Perinatal autopsy rates at the University Hospital of the West Indies: 2002-2008.

OBJECTIVES: High perinatal autopsy rates are necessary for institutional management protocols and national policy-making. This study reviews perinatal autopsy rates and factors affecting these rates at the University Hospital of the West Indies. METHOD: All perinatal deaths (stillborn infants > or = 24 weeks gestation or 500 g; early neonatal deaths ie 0-7 days old) at the University Hospital of the West Indies, between January 2002 and December 2008, were reviewed retrospectively, using the annual perinatal audit records. The annual autopsy rates were calculated and the reasons why autopsies were not done examined. RESULTS: The average stillbirth (SB) autopsy rate was 59.6% (range 51.9 - 76.7%), while that for early neonatal deaths (ENDs) was 47.9% (range 34.4 - 63.2), with an overall average perinatal autopsy rate of 54.0% (range 42.2 - 62.2). Autopsies were requested in 79.3% and 51.7% of SBs and ENDs, respectively. Of those requested, 81.7% were done (75.2% stillbirths; 92.5% ENDs). In the ENDs, failure to request an autopsy was predominantly noted in premature infants weighing < 1000 g (75.2% of those not requested). In stillbirths, the reasons for failure to request were largely unknown with failure to gain permission accounting for only 20.3% of these cases. CONCLUSIONS: The average annual perinatal autopsy rate at the University Hospital of the West Indies between 2002 and 2008 was 54.0%. This is below the internationally recommended rate of 75%. Failure to request an autopsy was the most significant factor contributing to this. The reasons for this are not entirely clear and require further study.

Monitoring of circulating monocyte HLA-DR expression in a large cohort of intensive care patients: relation with secondary infections.

INTRODUCTION: The reports of an early and profound acquired immunodepression syndrome (AIDs) in ICU patients had gained sufficient credence to modify the paradigm of acute inflammation. However, despite several articles published on AIDs and its assessment by monocytic HLA-DR monitoring, several missing informations remained: 1-Which patients' are more prone to benefit from mHLA-DR measurement, 2-Is the nadir or the duration of the low mHLA-DR expression the main parameter to consider? 3-What are the compared performances of leukocytes' count analyses (lymphocyte, monocyte). MATERIAL AND METHOD: We conducted an observational study in a surgical ICU of a French tertiary hospital. A first mHLA-DR measurement (fixed flow cytometry protocol) was performed within the first 3 days following admission and a 2nd, between day 5 and 10. The other collected parameters were: SAPS II and SOFA scores, sex, age, comorbidities, mortality and ICU-acquired infections (IAI). The associations between mHLA-DR and outcomes were tested by adjusted Fine and Gray subdistribution competing risk models. RESULTS: 1053 patients were included in the study, of whom 592 had a 2nd mHLA-DR measurement. In this cohort, 223 patients (37.7%) complicated by IAI. The initial decrement in mHLA-DR was not associated with the later occurrence of IAI, (p = 0.721), however, the persistence of a low mHLA-DR (< 8000 AB/C), measured between day 5 and day 7, was associated with the later occurrence of IAI (p = 0.01). Similarly, a negative slope between the first and the second value was significantly associated with subsequent IAI (p = 0.009). The best performance of selected markers was obtained with the combination of the second mHLA-DR measurement with SAPSII on admission. Persisting lymphopenia and monocytopenia were not associated with later occurrence of IAI. CONCLUSION: Downregulation of mHLA-DR following admission is observed in a vast number of patients whatever the initial motif for admission. IAI mostly occurs among patients with a high severity score on admission suggesting that immune monitoring should be reserved to the most severe patients. The initial downregulation did not preclude the later development of IAI. A decreasing or a persisting low mHLA-DR expression below 8000AB/C within the first 7 days of ICU admission was independently and reliably associated with subsequent IAI among ICU patients with performances superior to leukocyte subsets count alone.

Thoracic sarcopenia as a predictive factor of SARS-COV2 evolution.

PURPOSE: Evaluation of CT sarcopenia as a predictor of intensive care hospitalization during SARS-COV2 infection. MATERIALS AND METHODS: Single-center retrospective study of patients admitted to hospital with SARS-COV2 infection. The estimation of muscle mass (skeletal muscle index (SMI)) for sarcopenia, measurement of muscle density for muscle quality and body adiposity, were based on CT views on the T4 and L3 levels measured at admission. Demographic data, percentage of pulmonary parenchymal involvement as well as the orientation of patients during hospitalization and the risk of hospitalization in intensive care were collected. RESULTS: A total of 162 patients hospitalized for SARS-COV2 infection were included (92 men and 70 women, with an average age of 64.6 years and an average BMI of 27.4). The muscle area measured at the level of L3 was significantly associated with the patient's unfavorable evolution (124.4cm2 [97; 147] vs 141.5 cm2 [108; 173]) (p = 0.007), as was a lowered SMI (p < 0.001) and the muscle area measured in T4 (OR = 0.98 [0.97; 0.99]), (p = 0.026). Finally, an abdominal visceral fat area measured at the level of L3 was also associated with a risk of hospitalization in intensive care (249.4cm2 [173; 313] vs 147.5cm2 [93.1; 228] (p < 0.001). CONCLUSION: This study demonstrates that thoracic and abdominal sarcopenia are independently associated with an increased risk of hospitalization in an intensive care unit, suggesting the need to assess sarcopenia on admission during SARS-COV2 infection.

Neonatal screening for congenital hypothyroidism: Time to lower the TSH threshold in France.

Neonatal screening for congenital hypothyroidism (CH) is based on the measurement of thyroid-stimulating hormone (TSH) in whole dried blood samples on filter paper in all newborns. The objective of screening for CH is to prevent mental retardation, which is irreversible in the event of a late diagnosis, by setting up prompt treatment (before day 15) with levothyroxine. The threshold value of TSH on filter paper on day 3 is 17 mIU/L in France in the GSP method (GSP, Genetic Screening Processor, Perkin Elmer): It is one of the highest thresholds used in the world. In many countries, the TSH threshold is between 6 and 12 mIU/L. Studies have found that a threshold of > 17 mIU/L may miss as much as 30% of cases of CH, with 30-80% of these being permanent CH. Recent studies suggest that mild CH (currently missed by the French TSH threshold) is associated with cognitive consequences if left untreated. An inverse relationship between TSH at screening (below the current threshold) and cognitive development at preschool or school age has been shown. These studies advocate for the evaluation of a lowering of the threshold of TSH on filter paper in France: (a) to determine the number of CH diagnoses with the new threshold and whether these "new cases" would be transitory or permanent; and (b) to analyze the cost-effectiveness of the strategy.

Genetic evidence of the programming of beta cell mass and function by glucocorticoids in mice.

AIMS/HYPOTHESIS: Prenatal exposure to excess glucocorticoids associates with low birthweight in rodents, primates and humans and its involvement in programming glucose homeostasis is suspected. Our aim was to further dissect the role of glucocorticoids on beta cell development and function in mice. METHODS: Using the model of maternal general food restriction during the last week of pregnancy, we thoroughly studied in the CD1 mouse-mothers and fetal and adult offspring--the pancreatic, metabolic and molecular consequences of maternal undernutrition associated with excess glucocorticoids. The specific involvement of the glucocorticoid receptor (GR) was studied in mutant fetuses lacking GR in pancreatic precursors or mature beta cells. RESULTS: Maternal general food restriction in the mouse is associated with decreased maternal glucose and increased corticosterone levels. Fetuses from underfed dams had increased corticosterone levels, decreased pancreatic endocrine gene expression but increased exocrine gene expression and a lower beta cell mass. The offspring of these dams had a low birthweight, permanent postnatal growth retardation and, as adults, impaired glucose tolerance, decreased beta cell mass (-50%) and massively reduced islet expression (-80%) of most of the genes involved in beta cell function (e.g. Pdx1, Sur1 [also known as Abcc8], insulin). Moreover, using mutant fetuses lacking GR in pancreatic precursors or beta cells we show that the deleterious effect of undernutrition on fetal beta cell development requires the presence of the GR in pancreatic precursor cells. CONCLUSIONS/INTERPRETATION: These results demonstrate the crucial role of excess fetal glucocorticoids and the importance of GR signalling in progenitor cells to programme beta cell mass and dysfunction.

A review of granular cell tumours at the University Hospital of the West Indies: 1965-2006.

OBJECTIVE: Granular cell tumours are uncommon lesions that occur in a wide variety of sites. They are usually benign, but as they are infrequently diagnosed preoperatively, they may be confused clinically with malignant lesions. The objective of this study was to assess the relative frequency and the clinicopathologic characteristics of granular cell tumours identified at the University Hospital of the West Indies (UHWI) over a 41-year period. METHODS: The archives of surgical pathology reports in the Department of Pathology at the UHWI from 1965 to 2006 were searched for all cases of granular cell tumour. From these records, a number of demographic and other data were recorded and analyzed. RESULTS: One hundred and thirty cases of granular cell tumours were found in 122 patients. Of these, 99patients were female and 23 male, providing a male:female ratio of l to 4.3. The ages ranged from 5 days to 82 years with a mean age (excluding the 2 youngest cases) of 34.4 years. Lesions ranged in size from 0.2 cm to 10 cm in greatest dimension, the average size being 1.85 cm and were found in a diverse array of anatomic locations, the most common being the vulva, breast and tongue. The correct clinical diagnosis was proffered preoperatively in only one case. In contrast, a malignant diagnosis was suggested in 19 cases. CONCLUSIONS: Compared with other studies, there was a notable difference in the distribution of granular cell tumours in this series. In particular lesions of the tongue accounted for fewer than expected, while lesions of the breast and vulva were considerably increased. The well-recognized female predominance was also substantially higher than in other studies.

Correction to: Functional outcomes in adult patients with herpes simplex encephalitis admitted to the ICU: a multicenter cohort study.

The original article unfortunately contained a mistake. Due to technical problems the study group was not tagged correctly. Please find the correct tagging down below. We apologize for the mistake.

Functional outcomes in adult patients with herpes simplex encephalitis admitted to the ICU: a multicenter cohort study.

PURPOSE: We aimed to study the association of body temperature and other admission factors with outcomes of herpes simplex encephalitis (HSE) adult patients requiring ICU admission. METHODS: We conducted a retrospective multicenter study on patients diagnosed with HSE in 47 ICUs in France, between 2007 and 2017. Fever was defined as a body temperature higher or equal to 38.3 °C. Multivariate logistic regression analysis was used to identify factors associated with poor outcome at 90 days, defined by a score of 3-6 (indicating moderate-to-severe disability or death) on the modified Rankin scale. RESULTS: Overall, 259 patients with a score on the Glasgow coma scale of 9 (6-12) and a body temperature of 38.7 (38.1-39.2) °C at admission were studied. At 90 days, 185 (71%) patients had a poor outcome, including 44 (17%) deaths. After adjusting for age, fever (OR = 2.21; 95% CI 1.18-4.16), mechanical ventilation (OR = 2.21; 95% CI 1.21-4.03), and MRI brain lesions > 3 lobes (OR = 3.04; 95% CI 1.35-6.81) were independently associated with poor outcome. By contrast, a direct ICU admission, as compared to initial admission to the hospital wards (i.e., indirect ICU admission), was protective (OR = 0.52; 95% CI 0.28-0.95). Sensitivity analyses performed after adjustment for functional status before admission and reason for ICU admission yielded similar results. CONCLUSIONS: In HSE adult patients requiring ICU admission, several admission factors are associated with an increased risk of poor functional outcome. The identification of potentially modifiable factors, namely, elevated admission body temperature and indirect ICU admission, provides an opportunity for testing further intervention strategies.

[Observance and results of concurrent chemoradiotherapy after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil for locally advanced head and neck cancers]. / Observance et résultats de la chimioradiothérapie concomitante après chimiothérapie d'induction par docétaxel, cisplatine et 5-fluoro-uracile pour les cancers de la tête et du cou localement évolués.

PURPOSE: Retrospectively evaluate the safety, feasibility and efficacy of concomitant chemoradiotherapy after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil for locally advanced head and neck cancers. PATIENTS AND METHODS: Patients' data from three radiotherapy centres in South of France, with locally advanced head and neck cancers, and treated between December 2007 and July 2013 by concomitant chemoradiotherapy, after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil, were analysed. Adverse effects were graduated according to CTCAE v3.0 criteria. Overall survival and disease-free survival were calculated according to Kaplan-Meier method. RESULTS: One hundred and sixty-eight patients, mostly oropharynx (38%) T4 (46%) N2 (54%) tumors, received, after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil, a concomitant chemoradiotherapy with platin or cetuximab, which delivered 66 to 70Gy. Grade 3-4 adverse effects were less frequent in the group of patients who received cisplatin (with or withour 5-fluoro-uracil) at 100mg/m(2) each 21 days compared to cetuximab (radiomucositis: 32.5% vs 61%, P=0.018; radioepithelitis: 13% vs 61 %, P<0.0001). Chemopotentiation was incomplete for 21% of patients without impacting survival. Two years overall survival and disease-free survival were respectively of 81% and 64%. Lymph nodes status and WHO status significantly influenced these survivals (overall survival 84% if N<3 vs 56% if N3, P=0.017 and 85 % if WHO status ≤ 1 vs 50% if WHO status>1, P=0.006; disease-free survival 66% if N<3 vs 47% if N3, P=0.046). CONCLUSION: The association of induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil and concomitant chemoradiotherapy shows satisfying results with an acceptable toxicity. The terms of the chemopotentiation and its superiority to a single concomitant chemoradiotherapy treatment still remain to be clarified.

[Metastatic medullary thyroid carcinoma in a child with multiple endocrine neoplasia 2B. Efficiency of medium-term treatment with vandetanib without thyroid surgery]. / Carcinome médullaire de la thyroïde métastatique : efficacité à moyen terme d'un traitement par vandétanib sans chirurgie thyroïdienne chez un enfant porteur d'une néoplasie endocrinienne multiple de type 2B.

Medullary thyroid carcinoma (MTC) is a rare cancer during childhood. MTC is sporadic in approximately 80% of cases and hereditary in 20%. When hereditary, it can be associated with other endocrine neoplasias and/or typical nonendocrine diseases, thus configuring the multiple endocrine neoplasia (MEN) syndromes. Children with clinically obvious MTC belong to MEN 2A or 2B families, related to RET mutations. The standard treatment is total thyroidectomy and central neck dissection. However, treatment of advanced MTC has not yet been standardized, even if a new tyrosine kinase inhibitor specific to RET mutation has changed the outcome of such patients. Vandetanib plays a role in the treatment of children with metastatic, locally advanced and nonoperable MTC, with good tolerance. We report the 5-year treatment of an 11-year-old patient, with vandetanib and without thyroid surgery.

Percutaneous transluminal balloon valvuloplasty of congenital pulmonary valve stenosis, with a special report on infants and neonates.

Fifty-six percutaneous transluminal balloon valvuloplasty procedures were performed in 51 patients suffering from congenital pulmonary valve stenosis. The patients ranged in age from 1 day to 60 years (mean 6.9 years); 21 were infants less than 1 year of age, including 8 neonates. The peak systolic pressure gradient was greater than 50 mm Hg (mean 81.5) in 47 cases, and less than 50 mm Hg (mean 34.6) in 9. Valvuloplasty enabled a reduction in the mean right ventricular peak systolic pressure from 93.1 to 51.6 mm Hg (p less than 0.001), the mean transvalvular gradient from 73.4 to 27.0 mm Hg (p less than 0.001) and the mean right ventricular pressure expressed as a percent of systemic pressure from 99.5 to 52.0% (p less than 0.001). In infants and neonates, the mean right ventricular pressure expressed as a percent of systemic pressure decreased from 117.3 to 64.4% (p less than 0.001). In 23 patients, follow-up cardiac catheterization at 1 to 17 months revealed a significant change in the right ventricular systolic pressure, which decreased from 54.0 to 46.7 mm Hg (p less than 0.05), and in the peak systolic pressure gradient, which decreased from 27.3 to 22.6 mm Hg (p less than 0.05). Valvuloplasty is an effective procedure in relieving pulmonary stenosis in patients of all ages, including neonates.

Percutaneous balloon angioplasty in an infant with obstructed total anomalous pulmonary vein return.

This is a report of successful dilation of stenosis of the common trunk in a case of total anomalous pulmonary vein return into the left superior vena cava in a 3 month old infant. Percutaneous angioplasty was performed with a 6 mm diameter balloon catheter. Right ventricular systolic pressure decreased from 96 to 60 mm Hg, mean pulmonary vein pressure decreased from 26 to 14 mm Hg and left ventricular systolic pressure increased from 70 to 90 mm Hg.

Isolated ventricular discordance and complete atrioventricular canal in situs inversus. Report of successful surgical repair.

Isolated ventricular discordance is a very rare malformation, most often lethal in the first months of life. A patient with this lesion survived to age 9 years in spite of the coexistence of a complete form of atrioventricular (A-V) canal. Surgical repair with a Mustard procedure was associated with correction of the endocardial cushion defect. Situs inversus itself caused no problem. Although permanent complete A-V block occurred, the result has been satisfactory so far. This case is thought to be the first successful correction of this malformation.

"Infantile" form of the scimitar syndrome with pulmonary hypertension.

Twenty-five newborns and infants aged < 1 year with the scimitar syndrome and pulmonary hypertension from 12 European pediatric centers were examined. Cardiac failure and severe respiratory insufficiency were always present. In 23 cases, pulmonary hypertension was due to a large shunt between abnormal arteries originating from the abdominal aorta and supplying the lower part of the right lung (vascular sequestration). In the last 2 cases, pulmonary hypertension was secondary to stenosis of the common trunk of the right pulmonary veins. Three of 10 patients who received only medical treatment survived; 2 are doing well, with pulmonary arterial pressures that have returned to normal, and the other had severe residual pulmonary hypertension. Six of 15 patients who underwent surgery survived. There were 5 ligations of a patent ductus arteriosus with 5 deaths, 3 pulmonary resections with 2 deaths, 1 dilation of a tight stenosis of the common trunk of the right pulmonary veins with 1 death, and 6 ligations of the abnormal arterial vessels with 5 surviving patients who are in good condition. Ligation of the abnormal arterial vessels appears to be the best type of treatment.

Asymptomatic form of left pulmonary artery sling.

Eight patients with left pulmonary artery sling, which were asymptomatic at the time of the last consultation, are described: 2 adults and 1 child with no history of symptoms, 3 children with mild forms of airways obstruction and 2 patients with typical severe symptoms of airways obstruction in infancy. The mean follow-up of these 8 patients was 10 years (range 4 to 23), and in 1986, all were in good health and free of respiratory symptoms. The long-term prognosis is usually good.

Bacterial pericarditis in infancy and childhood.

The authors report on a cooperative study of 43 cases of bacterial pericarditis observed in children. This disorder was suspected in patients with septicemia who developed symptoms and signs of pericarditis (precordial pain, muffled heart sounds, pericardial friction rub, cardiomegaly). Early diagnosis of this condition is now facilitated by echocardiography. A combination of medical and surgical treatments (appropriate antibiotic therapy after culture and sensitivity tests and early pericardial drainage) led to complete recovery in almost all of the cases (42 of 43). After long-term follow-up, no cases of constrictive pericarditis were observed.

The "adult" form of the scimitar syndrome.

One hundred twenty-two cases of the adult form of the scimitar syndrome were collected from different cardiologic centers. The clinical, radiographic and hemodynamic findings are described. The scimitar syndrome is defined as an anomalous right pulmonary venous drainage, partial or complete, to the inferior vena cava. Additional characteristics of this syndrome such as hypoplasia and abnormalities of the vascular supply to the right lung, dextrocardia and abnormalities of the bronchial segmentation are common; bronchiectases are rare. The left to right shunt was less than 50% in 100 of the 122 patients. The pulmonary arterial pressures were normal in 94 patients and slightly elevated in 28. A follow-up study of these patients showed that, without surgical correction, they lead a normal life. An awareness of this syndrome may avoid unnecessary invasive diagnostic procedures and surgical treatment for most patients.

Influence of clinical and hemodynamic characteristics on signal-averaged electrocardiogram in postoperative tetralogy of Fallot.

This study examines the relation between signal-averaged electrocardiographic measurements and the occurrence of spontaneous ventricular arrhythmias in 86 patients with a postoperative right bundle branch block after repair of tetralogy of Fallot; special attention was given to the influence of age, body surface area and right ventricular systolic pressure on signal-averaged electrocardiograms. Twenty-eight of the 86 patients had significant ventricular arrhythmias on 24-hour ambulatory monitoring. A positive linear correlation was found between filtered QRS duration and age at evaluation or body surface area (r = 0.45, p = 0.00001; r = 0.54, p < 0.00001, respectively) and between amplitude of the last 40 ms of the filtered QRS and right ventricular systolic pressure (r = 0.48, p < 0.001). A negative linear correlation was found between amplitude of the last 40 ms of the filtered QRS and age at evaluation or body surface area (r = -0.27, p = 0.01; r = -0.34, p = 0.002, respectively). When the age of the patients or the body surface area was considered with an analysis of covariance, the presence of ventricular arrhythmias was associated with a higher amplitude of the last 40 ms of the filtered QRS. In addition, an amplitude of the last 40 ms of the filtered QRS > 170 microV had an excellent sensitivity (100%) and a good specificity (88%) for identifying patients with both right ventricular systolic hypertension and spontaneous ventricular arrhythmia. Thus, adjustment of signal-averaged parameters for age at evaluation and body size is mandatory when studying postoperative tetralogy of Fallot.

Functional evidence for NO-synthase activation by substance P through a mechanism not involving classical tachykinin receptors in guinea-pig ileum in vitro.

1. This study tested the hypothesis that a nitric oxide synthase (NOS) was activated in guinea-pig ileum in vitro in response to substance P (SP), and attempted to characterize the tachykinin receptor involved in this activation by the use of selective receptor agonists and antagonists. 2. Strips of guinea-pig ileum (8 x 2 mm) were superfused (Krebs, 37 degrees C, 2 ml min-1) with: (i) tachykinin receptor agonists: SP, GR 73,632 (NK1), GR 64,349 (NK2), senktide (NK3), and neuropeptide (NP) gamma; (ii) tachykinin receptor antagonists: CP 99,994 (NK1), SR 48,968 (NK2), SR 142,801 (NK3); (iii) nerve-related agents: carbachol (CCh), atropine, tetrodotoxin (TTX), hexamethonium; (iv) NOS inhibitors: N omega-nitro-L-arginine-methyl-ester (L-NAME), N omega-monomethyl-L-arginine (L-NMMA) and aminoguanidine (AG); (v) NO-related agents, L-arginine (L-Arg), D-arginine (D-Arg), sodium nitroprusside (NaNP) and methaemoglobin. Muscle contractility was recorded isometrically and quantified as integrated area of activity. 3. SP, tachykinin receptor agonists and NP gamma (10 pM to 10 microM), produced concentration-dependent contractions of ileal strips, with EC50s in the nanomolar range, and maximal responses (Emax) attained at 0.1 microM for SP and 1 microM for the other agonists. The Emax response to SP equalled that to KCl (60 mM) taken as a 100% control (99.3% [93.0-105.7]; mean and 95% CI; n = 12); a comparable Emax contraction was obtained with the other tachykinin receptor agonists (1 microM) as well as with CCh (1 microM). 4. Under baseline conditions, L-NAME (1 microM), L-NMMA (1 microM) and AG (1 microM), failed to contract the muscle strip. In contrast, when superfused for 3 min, 10 min after SP (0.1 microM), they induced a transient contraction of the strip (e.g. for 1 microM L-NAME: 50 to 70 s duration; amplitude 73 +/- 12%, n = 24). 5. The NOS inhibitor-induced contractile response was not obtained after KCl (60 mM), GR 73,632, GR 64,349, senktide or CCh (all up to 1 microM). In contrast, this contractile response was obtained after NP gamma (1 microM). 6. Blockade of tachykinin NK1, NK2 and NK3 receptors by continuous superfusion of CP 99,994, SR 48,968 and SR 142,801 (1 microM) respectively, starting 5 min before SP, did not modify the response to L-NAME, superfused 10 min after SP (0.1 microM). The contractile response to L-NAME (1 microM) was blocked by atropine (1 microM), superfused either before or after SP. In contrast, it persisted after TTX or hexamethonium (1 microM) superfused in the same conditions. 7. The amplitude of NOS inhibitor-induced contraction (1 microM) was dependent on the concentration of priming SP (1 pM to 1 microM). In contrast, the contractile response to NOS inhibitors (1 nM to 10 microM) of the ileum strip primed with SP (0.1 microM) was not concentration-related. 8. L-NAME-induced contraction was prevented by continuous superfusion of L-Arg (1 microM), but not D-Arg (1 microM). In addition, the NO donor, sodium nitroprusside (1 microM) and the NO scavenger, methaemoglobin (10 micrograms ml-1), both prevented the contractile response to L-NAME. 9. In summary, SP and to a lesser extent NP gamma, exert a permissive action allowing contractile stimulating effects of L-NAME, L-NMMA and AG, in guinea-pig ileum in vitro, by a mechanism which apparently does not involve tachykinin NK1, NK2 and NK3 receptors. This action is likely to result from the activation of a NO-synthase by SP in the vicinity of intestinal myocytes. Thus, L-NAME, L-NMMA or AG, by blocking this SP-induced NO production, unveiled a smooth muscle contraction which involves a cholinoceptor (atropine-sensitive) mechanism.

Comparative biopharmaceutical performance of imipramine formulations in man.

The systemic availability of an investigational liquid formulation of imipramine was compared to that of a commercially available tablet (Tofranil) whose therapeutic efficacy has been established by usage. The experiment was conducted under controlled conditions and a balanced 2-by-2 crossover design was used to dissociate the significance of formulation effects from subject, group, and experimental period sources of variation. Pharmacokinetic interpretation and statistical analysis of plasma concentrations as a function of time and of systemic availability indicators reveal a nearly identical biopharmaceutical behavior for the two preparations. Significant differences (P less than 0.05) were found in the cumulative area under the plasma concentration--time curve (AUC) up to 4 hours after administration and the availability lag time, but not in the maximum plasma concentration, the time at which this concentration is reached, the first-order availability rate constant, and the AUC to infinity. These results collectively indicate a very similar biopharmaceutical performance, where the differences in the early AUC values are partly attributable to a longer availability lag time for the tablet formulation.