Expression of cyclooxygenase-2 in human transitional cell carcinoma of the urinary bladder

Recent studies suggest that expression of cyclooxygenase-2 (Cox-2) is elevated in transitional cell carcinoma (TCC) of the urinary bladder and that inhibition of Cox-2 activity suppresses bladder cancer in experimental animal models. We have investigated the expression of Cox-2 protein in human TCCs (n = 85), in in situ carcinomas (Tis) of the urinary bladder (n = 17), and in nonneoplastic urinary bladder samples (n = 16) using immunohistochemistry. Cox-2 immunoreactivity was detected in 66% (67 of 102) of the carcinomas, whereas only 25% (4 of 16) of the nonneoplastic samples were positive (P: < 0.005). Cox-2 immunoreactivity localized to neoplastic cells in the carcinoma samples. The rate of positivity was the same in invasive (T1-3; 70%, n = 40) and in noninvasive (Tis and Ta; 65%, n = 62) carcinomas, but noninvasive tumors had a higher frequency (32%) of homogenous pattern of staining (>90% of the tumor cells positive) than the invasive carcinomas (10%) (P: < 0.05). However, several invasive TCCs exhibited the strongest intensity of Cox-2 staining in the invading cells, whereas other parts of the tumor were virtually negative. Finally, strong Cox-2 positivity was also found in nonneoplastic ulcerations (2 of 2) and in inflammatory pseudotumors (2 of 2), in which the immunoreactivity localized to the nonepithelial cells. Taken together, our data suggest that Cox-2 is highly expressed in noninvasive bladder carcinomas, whereas the highest expression of invasive tumors associated with the invading cells, and that Cox-2 may also have a pathophysiological role in nonneoplastic conditions of the urinary bladder, such as ulcerations and inflammatory pseudotumors.     

Protective efficacy of monoclonal antibodies to class 1 and class 3 outer membrane proteins of Neisseria meningitidis B:15:P1.16 in infant rat infection model: new prospects for vaccine development

The protective efficacy of monoclonal antibodies to class 1 and class 3 outer membrane proteins of Neisseria meningitidis B:15:P1.16 was tested in an infant rat infection model. Four monoclonal antibodies to class 1 protein had bactericidal titres exceeding 20,000 and they protected infant rats completely against bacterial challenge with meningococci carrying the same class 1 protein, P1.16. One monoclonal antibody to class 3 protein was highly bactericidal (titer greater than 20,000), whereas two others had no bactericidal activity. All these antibodies gave some protection from infection, resulting in mortalities varying from 66 to 83% as compared to 100% in control rats who had received either unrelated monoclonal antibody or saline. These results strongly speak for class 1 outer membrane protein as a vaccine candidate for meningococcus group B.     

Costimulation of CD28− T Cells Through CD3 and β1-Integrins Induces a Limited Th1 Cytokine Response

The costimulatory molecule CD28 regulates antigen-specific T-cell proliferation and the synthesis of multiple cytokines. The absence of CD28 on a subset of CD8bright+ T cells suggests that these cells may utilize alternative costimulatory pathways or have a limited cytokine response to presented antigen. We used fibronectin, a ligand for the beta1-integrins alpha4beta1 and alpha5beta1, as an alternate costimulatory ligand to assess the functional phenotype of CD8bright+CD28- T cells. CD25 expression was significantly up-regulated in CD8bright+CD28- T cells by immobilized anti-CD3i with fibronectin. Costimulation with fibronectin also significantly augmented anti-CD3i-induced IFN-gamma production only among CD8bright+CD28- T cells. The CD8bright+CD28- T cells did not produce significant IL-2 and IL-10 even in response to maximal stimulation with phorbol myristate acetate and ionomycin. These data support a costimulatory role for ss1-integrins in CD8bright+CD28- T cells and indicate that CD8bright+ CD28- T cells have a restricted Th1 cytokine repertoire.     

Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes

GH hypersecretion in type 1 diabetes has been implicated in the pathogenesis of insulin resistance, and microangiopathic complications, and may result from reduced circulating IGF levels. We examined the effects of recombinant human (rh)IGF-I [complexed in equimolar ratio with rhIGF binding protein (BP)-3 (rhIGF-I/IGFBP-3)] replacement on overnight GH levels and insulin sensitivity in type 1 diabetes. Fifteen subjects, 13-24 yr old (10 male), were given rhIGF-I/IGFBP-3 or placebo as a daily sc injection for 2 d. After the second injection overnight, insulin requirements for euglycemia were determined (0400-0800 h), followed by a 4-h, two-step (insulin, 0.6 and 1.5 mU/kg.min) hyperinsulinemic euglycemic [90 mg/dl (5 mmol/liter)] clamp. In each subject, the protocol was repeated on three occasions in random order. Seven subjects received placebo and rhIGF-I/IGFBP-3 (0.1 mg/kg.d and 0.4 mg/kg.d), and eight subjects received placebo and rhIGF-I/IGFBP-3 (0.2 mg/kg.d and 0.8 mg/kg.d). We found dose-dependent increases in circulating IGF-I and IGFBP-3 concentrations after rhIGF-I/IGFBP-3. These were paralleled by significant reductions in mean overnight GH levels and GH pulse amplitude. We also observed dose-dependent effects of rhIGF-I/IGFBP-3 on overnight insulin requirements for euglycemia, with reductions of up to 41%. Insulin sensitivity, defined by M-values, was improved with rhIGF-I/IGFBP-3 (0.4 and 0.8 mg/kg.d). Thus, restoration of circulating IGF-I and IGFBP-3 levels with rhIGF-I/IGFBP-3 suppresses GH secretion in adolescents with type 1 diabetes, leading to reduced insulin requirements and improvements in insulin sensitivity.     

Starting or switching to biphasic insulin aspart 30 (BIAsp 30) in type 2 diabetes: a multicenter, observational, primary care study conducted in Finland

Aims

Assess safety and glycaemic control in patients initiating insulin with, or switching from basal insulin to, biphasic insulin aspart 30/70 (BIAsp 30) in primary care in Finland.

Methods

A non-randomised, non-interventional, open-label, 26-week study of type 2 diabetes (T2D) patients prescribed BIAsp 30 by their physician, who determined starting dose, titration and injection frequency.

Results

496 patients provided safety data (insulin-naïve n = 197; prior insulin n = 299 [84.9% received NPH insulin]). Three patients (0.6%) reported four SADRs (three hypoglycaemia, one hypoglycaemia with unconsciousness). HbA1c was significantly (p < 0.0001) reduced after 26 weeks’ BIAsp 30 therapy (final dose): insulin-naïve −1.4% (44.4 IU); prior insulin −1.1% (77.4 IU). HbA1c < 7.0% was achieved by 10% of insulin-naïve patients at baseline and 51% at 26-week follow-up. In the prior insulin group, 7% and 30% of patients had HbA1c < 7.0% at baseline and 26 weeks, respectively. Minor hypoglycaemia increased significantly from baseline to study end: insulin-naïve 0.66-6.45 events/patient/year (p < 0.0001); prior insulin 5.11-8.58 events/patient/year (p < 0.05). Weight increased by 1.0 kg (insulin-naïve) and 1.3 kg (previous insulin).

Conclusion

BIAsp 30, initiated and titrated in T2D patients in primary care in Finland, showed a good safety profile and significantly improved glycaemic control.     

The effect of emergency department delay on outcome in critically ill medical patients: evaluation using hospital mortality and quality of life at 6 months

OBJECTIVE: To assess the impact of delay in emergency department (ED) on outcome of critically ill patients admitted to the medical intensive care unit (MICU). Outcome was defined as hospital mortality and as health-related quality of life (HRQoL) at 6 months after intensive care assessed by the 15D measure. The 15D is a generic, 15-dimensional, standardized measure of HRQoL. We hypothesized that prolonged stay in the ED is related to worse outcome. DESIGN AND SETTING: A prospective follow-up cohort study in university hospital. SUBJECTS: All consecutive 1675 patients admitted to the MICU between July 2002 and June 2004. RESULTS: The 15D questionnaire was mailed to all patients alive at 6 months after admission. Of all MICU patients, 64% were admitted from ED. The mean length of stay in the ED was 6.2 h (95%CI 5.9-6.5 h). The hospital mortality rate was 24.4% (20.0% in the ED vs. 33.0% in the non-ED cohort, P < 0.001) and it was associated with higher age and degree of physiological derangement at admission. Neither the length of ED stay was associated with hospital mortality (P = 0.82) nor with HRQoL at 6 months after MICU admission (P = 0.34). Altogether, HRQoL at 6 months was significantly lower compared with the age- and sex-matched general population (P < 0.001). CONCLUSIONS: In a university hospital, the length of ED stay was not associated with the outcome of critically ill medical patients. However, we feel that the effect of ED treatment and delay on outcome and outcome prediction in the critically ill patients deserves further evaluation.     

Subacute sclerosing panencephalitis as a cause of chronic dementia and relapsing brain disorder

Two patients with subacute sclerosing panencephalitis (SSPE) are described because of the course of the disease, which is still thought to be unusual but might prove to be rather common. In both cases there was apparent recovery after about two years of illness. One of the patients had a relapse after eight years of remission and seems to have recovered also from this second period of illness, though with a more severe mental defect than after the first one. Thus, SSPE should be kept in mind as a possible aetiological factor in patients with a persisting slight to severe dementia after a brain disorder. Apparent recovery from SSPE does not exclude the possibility of relapse even many years later.     

A whole-blood lymphocyte stimulation test for the diagnosis of human tularemia

A whole-blood lymphocyte stimulation test was used in the diagnosis of 200 cases of tularemia. Ninety-one of the patients involved had ulceroglandular infection, 81 had pulmonary infection, 13 had glandular infection, four had oropharyngeal infection, and one had oculoglandular infection. The clinical picture was obscure in the remaining 10 cases. Results of the lymphocyte stimulation test became positive in 21.3% of cases during the first week, when an agglutinating titer of greater than or equal to 1:80 was found in 2.1% of patients. During the second week, these proportions were 96.8% and 53.3%, respectively. In only one patient with tularemia (0.5%) did the stimulation test result remain negative, and only one (0.5%) of the 211 control patients had a positive result in the first test. The development of cell-mediated immunity followed the same pattern in patients with ulceroglandular tularemia as in those with pulmonary tularemia.