Wounding,shock and stress lesions of the upper gastrointestinal tract

This retrospective study included 2532 wounded, of whom 354 (14 per cent) were treated in surgical intensive care units. In 32 patients, 1.3 per cent of all admissions, upper gastrointestinal bleeding was detected. It occurred on average 8.9 days (3–21 days) after the wounding or surgical procedure in severely injured patients and those treated in intensive care units, respectively (32 of 354 patients, 9.0 per cent). All patients received different analgesic drugs and 17 of a group that presented with bleeding were given psychotropic agents as well. The majority of patients (96.3 per cent) were administered H₂-receptor antagonists as prophylaxis against stress ulcer disease. There was a statistically significant difference between these patients treated with H₂-receptor antagonists and those on no prophylactic therapy. No statistically significant difference was found between cimetidine and ranitidine in terms of their efficacy. Endoscopic examination revealed multiple bleeding gastric and duodenal erosions. The lesions were most commonly located in the corpus of the stomach. In the majority of patients (56.25 per cent), the haemorrhage stopped spontaneously and rebleeding presented in four of 32 (12.5 per cent) patients. Of 354 patients treated in intensive care units, five (1.4 per cent) had to be operated on because of bleeding arrest. Despite all therapeutic and surgical procedures undertaken, five of 32 (15.6 per cent) patients died.     

Medullary control of the pontine swallowing neurones in sheep

Summary The origin of the inputs from the medullary swallowing centre (dorsal region including the nucleus of the solitary tract, or ventral region corresponding to the reticular formation surrounding the nucleus ambigous) to the pontine swallowing neurones (PSNs) was studied in sheep anaesthetized with halothane.Out of 101 PSNs located in the posterior part of the trigeminal (Vth) motor nucleus, 46 were activated by stimulating either the dorsal (21 neurones) or the ventral (25 neurones) region of the ipsilateral medullary swallowing centre, 3–4 mm rostral from the obex. Thirty-one neurones out of the 46 were identified as a motoneurones supplying swallowing muscles (mylohyoïd, anterior body of digastric and medial pterygoïd). Their average activation latency through stimulation of the dorsal medullary region was about 1 ms longer than through stimulation of the ventral region (3.63 ms±0.81 versus 2.72 ms±0.32).To determine the origin of the medullary input to the PSNs, we tried to activate the medullary swallowing neurones (MSNs) antidromically through stimulating the posterior part of the Vth motor nucleus, which contains the swallowing motoneurones. Seventy-three MSNs were tested (25 located in the dorsal and 48 in the ventral region). None of the dorsal neurones tested could be antidromically activated by pontine stimulation: 15 ventral neurones showed a clear antidromic response (collision test) with an average latency of 2.5 ms±0.73. These neurones, which send their axons into the pons, were all located in the reticular formation, above the nucleus ambiguus, 3–4 mm rostral from the obex.These results suggest that MSNs in the ventral reticular formation connect the medullary swallowing centre to the Vth motor nucleus. They also suggest that during swallowing, inputs originating from the dorsal region of the medullary centre (interneurones programming the motor sequence) are relayed in the ventral region (reticular formation adjacent to the nucleus ambiguus) before reaching the PSNs.This work was supported, in part, by grants from CNRS (LA 205), INRA and M.R.I. (82 E 0685)     

Atypical antipsychotic-induced neutropenia in dogs

DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects through selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtypes. Clozapine therapy is clinically associated with severe granulocytopenia in a small subset of patients. In the course of a 3-month toxicity study in dogs, severe neutropenia, thrombocytopenia, marked myeloid and erythroid left-shifted bone marrow hyperplasia with increased erythrophagocytosis, positive Coombs' tests, and hypergammaglobulinemia occurred in individual females dosed with 30 mg/kg/day of DMP 406. Related but less severe changes were also observed in males. Sera or purified immunoglobulins from affected and control dogs were tested in methylcellulose-based, canine hematopoietic colony-forming unit (CFU) assays with or without DMP 406. Neither size nor number of erythroid or myeloid CFUs differed between cultures containing control or affected dog serum components. Sera from individual affected dogs but not controls resulted in moderate numbers of fibroblast-like CFUs, suggesting DMP 406-associated marrow stromal cell-modifying, serum activities to be present. DMP 406 alone resulted in a concentration-dependent reduction of erythroid and myeloid CFUs with an approximate IC50 of 3.0 microg/mL. Taken together, DMP 406-induced granulocytopenia and bone marrow dyscrasia appear likely to result from both immune-mediated and direct drug-induced myelotoxicity.     

Increased hepatobiliary clearance of unconjugated thyroxine determines DMP 904-induced alterations in thyroid hormone homeostasis in rats.

4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine (DMP 904) is a potent and selective antagonist of corticotropin releasing factor receptor-1 (CRF1 receptor) with an efficacious anxiolytic profile in preclinical animal models. In subchronic toxicity studies in Sprague-Dawley rats, DMP 904 produced thyroid follicular cell hypertrophy and hyperplasia, and a low incidence of follicular cell adenoma. The current investigations were designed to determine the mode of action by which DMP 904 disrupts thyroid homeostasis in male rats. Five-day treatment with DMP 904 (300 mg/kg/day) dramatically lowered serum thyroxine (T4) to levels below detectable limits (< 1 microg/dl) by 72 h, with concurrent decreases in triiodothyronine (T3, about a 70% decrease) and increases in thyroid stimulating hormone (TSH; about a three-fold increase). DMP 904 increased [125I]T4 total body clearance (Cl tb) (38.21 +/- 10.45 ml/h) compared to control (5.61 +/- 0.59 ml/h) and phenobarbital-treated rats (7.92 +/- 1.62 ml/h). This increase in Cl(tb) was associated with a significant increase in biliary clearance (Cl bile) of unconjugated [125I]T4 (nearly 80-times control rates) and increased liver:blood ratios of T4, suggestive of enhanced hepatic uptake of T4. A single dose of DMP 904 (200 mg/kg) increased mRNA levels of hepatic cytochrome P450s (CYP 3A1 and CYP 2B1) and UDP-glucuronosyltransferases (UGT 1A1 and UGT 1A2). DMP 904 also induced mRNAs of the canalicular transporter, multi-drug resistance protein-2 (Mrp2) and sinusoidal transporters, organic anion transporting proteins (Oatp1 and Oatp2) within 24 h. Western blot analysis confirmed DMP 904 related increases in Oatp2 protein expression. Collectively, these data suggest that DMP 904 is an agonist of the constitutive androstane receptor (CAR) and pregnane X receptor (PXR) and that the decreased serum levels of T4 and T3 resulted from increased hepatobiliary clearance. However, DMP 904 is distinguished from other compounds associated with similar effects on thyroid hormone homeostasis because its effects were primarily related to increased biliary excretion of unconjugated T4.     

Intrathecal/intraventricular colistin in external ventricular device-related infections by multi-drug resistant Gram negative bacteria: case reports and review

We report three cases of external ventricular derivation infections caused by multidrug-resistant Gram-negative rods and treated successfully with intraventricular colistin. The intrathecal or intraventricular use of colistin have been reported in more than 100 cases without any consensus on dosage, duration and type (monotherapy or combination therapy) of treatment. Based on our comprehensive review of the relevant literature relating to both clinical and pharmacokinetic data, we conclude that the intrathecal/intraventricular administration of colistin is a safe and effective option to treat central nervous system infections caused by multidrug-resistant Gram-negative bacteria.     

Gas exchange and metabolic transients in heart transplant recipients

In human heart transplant recipients (HTR) an impairment of the cardiac function was expected to reduce peak oxygen consumption and the kinetics of the adjustment of respiratory gas exchange at the onset of rectangular work loads. In nine patients (males, 23-59 yr) 1 to 8 months after cardiac transplantation average peak VO2 (VO2p) was 1.1 L.min-1 +/- 0.3 (SD), i.e. 45% of that of the controls, the corresponding VCO2p value being 1.4 L.min-1 +/- 0.3 (SD). Mean VEp was 62.9 L.min-1 +/- 20.3 (SD), mean HRp was 136 beats.min-1 +/- 11 (SD), i.e. 45 beats.min-1 higher than preexercise values. Mean [Lab]p was 7.7 mM +/- 1.7 (SD), indicating that at the heaviest load the HTR were performing work at or above their maximum aerobic power. During the initial 60-90 sec of the transition from rest to graded rectangular exercise HR did not change from the resting value, increasing thereafter almost linearly with time. The half time (t1/2) of the VE on-response was 112 sec +/- 30 (SD) (controls values: 59 sec +/- 16), that of the VCO2 on- was 95 sec +/- 18 (SD) (58 sec +/- 11), and that of the VO2 on- was 78 sec +/- 24 (SD) (38 sec +/- 6). In spite of the slow kinetics of the VO2 on- response, no massive accumulation of lactate was found in the early phase of exercise. The limitation of the peak exercise in HTR appears to be imposed by a reduced maximal cardiac performance. The slow readjustment of the latter, as expected from the sluggish heart rate response, however, does not impair substantially the work load transients nor reduce the anaerobic threshold.