Melatonin suppresses NO-induced apoptosis via induction of Bcl-2 expression in PGT-beta immortalized pineal cells

In the present study, we investigated whether melatonin would prevent nitric oxide (NO)-induced apoptotic death of PGT-beta immortalized pineal cells. To examine the protective effect of melatonin, cytotoxicity assay, DNA fragmentation analysis, caspase-3 activity assay, and Western blotting for caspase-3 and poly(ADP-ribose) polymerase (PARP) were performed. Treatment of cells with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, was shown to induce apoptotic cell death in a dose-dependent manner, and pretreatment with melatonin (0.1 mm) attenuated the occurrence of NO-induced apoptotic cell death. DNA fragmentation in response to NO was also arrested by melatonin. Caspase-3 activity induced by NO was decreased with melatonin treatment. Furthermore, the active fragments of caspase-3 and PARP were almost completely absent following exposure to melatonin. To elucidate the protective mechanisms of action of melatonin, Western blot analyses for Bcl-2 expression and cytochrome c release were carried out. Pretreatment with melatonin (0.1 mm) induced the expression of Bcl-2 and suppressed the release of cytochrome c into the cytosol, thereby arresting NO-induced apoptotic cell death. These results suggest that the antiapoptotic effect of melatonin is associated with induction of Bcl-2 expression in PGT-beta cells, which in turn blocks caspase-3 activation and inhibits cytochrome c release into the cytosol.     

The effectiveness of interventions to reduce the household economic burden of illness and injury: a systematic review

Objective

To determine the nature, scope and effectiveness of interventions to reduce the household economic burden of illness or injury.

Methods

We systematically reviewed reports published on or before 31 January 2014 that we found in the CENTRAL, CINAHL, Econlit, Embase, MEDLINE, PreMEDLINE and PsycINFO databases. We extracted data from prospective controlled trials and assessed the risk of bias. We narratively synthesized evidence.

Findings

Nine of the 4330 studies checked met our inclusion criteria – seven had evaluated changes to existing health-insurance programmes and two had evaluated different modes of delivering information. The only interventions found to reduce out-of-pocket expenditure significantly were those that eliminated or substantially reduced co-payments for a given patient population. However, the reductions only represented marginal changes in the total expenditures of patients. We found no studies that had been effective in addressing broader household economic impacts – such as catastrophic health expenditure – in the disease populations investigated.

Conclusion

In general, interventions designed to reduce the complex household economic burden of illness and injury appear to have had little impact on household economies. We only found a few relevant studies using rigorous study designs that were conducted in defined patient populations. The studies were limited in the range of interventions tested and they evaluated only a narrow range of household economic outcomes. There is a need for method development to advance the measurement of the household economic consequences of illness and injury and facilitate the development of innovative interventions to supplement the strategies based on health insurance.     

CaMKIIδ and cardiomyocyte Ca2+ signalling new perspectives on splice variant targeting

Control of cardiomyocyte cytosolic Ca²⁺ levels is crucial in determining inotropic status and ischemia/reperfusion stress response. Responsive to fluctuations in cellular Ca²⁺, Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII) is a serine/threonine kinase integral to the processes regulating cardiomyocyte Ca²⁺ channels/transporters. CaMKII is primarily expressed either in the δ_B or δ_C splice variant forms, which may mediate differential influences on cardiomyocyte function and pathological response mechanisms. Increases in myocyte Ca²⁺ levels promote the binding of a Ca²⁺/calmodulin complex to CaMKII, to activate the kinase. Activity is also maintained through a series of post‐translational modifications within a critical region of the regulatory domain of the protein. Recent data indicate that the post‐translational modification status of CaMKIIδ_B/δ_C variants may have an important influence on reperfusion outcomes. This study provided the first evidence that the specific type of CaMKII post‐translational modification has a role in determining target selectivity of downstream Ca²⁺ transporters. The study was also able to demonstrate that the phosphorylated form of CaMKII closely co‐localizes with CaMKIIδ_B in the nuclear/myofilament fraction, contrasting with a co‐enrichment of oxidized CaMKII in the membrane fraction with CaMKIIδ_C. It has also been possible to conclude that a hyper‐phosphorylation of CaMKII (Thr287) in reperfused hearts represents a hyper‐activation of the CaMKIIδ_B, which exerts anti‐arrhythmic actions through an enhanced capacity to selectively increase sarcoplasmic reticulum Ca²⁺ uptake and maintain cytosolic Ca²⁺ levels. This suggests that suppression of global CaMKIIδ may not be an efficacious approach to developing optimal pharmacological interventions for the vulnerable heart.     

Laypersons' views of material incentives for enhancing colorectal cancer screening

Background

Colorectal cancer (CRC) early detection improves health outcomes; screening programmes invest efforts in initiating invitations to target populations to be tested. Enhanced adherence is essential for reduction of morbidity and mortality. Participation rates in Israel are still relatively low.

Objective

To explore lay views regarding the concept of receiving material incentives in exchange for enhanced adherence to CRC screening.

Research design

Qualitative study. Between November 2009 and February 2010 six focus group discussions were carried out in two urban, middle and low socio‐economic status primary care clinics in a Northern city in Israel. Participants were eligible individuals for CRC screening, aged 50–68 (N = 24). Data analysis followed the principles of grounded theory, supported by qualitative software.

Results

Participants found administering incentives in exchange for CRC screening inappropriate on rational and moral grounds. They valued their relations with the medical team and the health system more than the potential gain expected. Individuals eligible for CRC screening perceived themselves as responsible for their health, admitting difficulties in realizing this responsibility. Incentives were reported unsuitable for solving reported screening difficulties and a potential harm to the doctor–patient relationship.

Conclusions

Focus group participants expressed an unconventional voice towards the use of material incentives. They pointed to the need for focused support of health behaviour change and valued their autonomy. While a proportion of the invitees in the target population see the importance of screening and appreciate the HMO''s initiative to invite them for testing, they also expressed their need for support from the HMO in realizing the recommended health behaviour.     

Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant naive controls. Two hundred twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial, and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single-nucleotide polymorphisms (rs4570625 and rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole-blood samples. Several significant gene × environment interactions between 5-HT genotypes and cocaine use on WM emerged: in cocaine users, the long/long (5-HTTLPR), 9+10/9+10 (VNTR In2) and C/C (TPH2 rs1386497) genotypes were risk alleles for WM impairments, whereas in healthy controls these polymorphisms were associated with improved WM performance. Analogously, high 5-HTT mRNA levels were associated with worse executive WM performance in cocaine users but with increased performance in controls. These gene × environment interactions suggest that the 5-HT system has an important role in the development of cognitive deficits in chronic cocaine users. Hence, pharmacological compounds targeting 5-HT neurotransmission might be promising for the treatment of cognitive deficits in cocaine dependence.     

Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy

Journal of Gastroenterology - We aimed to assess whether residual hepatitis B virus (HBV) viraemia is associated with HCC development. This is a case–control study of 104 patients [52 HCC and...     

The influence of the polyphenols of cider on plasmin and plasminogen activators

Preliminary findings suggested that the inhibitory activity on fibrinolysis produced by most varieties of cider is due to their content of polyphenols. In particular, the inhibitory activity co-eluted with the brown coloration on gel filtration, was removed by adsorption with polyvinylpyrrolidine, and was greatly reduced in a type of cider with a low concentration of phenolic compounds. The individual polyphenols of apple juice and ciders were examined for their ability to inhibit tissue activator, urokinase and plasmin. Neither phloridzin nor chlorogenic acid had any inhibitory activity at concentrations of 500 micrograms/ml while epicatechin had only a slight inhibitory effect at this concentration. The procyanidin fractions were markedly inhibitory on urokinase-induced clot lysis, the amidolytic activity of plasmin and on the fibrinolytic activities of plasmin, urokinase and tissue activator on fibrin plates: inhibition was noted at concentrations as low as 0.25 micrograms/ml. The order of inhibition was polymer greater than oligomer greater than trimer greater than dimer.     

Irritable bowel syndrome, chronic pelvic inflammatory disease and endometriosis: a comparison of symptomatology

BACKGROUND AND OBJECTIVES: Both irritable bowel syndrome and some gynaecological diseases can give rise to lower abdominal pain, which may result in diagnostic confusion. Disorders such as endometriosis and chronic pelvic inflammatory disease can be diagnosed definitively only by laparoscopy, which is seldom undertaken in the gastroenterological setting. It was the aim of this study to compare the symptomatology of irritable bowel syndrome with that of laparoscopically confirmed chronic pelvic inflammatory disease and endometriosis. PATIENTS AND METHODS: A symptom questionnaire was administered to 50 women with irritable bowel syndrome and 51 gynaecological patients (30 patients with endometriosis, 21 patients with chronic pelvic inflammatory disease). As the symptoms of the two gynaecological conditions were so similar, the groups were combined for the purposes of comparison with irritable bowel syndrome. RESULTS: Patients with irritable bowel syndrome suffered significantly more upper abdominal pain, colicky pain and exacerbation of pain by food or stress. They also experienced more disturbance of bowel habit, distension and nausea. In contrast, the only gynaecological features that were more common in the gynaecological patients were intermenstrual bleeding, premenstrual exacerbation of pain and forniceal tenderness. CONCLUSION: The presence of gastrointestinal symptomatology, especially bowel dysfunction, in a woman with lower abdominal pain is suggestive of irritable bowel syndrome. However, the history may not be so helpful in detecting gynaecological disease.     

Seasonal changes in concentrations of plasma hormones in the male ring dove (Streptopelia risoria)

Seasonal changes in concentrations of plasma LH, prolactin, thyroxine (T4), GH and corticosterone were measured in captive male ring doves exposed to natural lighting at latitude 56 degrees N. Plasma LH levels decreased steeply in autumn when the daylength fell below about 12.5 h but increased in November as the birds became short-day refractory. In comparison with plasma LH concentrations in a group of short-day refractory birds exposed to 6 h light/day from the winter solstice, plasma LH levels in birds exposed to natural lighting increased further in spring after the natural daylength reached about 12.5 h. There were no seasonal changes in plasma prolactin concentrations and plasma T4 concentrations were at their highest during December, January and February, the coldest months of the year. The seasonal fall in plasma LH levels in September was associated with a transitory increase in plasma T4, a transitory decrease in plasma corticosterone and a sustained increase in plasma GH. It is suggested that in the ring dove, short-day refractoriness develops rapidly in November to allow the bird to breed when the opportunity arises, during the winter and early spring. The annual breeding cycle is synchronized by a short-day induced regression of the reproductive system in the autumn, the primary function of which may be to enable the birds to meet the energy requirements for the annual moult. The changes in plasma T4, corticosterone and especially of GH at this time of year are probably concerned with the control of moult or the associated changes in energy requirements.