Imported tropical diseases

Imported tropical diseases are among the top three leading causes for morbidity and may affect up to 8% of returning travelers. Because the spectrum of dermatological manifestations seen in travelers is broad, it can be challenging for physicians to recognize and treat such conditions in a timely and efficient manner. Therefore, the present review highlights common imported tropical diseases with a focus on treatment regimens. Specifically, cutaneous larva migrans, myiasis, swimmer's itch, mycetoma, Chagas disease, and leishmaniasis are discussed. As awareness increases among travelers, immigrants, and health care providers regarding imported tropical diseases, early intervention and proper diagnosis can ensue, thus reducing morbidity and mortality in affected individuals.     

Novel and sensitive ELISA for the rapid quantification of recombinant p64K protein

The antigenic P64k protein from the pathogenic bacterium Neisseria meningitidis has been used as an immunological carrier in several conjugated vaccines. The aim of this report was to develop and validate a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the quantification of recombinant p64k protein, to perform both manufacturing process and identification in different vaccine preparations. Validation studies were performed according to the guidelines of the International Conference of Harmonization (ICH). The reference curve showed to be precise and accurate over the entire linear range of 1.25 and 20ng/mL with a limit of quantification validated to 1.25ng/mL. The intra- and inter-assay coefficient of variation ranged from 0.35 to 6.65% and 4.70 to 10.63%, respectively. The ANOVA test used in the specificity/interference study revealed parallelism among curves (p>0.1), which indicates the lack of interference in the working range. Recovery obtained from the accuracy test, using three concentration levels, varied between 94 and 111%, confirming the assay's reliability. The short-term study shown the P64k is stable to -20°C up to 1-week. This ELISA was fully used to assess its manufacturing process and molecular interaction issues in several vaccine preparations. Thus, this immunoassay could be an excellent analytical choice to characterize the quality of that recombinant protein in several contexts as manufacturing process and molecular conjugates.     

Metastatic-promoting effects of LPS: sexual dimorphism and mediation by catecholamines and prostaglandins

Inflammation is implicated in several medical conditions that are sexually dimorphic, including depression, cardiovascular diseases, autoimmunity, and presumably cancer progression. Here we studied the effects of the proinflammatory agent, LPS, on MADB106 lung tumor retention (LTR), and sought to elucidate underlying mechanisms and sexual dimorphism. F344 male and female rats were administered with LPS (0.001-1mg/kg i.v.) simultaneously with tumor cell inoculation, and treated with a beta-blocker (nadolol, 0.2-0.3mg/kg s.c.), a COX inhibitor (indomethacin, 4mg/kg s.c.) or both drugs. To study the role of NK cells, numbers and cytotoxicity of marginating-pulmonary NK cells were studied, and selective in vivo NK-depletion was employed. Serum levels of corticosterone, IL-6, and TNF-alpha were also assessed. The findings indicated that LPS increased LTR in both sexes, but 10-fold higher doses were needed in females to reach the increase evident in males. Additionally, nadolol and indomethacin reduced the effects of LPS, more so in males. In vivo NK-depletion and ex vivo NK activity studies suggested that LPS affected LTR through both NK-independent and NK-dependent mechanisms, the latter mediated through prostaglandin release in males. Corticosterone, IL-6, and TNF-alpha responses to LPS were sexually dimorphic, but were not associated with LPS or drugs' impacts on LTR. Overall, our findings demonstrate sexual dimorphism in LPS-induced elevated susceptibility to MADB106 experimental metastasis, and in potential humoral underlying mechanisms. Further studies are needed to elucidate additional immunological and non-immunological mediators of these dimorphisms, as well as to assess their involvement in other sexually dimorphic pathologies that are associated with inflammation.     

The Relative Rate of Immunoglobulin Gamma 1 Fragmentation

The physicochemical stability of protein therapeutics is of significant pharmaceutical interest. Immunoglobulin gamma (IgG) hinge region fragmentation has recently garnered attention as an important degradation route of therapeutic monoclonal antibodies. In this work, the rates and relative amount of fragment species are compared for five different IgGs (IgG1–5) with widely varying solution properties. Native size-exclusion chromatography (SEC), sodium dodecyl sulfate (SDS)-based SEC, and capillary electrophoresis-SDS were used to characterize IgG1 fragmentation after storage at 30°C, 40°C, and 50°C. Two-dimensional correlation analysis of the chromatograms as a function of time was used to illustrate the relative rates of cleavage. Interestingly, the relative rate of Fab cleavage was greater than that of other species. An average apparent energy of activation for IgG1 fragmentation was also measured for all five molecules. This work suggests that IgG1 fragmentation is primarily hinge sequence dependent and other IgG1 molecules should behave similarly within the limits of the solution conditions used.     

Acquired Palmoplantar Keratoderma

Palmoplantar keratodermas (PPKs) are a diverse entity of disorders that are characterized by abnormal thickening of the skin on the palms and soles. Traditionally they have been classified as either hereditary or acquired and are distinguished from each other on the basis of mode of inheritance, presence of transgrediens (defined as contiguous extension of hyperkeratosis beyond the palmar and/or plantar skin), co-morbidities with other symptoms, and extent of epidermal involvement, namely diffuse, focal, and punctate. As the terms hyperkeratosis and keratoderma have been used interchangeably throughout the literature, we define acquired keratoderma as a non-hereditary, non-frictional hyperkeratosis of the palms and/or soles that involves >/=50% of the surface of involved acral areas and that may or may not be associated with clinical and histologic inflammation. Given the numerous possible underlying causes for acquired PPKs, evaluation of patients presenting with acquired PPK can be a perplexing task. To facilitate such evaluations, this review categorizes the acquired PPKs as: keratoderma climactericum, drug related, malnutrition associated, chemically induced, systemic disease related, malignancy associated, dermatoses related, infectious, and idiopathic. In order to avoid the possibility of overlooking an underlying etiology and to eliminate excessive testing, we present an algorithm for assessing patients presenting with acquired PPK. The first step should include a comprehensive history and a physical examination, including a complete skin examination. If findings are consistent with a hereditary keratoderma, then a genetics consultation should be considered. Any findings suggestive of underlying conditions should be aggressively evaluated and treated. If no pertinent findings are identified after a history and a physical examination, laboratory and radiology studies should be undertaken in a systematic, logical fashion. In terms of treatment, the most successful results occur when the underlying etiology is diagnosed and treated. If no such etiology is evident, then conservative treatment options include topical keratolytics (urea, salicylic acid, lactic acid), repeated physical debridement, topical retinoids, topical psoralen plus UVA, and topical corticosteroids. Etretinate and acitretin have also shown some success as alternative treatments in recalcitrant cases.     

Examining the Efficacy and Safety of Squaric Acid Therapy for Treatment of Recalcitrant Warts in Children

The objective of the study was to determine the safety and efficacy of squaric acid dibutyl ester (SADBE) therapy on the treatment of recalcitrant warts in children. This retrospective chart review examined 72 patients treated using SADBE from July 2002 to December 2012. Patients were followed for 6 months to 11 years. Patients were treated at a pediatric dermatology outpatient clinic at the University of North Carolina at Chapel Hill. Seventy‐two children with verrucae who failed initial treatment for warts were selected for the study. Full long‐term follow‐up was obtained in 48 patients. Four patients discontinued the use of SADBE because of adverse effects. The primary study outcome was efficacy of SADBE treatment. Adverse effects, dosages administered, type of wart, other cutaneous disease present, and level of immunosuppression were measured. Forty of 48 (83%) patients in whom treatment outcomes could be obtained reported complete resolution of their warts. Seventy percent of patients used a maximum concentration of 0.4% SADBE and 60% of patients reported no adverse effects. The majority of patients treated with SADBE reported complete resolution of warts. Most patients reported no adverse effects even while receiving doses as high as 2% daily. This study shows that SADBE is a safe and effective treatment for recalcitrant warts in children.     

Involvement of Extracellular Signal-Regulated Kinase (ERK1/2)-p53-p21 Axis in Mediating Neural Stem/Progenitor Cell Cycle Arrest in Co-Morbid HIV-Drug Abuse Exposure

Neurological complications in opioid abusing Human Immunodeficiency Virus-1 (HIV-1) patients suggest enhanced neurodegeneration as compared to non-drug abusing HIV-1 infected population. Neural precursor cells (NPCs), the multipotent cells of the mammalian brain, are susceptible to HIV-1 infection and as opiates also perturb their growth kinetics, detailed mechanistic studies for their co-morbid exposure are highly warranted. Using a well characterized in vitro model of human fetal brain-derived neural precursor cells, we investigated alterations in NPC properties at both acute and chronic durations. Chronic morphine and Tat treatment attenuated proliferation in NPCs, with cells stalled at G1-phase of the cell cycle. Furthermore HIV-Tat and morphine exposure increased activation of extracellular signal-regulated kinase-1/2 (ERK1/2), enhanced levels of p53 and p21, and decreased cyclin D1 and Akt levels in NPCs. Regulated by ERK1/2 and p53, p21 was found to be indispensible for Tat and morphine mediated cell cycle arrest. Our study elaborates on the cellular and molecular machinery in NPCs and provides significant mechanistic details into HIV-drug abuse co-morbidity that may have far reaching clinical consequences both in pediatric as well as adult neuroAIDS.