The ability of PK 8165, a quinoline derivative, to reduce responses to a stressful situation in a double-blind study in man

A double-blind and cross-over study was carried out in order to explore the effects of PK 8165 (a quinoline derivative) on the heart rate, respiratory rate and motor reflex responses produced by an experimental model of stress in 8 healthy volunteers. The stress was induced by repetitive sequences of anticipation of pain (stressful stimulus: S) spaced by resting periods (R). In a control session, the cumulative effects of S resulted, in all subjects, in a progressive increase in heart and respiratory rates; 5 subjects showed a cumulative facilitation in the H reflex (motor reflex response) while the 3 others exhibited a cumulative depression in this motor parameter as a function of repetition of S during the session. The three doses (50, 100, 150 mg) of PK 8165 produced a very significant dose-dependent reduction in these responses during both stressful periods and resting sequences. Furthermore, the baseline values of respiratory and especially heart rate were also significantly reduced in a dose-dependent fashion by PK 8165. In contrast, the treatment with placebo did not significantly modify these parameters, compared to control values. The functional implications of these data are discussed in terms of stress-induced activation of some CNS structures and of the possible mechanisms of the "anti-stress" effect of PK 8165.     

Prostate cancer presentation,treatment selection,and outcomes among men with HIV/AIDS: A clinical stage,race, and age-matched contemporary analysis

PurposeTo compare the clinical presentation, treatment receipt, and oncologic outcomes between human immunodeficiency virus-seropositive (HIV+) and seronegative (HIV?) men with prostate cancer (CaP) matched by age, clinical stage, and race.Materials and methodsA retrospective review of 3,135 men treated for CaP from 2000 to 2016 was performed. HIV+ patients (N = 46) were matched 1:2 to 3 to HIV? men (N = 137) by age, race, and clinical stage. Clinicopathologic features and primary treatment received were compared between cohorts. Associations between HIV status and progression-free, cancer-specific, and overall survival were compared by HIV status using the Kaplan-Meier method and Cox proportional hazards analysis.ResultsAfter matching, men with and without HIV were similar with respect initial prostate-specific antigen, Gleason Sum, and Eastern Cooperative Oncology Group (ECOG) performance status. Among HIV+ men, 67.4% had a history of acquired immune deficiency syndrome, and 91.3% were on highly active antiretroviral therapy at CaP diagnosis. Among men with localized disease, HIV+ men were more likely to receive radiation (59.5% vs. 44.8%) or no therapy (13.5% vs. 4.3%) and less likely to receive surgery (16.2% vs. 30.2%), or to initiate active surveillance (10.8% vs. 16.4%; P = 0.04 overall). There were no differences in rates of clinical progression, development of castration resistance, or CaP death by HIV status. However, HIV+ status was associated with inferior overall survival (hazard ratio 2.89, P = 0.04).ConclusionsWhile most HIV+ patients had a history of acquired immune deficiency syndrome; HIV was well controlled in the majority of patients at the time of CaP diagnosis. While oncologic outcomes were similar between HIV+ and HIV? men, significant differences in treatment selection were observed. Further research is necessary to understand differences in treatment election by HIV status and to define optimal CaP treatment selection in men with HIV.     

Telomerase and telomere inhibitors in preclinical development

Telomerase is an enzyme required by actively dividing cells to maintain the ends of chromosomes (telomeres). It is present in germline tissue, stem cells and cancer cells, but is repressed in somatic cells. Efforts are underway to exploit this selective expression of telomerase in cancer therapeutics. This review describes the status of telomerase research, which although at present predominantly preclinical, has the potential to enter clinical research.     

Decrease of mucosal glutamine concentration in the nutritionally depleted patient

A diminished glutamine delivery by peripheral tissues is suggested to play an important role in the etiology of postoperative complications of nutritionally depleted patients. Decreased glutamine supply to the gut mucosa in these nutritionally depleted patients may have important consequences for the integrity of the gut mucosa barrier. To evaluate whether glutamine concentration in the gut mucosa of depleted patients is altered, patients with either a fat-free mass index below 90% or percentage ideal body weight below 90% as a result of weight loss were studied. 22 patients admitted to the University Hospital Maastricht and 14 controls were studied. After an overnight fast, venous blood was sampled and duodenal biopsies were obtained by endoscopy. Plasma and tissue amino acids were measured. Fat-free mass was determined by bioelectrical impedance measurement. In 10 depleted patients glutamine concentration in the duodenal mucosa was 2883 +/- 250 mumol/kg dry weight. Concentration of alanine was 2570 +/- 263 mumol/kg dry weight. In the non-depleted patients glutamine and alanine concentrations were respectively 3463 +/- 171 mumol/kg dry weight and 3540 +/- 315 mumol/kg dry weight. Concentrations in controls were 3296 +/- 176 mumol/kg dry weight for glutamine and 3682 +/- 372 mumol/kg dry weight for alanine. Concentrations for alanine and glutamine were significantly lower in depleted patients compared to non-depleted patients (p < 0.05). Also, alanine and glutamine concentrations were significantly correlated with percentage ideal body weight (r=0.43, p < 0.005 for glutamine and r=0.62, p < 0.001 for alanine) and fat-free mass index (r=0.42, p < 0.05 for glutamine and r=0.48, p < 0.01 for alanine) This study suggests that in patients depletion appears to be related to decreased plasma and mucosa glutamine and alanine concentrations.     

Activity of the morpholino anthracycline 3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin (MX2) against human tumor colony-forming unitsin vitro

Summary In several preclinical systems, the morpholino anthracycline MX2 has greater antitumor activity than doxorubicin, is less cardiotoxic, and is effective against multidrug resistant cancer cells. We used a human tumor soft-agar cloning assay to test the cytotoxicity of MX2 against single cell suspensions from freshly obtained human tumors. Tumor cells were exposed to MX2 at 0.05 and 0.5 g/ml either for 1 hour (201 specimens; 77 [38%] assessable) or continuously (231 specimens; 91 [39%] assessable). Superior antitumor activity was observed with continuous exposure (19%in vitro response at 0.05 g/ml and 69% at 0.5 g/ml) than with 1-hour exposure (1.3% at 0.05 g/ml and 12% at 0.5 g/ml). Activity was seen against all types of cancer tested including renal (91%), melanoma (88%), ovarian (73%), breast (71%) and non-small-cell lung (67%) cancer at a MX2 concentration of 0.5 g/ml after continuous exposure. If appropriate plasma levels can be achieved in patients, MX2 could have significant clinical activity in patients with those tumors.     

The effect of encapsulated soluble fiber on carohydrate metabolism during exercise

Previous investigations have reported that soluble fiber reduces the plasma glucose and insulin changes after an oral glucose load. To improve the palatability of a soluble-fiber feeding, this study addressed how a combined, soluble fiber (delivered in capsule form) and a preexercise CHO feeding would affect metabolic responses during exercise. On 3 different days, participants ingested a placebo (CON), 75 g liquid CHO (GLU), or 75 g liquid CHO with 14.5 g encapsulated guar gum (FIB) 45 min before cycling for 60 min at 70% VO2 peak. Peak concentrations of plasma glucose and insulin were similar and significantly greater than CON preexercise (p < 05). Similarities in carbohydrate reliance were observed in GLU and FIB. Muscle glycogen use did not differ significantly among trials. These results demonstrate that encapsulated soluble fiber delivered with liquid CHO feeding does not affect plasma glucose, insulin, or muscle glycogen utilization during exercise.     

Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte transketolase activity and thiamin pyrophosphate effect

BACKGROUND AND AIMS: The aim of the study was to determine the thiamin status in HIV-positive patients. METHODS: Measurement of erythrocyte transketolase activity (ETK) and thiaminpyrophosphate (TPP) effect in 55 consecutive HIV-positive patients of a specialized outpatient clinic were grouped into five groups according to their CD4 counts. Comparison of results of HIV-positive patients with age-matched control group of 22 healthy subjects. RESULTS: Of the patients, 27% had a pathologically-increased TPP effect, 18% of the patients had pathologically-low ETK. The percentage of pathological values of TPP effect in the patients was significantly higher compared with the control group. There was no statistically significant correlation between pathological thiamin status and stage of the disease, zidovudine therapy or nutritional status of the patients. CONCLUSIONS: Thiamin deficiency in HIV-positive patients was found in a higher percentage than previously reported. Thiamine deficiency is not only present in advanced stages of HIV-infection, but also in clinically asymptomatic patients.     

Assessment of physical activity and sleep by actigraphy: examination of gender differences

Research evidence suggests that actigraphy is a very important instrument in documenting sleep/wake patterns of people with a variety of sleep disorders or motor dysfunctions. The present actigraphic investigation examined physical activity and sleep profiles as a function of gender in volunteers monitored in their natural environment. Irrespective of age, women exhibited better sleep quality than did men. This was demonstrated by higher sleep efficiency index and lower frequency of transitions between sleep and wakefulness. Additionally, women slept more than men and had shorter sleep onset latency. However, no significant gender effect on daytime activity level and circadian activity amplitude was observed.