to close down.  Much worse is the situation prevailing in each college. Either through compromise or because of influence these colleges, both in the private and government sectors, are surviving each year”, Dr Padmaram Chandra told Pharmabiz.
There are two government colleges and five private colleges in Tamil Nadu to teach the Siddha system to the students. The two government colleges are located in northernmost and southernmost parts of the state. Both of them are facing shortage of faculties and essential medicines also.
Akhila Thiruvithamcore Siddha Vaidya Kalloory in Kanyakumari,      Sri Sai Ram Siddha Medical College & Research Centre in Chennai, Velumailu Siddha Medical College in Kancheepuram, R V S Siddha Medical College in Coimbatore and Sivaraj Siddha Medical College in Salem are the five institutions in the private sector running the course of traditional system.
Regarding the activities of ISMGA, the national secretary said the Chennai zonal committee is not active and not functioning well. Otherwise, the problems of the academic institutions would have been intimated to the government on time. He said a CME program for the Chennai members of the association would be conducted in the third week of this month. Dr Stanely John, vice-president (Siddha) of CCIM would participate in the programme.
Source:Pharmabiz

Genes Associated With Cerebral Palsy and Death in Very Preterm Babies

Researchers will report that a variant in SERPINE1, a gene involved in inflammation and blood clotting, is associated with cerebral palsy and death in very preterm babies.
 This gene has been associated with increased risk of cerebral palsy in one previous study of preterm babies. The study will be presented on Feb. 6 at 2:45 p.m. CST, at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting™, in New Orleans. 

Previous genetic studies of very preterm babies have suggested several genetic variations that might predispose to brain injury and developmental problems. However, different studies have had different results. 

This study, titled Genetic Predisposition to Adverse Neurodevelopmental Outcome After Early Preterm Birth: A Validation Analysis, was a collaborative effort between the Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units and Neonatal Research Networks. 

Researchers evaluated two different populations of very early preterm births (earlier than 32 weeks) with the goal of confirming the same genetic risk factors in both groups. The first population of preterm births was enrolled in a large Neonatal Research Network study, and the other group was of births that were enrolled in a Maternal Fetal Medicine Units Network study of magnesium sulfate before preterm birth for prevention of cerebral palsy. 

Results revealed a variant in the gene SERPINE1, a gene involved in inflammation and blood clotting, was associated with cerebral palsy and death after early preterm birth in both populations of preterm babies. 

"Preterm birth is the leading cause of childhood brain injury in otherwise normal children. The earlier a baby is born, the higher the risk of brain injury. However, even among the tiniest preemies, some babies develop quite normally, while others have devastating brain injury and life-long disability," said Erin Clark, M.D., the study's author. "The reason for this difference in outcomes is not well understood. Genetics may allow identification of babies at increased risk so that we can target those babies for prevention and treatment strategies. These results add to the evidence that genes may play a role in risk of brain injury and death in preterm babies." 

Clark, assistant professor of Maternal Fetal Medicine, University of Utah School of Medicine's Department of Obstetrics and Gynecology, also noted that additional research is necessary to further evaluate genes that may influence risk and to determine how to apply these results to clinical care. 

Source:Maternal Fetal Medicine, University of Utah School of Medicine's Department of Obstetrics and Gynecology
 

Cancer is Curable If Addressed Timely

 

Many people believe cancer is incurable, quite a few think it is contagious and many others feel it can be caused by hair-dyes and anti-perspirants. 

Myths like these expose our little knowledge about the much-feared disease which, if addressed timely, can be cured, doctors say.
One of the biggest myths about cancer, according to Rajeev Kumar, senior consultant oncologist, Rockland Hospital, Qutab Institutional Area, is that cancer is incurable. 

"Rather, cancer is the most curable of all chronic diseases," Kumar told IANS. 

"One can never cure diabetes or hypertension, but cancer, if detected early and treated well, can be cured," Kumar added. 

Agreed Preeti Jain, consultant oncology surgeon, Columbia Asia Hospital, who said that people with cancer can live "happier lives" if detected early. 

"Neither is it true that surgery increases the risk of cancer," Jain said, adding that surgeries rather help combat the disease. 

Explaining the reasons behind the lack of awareness related to cancer, Manish Singhal, senior consultant medical oncology, IOSPL at Fortis Hospital, Noida, said that it is because people believe in self-medication. 

"Such misconceptions prevail despite information being available, because a majority of the population believes in self-medication with little or no access to complete information on the disease," Singhal told IANS. 

Jain added that lack of information can be attributed to cancer being a mass disease. 

"If we penetrate India geographically, we will find that many people are still unaware about the disease. They know that cancer is a disease; but its type or detection, is not known to many," she said. 

Singhal further said that neither is cancer hereditary or contagious, nor is caused by hair dyes and anti-perspirants. 

"Only in five to 10 percent of cases, cancers are hereditary. But the most common symptoms of cancer are caused by genetic changes that occur throughout a person's lifetime," he said. 

Singhal added that such changes are caused by tobacco use, too much ultraviolet radiation and exposure to certain chemicals. 

Another myth, according to experts, is that women fear one of the causes of breast cancer are "underwire brassieres", though there is no substantial evidence to 

support this theory. 

Suggesting a comprehensive campaign to help raise awareness, Kumar said that apart from the media, doctors and health workers should also participate. 

"Cancer survivors are probably the best source of spreading awareness," he said. 

According to Singhal, diligently following eight norms, including maintaining a healthy weight, exercising regularly, eating a healthy diet, protecting oneself from the sun and getting screening tests done, can help lower one's risk of cancer. 

"Diet can also influence some cancers. Cancers of the stomach, bowel, lung, prostate and uterus are more likely to develop if your diet is high in fat and low in fruit, vegetables and fibre," Singhal told IANS.
Source:IANS
 

Red alert: Body kills 'spontaneous' blood cancers on a daily basis

Immune cells undergo 'spontaneous' changes on a daily basis that could lead to cancers if not for the diligent surveillance of our immune system, Melbourne scientists have found.

The research team from the Walter and Eliza Hall Institute found that the immune system was responsible for eliminating potentially cancerous immune B cells in their early stages, before they developed into B-cell lymphomas (also known as non-Hodgkin's lymphomas). The results of the study were published today in the journal Nature Medicine.

This immune surveillance accounts for what researchers at the institute call the 'surprising rarity' of B-cell lymphomas in the population, given how often these spontaneous changes occur. The discovery could lead to the development of an early-warning test that identifies patients at high risk of developing B-cell lymphomas, enabling proactive treatment to prevent tumours from growing.

Dr Axel Kallies, Associate Professor David Tarlinton, Dr Stephen Nutt and colleagues made the discovery while investigating the development of B-cell lymphomas.

Dr Kallies said the discovery provided an answer to why B-cell lymphomas occur in the population less frequently than expected. "Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function," Dr Kallies said. "It is then somewhat of a paradox that B cell lymphoma is not more common in the population.

"Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle, and proves that immune surveillance is essential to preventing the development of this blood cancer."

B-cell lymphoma is the most common blood cancer in Australia, with approximately 2800 people diagnosed each year and patients with a weakened immune system are at a higher risk of developing the disease.

The research team made the discovery while investigating how B cells change when lymphoma develops. "As part of the research, we 'disabled' the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years," Dr Kallies said. "It seems that our immune system is better equipped than we imagined to identify and eliminate cancerous B cells, a process that is driven by the immune T cells in our body."

Associate Professor Tarlinton said the research would enable scientists to identify pre-cancerous cells in the initial stages of their development, enabling early intervention for patients at risk of developing B-cell lymphoma.

"In the majority of patients, the first sign that something is wrong is finding an established tumour, which in many cases is difficult to treat" Associate Professor Tarlinton said. "Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumours develop and they progress to cancer. There are already therapies that could remove these 'aberrant' B cells in at-risk patients, so once a test is developed it can be rapidly moved towards clinical use."
Source:Nature Medicine

Split decision: Stem cell signal linked with cancer growth

Researchers at the University of California, San Diego School of Medicine have identified a protein critical to hematopoietic stem cell function and blood formation. The finding has potential as a new target for treating leukemia because cancer stem cells rely upon the same protein to regulate and sustain their growth.
Hematopoietic stem cells give rise to all other blood cells. Writing in the February 2, 2014 advance online issue of Nature Genetics, principal investigator Tannishtha Reya, PhD, professor in the Department of Pharmacology, and colleagues found that a protein called Lis1 fundamentally regulates asymmetric division of hematopoietic stem cells, assuring that the stem cells correctly differentiate to provide an adequate, sustained supply of new blood cells.
Asymmetric division occurs when a stem cell divides into two daughter cells of unequal inheritance: One daughter differentiates into a permanently specialized cell type while the other remains undifferentiated and capable of further divisions.
"This process is very important for the proper generation of all the cells needed for the development and function of many normal tissues," said Reya. When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.
"During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide," Reya said. "Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell. By analogy, imagine the difference between cutting the Earth along the equator versus halving it longitudinally. In each case, the countries that wind up in the two halves are different."
When researchers deleted Lis1 from mouse hematopoietic stem cells, differentiation was radically altered. Asymmetric division increased and accelerated differentiation, resulting in an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.
"What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand," said Reya. "Instead of undergoing symmetric divisions to generate two stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production."
The scientists next looked at how cancer stem cells in mice behaved when the Lis1 signaling pathway was blocked, discovering that they too lost the ability to renew and propagate. "In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal," Reya said.
Reya said the findings shed new light on the fundamental regulators of cell growth both in normal development and in cancer.
"Our work shows that elimination of Lis1 potently inhibits cancer growth, and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy."

In the long term, Reya noted, it remains to be determined whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well. "A number of commonly used hemotherapy agents target the machinery that controls cell division. Although these agents can be toxic, their effects on cancer cells are much more potent than their effects on normal cells, and so they continue to be used. Agents that target Lis1 might be more specific and less toxic, which would give them significant clinical value."

Source:Nature Genetics

Making your brain social

Failure to eliminate links between neurons produces autistic-like mice

In many people with autism and other neurodevelopmental disorders, different parts of the brain don't talk to each other very well. Scientists have now identified, for the first time, a way in which this decreased functional connectivity can come about. In a study published online today in Nature Neuroscience, scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, and collaborators at the Istituto Italiano di Tecnologia (IIT), in Rovereto, and La Sapienza University in Rome, demonstrate that it can be caused by cells called microglia failing to trim connections between neurons.
"We show that a deficit in microglia during development can have widespread and long-lasting effects on brain wiring and behaviour," says Cornelius Gross, who led the study. "It leads to weak brain connectivity, decreased social behaviour, and increased repetitive behaviour, all hallmarks of autism."
The findings indicate that, by trimming surplus connections in the developing brain, microglia allow the remaining links to grow stronger, like high-speed fibre-optic cables carrying strong signals between brain regions. But if these cells fail to do their job at that crucial stage of development, those brain regions are left with a weaker communication network, which in turn has lifelong effects on behaviour.
Yang Zhan, a postdoctoral fellow in Gross' lab at EMBL, analysed the strength of connections between different areas of brain in mice that were genetically engineered to have fewer microglia during development. Working with Alessandro Gozzi's lab at IIT and Davide Ragozzino at La Sapienza University, the EMBL scientists combined this approach with high-resolution fMRI (functional Magnetic Resonance Imaging) scans of the mice's brains, taking full advantage of a novel technique developed at IIT, which enables scientists to obtain detailed, three-dimensional maps of the brain's functional connections. The team found that mice with fewer microglia had weaker connections between neurons, and less cross-talk between different brain regions. When Rosa Paolicelli, a PhD student in Gross' lab, studied the mice's behaviour, she discovered that mice with fewer microglia and decreased connectivity displayed behaviours commonly associated with autism spectrum disorders. These mice spent more time repeatedly grooming themselves, and avoided social interactions.
"This is an exciting time to be studying microglia," Gross concludes: "they're turning out to be major players in how our brain gets wired up."
Source:Nature Neuroscience