Friday, April 18, 2014

The Frequency of Diagnostic Errors in Outpatient Care

Singh H, Meyer AND, Thomas EJ. The frequency of diagnostic errors in outpatient care: estimations from three large observational studies involving US adult populations. BMJ Quality & Safety.   

Background The frequency of outpatient diagnostic errors is challenging to determine due to varying error definitions and the need to review data across multiple providers and care settings over time. We estimated the frequency of diagnostic errors in the US adult population by synthesising data from three previous studies of clinic-based populations that used conceptually similar definitions of diagnostic error.

Methods Data sources included two previous studies that used electronic triggers, or algorithms, to detect unusual patterns of return visits after an initial primary care visit or lack of follow-up of abnormal clinical findings related to colorectal cancer, both suggestive of diagnostic errors. A third study examined consecutive cases of lung cancer. In all three studies, diagnostic errors were confirmed through chart review and defined as missed opportunities to make a timely or correct diagnosis based on available evidence.

We extrapolated the frequency of diagnostic error obtained from our studies to the US adult population, using the primary care study to estimate rates of diagnostic error for acute conditions (and exacerbations of existing conditions) and the two cancer studies to conservatively estimate rates of missed diagnosis of colorectal and lung cancer (as proxies for other serious chronic conditions).

Results Combining estimates from the three studies yielded a rate of outpatient diagnostic errors of 5.08%, or approximately 12 million US adults every year. Based upon previous work, we estimate that about half of these errors could potentially be harmful.

Conclusions Our population-based estimate suggests that diagnostic errors affect at least 1 in 20 US adults. This foundational evidence should encourage policymakers, healthcare organisations and researchers to start measuring and reducing diagnostic errors.

Regulation of the Proliferation and Differentiation of Leydig Stem Cells

Odeh HM, Kleinguetl CE, Ge R, Zirkin BR, Chen H. Regulation of the Proliferation and Differentiation of Leydig Stem Cells in the Adult Testis. Biol Reprod.   

We reported previously that stem cells associated with adult rat testis seminiferous tubules are able to give rise to differentiated Leydig cells in vitro. The regulatory mechanisms by which they do so, however, are uncertain.

Here, we hypothesized that the proliferation and differentiation of the Leydig cell stem cells (stem Leydig cells, SLCs) depend upon locally produced factors from the seminiferous tubules.

Microarray analysis revealed that platelet-derived growth factor receptor alpha (PDGFRalpha) is up-regulated and PDGFRbeta down-regulated with the postnatal differentiation of the SLCs. This suggested that their ligands, PDGF-AA and PDGF-BB, respectively, might play important roles in SLC proliferation and differentiation.

To test this, we developed a unique in vitro culture system in which SLCs proliferate on the surfaces of cultured seminiferous tubules largely during week 1 of culture, and their progeny subsequently differentiate to testosterone-forming Leydig cells during weeks 2-4. Using this system, seminiferous tubules from adult rat testes were cultured with PDGF-AA or PDGF-BB for up to 4 weeks.

Both ligands stimulated SLC proliferation during the first week of culture, with PDGF-BB significantly more potent than PDGF-AA. PDGF-AA also had a stimulatory effect on SLC differentiation from weeks 2-4 of culture. In contrast, PDGF-BB, which stimulated cell proliferation during week 1, had a significant inhibitory effect on differentiation during weeks 2-4.

These findings, made possible by the development of the seminiferous tubule culture system, reveal distinct roles played by locally produced PDGFs in SLC regulation.

Performance of Massachusetts Male Aging Study (MMAS) and Androgen Deficiency in the Aging Male (ADAM) Questionnaires

Cabral RD, Busin L, Rosito TE, Koff WJ. Performance of Massachusetts Male Aging Study (MMAS) and androgen deficiency in the aging male (ADAM) questionnaires in the prediction of free testosterone in patients aged 40 years or older treated in outpatient regimen. Aging Male.   

Objective: At present, calculated free testosterone assessment is considered as the gold standard in diagnosing male hypogonadism. However, this assessment is not available for all the individuals diagnosed with decreased testicular function.

The investigators of this study were, thus, prompted to evaluate whether the androgen deficiency in the aging male (ADAM) and the Massachusetts Male Ageing Study (MMAS) questionnaires could be used to replace biochemical parameters in the diagnosis for hypogonadism in men aged 40 years and above.

Methods: We evaluated 460 men, aged 40 years and above, all volunteers of a screening program for prostate cancer based at the Hospital de Clinicas of Porto Alegre. In this study, we assessed the efficiency of the ADAM and MMAS questionnaires in diagnosing Brazilian men with low levels of total, calculated free and bioavailable testosterone.

Results: The sensitivity of the ADAM questionnaire in diagnosing the calculated free testosterone was 73.6%, whereas specificity was 31.9%.

ADAM could be used to properly classify our cohort into normal or hypogonadal individuals in 52.75% of the cases. The sensitivity of the MMAS questionnaire was 59.9%, whereas the specificity was 42.9%, resulting in a successful classification of 51.4% of the patients.

Conclusion: The ADAM and MMAS questionnaires showed adequate sensitivity in diagnosing male patients with low levels of free testosterone. However, because of the lack of specificity, these tools cannot replace calculated free testosterone assessments in men aged 40 years and above.

Effects of Growth Hormone and Testosterone Therapy on Aerobic and Anaerobic Fitness, Body Composition and Lipoprotein Profile

Zajac A, Wilk M, Socha T, Maszczyk A, Chycki J. Effects of growth hormone and testosterone therapy on aerobic and anaerobic fitness , body composition and lipoprotein profile in middle-aged men. Ann Agric Environ Med 2014;21(1):156-60.   

Introduction. Andropause and aging are associated with neuroendocrine dysfunctions. Growth hormone and testosterone play a significant role in several processes affecting adaptation and thereby also everyday functioning. 

The aim of this research project was to evaluate the effects of recombinant human growth hormone and testosterone enanthate injections on body mass and body composition, aerobic and anaerobic fitness and lipid profile in middle-aged men.

Materials and Method. The research group was comprised of 14 men aged 45 - 60 years. Two series of laboratory analyses were performed. Independent tests were carried out at baseline and after 12 weeks of the experiment. The data were analyzed using Statistica 9.1 software.

Results. A two-way repeated measures ANOVA revealed a statistically significant effect of the intervention programme on fat-free mass (eta2=0.34), total body fat (eta2=0.79), total cholesterol (eta2=0.30), high-density lipoprotein cholesterol (eta2=0.31), low-density lipoprotein cholesterol (eta2=0.42), triglyceride (eta2=0.28), testosterone (eta2=0.52), insulin-like growth factor 1 (eta2=0.47) and growth hormone (eta2=0.63).

Furthermore, ANOVA revealed a statistically significant effect of the rhGH and T treatment on maximal oxygen uptake (eta2=0.63), anaerobic threshold (eta2=0.61) and maximal work rate (eta2=0.53).

Conclusion. It should be emphasized that the lipid profile was affected not only by rhGH+T replacement therapy, but also by the prescribed physical activity programme. The strength and endurance fitness programme alone did not cause significant changes in body mass and composition, nor the anaerobic and aerobic capacity. On the other hand, the rhGH=T treatment stimulated these changes significantly.

Thursday, April 17, 2014

Low Glucose Relates To Greater Aggression in Married Couples

Bushman BJ, DeWall CN, Pond RS, Hanus MD. Low glucose relates to greater aggression in married couples. Proceedings of the National Academy of Sciences.   

Intimate partner violence affects millions of people globally. One possible contributing factor is poor self-control. Self-control requires energy, part of which is provided by glucose. For 21 days, glucose levels were measured in 107 married couples. To measure aggressive impulses, each evening participants stuck between 0 and 51 pins into a voodoo doll that represented their spouse, depending how angry they were with their spouse. To measure aggression, participants competed against their spouse on a 25-trial task in which the winner blasted the loser with loud noise through headphones. As expected, the lower the level of glucose in the blood, the greater number of pins participants stuck into the voodoo doll, and the higher intensity and longer duration of noise participants set for their spouse.

Activation of GPER-1 Estradiol Receptor Downregulates Production of Testosterone

Vaucher L, Funaro MG, Mehta A, et al. Activation of GPER-1 Estradiol Receptor Downregulates Production of Testosterone in Isolated Rat Leydig Cells and Adult Human Testis. PLoS One 2014;9(4):e92425.   

PURPOSE: Estradiol (E2) modulates testicular functions including steroidogenesis, but the mechanisms of E2 signaling in human testis are poorly understood. GPER-1 (GPR30), a G protein-coupled membrane receptor, mediates rapid genomic and non-genomic response to estrogens. The aim of this study was to evaluate GPER-1 expression in the testis, and its role in estradiol dependent regulation of steroidogenesis in isolated rat Leydig cells and human testis.

MATERIALS AND METHODS: Isolated Leydig cells (LC) from adult rats and human testicular tissue were used in this study. Expression and localization studies of GPER-1 were performed with qRT-PCR, immunofluorescence, immunohistochemistry and Western Blot. Luteinizing Hormone (LH) -stimulated, isolated LC were incubated with estradiol, G-1 (GPER-1-selective agonist), and estrogen receptor antagonist ICI 182,780. Testosterone production was measured with radioimmunoassay. LC viability after incubation with G-1 was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetr azolium, inner salt (MTS) assay.

RESULTS: GPER-1 mRNA is abundantly expressed in rat LC and human testis. Co-localization experiments showed high expression levels of GPER-1 protein in LC. E2-dependent activation of GPER-1 lowers testosterone production in isolated rats LCs and in human testis, with statistically and clinically significant drops in testosterone production by 20-30% as compared to estradiol-naive LC. The exposure to G-1 does not affect viability of isolated LCs.

CONCLUSIONS: Our results indicate that activation of GPER-1 lowers testosterone levels in the rat and human testis. The expression of GPER-1 in human testis, which lack ERalpha, makes it an exciting target for developing new agents affecting testosterone production in men.

Effects of Long-Term Testosterone Therapy On Patients with "Diabesity”

Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol. 2014.   

To investigate effects of long-term testosterone (T) therapy in obese men with T deficiency (TD) and type 2 diabetes mellitus (T2DM), data were collected from two observational, prospective, and cumulative registry studies of 561 men with TD receiving T therapy for up to 6 years. A subgroup of obese hypogonadal men with T2DM was analyzed.

Weight, height, waist circumference (WC), fasting blood glucose (FBG), glycated haemoglobin (HbA1c) blood pressure, lipid profile, C-reactive protein (CRP), and liver enzymes were measured. A total of 156 obese, diabetic men with T deficiency, aged 61.17 +/- 6.18 years, fulfilled selection criteria.

Subsequent to T therapy, WC decreased by 11.56 cm and weight declined by 17.49 kg (15.04%). Fasting glucose declined from 7.06 +/- 1.74 to 5.59 +/- 0.94 mmol/L (P < 0.0001 for all). HbA1c decreased from 8.08 to 6.14%, with a mean change of 1.93%. Systolic and diastolic blood pressure, lipid profiles including total cholesterol: HDL ratio, CRP, and liver enzymes all improved (P < 0.0001).

Long-term T therapy for up to 6 years resulted in significant and sustained improvements in weight, T2DM, and other cardiometabolic risk factors in obese, diabetic men with TD and this therapy may play an important role in the management of obesity and diabetes (diabesity) in men with T deficiency.