Anthony J. O’Sullivan

Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content.

Insulin resistance is associated with increased circulating lipids and skeletal muscle lipid content. Chronic nicotinic acid (NA) treatment reduces insulin sensitivity and provides a model of insulin resistance. We hypothesized that the reduction in insulin sensitivity occurs via elevation of circulating nonesterified fatty acids (NEFAs) and an increase in intramyocellular lipid (IMCL). A total of 15 nondiabetic males (mean age 27.4 +/- 1.6 years) were treated with NA (500 mg daily for 1 week, 1 g daily for 1 week). Insulin sensitivity (glucose infusion rate [GIR]) was determined pre- and post-NA by euglycemic-hyperinsulinemic clamp. Substrate oxidation was determined by indirect calorimetry. Skeletal muscle lipid was assessed by estimation of long-chain acyl-CoA (LCACoA) and triglyceride (TG) content and by (1)H-magnetic resonance spectroscopy quantification of IMCL (n = 11). NA reduced GIR (P =.03) and nonoxidative glucose disposal (P <.01) and increased fasting NEFAs (P =.01). The decrease in GIR related significantly to the increase in fasting NEFAs (r(2) =.30, P =.03). The intrasubject increase in basal and clamp fat oxidation correlated with the decrease in GIR (r(2) =.45, P <.01 and r(2) =.63, P <.01). There were no significant changes in muscle LCACoA, TG, or IMCL content. Therefore, induction of insulin resistance by NA occurs with increased availability of circulating fatty acids to muscle rather than with increased muscle lipid content.

Sex Steroid Regulation of Growth Hormone Secretion and Action

Evidence that oestrogen is involved in the regulation of the somatotrophic axis in adult humans is provided by the observations that mean growth hormone (GH) levels are higher in women than men, that the fall in GH and insulin-like growth factor-1 (IGF-1) with aging are correlated to oestradiol levels and that oestrogen increases the GH responses to provocative stimuli. To investigate whether oestrogen modulates GH secretion and action in adult life, we studied the impact of oestrogen replacement on circulating GH and IGF-1 levels in postmenopausal women. Since the liver is the major source of circulating IGF-1 and the oral route of oestrogen delivery causes nonphysiologic effects on hepatic proteins, we compared the effects of oral and transdermal routes of delivery. Oral ethinyl oestradiol administration resulted in a significant fall in mean IGF-1 levels and a threefold increase in mean 24-hour GH. Transdermal administration of 17 beta-oestradiol resulted in a slight increase in serum IGF-1 but no change in mean 24-hour GH levels. To determine whether differences in oestrogen type rather than in the route of delivery caused the different effects on the GH/IGF-1 axis, we compared the effects of three oral oestrogen formulations. Ethinyl oestradiol, conjugated equine oestrogen and oestradiol valerate each induced a fall in IGF-1 and a rise in mean 24-hour GH levels in postmenopausal women. To determine the significance of oestrogen-induced changes on IGF-1, we studied effects on markers of connective and bone tissue activity. We found that propeptide concentrations of type III and type I collagen, and osteocalcin rose and fell in parallel with IGF-1 during oral or transdermal oestrogen therapy. Oestrogen causes distinct, route-dependent effects on the somatotrophic axis. The dissociation of the GH/IGF-1 axis by the oral route is likely to arise from impaired hepatic IGF-1 production which causes increased GH secretion through reduced feedback inhibition. Oestrogen treatment may have longer-term metabolic effects on hypogonadal women exerted through effects on the somatotrophic axis.

Changes in insulin resistance and HbA1c are related to exercise-mediated changes in body composition in older adults with type 2 diabetes: interim outcomes from the GREAT2DO trial.

OBJECTIVE To investigate changes in body composition after 12 months of high-intensity progressive resistance training (PRT) in relation to changes in insulin resistance (IR) or glucose homeostasis in older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS One-hundred three participants were randomized to receive either PRT or sham exercise 3 days per week for 12 months. Homeostasis model assessment 2 of insulin resistance (HOMA2-IR) and glycosylated hemoglobin (HbA1c) were used as indices of IR and glucose homeostasis. Skeletal muscle mass (SkMM) and total fat mass were assessed using bioelectrical impedance. Visceral adipose tissue, mid-thigh cross-sectional area, and mid-thigh muscle attenuation were quantified using computed tomography. RESULTS Within the PRT group, changes in HOMA2-IR were associated with changes in SkMM (r = −0.38; P = 0.04) and fat mass (r = 0.42; P = 0.02). Changes in visceral adipose tissue tended to be related to changes in HOMA2-IR (r = 0.35; P = 0.07). Changes in HbA1c were related to changes in mid-thigh muscle attenuation (r = 0.52; P = 0.001). None of these relationships were present in the sham group (P > 0.05). Using ANCOVA models, participants in the PRT group who had increased SkMM had decreased HOMA2-IR (P = 0.05) and HbA1c (P = 0.09) compared with those in the PRT group who lost SkMM. Increases in SkMM in the PRT group decreased HOMA2-IR (P = 0.07) and HbA1c (P < 0.05) compared with those who had increased SkMM in the sham group. CONCLUSIONS Improvements in metabolic health in older adults with type 2 diabetes were mediated through improvements in body composition only if they were achieved through high-intensity PRT.

Assessment of professionalism in undergraduate medical students

Background: Professionalism is comprised of a set of values and behaviours that underpin the social contract between the public and the medical profession. Medical errors are reported to result in significant morbidity and mortality and are in-part related to underdeveloped professionalism. Aims: The aim was to determine whether specific aspects of professionalism were underdeveloped in medical students. Method: A questionnaire with 24 vignettes was taken by Year 2, 4, and 6 medical students and their responses were compared to responses from practicing Medical Academics. Results: Second, fourth and sixth Year medical students’ responses differed from Academics in two aspects of professionalism, firstly, high ethical and moral standards and secondly, humanistic values such as integrity and honesty. Only Year 2 medical students’ responses were different from Academics when it came to responsibility and accountability. Conclusions: Certain aspects of professionalism seem to be underdeveloped in medical students. These aspects of professionalism may need to be targeted for teaching and assessment in order that students develop as professionally responsible practitioners. In turn, students with well-developed professionalism may be less involved in medical error, and if involved they may have the personal values which can help them deal with error more honestly and effectively.

The Teamwork Mini-Clinical Evaluation Exercise (T-MEX): a workplace-based assessment focusing on collaborative competencies in health care.

Purpose Teamwork is an important and challenging area of learning during the transition from medical graduate to intern. This preliminary investigation examined the psychometric and logistic properties of the Teamwork Mini-Clinical Evaluation Exercise (T-MEX) for the workplace-based assessment of key competencies in working with health care teams. Method The authors designed the T-MEX for direct observation and assessment of six collaborative behaviors in seven clinical situations important for teamwork, feedback, and reflection. In 2010, they tested it on University of New South Wales senior medical students during their last six-week clinical term to investigate its overall utility, including validity and reliability. Assessors rated students in different situations on the extent to which they met expectations for interns for each collaborative behavior. Both assessors and students rated the tool’s usefulness and feasibility. Results Assessment forms for 88 observed encounters were submitted by 25 students. The T-MEX was suited to a broad range of collaborative clinical practice situations, as evidenced by the encounter types and the behaviors assessed by health care team members. The internal structure of the behavior ratings indicated construct validity. A generalizability study found that eight encounters were adequate for high-stakes measurement purposes. The mean times for observation and feedback and the participants’ perceptions suggested usefulness for feedback and feasibility in busy clinical settings. Conclusions Findings suggest that the T-MEX has good utility for assessing trainee competence in working with health care teams. It fills a gap within the suite of existing tools for workplace-based assessment of professional attributes.

Psychiatric symptoms as a clinical presentation of Cushing’s syndrome

Cushing’s syndrome can present with a spectrum of symptoms; however, it is less recognised that psychiatric symptoms can form part of the clinical presenting features. In the investigations for an organic cause for a psychiatric illness, Cushing’s syndrome needs to be considered, especially if there are other features such as hirsutism or hypertension. In this article, the two cases reported demonstrate that a prompt diagnosis is not only important for psychiatric management but also crucial for timely institution of the necessary treatment of life-threatening causes of hypercortisolaemia such as metastatic adrenal carcinoma.

Clinical capabilities of graduates of an outcomes-based integrated medical program

BackgroundThe University of New South Wales (UNSW) Faculty of Medicine replaced its old content-based curriculum with an innovative new 6-year undergraduate entry outcomes-based integrated program in 2004. This paper is an initial evaluation of the perceived and assessed clinical capabilities of recent graduates of the new outcomes-based integrated medical program compared to benchmarks from traditional content-based or process-based programs.MethodSelf-perceived capability in a range of clinical tasks and assessment of medical education as preparation for hospital practice were evaluated in recent graduates after 3 months working as junior doctors. Responses of the 2009 graduates of the UNSW’s new outcomes-based integrated medical education program were compared to those of the 2007 graduates of UNSW’s previous content-based program, to published data from other Australian medical schools, and to hospital-based supervisor evaluations of their clinical competence.ResultsThree months into internship, graduates from UNSW’s new outcomes-based integrated program rated themselves to have good clinical and procedural skills, with ratings that indicated significantly greater capability than graduates of the previous UNSW content-based program. New program graduates rated themselves significantly more prepared for hospital practice in the confidence (reflective practice), prevention (social aspects of health), interpersonal skills (communication), and collaboration (teamwork) subscales than old program students, and significantly better or equivalent to published benchmarks of graduates from other Australian medical schools. Clinical supervisors rated new program graduates highly capable for teamwork, reflective practice and communication.ConclusionsMedical students from an outcomes-based integrated program graduate with excellent self-rated and supervisor-evaluated capabilities in a range of clinically-relevant outcomes. The program-wide curriculum reform at UNSW has had a major impact in developing capabilities in new graduates that are important for 21st century medical practice.

Predictive validity of a new integrated selection process for medical school admission

BackgroundThis paper is an evaluation of an integrated selection process utilising previous academic achievement [Universities Admission Index (UAI)], a skills test [Undergraduate Medicine and Health Sciences Admission Test (UMAT)], and a structured interview, introduced (in its entirety) in 2004 as part of curriculum reform of the undergraduate Medicine Program at the University of New South Wales (UNSW), Australia. Demographic measures of gender, country of birth, educational background and rurality are considered.MethodAdmission scores and program outcomes of 318 students enrolled in 2004 and 2005 were studied. Regression analyses were undertaken to determine whether selection scores predicted overall, knowledge-based and clinical-based learning outcomes after controlling for demographics.ResultsUAI attained the highest values in predicting overall and knowledge-based outcomes. The communication dimension of the interview achieved similar predictive values as UAI for clinical-based outcomes, although predictive values were relatively low. The UMAT did not predict any performance outcome. Female gender, European/European-derived country of birth and non-rurality were significant predictors independent of UAI scores.ConclusionResults indicate promising validity for an integrated selection process introduced for the Medicine Program at UNSW, with UAI and interview predictive of learning outcomes. Although not predictive, UMAT may have other useful roles in an integrated selection process. Further longitudinal research is proposed to monitor and improve the validity of the integrated student selection process.

Short-term oral oestrogen therapy dissociates the growth hormone/insulin-like growth factor-I axis without altering energy metabolism in premenopausal women.

OBJECTIVE Oral oestrogen has been shown to dissociate the growth hormone (GH)/insulin-like growth factor (IGF)-I axis and alter energy metabolism in postmenopausal women. This study was designed to determine whether these metabolic changes occur with short-term oral oestrogen in premenopausal women. STUDY DESIGN A double-blind placebo controlled randomised-crossover design study was performed in 12 premenopausal women. Investigations were performed after either 5 days of oral 17beta-oestradiol valerate 2mg twice daily or placebo. Outcomes included body composition measured by bio-impedance, energy metabolism measured by indirect calorimetry and blood sampling. RESULTS Oral oestrogen significantly suppressed IGF-I levels and increased fasting GH levels. No significant changes in energy metabolism or body composition were detected. CONCLUSIONS Short-term oral oestrogen suppresses IGF-I and elevates GH levels in premenopausal women. No effects were seen on body composition and energy metabolism. Further research is required to determine whether metabolic effects of oral oestrogen may become apparent if longer courses of treatment were administered to premenopausal women.

X-Ray Crystal Structure of a Monoclonal Antibody That Binds to a Major Autoantigenic Epitope on Thyroid Peroxidase

Thyroid peroxidase (TPO) catalyzes the production of thyroid hormones and is a major autoantigen in autoimmune thyroid disease (AITD). It is believed that the majority of TPO autoantibodies bind to an immunodominant region consisting of two overlapping domains. Precise location of these domains would help our understanding of the interaction between TPO and TPO autoantibodies. 4F5 is a mouse monoclonal antibody (IgG1, kappa) that reacts with high affinity (2.6 x 10(10) mol/L(-1)) with one of the major autoantigenic regions on TPO. Heavy chain genes of 4F5 were from the VH1 germline gene family, germline genes for the D region could not be assigned and the J region was from the JH2 germline. Light chain genes were from Vkappa4/5 and Jkappa2, germline gene families. The Fab fragment of 4F5 was prepared by papain digestion, purified, crystallized, and the structure solved to 1.9 A using molecular replacement. The refined structure had an R factor of 19.5% and a free R factor of 23.9%. Deduced amino acid sequence and amino acid sequence obtained from diffraction analysis were compared and used to finalize the 4F5 Fab model. Structural analysis indicated that the structure of 4F5 is that of a standard Fab and its combining site is flat and is rich in tyrosine residues. Comparison of the structure of 4F5 with that of a TPO autoantibody Fab, TR1.9 suggests that the two antibodies are unlikely to recognise the same structures on TPO.