ß-arrestin-1 participates in thrombosis and regulates integrin aIIbß3 signalling without affecting P2Y receptors desensitisation and function.

ß-arrestin-1 (ß-arr1) and ß-arrestin-2 (ß-arr2) are cytosolic proteins well-known to participate in G protein-coupled receptor desensitisation and signalling. We used genetically-inactivated mice to evaluate the role of ß-arr1 or ß-arr2 in platelet function, P2Y receptor desensitisation, haemostasis and thrombosis. Platelet aggregation, soluble fibrinogen binding and P-selectin exposure induced by various agonists were near normal in ß-arr1-/- and ß-arr2-/- platelets. In addition, deficiency in ß-arr1 or ß-arr2 was not critical for P2Y receptors desensitisation. A functional redundancy between ß-arr1 and ß-arr2 may explain these unchanged platelet responses. Interestingly, ß-arr1-/- but not ß-arr2-/- mice were protected against laser- and FeCl3-induced thrombosis. The tail bleeding times, number of rebleeds and volume of blood loss were unchanged in ß-arr1-/- and ß-arr2-/- mice, suggesting no defect in haemostasis. ß-arr1-/- platelet activation upon adhesion to immobilised fibrinogen was inhibited, as attested by a 37 ± 5% (n = 3, p<0.0001) decrease in filopodia extension, suggesting defective signalling through integrin αIIbß3. ß-arr1 appeared to be located downstream of Src family kinases and to regulate αIIbß3 signalling by increasing Akt phosphorylation. Overall, this study supports a role for ß-arr1 in promoting thrombus formation, in part through its participation in αIIbß3 signalling, and no role of ß-arr1 and ß-arr2 in agonist-induced platelet activation and P2Y receptors desensitisation.

Economic evaluation of maintenance treatment with tacrolimus 0.1% ointment in adults with moderate to severe atopic dermatitis.

BACKGROUND: Rational health care decision-making based on outcomes and economic evidence is essential to provide the best possible care for individual patients with atopic dermatitis (AD). OBJECTIVES: To describe treatment outcomes and to evaluate resource utilization and associated cost of maintenance use of tacrolimus ointment (MU) vs. standard use of tacrolimus ointment (SU) in adults with AD. METHODS: A pan-European, phase III multicentre randomized clinical trial was conducted. Patients with mild to severe AD were randomized to tacrolimus 0.1% ointment (MU) or vehicle (SU) twice per week for 12 months. Disease exacerbations were treated by using open-label tacrolimus 0.1% ointment twice daily. Resource utilization data were collected prospectively alongside the clinical trial. Costs of pooled resource data were determined using German unit cost data. Direct and indirect costs were considered from third party payer, patient and societal perspectives. RESULTS: All patients with moderate and severe AD were included in a subanalysis, 75 patients in the MU arm (57% moderately affected) and 59 patients in the SU arm (59% moderately affected). In patients with moderate AD, the number of disease exacerbations in the MU arm was 2.4 vs. 5.5 in the SU arm (P<0.001); in patients with severe AD corresponding figures were 2.3 vs. 7.4 (P<0.001), respectively. Mean+/-SD total annual cost per patient was euro1525+/-1081 (MU) vs. euro1729+/-1209 (SU) in patients with moderate AD and euro2045+/-2013 (MU) vs. euro2904+/-1510 (SU) in patients with severe AD. CONCLUSIONS: Maintenance treatment with 0.1% tacrolimus ointment is more effective and leads to cost savings and improved health-related quality of life in comparison with standard use of 0.1% tacrolimus ointment, especially in patients with severe AD.

Efficacy of autologous peripheral blood stem cell (PBSC) harvest and engraftment after ablative chemotherapy in pediatric patients.

Thirty-five pediatric patients, 1-16 years of age (median 6.3 years), with neoplastic solid tumors (n=32) or acute leukemia (n=3) underwent peripheral blood stem cell (PBSC) harvest and transplantation at Children's Memorial Hospital between September 1992 and April 1997. A median of four phereses were performed on each patient. Blood samples from 34 of the 35 patients were harvested through existing double-lumen central catheters, using either a Fenwal CS-3000 or COBE Spectra pheresis machine. The pheresis procedures were well tolerated overall. A median of 3.7 x 10(6)/kg CD34+ cells were infused (range, 0.2-15.5 x 10(6)/kg), and all patients engrafted. The median time to an absolute neutrophil count >500/microL was 13 days (range, 9-44 days) and to a platelet count >20,000/microL was 21 days (range, 9-210 days). Two patients died from transplant-related complications. Patients were discharged from the hospital after a median of 22 days (range, 15-64 days). Twenty of the 35 patients are alive, 17 of whom remain disease-free with a median follow-up of 1144 days. According to this study, PBSCs can be successfully harvested and re-infused for marrow reconstitution after myeloablative therapy in children for a variety of pediatric malignancies with low morbidity and mortality.

Acute and chronic effects of winter swimming on LH, FSH, prolactin, growth hormone, TSH, cortisol, serum glucose and insulin.

The present investigation is based on a 2.5 months selbstversuch (self-experiment) of the authors, between October 21 1992, and January 6 1993. 11 healthy students, five females and six males, age 24 to 29 years, and their teachers underwent regular winter swimming at least once a week, for 2 to 10 minutes, at the natural water temperature (6.8 degrees C (October 1992) to 2.0 degrees C (January 1993)) in the southern Baltic Sea. Blood samples were drawn before and 30 and 60 minutes after the cold bath, both at the first and the last day of the swimming season. TSH increased from 0.96 mU/l to 1.42 mU/l (p < 0.01) in the untrained, and from 0.93 mU/l to 1.43 mU/l (p < 0.01) in the cold-trained persons, and decreased thereafter (p < 0.01). Similar changes occurred in cortisol serum concentrations, though psychological stress seemed to interfere with cold stress. Cortisol increased from 99 ng/ml to 133 ng/ml in the untrained, and from 101 ng/ml to 137 ng/ml (p < 0.05) in the cold-trained persons within 30 minutes after cold water immersion, and decreased thereafter (p < 0.01). There were mild decreases in prolactin serum levels after cold stress, whereas FSH, LH and growth hormone remained unaltered. There was a mild initial elevation of serum glucose after cold stress (plus 12 mg/dl, (p < 0.01)) which disappeared after training. There were long term training effects besides the effects on glucose: Basal prolactin levels increased by almost the factor two, and insulin serum levels dropped by almost 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the antibody responses to the 77 Klebsiella capsular types in ankylosing spondylitis and various rheumatic diseases.

The production of antibodies to Klebsiella capsular polysaccharides was measured in sera from either HLA-B27-positive (HLA-B27+) or HLA-B27-negative (HLA-B27-) patients with classical ankylosing spondylitis (n = 54). These sera were compared with sera from patients with various rheumatic diseases (n = 82) and HLA-B27+ or HLA-B27- healthy individuals (n = 85). All sera were analyzed by means of an enzyme-linked immunosorbent assay specific to each of the 77 Klebsiella serotypes. The sera from HLA-B27+ patients with ankylosing spondylitis showed a significantly higher antibody frequency to the capsular types K26, K36, and K50 than the sera from HLA-B27- ankylosing spondylitis patients, patients with psoriatic arthritis, systemic lupus erythematosus, rheumatoid arthritis, or reactive arthritis after Yersinia enterocolitica infection, or healthy controls (P < 0.02). The antibodies were of the immunoglobulin G type. No significant antibody response to the other 74 Klebsiella serotypes, noncapsulated mutants of K26, K36, and K50, or preparations of Citrobacter, Serratia, Hafnia, or Morganella spp. or Streptococcus pneumoniae could be detected. The results might suggest a specific association between these capsular types and HLA-B27+ ankylosing spondylitis and might imply their predominance in this disease.

Divalproex sodium in the treatment of refractory affective disorders.

BACKGROUND: Anticonvulsants have been shown to be effective in many patients with psychiatric disorders, especially those with bipolar affective disorder. We present our clinical experience with divalproex sodium in the treatment of 63 patients with a variety of affective disorders that had proved refractory to conventional pharmacotherapy. METHOD: We reviewed the charts of 63 patients diagnosed as bipolar I (35 patients), bipolar II (23 patients), or schizoaffective, bipolar type (5 patients). Twelve patients who appeared to have recurrent unipolar depression had a retrospectively recognized history of "covert cycling," with brief periods of socially acceptable hypomania occurring between depressive episodes. Prior to treatment with divalproex, 45 patients had been classified as treatment failures with lithium, 29 patients had been classified as treatment failures with carbamazepine, and 35 patients had also failed on a combination of lithium and carbamazepine. Divalproex was given to these patients and titrated to achieve blood levels in the range of 50 to 100 mg/L. RESULTS: Forty-seven (75%) of the 63 patients responded positively to the addition of divalproex to their regimens. Of 45 patients who had failed to respond to lithium, 38 (84%) responded when divalproex was added. Of 29 patients who had failed to respond to carbamazepine, 20 (69%) responded when divalproex was added. Of 26 rapid-cycling patients, 21 (81%) responded to the addition of divalproex. Side effects required drug withdrawal in 9 patients (14%). CONCLUSION: The results confirm previous findings that both mania and rapid mood cycling may respond to a pharmacologic regimen that includes divalproex. Many patients who appear to have recurrent, major unipolar depression may actually be convert cyclers who will respond to divalproex, sometimes in combination with an antidepressant medication.

CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression.

We report on our clinical experience with a combination of a CNS stimulant (either pemoline or dextroamphetamine) and a monoamine oxidase inhibitor (MAOI) for treating 32 depressed patients (mainly outpatients) refractory to standard antidepressant pharmacotherapy. This combination, though not approved by the FDA, appears to be safe and effective. Twenty-five (78%) of these patients experienced at least 6 months of symptom remission with a stimulant + MAOI combination. Many patients required adjunctive antidepressant treatment, including tricyclics and lithium. Side effects were not excessive, though 6 patients (3 unipolar and 3 bipolar) cycled to mania (N = 1) or hypomania (N = 5). None developed hypertensive crises. With properly motivated and complaint patients and careful clinical monitoring by the prescribing psychiatrist, stimulant potentiation of MAOIs may be a viable option for treatment-resistant depressed patients.

The role of serotonin in sexual dysfunction: fluoxetine-associated orgasm dysfunction.

Iatrogenic sexual dysfunction has been associated with many pharmacologic agents. The authors report 6 cases of orgasm dysfunction associated with the use of fluorxetine in 77 depressed outpatients. Fluoxetine is a novel antidepressant known to block the reuptake of serotonin with little effect on other neurotransmitter systems. Because fluoxetine has a specific mechanism of action, it serves as a useful model to hypothesize about potential mechanisms of drug-induced sexual dysfunction. The possible effects of serotonin on central, spinal, and peripheral anatomical areas are discussed in relation to drug-induced sexual dysfunction.