After hMSH2 and hMLH1- what next? Analysis of three-generational, population-based, early-onset colorectal cancer families

The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first-and second-degree relatives, were interviewed. Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first-or second-degree relative with colorectal cancer with an excess of colorectal cancer in first-degree relatives (SMR = 2.7, 95% CI = 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0-12.8%), compared to the Victorian population risk of 3.2% (p = 0.01). The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI = 24-100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer.

Lupin (Lupinus albus) protein isolate (L-ISO) has adequate nutritional value and reduces large intestinal weight in rats after restricted and ad libitum feeding.

Background: A protein isolate from white lupin (Lupinus albus; L-ISO) has potential as a novel human food ingredient, but its nutritional effects are unknown.

Methods: We evaluated protein quality and effects on body composition in rats of isoenergic diets of L-ISO, lactalbumin, or casein with both restricted (10-day) and ad libitum (28-day)intake. The diets were equivalent in protein per se, but supplementation was used to balance essential amino acid levels.

Results: In both studies, the rats consumed similar amounts of each diet, and no effect of diet on the gain:feed ratio was observed--though gain:N ratio and net protein utilization were slightly lower for the L-ISO diet. Lower large intestinal weights after the L-ISO than after the lactalbumin diet were observed in both studies. The L-ISO diet resulted in lowered body fat percentage in the 10-day study but in an elevated level in the 28-day study. Liver composition (DNA, RNA, glycogen, and fat) and plasma levels of some amino acids (His, Thr, Ala, Pro, Tyr, Val and Met) were affected by diet, but no effects on plasma lipid, glucose, or uric acid were observed.

Conclusion: The L-ISO diet did not affect feed intake and has adequate nutritional quality in rats whilst modifying large intestinal weight in a potentially beneficial manner--suggesting potential for this protein in human nutrition.

Succession of small mammal communities after fire and reintroduction of the swamp antechinus 'Antechinus minimus'

This thesis is involved with changes that have occurred to small mammal populations following a major disturbance in the Anglesea region as a result of the 1983 Ash Wednesday fires. Fire, with its effects on spatial and temporal heterogeneity, was found to be an important factor in the maintenance of vegetation and small mammal community structure and diversity in the region. Successional changes in vegetation and small mammal communities were described by multivariate analyses, using data collected annually from 22 study sites. The use of factor analysis techniques, in reducing the annual capture data content, enabled long-term changes in the structure of mammal communities to be interpreted. The small mammal communities in the coastal heath and forest vegetation in the Anglesea region show evidence of a general resilience, (the degree and speed of recovery), to disturbance. Two phases of successional response to fire by mammal species have been proposed; a ‘re-establishment’ phase which occurs in the initial 5-6 years post-fire and is accompanied by rapid increase in species’ abundance, and a subsequent ‘maintenance’ phase accompanied by relatively minor changes in abundance. Habitat Suitability Indices were produced relating to these phases. Vertical density measures of understorey shrubs and herb layers showed significant relationships with small mammal species abundance at the study sites. Long term studies following major disturbances are needed to distinguish between short term recovery of plant and animal species and long term changes in these species. Studies extending over a number of years enable a better directional view of changes in small mammal communities than can be determined from . observations made over a short period. As a part of the investigation into temporal change, it was proposed to undertake trial reintroductions of the Swamp antechinus, Ant echinus minimus, a marsupial dasyurid species which was trapped in the area prior to the 1983 fire, but rarely subsequently. Other more commonly observed native small mammal species (e.g. Rattus fuscipes,R. lutreolus, Antechinus stuartii, Sminthopsis leucopus) had re-invaded the proposed reintroduction site after this fire. Failure of A. minimus to re-establish may have been due to spatial separation of the pre-fire populations coupled with the extensive area burnt in 1983, A source population of the species was located about 100km to the west and habitat utilization and interspecific and niche relationships between the species making the small mammal community explored. Discriminant analysis revealed some spatial separation of species within a habitat based on structural vegetation factors rather than floristic factors. Temporal separation of species was observed, asA. minimus were more active than Rattus species during daylight periods. There was evidence of micro-habitat selection by species, and structural vegetation factors were most commonly identified in statistical analyses as contributing towards selection by small mammal species. Following a theoretical modelling study three reintroduction trials were carried out near Anglesea during 1992-94. Individuals were subsequently radio tracked, and habitat relationships between the species in the small mammal community investigated. Although successful breeding of A, minimus occurred during the latter two trials, the subsequent fate of offspring was not determined. Invasive techniques required to adequately monitor young animals were considered potentially too damaging. Telemetry studies indicated a preference of A. minimus for short, wet heath vegetation. Structural vegetation factors were identified as being significant in discriminating between capture locations of species. Small scale and inexpensive trial reintroductions have yielded valuable additional data on this species and may be viewed as a useful tool in the conservation of other small native mammals.

Degradation of the strength of porous titanium after alkali and heat treatment

Porous titanium with a porosity of 75% was fabricated by space-holder sintering through powder metallurgy. The effect of the alkali and heat treatment on the strength of the porous titanium was investigated. Results indicated that the alkali and heat treatment led to a significant decrease in the strength of the porous titanium, whichwas causedby the degradation due to corrosion of the struts of the porous titanium with a layer of the reaction products, grain pullout and micro-cracks.

PISA – Shocks, after shocks and misconceptions

The Program for International Student Assessment (PISA) is as a triennial event of ranking compulsory education performance of students in participating countries. The results are published as a leagues table, which attracts much attention from politicians, media, employer groups, academics and other interest groups. Many of the responses and much of interpretation of PISA results are arguably misguided, for they mistake quality of education within performance of education systems. In this paper we are attempting to demystify PISA results by focusing on issues OECD-PISA education concept, test results and its limitations from a quality of education perspective.

Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents

Background Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians. Objective To describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents. Design, setting, and participants We report on a cohort of 59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of whom had received prior enzalutamide. Outcome measurements and statistical analysis Changes in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy. Results and limitations The post-endocrine-therapy patients received abiraterone (n = 32), sequential abiraterone and enzalutamide (n = 5) or enzalutamide (n = 4). These patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median of six cabazitaxel cycles (range: 1-10 cycles) were delivered, with ≥50% PSA declines in 16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naïve cohort (n = 18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis. Conclusions This is the first report of cabazitaxel activity in CRPC progressing after treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant cabazitaxel activity in this setting. Patient summary We looked at the antitumour activity of the chemotherapy drug cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after these novel endocrine treatments. © 2013 European Association of Urology.

Effect of creatine ingestion on glucose tolerance and insulin sensitivity in men

Purpose: This study investigated whether acute (5 d) and/or short-term (28 d) creatine (Cr) ingestion altered glucose tolerance or insulin action in healthy, untrained men (aged 26.9 ± 5.7 yr; SD). Methods : Subjects were randomly allocated to either a Cr (N = 8) or placebo group (N = 9) and were tested in the control condition (presupplementation), and after 5 and a further 28 d of supplementation. The Cr group ingested 20 g and 3 g·d-1 of Cr for the first 5 and following 28 d, respectively. The placebo group ingested similar amounts of glucose over the same time period. During each testing period, subjects underwent an oral glucose tolerance test (OGTT) to determine insulin sensitivity, and six subjects from each group underwent a muscle biopsy before each OGTT. Results : Cr supplementation resulted in an increased (P < 0.05) muscle TCr content after both the acute and short-term loading phase compared with placebo. Neither acute nor short-term Cr supplementation influenced skeletal muscle glycogen content, glucose tolerance, or measures of insulin sensitivity. Conclusions: These findings demonstrated that acute Cr supplementation (20 g·d-1 for 5 d) followed by short-term Cr supplementation (3 g·d-1 for 28 d) did not alter insulin action in healthy, active untrained men.

Deformation and annealing of (011)[011] oriented A1 single crystals

High purity Al single crystals of the (011)[011] orientation have been deformed in plane strain compression in a channel die. Deformation was carried out at a strain rate of 0.01 s−1 to true strains of 0.5 and 1.0, and at temperatures of 25, 200 and 300 °C. The as-deformed microstructure has been characterized using electron backscattered diffraction (EBSD) and X-ray diffraction (XRD). No recrystallization was detected after deformation, and the deformation texture analysis showed that the stability of the orientation decreased with increasing temperature, contrary to reports for other orientations.

Annealing was carried out for various times at 300 °C. Nucleation of recrystallization exhibited periodicity, with distinct bands of recrystallized grains forming parallel to the transverse direction. This recrystallized microstructure has been examined using EBSD. A model is proposed to account for the origin of the periodicity of nucleation and the retention of rods or cylinders of unrecrystallized material after significant annealing times.

Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting

Fasting forces adaptive changes in whole body and skeletal muscle metabolism that increase fat oxidation and decrease the oxidation of carbohydrate. We tested the hypothesis that 40 h of fasting would decrease pyruvate dehydrogenase (PDH) activity and increase PDH kinase (PDK) isoform mRNA expression in human skeletal muscle. The putative transcriptional activators of PDK isozymes, peroxisome proliferator-activated receptor-α (PPAR-α) protein, and forkhead homolog in rhabdomyosarcoma (FKHR) mRNA were also measured. Eleven healthy adults fasted after a standard meal (25% fat, 60% carbohydrate, 15% protein) with blood and skeletal muscle samples taken at 3, 15, and 40 h postprandial. Fasting increased plasma free fatty acid, glycerol, and β-hydroxybutyrate concentrations and decreased glucose and insulin concentrations. PDH activity decreased from 0.88 ± 0.11 mmol acetyl-CoA · min^-1 · kg wet muscle wt^-1 at 3 h to 0.62 ± 0.10 (P = not significant) and 0.39 ± 0.06 (P < 0.05) mmol · min^-1 · kg wet mass^-1 after 15 and 40 h of fasting. Although all four PDK isoforms were expressed in human skeletal muscle, PDK^-2 and -4 mRNA were the most abundant. PDK^-1 and ^-3 mRNA abundance was ~1 and 15% of the PDK^-2 and 4^- levels, respectively. The 40-h fast had no effect on PDK^-1, ^-2, and ^-3 mRNA expression. PDK-4 mRNA was significantly increased ~3-fold after 15 h and ~14-fold after 40 h of fasting. Skeletal muscle PPAR-α protein and FKHR mRNA abundance were unaffected by the fast. The results suggest that decreased PDH activation after 40 h of fasting may have been a function of the large increase in PDK-4 mRNA expression and possible subsequent increase in PDK protein and activity. The changes in PDK-4 expression and PDH activity did not coincide with increases in the transcriptional activators PPAR-α and FKHR.

Thrifty metabolism that favors fat storage after caloric restriction: a role for skeletal muscle phosphatidylinositol-3-kinase activity and AMP-activated protein kinase

Energy conservation directed at accelerating body fat recovery (or catch-up fat) contributes to obesity relapse after slimming and to excess fat gain during catch-up growth after malnutrition. To investigate the mechanisms underlying such thrifty metabolism for catch-up fat, we tested whether during refeeding after caloric restriction rats exhibiting catch-up fat driven by suppressed thermogenesis have diminished skeletal muscle phosphatidylinositol-3-kinase (PI3K) activity or AMP-activated protein kinase (AMPK) signaling—two pathways required for hormone-induced thermogenesis in ex vivo muscle preparations. The results show that during isocaloric refeeding with a low-fat diet, at time points when body fat, circulating free fatty acids, and intramyocellular lipids in refed animals do not exceed those of controls, muscle insulin receptor substrate 1-associated PI3K activity (basal and in vivo insulin-stimulated) is lower than that in controls. Isocaloric refeeding with a high-fat diet, which exacerbates the suppression of thermogenesis, results in further reductions in muscle PI3K activity and in impaired AMPK phosphorylation (basal and in vivo leptin-stimulated). It is proposed that reduced skeletal muscle PI3K/AMPK signaling and suppressed thermogenesis are interdependent. Defective PI3K or AMPK signaling will reduce the rate of substrate cycling between de novo lipogenesis and lipid oxidation, leading to suppressed thermogenesis, which accelerates body fat recovery and furthermore sensitizes skeletal muscle to dietary fat-induced impairments in PI3K/AMPK signaling.—Summermatter, S., Mainieri, D., Russell, A. P., Seydoux, J., Montani, J. P., Buchala, A., Solinas, G., Dulloo, A. G. Thrifty metabolism that favors fat storage after caloric restriction: a role for skeletal muscle phosphatidylinositol-3-kinase activity and AMP-activated protein kinase.

Similar metabolic adaptations during exercise after low volume sprint interval and traditional endurance training in humans

Low-volume ‘sprint’ interval training (SIT) stimulates rapid improvements in muscle oxidative capacity that are comparable to levels reached following traditional endurance training (ET) but no study has examined metabolic adaptations during exercise after these different training strategies. We hypothesized that SIT and ET would induce similar adaptations in markers of skeletal muscle carbohydrate (CHO) and lipid metabolism and metabolic control during exercise despite large differences in training volume and time commitment. Active but untrained subjects (23 ± 1 years) performed a constant-load cycling challenge (1 h at 65% of peak oxygen uptake before and after 6 weeks of either SIT or ET (n = 5 men and 5 women per group). SIT consisted of four to six repeats of a 30 s ‘all out’ Wingate Test (mean power output ∼500 W) with 4.5 min recovery between repeats, 3 days per week. ET consisted of 40–60 min of continuous cycling at a workload that elicited ∼65% (mean power output ∼150 W) per day, 5 days per week. Weekly time commitment (∼1.5 versus ∼4.5 h) and total training volume (∼225 versus ∼2250 kJ week−1) were substantially lower in SIT versus ET. Despite these differences, both protocols induced similar increases (P < 0.05) in mitochondrial markers for skeletal muscle CHO (pyruvate dehydrogenase E1α protein content) and lipid oxidation (3-hydroxyacyl CoA dehydrogenase maximal activity) and protein content of peroxisome proliferator-activated receptor-γ coactivator-1α. Glycogen and phosphocreatine utilization during exercise were reduced after training, and calculated rates of whole-body CHO and lipid oxidation were decreased and increased, respectively, with no differences between groups (all main effects, P < 0.05). Given the markedly lower training volume in the SIT group, these data suggest that high-intensity interval training is a time-efficient strategy to increase skeletal muscle oxidative capacity and induce specific metabolic adaptations during exercise that are comparable to traditional ET.

Annual high-dose oral vitamin D and falls and fractures in older women : a randomized controlled trial

Context Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.

Objective To determine whether a single annual dose of 500 000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.

Design, Setting, and Participants A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.

Intervention 500 000 IU of cholecalciferol or placebo.

Main Outcome Measures Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.

Results Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.

Conclusion Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.