Costimulation and Autoimmune Diabetes in BB Rats

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55–120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.     

Clinicopathological profile of carcinoma of oesophagus at Aligarh.

Forty-seven patients with oesophageal carcinoma were managed in 6 years' time. Average duration of illness was 5.5 months. History of chronic smoking and/or tobacco chewing was present in 80.85% of patients. Carcinoma included squamous cell variety (80.85%) and adenocarcinoma (19.15%). Thirty-one patients were in stage III while 16 patients were in stage II. Surgery included oesophagogastrectomy/oesophagogastrostomy (16 patients), feeding gastrostomy (11 patients), Mousseau-Barbin tube insertion (10 patients), only 10 patients were subjected to palliative radiotherapy. All patients after palliative treatment died within one year whereas 3-year and 5-year survivals after oesophagogastrectomy/oesophagogastrostomy were 68.75% and 31.25% respectively. Local lymph node metastasis adversely affected the 5-year survival rate.     

The association between seated immobility and local lower-limb venous coagulability in healthy adult volunteers: a simulation of prolonged travel immobility.

This is the first study to examine the hypothesis that prolonged sitting is associated with procoagulant changes in the local lower-limb venous system. A comparison was made with upper-limb venous changes. Changes in markers of thrombin generation, fibrinolysis, endothelial perturbation and haemoconcentration were analysed as 10 healthy adult male participants sat for 8 h. The change in foot volume was estimated. Subjective venous thromboembolism assessment was undertaken hourly, along with 2-week and 4-week safety follow-up for clinical events.Expected increases in median prothrombin fragments 1 and 2, thrombin-antithrombin complex and D-dimer were not observed in either limb. An increase greater than 45% in the median tissue plasminogen activator and plasminogen activator-1 molar ratio (t-PA/PAI-1), and a decrease greater than 15% in median soluble thrombomodulin were noted in both limbs. Median haematocrit decreased minimally (1%) in the lower limbs, while the foot volume increased by 4%. Subjects experienced vague symptoms after 6 h of sitting, but none developed symptomatic venous thromboembolism. Upper and lower-limb changes in biomarkers did not correlate, except those in t-PA/PAI-1 ratio and plasminogen activator-1. Significant correlation was found between changes in the lower-limb t-PA/PAI-1 ratio and right foot volume.This study originally reveals that even in the lower limbs, prolonged daytime cramped sitting is not associated with significant procoagulant changes in healthy adult male volunteers, and confirms a previous observation that local lower-limb venous changes are not identically reflected in the upper limbs.     

Suppurative corneal ulceration in Bangladesh

Suppurative keratitis is an important preventable cause of blindness, particularly in the developing world. This study analyses 142 cases of suppurative keratitis referred to Chittagong Eye Infirmary, Bangladesh. Some 53.5% of cases were bacterial and 35.9% were fungal. The five most common pathogens were: Pseudomonas sp. 24%, Streptococcus pneumoniae 17%, Aspergillus sp. 13%, Fusarium sp. 7% and Curvularia sp. 6%. Gram stain and culture results were consistent in 62.6% of cases. Previous antibiotic treatment was a significant factor for failure of culture isolation and less so for Gram stain failure. On Gram stain, 55.9% of pseudomonal cases were missed, but only 2% of fungal cases were missed. Over all, Gram stain had a sensitivity of 62% and positive predictive value of 84% for bacterial cases, and 98% and 94% for fungal cases, respectively. Fungal ulcers were typically filamentous, but an antecedent history of trauma was not common. The most frequent injury was due to rice grains, but the inoculum appeared to be introduced during eye washing with contaminated water. Pseudomonal ulcers occurred most frequently in the monsoon season, and Fusarium cases were seen only in the hot, dry season.     

Efficacy of botulinum toxin injection before pneumatic dilatation in patients with idiopathic achalasia

Graded pneumatic dilatation (PD) is an appropriate long-term therapy and botulinum toxin injection (BT) is a relatively short-term therapy in idiopathic achalasia. Their combination has not been previously scrutinized. This study aimed to evaluate the role of BT in enhancing the efficacy of PD with 30 mm balloons. Patients who underwent PD with 30 mm balloons after botulinum toxin injections and a group of age- and sex-matched controls who were treated only with PD were enrolled in the study. Symptom scores were taken before, 1 month after and then every 3 months after PD. There were no significant differences between the two groups in gender, duration or severity of symptoms. One of the 12 patients in the case group relapsed 30 months after PD but the others were in remission for an average of 25.6 months. In the control group, all the patients relapsed after a mean of 12.6 months and needed a 35-mm PD. The cumulative remission rate was significantly higher in the case group compared with the control group (P < 0.01). The mean symptom score decreased by 76% in the case group (P < 0.001) and 53% in the controls (P < 0.01) at the end of the first month. Neither age, sex, nor duration or severity of symptoms were predictive of patients' responses to treatment. It seems that BT may be a meaningful enhancing factor in long-term efficacy of PD. PD with a 30 mm balloon after a BT session may resolve the need for the future higher grade PD.     

Präimplantationsdiagnostik, Pränataldiagnostik und Schwangerschaftsabbruch

Preimplantation genetic diagnosis (PGD) has been vigorously debated in Germany ever since the Bundesärztekammer (BÄK) published a draft of guidelines for PGD in March 2000. Many stakeholders such as churches, medical societies, and diverse associations have participated in the discussion. However, little is known about the attitudes of experts, directly affected patient groups, and the public in Germany. In several studies that are part of the German research program on ethical implications of the Human Genome Project, representative surveys were undertaken to assess the attitudes of the general population (n=1017), five relevant expert groups (n=879), and couples at high risk for genetic disorders(n=324) towards PGD and prenatal diagnosis (PD). All groups favor legislation for PGD. Differences exist in regard to the extent of their approval. For 17% of the high-risk couples with a persisting desire for a child, PGD performed in a neighboring country is the most probable reproductive option. These results should be carefully considered in the ongoing legislation process on human reproduction in our country.     

Traumatic work related fatalities in commercial fishermen in Australia.

OBJECTIVES--To describe the types and circumstances of traumatic work related fatalities in Australian commercial fishermen. METHODS--Work related traumatic fishing fatalities were studied as part of a larger study of all work related traumatic fatalities in Australia from 1982 to 1984. Data on 47 cases were obtained from inspection of coroners' files. RESULTS--The incidence of fatality of 143/100,000 person-years was 18 times higher than the incidence of fatality for the entire workforce, and considerably higher than that of the mining and agricultural workforces. 68% of decedents drowned and 13% died from physical trauma. Rough weather, non-seaworthy vessels, inadequate use of personal flotation devices, and inexperience were associated with many of the fatal incidents. DISCUSSION--Improved vessel and equipment maintenance, better training of workers, greater use of personal flotation devices, and development of improved clothing and personal flotation devices are recommended.     

Nonheme iron in sickle erythrocyte membranes: association with phospholipids and potential role in lipid peroxidation

Previous studies documented the abnormal association of heme and heme proteins with the sickle RBC membrane. We have now examined RBC ghosts and inside-out membranes (IOM) for the presence of nonheme iron as detected by its formation of a colored complex with ferrozine. Sickle ghosts have 33.8 +/- 18.2 nmol nonheme iron/mg membrane protein, and sickle IOM have 4.3 +/- 3.0 nmol/mg. In contrast, normal RBC ghosts and IOM have no detectable nonheme iron. The combination of heme and nonheme iron in sickle IOM averages nine times the amount of membrane- associated iron in normal IOM. Kinetics of the ferrozine reaction show that some of this nonheme iron on IOM reacts slowly and is probably in the form of ferritin, but most (72% +/- 18%) reacts rapidly and is in the form of some other biologic chelate. The latter iron compartment is removed by deferoxamine and by treatment of IOM with phospholipase D, which suggests that it represents an abnormal association of iron with polar head groups of aminophospholipids. The biologic feasibility of such a chelate was demonstrated by using an admixture of iron with model liposomes. Even in the presence of tenfold excess adenosine diphosphate, iron partitions readily into phosphatidylserine liposomes; there is no detectable association with phosphatidylcholine liposomes. To examine the bioavailability of membrane iron, we admixed membranes and t-butylhydroperoxide and found that sickle membranes show a tenfold greater peroxidation response than do normal membranes. This is not due simply to a deficiency of vitamin E, and this is profoundly inhibited by deferoxamine. Thus, while thiol oxidation in sickle membranes previously was shown to correlate with heme iron, the present data suggest that lipid peroxidation is related to nonheme iron. In control studies, we did not find this pathologic association of nonferritin, nonheme iron with IOM prepared from sickle trait, high-reticulocyte, postsplenectomy, or iron-overloaded individuals. These data provide additional support for the concept that iron decompartmentalization is a characteristic of sickle RBCs.