The role of global and regional DNA methylation and histone modifications in glycemic traits and type 2 diabetes: A systematic review.

BACKGROUND: New evidence suggests the potential involvement of epigenetic mechanisms in type 2 diabetes (T2D) as a crucial interface between the effects of genetic predisposition and environmental influences. AIM: To systematically review studies investigating the association between epigenetic marks (DNA methylation and histone modifications) with T2D and glycemic traits (glucose and insulin levels, insulin resistance measured by HOMA-IR). METHOD AND RESULTS: Six bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, PubMed, Cochrane Central and Google Scholar) were screened until 28th August 2015. We included randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined the association between epigenetic marks (global, candidate or genome-wide methylation of DNA and histone modifications) with T2D, glucose and insulin levels and insulin metabolism. Of the initially identified 3879 references, 53 articles, based on 47 unique studies met our inclusion criteria. Overall, data were available on 10,823 participants, with a total of 3358 T2D cases. There was no consistent evidence for an association between global DNA-methylation with T2D, glucose, insulin and insulin resistance. The studies reported epigenetic regulation of several candidate genes for diabetes susceptibility in blood cells, muscle, adipose tissue and placenta to be related with T2D without any general overlap between them. Histone modifications in relation to T2D were reported only in 3 observational studies. CONCLUSIONS AND RELEVANCE: Current evidence supports an association between epigenetic marks and T2D. However, overall evidence is limited, highlighting the need for further larger-scale and prospective investigations to establish whether epigenetic marks may influence the risk of developing T2D.

Electron Density Distribution in the Organic Superconductor (TMTSF)2AsF6.

Excellent crystals of (TMTSF)(2)AsF(6) (TMTSF, tetramethyltetraselenafulvalene) were employed to obtain x-ray diffraction data for a determination of the electron density distribution in this organic superconductor. Electron density was observed between molecules in a stack of donors of an organic metal and between certain interstack selenium atoms of these donors.

Efficacy of partially hydrolyzed guar gum-added oral rehydration solution in the treatment of severe cholera in adults.

BACKGROUND: Partially hydrolyzed guar gum (PHGG) is a water-soluble fiber if added to oral rehydration solution (ORS) and undergoes fermentation in the colon liberating short chain fatty acids (SCFAs). SCFAs potentiate the effect of ORS, reducing the severity of diarrhea. AIM: To examine the effect of PHGG-added ORS in reducing the stool output and duration of diarrhea in adult cholera. METHODS: 195 male patients were studied in a randomized controlled trial: (a) 65 received ORS + 25 g PHGG; (b) 65 received ORS + 50 g PHGG, and (c) 65 received ORS alone (control). Major outcomes were stool weight and duration of diarrhea. RESULTS: No significant differences were found in mean +/- SD stool weight (g/kg b.w.) during the first and second 24 h. In the subgroup analysis (excluding very high purging patients, stool weight in the first 24 h was >10 kg), the stool weight (g/kg b.w.) was significantly reduced in the first 24 h in both groups receiving PHGG (PHGG 25 g, 136 +/- 68 vs. PHGG 50 g, 144 +/- 49 vs. control, 176 +/- 43, p = 0.01). CONCLUSION: PHGG-added ORS might have a beneficial effect in moderately purging adult cholera. However, further studies are warranted to confirm the preliminary findings.

Chemotherapy at First Diagnosis of Advanced Prostate Cancer - Revolution or Evolution? Findings from a British Uro-oncology Group UK Survey to Evaluate Oncologists' Views on First-line Docetaxel in Combination with Androgen Deprivation Therapy in Castrate-sensitive Metastatic and High-risk/Locally Advanced Prostate Cancer.

AIMS: There have been three randomised trials investigating docetaxel in combination with androgen deprivation therapy as first-line therapy for hormone-sensitive metastatic and locally advanced/high-risk prostate cancer. The largest of these studies, UK STAMPEDE trial, recently presented in June 2015. The aim of this survey was to evaluate if oncologists' practice has changed as a result of these studies, or if their practice is likely to change in different clinical settings in the future. MATERIALS AND METHODS: The British Uro-oncology Group issued a semi-structured online questionnaire to its membership of 160 specialist urological oncologists practising in the UK. Links to the abstracts of GETUG-AFU-15, E3805 CHAARTED and STAMPEDE were attached with the survey for respondents to review before completing the survey. RESULTS: In total, 111 participants completed the survey; 87% stated that STAMPEDE will influence their clinical practice in the future. Almost all (96%) would offer docetaxel with androgen deprivation therapy to men presenting with high volume metastatic prostate cancer. Fewer oncologists would offer this treatment to men with low volume metastatic prostate cancer, locally advanced or relapsed disease. Various patient- and disease-related factors were considered in decision making, as well as resource implications. CONCLUSIONS: This survey reports oncologists' attitudes towards a major change in practice in the standard of care for men with newly diagnosed advanced prostate cancer in the UK. The survey highlighted the complexities surrounding the clinical implementation of the data from these studies, including changes in referral pathways, with the early involvement of oncologists in such patients' care, increases in workloads for oncologists and chemotherapy units and the need for national approval for re-imbursement of these treatments.

The effect of ageing and exercise on skeletal muscle function.

The contractile and selected biochemical properties of fast- and slow-twitch skeletal muscle were studied at 9, 18, and 28 months of age in sedentary and regularly exercised rats. The isometric twitch duration was prolonged with aging in both the fast- and slow-twitch muscle. This effect was primarily due to a prolonged one-half relaxation time (1/2RT), which developed late in life. Regular exercise tended to further prolong the twitch duration, particularly in the slow-twitch soleus. Surprisingly, twitch and tetanic tension (Po), peak rate of tension development and decline, and the maximal shortening velocity were all unaltered between 9 and 28 months of age. Furthermore, regular exercise (running or swimming) had little or no effect on these properties. The prolonged 1/2RT with aging could not be explained by a decreased rate of Ca2+ sequestration by the sarcoplasmic reticulum, as the rate of Ca2+ uptake measured in muscle homogenates was unaltered in any of the muscles studied between 9 and 28 months. The degree of muscle fatigue (decline in Po) with 30 min of contractile activity in the slow-twitch soleus was not affected by aging. However, lactate reached two-fold higher levels and glycogen fell to considerably lower levels in the muscles of the old rats. This suggests an increased glycolysis and glycogen utilization during contractile activity in aged rats.

Isotopic determination of glycolytic flux during intense exercise in humans.

We used a new stable isotope tracer approach incorporating muscle intracellular lactate enrichment to determine the flux of glucose/glucosyl toward lactate [i.e., nonoxidized pyruvate (Pyr) production (Pyrno)] in moderately trained cyclists exercising at approximately 80% (259 +/- 16 W; n = 6) and approximately 100% (341 +/- 9 W; n = 8) maximal O2 uptake (VO2max). Primed constant infusions of [6,6-2H2]glucose and [13C]lactate or [13C]Pyr tracers were given, and rapid achievement of plateau was obtained during exercise by increasing the infusion rates at exercise onset to correspond with expected increases in production. The accumulated O2 deficit was simultaneously determined over the 1st 3 min of exercise as an indirect means of quantifying glycolytic flux for comparison with our tracer-determined values and was significantly greater at the higher intensity (38 +/- 3 vs. 30 +/- 3 ml O2.kg-1.3 min-1; P < 0.02). Pyrno was also significantly higher (6.38 +/- 0.91 vs. 4.38 +/- 0.65 mmol.kg-1.min-1 over 3 min at 100 and 80% VO2max, respectively). The blood lactate rate of appearance at approximately 100% VO2max (828 +/- 69 mumol.kg-1.min-1) represented a higher percentage of Pyr rate of appearance (RaPyr; 31 +/- 3%) than that at approximately 80% VO2max (416 +/- 36 mumol.kg-1.min-1; 22 +/- 2%; P < 0.02). Although only approximately 27 +/- 2% of RaPyr was oxidized, this provided 78 +/- 2% of the total energy demand during the 1st 3 min of exercise at either intensity. Our new method provided values for Pyrno that were in the expected range and were highly correlated with respective accumulated O2 deficit values (r = 0.87, P < 0.0001). In conclusion, our new tracer method appears to be valid for the measurement of RaPyr and Pyrno during high-intensity exercise lasting even < 10 min.

Effect of high-intensity exercise training on functional capacity of limb skeletal muscle.

The purpose of this study was to determine whether a program of regular sprint exercise training alters the functional properties or protects against the development of fatigue in fast- and slow-twitch rat skeletal muscle. The training program consisted of 6 sprints of 4.5-min duration at 40 m/min and 15% slope with 2.5-min rest intervals, performed 5 days/wk for 6 wk. The exercise program significantly increased (P less than 0.05) citrate synthase activity (mumol X g-1 X min-1) in the predominantly type I soleus (SOL) from 28 +/- 2 to 44 +/- 2; the type IIb superficial region of the vastus lateralis (SVL) from 10 +/- 1 to 16 +/- 1; and the type IIa deep region of the vastus lateralis (DVL) from 34 +/- 2 to 53 +/- 2. Phosphofructokinase activity (mumol X g-1 X min-1) also increased with training in the SOL (17 +/- 1 vs. 23 +/- 1) and the DVL (64 +/- 5 vs. 79 +/- 5). Sprint training reduced (P less than 0.05) the contraction time (CT) (111 +/- 7 vs. 92 +/- 3 ms) and the one-half relaxation time (118 +/- 3 vs. 104 +/- 2 ms) in the slow-twitch soleus. The exercise program also induced a decreased CT in the fast-twitch extensor digitorum longus (EDL), but significance was limited to the P less than 0.1 level. Muscle fatigue was produced by electrical stimulation at 45 trains/min and either 15 trains/min in SOL or 10 trains/min in the EDL and SVL for 1, 5, or 10 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Running speed and spinal shrinkage in runners with and without low back pain.

Decreases in stature (shrinkage) are used to indicate exercise induced spinal loading. This study examined the effect of three running speeds on two groups of runners, one with chronic low back pain. The two groups of seven male marathon runners ran at 70%, 85%, and 100% of their marathon race pace for 30 min on separate occasions. Before and after exercise the subjects were seated for 20 min with the lumbar spine supported. Stature was measured before pre-exercise sitting, before running, after 15 min of running, after 30 min of running, and after post-exercise sitting. A stadiometer accurate to within 0.5 mm was used to record changes in stature. Results showed no differences in response to the three running regimens between the groups (P greater than 0.05). Shrinkage was greater during the first 15 min, being 3.26 (+/- 2.78) mm compared with 2.12 (+/- 1.61) mm for the second 15 min of the run (P less than 0.05). The faster the running speed the greater the resultant shrinkage. The 70%, 85%, and 100% conditions caused 3.37 (+/- 2.38), 5.10 (+/- 1.90), and 7.69 (+/- 3.69) mm of shrinkage, respectively (P less than 0.005). These results suggest that low back pain is independent of the shrinkage induced by running. Further research is required to determine the effect of longer duration runs on spinal shrinkage.

Relationship between power and sprint freestyle swimming.

In an effort to determine the role played by power in sprint swimming, 40 competitive swimmers (22 females and 18 males) were tested for arm power at velocities ranging from 1.60-3.28 m . s-1 using an apparatus that was specifically designed to mimic the arm action during swimming. Measurements were also made to determine the contribution of fatigability to spring swimming performance. In addition, each swimmer performed a series of 25-yd (22.86 m) freestyle sprints. A close relationship was found between power output and sprint swimming performance (r = 0.90). The highest power recordings were obtained at test velocities of 2.05 and 2.66 m . s-1, with the average velocity required for peak power being 2.40 m . s-1. This point is referred to as the optimal velocity. Four detrained swimmers were tested before and after 4 wk of isokinetic strength training only. On the average, performance improved 3.76%, while arm power increased by 18.66%. The fatigability of the competitive swimmers was not related to their sprint ability (r = 0.01). It is concluded that power, as measured in this study, offers an objective assessment of a component essential for success in sprint swimming.

Changes in stature following drop jumping and post-exercise gravity inversion.

Spinal shrinkage, measured by changes in stature, is used as an index of spinal loading as alterations reflect changes in intervertebral disc height. Shrinkage induced by various physical activities may be reversed using gravity inversion. The present purpose was to examine the shrinkage induced by a drop jumping regimen and evaluate gravity inversion post-exercise. Eight males, aged 20-31, performed two separate experimental protocols, each on different dates at 1400 h. Subjects stood for 30 min before undertaking an exercise regimen, consisting of five sets of five drop jumps from a height of 1 m, rebounding over a hurdle 0.5 m high. For 20 min, directly following the exercise regimen, subjects on one occasion stood and on a second occasion undertook gravity inversion. Shrinkage was monitored for 40 min after this post-exercise treatment. The stadiometer used to measure shrinkage was accurate to 0.05 mm. The exercise regimen caused a mean shrinkage of 1.68 and 1.81 mm for the two testing sessions. Post-exercise inversion and standing for 20 min increased stature by 5.18 and 0.76 mm, respectively (P less than 0.01). The 40-min standing period following inversion caused a rapid loss in stature (4.07 mm). At 30 min into this recovery period, there was no significant difference in shrinkage for either of the regimens. Results suggest that effects of an inversion treatment are short-lasting.

Energy expenditure of swimmers during high volume training.

The purpose of this study was to examine the total energy expenditure (TEE) of swimmers during high volume training (17.5 +/- 1.0 km.d-1) using the doubly labeled water method. Five female swimmers (age, 19 +/- 1 yr; height, 178.3 +/- 2.2 cm; weight 65.4 +/- 1.6 kg) were administered a dose of 2H2(18)O and monitored for 5 days. Training consisted of two sessions per day, lasting a total of 5-6 h. Energy intake (EI) was calculated from dietary records. Resting energy expenditure (REE) was measured on a non-training day and averaged 7.7 +/- 0.5 MJ.d-1 (1840 +/- 130 kcal.d-1). There were no changes in body weight (day 1, 65.4 +/- 1.6; day 5, 65.2 +/ 1.5 kg) over the measurement period. TEE of the swimmers during the training period averaged 23.4 +/- 2.1 MJ.d-1 (5593 +/- 495 kcal.d-1). EI averaged 13.1 +/- 1.0 MJ.d-1 (3136 +/- 227 kcal.d-1), implying a negative energy balance of 43 +/- 2%. TEE expressed as a multiple of REE was 3.0 +/- 0.2. The results of this investigation describe the total energy demands of high volume swimming training, which may be used to address the dietary concerns of the competitive swimming athlete.

Circadian variation in human stature.

The aim of this study was to monitor the creep in stature due to compression and its recovery over 24 hr in eight adult males. Measurements of stature were made at nine times during the 24-hr cycle using a purpose built metal frame tilted 5 degrees to the vertical. Accessories for standardization of posture and prevention of unwanted muscular tension included a series of microswitches on the frame, cross-beams for controlling spinal curvatures, slit spectacles used in conjunction with a mirror for proper head alignment. A dead load BAYE micrometer recorded stature to 0.01 mm. A significant circadian rhythm was established, the trough to peak variation being 19.3 mm or 1.1% of overall stature. Peak stature was measured at 0730 on awakening and the trough occurred at midnight before assuming a recumbent posture for sleep. Altogether 71% of the height gained during the night was achieved in the first half of the night's sleep. Over 50% of the height loss in a day was lost within the first hour of rising, 80% being lost within 3 hr of arising: the rate of creep decelerated throughout the remainder of the waking day. It is concluded that the rate of change in creep throughout the day varies, being greatest in the morning whilst distension is most pronounced in the early hours of sleep.

Biomechanical considerations in the straight-leg-raising test. Cadaveric and clinical studies of the effects of medial hip rotation.

Studies of the sacral plexus have been made in six cadavers to demonstrate the increased tension due to medial hip rotation. A standard protocol was adopted for the straight-leg-raising test (SLR) and three qualifying tests--dorsiflexion of the ankle, medial hip rotation, and cervical flexion--when examining 442 patients. Positive signs on medial hip rotation were frequently associated with evidence of increased tension and neurologic dysfunction of lumbosacral roots. It is concluded that uncontrolled hip rotation reduces the value of the SLR is a useful qualifying test for increased root tension, and that the diagnostic value and repeatability of SLR would be improved by adopting a standardized protocol.

Circadian variation in stature and the effects of spinal loading.

Using a method comparable with that of Eklund and Corlett (1984) stature was measured with an accuracy of I mm in eight young adults. The mean circadian variation was 19.3 mm (1.1% of stature). Fifty-four percent of the diurnal loss in stature occurred in the first hour after rising. Approximately 70% was regained during the first half of the night. With static shoulder loads (2.5-40 kg), increases in the rate of shrinkage with increasing weight were nonlinear. Repetitive lifting led to greater shrinkage than with equivalent static loading. Rest in Fowler's position gave more rapid regains in stature than post-exercise recovery in standing positions. The technique is therefore suitable for assessment of the effects of manual work with both occupational and therapeutic applications.

1990 Volvo Award in clinical sciences. Lumbar spinal pathology in cadaveric material in relation to history of back pain, occupation, and physical loading.

The occurrence of symmetric disc degeneration, anular ruptures, end-plate defects, vertebral body osteophytosis, and facet joint osteoarthrosis was examined radiographically and osteologically in 86 male cadavers for whom occupational, physical loading, and back pain histories were obtained from the men's families. History of back pain and the parameters of spinal pathology were related to the highest and lowest degrees of physical loading. In multivariate analyses, history of back injury was related to the occurrence of symmetric disc degeneration, anular ruptures, and vertebral osteophytosis. Symmetric disc degeneration was associated with sedentary work, and vertebral osteophytosis was related to heavy work. History of back pain was related to occupational physical loading after control for the effects of the other covariates. The results indicate that the least pathology stemmed from moderate or mixed physical loading, but the least back pain was associated with sedentary work.

Radiographic measurements of lumbar spinal canal size and their relation to back mobility.

A total of 197 men and women with history of previous back pain were radiographed and clinically examined. Measurements related to the shape and size of the spinal canal were subsequently made from the lumbar radiographs. Interarticular distance and the ratio between interarticular and interpedicular distances were significantly less in women with restriction of lumbar extension, sidebending, and rotation: not in men. Anteroposterior (AP) foraminal distances and pedicular lengths were less in men with restricted extension and sidebending, although not in women. Midsagittal diameters were not significantly less in those with restricted mobility. The radiographic differences between men and women with restricted back mobility arise partly from the sexual differences in interarticular and AP foraminal distance, the former being less in women, the latter in men. This suggests a different pathogenetic factor in the two sexes.

Prediction of low-back trouble frequency in a working population.

This study was performed to estimate the discriminatory power of multiple combinations of risk indicators for the occurrence and recurrence of low-back trouble (LBT) in workers. Two categories of LBT provided groups for discrimination; 1) the presence or absence of LBT history, and 2) three patterns of recurrence characterized by the number of episodes (isolated, periodic, chronic). The risk indicators comprised data reflecting occupational and leisure demands on the back, measures of lumbar sagittal mobility, and anamnestic features of the first episode. Discriminant analysis was the statistical procedure used. The results showed that it was possible to find linear combinations of the discriminating variables that successfully allocated around two-thirds of the sample to the correct group. The presence of a history of LBT was predicted by the combined effect of increasing age and adult sports participation, but only in females did a heavier job contribute to such prediction. A reduction in risk was associated with lumbar flexibility and sports participation at school. Chronic LBT was more accurately identified than the two other groups; increasing age, a long initial spell, and an onset early in life were associated with increased likelihood of chronicity, while a report of symptoms being relieved by sitting reduced this risk. It is concluded that the occurrence and recurrence of LBT are related to combinations of risk indicators, and that it is imperative to consider the interactive effect of a multiplicity of factors in epidemiologic studies.

Variation in lumbar sagittal mobility with low-back trouble.

The influence of low-back trouble on lumbar sagittal mobility was explored in 958 individuals aged 10 to 84 years. Experience of low-back trouble was determined by questionnaire, and categorized as none, a previous history, or a current spell. Maximal mobility was estimated from flexicurve records of back surface curvature. The results for adults revealed that mean mobility values were reduced by both previous and current low-back trouble, particularly in the upper lumbar region, when compared with nonsufferers. Stepwise regression analyses showed that variation in mobility was best accounted for by the cumulative effects of age and sex. These variables accounted for approximately one-third of the variation in mobility: low-back trouble only accounted for an additional 1%. At the extremes of the range, both hypomobility and hypermobility were identified as risk indicators for low-back trouble. Relative hypermobility was not confined to subjects with no history of back trouble; some current sufferers had particularly high levels of mobility. Similarly hypomobility was found in nonsufferers as well as in those with back trouble. The data indicated that young adults (notably males) with previous low-back trouble may not recover their previous mobility on symptomatic resolution. The finding of hypermobility in current sufferers indicates that mobilization therapy may not be appropriate for such patients.

Back pain in industry. A prospective survey.

Eight hundred and two subjects employed in N.W. England have been interviewed and examined after episodes of back or sciatic pain, using a standardized procedure. Data on recurrence of symptoms leading to further treatment or absence from work in the following two 12-month periods were obtained by postal questionary. Residual pain in the leg and a number of positive clinical signs of return to work, longer sickness--absence for the current attack, and two or more previous attacks were all associated with recurrence or persistence of symptoms. The prognosis also varied according to the cause of back pain, falls being associated not only with longer periods of absence in the current attack but with a higher rate of recurrence. The results have underlined the significance of a thorough examination on return to work after back pain for the industrial medical officer, as well as the epidemiological importance of this phase in the natural history of back and sciatic pain.