Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine

To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied human immunodeficiency virus-seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of isoniazid were associated with failure/relapse with once-weekly isoniazid/rifapentine (median isoniazid area under the concentration-time curve for 12 hours after the dose [AUC(0-12)] was 36 microg x hour/ml in failure/relapse versus 56 microg x hour/ml in control cases p = 0.005), but not with twice-weekly isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly isoniazid/rifapentine (p = 0.03) but not twice-weekly isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine.     

Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression.

OBJECTIVES: This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. BACKGROUND: Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). METHODS: The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. RESULTS: Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. CONCLUSIONS: Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.     

Production of interleukin-18 in human tuberculosis

To investigate the role of interleukin (IL)-18 in human tuberculosis, IL-18 production was evaluated in blood and at the site of disease in patients with tuberculosis. Mycobacterium tuberculosis-stimulated peripheral blood mononuclear cells (PBMC) from tuberculosis patients secreted less IL-18 and interferon-gamma (IFN-gamma) than did PBMC from healthy persons reactive to tuberculin. M. tuberculosis-induced IFN-gamma production was inhibited by anti-IL-18 and enhanced by recombinant IL-18. Alveolar macrophages secreted IL-18 in response to M. tuberculosis, and IL-18 and IFN-gamma concentrations were higher in pleural fluid of patients with tuberculosis than in pleural fluid of patients with nontuberculous diseases. These findings demonstrate that IL-18 production by PBMC correlates with IFN-gamma production and effective immunity to tuberculosis, suggesting that IL-18 contributes to a protective type 1 cytokine response in persons with mycobacterial infection.     

Shear Wave Elastography of Peripheral Muscle Weakness in Patients with Chronic Congestive Heart Failure

Forty-five study participants (28 chronic heart failure [CHF] patients and 17 control participants) were prospectively enrolled in this study to investigate the clinical potential of ultrasound shear wave elastography (SWE) in identifying peripheral muscle weaknesses in chronic heart failure patients. Muscle stiffness in the gastrocnemius muscle during extension (stretch) and the lower arm flexor muscles during flexion was assessed via shear wave elastography, measuring the shear modulus (kPa) for the resting and contractile states in a range of 0–300 kPa. Resting kPa revealed no significant difference between CHF and CP, but exercise kPa for extension and flexion was significantly lower in CHF than CP. The area under the receiver operating characteristic curve of the denominator kPa-Exercise stretch was 0.916, associated with a sensitivity of 89%, a specificity of 71% and a corresponding cutoff value of 81.1 kPa. Shear wave elastography is thus a reproducible and sensitive ultrasound method for evaluating peripheral muscle deficits in patients with CHF.     

Tuberculosis control in a border state. Treatment of the foreign-born

As the epidemiology of TB in the United States changes, with more foreign-born and fewer native-born residents developing the disease, treatment can be expected to become more complicated and expensive.     

Rehabilitation of therapy-related cognitive deficits in patients after hematopoietic stem cell transplantation

Neuropsychological deficits are potential side effects of hematopoietic stem cell therapy (HSCT). Systematic data on the long-term course of and therapeutic options for these consequences are limited. One hundred fifty-seven patients were screened for cognitive deficits following HSCT for malignant diseases at an in-patient oncologic rehabilitation clinic. Patients showing evidence of impairment were randomly assigned to one of two training groups: individualized PC-supported training or neuropsychological group therapy. The control group consisted of patients who received no specific training. During in-patient rehabilitation, the results of a comprehensive neuropsychological test battery improved significantly in all three groups, and no specific intervention effects were identified. Neuropsychological deficits were still evident in a subgroup of patients 6 months later. Correlation between neuropsychological testing and patients' self-evaluation of cognitive functioning in daily life was generally low. Sustained attention and verbal-semantic memory played the main role for self-appraisal and in the designation as 'neuropsychologically impaired'. In conclusion, a substantial number of patients revealed evidence of cognitive deficits a long time after HSCT. There is a need for more studies and for the development of differentiated rehabilitative measures for such therapeutic consequences.     

Dielectric constant of atomic fluids with variable polarizability

The Clausius-Mossotti function for the dielectric constant is expanded in terms of single atom and pair polarizabilities, leading to contributions that depend on both the trace and the anisotropy of the pair-polarizability tensor. The short-range contribution of the anisotropic part to the pair polarizabilities has previously been obtained empirically from light scattering experiments, whereas the trace contribution is now empirically determined by comparison to dielectric experiments. For helium, the short-range trace part agrees well with electronic structure calculations, whereas for argon qualitative agreement is achieved.