Short communication: liver toxicity of lopinavir-containing regimens in HIV-infected patients with or without hepatitis C coinfection

Liver toxicity is a common side effect of antiretroviral therapy, particularly in subjects coinfected with the hepatitis C virus (HCV). The incidence of severe liver toxicity after initiation of treatment with lopinavir (LPV) as well as its possible association with LPV plasma levels were assessed in 120 HIV-infected patients (52% coinfected by HCV). The incidence of severe liver toxicity at 3 months was 1.7% and the cumulative incidence at 12 months was 4%. The development of severe liver toxicity was associated with HCV coinfection but not with LPV plasma levels.     

Risperidone in the treatment of patients with delirium

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of risperidone in the treatment of patients with delirium. METHOD: We conducted a prospective, multicenter, observational 7-day study in 5 university general hospitals. Sixty-four patients (62.5% male [N = 40]; mean age: 67.3 +/- 11.4 years) hospitalized due to a medical condition who met criteria for delirium according to DSM-IV were enrolled in the study. Fifty-six patients received 7 days of treatment or less, while 8 patients continued treatment for more than 7 days. Effectiveness was assessed using the Trzepacz Delirium Rating Scale (DRS), the positive subscale of the PANSS (PANSS-P), the Mini-Mental State Examination (MMSE), and the Clinical Global Impressions scale (CGI). Safety assessment included the UKU Side Effect Rating Scale. Risperidone was administered at the time of diagnosis, and treatment was maintained according to clinical response. Response to treatment was defined as a reduction in DRS score to below 13 within the first 72 hours. Data were gathered from April to December 2000. RESULTS: Risperidone (mean dose = 2.6 +/- 1.7 mg/day at day 3) was effective in 90.6% (58/64) of the patients and significantly improved all symptoms measured by the scales from baseline to day 7 (mean scores: DRS, 22.5 +/- 4.6 at baseline to 6.8 +/- 7.0 at day 7; PANSS-P, 21.5 +/- 8.8 to 10.1 +/- 7.3; MMSE, 13.1 +/- 10.9 to 26.4 +/- 8.9; and CGI, 4.5 +/- 0.9 to 1.9 +/- 1.2) (Friedman test, p <.001 in all cases). Two patients (3.1%) experienced adverse events, but none showed extrapyramidal symptoms. CONCLUSIONS: Low-dose risperidone proved to be a safe and effective drug in the treatment of symptoms of delirium in medically hospitalized patients. These data provide the rationale for a prospective randomized controlled trial.     

Corticosterone strongly increases the affinity of dorsal raphe 5-HT1A receptors

The effects of corticosterone (10 mg/kg, s.c., 6 h) on dorsal raphe 5-HT1A autoreceptors have been studied in adrenalectomized rats with or without porcine galanin modulation. Adrenalectomy diminishes 5-HT1A autoreceptors affinity. Corticosterone increases 5-HT1A autoreceptor agonist affinity (+90%, p<0.001) in adrenalectomized rats. Galanin (10 nM) increases dorsal raphe 5-HT1A autoreceptor density (+65%, p<0.05) and its Kd value (+248%, p<0.05) only in adrenalectomized rats treated with corticosterone. Dorsal raphe glucocorticoid receptors activation by corticosterone may therefore lead to an increased signalling of 5-HT1A autoreceptors that may become counteracted by galanin receptor activation. Glucocorticoids, by enhancing dorsal raphe 5-HT1A autoreceptor function, may therefore cause reduced 5-HT neuronal activity and thus lead to a depressive state.     

Absence of Meissner corpuscles in the digital pads of mice lacking functional TrkB

The TrkB-expressing sensory neurons seem to be involved in touch and other discriminative sensibilities. Thus, several slowly and rapidly adapting cutaneous mechanoreceptors, as well as muscle spindles, are reduced or absent in the territory of the trigeminal nerve in functionally TrkB-deficient mice. Whether this also occurs in the cutaneous or muscular territories of dorsal root ganglia has not been analyzed. Here we used immunohistochemistry and transmission-electron microscopy to analyze the impact of a mutation in the gene coding for TrkB on Meissner and Pacinian corpuscles, and muscle spindles. The animals were studied at the post-natal days 15 and 25, because at this time all the mechanoreceptors examined are fully developed. Typical Meissner's corpuscles, displaying S-100 protein immunoreactivity, were found in the digital pads of wild-type and TrkB+/- mice whereas they were absent in the TrkB-/- animals. Regarding Pacinian corpuscles, the mutation in the trkB gene does not alter either the immunohistochemical or the ultrastructural characteristics. Finally, in muscle spindles the arrangement of the intrafusal muscle fibers and nerve fibers was unchanged in the mutated animals. Nevertheless, about 10% of muscle spindles showed increased number of the intrafusal cells (between 6 and 12) and were supplied by more than one large myelinic nerve fiber. The present results strongly suggest that TrkB-expressing sensory neurons in dorsal root ganglia, like those of the trigeminal ganglion, are responsible for the development and maintenance of several rapidly adapting cutaneous mechanoreceptors, i.e. Meissner's corpuscles.     

Purging behaviors and comorbidity as predictive factors of quality of life in anorexia nervosa

OBJECTIVE: This study examined the predictive factors for the physical and mental summary components (PCS and MCS) of quality of life (SF-36) in patients with anorexia nervosa. METHOD: Forty-seven patients with anorexia nervosa were studied. Assessment comprised psychiatric diagnosis by a clinical structured interview for Axis I disorders (SCID-I) and personality disorders (SCID-II), Clinical Global Impression (CGI), and Quality of Life (SF-36). RESULTS: Anorexia nervosa, restrictive type, was diagnosed in 73.9% of the patients and 51% of the patients presented with comorbidity on Axis I or Axis II or both. The predictive variables for the PCS were poor outcome in previous year, comorbidity on Axes I and II, and female gender. The predictive variables for the MCS were the presence of comorbidity in one or the other of the Axis I or II disorders and purging behaviors. DISCUSSION: The current study suggests the importance of comorbidity and purging behaviors in the quality of life of these patients with anorexia nervosa.     

Telomerase is frequently activated in tumors with microsatellite instability

Telomeres are specialized structures at the ends of eukaryotic chromosomes that are required for the complete replication and stability of naturally occurring chromosome ends. Telomere stabilization is critical for the unlimited cellular proliferation that is necessary for tumor formation. While most tumors achieve telomere stabilization through activation of telomerase, a subset of tumors utilize a recombination-based mechanism termed Alternative Lengthening of Telomeres (ALT) to maintain chromosome termini. Tumors utilizing ALT for telomere preservation will likely be refractory to treatment with telomerase inhibitors. Furthermore, tumors carrying mutations that predispose a cell to utilize ALT may activate this pathway when challenged by telomerase inhibition. Mutation of the mismatch repair (MMR) pathway enhances telomerase independent survival in yeast, with the survivors using recombination-based pathways for telomere maintenance. One possibility is that mutation of the MMR pathways alleviates suppression of recombination, thereby abrogating the need for telomerase activation. If true, one might predict an increased frequency of tumors harboring MMR mutation to use ALT for telomere maintenance. Here we characterized tumors with and without MMR mutation for the presence of telomerase activity versus ALT. We found similarly frequent activation of telomerase in tumors with and without MMR mutation, suggesting that human tumors with MMR mutation may respond favorably to treatment with telomerase inhibitors.     

Acquired and inherited thrombophilia in women with unexplained fetal losses

OBJECTIVE: The purpose of this study was to investigate the possible role of inherited and acquired thrombophilia in women with unexplained abortions and intrauterine fetal death. STUDY DESIGN: We included 75 women with >/=1 unexplained fetal loss, and 75 control subjects with at least 1 healthy term infant and without gestational complications. All of these women were tested for mutations of factor V Leiden, methylenetetrahydrofolate reductase, and prothrombin gene; deficiencies of antithrombin-III, protein C, and protein S; and the presence of antiphospholipid antibodies and fasting homocysteine concentration. A placental histologic study was also carried out. RESULTS: Thirty-five percent of the 75 patients had thrombophilia (control subjects, 16%; P =.008; odds ratio, 2.78). This prevalence was more prominent in second and third trimesters (P =.0002; odds ratio, 6.3), and the presence of combined genetic defects was associated with intrauterine fetal death (P =.04; odds ratio, 12; 95% CI, 1.44-102). When we analyzed the overall gestations of the patients, we observed an increase of intrauterine fetal death in patients with thrombophilia (P =.01) and early pregnancy loss in patients without thrombophilia (P =.02). The analysis of the correlation between extensive placental infarctions and thrombophilic defects rendered values in the boundaries of significance (P =.05). CONCLUSION: The significant high prevalence of biologic causes in patients with late fetal loss suggests that a study of thrombophilia should be carried out, together with an assessment of a preventive treatment.     

Disparity in total hip replacement affecting Hispanic Medicare beneficiaries

OBJECTIVE: To compare the utilization of total hip replacement (THR) between Hispanic persons and non-Hispanic persons in a sample with health insurance. RESEARCH DESIGN: Case-control study using Medicare claims data. PATIENTS: The cases were Medicare beneficiaries from Arizona, Illinois, New Mexico, or Texas who underwent a primary THR. The controls were Medicare beneficiaries who did not receive a THR, matched by age, sex, and county of residence. MEASURES: Beneficiary surnames and the race indicator in Medicare records were used to classify beneficiaries' probability of being Hispanic. Conditional logistic regression was used to estimate the odds of receiving of THR, adjusting for Medicaid eligibility. RESULTS: Six thousand four hundred thirty-seven recipients of a primary THR were matched to 12,874 controls. According to the Medicare race indicator, 1% of recipients of THR and 3.3% of controls were Hispanic (P < or =0.001). The odds of THR decreased as the probability of Hispanic ethnicity increased, from an odds ratio (OR) of 1.00 among beneficiaries with non-Hispanic surnames, to an OR of 0.36 among those with heavily Hispanic surnames (95% CI, 0.31, 0.43). Poverty, as reflected by eligibility for Medicaid, did not modify the low odds of THR among Hispanic persons (OR, 0.25 among Medicaid-eligible Hispanic persons; 95% CI, 0.19, 0.33; and OR, 0.30 among Hispanic persons not Medicaid eligible; 95% CI, 0.24, 0.38). CONCLUSION: Hispanic persons with Medicare receive THR at lower rates than do non-Hispanic persons. Because Medicare covers THR, our findings suggest that under utilization of THR by Hispanic persons cannot be attributed to lack of health insurance alone.