Autoimmunity in chronic bullous skin diseases. Immunofluorescent demonstration of three types of antibodies to skin in sera of patients with pemphigus, bullous pemphigoid and in other human sera

Antibodies to an intercellular substance of epidermis and other stratified squamous epithelia demonstrable by immunofluorescent staining have been reported to occur in the sera of patients with pemphigus vulgaris. Using sera of patients with bullous pemphigoid, antibodies to a component of the basement zone of skin had been found by the same technique. In the present study these observations have been confirmed and extended. In addition to the above mentioned immunofluorescent staining reactions, another type of antibody directed to a cytoplasmic or perinuclear component of epidermal cells was found in a variety of pathologic sera. This observation points to the need for differentiating other skin-reactive antibodies from those found only in pemphigus. Guinea-pig lip sections appeared to be satisfactory for these studies. Mixed immunofluorescence was found to yield staining reactions identical to those observed by the indirect staining method, and gave titres the same as or lower than those obtained by the indirect staining procedure. Using the indirect method with guinea-pig lip sections it was found that eight of ten sera of patients with pemphigus contained intercellular antibodies while 102 control sera failed to yield reactions of this type. The titres of antibodies appeared to be proportional to the severity of the disease process. Sera of two out of three patients suffering from bullous pemphigoid yielded immunofluorescence staining of the basement zone while 109 controls were negative for this antibody.     

Composition of TCR-CD3 complex in human intestinal intraepithelial lymphocytes: lack of Fc{varepsilon}Rl{gamma} chain

Human intestinal intraepithelial lymphocytes (DEL) are a uniquepopulation of predominantly CD8ß⁺ TCRß⁺lymphocytes and, to a lesser extent, TCR⁺ lymphocytes that proliferatepoorly to anti-CD3 mitogenic signals but display significantcytolytic activity. Studies in mouse model systems have shownthat the chain of the high-CD3 affinity receptor for IgE (FcRl)may substitute for the chain in the TCR-CD3 complex of iIEL.This has suggested that the functional properties of these cellsmay be associated with an altered composition of the TCR-CD3complex. We therefore analyzed the TCR-CD3 complex of normalhuman iIEL. One-and two-dimensional non-reducing/reducing SDS-PAGEanalysis of CD3, CD3, CD3, and FcRr chain immunopreclpitatesof cell surface radiolabeled proteins with subunit-specificantibodies revealed a TCR-CD3 complex without associated FcRrchains. Thus, normal human NEL contain a TCR-CD3 complex thatconsists predominantly of , homodimers in association with theß TCR and CD3, and , similar to the majority of peripherallymphocytes. This indicates that the distinct properties ofhuman DEL are not associated with substitutions of the FcRlchain in the TCR-CD3 complex.     

Discriminating adaptive attributions: Agreement between self-report and objective ratings

According to the reformulated learned helplessness model of depression, causal attributions are an important mediator of the effects on mood of positive and negative experiences. Adaptive attributions for negative events are assumed to be external, unstable, and specific. In the present study, subjects exposed to one of two attribution training procedures or a control condition made attributions for hypothetical events under neutral and adaptive instructional sets. Attributions were rated by subjects and coders blind to the purpose of the study. Results indicated that subjects' views of adaptive causal attributions were congruent with predictions from the learned helplessness model. The ratings of the objective coders indicated that subjects' attributions really did change in response to the adaptive instructions in the predicted direction. Implications of these results for the reformulated learned helplessness model and depression therapies that include an attribution retraining component are discussed.The authors would like to thank Dan Russell for his very helpful comments on earlier drafts of this paper.     

Effect of verapamil on daunorubicin accumulation in Ehrlich ascites tumor cells

Summary Previous studies have demonstrated that verapamil may overcome resistance to anthracyclines. In vitro and in vivo experiments were performed on wild-type and resistant Ehrlich ascites tumor cells.Verapamil in concentrations of 25–50 M enhances the accumulation of daunorubicin (DNR) in resistant cells to the same level as in wild-type cells. No significant effect of verapamil on influx or nuclear binding could be demonstrated, indicating that verapamil enhances DNR uptake by blocking active drug extrusion. Exposure of cells to a high concentration of Ca²⁺ did not influence the effect of verapamil on DNR accumulation, suggesting a different mode of verapamil action apart from the Ca²⁺-blocking effect. Attempts to circumvent acquired resistance to DNR in vivo with verapamil showed that the combination of the two drugs was more toxic than DNR given alone. The LD₁₀ of DNR was determined as 3 mg/kg and the LD₁₀ of the combination, as 2.5 mg/kg. The therapeutic effect of verapamil at a dose of 50 mg/kg and DNR of 2.5 mg/kg increased the life span of the mice by 50%. No difference was seen in the wild-type tumor in vivo.These data lead us to conclude that verapamil can reverse DNR resistance completely, but that verapamil at non-toxic dosage only reduces DNR resistance by 50% in vivo.The Danish Cancer Society, Copenhagen, Denmark, the Kathrine and Vigo Skovgaard Foundation, Holbæk, Denmark and the Anders Hasselbalch Foundation, Copenhagen, Denmark, kindly supported this work.     

Simultaneous liquid-chromatographic determination of five antiarrhythmic drugs and their major active metabolites in serum

We report an isocratic "high-performance" liquid chromatographic method for the simultaneous measurement of tocainide, lidocaine, procainamide, quinidine, disopyramide, and their major active metabolites in serum. The drugs are extracted from 200 microL of serum at pH 9.5 with 1.5 mL of 1,2-dichloromethane, concentrated by evaporation, and separated on a CN-bonded-phase column at 40 degrees C (flow rate 2 mL/min) with a pH 7.1 mobile phase of acetonitrile/methanol/phosphate buffer (60/7/33, by vol); the phosphate buffer contains 10 mmol of KH2PO4 and 0.5 mmol of triethylamine per liter. The antiarrhythmic drugs elute in the K' (capacity factor) range of 1.43 (lidocaine) to 5.7 (disopyramide). Results vary linearly with drug concentration to at least 30 mg/L; the detection limit is 0.1-0.2 mg/L. Within-run precision (CV) ranges from 0.9% to 5.0% and day-to-day precision from 2.1% to 6.2%, depending on the specific drug and its concentration in serum. Extraction efficiencies vary from 76% to 85% and analytical recoveries from 98.5% to 103%. At toxic serum concentrations, several basic drugs may interfere with the assay of some antiarrhythmics, but only hydroxyzine, verapamil, and certain local anesthetics interfere at therapeutic concentrations.     

Effect of heated humidified gases on temperature drop after cardiopulmonary bypass

In an attempt to prevent the decrease in nasopharyngeal temperature (NPT) ("afterdrop") after cardiac surgery, 30 patients undergoing hypothermic cardiopulmonary bypass (CPB) were randomly assigned to receive humidified heated inspired gases at 45 degrees C at the proximal end of the endotracheal tube (group I) or dry gases at room temperature (group II), from the time of termination of CPB. All patients received high flow rates on CPB during the rewarming period with the use of vasodilator drugs when necessary. Both groups were comparable with respect to total bypass time, rewarming time, and temperature at termination of CPB. In addition, the NPT was compared with the tympanic membrane temperature (TMT) in group I to assess the validity of the NPT under these conditions. The results indicate that heating and humidifying inspired gases do not prevent afterdrop and do not falsely increase the nasopharyngeal temperature. The reasons for the ineffectiveness of heated humidified gases may include a large heat deficit at termination of CPB despite a normal NPT, and the very small heat content of heated gases. Monitoring the temperature of a site that reflects the heat deficit, and a more complete rewarming during CPB are suggested as a better approach to the prevention of afterdrop.     

A Pilot Trial of a Health Promotion and Illness Prevention Paradigm in the Perinatal Period

Maternal and Child Health Journal - This is a pilot study of the Vermont Family Based Approach, an innovative health promotion program designed to address behavioral health prevention in primary...     

Acceptability and Feasibility of a 13-Week Pilot Randomised Controlled Trial Testing the Effects of Incremental Doses of Beetroot Juice in Overweight and Obese Older Adults

Nitrate-rich food can increase nitric oxide production and improve vascular and brain functions. This study examines the feasibility of a randomised controlled trial (RCT) testing the effects of prolonged consumption of different doses of dietary nitrate (NO₃⁻) in the form of beetroot juice (BJ) in overweight and obese older participants. A single-blind, four-arm parallel pilot RCT was conducted in 62 overweight and obese (30.4 ± 4 kg/m²) older participants (mean ± standard deviation (SD), 66 ± 4 years). Participants were randomized to: (1) high-NO₃⁻ (HN: 2 × 70 mL BJ/day) (2) medium-NO₃⁻ (MN: 70 mL BJ/day), (3) low-NO₃⁻ (LN: 70 mL BJ on alternate days) or (4) Placebo (PL: 70 mL of NO₃⁻-depleted BJ on alternate days), for 13 weeks. Compliance was checked by a daily log of consumed BJ, NO₃⁻ intake, and by measuring NO₃⁻ and NO₂⁻ concentrations in plasma, saliva, and urine samples. Fifty participants completed the study. Self-reported compliance to the interventions was >90%. There were significant positive linear relationships between NO₃⁻ dose and the increase in plasma and urinary NO₃⁻ concentration (R² = 0.71, p < 0.001 and R² = 0.46 p < 0.001, respectively), but relationships between NO₃⁻ dose and changes in salivary NO₃⁻ and NO₂⁻ were non-linear (R² = 0.35, p = 0.002 and R² = 0.23, p = 0.007, respectively). The results confirm the feasibility of prolonged BJ supplementation in older overweight and obese adults.     

Human Milk Exosomal MicroRNA: Associations with Maternal Overweight/Obesity and Infant Body Composition at 1 Month of Life

Among all the body fluids, breast milk is one of the richest sources of microRNAs (miRNAs). MiRNAs packaged within the milk exosomes are bioavailable to breastfeeding infants. The role of miRNAs in determining infant growth and the impact of maternal overweight/obesity on human milk (HM) miRNAs is poorly understood. The objectives of this study were to examine the impact of maternal overweight/obesity on select miRNAs (miR-148a, miR-30b, miR-29a, miR-29b, miR-let-7a and miR-32) involved in adipogenesis and glucose metabolism and to examine the relationship of these miRNAs with measures of infant body composition in the first 6 months of life. Milk samples were collected from a cohort of 60 mothers (30 normal-weight [NW] and 30 overweight [OW]/obese [OB]) at 1-month and a subset of 48 of these at 3 months of lactation. Relative abundance of miRNA was determined using real-time PCR. The associations between the miRNAs of interest and infant weight and body composition at one, three, and six months were examined after adjusting for infant gestational age, birth weight, and sex. The abundance of miR-148a and miR-30b was lower by 30% and 42%, respectively, in the OW/OB group than in the NW group at 1 month. miR-148a was negatively associated with infant weight, fat mass, and fat free mass, while miR-30b was positively associated with infant weight, percent body fat, and fat mass at 1 month. Maternal obesity is negatively associated with the content of select miRNAs in human milk. An association of specific miRNAs with infant body composition was observed during the first month of life, suggesting a potential role in the infant’s adaptation to enteral nutrition.     

Hybrid Approach to Estimation of Underreporting of Tuberculosis Case Notification in High-Burden Settings With Weak Surveillance Infrastructure: Design and Implementation of an Inventory Study

BackgroundThe greatest risk of infectious disease undernotification occurs in settings with limited capacity to detect it reliably. World Health Organization guidance on the measurement of misreporting is paradoxical, requiring robust, independent systems to assess surveillance rigor. Methods are needed to estimate undernotification in settings with incomplete, flawed, or weak surveillance systems. This study attempted to design a tuberculosis (TB) inventory study that balanced rigor with feasibility for high-need settings.ObjectiveThis study aims to design a hybrid TB inventory study for contexts without World Health Organization preconditions. We estimated the proportion of TB cases that were not reported to the Ministry of Health in 2015. The study sought to describe TB surveillance coverage and quality at different levels of TB care provision. Finally, we aimed to identify structural-, facility-, and provider-level barriers to notification and reasons for underreporting, nonreporting, and overreporting.MethodsRetrospective partial digitalization of paper-based surveillance and facility records preceded deterministic and probabilistic record linkage; a hybrid of health facilities and laboratory census with a stratified sampling of HFs with no capacity to notify leveraged a priori knowledge. Distinct extrapolation methods were applied to the sampled health facilities to estimate bacteriologically confirmed versus clinical TB. In-depth interviews and focus groups were used to identify causal factors responsible for undernotification and test the acceptability of remedies.ResultsThe hybrid approach proved viable and instructive. High-specificity verification of paper-based records in the field was efficient and had minimal errors. Limiting extrapolation to clinical cases improved precision. Probabilistic record linkage is computationally intensive, and the choice of software influences estimates. Record absence, decay, and overestimation of the private sector TB treatment behavior threaten validity, meriting mitigation. Data management demands were underestimated. Treatment success was modest in all sectors (R=37.9%–72.0%) and did not align with treatment success reported by the state (6665/8770, 75.99%). One-fifth of TB providers (36/178, 20%) were doubtful that the low volume of patients with TB treated in their facility merited mastery of the extensive TB notification forms and procedures.ConclusionsSubnational inventory studies can be rigorous, relevant, and efficient in countries that need them even in the absence of World Health Organization preconditions, if precautions are taken. The use of triangulation techniques, with minimal recourse to sampling and extrapolation, and the privileging of practical information needs of local decision makers yield reasonable misreporting estimates and viable policy recommendations.