Response from lieberman and colleagues

Respond on comments on Lieberman's article: Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice. Environ Health Perspect 107:161-165     

Lumbopelvic kinematics and trunk muscle activity during sitting on stable and unstable surfaces

STUDY DESIGN: A single-group comparative study. OBJECTIVES: To compare lumbopelvic kinematics and muscle activation patterns while sitting on stable and unstable surfaces. BACKGROUND: Unstable surfaces are commonly used during the rehabilitation of certain low back pain disorders. The benefits postulated are increased muscle activity and facilitation of sustainable midrange positions via neuromuscular control. The use of unstable sitting devices in the workplace is controversial, as the postulated increase in muscle activity is thought to lead to a muscle fatigue/pain response. However, little evidence exists for or against the ability of these devices to alleviate or prevent spinal pain. METHODS AND MEASURES: This study included 26 healthy adults (14 male, 12 female). Fastrak 3-dimensional motion analysis detected lumbar curvature, pelvic tilt, and postural sway during sitting on a stable and unstable surface over 5-minute periods. Surface electromyography was used to measure activity in the superficial lumbar multifidus, transverse fibers of internal oblique, and iliocostalis lumborum pars thoracis. RESULTS: Spinal postures were similar for sitting on a stable and unstable surface. Significant increases in postural sway were detected (P = .013) in 3 dimensions of movement during sitting on an unstable surface. Gender differences were noted. No EMG amplitude or variance differences were detected between seating conditions. CONCLUSIONS: Preliminary data show that sitting on unstable surfaces induces greater spinal motion, but does not significantly alter the lumbosacral posture nor the amount of activity in the superficial trunk muscles under investigation.     

‘Sometimes,it's easier to write the prescription’: physician and patient accounts of the reluctant medicalisation of sleeplessness

The medicalisation of sleep is a rich and growing area of sociological interest. Previous research suggests that medicalisation is occurring within the context of physician office visits, but the inner workings remain unclear. This study is the first to provide perspectives on the office visit interaction from both sleepless patients (n = 27) and the physicians (n = 8) who treat them. Analyses of semi‐structured qualitative interviews reveal that sleep‐related conversations are typically patient‐initiated in routine office visits. Physicians and patients conceptualised insomnia as a symptom of another issue (depression), an everyday problem of living (stress) or the result of a natural life process (aging). Lack of sleep was not necessarily linked to daytime impairment. Even though sleep aids were routinely requested and prescribed, patients and physicians consistently expressed attitudes of reluctance toward the use of sedative hypnotics. I call this a case of ‘reluctant medicalisation’ and highlight the liminal space between pathology and normalcy inhabited by patients and physicians. I also build on recent work acknowledging the dynamics between macro and micro levels of medicalisation and illustrate the influence of multilevel ‘engines’ (consumerism, biotechnology, managed care and physicians) in patients’ and physicians’ accounts. A virtual abstract of this paper can be viewed at: https://youtu.be/7uLHOJPHF0I     

Effect of hepatic dysfunction on oral cyclosporin pharmacokinetics in marrow transplant patients

The effect of hepatic dysfunction, defined as abnormal serum bilirubin level, on oral cyclosporin (CSP) pharmacokinetics was examined in 28 marrow transplant patients who received CSP for prophylaxis of graft-v- host disease. Serum CSP concentrations were measured by radioimmunoassay. Forty-one concentration-time courses were studied, divided among patients with no (less than 1.2 mg/dL), mild (1.2 to 2.0 mg/dL), and moderate (2.0 to 5.0 mg/dL) hepatic dysfunction. CSP elimination, as determined by elimination rate constant and clearance, was delayed in patients with moderate hepatic dysfunction compared to those with no hepatic dysfunction (P less than .05). The volume of distribution, lag time for absorption, maximum serum concentration, and time at which the maximum concentration was achieved was not affected by hepatic function. These data indicate that patients with moderate hepatic dysfunction have delayed CSP or CSP metabolite elimination and may be at higher risk for developing CSP-related toxicity.     

Suicide in Northern Ireland: a comparison of two quinquennia (1982–1986 and 1987–1991)

This study compares government records of death by suicide, in Northern Ireland, during two quinquennia in the decade 1982–1991. Specifically these quinquennia are 1982–1986 l 1987–1991. During the latter quinquennium there was an increse m rate for males in most age groups, except the 45–54 and the over 65 years age groups. However, females had an increased rate in the 15–24 and 35–54 years age groups, but have a decreased rate in the other age groups. There has been a decrease in the rate of suicides by poisoning with solids and liquids for both sexes. However, male suicide rates by more violent methods have increased substantially during the latter quinquennium. Three cohorts of males, those in the 15–24, 25–34, and 55–64 age groups, have shown substantial increases during the latter quinquennium. Suggestions for psychiatric intervention strategies are made.     

Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link

The association of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) raises the yet unresolved questions as to whether these two disorders are different forms of the same disease. We compared two groups of patients with respect to cytogenetic features, glycosylphosphatidylinositol (GPI)-linked protein expression, protein C/protein S/thrombomodulin/antithrombin III activity, and PIG-A gene expression. The first group consisted of eight patients with PNH (defined as positive Ham and sucrose tests at diagnosis), and the second, 37 patients with AA. Twelve patients with AA later developed a PNH clone. Monoclonal antibodies used to study GPI-linked protein expression (CD14 [on monocytes], CD16 [on neutrophils], CD48 [on lymphocytes and monocytes], CD67 [on neutrophils and eosinophils], and, more recently, CD55, CD58, and CD59 [on erythrocytes]) were also tested on a cohort of 20 normal subjects and five patients with constitutional AA. Ham and sucrose tests were performed on the same day as flow- cytometric analysis. Six of 12 patients with AA, who secondarily developed a PNH clone, had clinical symptoms, while all eight patients with PNH had pancytopenia and/or thrombosis and/or hemolytic anemia. Cytogenetic features were normal in all but two patients. Proteins C and S, thrombomodulin, and antithrombin III levels were within the normal range in patients with PNH and in those with AA (with or without a PNH clone). In patients with PNH, CD16 and CD67 expression were deficient in 78% to 98% of the cells and CD14 in 76% to 100%. By comparison, a GPI-linked defect was detected in 13 patients with AA, affecting a mean of 32% and 33% of CD16/CD67 and CD14 cell populations, respectively. Two of three tested patients with PNH and 1 of 12 patients with AA had a defect in the CD48 lymphocyte population. In a follow-up study of our patient cohort, we used the GPI-linked molecules on granulocytes and monocytes investigated earlier and added the study of CD55, CD58, and CD59 on erythrocytes. Two patients with PNH and 14 with AA were studied for 6 to 13 months after the initial study. Among patients with AA, four in whom no GPI-anchoring defect was detected in the first study had no defect in follow-up studies of all blood-cell subsets (including erythrocytes). Analysis of granulocytes, monocytes, and erythrocytes was performed in 7 of 13 AA patients in whom affected monocytes and granulocytes were previously detected. A GPI-anchoring defect was detected on erythrocytes in five of six.(ABSTRACT TRUNCATED AT 400 WORDS)     

A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release

Pancreatic beta-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic beta-cell mass. These effects are mediated via stimulation of cAMP through beta-cell GLP-1 receptors. We report that the Galpha(s)-coupled receptor GPR119 is largely restricted to insulin-producing beta-cells of pancreatic islets. Additionally, we show here that GPR119 functions as a glucose-dependent insulinotropic receptor. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 was suitable for the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cAMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice but not in GPR119-deficient mice. Diabetic KK/A(y) mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel antihyperglycemic agents acting in a glucose-dependent fashion.