The program for phenotyping of genetically modified animals at AstraZeneca

Genetically modified mice offer a wide range of possibilities in preclinical drug discovery, e.g. for use in target identification, target validation and disease model generation. However, genomic modification and alteration in gene expression may cause unpredicted phenotypic alterations in the organism other than the intended ones. The aim of this study was to determine the importance of establishing the phenotype of transgenic and knockout mice models for use in pharmaceutical research.

A total number of 51 mouse models (transgenic and knockout) produced at AstraZeneca during a 4 year period were subjected to a thorough phenotyping package covering clinical as well as morphological aspects. Phenotype abnormalities were recorded in 36 (70.6%) of the mouse models. The majority of findings were considered to be minor in magnitude. Histopathological changes related to the genotype of the animals were observed in 33% of the mouse models, underlining the importance of pathology in the phenotyping program.     

Impact of major co-morbidities on mortality and complications after gastric bypass

BACKGROUND: We hypothesized that major co-morbidities affect survival and complications after gastric bypass. METHODS: A total of 1465 patients undergoing laparoscopic and open gastric bypass between 1995 and 2002 were studied. Patients with a body mass index >or= 35 kg/m(2) and major co-morbidities (group 1, n = 1045) were compared with patients with a body mass index >or= 40 kg/m(2) with minor/no co-morbidities (group 2, n = 420). RESULTS: Group 1 patients were older (43 versus 36 years, P < 0.001) and had a greater BMI (53 versus 50 kg/m(2), P < 0.001). Early postoperative complications were greater in group 1 than in group 2 and included leaks (4.1% versus 1.2%, P < 0.0032) and wound infections (3.9% versus 1.4%, P < 0.0133). Procedure-related mortality in the series was 1.7%. Mortality was 10-fold greater in group 1 (2.3% versus 0.2%, P < 0.0032). The incidence of small bowel obstruction, incisional hernia, and pulmonary embolism was similar in the two groups. Excess weight loss was significantly greater in group 2 (68% versus 62%, P < 0.001) at 1 year. Resolution of group 1 co-morbidities was great, including hypertension in 62%, diabetes in 75%, venous stasis disease in 96%, and pseudotumor cerebri in 98%. CONCLUSION: Outcomes analysis of obesity surgery requires risk stratification. The very low mortality rates in published studies are likely explained by surgical treatment of low-risk patients with minor co-morbidities, such as those seen in group 2. However, despite the increased perioperative risk, the group 1 patients (with major co-morbidities) demonstrated dramatic resolution of their co-morbid conditions, justifying the decision to go forward with surgery. The data support a radical change in treatment philosophy in which morbidly obese individuals should be offered bariatric surgery before major co-morbid conditions develop as a strategy to decrease the operative risk.     

Cystic echinococcosis in Central Saudi Arabia: A 5-year experience.

Background/aims: In this series of patients we aim to describe aspects of presentation, diagnosis and management of patients suffering from Echinococcosis in an endemic region. Methods: This is an observational study done at Riyadh Medical Complex, Saudi Arabia from 1999 to 2004. All adult patients admitted with the primary or incidental diagnosis of echinococcosis were included. These patients were followed up for 6 months. Data relating to patients' demographic characteristics, mode and duration of presentation, investigations, complications and treatment offered was collected. This data was then analyzed using SPSS 11.0. Result: 117 patients with a mean age of 40.9+/-20.7 years were admitted, male to female ratio being 1.7:1. 114 (97.4%) originated from Middle East which is an endemic area. Pain right upper quadrant (RUQ), followed by cough were the commonest symptoms. Nine patients presented with jaundice +/- choleangitis: 3 patients had intrabiliary rupture of the hydatid cyst, while 6 had extrinsic compression. Six patients had infected cyst. Fourteen patients had intrabronchial rupture diagnosed on bronchoscopy. Twenty five (21.4%) patients presented with recurrent disease. The Haemagglutination Inhibition test gave a sensitivity of 78.6. All cysts were visualized using USG, CXR and CT scan. Endocystectomy was the most frequent procedure. Post op 8 patients had biliary leakage and 3 had bronchopleural fistula a majority of whom settled conservatively while two required ERCP and one patient with bronchopleural fistula required surgery. Fifteen patients had infection related complications. During our follow up period no recurrences were recorded. All patients undergoing surgery also received medical treatment. Twenty five patients (21.4%) were unable to undergo operative treatment due to multiple reasons. They were medically treated. Conclusion: Cystic Echinococcosis is a disease of the middle aged. Ultrasonogram combined with a serological assay is the best diagnostic tool available for abdominal echinococcosis allowing diagnosis and staging, while chest X ray is the best screen for the pulmonary disease. The recommended treatment is endocystectomy with antihelmenthic therapy. But the problem of early detection of echinococcosis in endemic areas needs attention by workers as this approach can potentially prevent the devastating complications due to this disease.     

Role of Intralesional Bleomycin in the Treatment of Complicated Hemangiomas: Prospective Clinical Study

BACKGROUND: Hemangioma is the most common tumor of infancy. Although it has a basically benign nature and usually spontaneously regresses, a small percentage (5%) have complications that need treatment. Many different therapeutic modalities can be used in this tumor. OBJECTIVE: To investigate the effect of a new method of treatment (intralesional bleomycin injection) in complicated hemangiomas. MATERIALS AND METHODS: In the Department of Radiation Oncology at Nemazee Hospital in Shiraz, Iran, from April 1992 to October 1998, 32 patients with complicated hemangioma were treated with four to six courses of direct injection of bleomycin into the lesion. RESULTS: After a minimum follow-up of 6 years, there was 70 to 100% regression in 18 patients, 50 to 70% in 7 cases, and less than 50% reduction in 7 patients. CONCLUSION: Intralesional injection of bleomycin is an easy, safe, and effective therapeutic modality in complicated cutaneous hemangiomas.     

Loss of Anticoagulant Effect of Heparin During Circulation of Human Blood In Vitro

Device-induced thrombogenesis was studied in an in vitro model using human blood circulated through an artificial ventricle. A new constant pressure filtration technique was used to detect circulating microemboli, the activated partial thromboplastin time (APTT) test was used to monitor the blood for the presence of anticoagulant activity of heparin, and hemolysis was quantified by measuring the plasma free hemoglobin level. Circulation of blood through a 20-ml stroke volume pneumatically driven ventricle for 6-9 h resulted in a significant reduction of APTT, indicating the loss of the anticoagulant effect of heparin. Microemboli concentration was minimal until the APTT decreased below 125 s, at which time the microemboli concentration increased rapidly. This was presumed to be due to the formation of thrombi following a decrease in heparin activity. A significant increase in hemolysis was also noted when blood was pumped. None of these changes was noted in the nonpumped control blood. Spontaneous loss of heparin activity in blood circulated by a pneumatically driven pump may have clinical implications and may help understanding of the problems associated with device-induced thrombogenesis.     

The depressing effect of tetracaine and ryanodine on the slow outward current correlated with that of contraction in voltage-clamped frog muscle fibres

The effects of tetracaine (10–50 M) and ryanodine (0.1–10 M) were tested on the slow outward K⁺ current (I _so) and the mechanical tension of isolated frog muscle fibres in a voltage-clamp device (double mannitol-gap) connected to a mechanoelectric transducer. In the concentration range tested, both drugs induced a simultaneous inhibition of tension and current. In all cases the effect on tension was twice that on current. The tetracaine-induced current and tension blocks were fully reversible and dose-dependent. In contrast the ryanodine effects on current and tension were not reversible and did not exhibit a dose dependence except for the delay before the onset of the response, which was shortened when the concentration was raised. Linear regression analysis of the time-dependent and dose-dependent effects of both drugs indicated a strong correlation between the decreases in tension and current. It is concluded that the slow outward current is partly under the control of the Ca²⁺ release from sarcoplasmic reticulum during contraction.