Effect of Cnidoscolus aconitifolius leaf extract on the blood glucose and insulin levels of inbred type 2 diabetic mice.

The effects of Cnidoscolus aconitifolius (CA) leaf extract and chlorpropamide on blood glucose and insulin levels in the inbred type 2 diabetic mice are reported. After treatment with CA, the glucose levels were measured at 0 and 2-hour intervals in experimental groups and controls. Group I received no treatment and served as control; Group II was the reference and it received chlorpropamide; Groups I-III were moderately diabetic, 100-300 mg/dL blood glucose levels while Group IV were severely diabetic (> 300 mg/dL). Groups III and IV received CA and served as test groups. There was no significant difference between the blood glucose levels at 0 and 2 hours for the control group, (P>0.23) but there were statistically significant differences for Group II (P<0.0002); Group III (P<0.002) and Group IV (P<0.0001). For moderately diabetic mice, CA and chlorpropamide decreased the glucose levels by 25.6% and 16.3% respectively while for the severely diabetic mice CA decreased the blood glucose by 43.7%. It is proposed that CA has an insulinogenic property that possibly stimulated dormant beta-cells to secrete insulin. The histopathology of several organs in the treated animals was found to differ from the expected. The islets of Langerhans for example were found to be preserved in the time frame examined. Also the liver and kidney were found to display milder pathology in the treated groups.

A randomised controlled trial to assess the effectiveness and cost of a patient orientated self management approach to chronic inflammatory bowel disease.

OBJECTIVES: We developed a patient centred approach to chronic disease self management by providing information designed to promote patient choice. We then conducted a randomised controlled trial of the approach in inflammatory bowel disease (IBD) to assess whether it could alter clinical outcome and affect health service use. DESIGN: A multicentre cluster randomised controlled trial. SETTING: The trial was conducted in the outpatient departments of 19 hospitals with randomisation by treatment centre, 10 control sites, and nine intervention sites. For patients at intervention sites, an individual self management plan was negotiated and written information provided. PARTICIPANTS: A total of 700 patients with established inflammatory bowel disease were recruited. MAIN OUTCOME MEASURES: Main outcome measures recorded at one year were: quality of life, health service resource use, and patient satisfaction. Secondary outcomes included measures of enablement-confidence to cope with the condition. RESULTS: One year following the intervention, self managing patients had made fewer hospital visits (difference -1.04 (95% confidence interval (CI) -1.43 to -0.65); p<0.001) without increase in the number of primary care visits, and quality of life was maintained without evidence of anxiety about the programme. The two groups were similar with respect to satisfaction with consultations. Immediately after the initial consultation, those who had undergone self management training reported greater confidence in being able to cope with their condition (difference 0.90 (95% CI 0.12-1.68); p<0.03). CONCLUSIONS: Adoption of this approach for the management of chronic disease such as IBD in the NHS and other managed health care organisations would considerably reduce health provision costs and benefit disease control.

Effect of acute ethanol on striatal dopamine neurotransmission in ambulatory rats.

The effect of ethanol on evoked dopamine release in the caudate putamen has been measured in behaving animals with in vivo electrochemistry. Dopamine was measured with fast-scan cyclic voltammetry in adult male rats to resolve the competing processes of dopamine uptake and release. Ethanol dose dependently decreased dopamine efflux compared with saline-treated animals: to 89% of controls with 0.5 g/kg, 70% with 1 g/kg, 34% with 2.5 g/kg, and 18% with 5 g/kg. This decrease was not due to a change in uptake, as measured by the rate of dopamine disappearance after stimulation, and therefore can be attributed to decreased dopamine release. Additionally, it was not mediated by a decrease in biosynthesis, as measured by L-DOPA accumulation after NSD 1015 administration. The selective dopamine uptake inhibitor GBR 12909 compensated for the effects of high doses of ethanol on dopamine release. Moreover, GBR 12909 induced faster restoration of the righting reflex in rats sedated with 2.5 g/kg, but not 5 g/kg, ethanol. In brain slices containing the caudate putamen, ethanol suppressed dopamine release only at the highest dose tested (200 mM). The difference in responses between the slice and the intact animal indicates that ethanol exerts its effects in the cell body regions of dopamine neurons as well as in terminals. These neurochemical results, combined with published accounts of microdialysis measures of extracellular dopamine and electrophysiological recordings of dopamine neurons, demonstrate that ethanol has a profound effect on dopamine neurons whose net result is a suppression of dopamine neurotransmission at high doses.

Multiple gastrointestinal atresias with cystic dilatation of the biliary duct.

A term newborn developed signs and symptoms of an upper-intestinal obstruction. A palpable transverse upper-abdominal mass was identified. An ultrasound examination demonstrated a cystic mass with massive dilatation of the biliary tree. At laparotomy, dozens of segmental intestinal atresias (IA) from the jejunum to the rectum were identified. The cystic mass was the duodenum, obstructed distally from the atresias and proximally from an antral web. The biliary dilatation was due to normal drainage into a closed-loop duodenal obstruction, and was relieved by division of the web. The multiple atresias were explored, but establishment of intestinal continuity was impossible. The entity of multiple segmental IAs in association with cystic biliary dilation has been previously described, but there are no recorded survivors; 35 patients have been reported in the world literature. Our patient was the longest survivor; she finally died after 2 years of gastrostomy-tube drainage and total parenteral nutrition while awaiting intestinal transplantation. Only 5 patients other than ours had documented immune-system abnormalities. We review the findings and management of this rare syndrome.

Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin.

Members of the phosphatidylinositol-3 kinase related kinase (PIKK) family function in both cell cycle progression and DNA damage-induced cell cycle checkpoints. The fungal metabolite, wortmannin, is an effective radiosensitizer that irreversibly inhibits certain members of the PIKK family. Based on their roles in DNA damage responses, several PIKKs, DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and the ataxia- and Rad3-related protein (ATR), are potential targets for the radiosensitizing effect of wortmannin. In this report, we demonstrate that wortmannin is a relatively potent inhibitor of DNA-PK (IC50, 16 nM) and ATM (IC50, 150 nM) activities, whereas ATR activity is significantly less sensitive to this drug (IC50, 1.8 microM). In intact A549 lung adenocarcinoma cells, wortmannin inhibited both DNA-PK and ATM at concentrations that correlated closely with those required for radiosensitization. Furthermore, pretreatment of A549 cells with wortmannin resulted in radioresistant DNA synthesis, a characteristic abnormality of ATM-deficient cells. These results identify wortmannin as an inhibitor of ATM activity and suggest that ATM and DNA-PK are relevant targets for the radiosensitizing effect of this drug in cancer cells.

Polyomavirus middle T antigen as a probe for T cell antigen receptor-coupled signaling pathways.

Stimulation of the T cell antigen receptor (TCR) triggers a complex series of signaling events that culminate in T cell activation and proliferation. The complex structure of the TCR has hindered efforts to link specific signaling events induced by TCR cross-linkage to downstream activation responses, such as interleukin-2 (IL-2) gene transcription. Previous studies have shown that the polyomavirus-derived oncoprotein, middle T antigen (mT), transforms rodent fibroblasts by interacting with and activating several cytoplasmic signaling proteins (Src kinases, phospholipase C (PLC)-gamma1, Shc, and phosphoinositide 3-kinase (PI3-K) implicated in cell growth control. In this study, we demonstrate that expression of mT activates Jurkat T cells, as measured by increases in IL-2 promoter- and NFAT (nuclear factor of activated T cells)-dependent reporter gene transcription. The transcriptional response provoked by mT was blocked by the immunosuppressive drug FK506, a potent inhibitor of TCR-mediated IL-2 gene expression. Mutations that disrupted the binding of mT to Src kinases or PLC-gamma1 abrogated the ability of mT to deliver the signals needed for IL-2 promoter activation. In contrast, a mT mutant that failed to bind PI3-K induced a markedly elevated transcriptional response in Jurkat cells, whereas mutation of the Shc binding site in mT had little effect on the transactivating potential of this viral oncoprotein. Additional studies demonstrated that the association of mT with PLC-gamma1 was necessary and sufficient to activate both Ca2+- and Ras-dependent signaling cascades in Jurkat cells. These results indicate that PLC-gamma1 activation plays pivotal and pleiotropic roles in the stimulation of IL-2 gene expression, whereas activation of PI3-K negatively modulates this response in Jurkat T cells.

Comparison of muscle-sparing thoracotomy and thoracoscopic ligation for the treatment of patent ductus arteriosus.

PURPOSE: We reviewed our experience with the treatment of patent ductus arteriosus (PDA), and compared two therapeutic techniques; muscle-sparing thoracotomy (MST) and thoracoscopic PDA ligation (TPDAL). METHODS: We reviewed the clinical records and operative reports of 19 nonnewborn patients who were treated at our institution for PDA. Eleven patients underwent TPDAL and eight patients MST. The TPDAL patients underwent thoracoscopic clipping (ligation) of the PDA, whereas the MST group had a complete division of the ductus. A two-tailed Student's t test was used to calculate the 95% confidence intervals for length of operation, number of doses of intravenous narcotics and hospital stay. Costs were also compared. RESULTS: All patients underwent diagnostic echocardiography in the evaluation of an asymptomatic murmur. Both groups were similar in age (average, 4 years) and gender. All procedures were performed electively. Two thoracoscopic attempts were aborted, one for bleeding and the other for inadequate clip size. The length of the procedure averaged 1.3 hours +/- 0.330 SD for TPDAL versus 1.4 hours +/- 0.335 SD for MST. Five of the nine successful TPDAL patients were admitted to the Pediatric Intensive Care Unit (PICU) with an average length of stay of 20 hours, and two of eight MST patients stayed in the PICU for average of 18 hours. All patients were extubated after the procedure. Chest tubes were placed in two TPDAL patients and three MST patients. However, two patients who underwent TPDAL required tube thoracostomy for persistent postoperative pneumothorax. Average number of intravenous narcotics administered for the TPDAL was 1.2 doses per patient and for MST, 1.75 doses per patient. Mean hospital stay for TPDAL was 1.33 +/- 0.71 SD days and for MST 1.8 +/- 0.83 SD days. Ninety-five percent (95%) confidence intervals for the difference in means demonstrated no difference between the two groups for length of operation, hospital stay, or number of doses of intravenous narcotics administered. CONCLUSIONS: The authors were unable to identify any benefit to thoracoscopic patent ductus arteriosus ligation versus muscle-sparing thoracotomy in terms of hospital stay, length of operation, or morbidity. Additionally, with MST there is a complete division of the PDA theoretically decreasing the risk of recurrence in comparison with clip ligation.

Balloon extraction of esophageal foreign bodies in children.

BACKGROUND: Whereas esophageal foreign bodies are commonly removed with rigid esophagoscopy under general anesthesia, selected foreign bodies also can be removed using a Foley catheter balloon under fluoroscopic control without anesthesia. The authors prefer to initially attempt removal of smooth, radiopaque esophageal foreign bodies using the balloon technique and then proceed to rigid esophagoscopy if unsuccessful. METHODS: The authors reviewed their 7-year experience with this approach in 276 children with esophageal foreign bodies. RESULTS: One hundred seventy-three children underwent attempted balloon extraction, and 146 of these underwent successful removal with this method. Fifteen remained lodged in the esophagus and were subsequently removed by esophagoscopy, and 12 passed into the stomach and were observed. The only complication was one episode of epistaxis that resolved. Success of the balloon method was not related to patient age, foreign body duration, location, or presenting symptoms. The use of more than 5 minutes of fluoroscopy time was associated with a low likelihood of successful extraction. CONCLUSION: The balloon extraction technique is a safe and effective alternative to rigid esophagoscopy for the removal of selected esophageal foreign bodies in children.

Pediatric intestinal leiomyosarcomas: case report and review of the literature.

Primary intestinal leiomyosarcomas in children are rare tumors. Twenty-seven previous cases are documented in the literature with little information available on the treatment, survival, and prognostic factors surrounding these tumors. The authors report the 28th case of pediatric intestinal leiomyosarcoma and its follow-up, that of a newborn presenting with intestinal obstruction. Follow-up from all previously reported cases is not recorded and is needed. Our patient, like most children with this tumor, underwent complete excision with no evidence of recurrence at 5 years. Visceral metastases from these neoplasms are atypical, and recorded long-term prognosis may be favorable, unlike their counterpart in the adult population.

Efficacy of partial wrap fundoplication for gastroesophageal reflux after repair of esophageal atresia.

Gastroesophageal reflux (GER) often develops in children who have undergone prior repair of esophageal atresia/tracheoesophageal fistula (EA/TEF). Fundoplication is necessary in many of these children. The complete wrap (Nissen) fundoplication is often used in this setting. However, poor results have been noted, with a mean failure rate of 30% reported in four recent studies. A partial wrap fundoplication for GER associated with EA/TEF is theoretically attractive, because the poor esophageal motility and diminished acid clearance (already physiologically present) is exacerbated by a complete wrap fundoplication. The authors reviewed their extensive experience with partial wrap (Thal) fundoplication in EA/TEF to determine if the failure rate was better than that reported for the Nissen fundoplication. In the past 18 years, the authors performed 1,467 fundoplication procedures. During the same period, 143 children underwent repair of EA/TEF. Fifty-nine children underwent fundoplication after a previous EA/TEF repair. Most of the fundoplications (58 of 59, 98%) were Thal procedures. Defining failure strictly as a need for reoperation, the failure rate in our series was 15% (9 of 59 children). Compared with the failure rate in the 1,408 non-EA/TEF patients (61 of 1408, 4.3%), results were significantly worse for the EA/TEF group (P > .001). The failure rate of Thal fundoplication performed for GER in the EA/TEF population is substantially higher than the non-EA/TEF patients. The same factors responsible for the development of reflux in these children (poor acid clearance, altered motility, esophageal shortening) may contribute to the higher failure rate. Although partial wrap fundoplication frequently failed (15%), the results were still substantially better than those reported for Nissen fundoplication in these children (30% failure rate).

Primary adenocarcinoma, signet-ring, and transitional cell carcinoma of the bladder with penile metastasis.

This article reports a rare case of primary signet-ring cell carcinoma of the bladder with transitional cell and adenocarcinoma variants and metachronous metastases to the penis and lungs. This combination of lesions has not previously been reported. Together, they portend widespread dissemination and an early demise as is frequently the case with signet-ring cell carcinomas arising in other organs such as the breast and gastrointestinal tract. The optimal therapeutic intervention for this myriad of neoplasms with metastasis to the penis has yet to be ascertained because of the rarity of the lesions. Early diagnosis and an aggressive surgical approach appear to offer the best chance for quality survival and possible cure.

Covalent modification of transmembrane span III of the A1 adenosine receptor with an antagonist photoaffinity probe.

Structure-based design of subtype-selective ligands for the A1 adenosine receptor will require a reliable model of the ligand-binding pocket. It should be possible to develop a reliable model based on the results of affinity labeling experiments that provide atomic coordinates for the ligand in relation to predicted receptor helices. A high affinity, A1-selective xanthine antagonist photoaffinity probe, 125l-3-(4-azidophenethyl)-1-propyl-B-cyclopentylxanthine, was used to covalently modify the A1 receptor. Chemical or enzymatic fragmentation experiments were performed to localize the region or regions of incorporation within the receptor. The fragmentation profiles for radiolabeled A1 receptor obtained with endoproteinase Glu-C, endoproteinase Lys-C, cyanogen bromide, and hydroxylamine were consistent with the interpretation that the covalent linkage was within the first four predicted transmembrane regions. This interpretation was confirmed by the demonstration that the radioactive endoproteinase Glu-C fragment derived from an A1 receptor that contains an amino-terminal FLAG epitope was recognized by an anti-FLAG monoclonal antibody. Sequential digestion with endoproteinase Glu-C/endoproteinase Lys-C limited the possible labeling to the first three predicted transmembrane spans, and endoproteinase Glu-C/trypsin digestion refined this prediction to include only transmembrane spans III and IV. Taken together, our findings suggest that the adenosine antagonist 125l-3-(4-azidophenethyl)-1-propyl-8-cyclopentyl-xanthine covalently modifies transmembrane III of the A1 receptor because this was the only receptor region common to all radiolabeled fragments.

Receptors coupled to pertussis toxin-sensitive G-proteins traffic to opposite surfaces in Madin-Darby canine kidney cells. A1 adenosine receptors achieve apical and alpha 2A adrenergic receptors achieve basolateral localization.

The alpha 2A adrenergic receptor (alpha 2AAR) previously was shown to be directly delivered to and retained on the lateral subdomain of renal epithelial cells. The present studies demonstrate that, in contrast, wild-type and epitope-tagged canine A1 adenosine receptors (A1AdoR) are apically enriched (65-83%) in Madin-Darby canine kidney (MDCKII) and porcine renal epithelial (LLC-PKI) cells, based on surface biotinylation strategies detecting photoaffinity-labeled A1AdoR. Confocal microscopy corroborated the apical enrichment of the epitopetagged A1AdoR. Metabolic labeling studies revealed that this steady-state polarization is achieved by direct delivery to both the apical (60-75%) and basolateral surface. Growth of A1AdoR-expressing cells as monolayers presence of A1AdoR antagonists, which decreased cell growth, suggesting that A1AdoR elicit MDCKII cell proliferation. The preferential apical but detectable basolateral localization of A1AdoR provides a molecular understanding of published reports that functional responses can be elicited following apical as well as basolateral delivery of adenosine agonists in varying renal preparations. These findings also suggest that receptor chimeras derived from the Gi/Go-protein-coupled alpha 2AAR and A1AdoR will be informative in revealing structural features critical for basolateral versus apical targeting.

Colon patch esophagoplasty for caustic esophageal stricture.

Severe caustic injury with stricture may require esophageal reconstruction. The available methods of esophageal substitution do not satisfactorily replace the peristaltic and antireflux properties of the native esophagus. The authors report the results of two children treated with colon patch esophagoplasty and preservation of the injured esophagus. Both were 2 years of age when they accidently swallowed lye. Long esophageal strictures developed, which were resistant to repeated dilatation. Eleven and 13 months after the injury, the patients underwent colon patch esophagoplasty. A segment of the left colon was tailored to the length and shape of the opened stricture and was anastomosed side-to-side to the esophagotomy. One child later had a short recurrent stricture and diverticulum, which required revision of the distal end of the anastomosis. Follow-up endoscopic examination has shown healing of the esophagus and resolution of the strictures; both children are eating normally 3 years after surgery, without symptoms of gastroesophageal reflux. Colon patch esophagoplasty is an alternative to esophageal replacement for long caustic esophageal strictures. Its advantage is preservation of the peristaltic and antireflux mechanisms of the conserved esophagus.

Assessment of the use of bladder washouts/instillations in patients with long-term indwelling catheters.

A randomised cross-over study of 3 bladder washout treatments--saline, Suby G and Solution R--was conducted on 25 elderly females with long-term catheters in order to examine crystal formation and catheter encrustation. With 2 exceptions, all patients produced crystals; only 14 completed the study. While a significant reduction in struvite crystals was found in the returned acidic washout fluid, there was no significant reduction of crystals in the neutral (saline) washout following any of the 3-week periods of treatment. Uric acid crystals appeared with Suby G and Solution R and these solutions were associated with higher red cell deposits in the urine. There was no significant difference in catheter encrustation between the various washouts.

Utilization of trauma-related deaths for organ and tissue harvesting.

A randomized retrospective analysis of patients who suffered trauma-related deaths over 36 months (May 1987-April 1990) was performed to study their utilization as candidates for organ and tissue harvesting. There were a total of 108 patients: 79 males, 29 females. The average age was 46.2 years; 38 (36%) of these patients were 65 years of age or older. Over 50% of fatalities were the result of motor vehicle crashes. There were 61 potential tissue donors. Forty-three were lost without documentation of a request for organ procurement. There were 23 patients with potentially salvageable organs: one candidate was lost without documentation of a request for organ procurement. Twenty-eight (26%) of the patients had support withdrawn; 16 were 65 years old or older. Brain death protocol was instituted in 17 (20%); organs were obtained from 70% of these patients. Reasons for failure of procurement after request by a physician included family refusal in seven cases, cardiopulmonary arrest during brain death protocol in two cases, and religious bias in one candidate. Twelve patients were organ donors: 10 patients were tissue donors. We conclude that the greatest source of underutilization lies in the failure to request tissue for harvesting, since there were no isolated tissue donors. Pertinent information should be more widely distributed to physicians regarding candidacy for tissue donation. Further consideration of the adequacy of organs or tissue in relation to the candidates' age should be given, since patients aged 65 years and older can be a significant source of potential donor candidates.(ABSTRACT TRUNCATED AT 250 WORDS)

A new urethral catheter.

A new balloon catheter for women with a flexible urethral portion that conforms to the shape of the closed urethra was tested. In sheep control catheters caused epithelial destruction, which was absent with the conformable catheter. A 12 week crossover trial compared control catheters in 52 long stay geriatric patients. Eighty two out of 91 conformable catheters were rated as comfortable compared with 68 of 87 control (p = 0.006). The average length of time in situ was 15.9 days for the conformable catheter compared with 12.9 days for the control (p = 0.001). The average number of bypasses a week with the conformable catheter was 1.1 compared with 1.3 for the control; this difference was not significant. Examination of 249 used catheters showed significantly fewer with intraluminal obstruction with struvite among the conformable than control catheters (1 (0.8%) versus 15 (11.5%); p less than 0.001). This new catheter for women is a substantial improvement over the Foley catheter and (except in urethral stricture) is suitable for all forms of drainage.

Regional and temporal variation in oscillatory blood flow in sickle cell disease.

We examined 55 patients with sickle cell anemia (HbSS) and 16 with hemoglobin SC disease (HbSC) to ascertain the presence of periodic microcirculatory flow (PMF) using laser-Doppler velocimetry. Forty-nine percent of patients with HbSS and 12.5% of HbSC patients had PMF on at least one occasion and in at least one site. The presence of PMF could be correlated with an increase in packed cell volume (PCV) and hemoglobin in individuals with HbSS and an increased white blood cell and platelet count in patients with HbSC. PMF may result from complex interactions among perfusion pressure, capillary tone, and the numbers and intrinsic properties of formed blood elements.

Calcium phosphate in catheter encrustation.

Encrusted catheters from nine female patients were the source of samples of deposits which were examined by X-ray diffraction, atomic absorption spectroscopy, infra-red spectroscopy and extended X-ray absorption fine structure (EXAFS) spectroscopy. In eight samples the only crystalline phase which could be clearly distinguished by X-ray diffraction was ammonium magnesium orthophosphate hexahydrate, NH4MgPO4 X 6H2O, which occurs naturally as the mineral struvite. However, atomic absorption spectroscopy revealed an appreciable concentration of calcium in all samples. Calcium phosphates have previously been detected in catheter deposits. Infra-red and EXAFS spectra were consistent with the calcium phosphate being present as a poorly crystalline hydroxyapatite. Thus the deposits appear to consist of a mixture of crystalline struvite and a form of hydroxyapatite which is not fully crystalline.

Influence of HbS levels upon the hematological and clinical characteristics of sickle cell trait.

The variable concentration of HbS in individuals with sickle cell trait led us to study the relationship between HbS level and selected vascular events in 355 hospitalized black men with sickle cell trait. There were significant differences in hemoglobin concentration and mean corpuscular volume found in four groups divided by their HbS level, the lowest proportion of HbS (less than 30%) being associated with the lowest hemoglobin concentration (12.6 g/dl) and MCV (77 fl). The percent HbS did not influence the incidence of pulmonary embolism, thrombophlebitis, myocardial infarction, cerebrovascular accident, or idiopathic hematuria. Our results suggest that HbS level does not influence vascular disease, and while certain hematological alterations occur, they are very unlikely to have any clinical significance. Regardless of the proportion of HbS, sickle cell trait in black men is benign.