The physiological regulation of toll-like receptor expression and function in humans

Eleven mammalian toll-like receptors (TLRs 1–11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14⁺ monocytes following activation with specific TLR ligands was greater ( P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34°C). Strenuous exercise resulted in a decrease ( P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14⁺ monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14⁺ monocytes following activation with specific TLR ligands was decreased ( P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.     

The effect of sweetness on the efficacy of carbohydrate supplementation during exercise in the heat.

The aim of the present study was to investigate potential mechanisms responsible for the improvement in prolonged exercise capacity in hot environments with exogenous carbohydrate. Eight endurance-trained men (VO(2)max 60.5 +/- 2.4 ml.kg(-1).min(-1), mean +/- SE) cycled to exhaustion on three occasions at 60% VO(2)max at an ambient temperature of 35 degrees C. They ingested either a sweet 6.4% carbohydrate solution (SC), a nonsweet 6.4% carbohydrate solution (NSC), or water (W). Exercise capacity was significantly increased with SC and NSC compared to W, the improvements corresponding to 15.8% and 11.8%, respectively. No difference in exercise capacity was seen between SC and NSC solutions. Plasma glucose concentrations were higher during the SC and NSC trials compared to W, significantly so at 10 min and at fatigue. Rates of carbohydrate oxidation were higher in the SC and NSC trials, although the rates never declined below 2.1 +/- 0.2 g.min(-1) in the W trial. There was no difference in the rate of rise of rectal temperature between trials, but there was a trend for subjects to fatigue at higher temperatures during the two carbohydrate trials. In conclusion, exogenous carbohydrate, independent of sweetness, improves exercise capacity in the heat compared to water alone.     

Fundus-first laparoscopic cholecystectomy

Removal of the gallbladder with commencement of dissection at the fundus is well recognized as a safe technique during difficult open cholecystectomy because it minimizes the risks of damage to the structures in or around Calot's triangle. We report here the routine employment of liver retractors and fundus-first dissection during laparoscopic cholecystectomy (LC) as an alternative to techniques previously described.Retraction of the liver and fundus-first dissection was used in 53 patients who underwent laparoscopic cholecytectomy. There were 16 male and 37 female patients. Seven were operations performed during an acute admission and 20 had moderate or severe adhesions involving the gallbladder. Thirteen patients had a preexisting abdominal incision.The procedure was successful in 52 patients (98%), but in one patient it was converted to open operation because of dense adhesions. Median duration of operation was 90 min (range 35–240 min). There was no mortality and two complications (persistent right upper quadrant pain for 2 weeks after operation and bile leakage from the gallbladder bed).The facility to retract the liver and carry out a fundus-first dissection extends techniques developed for open surgery into the laparoscopic arena. It offers the surgeon the safety and versatility during laparoscopic cholecystectomy that it confers during conventional open surgery.Presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES), Nashville, Tennessee, USA, 18–19 April 1994     

Effect of hydrazine upon vitamin B12-dependent methionine synthase activity and the sulphur amino acid pathway in isolated rat hepatocytes

The effect of the industrial chemical, hydrazine (4-12 mM), on methionine synthase (EC 2.1.1.13) activity and levels of the sulphur amino acids homocysteine, cysteine, and taurine as well as GSH were investigated in vitro in isolated rat hepatocyte suspensions and monolayers in order to explain some of the adverse in vivo effects of hydrazine. None of the concentrations of hydrazine were overtly cytotoxic in hepatocyte suspensions (measured as lactate dehydrogenase [LDH] leakage) after 3 hr. However, after 24 hr in culture cells treated with 12 mM, hydrazine showed a significant increase in LDH leakage. Methionine synthase activity was reduced by hydrazine (8 and 12 mM) in suspensions (by 45 and 55%, after 3 hr) and monolayers (12 mM; 65-80% after 24 hr). This was not due to nitric oxide production and the inhibitor of nitric oxide synthase, Nomega-nitro-L-arginine, failed to protect against the hydrazine-induced loss of ATP and GSH and the reduction in urea synthesis at 24 hr. Homocysteine export was increased by 6 mM hydrazine, and total taurine content of treated cells was increased by 12 mM hydrazine. Thus, hydrazine was found to have several important and possibly deleterious effects on some parts of the sulphur amino acid pathway.     

Assessments of the associations of thrombus localization with accompanying disorders,risk factors,D-dimer levels,and the red cell distribution width in pulmonary embolism

OBJECTIVE:

Pulmonary embolisms occur as a wide spectrum ranging from clinically asymptomatic thrombi to massive thrombi that lead to cardiogenic shock. The purpose of this study was to determine the associations of thrombus localization with risk factors, accompanying disorders, D-dimer levels and the red blood cell distribution width in patients with pulmonary embolism.

MATERIAL AND METHODS:

In 148 patients diagnosed with pulmonary embolism, the presence and anatomical localization of the thrombus were assessed via computed tomographic pulmonary angiography. The accompanying disorders, risk factors, serum D-dimer levels, and red blood cell distribution width of the patients were retrospectively evaluated. ClinicalTrials.gov: NCT02388841.

RESULTS:

The mean age of the patients was 54±16.0 years, and 48 patients were ≥65 years of age. The most frequent accompanying disorders were chronic obstructive pulmonary disease (22%) and malignancy (10.1%), and the most frequent risk factors were recent operation (14.1%) and immobilization (18.2%). Thrombi were most frequently observed in the right pulmonary artery (37.8%). In 31% of the patients, the thrombus was localized to the main pulmonary arteries. Immobile patients exhibited a higher proportion of thrombi in the main pulmonary arteries than mobile patients. The mean D-dimer level and the mean red blood cell distribution width in the patients with thrombi in the main pulmonary arteries were higher than those in the patients with thrombi in more distal pulmonary arterial branches.

CONCLUSION:

Significant associations of proximally localized thrombi with immobilization, the D-dimer levels, and the red blood cell distribution width were observed.     

Effect of acute and short-term administration of vanadyl sulphate on insulin sensitivity in healthy active humans

Vanadium compounds have been shown to have insulin-like properties in rats and non-insulin-dependent diabetic humans. The purpose of the present study was to examine whether the effects of acute and short-term administration of vanadyl sulfate (VA) on insulin sensitivity also exist in healthy active individuals. Five male and two female participants (age: 24.9 +/- 1.5 years; height: 176.1 +/- 2.9 cm; body mass: 70.1 +/- 2.9 kg) underwent 3 oral glucose tolerance tests (OGTT). The first OGTT was performed to obtain a baseline index of insulin sensitivity (ISI). On the night preceding the second OGTT, participants ingested 100 mg of VS, and the acute effects of VS on ISI were examined. For the next 6 days, participants were instructed to ingest 50 mg of VS twice daily, and a final OGTT was performed on day 7 to determine the short-term effects of VS on ISI. No differences were found in fasting plasma glucose and insulin concentrations after VS administration. Furthermore, ISI after 1 day and 7 days of VS administration was not different compared with baseline ISI (4.8 +/- 0.1 vs. 4.7 +/- 0.1 vs. 4.7 +/- 0.1, respectively). These results demonstrate that there are no acute and short-term effects of VS administration on insulin sensitivity in healthy humans.     

Investigation of some materials as dry binders for direct compression in tablet manufacture. Part 7: Formulation and evaluation of ascorbic acid and phenobarbitone tablets.

Directly compressible powder blends containing either ascorbic acid or phenobarbitone, and utilizing tragacanth, Carbowax 4000, Plasdone, and mannitol as dry binders, were formulated. The flowability of the powder mixes prior to compression was determined. Furthermore, the tablets prepared according to the suggested formulae were tested for hardness, friability, uniformity of weight, distribution of active ingredient, disintegration, and dissolution. The effect of aging on the qualities of the tablets was also studied.