Terbinafine-induced cholestatic liver disease

Hepatobiliary disorders associated with orally administered terbinafine have rarely been reported. We describe a case of prolonged terbinafine-induced cholestatic liver disease. Extrahepatic cholestasis, viral hepatitis and autoimmune liver disorders were excluded. The histological findings of marked cholestasis without evidence of extrahepatic biliary obstruction or acute hepatitis were compatible with the diagnosis of drug-induced liver disease. Biochemical parameters of liver cell damage returned to normal levels 6 months later.     

COPD Assessment Test: A Simple Tool to Evaluate Disease Severity and Response to Treatment

The COPD assessment test (CAT) is a short questionnaire designed to assess the impairment in health status of COPD patients. We aimed to determine the change of the CAT in COPD patients after 1 year of treatment and test the association between the score and clinical and lung function variables. Methods A cohort of 111 newly diagnosed COPD patients in primary care was evaluated at baseline and one year after the implementation of the recommended treatment according to the Global Initiative for the management of COPD (GOLD). Results Most of the patients (82%) were diagnosed with mild to moderate airflow limitation (mean FEV₁ 72 ± 21.5% predicted) and the CAT score increased in proportion with the GOLD stage of severity. The CAT significantly correlated with the number of exacerbations, visits to general practitioners and days of hospitalization both at the beginning and at 1 year follow-up. A strong negative correlation between the CAT score and FEV₁ predicted was also observed. The CAT was responsive to the application of treatment with a significant improvement in the mean score (95% confidence interval) following 12 months of treatment by –2.4 (–2.9, –1.9) despite the small decline in lung function indices. The number of exacerbations in the preceding year and FEV₁ were independent predictors of the CAT score in the general linear model. Conclusion The CAT questionnaire may serve as a simple, measurable tool complementary to spirometry in the assessment of severity and of response to treatment in unselected COPD patients in primary care.     

Reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy with a peak incidence over the age of 55 years. AML of older patients is less curable with conventional chemotherapy, and, when it relapses, is almost uniformly fatal. Novel treatments hold the promise of improving the results of therapy, but have failed so far to show dramatic change in the prognosis. Allogeneic stem cell transplantation using traditional myeloablative preparative regimens is not easily tolerated by the elderly and/or frailer patient, and may lead to prohibitive treatment-related mortality rates. Most patients treated in the past were younger and devoid of comorbid clinical conditions. Novel reduced-intensity regimens made allogeneic transplants applicable to the elderly, providing the benefit of the graft-versus-leukemia effect to a larger number of patients in need. Here we review the indications for allogeneic transplants in AML and discuss reduced-intensity conditioning regimens.     

Conjunctival surface changes in patients with Sjogren's syndrome: a transmission electron microscopy study

PURPOSE: To demonstrate the ultrastructural appearance of the conjunctival surface epithelium in patients with Sj?gren's syndrome (SS) compared with normal subjects. METHODS: Conjunctival tissue specimens from seven normal subjects and eight patients with SS were obtained by bulbar conjunctival biopsy and examined by transmission electron microscopy. RESULTS: The average number of microvilli per 8.3 microm epithelial length was significantly lower in the SS group than that in the control group (19.6 +/- 2.5 vs. 28.0 +/- 3.4, P < 0.0001). The microvillus height (0.539 +/- 0.151 microm) and height-width ratio (1.825 +/- 0.549) in the conjunctival epithelium in the SS group were significantly lower than those (height: 0.946 +/- 0.117 microm, P < 0.001; and height-width ratio: 3.717 +/- 0.696, P < 0.0001) in normal individuals. The microvilli in the SS group were wider than those in the control group (P = 0.003). Furthermore, the average number of secretory vesicles (per 8.3 microm epithelial length) in the apical conjunctival epithelial cell was significantly reduced in the SS group (16.4 +/- 6.8 vesicles), compared with the control group (34.7 +/- 1.2 vesicles, P = 0.003). In addition, although the ocular surface glycocalyx (OSG) was always present in control subjects, it was not detectable in all but one of the SS conjunctival specimens. CONCLUSIONS: The ultrastructural morphology of the apical conjunctival epithelium is altered in patients with SS. The findings suggest that an intact OSG may play a key role in the maintenance of a healthy ocular surface, possibly by preventing abrasive influences on the apical epithelial cells.     

Time of neuron origin and gradients of neurogenesis in midbrain dopaminergic neurons in the mouse

Previous [³H]thymidine studies in Nisslstained sections in rats established that the substantia nigra pars compacta and the ventral tegmental area originate sequentially according to an anterolateral to posteromedial neurogenetic gradient. We investigated whether that same pattern is found in mice in the dopaminergic neurons in each of these structures. Using tyrosine hydroxylase immunostaining combined with [³H]thymidine autoradiography, the time of origin of dopaminergic midbrain neurons in the retrorubral field, the substantia nigra pars compacta, the ventral tegmental area, and the interfascicular nucleus was determined in postnatal day 20 mice. The dams of the experimental animals were injected with [³H]thymidine on embryonic days (E) 11–E12, E12–E13, E13–E14, and E14–E15. The time of origin profiles for each group indicated significant differences between populations. The retrorubral field and the substantia nigra pars compacta arose nearly simultaneously and contained the highest proportion of neurons, 49 to 37%, generated on or before E11. Progressively fewer early-generated neurons were found in the ventral tegmental area (20%), and the interfascicular nucleus (8.5%). In addition, anterior dorsolateral neurons in the substantia nigra and ventral tegmental area were more likely to be generated early than the posterior ventromedial neurons. These findings indicate that mouse and rat brains have nearly identical developmental patterns in the midbrain, and neurogenetic gradients in dopaminergic neurons are similar to those found in Nissl studies in rats.     

Restless legs syndrome/Willis–Ekbom disease prevalence in beta thalassemia patients

Sleep and Breathing - Both beta thalassemia and restless legs syndrome (RLS) patients share some common pathophysiological characteristics related to iron handling. In the present study, the aim...     

Inflammation and cardiovascular disease

Cardiovascular disease (CVD) has been associated with the so-called traditional risk factors, such as hypertension, hypercholesterolemia and cigarette smoking. Chronic inflammation, exemplified by elevated high sensitivity C-reactive protein, has been added to these risk factors for CVD as non-traditional risk factor. There are two aspects in this association. The first is whether inflammation plays a pathogenic role in traditional risk factors-mediated CVD or it is just an epiphenomenon. The second is whether chronic inflammation caused by an inflammatory disease has any impact on CVD. Accumulated data have shown that inflammation has a central and inciting role in the development of atherosclerosis leading to increased CVD risk. How inflammation contributes to CVD is a topic of continuous research where mechanisms involving both innate and adaptive immune pathways are involved. Endothelial dysfunction, oxidative stress in vascular endothelial cells, macrophage accumulation, formation of inflammasome, production of tumor necrosis factor (TNF)-a, IL-1 and IL-6 characterize the inflammatory process leading to atherogenesis. Recently clonal hematopoiesis of indeterminate potential represents a surprising and novel mechanism underlying atherogenesis. Data from chronic rheumatic inflammatory diseases exemplify the complexity of mechanisms leading to increased CVD, while they also provide evidence that anti-inflammatory biologic drugs, such as anti-TNF and anti-IL6 agents, could control atherogenesis and ameliorate CVD risk. Recent groundbreaking work using biologic anti-IL-1b therapy to treat men and women who have had a prior heart attack provides the best proof of the pathogenic contribution of inflammation in the development of CVD.     

Protective effect of atorvastatin in cultured osteoarthritic chondrocytes

The aim of our study was to evaluate the in vitro effect of an HMG‐CoA reductase inhibitor, atorvastatin, on the expression of significant anabolic and catabolic genes in human osteoarthritic chondrocytes and to explore the metabolic pathways involved in this process. Human articular osteoarthritic chondrocytes were cultured in the presence and absence of atorvastatin (10 and 50 µmol/L) for 24 h. Metalloproteinase 13 (MMP‐13), collagen type II (COL2A1), and aggrecan (AGC) mRNA expression levels were evaluated by real‐time PCR, and protein expression levels by Western blot analysis. IL‐1β levels in culture medium was analyzed with ELISA. The effect of the treatment with the mevalonate isoprenoid derivatives farnesol and geranylgeraniol, or the cholesterol precursor squalene, was evaluated in the atorvastatin osteoarthritic chondrocyte cultures. Incubation of osteoarthritic chondrocyte cultures with atorvastatin produced a significant dose‐dependent reduction in IL‐1β production. Atorvastatin supplementation in cultures produced a decrease in MMP‐13 mRNA and protein expression levels, which was reversed by the addition of farnesol. Regarding AGC and COL2A1 mRNA expression, a significant increase was observed only in chondrocytes cultures treated with 50 µmol/L atorvastatin. Our findings suggest that atorvastatin may have potential chondroprotective effects mostly by reducing cartilage degradation. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:110–115, 2010