Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations

The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.     

Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors

The blood-brain barrier (B-BB) protects the free passage of substances into the brain and maintains the homeostasis of the central nervous system. It is commonly accepted that astrocytes surrounding brain endothelial cells influence the B-BB formation and the exhibition of B-BB function of capillaries. To begin the in vitro study on the B-BB, it is essential to obtain a homogenous and sufficient supply of brain endothelial cells as well as astrocytes. We thus immortalized the bovine brain endothelial cell (BBEC) by transfection of the SV40 large T antigen and obtained a single clone, t-BBEC-117, which retained the brain endothelial cell phenotype. Astrocyte in co-culture was found to tighten the intercellular contacts of the immortal cells resulting in a reduced L-glucose permeability, and its conditioned medium (CM) augmented a B-BB phenotype, alkaline phosphatase (ALP) activity. Among known astrocytic factors, only fibroblast growth factor-basic (bFGF) could mimic the actions of astrocytes as measured by L-glucose permeability and ALP activity. Moreover, anti-bFGF antibody canceled 90% of ALP activation by astrocyte CM. Basic FGF, however, failed to induce other B-BB phenotypes such as the expressions of multidrug resistance (mdr) and glucose transporter (GLUT-1) genes. These data suggest that bFGF is one of the most plausible astrocytic factors to induce the B-BB properties of immortal brain endothelial cells together with some unknown factors in the astrocyte CM.     

Direct measurement of the thermal responses of nude resting men in dry environments

Summary Two nude resting men were exposed for two-hour periods to each of 25 dry environments, with air temperatures ranging between 12.8° C and 49.1° C and wind speeds between 0.67 m/sec and 4.94 m/sec. The mean radiant temperature of the surroundings was kept equal to the air temperature. Rates of radiant and convective heat exchange were measured directly, separately and continuously. The men had reached a thermal steady state after 105 min in the warm environments, but not in the cold environments. Graphs are presented to show the effect of ambient temperature and wind speed on the radiation and convection rates attained after 105 min, as well as on metabolic rate, sweat evaporation rate, rectal temperature and mean skin temperature. These graphs revealed some important aspects of the behaviour of man's thermal control system. In particular the physiological conductance increased with increasing ambient temperature and then saturated at an ambient temperature near 35° C. This saturation resulted in a constant difference between rectal temperature and mean skin temperature irrespective of the environmental conditions.Published with the permission of the Chamber of Mines of South Africa.     

Effects of spaceflight on rhesus quadrupedal locomotion after return to 1G.

Effects of spaceflight on Rhesus quadrupedal locomotion after return to 1G. Locomotor performance, activation patterns of the soleus (Sol), medial gastrocnemius (MG), vastus lateralis (VL), and tibialis anterior (TA) and MG tendon force during quadrupedal stepping were studied in adult Rhesus before and after 14 days of either spaceflight (n = 2) or flight simulation at 1G (n = 3). Flight simulation involved duplication of the spaceflight conditions and experimental protocol in a 1G environment. Postflight, but not postsimulation, electromyographic (EMG) recordings revealed clonus-like activity in all muscles. Compared with preflight, the cycle period and burst durations of the primary extensors (Sol, MG, and VL) tended to decrease postflight. These decreases were associated with shorter steps. The flexor (TA) EMG burst duration postflight was similar to preflight, whereas the burst amplitude was elevated. Consequently, the Sol:TA and MG:TA EMG amplitude ratios were lower following flight, reflecting a "flexor bias." Together, these alterations in mean EMG amplitudes reflect differential adaptations in motor-unit recruitment patterns of flexors and extensors as well as fast and slow motor pools. Shorter cycle period and burst durations persisted throughout the 20-day postflight testing period, whereas mean EMG returned to preflight levels by 17 days postflight. Compared with presimulation, the simulation group showed slight increases in the cycle period and burst durations of all muscles. Mean EMG amplitude decreased in the Sol, increased in the MG and VL, and was unchanged in the TA. Thus adaptations observed postsimulation were different from those observed postflight, indicating that there was a response unique to the microgravity environment, i.e., the modulations in the nervous system controlling locomotion cannot merely be attributed to restriction of movement but appear to be the result of changes in the interpretation of load-related proprioceptive feedback to the nervous system. Peak MG tendon force amplitudes were approximately two times greater post- compared with preflight or presimulation. Adaptations in tendon force and EMG amplitude ratios indicate that the nervous system undergoes a reorganization of the recruitment patterns biased toward an increased recruitment of fast versus slow motor units and flexor versus extensor muscles. Combined, these data indicate that some details of the control of motor pools during locomotion are dependent on the persistence of Earth's gravitational environment.     

Attenuation and vaccine potential of aroQ mutants of Corynebacterium pseudotuberculosis.

Corynebacterium pseudotuberculosis, a gram-positive intracellular bacterial pathogen, is the etiological agent of the disease caseous lymphadenitis (CLA) in both sheep and goats. Attenuated mutants of C. pseudotuberculosis have the potential to act as novel live veterinary vaccine vectors. We have cloned and sequenced the aroB and aroQ genes from C. pseudotuberculosis C231. By allelic exchange, aroQ mutants of both C231, designated CS100, and a pld mutant strain TB521, designated CS200, were constructed. Infection of BALB/c mice indicated that introduction of the aroQ mutation into C231 and TB521 attenuated both strains. In sublethally infected BALB/c mice, both CS100 and CS200 were cleared from spleens and livers by day 8 postinfection. The in vivo persistence of these strains was increased when the intact aroQ gene was supplied on a plasmid in trans. Mice infected with TB521 harbored bacteria in organs at least till day 8 postinfection without ill effect. When used as a vaccine, only the maximum tolerated dose of CS100 had the capacity to protect mice from homologous challenge. Vaccination with TB521 also elicited protective immunity, and this was associated with gamma interferon (IFN-gamma) production from splenocytes stimulated 7 days postvaccination. The role of IFN-gamma in controlling primary infections with C. pseudotuberculosis was examined in mice deficient for the IFN-gamma receptor (IFN-gammaR(-/-) mice). IFN-gammaR(-/-) mice cleared an infection with CS100 but were significantly more susceptible than control littermates to infection with C231 or TB521. These studies support an important role for IFN-gamma in control of primary C. pseudotuberculosis infections and indicate that aroQ mutants remain attenuated even in immunocompromised animals. This is the first report of an aroQ mutant of a bacterial pathogen, and the results may have implications for the construction of aromatic mutants of Mycobacterium tuberculosis for use as vaccines.     

Possible savings with appropriate antibiotic prophylaxis

Antibiotic utilization was studied for one month in 52 patients from two surgical wards and one urology ward in an 835 bed teaching hospital. The use of antibiotics was classified as prophylaxis or treatment and the cost of each regimen was determined. The appropriate antibiotic for prophylaxis was chosen according to the surgical procedure and as a result of a literature review. Using cefazolin as the drug of choice in suitable general surgery cases resulted in a justifiable cost for prophylaxis of $17.64 per patient and a possible saving of up to $67.01 per patient (possible total saving of up to $670.05 for the study population). It was concluded that appropriate antibiotic prophylaxis in surgical patients could lead to significant cost savings. Some techniques for improving antibiotic prescribing are reviewed.     

Musculoskeletal injury survivors’ resiliency: A systematic review

BackgroundMusculoskeletal traumas are on the rise in the United States; however, limited studies are available to help trauma providers assess and treat concerns beyond the physical impact. Little is understood about the psychological, social, and spiritual factors that protect patients from adverse effects after a physical trauma or their experiences with each factor afterward.ObjectiveThis systematic review was conducted to investigate and review advancements in research related to risk and resiliency factors experienced by survivors of traumatic musculoskeletal injuries. The use of biopsychosocial-spiritual (BPS–S) framework and resiliency theory guided the analysis.MethodsResearchers reviewed 1003 articles, but only seven met the search criteria. Due to the complexity and uniqueness of traumatic brain injuries, studies on that target population were excluded.ResultsOf the seven articles reviewed, three identified psychological protective factors that protect against negative health outcomes; three identified negative psychological, social, or spiritual outcomes; and none investigated social or spiritual health.ConclusionsThere are significant gaps in the literature surrounding risk and resiliency factors related to the BPS-S health of musculoskeletal injury survivors.     

Association between Fruit and Vegetable Intakes and Mental Health in the Australian Diabetes Obesity and Lifestyle Cohort

Increasing prevalence of mental health disorders within the Australian population is a serious public health issue. Adequate intake of fruits and vegetables (FV), dietary fibre (DF) and resistant starch (RS) is associated with better mental and physical health. Few longitudinal studies exist exploring the temporal relationship. Using a validated food frequency questionnaire, we examined baseline FV intakes of 5845 Australian adults from the AusDiab study and estimated food group-derived DF and RS using data from the literature. Perceived mental health was assessed at baseline and 5 year follow up using SF-36 mental component summary scores (MCS). We conducted baseline cross-sectional analysis and prospective analysis of baseline dietary intake with perceived mental health at 5 years. Higher baseline FV and FV-derived DF and RS intakes were associated with better 5 year MCS (p < 0.001). A higher FV intake (754 g/d vs. 251 g/d, Q4 vs. Q1) at baseline had 41% lower odds (OR = 0.59: 95% CI 0.46–0.75) of MCS below population average (<47) at 5 year follow up. Findings were similar for FV-derived DF and RS. An inverse association was observed with discretionary food-derived DF and RS. This demonstrates the association between higher intakes of FV and FV-derived DF and RS with better 5 year mental health outcomes. Further RCTs are necessary to understand mechanisms that underlie this association including elucidation of causal effects.     

A comparison of spinal and general anaesthesia for elective caesarean section: effect on neonatal condition at birth

The condition of 74 neonates delivered by elective caesarean section under general anaesthesia was compared with that of 63 neonates delivered under spinal anaesthesia. When the uterine incision - delivery interval was less than 3 min, neonates in the spinal group exhibited a higher Apgar score at 1 min (P < 0.002) and a higher mean umbilical venous pH (P < 0.05) than the equivalent general anaesthesia group; a significantly greater proportion of the neonates delivered under general anaesthesia had an umbilical venous pH<7.28 at delivery (P < 0.05), a fact which previous work suggests is important. Among anaesthetized mothers inspired oxygen concentration (33% or 50%) before delivery had no significant effect upon neonatal outcome. It is concluded that neonates delivered at elective Caesarean section under spinal anaesthesia are in better condition than those delivered under general anaesthesia.