Clinical oxidative stress during leprosy multidrug therapy:impact of dapsone oxidation

This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.518±0.029 μg/mL) and paucibacillary (0.662±0.123 μg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDTsupervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software

Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. METHODS AND FINDINGS: A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)-glycoprotein (GP)-specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%-100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264-908), 556 (95% CI: 280-1,101), 1,245 (95% CI: 899-1,724), and 1,503 (95% CI: 931-2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647-1,591), 1,887 (1,154-3,085), 1,445 (1,013-2,062), and 3,958 (2,249-6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025-1,989), and children, 1,620 (95% CI: 806-3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. CONCLUSIONS: Our data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000919191

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation

Thyrotoxic periodic paralysis

Thyrotoxic periodic paralysis (TPP), a disorder most commonly seen in Asian men, is characterized by abrupt onset of hypokalemia and paralysis. The condition primarily affects the lower extremities and is secondary to thyrotoxicosis. It has been increasingly reported in the USA due to the rise in the immigrant population. Hypokalemia in TPP results from an intracellular shift of potassium induced by the thyroid hormone sensitization of Na + /K + -ATPase rather than depletion of total body potassium. Treatment of TPP includes prevention of this shift of potassium by using nonselective beta-blockade, correcting the underlying hyperthyroid state, and replacing potassium. TPP is curable once a euthyroid state is achieved. It is important for physicians to distinguish TPP from familial hypokalemic periodic paralysis, a more common cause of periodic paralysis in Caucasians. The absence of a family history of paralysis, male sex, presentation in the second to fourth decades of life, and signs of thyrotoxicosis like sinus tachycardia help in the diagnosis of this disorder. Early recognition of TPP is vital to initiating appropriate treatment and to avoiding the risk of rebound hyperkalemia that may occur if high-dose potassium replacement is given. T hyrotoxic periodic paralysis (TPP) is most common in Asian populations, with an incidence of approximately 2% in patients with thyrotoxicosis of any cause. It has been recognized in ais, Filipinos, Vietnamese, Koreans, Malaysians, Hispanics, African Americans, and Caucasians (1-5). TPP is characterized by acute onset of severe hypokalemia and profound proximal muscle weakness in patients with thyrotoxicosis (1). TPP is commonly misdiagnosed in western countries because of its similarities to familial periodic paralysis. Familial periodic paralysis is an autosomal dominant disorder caused by a defect in the gene coding for L-type calcium channel 1-subunit (CACNA1S) on chromosome 1q31-32 (2). e neuromuscular presentations of both are identical, and to enhance diagnosis of TPP, physicians need to look for subtle features of hyperthyroidism in the presence of hypokalemic periodic paralysis. Early diagnosis not only aids in definitive management with nonselective beta-blockers and correction of hyperthyroidism, but also prevents the risk of rebound hyperkalemia due to excessive potassium replacement. CASE REPORT A 33-year-old Hispanic man with a history of recurrent hypokalemia and muscle weakness presented to our emergency department with generalized muscle weakness more pronounced in his lower extremity. e patient's symptoms started in the early morning, and he was unable to walk to the bathroom. He had had similar episodes before and took potassium supplements sporadically. His initial episode of hypokalemia and paralysis had occurred 2 years earlier. He denied use of diuretics, laxatives, alcohol, or recreational drugs. He reported intermittent palpitations and diarrhea and had no family history of periodic paralysis. On physical examination, he had a mildly enlarged thyroid with firm consistency, an irregular heart rate, and decreased muscle strength and tendon reflexes in both lower extremities. He had no exophthalmos or sensory or cranial nerve deficits. In the emergency department, his initial potassium level was 1.7 mEq/L (reference range, 3.6-5.0 mEq/L) with normal acid-base status. His serum phosphorus level was 4.0 mg/dL (reference range, 2.7-4.5 mg/dL), and his serum magnesium level was 1.4 mg/dL (reference range, 1.7-2.6 mg/dL) on admission. Urine potassium per 24 hours was 83 mmol/day (reference range, 25-125 mmol/day), and an electrocardiogram showed atrial fibrillation with a ventricular rate of 90 beats per minute. An initial diagnosis of periodic hypokalemic paralysis was made. He was given 40 mEq of intravenous potassium chloride in the emergency department and was then started on a normal saline infusion with 20 mEq/L of potassium. He was also placed on an oral potassium replacement protocol, which resulted in resolution of his lower-extremity paralysis. On the second day of admission, his serum potassium level increased to 4.8 mEq/L; serum phosphorus, to 4.2 mg/dL; and serum magnesium, to 1.6 mg/dL. e results of a computed tomography scan of his abdomen were normal, and his reni

Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides

A number of structural analogues of the known toxicant para- aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia - with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20; compound 6 metHb% = 74.1 ± 2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10-16) and cyclic (17-20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30-32, sulfoxide 33, sulfone 34 and sulfonamides 35-36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity