Sarcoidosis: correlation of pulmonary parenchymal pattern at CT with results of pulmonary function tests

The appearances of the lungs on radiographs and computed tomographic (CT) scans were correlated with degree of uptake on gallium scans and results of pulmonary function tests (PFTs) in 27 patients with sarcoidosis. CT scans were evaluated both qualitatively and quantitatively. Patients were divided into five categories on the basis of the pattern of abnormality at CT: 1 = normal (n = 4); 2 = segmental air-space disease (n = 4); 3 = spherical (alveolar) masslike opacities (n = 4); 4 = multiple, discrete, small nodules (n = 6); and 5 = distortion of parenchymal structures (fibrotic end-stage sarcoidosis) (n = 9). The percentage of the volume judged to be abnormal (CT grade) was correlated with PFT results for each CT and radiographic category. CT grades were also correlated with gallium scanning results and percentage of lymphocytes recovered from bronchoalveolar lavage (BAL). Patients in CT categories 1 and 2 had normal lung function, those in category 3 had mild functional impairment, and those in categories 4 and 5 showed moderate to severe dysfunction. The overall CT grade correlated well with PFT results expressed as a percentage of the predicted value. In five patients, CT scans showed extensive parenchymal disease not seen on radiographs. CT grades did not correlate with the results of gallium scanning or BAL lymphocytes. The authors conclude that patterns of parenchymal sarcoidosis seen at CT correlate with the PFT results and can be used to indicate respiratory impairment.     

Protein tyrosine kinase inhibitors alter human dopamine transporter activity in Xenopus oocytes

The dopamine (DA) transporter (DAT) regulates dopaminergic synaptic transmission by controlling extracellular levels of DA. Thus, understanding signaling mechanisms that alter DAT function is critical for understanding dopaminergic neurotransmission. We have expressed the human DAT (hDAT) in Xenopus laevis oocytes to test the hypothesis that protein tyrosine kinases (PTKs) acutely regulate DAT function by altering cell surface expression of the transporter. Using a relatively high concentration of DA (10 microM), we found that several PTK inhibitors, namely, genistein, lavendustin A, and tyrphostin 25 (10 microM), decreased DA uptake velocity by 58, 41, and 30% of control, respectively. Furthermore, genistein potently inhibited DA uptake with a K(i) = 68 nM. Kinetic analysis confirmed that genistein decreased the V(max) of the DAT, with no change in K(m). The effects of PTK inhibition on hDAT-associated currents were also measured. All three PTK inhibitors attenuated substrate transport-associated currents to similar extents as DA uptake. In contrast, the potent Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) did not significantly inhibit either DA uptake or transport-associated currents. PTK inhibitors decreased hDAT-associated leak currents, however in a more variable manner than for uptake and transport-associated currents. Genistein also decreased cell surface binding of [(3)H]WIN 35,428 to hDAT by 48% of control. Together, these data provide several lines of evidence suggesting that PTK inhibition rapidly reduces hDAT activity via redistribution of the transporter away from the cell surface. Thus, PTKs likely represent another component of cellular signaling cascades that acutely regulate neurotransmitter transporters.     

Mortality of Tuberculosis in Very Old People

OBJECTIVES: To describe the clinical characteristics and outcomes of tuberculosis (TB) in elderly people.
DESIGN: Observational analysis of a prospective cohort of adults with TB (1995–2004). A case–control study to determine attributable mortality to TB in very old people was done.
RESULTS: Of 319 patients with TB, 109 (34.2%) were aged 65 and older. The older group was more likely to have comorbidities (1.4% vs 0.4%; P <.001), extrapulmonary and disseminated TB (50.4% vs 26.1%; P <.001), toxicity (22% vs 9.8%; P =.006), and 30-day mortality (18.3% vs 1.6%; P <.001). When patients aged 65 to 79 were compared with those aged 80 and older, only differences in TB-related mortality were detected (9.8% vs 44.4%; P =.01). In the attributable mortality analysis, 30-day and 6-month mortality were higher in very old patients with TB than in controls without TB (41.7% vs 11.1%, P =.005; 45.8% and 19.4%, P =.01, respectively). No differences in mortality were shown when excluding patients with postmortem TB diagnosis or those who died within the first 72 hours of diagnosis.
CONCLUSION: Older people with TB had a higher frequency of atypical features, more adverse drug reactions, and greater TB-related mortality than younger people. Data suggest that very old patients with TB have higher mortality, but if diagnosed early and adequately treated, very old patients with TB do not have greater mortality than those without.     

Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels

BACKGROUND & AIMS: Patients with chronic hepatitis C and persistently normal alanine aminotransferase (ALT) levels have been routinely excluded from large randomized treatment trials; consequently, the efficacy and safety of antiviral therapy in this population are unknown. METHODS: Patients with at least 3 normal ALT values over an 18-month period were randomized (3:3:1) to treatment with peginterferon alfa-2a 180 mug/wk plus ribavirin 800 mg/day for 24 weeks (212 patients), the same combination for 48 weeks (210 patients), or no treatment (69 patients) in a multinational study. All patients were monitored for 72 weeks. The primary measure of efficacy was sustained virologic response (SVR), defined as undetectable serum hepatitis C virus (HCV) RNA by qualitative polymerase chain reaction at the end of 24 weeks of untreated follow-up. RESULTS: No patient cleared HCV RNA in the untreated control group. SVR rates of 30% and 52% were obtained in the 24- and 48-week treatment groups, respectively. In patients infected with HCV genotype 1, SVR rates of 13% and 40% were obtained with 24 and 48 weeks of treatment, respectively (P < .0001). In patients infected with genotypes 2 or 3, SVR rates were 72% and 78% with 24 and 48 weeks of treatment, respectively (P = .452). Treatment-related flares in ALT activity were not observed. CONCLUSIONS: The efficacy and safety of peginterferon alfa-2a and ribavirin combination therapy in patients with chronic hepatitis C and persistently normal ALT levels are similar to that in patients with elevated ALT levels. The indication for treatment of hepatitis C can be evaluated independently from baseline ALT activity.     

Lack of an effect of age on beta-adrenoceptor-mediated lipolysis in isolated human adipocytes

We examined the effect of age on the beta-adrenoceptor response in adipocytes that contain both beta 1- and beta 2-adrenoceptors. Twelve healthy young and 12 old subjects on a 150 mEq/24 h sodium diet underwent gluteal fat biopsies. Isolated adipocytes from all the subjects were stimulated with increasing concentrations of isoproterenol for glycerol release. In 13 of the subjects (7 young and 6 old), we also performed beta-adrenoceptor binding studies on adipocyte membranes. In addition in eight subjects (four young and four old), we also utilized a competitive binding assay to calculate the percent of beta-adrenoceptors that were of the beta 1 subtype. Our data showed that old subjects, when treated under identical conditions as the young subjects prior to fat biopsy, did not demonstrate any differences in the beta-adrenoceptor stimulated lipolysis. The Vmax of lipolysis was 10.6 +/- 1.4 nmoles glycerol/mg lipid/2 h in the young group and 9.9 +/- 1.1 in the old group. The concentrations of isoproterenol that resulted in Vmax and 1/2 Vmax were also the same in the two age groups. The addition of 8-cyclopentyl-1,3-dimethylxanthine (CPT), a specific A1-adenosine receptor antagonist, resulted in mild but equivalent enhancement of glycerol release in both age groups. The beta-adrenoceptor numbers and affinities from adipocyte membranes did not demonstrate age-related differences either (Bmax 106 +/- 17 fmol/mg of protein in the young, and 137 +/- 27 in the old; Kd 79.6 +/- 21.3 pM in the young and 81.9 +/- 16.6 in the old). The percent of beta 1-adrenoceptors on the adipocyte membranes was also similar in the two age groups (35.2 +/- 2.6% in the young; 37.1 +/- 4.5% in the old). In conclusion, we could not demonstrate any differences in the beta-adrenoceptor responses from peripheral adipocytes that contain both beta 1- and beta 2-adrenoceptors, in a group of healthy elderly and young subjects who were subjected to identical dietary and orthostatic conditions prior to the biopsy. These data suggest that neither beta 1- nor beta 2-adrenoceptor responses in human adipocytes show significant changes due to aging.     

Acute cocaine differentially alters accumbens and striatal dopamine clearance in low and high cocaine locomotor responders: behavioral and electrochemical recordings in freely moving rats

Behavioral responses of rodents to cocaine are characterized by marked individual variability. Here, outbred male Sprague-Dawley rats were profiled based on concomitant recording of behavioral and electrochemical responses. Rats were categorized as either low or high cocaine responders (LCRs or HCRs, respectively) based on their differential locomotor responsiveness to an acute, low-dose injection of cocaine (10 mg/kg i.p.). LCRs and HCRs also differed in other cocaine-induced behaviors. The role of the dopamine transporter (DAT) in mediating the behavioral differences in cocaine responsiveness in LCRs and HCRs was investigated by high-speed chronoamperometric recording of exogenous dopamine (DA) clearance signals in nucleus accumbens (NAc) and dorsal striatum (dSTR). Higher volumes of DA were required in NAc of HCRs, than of LCRs, to produce equivalent peak DA signal amplitude (A(max)) responses. In HCRs, systemic cocaine administration evoked an immediate and prolonged 2-fold augmentation in A(max) in both brain regions, coincident with locomotor activation. The cocaine-induced decrease in the efficiency of DA clearance (k) in NAc of HCRs was more immediate and prolonged than in dSTR, where the transient decrease coincided with maximal stereotypic behavior. In contrast, in LCRs, A(max) was not altered by cocaine, and decay rate constant (k) was transiently attenuated only in dSTR. Correlation analyses of individual responses revealed that cocaine-induced changes in DA clearance signal parameters accounted for 20 to 40% of the variation in behavioral responsiveness to cocaine. Overall, our findings emphasize the importance of characterizing individual responses to understand more fully the range of functional consequences resulting from DAT inhibition.