Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness

OBJECTIVE: We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects. RESULTS: Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg). CONCLUSIONS: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.     

The role of adhesion molecules in human leukocyte attachment to porcine vascular endothelium: implications for xenotransplantation

Many obstacles still prevent successful xenotransplantation of porcine donor organs. When hyperacute rejection is averted, transplanted pig organs are subject to acute vascular and cellular rejection. In autologous systems, leukocyte recruitment into inflamed tissues involves selectins, integrins, and Ig family members. To determine whether these mechanisms allow human leukocytes to effectively enter porcine grafts, the pathways by which human leukocytes adhere to TNF-alpha-stimulated porcine aortic endothelium were examined under static and physiologic flow conditions. L-selectin and E-selectin had overlapping functions in neutrophil capture and rolling, whereas Ab blockade of E-selectin and the beta2 integrins inhibited firm arrest of rolling neutrophils. Combined blockade of selectins and beta2 integrins resulted in negligible human neutrophil attachment to pig endothelium. Lymphocyte attachment to porcine endothelium was primarily L-selectin mediated, whereas beta2 integrin and VCAM-1/very late Ag-4 (VLA-4) interactions promoted static adhesion. Concurrent beta2 integrin, VLA-4, VCAM-1, and L-selectin blockade completely inhibited lymphocyte attachment. Thus, interactions between leukocyte-endothelial cell adhesion receptor pairs remained remarkably intact across the human-porcine species barrier. Moreover, disrupting the adhesion cascade may impair the ability of human leukocytes to infiltrate a transplanted porcine organ during rejection.     

Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma. Montelukast Asthma Study Group

The leukotrienes are known to be important mediators of bronchial asthma. The ability of montelukast, a potent and selective CysLT1 leukotriene receptor antagonist, to cause a dose-related improvement in chronic asthma was investigated in a placebo-controlled, multicentre, parallel-group study. After a two week placebo run-in period, chronic asthmatic patients with a forced expiratory volume in one second (FEV1) 40-80% predicted with > or = 15% increase (absolute value) after beta2-agonist were randomly assigned to one of four treatment groups (placebo or montelukast 2, 10, or 50 mg once daily in the evening) for a three week, double-blind treatment period. For patient-reported end-points (daytime symptom score, use of as needed inhaled beta2 agonist, asthma-specific quality of life) and frequency of asthma exacerbations, montelukast 10 and 50 mg caused similar responses, superior to 2 mg and significantly (p<0.05; linear trend test) different from placebo. All three doses caused improvements in FEV1 and morning and evening peak expiratory flow rate (PEFR) that were significantly (p<0.05) different from placebo. Differences (least square mean) between the pooled 10 and 50 mg montelukast treatment groups and placebo were: 7.1% change from baseline in FEV1, 19.23 L x min(-1) in morning PEFR, -0.29 in daytime asthma symptom score (absolute value), and -0.82 in beta2-agonist use (puff x day(-1)). The incidence of adverse experiences was neither dose-related nor different between montelukast and placebo treatments. We conclude that montelukast causes a dose-related improvement in patient-reported asthma end-points over the range 2-50 mg. Montelukast causes benefit to chronic asthmatic patients by improving asthma control end-points.     

Comparative evaluation of National Committee for Clinical Laboratory Standards broth macrodilution and agar dilution screening methods for testing fluconazole susceptibility of Cryptococcus neoformans

A simple screening method for fluconazole susceptibility of Cryptococcus neoformans using 2% dextrose Sabouraud dextrose agar (SabDex) with fluconazole was compared to the National Committee for Clinical Laboratory Standards (NCCLS) broth macrodilution method. By this method, fluconazole-susceptible C. neoformans isolates are significantly smaller on medium with fluconazole than on fluconazole-free medium. Isolates with decreased susceptibility have normal-size colonies on medium containing fluconazole. The 48-h NCCLS broth macrodilution MICs (NCCLS MICs) for isolates with normal-size colonies on 8- or 16-microg/ml fluconazole plates were predicted to be > or =8 or > or =16 microg/ml, respectively. On medium with 16 microg of fluconazole per ml, all strains (84 of 84) for which the NCCLS MICs were <16 microg/ml were correctly predicted, as were all isolates (7 of 7) for which the MICs were > or =16 microg/ml. Agar dilution appears to be an effective screening method for fluconazole resistance in C. neoformans.     

Double blind, randomised, placebo controlled study of oral vancomycin in prevention of necrotising enterocolitis in preterm, very low birthweight infants

AIMS: To evaluate the effectiveness of oral vancomycin in the prophylaxis of necrotising enterocolitis in preterm, very low birthweight infants. METHODS: A prospective, double blind, randomised, placebo controlled study in a tertiary referral centre of a university teaching hospital was conducted on 140 very low birthweight infants consecutively admitted to the neonatal unit. The babies were randomly allocated to receive oral vancomycin (15 mg/kg every 8 hours for 7 days) or an equivalent volume of placebo solution. Prophylaxis was started 24 hours before the start of oral feeds. All suspected cases of necrotising enterocolitis were investigated with a full sepsis screen and serial abdominal radiographs. Necrotising enterocolitis was diagnosed and staged according to modified Bell's criteria. RESULTS: Nine of 71 infants receiving oral vancomycin and 19 of 69 infants receiving the placebo solution developed necrotising enterocolitis (p = 0.035). Infants with necrotising enterocolitis were associated with a significant increase in mortality (p = 0.026) and longer duration of hospital stay (p = 0.002). CONCLUSIONS: Prophylactic oral vancomycin conferred protection against necrotising enterocolitis in preterm, very low birthweight infants and was associated with a 50% reduction in the incidence. However, widespread implementation of this preventive measure is not recommended, as it would only be effective in necrotising enterocolitis caused by Gram positive organisms and could increase the danger of the emergence of vancomycin resistant or dependent organisms. Its use should be restricted to a high prevalence nursery for a short and well defined period in a selected group of high risk patients.     

Linkage analysis of candidate genes in autoimmune thyroid disease: 1. Selected immunoregulatory genes. International Consortium for the Genetics of Autoimmune Thyroid Disease

Graves' and Hashimoto's diseases are autoimmune thyroid diseases in which the genetic contribution is complex. For this reason, identification of necessary susceptibility genes has been difficult. However, a number of immunoregulatory genes have been implicated by association studies, including: CTLA-4, a recently described protein involved in antigen presentation, located on chromosome 2q33; the T-cell receptor V alpha and V beta gene complexes, located on 14q11 and 7q35, respectively; and the Ig gene complex (IgH), located on 15q11. We used polymorphic microsatellite markers located within these genes, or gene complexes, to test for linkage (rather than association), to each of these candidates. Using markers within the loci allowed us to assume a fixed recombination fraction of 0.01 in the tested model. Three hundred eight subjects from 48 multiplex families were studied, with 142 affected subjects. Using this set of families, we have previously shown evidence of linkage with a major susceptibility locus for Graves' disease (GD-1) on 14q24.3-31, with a maximum lod (logarithm + odds) score of 2.1, at a penetrance of 80% and with a dominant mode of inheritance. In the present study, we obtained consistently negative lod scores for each of the candidate genes, assuming either dominant or recessive modes of inheritance. These data, therefore, showed evidence against linkage with all the candidate genes. Unlike association studies, linkage analyses detect major genetic influences on disease susceptibility exerted by the linked loci. The lack of linkage for the immunoregulatory genes that were studied indicated, therefore, that they were not major contributors to disease etiology.     

Tutor-student interaction in the operating theatre

This paper examines the view that productive teaching in the operating theatre requires a recognition of the unique set of factors which may influence the process of communication. For tutor-student interaction to occur in a productive manner, the tutor's behaviour will need to be modified to suit the demands of the other tasks in which both tutor and student are involved. The particular value of recognizing the role of nonverbal behaviours during interaction is discussed, with the use of specific examples related to the positioning of the tutor and student, and their use of facial expression, the eyes and voice.     

Pleiotrophin stimulates tyrosine phosphorylation in NIH 3T3 and NB41A3 cells

Pleiotrophin (PTN) is a heparin-binding cytokine that functions as a neurite outgrowth promoting and mitogenic activity in vitro. PTN is highly conserved and its gene is widely expressed in mammalian tissues during development, suggesting important roles of PTN in vivo. However, the mechanisms by which PTN mediates its functional activities are unknown. We now report that an approximately 200 kDa (p200) protein is phosphorylated (pp200) in PTN stimulated NIH 3T3 and NB41A3 cells five minutes after stimulation with PTN. Phosphorylation is maximum at 15 minutes and is PTN concentration dependent. pp200 is recognized by antiphosphotyrosine antibodies and contains both phosphotyrosine and phosphoserine by phosphoamino acid analysis. The results suggest that PTN functions in part through activation of protein kinase(s) in NIH 3T3 and NB41A3 cells.