Genetic variation in the upstream region of ERG and prostate cancer

Objective  A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival. Methods  We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5′UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case–control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival. Results  One haplotype—′CTCGTATG′ located 100 kb upstream of ERG—was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2–1.9, p = 0.006). Carriers of the variant ‘T’ allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1–1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk. Conclusions  Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.     

‘You can tell a victim by the tilt of her head as she walks’: psychopathic personality and social–emotional processing

Much contention and speculation exists regarding the emotional and social skills associated with psychopathic personality, including the idea of a predatory perception. The current study examined the relationship between psychopathic personality and social and emotional processing. The study utilised a quasi-experimental design along with self-report measures to examine psychopathy in a community sample (N = 115) of males and females. To examine psychopathy and social information processing, a series of Mixed Design ANOVA’s were conducted to examine the effect of psychopathy on character recall. Psychopathy was found to significantly predict recall of the unsuccessful character, however, did not predict recall of character gender or emotion. Two hierarchical regressions analyses were conducted to examine emotional intelligence and empathy. Psychopathy was found to be a significant negative predictor of empathy, however, did not significantly predict emotional intelligence. Implications for the current study lie within advancing the empirical understanding on psychopathic personality and victim vulnerability.     

Hippocampal activation during a cognitive task is associated with subsequent neuroendocrine and cognitive responses to psychological stress

Increased activation of the hypothalamus pituitary adrenal (HPA) axis, marked by increased secretion of cortisol, is a biological marker of psychological stress. It is well established that the hippocampus plays an important role in the regulation of HPA axis activity. The relationship between cortisol (stress‐related elevation or exogenous administration) and the hippocampal‐related cognitive function is often examined. However, few human studies to date have examined the effect of stress on hippocampal activity and the interactions between stress‐induced activation of the HPA axis and hippocampal function during different phases of cognitive function. On the basis of our previous work, we hypothesized that group differences in stress‐sensitivity relate to differences in hippocampal‐related stress‐integration. To test this hypothesis, we conducted a functional MRI study using tasks known to involve the hippocampal formation: novel‐picture encoding, psychological stress, and paired‐picture recognition. On the basis of their cortisol responses to stress, we divided subjects into stress‐responders (increase in cortisol, n = 9) and nonresponders (decrease in cortisol, n = 10). Responders showed higher hippocampal deactivation during the stress task and lower recognition scores due to a larger number of misses. Intriguingly, stress‐responders showed significant differences in hippocampal activation already prior to stress, with higher levels of hippocampal activity during the picture encoding. Although effects of both cortisol and hippocampal activation on recognition were present in responders, similar effects were absent in the nonresponder group. Our results indicate that hippocampus plays an important role in adaptive behavioral responses. We hypothesize that states of hippocampal activation prior to stress might reflect states of vigilance or anxiety, which might be important for determining interindividual differences in subsequent stress response and cognitive performance. © 2009 Wiley‐Liss, Inc.     

Are Serbian gynaecologists in line with modern family planning?

Objectives In Serbia, gynaecologists could play an important role in achieving the transition from an abortion-based family planning culture to a modern contraception-based one. Exploring their knowledge, attitudes and practice regarding birth control is of particular importance for ensuring the quality of contraceptive counselling.

Methods A questionnaire was sent to all the 1,139 members of the Gynaecology and Obstetrics Section of the Serbian Medical Society. The response rate was 27%.

Results Of the respondents, 61.8% reported that either they or their partner had had one or more induced abortions; 37.6% stated that they usually used either coitus interruptus or no contraceptive method at all; 51.0% were unwilling to prescribe combined oral contraceptives (COCs) to girls younger than 18 years, and 76.5% advised women against the use of COCs for more than two years. Irrational concerns about the health risks of contraception were identified. The contraceptive needs of women aged 20 + were particularly hampered by the fact that 75.5% of respondents thought that intrauterine device use was unsafe for women with benign, non infectious cervicitis.

Conclusions The results indicate that a significant number of Serbian gynaecologists neither use modern methods of contraception themselves nor have adequate knowledge to advise their patients. Thus, education and training of gynaecologists in all methods of available contraception is a priority in Serbia.     

Anesthetic considerations in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome: a case series

Purpose

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) is a rare inherited mitochondrial disorder associated with severe multiorgan pathology and stress-induced episodes of metabolic decompensation and lactic acidosis. The purpose of this case series is to review the medical records of patients with MELAS who underwent anesthetic care at the Mayo Clinic to observe their perioperative responses to anesthesia and to assess outcomes.

Principal findings

From September 1997 to October 2010, nine patients with MELAS were identified who underwent 20 general anesthetics, 12 prior to MELAS diagnosis. Debilitating neurologic symptoms involved eight patients, and three patients had substantial cardiac comorbidities. The patients tolerated commonly used anesthetics and muscle relaxants, including succinylcholine. Lactated Ringer’s solution was used frequently. One patient was noted to have elevated postoperative serum lactate, but his serum lactate was chronically elevated. Metabolic acidosis was not observed in any patient. Hyponatremia and hyperkalemia, sometimes profound, were observed in seven patients, but these abnormalities also occurred at times remote from surgery. Two patients developed renal dysfunction following cardiac surgery and abdominal surgery for severe sepsis.

Conclusion

The MELAS patients developed episodes of hyponatremia and hyperkalemia of variable severity unrelated to the timing of surgery, suggesting these patients are prone to major electrolyte disturbances. Given the propensity to develop acid-base disturbances and lactacidemia, it is prudent to review and normalize electrolyte abnormalities and to adjust the anesthetic plan accordingly. Fortunately, the limited data suggest that patients with MELAS tolerate commonly used anesthetic drugs well.     

Resection of Distal Tracheal and Carinal Tumours With the Aid of Cardiopulmonary Bypass

Objectives. The aim of the study was to assess long-term state and trait anxiety in cardiac surgical risk patients. Design. Thirty two patients with serum S100B > 0.3 µg/l 48 hours after cardiac surgery with cardiopulmonary bypass were matched according to age, gender, type, date and length of surgery with 35 operated patients without elevated S100B. They completed Spielberger's Anxiety Inventory (STAI). Results. Patients with elevated S100B reported more state anxiety and trait anxiety. S100B was an independent predictor of both state and trait anxiety when controlling for perioperative variables. Conclusions. Patients with elevated S100B reported more anxiety 3–6 years after cardiac surgery. A postoperative blood sample can identify risk patients and facilitate appropriate follow-up.     

Radiolabeling of the cannabinoid receptor agonist AZD1940 with carbon-11 and PET microdosing in non-human primate

IntroductionN-(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1 H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure.MethodsAZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [¹¹C]pivalate was obtained via ¹¹C-carboxylation of tert-butyl lithium. The target compound, [¹¹C]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [¹¹C]pivalate and the o-phenylene diamine analog of AZD1940 (N-(3-amino-4-((4,4-difluorocyclohexyl)methylamino)phenyl)ethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey.ResultsThe overall radiochemical yield of final formulated radiochemically pure (> 99%) [¹¹C]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13 GBq/μmol at time of administration (58 min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous.ConclusionsAZD1940 was radiolabelled with carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure.     

The role of estrogen receptor-α gene TA polymorphism and aromatase gene TTTA polymorphism on peak bone mass attainment in males: is there an additive negative effect of certain allele combinations?

Idiopathic osteoporosis in males is influenced predominantly by low peak bone mass as a feature under a strong genetic control. Among a number of candidate genes, α-estrogen receptor (ERα) and CYP19 genes are of particular interest due to important role of estrogen in pathophysiology of osteoporosis. In the present study we examined the association of certain allelic combinations of ERα gene thymine–adenine (TA) polymorphism and aromatase gene TTTA polymorphism on bone mineral density (BMD) in young men. The study sample consisted of 92 unrelated healthy male volunteers, aged 21–35. In each subject, lumbar spine and proximal femur BMD, parameters of bone turnover and 25-OHD level were measured. Two ERα (TA) _n alleles, allele 19 and allele 21, were found to be associated with lower BMD. The presence of allele 19 was associated with significantly lower lumbar spine (P = 0.006) and trochanter (P = 0.02) BMD while the subjects positive for allele 21 had significantly lower lumbar spine (P = 0.04), trochanter (P = 0.02) and total hip (P = 0.03) BMD. Men with CYP19 (TTTA)_7-3/ERα (TA)₁₉ allele combination had significantly lower lumbar spine BMD (P = 0.02) and those with CYP19 (TTTA)_7-3/ERα (TA)₂₁ allele combination had significantly lower BMD for all three measurements, i.e. lumbar spine (P = 0.02), femoral neck (P = 0.02) and total hip (P = 0.008). These particular combinations of high-risk alleles were associated with lower median lumbar spine, femoral neck and total hip BMD than either of the allele alone suggesting that negative effect of two risk alleles on peak bone mass add up.     

Longer duration of operative time enhances healing metabolites and improves patient outcome after Achilles tendon rupture surgery

Purpose

The relationship between the duration of operative time (DOT), healing response and patient outcome has not been previously investigated. An enhanced healing response related to DOT may potentiate repair processes, especially in hypovascular and sparsely metabolized musculoskeletal tissues such as tendons. This study aimed to investigate the association between DOT and the metabolic healing response, patient-reported outcome and the rate of post-operative complications after acute Achilles tendon injury.

Methods

Observational cohort, cross-sectional study with observers blinded to patient grouping. A total of two-hundred and fifty-six prospectively randomized patients (210 men, 46 women; mean age 41 years) with an acute total Achilles tendon rupture all operated on with uniform anaesthetic and surgical technique were retrospectively assessed. At 2 weeks post-operatively, six metabolites were quantified using microdialysis. At 3, 6 and 12 months, patient-reported pain, walking ability and physical activity were examined using self-reported questionnaires, Achilles tendon total rupture score, foot and ankle outcome score and physical activity scale. At 12 months, functional outcome was assessed using the heel-rise test. Complications, such as deep venous thrombosis, infections and re-operations, were recorded throughout the study.

Results

Patients who underwent longer DOT exhibited higher levels of glutamate (p = 0.026) and glycerol (p = 0.023) at 2 weeks. At the 1-year follow-up, longer DOT was associated with significantly less loss in physical activity (p = 0.003), less pain (p = 0.009), less walking limitations (p = 0.022) and better functional outcome (p = 0.014). DOT did not significantly correlate with the rate of adverse events, such as deep venous thrombosis, infections or re-ruptures. Higher glutamate levels were associated with less loss in physical activity (p = 0.017). All correlations were confirmed by multiple linear regressions taking confounding factors into consideration.

Conclusion

The results from this study suggest a previously unknown mechanism, increased metabolic response associated with longer DOT, which may improve patient outcome after Achilles tendon rupture surgery. Allowing for a higher amount of traumatized tissue, as reflected by up-regulation of glycerol in patients with longer DOT, may prove to be an important surgical tip for stimulation of repair of hypometabolic soft tissue injuries, such as Achilles tendon ruptures.

Level of evidence

II.

     

Effects of physical activity on food intake

The understanding of the effect of physical activity (PA) on food intake is imperative for considering PA as an additional tool for prevention and treatment of many diseases. Prolonged strenuous PA performed on a regular basis causes an increase in overall energy turnover, and leads either to loss of body weight, or to an increased food intake. When leading to loss of body weight, PA may be used as a therapeutic adjunct in the treatment of obesity. When increasing food intake to compensate for increased energy expenditure and maintaining body weight, PA, by increasing intake of other constituents of food like minerals and vitamins, may contribute to micronutrient deficiency coverage. However, the type of activity, as well as body composition of the individuals engaging in sport, play an important role in food intake regulation and its changes with time. Some studies indicate that short-term exercise does not have the same effect on food intake as long-term exercise and that eventual increase in food intake due to increased PA does not follow the same pattern in obese as in lean individuals. To better understand the relationship between PA on food intake, current findings on this topic will be summarized in this paper.