A randomized crossover study of sulphonylurea and insulin treatment in patients with type 2 diabetes poorly controlled on dietary therapy

In 13 non-obese patients with Type 2 diabetes mellitus who failed to achieve adequate blood glucose control on dietary treatment (fasting blood glucose 13.4 +/- 2.7 (+/- SD) mmol l-1, glycosylated haemoglobin 13.0 +/- 1.7%), the effects of 6 months insulin or sulphonylurea therapy on blood glucose control and lipid metabolism were compared in a randomized crossover study. Three patients, who showed a clear improvement on insulin (median glycosylated haemoglobin fell from 14.7 to 8.6%), withdrew from the study prematurely because of subjective and objective signs of hyperglycaemia after crossover from insulin to sulphonylurea. Daily dose after 6 months was 2000 mg tolbutamide (n = 3), 18 +/- 1 mg glibenclamide (n = 7), or 34 +/- 3 U insulin. On insulin, fasting (8.0 +/- 1.9 mmol l-1) and postprandial blood glucose (10.4 +/- 2.7 mmol l-1), and glycosylated haemoglobin (9.5 +/- 1.1%) were lower than on sulphonylurea (11.0 +/- 3.4 mmol l-1, 14.4 +/- 4.8 mmol l-1 and 11.0 +/- 2.5%, respectively, p less than 0.05 in each case). Median increase in body weight was greater on insulin (4.2 vs 1.1 kg, p less than 0.05). Six patients experienced improved well-being on insulin compared with sulphonylurea. Median plasma non-esterified fatty acids decreased from 825 mumol l-1 to 476 mumol l-1 (sulphonylurea) and 642 mumol l-1 (insulin, both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction between attention demanding motor and cognitive tasks and static postural stability

BACKGROUND: Due to the often-reported decrease in postural stability in the elderly, it is important to understand factors that may contribute to reduced postural stability. It is possible that attention-demanding focal tasks performed concurrent with postural regulation influence postural stability. OBJECTIVE: This study utilized dual-task methodology to determine if motor or cognitive focal tasks interact with center of pressure (COP) excursion during static bipedal stance in healthy young and healthy elderly subjects (n = 18). METHODS: The cognitive task involved silently solving an orally-presented multi-step arithmetic problem over a 30-second period. The motor task was a 30-second bilateral static finger-thumb pinch task performed at 10% of maximal voluntary contraction with a pair of pinch-force transducers. Each focal task was performed separately, and in a condition in which both tasks were performed simultaneously. COP excursion was compared in quiet standing (no focal task) and during performance of the focal tasks with full vision and with vision occluded. RESULTS: Performance on the focal tasks was unaffected by increased postural demands during stance as compared to a seated baseline condition. This was the case for both age groups, and for the full vision and occluded vision conditions. Medio-lateral COP excursion was reduced over the quiet standing pretest condition when attentional focus was on the cognitive task, suggesting that COP was influenced centrally during cognition. In contrast, COP excursion increased over the quiet standing pretest condition when performing the motor focal task, suggesting a reduced ability to suppress sway when the motor system was concurrently occupied with a voluntary task that shared the same input-output resources. CONCLUSION: The ability to share attentional resources among focal and postural tasks was similar in healthy young and elderly subjects.     

Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene.

In the course of a systematic genomic survey, 22 manic-depressive (bipolar) families were examined for linkage to 11 chromosome 18 pericentromeric marker loci, under dominant and recessive models. Overall logarithm of odds score analysis for the pedigree series was not significant under either model, but several families yielded logarithm of odds scores consistent with linkage under dominant or recessive models. Affected sibling pair analysis of these data yielded evidence for linkage (P < 0.001) at D18S21. Affected pedigree member analysis also suggests linkage, with multilocus results for five loci giving P < 0.0001 and P = 0.0007 for weighting functions f(p) = 1 and 1/square root p, respectively, where p is the allele frequency. These results imply a susceptibility gene in the pericentromeric region of chromosome 18, with a complex mode of inheritance. Two plausible candidate genes, a corticotropin receptor and the alpha subunit of a GTP binding protein, have been localized to this region.     

Return on educational investment in geriatrics training

The graying of America will increase demand for specialists in geriatric medicine, but the proportion of filled fellowship positions in geriatric medicine has been falling recently. The objective of this study was to examine the financial return of additional training in geriatric medicine for general internists by using survey data from the American Medical Association and standard financial techniques. The return on educational investment over a working lifetime for a third-year resident in internal medicine who was considering specialty training in geriatric medicine between 1993 and 1999 was calculated. Physicians self-identified as geriatricians had lower incomes and lower incomes per hour than age-matched general internists, although the disparities decreased somewhat over the period examined. Regression modeling suggested that incomes for geriatricians are lower than expected and that this disparity increased in the last 2 years of the study. Some of the income disparities may be attributable to the fact that geriatricians obtain a greater proportion of their total revenue from Medicare than is optimal in the generalist setting. Returns on educational investment for geriatrics training were negative, although less so in recent years. Analysis suggests that the pursuit of additional specialty training in geriatric medicine has a negative financial return. Financial returns and the incentives they create should be carefully considered in meeting the anticipated geriatrics workforce needs of the nation.     

Comparative responsiveness of HL-60, HL-60R, and HL-60R+ (LRARSN) cells to retinoic acid, calcitriol, 9 cis-retinoic acid, and sodium butyrate

In HL-60 cells, retinoic acid (RA) and 9 cis-RA induce granulocytic differentiation, and calcitriol and sodium butyrate induce monocytic differentiation. To study the role of retinoid resistance on the response to these agents, we investigated their effects in HL-60 cells, retinoid-resistant HL-60R cells, and HL-60R+ cells in which retinoid sensitivity has been restored. In HL-60 cells, cathepsin D (ctsd) mRNA levels are increased by these agents and by cholera toxin after pretreatment with each agent. Calcitriol, 9 cis-RA, and sodium butyrate increase interleukin-8 (IL-8) mRNA expression, and pretreatment with these agents or RA potentiates the stimulation of IL-8 by phorbol ester (TPA). Pretreatment of HL-60 cells with all of the agents confers inducibility of cathepsin L (ctsl) mRNA by TPA in previously unresponsive cells. In HL-60R cells, none of the agents alone or in combination significantly enhances the expression of the ctsd, IL-8, or ctsl mRNAs. Retinoid stimulation (either alone or in combination with the other agents) of the three mRNAs is partially restored in the HL- 60R+ cells. Calcitriol does not alter the expression of any of these mRNAs, and only the stimulation of IL-8 mRNA by sodium butyrate is recovered. Treatment with all of the agents inhibits proliferation and stimulates differentiation of the HL-60 cells. RA and calcitriol are unable to inhibit proliferation of the HL-60R cells, whereas only calcitriol fails to inhibit proliferation of the HL-60R+ cells. None of the agents induces differentiation in either the HL-60R or HL-60R+ cells. Therefore, the mutation of the RA receptor alpha is insufficient to account for the altered responses of the HL-60R cells, and there are likely defects in other signaling pathways in these cells. These cells may prove useful in examining the mechanism of cross-resistance between various differentiating agents.     

Three-dimensional structure of holo 3 alpha,20 beta-hydroxysteroid dehydrogenase: a member of a short-chain dehydrogenase family.

The x-ray structure of a short-chain dehydrogenase, the bacterial holo 3 alpha,20 beta-hydroxysteroid dehydrogenase (EC 1.1.1.53), is described at 2.6 A resolution. This enzyme is active as a tetramer and crystallizes with four identical subunits in the asymmetric unit. It has the alpha/beta fold characteristic of the dinucleotide binding region. The fold of the rest of the subunit, the quaternary structure, and the nature of the cofactor-enzyme interactions are, however, significantly different from those observed in the long-chain dehydrogenases. The architecture of the postulated active site is consistent with the observed stereospecificity of the enzyme and the fact that the tetramer is the active form. There is only one cofactor and one substrate-binding site per subunit; the specificity for both 3 alpha- and 20 beta-ends of the steroid results from the binding of the steroid in two orientations near the same cofactor at the same catalytic site.     

Successful donor cell engraftment in a recipient of bone marrow from a cadaveric donor

A 12-year-old male with acute lymphocytic leukemia received donor bone marrow from his histocompatible father whose marrow was harvested 40 minutes postmortem after he suffered a myocardial infarction. The marrow was stored in liquid nitrogen for 17 days prior to infusion into the recipient. Trypan blue viability was greater than 99% for the fresh marrow. Progenitor cell assays revealed that 20% of the CFU-MIX, 16% of the BFU-E, 10% of the CFU-E, and 17% of the CFU-GM were spared during the cryopreservation period. Posttransplantation, the recipient had a leukocyte count greater than 10(3)/microL by day 26. Southern blotting analysis documented the donor origin of the peripheral blood mononuclear cells and granulocytes isolated 46 days posttransplantation. Unfortunately, the patient died of complications relating to graft-v-host disease 67 days following transplantation. This case demonstrates the feasibility of cadaveric marrow as a source of donor cells and is the first reported case of documented leukocyte engraftment in a recipient of cadaveric marrow.     

Deficiency of leukocyte surface glycoproteins Mo1, LFA-1, and Leu M5 in a dog with recurrent bacterial infections: an animal model

A dog with severe recurrent bacterial infections, impaired pus formation, delayed wound healing, and severe persistent leukocytosis was the result of a mother-son mating. Assessment of leukocyte function revealed profound abnormalities in adherence-dependent activities including impaired granulocyte adhesion to glass/plastic surfaces or nylon wool, decreased granulocyte aggregation and chemotaxis, and diminished lymphocyte blastogenesis, but normal neutrophil oxidative activity, serum immunoglobulin, and complement levels. By immunofluorescence analysis, CD11b and CD18 monoclonal antibodies specific for the 155-kd alpha polypeptide of Mo1 (gp 155, 94) and the 94 kd beta peptide common to Mo1, LFA-1 (gp 170, 94), and Leu M5 (p 150, 94) (surface molecules that promote leukocyte adhesion) failed to bind to unstimulated and A23187 calcium ionophore-stimulated granulocytes or mononuclear cells of the affected dog as compared with strong specific binding to canine control cells. The Mo1 glycoproteins were only barely detectable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of immunoprecipitates from lysates of 125I surface-labeled neutrophils from the affected dog as compared with intense bands seen with canine control cell precipitates. We conclude that this dog has a severe leukocyte surface glycoprotein deficiency syndrome that is similar, if not identical, to that recently recognized in humans. Dogs with deficiency of leukocyte Mo1, LFA-1, and Leu M5 expression may represent a useful animal model to characterize further the molecular basis for an inherited disorder in leukocyte effector function.