Bactericidal Activity in Whole Blood as a Potential Surrogate Marker of Immunity after Vaccination against Tuberculosis

The development of new tuberculosis (TB) vaccines will require the identification of correlates of human protection. This study examined the balance between immunity and virulence in a whole blood infection model in which intracellular mycobacterial survival was measured using BACTEC. In the blood of tuberculin-negative donors, counts of Mycobacterium tuberculosis H₃₇Ra organisms fell by 0.14 log₁₀ CFU during 96 h of whole blood culture, whereas counts of Mycobacterium bovis BCG, M. tuberculosis H₃₇Rv, and a clinical TB isolate's organisms increased by 0.13, 0.43, and 1.04 log₁₀ CFU, respectively (P < 0.001), consistent with their relative virulence. Inhibition of tumor necrosis factor alpha by the addition of methylprednisolone or pentoxifylline or removal of CD4⁺ or CD8⁺ T cells by magnetic beads had deleterious effects on immune control of intracellular growth only in the blood of tuberculin-positive donors. Repeated vaccination of eight tuberculin-negative volunteers with M. bovis BCG resulted in a 0.3 log (50%) reduction in BCG CFU counts in the model compared to baseline values (P < 0.05). Three of the volunteers responded only after the second vaccination. These experiments indicate that whole blood culture may be used to measure immunity to M. tuberculosis and that further studies of repeated BCG vaccination are warranted.     

Micafungin Population PK Analysis in Healthy and Septic Pigs: Can the Septic Porcine Model Predict the Micafungin PK in Septic Patients?

Pharmaceutical Research - To describe micafungin pharmacokinetic (PK) alterations of sepsis induced in piglets and to determine whether the porcine septic model is able to predict the PK of...     

Antagonism of the effects of 5-hydroxytryptamine on the rabbit isolated vagus nerve by BRL 43694 and metoclopramide

Summary Depolarization and reduction in the C fibre compound action potential (C spike) in response to 5-HT were recorded simultaneously from rabbit isolated vagus nerve. 5-HT (0.1–100 mol/l) was applied cumulatively and EC₅₀ and IC₅₀ values measured from individual concentration-response curves. Blockade of 5-HT responses by the 3-indazole carboxamide, BRL 43694, was investigated and compared with the blocking action of metoclopramide. BRL 43694 was a selective antagonist of 5-HT responses. A concentration of 10 nmol/l BRL 43694, which nearly abolished the depolarization and reduction of the C spike evoked by 5-HT (100 mol/l), had no effect on similar responses evoked by DMPP (100 mol/l) or GABA (100 mol/l). Blockade of 5-HT responses by BRL 43694 (0.3 nmol/l) was slow in onset, a plateau blockade occurring after equilibrium of tissue with antagonist for 2 to 3 h. Metoclopramide induced a blockade of rapid onset. The maximal blockade was apparent within 30 min of application. Full recovery in the responsiveness of the tissue to 5-HT was observed within 30 min of washing out metoclopramide. BRL 43694 at concentrations of 0.3, 1, 3 and 10 nmol/l caused a progressive rightward shift of the concentration-response curves to 5-HT. At the highest concentration of antagonist, there was some depression of the maximal 5-HT response. The apparent pA₂ estimated from the Schild equation was 10.03 ± 0.09 (mean ± SEM, n = 20) against 5-HT depolarization and 10.31 ± 0.1 against C spike reduction. Schild plots had slopes not significantly different from 1.0. The slopes and extrapolated pA₂ fitted by linear regression were 0.91 (0.58 – 1.24) and pA₂ 10.16 (9.74–10.58; mean and 95% confidence levels) for the depolarizations. For reduction in C spikes the slope was 0.74 (0.39–1.08) with a pA₂ of 10.86 (10.24–11.49). There was no apparent use-dependent element to the blockade by BRL 43694. Blockade of 5-HT depolarization or C spike reduction by BRL 43694 (0.3 nmol/l) was not significantly different on repeated testing in the presence of the antagonist or without testing of 5-HT until 3 h incubation had elapsed. Metoclopramide at concentrations of 0.3, 1, 3, or 10 mmol/l progressively shifted concentration-response curves to the right. However, the response maximum, especially that for depolarization, was enhanced in the presence of the antagonist. The apparent pA₂ values from the Schilde equation were 7.04 ± 0.04 (n = 20) against 5-HT depolarization and 7.13 ± 0.06 (n = 16) against C spike reduction. Schild plots had slopes significantly less than unity. The lines fitted to the relationship gave pA₂ values of 7.41 (7.25–7.57) with a slope of 0.79 (0.69–0.9) against depolarization and 7.63 (7.28–7.97) with a slope of 0.74 (0.54–0.93) against C spike reduction. Metoclopramide at concentrations above 30 mol/l directly reduced C spike amplitude; the IC₅₀ for the local anaesthetic action was 158 ± 40 mol/l (mean ± SEM). It is concluded that BRL 43694 is a potent and selective antagonist of 5-HT₃ receptors on the rabbit vagus nerve. At concentrations below 10 nmol/l, BRL 43694 appeared to behave as a competitive antagonist while at 10 nmol/l the antagonism was unsurmountable, suggesting a pseudo-irreversible antagonism due to slow dissociation of antagonist from the receptor. Although metoclopramide behaved as a surmountable antagonist, the low slope of the Schild plots and the increase in maximal response amplitude in the presence of the antagonist are unexplained features of its blocking action.Send offprint requests to D. I. Wallis at the above address     

Disparities in prostate cancer screening,diagnoses, management,and outcomes between Indigenous and non-Indigenous men in a universal health care system

Background

Indigenous Peoples have higher morbidity rates and lower life expectancies than non-Indigenous Canadians. Identification of disparities between Indigenous and non-Indigenous men regarding prostate cancer (PCa) screening, diagnoses, management, and outcomes was sought.

Methods

An observational cohort of men diagnosed with PCa between June 2014 and October 2022 was studied. Men were prospectively enrolled in the province-wide Alberta Prostate Cancer Research Initiative. The primary outcomes were tumor characteristics (stage, grade, and prostate-specific antigen [PSA]) at diagnosis. Secondary outcomes were PSA testing rates, time from diagnosis to treatment, treatment modality, and metastasis-free, cancer-specific, and overall survivals.

Results

Examination of 1,444,974 men for whom aggregate PSA testing data were available was performed. Men in Indigenous communities were less likely to have PSA testing performed than men outside of Indigenous communities (32 vs. 46 PSA tests per 100 men [aged 50–70 years] within 1 year; p < .001). Among 6049 men diagnosed with PCa, Indigenous men had higher risk disease characteristics: a higher proportion of Indigenous men had PSA ≥ 10 ng/mL (48% vs. 30%; p < .01), TNM stage ≥ T2 (65% vs. 47%; p < .01), and Gleason grade group ≥ 2 (79% vs. 64%; p < .01) compared to non-Indigenous men. With a median follow-up of 40 months (interquartile range, 25–65 months), Indigenous men were at higher risk of developing PCa metastases (hazard ratio, 2.3; 95% CI, 1.2–4.2; p < .01) than non-Indigenous men.

Conclusions

Despite receiving care in a universal health care system, Indigenous men were less likely to receive PSA testing and more likely to be diagnosed with aggressive tumors and develop PCa metastases than non-Indigenous men.     

Pilot process and outcome evaluation of the introduction of a clinical nutrition pathway in the care of in-hospital renal patients.

OBJECTIVE: Our objective was to investigate the effect of in-service education and the use of a clinical decision-making pathway on nurses' knowledge related to nutritional needs of renal patients and referrals to a dietitian. DESIGN: This was a before-and-after evaluation study of the effect of the implementation of a clinical nutrition pathway on nurses' knowledge and dietitian referrals. SETTING: The setting was a renal in-patient unit in southeast Queensland, Australia. PARTICIPANTS: There were two groups of participants. Part 1 consisted of 53 registered nurses working in the renal unit of a regional general hospital, and Part 2 consisted of the medical records of two cohorts of more than 100 patients admitted to the renal unit. INTERVENTION: A clinical nutrition pathway and a resource package were developed to support nurses' decision-making related to the nutritional care of renal patients. Thirty-minute in-service education sessions were conducted to explain the use of the pathway, and to develop nurses' confidence in dietary decision-making for renal patients. MAIN OUTCOME MEASURES: The main outcome measures consisted of the nurses' knowledge of nutritional interventions with renal patients and the frequency of dietitian referrals. RESULTS: The nurses' knowledge increased, and referrals to dietitians remained constant. CONCLUSIONS: In-service education and access to unit-based resources, including a decision-support clinical nutrition pathway, improved nurses' knowledge of nutritional care for renal patients. Nurses continued to refer patients for dietitian consultation after the intervention.