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By Dr Ananya Mandal, MD

Chromosomal theory of inheritance

Genes are located on chromosomes. Chromosomes are in pairs and genes, or their alleles, are located on each of these pairs.

When the cell divides in half, each chromosome ends up in a different cell. This is seen during meiosis in formation of egg cells of sperms. The genes also split into two halves. These are called alleles. Meiotic products have one of each homologous chromosome but not both. Meiosis is a series of cell divisions that creates haploid cells with half of the total number of chromosomes.

Once the egg and sperm meet, the pairs are restored but now the genetic combination of the pair is altered. One of the alleles thus comes from the mother and another from the father. This is how a defective gene causing a genetic disorder is also inherited by offspring.

Gene Linkage on Chromosomes

As per the Mendelian principles of inheritance genes need to be inherited independently of each other. However, there are far more genes than chromosome pairs. It is found that all of the genes on a chromosome are physically inherited together as a single linked group. Only genes that are located on different chromosomes have independent assortment during meiosis.

Crossing-Over and Recombination

According to the chromosomal theory 25% would resemble one parent, 25%, the second parent, 25% would have one trait from one parent and one from the other parent – and 25% would have also have the “other” traits from each parent.

Since each chromosome is a diploid, or occurs in pairs, genes on different chromosomes assort independently during sexual reproduction, recombining to form new combinations of genes. Genes on the same chromosome would theoretically never recombine.

However, genes do undergo cross over. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes. This process of chromosomal crossover generally occurs during meiosis.

The probability of crossover occurring between two given points on the chromosome is related to the distance between the points. If the distance is long there is a higher chance of a crossover. For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage that means that the alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map.

Autosomal recessive inheritance

Most genes have a second working copy and one of them may not be actively functional at all. When this is inherited it is known as autosomal recessive inheritance. With recessive genes, it is only if someone inherits two altered copies of the same gene from each of their parents, they are likely to be expressed.

For example, inheritance of thalassemia and cystic fibrosis occurs in an autosomal recessive pattern. If both parents carry the faulty gene on one of their alleles they are likely pass on their defective gene in only 25% of their offspring. The baby of this couple has a 75% chance of not developing the condition. There are also other inherited characteristics that are inherited in this way such as blue eyes or red hair.

Figure 1: Autosomal recessive inheritance. A person who has one altered copy and one working copy of the gene is known as a carrier for that particular altered gene. If two carriers have children together, they have a 25% chance in each pregnancy of their child inheriting two copies of the altered gene and having the condition.

Autosomal dominant inheritance

Sometimes the inherited gene is a dominant one. This means if a person carries even one copy of that gene, he or she is likely to develop the trait. In some dominant conditions, it is possible to inherit an altered gene without showing any signs of the condition: in other words, the gene is not fully penetrant. Examples of genetic conditions that are inherited in a dominant way are Huntington’s disease and Neurofibromatosis type 1 (NF1).

If a parent carries an altered gene for a dominant condition, each of their children has a 50% or 1 in 2 chance of inheriting the altered gene. This is same for all children irrespective of sex of the child.

Figure 2: Autosomal dominant inheritance – If a person who is a carrier for a dominant altered gene has children, there is a 50% chance of their child inheriting the altered copy of the gene.

X-linked inheritance

This is seen when an altered gene is located on the X chromosome (one of the sex chromosomes) rather than on one of the autosomes. Women have two X chromosomes while men have an X and a Y.

If this gene is a recessive one then a woman who carries an altered copy will either have no signs of the condition caused by that gene or will have minor signs of the condition. She is said to be a carrier of that X-linked condition. If a man has an altered gene on his X chromosome, then he will have the condition as he has only one X chromosome.

According to inheritance patterns if the woman has a boy there is a 50% chance that her son will have the condition. If she has a girl, there is a 50% (1 in 2) chance that her daughter will inherit the faulty copy and be a carrier like her mother.

If the father is has the faulty gene inherited from his mother he is likely to pass it on to all (100%) his daughters and they will be carriers themselves. Because men do not pass on their X chromosome to their sons, none of their sons will have the same X-linked condition as their father (0%).

Haemophilia and Duchenne muscular dystrophy as well as red-green colour blindness is inherited this way.

Figure 3: X-linked inheritance – X-linked recessive conditions affect men more often and more severely than women because men only have one X chromosome and women have two X chromosomes so usually have a second working copy of the gene. A woman who is a carrier for an X-linked condition has a 50% chance in each pregnancy of a son having the condition and a 50% chance of a daughter being a carrier for the condition. Men who have an X-linked condition will pass on the altered gene to all their daughters (100%), but none of their sons (0%).

Reviewed by April Cashin-Garbutt, BA Hons (Cantab)

Sources

1. scidiv.bellevuecollege.edu/…/ChromosomeInheritance211.pdf
2. www.genetics.edu.au/…/Genes-and-Chromosomes-FS1
3. http://www.nlm.nih.gov/exhibition/harrypottersworld/pdf/prelesson.pdf
4. www.ornl.gov/sci/techresources/Human_Genome/publicat/primer/primer.pdf
5. http://www.genome.gov/Pages/Education/Modules/BasicsPresentation.pdf
6. http://www.angrau.net/StudyMaterial/GPBR/GPBR111.pdf

Further Reading

• What is Genetics?
• History of Genetics
• Genetics and Gene Expression
• Genetic Change
• Genetics Research and Technology

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By Sally Roberson

Gene therapy is a strategy used to treat disease by correcting defective genes or modifying  how genes they are expressed. The techniques used involve administrating a specific DNA or RNA sequence. Researchers hope that in the future, gene therapy will enable patients to be treated by inserting genes into their cells rather than administering drugs or subjecting them to surgery.

This therapy offers a promising new approach to treating a range of diseases including various forms of cancer, inherited disease and certain viral infections. However, further studies are still required to ensure the safety and effectiveness of these techniques. Currently, the therapy is only used to treat diseases where other therapies are already known to be ineffective.

There are two basic types of gene therapy: germline therapy and somatic gene therapy. These are described in more detail below.

Germline therapy

This therapy involves the modification of the genes inside germ cells (sperm or ova). During reproduction, these gamete cells fuse to form a zygote, which would divide and pass on the modified gene into all other cells of the body during the development of offspring. In this way, the therapy alters the genome of future generations to come.

Although theoretically this could counteract hereditary disease, jurisdictions in various countries such as Switzerland, Australia and Germany prohibit the use of germline therapy due to fears over unknown risks and long-term effects in future generations. In addition, the therapy is very costly.

Somatic gene therapy

Unlike germline therapy, somatic gene therapy only involves the insertion of therapeutic DNA into body cells and not the germ cells or gametes. This means any effects of the therapy are confined to the individual being treated and are not inherited by future offspring.

The field of somatic gene therapy is surrounded by fewer ethical issues compared with germline gene therapy, although the therapeutic approach is also still in the early stages of design and prone to obstacles.

The first hurdle is successful incorporation into the genome; integrating the modified gene into the wrong part of the DNA could induce rather than prevent disease. Secondly, the desired gene needs to be expressed. Thirdly, the gene expression needs regulating to prevent over expression triggering any disease.

Inserting genes into cancer cells

One of the most challenging aspects of gene therapy is inserting genes into cancer cells and experts are striving to find new and improved techniques for achieving this. One of the main ways this is carried out is through the use of a vector, which carries a gene into a cancer cell. Usually, the vector is a virus because viruses are built to target and enter cells so they can deliver the their genetic material once inside them. Scientists have found ways to alter these viruses so that they only deliver genes to cancer cells rather than healthy cells. Other vectors are also being tested such as inactivated bacteria.

Gene therapy techniques in cancer treatment

Some of the techniques that may be used in gene therapy to treat cancer are described below.

Harnessing the immune response

Some forms of gene therapy are designed to strengthen the body’s existing ability to target and kill cancer cells. The role of certain cells of the immune system is to recognise and kill these cells. Adding certain genes to a patient’s immune cells can improve their ability to find or kill certain forms of cancer. These techniques are currently being tested in a few trials across the UK.

Gene therapy to enhance cancer treatment

Some techniques insert genes into cancer cells that can make the cancer cells more vulnerable to radiotherapy or chemotherapy, therefore improving the effectiveness of these treatments.

Blocking the protection of cancer cells

Certain processes cancer cells use to survive can be blocked using gene therapy. For example, one process called apoptosis refers to the programmed cell death a cell undergoes if it contains DNA that is damaged and beyond repair. In cancer cells, apoptosis is stopped and the cells divide to form new cells that also contain the damage DNA. Some gene therapy techniques are designed to prevent this inhibition of apoptosis to ensure that the cancer cells do in fact die rather than survive.

Pro-drug gene therapy

Certain gene therapy techniques insert genes into cancer cells that allow conversion of an inactive drug called a pro-drug into the active form. The converting gene is given in the form of a tablet or capsule and the pro-drug is then administered. The pro-drug does not harm normal cells and only reaches cancer cells, where it is activated by the gene to become destructive.

Further Reading

• What is Gene Therapy?
• Gene Therapy History
• Gene Therapy Issues
• Gene Therapy Vectors
• ————–
• http://www.news-medical.net/health/Gene-Therapy-Types.aspx

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While controlling blood pressure, blood sugar and LDL-cholesterol levels reduces the risk of cardiovascular disease in people with diabetes, only 7 percent of diabetic participants in three major heart studies had recommended levels of these three factors, according to research from the Heart Disease Prevention Program at the University of California, Irvine School of Medicine.

The findings illustrate the need for persons with diabetes to better manage their blood pressure, blood sugar and LDL-cholesterol levels, which are prime indicators of future cardiovascular disease. The diabetic participants surveyed in the UCI review were enrolled in the three heart studies between the late ’80s and early 2000s, when treatment was not as good as it is now. Still, more recent data show that only 25 percent of Americans with diabetes achieve all three of these targets.

The good news is that those in the heart studies who did control all three factors had a 62 percent lower risk of developing cardiovascular disease, according to Nathan D. Wong, lead author of the UCI report, which appears online in Diabetes Care.

“But we have done a dismal job nationally at getting most of our patients with diabetes controlled for even just these three measures,” said Wong, director of the Heart Disease Prevention Program and a cardiology professor at UCI.

“Since cardiovascular diseases – including coronary heart disease, stroke and heart failure – are leading causes of death for people with diabetes, these findings underscore the value of achieving target or lower levels of these modifiable risk factors,” he added.

Wong and colleagues studied 2,018 adults (57 percent female) with diabetes mellitus but without known cardiovascular diseases who participated in the Atherosclerosis Risk in Communities Study, the Multi-Ethnic Study of Atherosclerosis or the Jackson Heart Study. Fifty-five percent were African American, 30 percent white, 11 percent Hispanic and 4 percent Asian/Pacific Islander.

The researchers compared measurements of the three key factors to American Diabetes Association guidelines that were in effect at the time – blood pressure under 130/80 mmHg, LDL (or bad) cholesterol less than 100 mg/dL and blood HbA1c (glycated hemoglobin) under 7 percent. Forty-one percent of the study group were on target in one of the three categories; 27 percent had achieved two of the benchmarks; but only 7 percent met the recommended scores in all three.

Study participants’ control of individual and composite factors was also examined in relation to the occurrence of new cardiovascular events (including heart attacks, coronary deaths, strokes, heart failure, percutaneous interventions and bypass surgeries) over an average follow-up of 11 years.

Wong said that proper management of any one factor translated to a 36 percent lower risk, proper management of any two factors was linked to a 52 percent lower risk, and proper management of all three factors correlated to a 62 percent lower risk of cardiovascular events compared to those without any factors controlled.

Blood pressure management appeared to benefit African Americans and women more than other ethnic groups or men; however, the converse was true for LDL control.

“Our analysis of three large U.S. cohorts including persons in whom diabetes has been diagnosed shows those who were at target levels for HbA1c, blood pressure and LDL to have substantially lower risks for cardiovascular disease than persons with diabetes who were not at target levels for such factors,” Wong said. “These findings emphasize the importance of composite control of these modifiable risk factors to better address the cardiovascular disease risks seen in persons with diabetes, the need for the development of healthcare strategies to better ensure such management, and the need for studies to evaluate and eliminate barriers to risk factor control in persons with diabetes.”

Source: University of Irvine

http://www.news-medical.net/?tag=/Genetic&page=174

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Professor Jonathan Stamler’s latest findings regarding nitric oxide have the potential to reshape fundamentally the way we think about the respiratory system – and offer new avenues to save lives. It may be time to rewrite the textbooks.

Scientific dogma has the respiration process involving only two elements — oxygen and carbon dioxide. Specifically, the delivery of oxygen from lungs to tissues, and the removal of the waste product, carbon dioxide, through exhaling.

Recently published online in the journal Proceedings of the National Academy of Sciences(PNAS), Stamler and colleagues demonstrate that nitric oxide is essential for the delivery of oxygen to the cells and tissues that need it.

Stamler, MD, a Professor of Medicine at Case Western Reserve University School of Medicine and Cardiologist at University Hospitals Case Medical Center, led a team that showed that nitric oxide must accompany hemoglobin to enable blood vessels to open and then supply oxygen to tissues.

Doctors have long known that a major disconnect exists between the amount of oxygen carried in the blood and the amount of oxygen delivered to the tissues. Until now, they had no way to explain the discrepancy. The new findings show that nitric oxide within the red blood cell itself is the gatekeeper to the respiratory cycle – nitric oxide makes the cycle run.

“The bottom line is that we have discovered the molecular basis of blood flow control in the respiratory cycle loop,” Stamler said. “It’s in the hemoglobin protein itself, which has the ability to deliver the nitric oxide together with oxygen. The simplified textbook view of two gases carried by hemoglobin is missing an essential element – nitric oxide – because blood flow to tissues is actually more important in most circumstances than how much oxygen is carried by hemoglobin. So the respiratory cycle is actually a three-gas system.”

Stamler’s previous research had revealed that the respiratory cycle was more than an oxygen and carbon dioxide exchange proposition. Stamler and colleagues also had shown that red blood cells carry and release nitric oxide, but had not yet explained the exact physiologic ramifications of nitric oxide release.

In this most recent research, investigators uncovered the key role of nitric oxide in controlling the blood flow in small vessels within tissues responsible for delivering oxygen (known as “blood flow autoregulation”) – a process whose molecular basis had been a longstanding mystery in medicine. Investigators specifically examined the respiratory cycle in mice lacking the one amino acid site that carries nitric oxide in their red blood cells. Low and behold, blood flow autoregulation was eliminated entirely – the animals could not oxygenate tissues.

Initially, investigators found low oxygen levels in the animals’ muscles at baseline, despite the animals’ red blood cells carrying a full load of oxygen. When the mice were then stressed to bring on slight oxygen deprivation (hypoxia), the blood flow to their organs dropped precipitously. The lack of oxygen should have prompted a spike in blood flow to send more oxygenated blood to tissues and cells. Instead, the reduced blood flow and ensuing oxygen shortfall triggered heart attacks and heart failure in these nitric oxide-deficient animals.

The experiment demonstrated that the nitric oxide-release mechanism regulates oxygen delivery. When nitric oxide flows from the cysteine-binding site in hemoglobin, blood vessels dilate (stretch) and allow oxygen-carrying red blood cells access to tissues.

“These mice had red blood cells that by all traditional measures are completely normal in carrying oxygen and releasing it and then in picking up carbon dioxide, yet these animals cannot oxygenate their tissues,” said Stamler, director of Case Western Reserve’s Institute for Transformative Molecular Medicine. “Lacking nitric oxide in red cells, oxygen deficiency could not induce vasodilation, which is essential for sustaining life as we know it.”

Historically, the control of blood flow has been thought to be the purview of blood vessels and their endothelial linings, while the role of the red blood cell went unappreciated. Blood flow deficits that cause heart attacks and strokes were thought not to be linked to red blood cells.

“Within the tissues, the tiny vessels and the red blood cells together make up the critical entity controlling blood flow,” Stamler said. “Red blood cell dysfunction is likely a hidden contributor to diseases of the heart, lung and blood such as heart attack, heart failure, stroke and ischemic injury to kidneys.”

Low nitric oxide levels in red blood cells make blood disorders, such as sickle cell anemia, particularly dangerous. Laboratory research has shown that the red blood cells in individuals with these conditions do not trigger the hypoxic vasodilation required for blood flow autoregulation to work well.

In addition, blood transfusions, which have recently been shown to be deficient in nitric oxide, are associated with increased morbidity and mortality, including heart attacks. The effects of blood transfusions are suspiciously similar to effects seen in the mice, Stamler said. They both lack nitric oxide.

“It’s not enough to increase to oxygen content of blood by transfusion; if the nitric oxide mechanism is shot, oxygen cannot make it to its destination,” he said. “We know that blood in a blood bank is deficient in nitric oxide, so infusing that blood may cause plugging of blood vessels in tissues, making things worse. Essentially, blood flow cannot autoregulate (increase) without nitric oxide. In terms of developing future therapies, the goal must be restoring red blood cell function, complete with nitric oxide delivery capability. As for the nation’s blood supply, the blood should be replenished with nitric oxide.”

You’ve tried all the diets. No matter: you’ve still regained the weight you lost, even though you ate well and you exercised regularly! This may be due to a particular enzyme in the brain: the alpha/beta hydrolase domain-6 enzyme, better known as ABHD6. A study published this week in Cell Reports demonstrates that when this enzyme is blocked in certain neurons of the mouse hypothalamus, it becomes impossible for them to lose weight, even if they adhere to an ideal regimen… ideal for mice that is!

A research team at the University of Montreal Hospital Research Centre (CRCHUM) has generated genetically engineered mice, deprived of the ABHD6 enzyme in a localized area of the brain, namely in a specific population of hypothalamic neurons. Alexandre Fisette, postdoctoral researcher at CRCHUM and first author of the study, explains that, “under normal conditions of housing and food, these mice are identical to normal mice. However, when challenged, they are unable to adapt. They no longer consume food after a fast, they cannot maintain their body temperature during exposure to cold, and they are more susceptible to become obese when fed a high-fat diet. What’s more, once they are obese and we try to make them lose weight by feeding them a normal diet, they do not lose weight.”

The researchers have discovered that this enzyme acts as a sort of switch for the body’s adjustment to extremes. “It is a mechanism we had not suspected. Strikingly, the absence of one single enzyme within a precise region of the brain completely disrupts the normal metabolism and prevents the mice from losing weight,” comments Thierry Alquier, CRCHUM researcher and professor at the University de Montréal.

Is there an identical process taking place in humans? Thierry Alquier thinks that clinical studies will be required to find out. However, according to Alquier, “ABHD6 has a key role in the rebound effect that is often observed after a dietary regimen. People who experience difficulty losing weight might have a deficiency of this enzyme.”

Weight is controlled by several signals. Scientists have known for a long time that endocannabinoids – molecules secreted by the brain – are involved in the ingestion of nutrients and the expenditure of energy. The endocannabinoids stimulate appetite. Thus, this is an interesting area of exploration in the search for an appetite-suppressant drug. But all the products developed until now have been associated with serious side effects.

The pursuit of the ABHD6 enzyme appears to be promising. In 2014, the team of Marc Prentki, another CRCHUM researcher, discovered that this enzyme breaks down endocannabinoids. Blocking ABHD6 in peripheral organs and adipose tissues protects against obesity and against type 2 diabetes.

“We know today that ABHD6 plays a completely different role in certain neurons of the hypothalamus. Blocking the enzyme in this location promotes obesity, whereas blocking it elsewhere in the body has beneficial effects,” emphasizes Stephanie Fulton, CRCHUM researcher and study co-author.

Multiple signals and neuronal networks are involved in regulating the balance of energy so as to maintain a stable body weight. “We have shown the critical part played by the ABHD6 enzyme in preserving homeostasis in specific neurons of the hypothalamus. But we don’t know what happens when we block the enzyme in the entire brain. This is what we are currently investigating in an ongoing study,” the researcher explains.

Many more years of research will be needed to develop an effective treatment for obesity. As science advances, we learn that weight management does indeed take place inside the head, but that it is not necessarily a question of lack of will.

A persistent scarcity of oxygen in body tissues – a widespread problem in patients with heart or lung disease – can create a defect of red blood cells that further exacerbates the condition by constricting blood vessels in the lung, Howard Hughes Medical Institute researchers at Duke University Medical Center have found.

What’s more, the team demonstrated through studies in people and animals that inhalation of a ‘souped up’ form of nitric oxide, which targets red blood cells, reverses the blood abnormality to restore normal lung pressure.

The team’s findings appear in the online Early Edition of Proceedings of the National Academy of Sciences (October 3-7, 2005). The work was supported by the National Heart, Lung, and Blood Institute and the National Science Foundation. Stamler is a paid consultant for Nitrox LLC, a biotechnology company developing NO-based drugs for disorders of the heart, lung and blood.

The potentially fatal lung condition, pulmonary hypertension, is characterized by high blood pressure in the lungs. The disorder is a common complication of chronic diseases such as emphysema, arthritis, sickle cell disease and heart failure. However, pulmonary hypertension can also arise in otherwise healthy people for unknown reasons. Symptoms include shortness of breath under minimal exertion, fatigue, chest pain, dizzy spells and fainting.

“Many people suffer pulmonary hypertension as a complicating factor of other chronic disease,” said study senior author Jonathan Stamler, M.D. “In such cases, the lung condition is often predictive of poorer outcomes. For others, pulmonary hypertension is the primary disease.”

“We have now established a molecular defect of the red blood cells as an important contributing cause of hypertension in the lung,” added Timothy McMahon, lead author of the study. Physicians had previously considered an abnormality within the lung itself as the primary source of the condition, he explained. Physicians had not considered red blood cells as a cause of lung disease.

“We have found that when red blood cells are exposed to abnormally low oxygen for long periods, they become depleted of an essential substance that they normally release to relax blood vessels in the lung,” McMahon continued. “But not only do blood cells, which of course perfuse the lung, cause lung problems, we’ve also found that inhalation of a new drug designed to correct the blood defect can reverse this condition.”

Stamler’s group reported in 1996 that hemoglobin in red blood cells acts as a finely tuned biosensor, adjusting blood flow to provide exactly the optimum amount of oxygen to tissues and organs. The blood cell adjusts blood flow by changing shape and releasing a nitric oxide-like molecule called s-nitrosothiol (SNO), which the cell carries through the bloodstream along with oxygen.

When oxygen levels are high, hemoglobin scavenges excess oxygen and NO, constricting blood vessels and reducing blood flow. When oxygen levels drop, the NO is released to relax blood vessels and improve blood flow. The Duke team now finds that with prolonged oxygen shortage, or hypoxia, blood cells become depleted of SNOs, therefore losing their ability to relax blood vessels.

More recent evidence from the Duke group has indicated that other types of SNOs might offer new therapeutic approaches to diseases of the heart, lung and blood. For example, the researchers found that SNOs played a critical role in septic shock, a common cause of death in intensive care units. They later showed that the compounds are lacking in the blood of patients with sickle cell disease and also play a part in preventing asthma. The latest findings extend the role of SNOs in red blood cells to include pulmonary hypertension.

A new chemical therapy, which replenished SNO levels in the blood of patients, restored the red blood cells’ ability to dilate vessels, lowered pressures, and improved the transfer of oxygen to tissues. Similarly, in the lab, exposure of red blood cells to sustained hypoxia led to a deficiency of the SNO vessel relaxant, according to the researchers. The SNO-deficient blood cells failed to relax blood vessels of the lungs in laboratory studies and constricted pulmonary blood vessels in pigs, they reported. Restoration of SNO levels in the animals likewise lowered pressures in the lungs.

The researchers demonstrated that under conditions of prolonged oxygen deficiency, which is very common in sick patients, red cells become deficient for SNO, thereby losing their capacity to relax blood vessels and boost blood flow, Stamler said. Pressure came down in the lungs of animals given red blood cells replete in SNOs, whereas transfusion of red blood cells deficient in SNO raised pressures, the team reported.

To examine the relevance of the findings to human disease, the researchers compared the level of SNO in the blood of patients with pulmonary hypertension to that of healthy people. Normal individuals had five times more SNO in their blood than did those with elevated lung pressure. In fact, those with the lung condition almost completely lacked hemoglobin with bound SNO, a finding consistent with the effects of hypoxia observed in the lab, Stamler said. That SNO-deficiency led to impaired blood vessel dilation by the red cells, they showed.

The researchers reasoned that if deficiency of SNO in red blood cells causes the lung condition, then restoring SNO levels should reverse the disease. Ten patients treated with an inhaled SNO-generating gas exhibited an increase in SNO in the bloodstream, found the researchers. After therapy, patients’ red blood cells again relaxed blood vessels in a manner comparable to that of normal red cells. In addition, the pressures came down in the lungs of the patients.

“We have followed this process all the way from characterizing the molecular defect of red blood cells through the translation of this basic scientific finding into a promising new therapy,” Stamler said. A larger clinical trial effort now underway will further examine the therapy’s potential to relieve pulmonary hypertension, he said.

Collaborators on the study include Timothy McMahon, Gregory Ahearn, Martin Moya, Andrew Gow, Yuh-Chin Huang, Raphael Nudelman, Yun Yan, Abigail Krichman, Thomas Bashore, Robert Califf, Claude Piantadosi and Victor Tapson, all of Duke. Benjamin Luchsinger and David Singel of Montana State University also contributed to the research.

http://www.news-medical.net/news/2005/10/03/13511.aspx

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Virginia Commonwealth University School of Medicine researchers have discovered that the infiltration of white blood cells into an expectant mother’s blood vessels may explain high blood pressure in pregnancy.

The findings could lead to novel avenues of treatment for pregnant women with preeclampsia based on regulation of white blood cells called neutrophilis, their products or their cellular effects.

Preeclampsia is one of the most significant health problems in pregnancy and a leading cause worldwide of both premature delivery and of sickness and death of the mother and baby. Research has shown that the blood vessels of women with preeclampsia are dysfunctional, but the cause of preeclampsia is not known, and the only treatment is delivery of the baby.

In a study published online in the October issue of Hypertension, a journal of the American Heart Association, the VCU team reported that an infiltration of white blood cells may be responsible for the high blood pressure observed in preeclampsia. These white blood cells release reactive oxygen species that the team showed enhance the reactivity of the mother’s blood vessels to hypertensive hormones by activating the RhoA kinase pathway in the blood vessels. Read the study here.

According to corresponding author Scott W. Walsh, Ph.D., professor in the VCU Department of Obstetrics and Gynecology, the RhoA kinase pathway is an intracellular mechanism in the smooth muscle cells of blood vessels that makes the blood vessels more reactive to hormones that increase blood pressure.

“In other words, the blood vessels contract more easily to the hormones so blood pressure increases even though the hormone levels do not increase,” said Walsh.

“These findings may explain the enhanced blood pressure response of women who develop preeclampsia, which was first described almost 40 years ago,” he said.

Walsh said some potential treatments on the horizon for clinical studies are monoclonal antibodies that could prevent the infiltration of the white blood cells, and selective RhoA kinase inhibitors that could prevent the enhanced reactivity of the mother’s blood vessels.

http://www.news-medical.net/news/20111101/Infiltration-of-white-blood-cells-into-blood-vessels-may-explain-high-blood-pressure-in-pregnancy.aspx

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A decline in smoking rates may mean that many people who could have benefited from early detection of lung cancer are dying because they don’t qualify for low-dose CT scans, according to a group of Mayo Clinic researchers. Their research appears in the Feb. 24 issue of JAMA, the journal of the American Medical Association.

“As smokers quit earlier and stay off cigarettes longer, fewer are eligible for CT screening, which has been proven effective in saving lives,” says Ping Yang, M.D., Ph.D., an epidemiologist at Mayo Clinic Cancer Center. “Patients who do eventually develop lung cancer are diagnosed at a later stage when treatment can no longer result in a cure.”

Dr. Yang says researchers and policymakers need to re-examine screening criteria to identify a greater proportion of patients who develop lung cancer.

“The existing screening program will become less effective at reducing lung cancer mortality in the general population, if they continue to use the same criteria,” Dr. Yang says.

The study retrospectively tracked residents of Olmsted County in Minnesota who were older than 20 years from 1984 through 2011 — about 140,000 people. Lung cancer cases were identified using the Rochester Epidemiology Project database and confirmed by pathology definition of the World Health Organization.

Researchers determined the proportion of lung cancer patients who would have met CT scan screening criteria set by the U.S. Preventive Services Task Force. Those criteria, used by doctors and insurance companies, recommend CT screening for asymptomatic adults age 55 to 80 who have smoked at least 30 pack-years (one pack a day for 30 years), and are still smoking or have reduced consumption in the last 15 years.

A total of 1,351 people in the study developed primary lung cancer between 1984 and 2011. Researchers found that the incidence of primary lung cancer fell overall during the study period — but only for men by about one-third. Among women, the incidence of lung cancer rose 8 percent.

According to Dr. Yang, the data with greatest relevance to CT screening is the proportion of lung cancer patients who smoked at least 30 pack-years which declined over the study period. And the proportion of cancer patients who had quit for more than 15 years increased. “While more people have quit for a longer period of time, they are still getting lung cancer,” Dr. Yang says, “and they make up a larger proportion of newly diagnosed lung cancer patients.”

As a result, the proportion of lung cancer patients who would have been eligible for screening fell steadily during the study period — from 57 percent in 1984-1990 to 43 percent in 2005-2011. The proportion of women who would have been eligible under the criteria decreased from 52 percent to 37 percent, and among men from 60 percent to 50 percent.

That trend has important consequences, says Dr. Yang.

First, many more patients will miss out on early detection, when treatment of lung cancer is most successful. “That means more patients are going to be diagnosed at a later stage, because they could not take advantage of early detection,” she says. As a result, more patients will die.

Second, Dr. Yang hopes to see screening criteria adjusted to include smokers who have smoked less than 30 pack-years and those who quit more than 15 years ago. “We don’t want to penalize people who succeeded in smoking cessation,” she says.

Dr. Yang says she is aware of many smokers who are cancer-free but continue to smoke in order to be eligible for CT screening.

Third, CT screening — the only screening technology proven to save lives among patients with lung cancer — will become less and less effective unless screening criteria are revised to include more patients who are likely to develop cancer.

Dr. Yang acknowledges there is a danger in relaxing CT-screening criteria too much, citing concerns about cost, radiation exposure and over treatment due to false positives that increase patient pressure on physicians to remove tumors even if they do not appear dangerous.

“There are ways to screen at-risk patients while still avoiding false alarms and overtreatment,” says Dr. Yang. “Researchers need to discover biological markers, such as genetic or physiological traits, to help them better identify high-risk patients.” She says screening criteria might also be adjusted to include some smokers who have smoked less than 30 pack-years or quit more than 15 years ago. Dr. Yang says she and her colleagues are preparing papers on these issues to develop proposals for more effective CT screening that will save more lives from lung cancer.

http://www.news-medical.net/news/20150225/Smokers-who-quit-early-does-not-qualify-for-lung-cancer-screening-say-Mayo-Clinic-researchers.aspx

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https://clubalthea.com/2016/10/14/your-complete-dna-sequence-will-help-shape-the-future-of-medicine/

Children with acute lymphoblastic leukemia who had a certain gene variant experienced a higher incidence and severity of peripheral neuropathy after receiving treatment with the cancer drug vincristine, according to a study in the February 24 issue of JAMA.

Cancer remains the leading cause of death by disease in U.S. children despite major advances in the last 20 years. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and as cure rates have surpassed 85 percent, it becomes increasingly important to lessen the toxicities of treatment that adversely affect quality of life and longevity. Vincristine is one of the most widely used and effective anticancer agents for treating leukemias in both adults and children. The dose-limiting toxic effect of vincristine is peripheral neuropathy (damage to the nerves), characterized by neuropathic (nerve) pain and impaired manual dexterity, balance, and altered gait. Currently, there are no reliable means of identifying patients at high risk of vincristine­induced neuropathy nor strategies to reduce this drug toxicity, according to background information in the article.

William E. Evans, Pharm.D., of St. Jude Children’s Research Hospital, Memphis, and colleagues performed a genome-wide association study to determine whether there are genetic variants associated with vincristine-induced neuropathy. The study included patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genetic analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years) enrolled in 1994-1998 in a St. Jude Children’s Research Hospital cohort; and 99 patients (median age, 11.4 years) enrolled in 2007-2010 in a Children’s Oncology Group (COG) cohort.

Grade 2 (moderate) to 4 (life threatening) vincristine-induced neuropathy during therapy occurred in 28.8 percent of patients (64/222) in the St. Jude cohort and in 22.2 percent (22/99) in the COG cohort. The researchers found that an inherited variant in the gene CEP72 was associated with a higher incidence and severity of vincristine-related peripheral neuropathy in children with ALL. Among patients with the gene variant, 28 of 50 (56 percent) developed at least 1 episode of grade 2 to 4 neuropathy, compared with 21 percent (58/271) of other patients.

“If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent,” the authors write.

Editorial: Precision Medicine to Improve the Risk and Benefit of Cancer Care

“The study by Diouf et al has many key elements; genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute biologic plausibility,” writes Howard L. McLeod, Pharm.D., of the Moffitt Cancer Center, Tampa, Fla., in an accompanying editorial.

“However, vincristine remains a component of the most widely accepted treatment regimens for childhood ALL, although there is variation in both dose and intensity. It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect.”

“However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members. This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care.”

http://www.news-medical.net/news/20150225/Study-Gene-variant-linked-to-increased-risk-of-vincristine-induced-peripheral-neuropathy-in-children.aspx