Cells bounce back after exposure to toxins

The vast majority of cells that appear to be on a one-way track to death after exposure to toxins can bounce back completely after the toxins are removed, according to a report by Johns Hopkins scientists published in Molecular Biology of the Cell. The findings could offer some practical insight on how to save dying tissues after heart attacks, or strokes, as well as prevent cancer in cells transiently exposed to toxins.

Study leader Denise Montell, a professor in the Department of Biological Chemistry at the Johns Hopkins University School of Medicine, said: “There’s clearly some point when something is truly dead and can’t come back, but there’s been a controversy about what constitutes the point of no return for cells.”

The researchers exposed healthy mouse liver cells growing in petri dishes to ethanol. Within hours, the cells displayed the typical hallmarks of apoptosis, including cell body and nucleus shrinking, cell membrane blebbing and an altered appearance of cellular organelles. However, when the researchers washed the ethanol away, many of the cells plumped back up, smoothed their membranes and regained normal organelles. About 90% of the cells exposed to ethanol managed to survive, including mouse brain and rat heart cells. This suggests that the ability to defy death could be universal for all, or at least many kinds, of cells in the body. However, Montell notes that she and her team also found that sometimes cells made mistakes, missing pieces of DNA or stitching the wrong pieces back together, developing some hallmarks of cancer. The findings could have implications for explaining and treating cancer, as well as a variety of other diseases.

International study shows diabetes drug success

An extended trial for type two diabetes oral drug linagliptin monitored 2,121 individuals across 32 countries for 102 weeks, and found that the drug was successful in achieving sustained glycaemic control. The study, published in the August issue of the International Journal of Clinical Practice, followed participants who had taken part in four previous 24-week randomised, doubleblind, placebo controlled trials, in order to monitor them for a further 78 weeks.

Co-author David R Owens, professor at Cardiff University’s Centre for Endocrinology and Diabetes Sciences, said: “Initial 24-week trials showed that linagliptin, either on its own or with other glucose-lowering agents, was effective in improving glycaemic control without weight gain or an independent increased risk of hypoglycaemia. Linagliptin works by blocking the action of DPP-4, an enzyme that destroys the hormone GLP-1, which helps the body produce more insulin when it is needed.”

Linagliptin was administered orally once a day in all cases, either on its own, or in combination with metformin, or metformin plus a sulphonylurea, or pioglitazone. doi: 10.1111/j.1742-1241.2012.02975.x

Scientists unravel mitoKATP

A team led by Johns Hopkins researchers has defined the structure of the mitochondrial potassium channel, mitoKATP, which protects against muscle-damaging heart attacks. It is a cellular component so scarce, some scientists even doubted its existence, and many others gave up searching for its molecular structure, but this research team has managed to define its protein structural composition. Importantly, the newly found channel strongly improves heart cell survival, demonstrating an essential lifesaving role.

MitoKATP is an opening, or ‘pore’, responsible for potassium uptake into mitochondria, the powerhouses of the heart cell. This particular potassium channel is a key player in the heart’s intrinsic ability to protect itself from a loss of blood flow, speeding recovery from heart attacks and preventing cell death and scar tissue formation. Unexpectedly, the protein structure of mitoKATP matched that of another, much more plentiful and well-known potassium channel in the kidney, called ROMK.

Deaf brain processes touch differently

People who are born deaf process the sense of touch differently than people who are born with normal hearing, according to research funded by the US National Institutes of Health. The finding reveals how the early loss of a sense affects brain development. It adds to a growing list of discoveries that confirm the impact of experiences and outside influences in moulding the developing brain.

Previous research has shown that people who are born deaf are better at processing peripheral vision and motion. Deaf people may process vision using many different brain regions, especially auditory areas, including the primary auditory cortex. However, no one has tackled whether vision and touch together are processed differently in deaf people, primarily because in experimental settings, it is more difficult to produce the kind of precise tactile stimuli needed to answer this question.

Study researchers developed a unique apparatus that could be worn like headphones while subjects were in a MRI scanner. Flexible tubing delivered soundless puffs of air above the right eyebrow and to the cheek below the right eye. Brief pulses of light were delivered through fibre optic cables mounted directly below the air-puff nozzle. Functional MRI was used to measure reactions to the stimuli in Heschl’s gyrus, the site of the primary auditory cortex in the human brain’s temporal lobe as well as other brain areas.

The researchers took advantage of an already known perceptual illusion in hearing people known as the auditory induced double flash, in which a single flash of light paired with two or more brief auditory events is perceived as multiple flashes of light. In their experiment, the researchers used a double puff of air as a tactile stimulus to replace the auditory stimulus, but kept the single flash of light. Subjects were also exposed to tactile stimuli and light stimuli separately to establish a baseline for brain activity.

Hearing people exposed to two puffs of air and one flash of light claimed only to see a single flash. However, when exposed to the same mix of stimuli, the subjects who were deaf saw two flashes. Looking at the brain scans of those who saw the double flash, the scientists observed much greater activity in Heschl’s gyrus, although not all deaf brains responded to the same degree. The deaf individuals with the highest levels of activity in the primary auditory cortex in response to touch also had the strongest response to the illusion.

The finding suggests that, since the developing auditory cortex of profoundly deaf people is not exposed to sound stimuli, it adapts and takes on additional sensory processing tasks. Not only will the research be useful for education of deaf students, but it has the potential to help clinicians improve the quality of hearing after cochlear implants, especially among congenitally deaf children who are implanted after the ages of 3 or 4. These children, who have lacked auditory input since birth, may struggle with comprehension and speech because their auditory cortex has taken on the processing of other senses, such as touch and vision. These changes may make it more challenging for the auditory cortex to recover auditory processing function after cochlear implantation. Being able to measure how much the auditory cortex has been taken over by other sensory processing could offer doctors insights into the kinds of intervention programs that would help the brain retrain and devote more capacity to auditory processing.

Artificial scaffold created to imitate small bone structure

A research team at Soonchunhyang University, South Korea, have created an artificial scaffold that closely imitates the structure of small bones, such as those in fingers and toes, and also allows efficient growth of bone cells on its surface, thereby meeting the criteria of both strength and biocompatibility needed to be used in patients.

To achieve this, the researchers harnessed the advantages of two different materials. Both were ceramics already used in artificial bone, each with different benefits. The first was hydroxyapatite, a material based on calcium phosphate and which is a major constituent of natural bone. While hydroxyapatite encourages bone cell ingrowth, when it is porous like natural bone, it is mechanically weak. The second material, zirconium dioxide, is stronger but cells do not grow on it. The new scaffold has a layered structure of hydroxyapatite on the outer surfaces to encourage cell growth, and zirconium dioxide beneath to provide strength.

Previous attempts at similar composite structures have suffered because the traditional production process for ceramics requires heating to extremely high temperatures, and unequal expansion of the different materials can cause cracking. Using microwaves for heating allowed the researchers to produce a more stable scaffold. doi: 10.1088/1468-6996/13/3/035009

Insulin pump offers better quality of life for diabetics

Research from Johns Hopkins University School of Medicine, published in the Annals of Internal Medicine, suggests that diabetics who use an insulin pump are more satisfied with their treatment and quality of life than those who give themselves insulin shots many times a day. The study found that children, teens and adults with type 1 diabetes who used continuous monitoring had lower blood glucose levels than those who used finger stick testing alone, and spent less overall time with too much blood sugar. Both methods worked equally well to control hypoglycaemia.

They also found that while there was little difference in blood sugar control in those who give themselves multiple insulin shots a day versus those who used insulin pumps, patients who use sensoraugmented pumps that include real-time continuous glucose monitoring devices, did much better controlling blood sugar than those who used finger stick testing and shots.

Call for better pain management for paediatric patients

Despite advances in the understanding and treatment of paediatric pain, as many as 86% of hospitalised children continue to experience serious pain, according to a Johns Hopkins Children’s Centre study published by the journal Pain Management Nursing. For 40% of them, the pain was moderate or severe. The study revealed that most patients received appropriate and timely therapy, but that even with aggressive treatment, some children continued to experience persistent pain. The results are likely relevant to other paediatric hospitals, and should be heeded as a call to action by clinicians everywhere, the Hopkins team say.

Previous studies show that intense pain during infancy and childhood can create an exaggerated response to pain and make people more sensitive to pain for life. Research also shows that untreated, or undertreated, pain can exacerbate injury, delay healing, make people more prone to infection and, in rare cases, increase the risk of death.

Senior investigator Constance Monitto, a paediatric anaesthesiologist at Hopkins Children’s Center, said: “Pain is the fifth vital sign which, together with blood pressure, heart rate, breathing and temperature, can provide important clues about a patient’s wellbeing. Treating a child in pain is a fundamental responsibility of every physician and nurse.”

Specific goals for better pain management identified in the Hopkins study include reducing the overall number of hospitalised children who experience pain, understanding why some children experience disproportionately worse pain, and improving pain treatment among those with persistent pain that defies conventional treatment.

In the meantime, the Hopkins team advises physicians and nurses to take some basic steps to ensure timely and appropriate pain therapy, such as taking the time to talk to patients and involving parents in the assessment and treatment of a child by using their insight into the child’s behaviour and idiosyncrasies.

Other findings include the fact that children undergoing surgery experienced pain more often and more intensely than nonsurgical patients; some children, such as those undergoing cancer treatment, continue to experience pain despite aggressive therapy; and girls reported higher pain scores than boys, suggesting that hormonal and cultural differences may be at play. Interestingly, older children, who self-reported their pain, had higher pain scores than infants, toddlers and children with developmental delays, implying that pain-scoring tools currently used to assess pain in very young and nonverbal children may not be accurate.

Additionally, only one-third of the children who were prescribed opioids ‘as needed’ actually received the medication, which suggests the patient’s need may not be always properly assessed, verbalised, or conveyed to the health care team. Researchers suggest that, in light of this, pre-emptive, around-the-clock access to pain medication should be favoured over ‘as needed’ treatment, a cumbersome practice that requires children to contact a member of staff to request medication and can result in substantial delays or no treatment at all.

Breakthrough in HIV treatment

A new study by scientists on the Florida campus of The Scripps Research Institute in the US shows, in cell culture, a natural compound can virtually eliminate human immunodeficiency virus (HIV) in infected cells. The compound defines a novel class of HIV anti-viral drugs endowed with the capacity to repress viral replication in acutely and chronically infected cells.

The HIV/AIDS pandemic continues to affect 34 million individuals worldwide, including more than 3 million children, according to the World Health Organisation. Current treatment involves the use of several antiretroviral drugs, termed Highly Active Antiretroviral Therapy (HAART), which can extend the life expectancy of HIV-positive individuals and decrease viral load without, however, eradicating the virus.

“We know that there are reservoirs of HIV that aren’t being eliminated by current treatment and that keep replenishing the infection,” said Susana Valente, a Scripps Research biologist who led the study. “Viral production from these cellular reservoirs that harbour an integrated viral genome is not affected by current antiretroviral drugs, which only stop novel rounds of infection. The compound in the current study virtually eliminates all viral replication from already-infected cells where HIV hides.”

The new study, published in the journal Cell Host and Microbe, focuses on a medically promising compound known as Cortistatin A. This natural product was isolated in 2006 from a marine sponge, Corticium simplex, discovered more than 100 years ago. In 2008, Scripps research chemist Phil Baran and his team won the global race to synthesise the compound, presenting an efficient and economical method. In the new study, Valente and her colleagues collaborated with the Baran lab, using a synthetic version of Cortistatin A to study the effect of it on two strains of HIV: HIV-1, the most common form of the virus; and HIV-2, which is concentrated in West Africa and some parts of Europe.

The results showed that the compound reduced viral production by 99.7% from primary CD4+T cells (a type of immune cell) isolated from patients without levels of the virus in their bloodstream and who had been under HAART treatment for a long period of time. When the compound was added to other antiviral treatments, it further reduced by 20% viral replication from CD4+T cells isolated from patients with detectable amounts of virus in their bloodstreams.

The inhibitor works by binding tightly to the viral protein known as Tat, a potent activator of HIV gene expression, effectively preventing the virus from replicating even at miniscule concentrations, making it the most potent anti-Tat inhibitor described to date, Valente said. Another interesting feature of this compound is that withdrawal of the drug from cell culture does not result in virus rebound, which is normally observed with other antiretrovirals.

While most antiretroviral compounds block only new infections, didehydro- Cortistatin A reduces viral replication from already-infected cells, potentially limiting cell-to-cell transmission. Also, it already has a drug-like structure, is effective at very low concentrations, and has no toxicity associated with it, at least at the cellular level.

Skin has internal clock for repair

A collaboration between researchers at Charité – Universitätsmedizin Berlin and scientists at a company in Hamburg has discovered that human skin has an internal clock responsible for the timebased steering of its repair and regeneration, among other things.

The researchers took cell samples (keratinocytes) from the uppermost layer of skin from young, healthy test persons at various times of the day. Analysis of numerous genes in the keratinocytes showed that important factors for the regeneration and repair of skin cells are regulated by a biological clock. One of these factors, the molecule called the Krüppel-like-factor (Klf9) slows down cell division in the keratinocytes. When the researchers reduced the activity of this factor, they observed faster growth in the skin cell cultures. On the other hand, increased activity of Klf9 was connected with slower cell division. At the same time, it was shown that the stress hormone cortisol also controls the activity of Klf9 and can thus deploy a medical effect on common skin diseases like psoriasis.

doi: 10.1073/pnas.1118641109

Obese patients have higher risk of infection post surgery

A study published in the Journal of Bone and Joint Surgery (JBJS) looks at surgical site infections and hyperglycaemia and found that high blood sugar is a concern during the post-traumatic and post-operative period and it may help to preoperatively identify a population of patients with musculoskeletal injuries who are at significant risk for infectious complications.

Nearly, one-third of patients who are admitted to the hospital without a history of diabetes have hyperglycaemia, which is associated with a longer hospital stay, higher rates of admission to the intensive care unit (ICU), and increased mortality.

A similar study, also featured in JBJS, found that diabetes and morbid obesity increased the risk of infection following hip and knee replacement. Diabetes more than doubled the risk of a post-operative joint infection independent of obesity. The infection rate was the highest in morbidly obese, diabetic patients. The authors suggest that identifying, or treating, hyperglycaemic patients preoperatively, especially if they are obese, would help patients achieve a better outcome by avoiding complications caused by infection. In addition, identifying patients with undiagnosed diabetes would be important for their overall longterm prognosis. Authors further conclude that the benefits of joint replacement should be carefully weighed against the incidence of postoperative infection, especially among the morbidly obese patients.

Colon and rectal cancer grouped as one type

The pattern of genomic alterations in colon and rectal tissues is the same regardless of anatomic location or origin within the colon or the rectum, leading researchers to conclude that these two cancer types can be grouped as one, according to The Cancer Genome Atlas project (TCGA).

The National Cancer Institute (NCI) estimates that more than 143,000 people in the United States will be diagnosed with colorectal cancer and that 51,500 are likely to die from the disease in 2012. Colorectal cancer is the fourth most common cancer in men, after nonmelanoma skin, prostate and lung cancer. It is also the fourth most common cancer in women, after non-melanoma skin, breast and lung cancer. Harold E. Varmus, NCI director, said: “While it may take years to translate this foundational genetic data on colorectal cancers into new therapeutic strategies and surveillance methods, this genetic information unquestionably will be the spring-board for determining what will be useful clinically against colorectal cancers.”

The research also identified the genes ERBB2 and IGF2 as mutated or overexpressed in colorectal cancer and as potential drug targets. These genes are involved in regulating cell proliferation and were observed to be frequently overexpressed in colorectal tumours. This finding points to a potential drug therapy strategy in which inhibition of the products of these genes would slow the progression of the cancer.

Additionally, a key part of this study was the analysis of signalling pathways, which control gene activity during cell development and regulate the interactions between cells as they form organs or tissues. By identifying new mutations in a particular signalling cascade called the WNT pathway, researchers believe they have indicated a new class of drugs that could benefit colorectal cancer patients.

doi: 10.1038/nature11252.


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