Targeted mass treatment for syphilis with oral azithromycin

From mid 1997 to end of 1999, there was a sexually-transmitted infectious syphilis outbreak mainly in heterosexual people in British Columbia, Canada, that was concentrated in Vancouver. The rate across the province increased from less than 0.5 to 3.4 per 100000, and the rate in Vancouver reached 12.9 per 100000. We aimed to eliminate the syphillis outbreak by treating people at risk of infection. In 2000, a targeted mass treatment programme provided azithromycin (1.8 g orally) to 4384 at-risk residents in this city. After the programme, syphilis frequency fell significantly for 6 months (p=0.016), but rose again in 2001. Results from curve fitting analyses showed that the number of cases in 2001 (177) was higher than expected (0.0001相似文献   

Rapid intravenous loading of levodopa for human research: clinical results

Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P<0.0005).     

Early posthatch starvation induces myonuclear apoptosis in chickens

The effect of early posthatch starvation on myonuclear apoptosis was examined in chickens. Male broiler chickens were or were not provided feed for the first 3-d posthatch. Subsequently, all chickens were provided feed for an additional 4-d posthatch. Chickens were killed at 3- and 7-d posthatch, and the pectoralis thoracicus was harvested, fixed and embedded in paraffin. Muscle sections were labeled with the terminal deoxynucleotidyl transferase histochemical staining technique to identify apoptotic nuclei. At 3- and 7-d posthatch, there was a significantly (P < 0.05) smaller myofiber cross-sectional area for the starved compared with the fed chickens. A larger proportion (P < 0.05) of apoptotic nuclei relative to total nuclei was observed in the starved compared to the fed chickens killed at 3-d posthatch, but the proportion of apoptotic nuclei relative to total nuclei did not differ (P > 0.05) between the starved and fed chickens killed at 7-d posthatch. It appears that apoptosis is a mechanism contributing to the smaller myofiber size observed when feed is not provided early posthatch.     

Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects

Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system, and a key neurotransmitter in prefrontal cortical function. Converging lines of evidence implicate prefrontal cortical dysfunction in the neurobiology of schizophrenia. Thus, aberrant glutamate neurotransmission may underlie schizophrenia and other complex disorders of behavior. Group II metabotropic receptors (mGluRs) are important modulators of glutamatergic and non-glutamatergic neurotransmission. Moreover, in an animal model, an agonist for group II mGluRs has been shown to reverse the behavioral, locomotor, and cognitive effects of the psychotomimetic drug phencyclidine. Accordingly, group II mGluRs constitute attractive targets for the pharmacotherapeutics and study of schizophrenia. Using immunocytochemistry and Western immunoblotting, we compared the localization and levels of group II mGluRs in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects. Consistent with previous reports, we found that immunolabeling of group II mGluRs is prominent in Brodmann's area 46. The majority of labeling was present on axon terminals distributed in a lamina-specific fashion. No apparent difference in the cellular localization or laminar distribution of immunoreactive group II mGluRs was noted between the two diagnostic groups. Similarly, the levels of receptor immunoreactivity determined by quantitative Western immunoblotting were comparable between schizophrenic patients and normal subjects. We conclude that while the function of group II mGluRs in Brodmann's area 46 of dorsolateral prefrontal cortex may be altered in patients with schizophrenia, this is not evident at the level of protein expression using an antibody against mGluR2 and mGluR3.     

Coincident inactivation of 14-3-3sigma and p16INK4a is an early event in vulval squamous neoplasia

The structure and expression of 14-3-3 sigma(sigma) was analysed in squamous carcinomas (SCC) of the vulva and in the vulval pre-malignant lesion vulval intraepithelial neoplasia (VIN). Sequence analysis of the sigma coding region did not detect mutations in any case of SCC or VIN III and loss of heterozygosity (LOH) occurred in only 2 out of 27 informative cases. In contrast to the absence of genetic change, methylation-specific PCR (MSP) analysis revealed dense CpG methylation within the sigma gene in approximately 60% of cases of vulval SCC, but methylation was not detected in matched, normal epithelial tissue. Methylation was associated in all cases with reduced or absent expression of sigma mRNA. There was no correlation between sigma methylation and HPV or p53 status. Analysis of pre-malignant vulval intraepithelial neoplasia (VIN) revealed that sigma methylation was detectable early in neoplastic development. Co-incident methylation, accompanied by loss of expression, of sigma and p16INK4a was commonly detected in both SCC and VIN III, suggesting that epigenetic silencing of these two genes is an early and important event in vulval neoplasia.     

Effect of pregnancy on heart rate/oxygen consumption calibration curves

PURPOSE: The purpose of this investigation was to determine heart rate (HR)/oxygen consumption (VO2) calibration curves for exercising and sedentary women during pregnancy and the postpartum periods. METHODS: Fifty-two women were studied at three time points: 20 wk gestation, 32 wk gestation, and 12 wk postpartum. Subjects were grouped either as regular exercisers (N = 27) or sedentary controls (N = 25). At each time point, each woman had HR and VO2 measured at rest (lying, seated, and standing) as well as during steady-state treadmill exercise performed at three increasing intensities. Flex HRs were defined and calculated by averaging the value seen during the lowest exercise intensity and highest value during rest. Individual HR/VO2 calibration curves were generated for exercise at each time point. Statistical analyses of all dependent variables included comparisons of subject groups (exercise and sedentary) and pregnancy status (20 wk, 32 wk, and 12 wk postpartum). RESULTS: Resting VO2 (mL.kg-1.min-1) was approximately 6.5% greater during pregnancy compared with postpartum conditions (P < 0.005). Also, both resting and flex HRs were greater during pregnancy compared with postpartum (P < 0.01). Resting HR was lower in exercising women compared with sedentary controls at all time points (P < 0.01). Slopes of HR/VO2 regression curves were flatter during pregnancy (P < 0.005), but there was no difference between groups. Y-intercepts were less at 20 wk compared with 36 wk postpartum. CONCLUSIONS: A woman's HR, VO2, and the relationship between these two parameters are altered during pregnancy. Change in slope of HR/VO2 regression curves indicates less energy expenditure at a given HR as pregnancy progresses, compared with postpartum conditions. A woman's true energy expenditure would be overestimated at rest, and underestimated during physical activity, if these physiological changes are not taken into account.     

Intravesical pH: a potentially important variable affecting efficacy and the further development of anthracycline chemotherapy for superficial bladder cancer

OBJECTIVE: To assess, using epirubicin-sensitive and multidrug resistant (MDR) derivatives of human bladder cancer cell lines in vitro, the probable effect of intravesical pH changes, with and without the MDR antagonist verapamil, on the uptake, intracellular distribution and cytotoxicity of epirubicin during intravesical chemotherapy. MATERIALS AND METHODS: Incubations for cytotoxicity testing were carried out in buffered medium containing epirubicin, at pH values of 6.0-8.5, with verapamil where appropriate. The cytotoxicity of epirubicin, with and without verapamil, was determined using the tetrazolium cytotoxicity assay. Intracellular epirubicin fluorescence was assessed using flow cytometry and confocal microscopy. Flow cytometric total intracellular epirubicin fluorescence was measured at pH 6.0, 6.4, 6.8, 7.2, and 7.6, and confocal microscopy was carried out at pH 6.0 and 8.0. The MDR-reversing agent verapamil was added at 100 micro g/mL to some incubations. RESULTS: Epirubicin cytotoxicity in resistant cell lines appears considerably enhanced by adding verapamil and further improved, especially in MDR cells, by alkalinization of the drug solution to pH 8.0. Flow cytometry results showed striking and consistent differences in epirubicin handling with pH. Sensitive cells can be induced to absorb considerably more drug at alkaline pH, whilst resistant cells show no such behaviour. Nuclear drug fluorescence was greater in sensitive cells at alkaline pH, but cytoplasmic drug fluorescence in the resistant cells was little changed by pH. Adding verapamil to resistant cells restored the sensitive phenotype of drug handling. CONCLUSION: Buffering epirubicin to an alkaline pH before intravesical application should increase its intrinsic cytotoxicity. The potential for synergy at certain drug combinations will be enhanced by applying these findings. MDR reversal and fatty acid augmentation of drug uptake are discussed as examples.