Shorter Telomeres May Mark Early Risk of Dementia: Preliminary Analysis of 62 Participants from the Nurses' Health Study

Background: Dementia takes decades to develop, and effective prevention will likely require early intervention. Thus, it is critical to identify biomarkers of preclinical disease, allowing targeting of high-risk subjects for preventive efforts. Since telomeres shorten with age and oxidative stress both of which are important contributors to the onset of dementia, telomere length might be a valuable biomarker. Methodology/Principal Findings: Among 62 participants of the Nurses' Health Study,we conducted neurologic evaluations, including patient and caregiver interviews physical exam, neurologic exam and neuropsychologic testing. We also conducted magnetic resonance imaging (MRI) in a sample of 29 of these women. In these preliminary data, after adjustment for numerous health and lifestyle factors, we found that truncated telomeres in peripheral blood leukocytes segregate with preclinical dementia states, including mild cognitive impairment (MRI); the odds of MCI were 12 fold higher (odds ratio = 12.00, 95% confidence interval 1.24-116.5) for those with shorter telomere length compared to longer telomere length. In addition, decreasing telomere length was strongly related to decreasing hippocampal volume (p=0.038). Conclusions: These preliminary data suggest that telomere length may be a possible early marker of dementia risk, and merits further study in large, prospective investigations

The relationship of primary health care use with persistence of insomnia: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Prevalence of insomnia symptoms in the general population is high. Insomnia is linked with high health care use and within primary care there are a number of treatment options available. The objective of this study was to determine the association of persistence and remission of insomnia with primary health care using a longitudinal study.</p> <p>Methods</p> <p>A postal survey of registered adult (over 18 years) populations of five UK general practices, repeated after 1 year, linked to primary care records. Baseline survey responders were assessed for persistence of insomnia symptoms at 12 months. The association of primary care consultation or prescription for any mood disorder (defined as anxiety, depression, stress, neurosis, or insomnia) in the 12 months between baseline and follow-up surveys with persistence of insomnia was determined.</p> <p>Results</p> <p>474 participants reporting insomnia symptoms at baseline were followed up at 12 months. 131(28%) consulted for mood problem(s) or received a relevant prescription. Of these 100 (76%) still had insomnia symptoms at one year, compared with 227 (66%) of those with no contact with primary care for this condition (OR 1.37; 95% CI 0.83, 2.27). Prescription of hypnotics showed some evidence of association with persistence of insomnia at follow-up (OR 3.18; 95% CI 0.93, 10.92).</p> <p>Conclusion</p> <p>Insomniacs continue to have problems regardless of whether or not they have consulted their primary care clinician or received a prescription for medication over the year. Hypnotics may be associated with persistence of insomnia. Further research is needed to determine more effective methods of identifying and managing insomnia in primary care. There may however be a group who have unmet need such as depression who would benefit from seeking primary health care.</p

Using metrics and sustainability considerations to evaluate the use of bio-based and non-renewable Brønsted acidic ionic liquids to catalyse Fischer esterification reactions

Background Ionic liquids have found uses in many applications, one of which is the joint solvation and catalysis of chemical transformations. Suitable Brønsted acidic ionic liquids can be formed by combining lactams with sulphonic acids. This work weighs up the relative benefits and disadvantages of applying these Brønsted acidic ionic liquid catalysts in esterifications through a series of comparisons using green chemistry metrics. Results A new bio-based ionic liquid was synthesised from N-methyl pyrrolidinone and p-cymenesulphonic acid, and tested as a catalyst in three Fischer esterifications under different conditions. An evaluation of the performance of this Brønsted acidic ionic liquid was made through the comparison to other ionic liquid catalysts as well as conventional homogeneous Brønsted acids. Conclusion Extending the argument to feedstock security as well as mass utilisation, ultimately in most instances traditional mineral acids appear to be the most sensible option for Brønsted acid esterification catalysts. Ester yields obtained from Brønsted acidic ionic liquid catalysed procedures were modest. This calls into question the diversity of research exploring esterification catalysis and the role of ionic liquids in esterifications

Safety profile of Coartem®: the evidence base

This article reviews the comprehensive data on the safety and tolerability from over 6,300 patients who have taken artemether/lumefantrine (Coartem®) as part of Novartis-sponsored or independently-sponsored clinical trials. The majority of the reported adverse events seen in these studies are mild or moderate in severity and tend to affect the gastrointestinal or nervous systems. These adverse events, which are common in both adults and children, are also typical of symptoms of malaria or concomitant infections present in these patients. The wealth of safety data on artemether/lumefantrine has not identified any neurological, cardiac or haematological safety concerns. In addition, repeated administration is not associated with an increased risk of adverse drug reactions including neurological adverse events. This finding is especially relevant for children from regions with high malaria transmission rates who often receive many courses of anti-malarial medications during their lifetime. Data are also available to show that there were no clinically relevant differences in pregnancy outcomes in women exposed to artemether/lumefantrine compared with sulphadoxine-pyrimethamine during pregnancy. The six-dose regimen of artemether/lumefantrine is therefore well tolerated in a wide range of patient populations. In addition, post-marketing experience, based on the delivery of 250 million treatments as of July 2009, has not identified any new safety concerns for artemether/lumefantrine apart from hypersensitivity and allergies, known class effects of artemisinin derivatives

Shortened Telomere Length Is Associated with Increased Risk of Cancer: A Meta-Analysis

BACKGROUND: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. METHODS: A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the χ(2)-based Q statistic test and Egger's test, respectively. RESULTS: The results showed that shorter telomeres were significantly associated with cancer risk (OR = 1.35, 95% CI = 1.14-1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR = 1.84, 95% CI = 1.38-2.44), lung cancer (OR = 2.39, 95% CI = 1.18-4.88), smoking-related cancers (OR = 2.25, 95% CI = 1.83-2.78), cancers in the digestive system (OR = 1.69, 95% CI = 1.53-1.87) and the urogenital system (OR = 1.73, 95% CI = 1.12-2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Egger's test suggested that there was no publication bias in the current meta-analysis (P = 0.532). CONCLUSIONS: The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings

Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview

As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular factors which are also involved in the replication of HIV and hence their role as potential candidates will be discussed. HIV/AIDS being an exceptional epidemic, demands an exceptional approach and that forms very much focus for the current review

A wake-active locomotion circuit depolarizes a sleep-active neuron to switch on sleep

Sleep-active neurons depolarize during sleep to suppress wakefulness circuits. Wake-active wake-promoting neurons in turn shut down sleep-active neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-active neuron depolarization when the system is set to sleep. Using optogenetics in Caenorhabditis elegans, we solved the presynaptic circuit for depolarization of the sleep-active RIS neuron during developmentally regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires neurons that have known roles in wakefulness and locomotion behavior. The RIM interneurons-which are active during and can induce reverse locomotion-play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interneurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggest that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both forward (PVC) and reverse (including RIM) circuit activity overlap. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interneurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-active neurons by locomotion circuits suggests that sleep control may have evolved from locomotion control. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-active sleep-promoting neurons that translate wakefulness into the depolarization of a sleep-active neuron when the worm is sleepy. Wake-active sleep-promoting circuits may also be required for sleep state switching in other animals, including in mammals

Telomere length and bipolar disorder

Variation in telomere length is heritable and is currently considered a promising biomarker of susceptibility for neuropsychiatric disorders, particularly because of its association with memory function and hippocampal morphology. Here, we investigate telomere length in connection to familial risk and disease expression in bipolar disorder (BD). We used quantitative polymerase chain reactions and a telomere-sequence to single-copy-gene-sequence ratio method to determine telomere length in genomic DNA extracted from buccal smears from 63 patients with BD, 74 first-degree relatives (49 relatives had no lifetime psychopathology and 25 had a non-BD mood disorder) and 80 unrelated healthy individuals. Participants also underwent magnetic resonance imaging to determine hippocampal volumes and cognitive assessment to evaluate episodic memory using the verbal paired associates test. Telomere length was shorter in psychiatrically-well relatives (p=0.007) compared to unrelated healthy participants. Telomere length was also shorter in relatives (regardless of psychiatric status; p<0.01) and patients with BD not on lithium (p=0.02) compared to lithium-treated patients with BD. In the entire sample, telomere length was positively associated with left and right hippocampal volume and with delayed recall. This study provides evidence that shortened telomere length is associated with familial risk for BD. Lithium may have neuroprotective properties that require further investigation using prospective designs