Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant

The lead candidate plague subunit vaccine is the recombinant fusion protein rF1-V adjuvanted with alum. While alum generates Th₂ regulated robust humoral responses, immune protection against Yersinia pestis has been shown to also involve Th₁ driven cellular responses. Therefore, the rF1-V-based subunit vaccine may benefit from an adjuvant system that generates a mixed Th₁ and humoral immune response. We herein assessed the efficacy of a novel SA-4-1BBL costimulatory molecule as a Th₁ adjuvant to improve cellular responses generated by the rF1-V vaccine. SA-4-1BBL as a single adjuvant had better efficacy than alum in generating CD4⁺ and CD8⁺ T cells producing TNFα and IFNγ, signature cytokines for Th₁ responses. The combination of SA-4-1BBL with alum further increased this Th₁ response as compared with the individual adjuvants. Analysis of the humoral response revealed that SA-4-1BBL as a single adjuvant did not generate a significant Ab response against rF1-V, and SA-4-1BBL in combination with alum did not improve Ab titers. However, the combined adjuvants significantly increased the ratio of Th₁ regulated IgG_2c in C57BL/6 mice to the Th₂ regulated IgG₁. Finally, a single vaccination with rF1-V adjuvanted with SA-4-1BBL + alum had better protective efficacy than vaccines containing individual adjuvants. Taken together, these results demonstrate that SA-4-1BBL improves the protective efficacy of the alum adjuvanted lead rF1-V subunit vaccine by generating a more balanced Th₁ cellular and humoral immune response. As such, this adjuvant platform may prove efficacious not only for the rF1-V vaccine but also against other infections that require both cellular and humoral immune responses for protection.     

Residual Periodontal Ligament in Extracted Teeth – Is It Associated With Indication for Extraction?

BackgroundPeriodontal disease is a major cause of tooth loss. Few studies have evaluated the residual area of the periodontal ligament in extracted teeth and, to the best of our knowledge, none from Latin America have done so regarding indications for extraction. The aim of this study was to evaluate the residual periodontal ligament (RPL) with respect to indication for extraction in a sample of teeth from a Brazilian Public Health Service district.Materials and methodsAll teeth extracted within the Public Health Service district of Santa Maria, Brazil, over a 5-month period were requested for analysis. A total of 414 teeth eligible for measurement were stained and evaluated for RPL using a stereo microscope. Participating Public Health Service dentists completed a questionnaire detailing demographic variables and indication for each extracted tooth. The percentage of RPL was determined for each tooth. Comparisons of RPL between teeth extracted on periodontal versus other indications were made using the Mann-Whitney test.ResultsRPL averaged 34.8% for teeth extracted on periodontal indications versus 79.5% for other teeth (P ≤ 0.001). When considering teeth with an RPL ≥ 30% as possible to maintain, 189 (76%) of the teeth extracted on periodontal indications could have been maintained. When RPL cut-off limits of ≥ 40% or ≥ 50% are applied, 93 (37%) and 43 (17%) teeth, respectively, could have been maintained.ConclusionThis study suggests that strictly based on RPL, a large number of teeth extracted on periodontal indications conceivably could be maintained.Key words: Cross-sectional studies, Prognosis, Tooth extraction, Tooth loss     

Anxiety,depression, and stress in caregivers of children and adolescents with mental disorders in Ghana and implications for medication adherence

ObjectiveThis study assessed levels of anxiety, depression, and stress among family caregivers of children and adolescents with mental disorders in Ghana and the implication on medication adherence.DesignA cross-sectional study.SettingThe study was conducted at the outpatient departments of the three main public psychiatric hospitals in Ghana.ParticipantsTwo hundred and ten non-paid family caregivers of children and adolescents with mental disorders were recruited for this study.Main Outcome MeasureThe study assessed symptoms of anxiety, depression and stress among the caregivers and estimated caregiver-reported medication adherence.ResultsAbout 56.2%, 66.2% and 78% of the caregivers experienced severe anxiety, severe depression and moderate to severe stress symptoms respectively. From the multiple logistic regression model, while anxiety was significantly affected by religion and education, depression was influenced by sex, age, marital status, proximity to facility, and employment status. Female caregivers had about four times higher odds of being depressed compared to male caregivers (aOR: 3.81, 95% CI: 1.66 – 8.75). The caregiver-reported medication adherence was 11.9%. Anxiety was significantly predictive of medication adherence.ConclusionMost family caregivers of children and adolescents with mental disorders experienced symptoms of anxiety, depression and stress with anxiety having implications for medication adherence. The study findings underscore the need to consider psychological characteristics of caregivers and the provision of mental health support for them, as part of the routine health care for children and adolescents with mental disorders.FundingNone indicated     

Alcohol metabolism and fetal hypoplasia in chick brain

Chick embryos given a single dose of ethanol (1.0 g/kg) at the start of incubation (day 0) had widely differing levels of blood alcohol when sacrificed on day 7 and the blood alcohol levels were inversely correlated with whole body and brain weight. Clearance of the alcohol by the embryos was inhibited by simultaneous treatment with 4-methyl pyrazole and this treatment potentiated the brain growth inhibition due to ethanol. Treatment with indomethacin lowered blood alcohol levels on day 7 and protected against the growth inhibition. These data suggest that early chick embryos have varying amounts of alcohol dehydrogenase-like metabolic activity and that higher levels of this activity protect against alcohol-induced brain growth inhibition in this model. If similar variations in the ability to metabolize alcohol exist in human fetuses, it may represent a mechanism by which comparable maternal doses of alcohol produce widely varying fetal effects.     

Toxicological effects of the sunscreen UV filter,benzophenone-2, on planulae and in vitro cells of the coral,Stylophora pistillata

Benzophenone-2 (BP-2) is an additive to personal-care products and commercial solutions that protects against the damaging effects of ultraviolet light. BP-2 is an “emerging contaminant of concern” that is often released as a pollutant through municipal and boat/ship wastewater discharges and landfill leachates, as well as through residential septic fields and unmanaged cesspits. Although BP-2 may be a contaminant on coral reefs, its environmental toxicity to reefs is unknown. This poses a potential management issue, since BP-2 is a known endocrine disruptor as well as a weak genotoxicant. We examined the effects of BP-2 on the larval form (planula) of the coral, Stylophora pistillata, as well as its toxicity to in vitro coral cells. BP-2 is a photo-toxicant; adverse effects are exacerbated in the light versus in darkness. Whether in darkness or light, BP-2 induced coral planulae to transform from a motile planktonic state to a deformed, sessile condition. Planulae exhibited an increasing rate of coral bleaching in response to increasing concentrations of BP-2. BP-2 is a genotoxicant to corals, exhibiting a strong positive relationship between DNA-AP lesions and increasing BP-2 concentrations. BP-2 exposure in the light induced extensive necrosis in both the epidermis and gastrodermis. In contrast, BP-2 exposure in darkness induced autophagy and autophagic cell death. The LC₅₀ of BP-2 in the light for an 8 and 24 h exposure was 120 and 165 parts per billion (ppb), respectively. The LC₅₀s for BP-2 in darkness for the same time points were 144 and 548 ppb. Deformity EC20 levels (24 h) were 246 parts per trillion in the light and 9.6 ppb in darkness.     

The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS

Through a combination of fluorescence microscopy and patch-clamp analysis we have identified a striking alteration in K(+) channel expression in terminally differentiated human CCR7(-)CD45RA(-) effector memory T lymphocytes (T(EM)). Following activation, T(EM) cells expressed significantly higher levels of the voltage-gated K(+) channel Kv1.3 and lower levels of the calcium-activated K(+) channel IKCa1 than naive and central memory T cells (T(CM)). Upon repeated in vitro antigenic stimulation, naive cells differentiated into Kv1.3(high)IKCa1(low) T(EM) cells, and the potent Kv1.3-blocking sea anemone Stichodactyla helianthus peptide (ShK) suppressed proliferation of T(EM) cells without affecting naive or T(CM) lymphocytes. Thus, the Kv1.3(high)IKCa1(low) phenotype is a functional marker of activated T(EM) lymphocytes. Activated myelin-reactive T cells from patients with MS exhibited the Kv1.3(high)IKCa1(low) T(EM) phenotype, suggesting that they have undergone repeated stimulation during the course of disease; these cells may contribute to disease pathogenesis due to their ability to home to inflamed tissues and exhibit immediate effector function. The Kv1.3(high)IKCa1(low) phenotype was not seen in glutamic acid decarboxylase, insulin-peptide or ovalbumin-specific and mitogen-activated T cells from MS patients, or in myelin-specific T cells from healthy controls. Selective targeting of Kv1.3 in T(EM) cells may therefore hold therapeutic promise for MS and other T cell-mediated autoimmune diseases.     

The changing profile of the patient undergoing coronary artery bypass surgery

The first 100 consecutive patients undergoing isolated coronary artery bypass surgery in 1975 were evaluated with respect to the incidence of operative risk factors and outcome. When compared with an identically selected group from 1985, there was significant worsening of the preoperative condition over the decade with regard to mean age (p less than 0.0005), presence of congestive heart failure (p less than 0.05), left ventricular dysfunction (p less than 0.05), severity of coronary artery disease (p less than 0.001) and incidence of emergency operation (p less than 0.05). More patients in 1985 had associated medical diseases such as diabetes (p less than 0.01) and chronic lung disease (p less than 0.005). There was an increase in the occurrence of vascular diseases (hypertension, renal dysfunction, peripheral vascular and cerebrovascular disease) (p less than 0.05). Overall operative mortality increased from 1 to 8% (p less than 0.05) over the decade. Despite the deterioration in the clinical profile of the patient undergoing coronary bypass surgery, elective procedures were still performed with low mortality. The significant increase in overall mortality was chiefly in patients undergoing emergency operation (p less than 0.05). There were also increases in operative morbidity including low output syndrome (p less than 0.01) and respiratory (p less than 0.005) and neurologic (p = 0.06) complications.