Hypokalemia among patients receiving treatment for multidrug-resistant tuberculosis

INTRODUCTION: Between January 1999 and December 2000, 125 patients in Lima, Peru were enrolled in individualized treatment for multidrug-resistant tuberculosis (MDR-TB). Hypokalemia was observed to be an important adverse effect encountered in this cohort. OBJECTIVE: To identify risk factors associated with the development and persistence of hypokalemia during MDR-TB therapy, and to review the incidence and management of hypokalemia in patients receiving MDR-TB therapy. METHODS: A retrospective case series of 125 patients who received individualized therapy for MDR-TB between January 1, 1999, and December 31, 2000. RESULTS: Among 115 patients who were screened for electrolyte abnormalities, 31.3% had hypokalemia, defined as a potassium level of < 3.5 mEq/L. Mean serum potassium at time of diagnosis was 2.85 mEq/L. Diagnosis of low serum potassium occurred, on average, after 5.1 months of individualized therapy. Multivariate analysis of risk factors for this adverse reaction identified two causes: administration of capreomycin, and low initial body weight. Normalization of potassium levels was achieved in 86% of patients. CONCLUSIONS: Electrolyte disturbance was frequently encountered in our cohort of patients with MDR-TB. Successful screening and management of hypokalemia was facilitated by training the health-care team in the use of a standardized algorithm. Morbidity from hypokalemia can be significant; however, effective management of this side effect is possible without sacrificing MDR-TB treatment efficacy.     

Effects of spatial transformation on regional brain volume estimates

Spatial transformation of MR brain images is a standard tool used in automated anatomical parcellation and other quantitative and qualitative methods to assess brain tissue volume, composition, and distribution. Despite widespread use, the quantitative effects of spatial transformation on regional brain volume estimates have been little studied. We report on the effects of transformation on regional brain volumes of 38 (17M, 21F) manually parcellated brains. After tracing in native space, regions of interest were transformed using a classic piecewise-linear Talairach transformation (Tal) or a nonlinear registration (AIR 5th order nonlinear algorithm, 158 parameters) to one of three Talairach-based templates: 1) Tal50, constructed from 50 Talairach-transformed normal brains, 2) the MNI 305 atlas, 3) IA38, constructed from MNI305-transformed scans of the 38 subjects used in this study. Native volumes were compared to the transformed volumes. We found that: 1) significant group-level differences can be obtained in transformed data sets that are in the opposite direction of effects obtained in native space; 2) the effects of transformation are heterogeneous across brain regions, even after covarying for total brain volume and age; 3) volumetric intra-class correlations between native and transformed brains differ by registration method and template choice, region, and tissue type; and 4) transformed brains produced hippocampus and corpus callosum volume proportions that were significantly different from those obtained in native space. Our results suggest that region-based volumetric differences uncovered by spatial-transformation-based methods should be replicated in native-space brains, and that meta-analyses should take into account whether volumes are determined using spatially-transformed images and/or specific automated methods.     

Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade

Capsaicin, the active ingredient in some pain-relieving creams, is an agonist of a nonselective cation channel known as the transient receptor potential vanilloid type 1 (TRPV1). The pain-relieving mechanism of capsaicin includes desensitization of the channel, suggesting that TRPV1 antagonism may be a viable pain therapy approach. In agreement with the above notion, several TRPV1 antagonists have been reported to act as antihyperalgesics. Here, we report the in vitro and in vivo characterization of a novel and selective TRPV1 antagonist, N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide I (AMG 517), and compare its pharmacology with that of a closely related analog, tert-butyl-2-(6-([2-(acetylamino)-1,3-benzothiazol-4-yl]oxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate (AMG8163). Both AMG 517 and AMG8163 potently and completely antagonized capsaicin, proton, and heat activation of TRPV1 in vitro and blocked capsaicin-induced flinch in rats in vivo. To support initial clinical investigations, AMG 517 was evaluated in a comprehensive panel of toxicology studies that included in vivo assessments in rodents, dogs, and monkeys. The toxicology studies indicated that AMG 517 was generally well tolerated; however, transient increases in body temperature (hyperthermia) were observed in all species after AMG 517 dosing. To further investigate this effect, we tested and showed that the antipyretic, acetaminophen, suppressed the hyperthermia caused by TRPV1 blockade. We also showed that repeated administration of TRPV1 antagonists attenuated the hyperthermia response, whereas the efficacy in capsaicin-induced flinch model was maintained. In conclusion, these studies suggest that the transient hyperthermia elicited by TRPV1 blockade may be manageable in the development of TRPV1 antagonists as therapeutic agents. However, the impact of TRPV1 antagonist-induced hyperthermia on their clinical utility is still unknown.     

A Follow-up Analogue Study on the Effectiveness of the Cognitive Rationale

Cognitive Therapy (CT) for depression presents a rationale for symptom reduction early in treatment. The rationale is described in lay terms as an ABC sequence, such that A represents a recent event, B represents automatic thoughts about the event, and C represents the resulting affective response. A previous study (Kanter, J. W., Kohlenberg, R. J., & Loftus, E. F. (2004). Cognitive Therapy and Research, 28, 229) that compared the CT rationale to an alternative (by flipping the terms of ABC into an ACB theory in which affect is assumed to proceed and cause cognition) suggested that the CT rationale may operate through demand characteristics because the alternative was equally influential. However, that study did not allow for the possibility that demand characteristics were differentially operative (perhaps one rationale produced real changes in identification of automatic thoughts while the other produced demand responding). The current study extended the previous study by manipulating demand characteristics directly and by adding a 1-week follow-up condition. Results indicate that the influence of the cognitive rationale is robust and, in contrast to the previous study, may not be dependent on demand characteristics.

Cytogenetic abnormalities additional to t(11;14) correlate with clinical features in leukaemic presentation of mantle cell lymphoma, and may influence prognosis: a study of 60 cases by FISH

Mantle cell lymphoma (MCL), characterised by t(11;14)(q13;q32), has a poor prognosis. Many cases have additional cytogenetic abnormalities, and often have a complex karyotype. Fluorescence in situ hybridisation (FISH) was used to study 60 cases with leukaemic presentation of MCL, to determine the frequency, clinical correlations and prognostic impact of a panel of molecular cytogenetic abnormalities: 17p13 (TP53 locus), 13q14, 12 p11.1-q11 (centromere), 6q21 and 11q23. CD38 expression, of prognostic value in chronic lymphocytic leukaemia (CLL), was also studied, and correlations with clinical and cytogenetic abnormalities sought. Eighty per cent of cases had at least one abnormality in addition to t(11;14). Deletions at 17p13 (TP53) and 13q14 were most frequent and involved the majority of the leukaemic clone. Cases with TP53 deletion were more likely to have splenomegaly and marked leucocytosis (>30 x 10(9)/l), and less likely to have lymphadenopathy than those without deletion. Deletions at 11q23 and 6q21 were associated with extranodal disease. 13q14 and 11q23 deletions showed a trend towards worse prognosis by univariate analysis. In multivariate analysis, deletions at 13q14 and 6q21 were independent predictors of poor outcome. Deletion at 17p13 did not show prognostic impact in this series. CD38, positive in two-thirds of cases, was associated with male gender and nodal disease but not with any cytogenetic abnormality, or with survival.     

Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, increased ventricular stiffness and impaired diastolic filling. We investigated to what extent myocardial functional defects can be explained by alterations in the passive and active properties of human cardiac myofibrils. Skinned ventricular myocytes were prepared from patients with obstructive HCM (two patients with MYBPC3 mutations, one with a MYH7 mutation, and three with no mutation in either gene) and from four donors. Passive stiffness, viscous properties, and titin isoform expression were similar in HCM myocytes and donor myocytes. Maximal Ca²⁺-activated force was much lower in HCM myocytes (14 ± 1 kN/m²) than in donor myocytes (23 ± 3 kN/m²; P < 0.01), though cross-bridge kinetics (k_tr) during maximal Ca²⁺ activation were 10% faster in HCM myocytes. Myofibrillar Ca²⁺ sensitivity in HCM myocytes (pCa₅₀ = 6.40 ± 0.05) was higher than for donor myocytes (pCa₅₀ = 6.09 ± 0.02; P < 0.001) and was associated with reduced phosphorylation of troponin-I (ser-23/24) and MyBP-C (ser-282) in HCM myocytes. These characteristics were common to all six HCM patients and may therefore represent a secondary consequence of the known and unknown underlying genetic variants. Some HCM patients did however exhibit an altered relationship between force and cross-bridge kinetics at submaximal Ca²⁺ concentrations, which may reflect the primary mutation. We conclude that the passive viscoelastic properties of the myocytes are unlikely to account for the increased stiffness of the HCM ventricle. However, the low maximum Ca²⁺-activated force and high Ca²⁺ sensitivity of the myofilaments are likely to contribute substantially to any systolic and diastolic dysfunction, respectively, in hearts of HCM patients.     

Validation and abbreviation of an HIV stigma scale in an adult spanish-speaking population in urban Peru

The purpose of this study was to validate the Spanish version of the Berger HIV Stigma Scale in an urban Spanish-speaking population in Peru and create a valid and reliable abridged version of the scale. Participants were HIV-infected adults enrolled in an observational study to examine the effectiveness of a community-based antiretroviral therapy adherence intervention. Approximately half of participants were female, and the median age at enrollment was 30.5 years. The Spanish version of the full HIV Stigma Scale was internally reliable, demonstrated good construct validity, and was sensitive to change over time. The full HIV Stigma Scale was abbreviated by removing items that impaired subscale internal reliability, did not correlate with other subscale items, or demonstrated low factor correlations. The resulting abridged scale contained 21 of the 40 original items and revealed properties similar to the full Spanish version.     

Sex-related differences in heart failure

Heart failure (HF) is a complex syndrome that is generally defined as cardiac output not adequate to meet the circulatory demands of the body. HF is at the end of the continuum of cardiovascular disease and preceded by an initiating event such as myocardial infarction, untreated hypertension, idiopathic cause, congenital heart disease, or pulmonary hypertension. In recent years, research has revealed differences in various aspects of HF between men and women including risk factors, pathophysiology, clinical manifestations, and response to treatment. Therefore, the purpose of this review is to review these sex-related differences between men and women who live with HF.