Potentiation of antidiuretic response to systemic angiotensin II by elevation of CSF NaCI concentration

The antidiuretic effect of the simultaneous intracerebroventricular (ICV) infusion of 0.24 M NaCl (0.02 ml/min) and intravenous (i. v.) infusion of angiotensin II (12 ng/kg. min) was studied in hydrated goats, and was compared to the antidiuretic effects of the separate infusions. The combined infusions inhibited the water diuresis for 30 min, whereas the separate infusions only reduced the water diuresis by 25% (ICV NaCl) and by 50% (i. v. angiotensin). The combined infusions increased the urine osmolality on the average by 415%. Corresponding increases induced by ICV NaCl and by i. v. angiotensin were 100 and 160%. The results suggest that systemic angiotensin II and elevated CSF NaCl concentration interact and potentiate each other as stimuli for antidiuretic hormone secretion. It is postulated that this synergism may help to preserve body water in hypovolemic conditions associated with hyperactivity of the renal renin-angiotensin system.     

Antigen presentation in the murine oral epithelium

We have previously reported that the buccal mucosa can support delayed type hypersensitivity (DTH) reactions to contact sensitizers. In the present study, we show that cells isolated from the buccal epithelium are able to present soluble exogenous antigens to specific T cells. Single cell suspensions obtained by enzymatic dispersion of buccal epithelial sheets could present the native protein antigen hen-egg lysozyme (HEL) to the I-A^k-restricted CD4⁺ T-cell hybridoma specific for a.a 46–61 on HEL. T-cell activation resulted in interleukin-2 (IL-2) production which could be inhibited by anti-major histocompatibility complex (MHC) class-II antibodies of pertinent specificity. Immunohistochemical staining of whole buccal epithelial sheets revealed that all MHC II positive cells had a dendritic morphology and expressed ATPase activity, indicating that these cells represent a major antigen-presenting cell (APC) population in this tissue. Furthermore, single cell suspensions isolated from buccal epithelium (BEC) after local in vivo administration of either a native soluble protein, a synthetic dodecapeptide, or a contact sensitizer were able to activate antigen-specific T cells ex vivo. Kinetic analyses indicated that maximal APC activity in the oral epithelium occurred within 1 hr after local antigen administration, and had essentially vanished after 24 hr. Conversely, APC activity was undetectable in draining cervico-mandibular lymph node cell suspensions recovered 1 hr after local antigen injection but became manifest after 3–24 hr. These observations suggest that dendritic cells can acquire antigens in the buccal epithelium and migrate to draining lymph nodes where they present processed antigen to MHC class II-restricted T cells. This APC population may thus be a critical element in the initiation of Th1-driven DTH responses in the oral mucosa.     

Cyanide Detoxification in Rats Exposed to Acetonitrile and Fed a Low Protein Diet

Different neurological syndromes have been associated with exposureto cyanide. Dietary cyanide exposure from cassava roots combinedwith a low intake of the sulfur amino acids necessary for cyanidedetoxification has been implicated in the causation of konzo,an upper motoneuron disease identified in Africa. We have investigatedthe effect of a low protein diet on the capacity for cyanidedetoxification. Rats were fed normal chow containing 18% proteinor a low protein diet with 5% protein. To expose rats to cyanidethe drinking water was supplemented with 40 or 80 mM acetonitrile(CH₃CN) for up to 4 weeks. Weight gain was monitored and 24-hrurines were collected for analyses of total sulfur, inorganicsulfate, thiocyanate, and 2-aminothiolazine-4-carboxylic acid(ATC). Blood was collected for analyses of cyanide and cyanate.Rats on a normal diet grew throughout the experiment, whilethose on a low protein diet initially lost weight and then stabilizedat a constant weight. Rats exposed to acetonitrile all progressivelylost weight, those on a low protein diet at the highest rate.Signs of neurological damage were not observed. Rats not exposedto acetonitrile excreted <0.2% of sulfur as thiocyanate andthose on a low protein diet reduced their total sulfur excretionto one-third that of rats on the normal diet. Rats on the normaldiet did not change total sulfur excretion during exposure toacetonitrile, although thiocyanate now contributed more thantwo-thirds of excreted sulfur. Rats on a low protein diet exposedto acetonitrile increased both total sulfur and thiocyanateexcretion to the levels of rats on a normal diet. Rats exposedto acetonitrile had manyfold increases of circulating concentrationsof cyanide and cyanate and of urinary excretion of ATC. Therewas a positive correlation between blood cyanide concentrationsand the plasma concentration of cyanate. It is concluded thatthe rat has a high capacity for detoxification of cyanide. Duringadaptation to a low protein intake, sulfur is conserved butcyanide detoxification is still possible at the cost of extensiveprotein catabolism. It is thus possible that subclinical cyanideexposure could interfere with normal growth and development.The observation of a relationship between circulating cyanideon the one hand and circulating cyanate and urinary excretionof ATC on the other highlights the possibility that cyanidemetabolites may mediate neurotoxic effects of cyanide.     

Oro-gastro-intestinal inhibition of hypernatremia-induced drinking in the goat

Reduction of drinking by slow (5 ml/min) administration for 20 min of nearly body-warm (35°C) and cold (15°C) water into the mouth, the abomasum, or the duodenal bulb was studied in goats made thirsty by the simultaneous i. v. infusion of hypertonic (2 M) NaCl at 2 ml/min. During the control experiments the drinking response to corresponding infusion of 1.7 M NaCl was recorded. This in order to eliminate the possible influence on the results of a postabsorptive thirst inhibition which would occur if the administered water was completely absorbed already during the saline infusion. The entrance of warm water into the mouth or into the abomasum caused about 20%, and into the duodenal bulb about 30% reduction of drinking during the infusion of hypertonic NaCl. The corresponding reduction for cold water was when introduced into the mouth and duodenal bulb about 50% and into the abomasum about 60%. Cold water also considerably delayed the onset of dringing. The inhibition obtained during cold water administration was partially compensated for by increased post-infusional dringing. As regards the sensory input underlying preabsorptive inhibition of thirst, it is concluded that (regardless of distension, swallowing, and other mechanical factors) the entrance of pure water into various parts of the alimentary tract contributes to reduce the thirst drive. In addition, stimulation of oral, gastric, and duodenal cold receptors obviously diminish the urge to drink considerably.     

Signs of critical illness polyneuropathy and myopathy can be seen early in the ICU course

Background: Critical illness polyneuropathy and myopathy (CIPNM) is recognized as a common condition that develops in the intensive care unit (ICU). It may lead to a prolonged hospital stay with subsequent increased ICU and hospital costs. Knowledge of predisposing factors is insufficient and the temporal pattern of CIPNM has not been well described earlier. This study investigated patients with critical illness in need of prolonged mechanical ventilation, describing comprehensively the time course of changes in muscle and nerve neurophysiology, histology and mitochondrial oxidative function.
Methods: Ten intensive care patients were investigated 4, 14 and 28 days after the start of mechanical ventilation. Laboratory tests, neurophysiological examination, muscle biopsies and clinical examinations were performed. Neurophysiological criteria for CIPNM were noted and measurements for mitochondrial content, mitochondrial respiratory enzymes and markers of oxidative stress were performed.
Results: While all patients showed pathologic changes in neurophysiologic measurements, only patients with sepsis and steroid treatment (5/5) fulfilled the CIPNM criteria. The presence of CIPNM did not affect the outcome, and the temporal pattern of CIPNM was not uniform. All CIP changes occurred early in ICU care, while myopathy changes appeared somewhat later. Citrate synthase was decreased between days 4 and 14, and mitochondrial superoxide dismutase was increased.
Conclusion: With comprehensive examination over time, signs of CIPNM can be seen early in ICU course, and appear more likely to occur in patients with sepsis and corticosteroid treatment.     

Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study

Summary.  Background:  Inhibitors of factor (F) IXa show potent antithrombotic activity with a low risk of bleeding in preclinical models. We investigated the anticoagulant potential of oral TTP889, a small molecule that inhibits up to 90% of FIXa activity at therapeutic doses, using a clinical model of extended prophylaxis in hip fracture surgery (HFS). Methods:  In this multicenter, randomized, double-blind study, 261 patients received oral TTP889 (300 mg once daily) or placebo starting 6–10 days after HFS, and standard thromboprophylaxis for 5–9 days. Treatment was continued for 3 weeks and all patients then underwent mandatory bilateral venography. The primary efficacy outcome was venous thromboembolism (VTE; venographic or symptomatic deep vein thrombosis or pulmonary embolism) during treatment, and it was evaluated centrally by an independent adjudication panel. The main safety outcome was bleeding (major, clinically relevant non-major, and minor events). Results:  Two hundred and twelve patients with an evaluable venogram were included in the efficacy analysis. The primary efficacy outcome occurred in 32.1% (35/109) of patients who had been allocated TTP889, and 28.2% (29/103) of patients on placebo ( P  =   0.58). There were no major bleeding events, and only two clinically relevant non-major bleeding events with TTP889. Conclusion:  Partial FIXa inhibition with TTP889 300 mg daily was not effective for extended prevention of VTE after standard prophylaxis for up to 9 days. Coupled with the low incidence of bleeding episodes, this suggests a lack of antithrombotic potential. Further investigation of TTP889 in different clinical settings is needed.
(Clinical trial registration information URL: http://www.clinicaltrials.gov . Unique identifier: NCT00119457) .     

Prevention of venous thromboembolism with an oral factor Xa inhibitor,YM150, after total hip arthroplasty. A dose finding study (ONYX‐2)

Background: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. Objectives: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. Patients/methods: Patients were randomized to postoperative, once‐daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double‐blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. Results: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose‐related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. Conclusions: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.     

Alloiococcus otitidis —otitis media pathogen or normal bacterial flora?

During the last decade a new potential otitis media pathogen, Alloiococcus otitidis, has been studied. It is still not clear whether this bacterium really is a pathogen, although it has been found in a high percentage of middle ear effusions in children. The present study aimed to investigate the presence of A. otitidis in the nasopharynx and outer ear canals, and to develop a culture method that would make it possible to isolate A. otitidis from these locations. Nasopharyngeal samples (n=129) from children below 6 years were investigated by conventional culture on blood agar plates with 6% saline and rabbit antisera against A. otitidis, and by a PCR method. In the same way, we investigated 10 samples from vestibulum nasi of healthy persons, 68 samples from outer ear canals of patients with acute or chronic ear problems, and 24 samples from outer ear canals of healthy persons. In a rat model of acute otitis media, we instilled living A. otitidis into rat middle ears through the tympanic bulla and evaluated the outcome clinically by otomicroscopy at days 3, 6 and 14. Of the 129 nasopharyngeal cultures, 9 were positive for A. otitidis by PCR, but none by the culture method. Of the 68 samples from patients with running ears, 4 were positive for A. otitidis by PCR, but none by the culture method. Of the 24 healthy ear canals, 7 were positive for A. otitidis by PCR and 3 of them also by the culture method. No A. otitidis could be found from the vestibulum nasi. The rat experiment showed that the reactions in the middle ears were mild; we could not provoke a purulent acute otitis media in any of the rats. There was a 7% prevalence of A. otitidis in children below 6 years. The highest prevalence (29%) was found in outer ear canals of healthy persons, which strongly suggests that A. otitidis is part of the normal bacterial flora of the outer ear canal. The doubtful pathogenicity is also confirmed by the fact that—in the rat model—A. otitidis elicited only a mild response in the middle ear. It was possible to isolate A. otitidis using a blood agar plate with 6% saline.     

Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study

The Swedish Ticlopidine Multicentre Study (STIMS) was a double-blind placebo-controlled trial designed to determine whether ticlopidine, a platelet antiaggregatory agent, reduces the incidence of myocardial infarction, stroke and transitory ischaemic attacks in patients with intermittent claudication. A total of 687 patients was monitored for a minimum of 5 years or until an end-point was reached. The number of end points (99 vs. 89), analysed according to the intention-to-treat principle, was 11.4% lower in the ticlopidine group (P = 0.24). The mortality rate was 29.1% lower in the ticlopidine group (64 vs. 89, P = 0.015); this observation could be accounted for by a reduced mortality from ischaemic heart disease. On-treatment analysis showed there to be significantly fewer end points in the ticlopidine group (47 vs. 76, P = 0.017). Diarrhoea was the most common side-effect. Reversible leucopenia or thrombocytopenia was reported in seven patients on ticlopidine. It is concluded that the high morbidity and mortality from cardio- and cerebrovascular disease in patients with intermittent claudication can be reduced by long-term treatment with ticlopidine.