Environmental risk factors for hepatitis A infection in the Zenica–Doboj Canton, Bosnia and Herzegovina

In the Zenica-Doboj Canton, 1106 hepatitis A virus (HAV) infections were reported during 2000 (an incidence rate of 252/100 000 population), with 996 (90.1%) cases occurring in nine community-wide outbreaks. Analysis of water supplies showed that 398 (19.1%) samples contained coliforms, including 202 (50.8%) that were contaminated with thermotolerant Escherichia coli. Sewage sanitation systems were absent or substandard in 53 910 (81.8%) rural households. The group most affected during outbreaks comprised children aged 7-14 years (incidence rate of 598/100 000). The development of health promotion and prevention initiatives in schools, combined with rigorous hygiene measures, will be necessary to achieve control of the spread of HAV.     

Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

Escalations in alcohol drinking associated with experiencing stressful life events and chronic life stressors may be related to altered sensitivity to the interoceptive/subjective effects of alcohol. Indeed, through the use of drug discrimination methods, rats show decreased sensitivity to the discriminative stimulus (interoceptive) effects of alcohol following exposure to the stress hormone corticosterone (CORT). This exposure produces heightened elevations in plasma CORT levels (eg, as may be experienced by an individual during stressful episodes). We hypothesized that decreased sensitivity to alcohol may be related, in part, to changes in metabotropic glutamate receptors-subtype 5 (mGluR5) in the nucleus accumbens, as these receptors in this brain region are known to regulate the discriminative stimulus effects of alcohol. In the accumbens, we found reduced mGluR5 expression (immunohistochemistry and Western blot) and decreased neural activation (as measured by c-Fos immunohistochemistry) in response to a moderate alcohol dose (1 g/kg) following CORT exposure (7 days). The functional role of these CORT-induced adaptations in relation to the discriminative stimulus effects of alcohol was confirmed, as both the systemic administration of 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) an mGluR5 positive allosteric modulator and the intra-accumbens administration of (R,S)-2-Amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt (CHPG) an mGluR5 agonist restored sensitivity to alcohol in discrimination-trained rats. These results suggest that activation of mGluR5 may alleviate the functional impact of the CORT-induced downregulation of mGluR5 in relation to sensitivity to alcohol. Understanding the contribution of such neuroadaptations to the interoceptive effects of alcohol may enrich our understanding of potential changes in subjective sensitivity to alcohol during stressful episodes.     

Modulation of sensitivity to alcohol by cortical and thalamic brain regions

The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally naïve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two‐lever drug discrimination task. As such, rats were administered water or alcohol (1 g/kg, IG) and brain tissue was processed for c‐Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c‐Fos IR in the mPFC, IC, Rh and AcbC. Lastly, site‐specific pharmacological inactivation with muscimol + baclofen (GABA_A agonist + GABA_B agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol‐like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol.     

Prevalence of chronic kidney disease in an urban Mexican population

BACKGROUND: The present study was primarily designed to assess the prevalence of chronic kidney disease in a Mexican urban population residing in Mexico and to evaluate certain biologic and socioeconomic conditions as risk factors for the development of renal disease. METHODS: A population-based cross-sectional survey was conducted, which included 3564 patients of either gender aged >18 years, who were randomly selected from lists of patients assigned to primary care facilities in the city of Morelia. A questionnaire about personal current health status, kidney disease, diabetes, hypertension, or heart disease in close relatives, anthropometric and blood pressure measurements, and blood and urine samples to measure glucose, blood urea nitrogen, and creatinine was obtained for each patient. Creatinine clearance (Ccr) was calculated by the Cockcroft-Gault formula. Patients were classified in 1 of the 5 Ccr categories established by the Kidney Disease Outcomes Quality Initiative guidelines. RESULTS: The prevalence rate of Ccr < 15 mL/min was 1142 per million population, and that of Ccr <60 mL/min 80,788 per million population. Alcohol and tobacco consumption, female gender, age >65 years, educational level < primary school, and income < US $4.00/day were significantly associated with reduced Ccr. CONCLUSION: Chronic kidney disease prevalence in this population is similar to that seen in industrialized countries. If these figures are similar to those of the entire Mexican population, only l out of 4 patients requiring renal replacement therapy in the country currently has access to it.     

The differential contribution of granzyme A and granzyme B in cytotoxic T lymphocyte-mediated apoptosis is determined by the quality of target cells

Complementary approaches with purified molecules or transfected cytolytic effector cells have suggested that both, granzyme A (gzmA) and granzyme B (gzmB), similarly contribute to CTL-mediatedand perforin (perf)-dependent apoptotic nuclear damage (DNA fragmentation) in target cells. Studies employing gzmA or gzmB single-knockout mice on the other hand indicated that gzmB is the prominent CTL effector molecule for the rapid induction of DNA fragmentation, with gzmA playing only a minor part. We have now taken ex vivo-derived virus-specific or in vitro generated alloreactive CTL from mice deficient in either gzmA or gzmB and a panel of three target cells to reinvestigate this unresolved issue. We show that rapid CTL-mediated DNA fragmentation of L1210.3 target cells is solely dependent on gzmB, whereas the DNA fragmentation of EL4.F15 target cells by the same CTL population is mainly induced by gzmA and only marginally by gzmB. Moreover, CTL-induced apoptosis of a third target cell, MC57G, was partially dependent on both gzmA and gzmB activities. The differential contribution of the two gzms to apoptosis was further verified by their distinct sensitivity tocaspase inhibitors. The data suggest that both, gzmA and gzmB, have a similar potential to induce rapid perf-mediated apoptosis but that their individual contribution to the underlying intracellular processes is dictated by the quality of the target cell.     

Liposome‐bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis

Objective

We previously observed that T lymphocytes present in synovial fluid (SF) from patients with rheumatoid arthritis (RA) were sensitive to APO2L/TRAIL. In addition, there was a drastic decrease in the amount of bioactive APO2L/TRAIL associated with exosomes in SF from RA patients. This study was undertaken to evaluate the effectiveness of bioactive APO2L/TRAIL conjugated with artificial lipid vesicles resembling natural exosomes as a treatment in a rabbit model of antigen‐induced arthritis (AIA).

Methods

We used a novel Ni²⁺‐(N‐5‐amino‐1‐carboxypentyl)‐iminodiacetic acid)–containing liposomal system. APO2L/TRAIL bound to liposomes was intraarticularly injected into the knees of animals with AIA. One week after treatment, rabbits were killed, and arthritic synovial tissue was analyzed.

Results

Tethering APO2L/TRAIL to the liposome membrane increased its bioactivity and resulted in more effective treatment of AIA compared with soluble, unconjugated APO2L/TRAIL, with substantially reduced synovial hyperplasia and inflammation in rabbit knee joints. The results of biophysical studies suggested that the increased bioactivity of APO2L/TRAIL associated with liposomes was due to the increase in the local concentration of the recombinant protein, augmenting its receptor crosslinking potential, and not to conformational changes in the protein. In spite of this increase in bioactivity, the treatment lacked systemic toxicity and was not hepatotoxic.

Conclusion

Our findings indicate that binding APO2L/TRAIL to the liposome membrane increases its bioactivity and results in effective treatment of AIA.

     

The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling

The BH3-only protein Bim is required for maintaining the homeostasis of the immune system, since Bim regulates the down-modulation of T-cell responses, mainly through cytokine deprivation. Using T-cell blasts from healthy donors and also from patients with autoimmune lymphoproliferative syndromes (ALPSs) due to homozygous loss-of-function mutation of FasL (ALPS-Ic) or heterozygous mutation in the Fas/CD95 death domain (ALPS-Ia), it is shown that the induction of Bim expression during the process of human T-cell blast generation is strictly dependent on FasL/Fas-mediated signaling. The main pathway by which Fas signaling regulates the levels of Bim expression in human T-cell blasts is the death-domain- and caspase-independent generation of discrete levels of H2O2, which results in the net increase of Foxo3a levels. The present results connect the 2 main pathways described until the moment for the control of T-cell responses: death receptor-mediated activation-induced cell death and apoptosis by cytokine deprivation.