Cardiopulmonary and cerebrovascular acclimatization in children and adults at 3800 m.

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea-level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea-level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ), end-tidal partial pressures of oxygen ( P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ ) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V ̇ E ${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (-11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min-1 vs. +13 beats min-1 , P = 0.019). Between B1 and B4, adults increased V ̇ E ${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V ̇ E ${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆ P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2  = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V ̇ E ${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. KEY POINTS: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude. Children (ages 7-14) and adults (ages 23-44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week. Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults. PASP and CBF increased by a similar relative amount between children and adults at 3800 m. These results help us better understand age-related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults.

Cost-effectiveness analysis of tumor molecular classification in high-risk early-stage endometrial cancer.

PURPOSE: Tumor molecular analyses in endometrial cancer (EC) includes 4 distinct subtypes: (1) POLE-mutated, (2) mismatch repair protein (MMR) deficient, (3) p53 mutant, and (4) no specific molecular profile. Recently, a sub-analysis of PORTEC-3 demonstrated notable differences in treatment response between molecular classification (MC) groups. Cost of testing is one barrier to widespread adoption of MC. Therefore, we sought to determine the cost-effectiveness of MC in patients with stage I and II high-risk EC. METHODS: A Markov decision model was developed to compare tumor molecular classification (TMC) vs. no testing (NT). A healthcare payor's perspective and 5-year time horizon were used. Base case data were abstracted from PORTEC-3 and the molecular sub-analysis. Cost and utility data were derived from public databases, peer-reviewed literature, and expert input. Strategies were compared using the incremental cost-effectiveness ratio (ICER) with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness-to-pay threshold of $100,000 per QALY gained. Sensitivity analyses were performed to test model robustness. RESULTS: When compared to NT, TMC was cost effective with an ICER of $25,578 per QALY gained; incremental cost was $1780 and incremental effectiveness was 0.070 QALYs. In one-way sensitivity analyses, results were most sensitive to the cost of POLE testing, but TMC remained cost-effective over all parameter ranges. CONCLUSIONS: TMC in early-stage high-risk EC is cost-effective, and the model results were robust over a range of parameters. Given that MC can be used to guide adjuvant treatment decisions, these findings support adoption of TMC into routine practice.

An eating pattern characterised by skipped or delayed breakfast is associated with mood disorders among an Australian adult cohort.

BACKGROUND: Meal timing may influence food choices, neurobiology and psychological states. Our exploratory study examined if time-of-day eating patterns were associated with mood disorders among adults. METHODS: During 2004-2006 (age 26-36 years) and 2009-2011 (follow-up, age 31-41 years), N = 1304 participants reported 24-h food and beverage intake. Time-of-day eating patterns were derived by principal components analysis. At follow-up, the Composite International Diagnostic Interview measured lifetime mood disorder. Log binomial and adjacent categories log-link regression were used to examine bidirectional associations between eating patterns and mood disorder. Covariates included sex, age, marital status, social support, education, work schedule, body mass index and smoking. RESULTS: Three patterns were derived at each time-point: Grazing (intake spread across the day), Traditional (highest intakes reflected breakfast, lunch and dinner), and Late (skipped/delayed breakfast with higher evening intakes). Compared to those in the lowest third of the respective pattern at baseline and follow-up, during the 5-year follow-up, those in the highest third of the Late pattern at both time-points had a higher prevalence of mood disorder [prevalence ratio (PR) = 2.04; 95% confidence interval (CI) 1.20-3.48], and those in the highest third of the Traditional pattern at both time-points had a lower prevalence of first onset mood disorder (PR = 0.31; 95% CI 0.11-0.87). Participants who experienced a mood disorder during follow-up had a 1.07 higher relative risk of being in a higher Late pattern score category at follow-up than those without mood disorder (95% CI 1.00-1.14). CONCLUSIONS: Non-traditional eating patterns, particularly skipped or delayed breakfast, may be associated with mood disorders.

Interventions for sleep difficulties in adults with an intellectual disability: a systematic review.

BACKGROUND: Current literature highlights higher prevalence rates of sleep difficulties amongst adults with an intellectual disability. However, no synthesis has been conducted to assess the effectiveness of existing interventions in this population. Thus, the aim of this review was to assess the effectiveness of sleep interventions in adults with an intellectual disability (ID). METHOD: Eight databases were searched to identify interventions for sleep difficulties amongst adults with an ID. The study quality was assessed with the Risk Of Bias In Non-randomised Studies - of Interventions. Nine studies (n = 97) were eligible for inclusion in the review. RESULTS: There was a notable study on heterogeneity in terms of the population, study design, intervention studied, sleep assessment and outcome assessments used. Eight of the nine studies reported improvement in sleep following intervention. However, these findings need additional support as only 97 participants involving a variety of interventions and measurement systems were used across all studies. Furthermore, eight of the nine studies had serious to critical risk of bias. The only study identified as having low risk of bias was a placebo-controlled randomised controlled trial for the use of melatonin. CONCLUSIONS: This review highlights the need for objective measures such as actigraphy and studies with greater experimental control investigating sleep interventions in adults with ID.

Investigating the longitudinal association between diabetes and anxiety: a systematic review and meta-analysis.

AIM: Previous research has indicated an association between diabetes and anxiety. However, no synthesis has determined the direction of this association. The aim of this study was to determine the longitudinal relationship between anxiety and diabetes. METHODS: We searched seven databases for studies examining the longitudinal relationship between anxiety and diabetes. Two independent reviewers screened studies from a population aged 16 or older that examined either anxiety as a risk factor for incident diabetes or diabetes as a risk factor for incident anxiety. Studies that met eligibility criteria were put forward for data extraction and meta-analysis. RESULTS: In total 14 studies (n = 1 760 800) that examined anxiety as a risk factor for incident diabetes and two (n = 88 109) that examined diabetes as a risk factor for incident anxiety were eligible for inclusion in the review. Only studies examining anxiety as a risk factor for incident diabetes were put forward for the meta-analysis. The least adjusted (unadjusted or adjusted for age only) estimate indicated a significant association between baseline anxiety with incident diabetes (odds ratio 1.47, 1.23-1.75). Furthermore, most-adjusted analyses indicated a significant association between baseline anxiety and incident diabetes. Included studies that examined diabetes to incident anxiety found no association. CONCLUSIONS: There was an association between baseline anxiety and incident diabetes. The results also indicate the need for more research to examine the direction of association from diabetes to incident anxiety. This work adds to the growing body of evidence that poor mental health increases the risk of developing diabetes.

Protection of cerebral microcirculation, mitochondrial function, and electrocortical activity by small-volume resuscitation with terlipressin in a rat model of haemorrhagic shock.

BACKGROUND: During early treatment of haemorrhagic shock, cerebral perfusion pressure can be restored by small-volume resuscitation with vasopressors. Whether this therapy is improved with additional fluid remains unknown. We assessed the value of terlipressin and lactated Ringer's solution (LR) on early recovery of microcirculation, tissue oxygenation, and mitochondrial and electrophysiological function in the rat cerebral cortex. METHODS: Animals treated with LR replacing three times (3LR) the volume bled (n=26), terlipressin (n=27), terlipressin plus 1LR (n=26), 2LR (n=16), or 3LR (n=15) were compared with untreated (n=36) and sham-operated rats (n=17). In vivo confocal microscopy was used to assess cortical capillary perfusion, changes in tissue oxygen concentration, and mitochondrial membrane potential and redox state. Electrophysiological function was assessed by cortical somatosensory evoked potentials, spinal cord dorsum potential, and peripheral electromyography. RESULTS: Compared with sham treatment, haemorrhagic shock reduced the mean (SD) area of perfused vessels [82% (sd 10%) vs 38% (12%); P<0.001] and impaired oxygen concentration, mitochondrial redox state [99% (4%) vs 59% (15%) of baseline; P<0.001], and somatosensory evoked potentials [97% (13%) vs 27% (19%) of baseline]. Administration of terlipressin plus 1LR or 2LR was able to recover these measures, but terlipressin plus 3LR or 3LR alone were not as effective. Spinal cord dorsum potential was preserved in all groups, but no therapy protected electromyographic function. CONCLUSIONS: Resuscitation from haemorrhagic shock using terlipressin with small-volume LR was superior to high-volume LR, with regard to cerebral microcirculation, and mitochondrial and electrophysiological functions.

Depression and risk of type 2 diabetes: the potential role of metabolic factors.

The aim of the present study was to evaluate the interaction between depressive symptoms and metabolic dysregulations as risk factors for type 2 diabetes. The sample comprised of 2525 adults who participated in a baseline and a follow-up assessment over a 4.5-year period in the Emotional Health and Wellbeing Study (EMHS) in Quebec, Canada. A two-way stratified sampling design was used, on the basis of the presence of depressive symptoms and metabolic dysregulation (obesity, elevated blood sugar, high blood pressure, high levels of triglycerides and decreased high-density lipoprotein). A total of 87 (3.5%) individuals developed diabetes. Participants with both depressive symptoms and metabolic dysregulation had the highest risk of diabetes (adjusted odds ratio=6.61, 95% confidence interval (CI): 4.86-9.01), compared with those without depressive symptoms and metabolic dysregulation (reference group). The risk of diabetes in individuals with depressive symptoms and without metabolic dysregulation did not differ from the reference group (adjusted odds ratio=1.28, 95% CI: 0.81-2.03), whereas the adjusted odds ratio for those with metabolic dysregulation and without depressive symptoms was 4.40 (95% CI: 3.42-5.67). The Synergy Index (SI=1.52; 95% CI: 1.07-2.17) suggested that the combined effect of depressive symptoms and metabolic dysregulation was greater than the sum of individual effects. An interaction between depression and metabolic dysregulation was also suggested by a structural equation model. Our study highlights the interaction between depressive symptoms and metabolic dysregulation as a risk factor for type 2 diabetes. Early identification, monitoring and a comprehensive management approach of both conditions might be an important diabetes prevention strategy.

Depressive symptoms and glycated hemoglobin A1c: a reciprocal relationship in a prospective cohort study.

BACKGROUND: The aim of this study was to evaluate the dynamic association between depressive symptoms and glycated hemoglobin A1c (HbA1c) levels using data from the English Longitudinal Study of Ageing (ELSA). METHOD: The sample was comprised of 2886 participants aged ⩾50 years who participated in three clinical assessments over an 8-year period (21% with prediabetes and 7% with diabetes at baseline). Structural equation models were used to address reciprocal associations between depressive symptoms and HbA1c levels and to evaluate the mediating effects of lifestyle-related behaviors and cardiometabolic factors. RESULTS: We found a reciprocal association between depressive symptoms and HbA1c levels: depressive symptoms at one assessment point predicted HbA1c levels at the next assessment point (standardized ß = 0.052) which in turn predicted depressive symptoms at the following assessment point (standardized ß = 0.051). Mediation analysis suggested that both lifestyle-related behaviors and cardiometabolic factors might mediate the association between depressive symptoms and HbA1c levels: depressive symptoms at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted HbA1c levels 4 years later. A similar association was observed for the other direction: HbA1c levels at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted depressive symptoms 4 years later. CONCLUSIONS: Our results suggest a dynamic relationship between depressive symptoms and HbA1c which might be mediated by both lifestyle and cardiometabolic factors. This has important implications for investigating the pathways which could link depressive symptoms and increased risk of diabetes.

Bi-directional associations between healthy lifestyles and mood disorders in young adults: The Childhood Determinants of Adult Health Study.

BACKGROUND: Healthy lifestyles prevent cardiovascular disease and are increasingly recognized in relation to mental health but longitudinal studies are limited. We examined bi-directional associations between mood disorders and healthy lifestyles in a cohort followed for 5 years. METHOD: Participants were aged 26-36 years at baseline (2004-2006) and 31-41 years at follow-up (2009-2011). At follow-up, lifetime mood disorders (depression or dysthymia) were retrospectively diagnosed with the Composite International Diagnostic Interview. A five-item lifestyle score (comprising body mass index, non-smoking, alcohol consumption, leisure time physical activity and healthy diet) was measured at both time points. Linear and log multinomial regression determined if mood disorder before baseline predicted changes in lifestyle (n = 1041). Log binomial regression estimated whether lifestyle at baseline predicted new episodes of mood disorder (n = 1233). Covariates included age, sex, socio-economic position, parental and marital status, social support, major life events, cardiovascular disease history, and self-rated physical and mental health. RESULTS: A history of mood disorder before baseline predicted unfavourable trajectories of lifestyle over follow-up, including somewhat lower risk of improvement [relative risk (RR) 0.76, 95% confidence interval (CI) 0.56-1.03] and greater risk of worsening (RR 1.46, 95% CI 0.99-2.15) of lifestyle independent of confounding factors. Higher lifestyle scores at baseline were associated with a 22% (RR 0.76, 95% CI 0.61-0.95) reduced risk of first episodes of mood disorder, independent of confounding factors. CONCLUSIONS: Healthy lifestyles and mood disorders are closely related. Our results suggest that healthy lifestyles may not only reduce cardiovascular disease but also promote mental health.

In Vivo Imaging of Flavoprotein Fluorescence During Hypoxia Reveals the Importance of Direct Arterial Oxygen Supply to Cerebral Cortex Tissue.

Live imaging of mitochondrial function is crucial to understand the important role played by these organelles in a wide range of diseases. The mitochondrial redox potential is a particularly informative measure of mitochondrial function, and can be monitored using the endogenous green fluorescence of oxidized mitochondrial flavoproteins. Here, we have observed flavoprotein fluorescence in the exposed murine cerebral cortex in vivo using confocal imaging; the mitochondrial origin of the signal was confirmed using agents known to manipulate mitochondrial redox potential. The effects of cerebral oxygenation on flavoprotein fluorescence were determined by manipulating the inspired oxygen concentration. We report that flavoprotein fluorescence is sensitive to reductions in cortical oxygenation, such that reductions in inspired oxygen resulted in loss of flavoprotein fluorescence with the exception of a preserved 'halo' of signal in periarterial regions. The findings are consistent with reports that arteries play an important role in supplying oxygen directly to tissue in the cerebral cortex, maintaining mitochondrial function.

Cost-effectiveness of pediatric heart transplantation across a positive crossmatch for high waitlist urgency candidates.

Allosensitized children listed with a requirement for a negative prospective crossmatch have high mortality. Previously, we found that listing with the intent to accept the first suitable organ offer, regardless of the possibility of a positive crossmatch (TAKE strategy), results in a survival advantage from the time of listing compared to awaiting transplantation across a negative crossmatch (WAIT). The cost-effectiveness of these strategies is unknown. We used Markov modeling to compare cost-effectiveness between these waitlist strategies for allosensitized children listed urgently for heart transplantation. We used registry data to estimate costs and waitlist/posttransplant outcomes. We assumed patients remained in hospital after listing, no positive crossmatches for WAIT, and a base-case probability of a positive crossmatch of 47% for TAKE. Accepting the first suitable organ offer cost less ($405 904 vs. $534 035) and gained more quality-adjusted life years (3.71 vs. 2.79). In sensitivity analyses, including substitution of waitlist data from children with unacceptable antigens specified during listing, TAKE remained cost-saving or cost-effective. Our findings suggest acceptance of the first suitable organ offer for urgently listed allosensitized pediatric heart transplant candidates is cost-effective and transplantation should not be denied because of allosensitization status alone.

Comparison of listing strategies for allosensitized heart transplant candidates requiring transplant at high urgency: a decision model analysis.

Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.

Influence of high altitude on cerebral blood flow and fuel utilization during exercise and recovery.

We examined the hypotheses that: (1) during incremental exercise and recovery following 4-6 days at high altitude (HA) global cerebral blood flow (gCBF) increases to preserve cerebral oxygen delivery (CDO2) in excess of that required by an increasing cerebral metabolic rate of oxygen ( CM RO2); (2) the trans-cerebral exchange of oxygen vs. carbohydrates (OCI; carbohydrates = glucose + ½lactate) would be similar during exercise and recovery at HA and sea level (SL). Global CBF, intra-cranial arterial blood velocities, extra-cranial blood flows, and arterial-jugular venous substrate differences were measured during progressive steady-state exercise (20, 40, 60, 80, 100% maximum workload (Wmax)) and through 30 min of recovery. Measurements (n = 8) were made at SL and following partial acclimatization to 5050 m. At HA, absolute Wmax was reduced by ∼50%. During submaximal exercise workloads (20-60% Wmax), despite an elevated absolute gCBF (∼20%, P < 0.05) the relative increases in gCBF were not different at HA and SL. In contrast, gCBF was elevated at HA compared with SL during 80 and 100% Wmax and recovery. Notwithstanding a maintained CDO2 and elevated absolute CM RO2 at HA compared with SL, the relative increase in CM RO2 was similar during 20-80% Wmax but half that of the SL response (i.e. 17 vs. 27%; P < 0.05 vs. SL) at 100% Wmax. The OCI was reduced at HA compared with SL during 20, 40, and 60% Wmax but comparable at 80 and 100% Wmax. At HA, OCI returned almost immediately to baseline values during recovery, whereas at SL it remained below baseline. In conclusion, the elevations in gCBF during exercise and recovery at HA serve to maintain CDO2. Despite adequate CDO2 at HA the brain appears to increase non-oxidative metabolism during exercise and recovery.

Cost-effectiveness of prenatal screening strategies for congenital heart disease.

OBJECTIVE: The economic implications of strategies to improve prenatal screening for congenital heart disease (CHD) in low-risk mothers have not been explored. The aim was to perform a cost-effectiveness analysis of different screening methods. METHODS: We constructed a decision analytic model of CHD prenatal screening strategies (four-chamber screen (4C), 4C + outflow, nuchal translucency (NT) or fetal echocardiography) populated with probabilities from the literature. The model included whether initial screens were interpreted by a maternal-fetal medicine (MFM) specialist and different referral strategies if they were read by a non-MFM specialist. The primary outcome was the incremental cost per defect detected. Costs were obtained from Medicare National Fee estimates. A probabilistic sensitivity analysis was undertaken on model variables commensurate with their degree of uncertainty. RESULTS: In base-case analysis, 4C + outflow referred to an MFM specialist was the least costly strategy per defect detected. The 4C screen and the NT screen were dominated by other strategies (i.e. were more costly and less effective). Fetal echocardiography was the most effective, but most costly. On simulation of 10 000 low-risk pregnancies, 4C + outflow screen referred to an MFM specialist remained the least costly per defect detected. For an additional $580 per defect detected, referral to cardiology after a 4C + outflow was the most cost-effective for the majority of iterations, increasing CHD detection by 13 percentage points. CONCLUSIONS: The addition of examination of the outflow tracts to second-trimester ultrasound increases detection of CHD in the most cost-effective manner. Strategies to improve outflow-tract imaging and to refer with the most efficiency may be the best way to improve detection at a population level.

Self-reported use of diabetes healthcare services in a Quebec community-based sample: impact of depression status.

OBJECTIVES: To ascertain the impact of minor and major depression on self-reported use of and access to diabetes healthcare services, and the care components received in a community-based Quebec sample with type 2 diabetes. STUDY DESIGN: Adults with type 2 diabetes who took part in baseline and 1-year follow-up telephone interviews for the Diabetes Health Study were assessed (n = 1175). METHODS: Information was collected regarding depression status (i.e. minor or major depression), use of and access to diabetes healthcare services, sociodemographic and diabetes characteristics, treatment, diabetes complications, disability, body mass index, residential area and depression. RESULTS: People with major depression were more likely to be high users or non-users of diabetes healthcare services. The high users reported more diabetes complications. People with major depression also reported more problems with accessing diabetes healthcare services, specifically having to wait too long between making their appointment and their visit, specialist care not being available in their area, general health deterioration, being unable to leave their house due to their health and problems with transportation. People with major depression were less likely to report having their feet checked by their doctor, and were more likely to report problems with getting advice from their doctor. CONCLUSIONS: People with diabetes need to use healthcare services in order to receive recommended care components. People with major depression and no complications are less likely to report using healthcare services; conversely, people with major depression and complications are more likely to be high users of healthcare services. People with major depression perceive more problems with the health care they receive.

Regional brain blood flow in man during acute changes in arterial blood gases.

Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso-oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (PaCO2 =∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63±0.26; P<0.05); VA diameter was unaltered in response to changed PaCO2 but yielded a diameter increase of +9% with severe hypoxia. (3) Intra- vs. extra-cerebral measures: MCA and PCA blood velocities yielded smaller reactivities and estimates of flow than VA and ICA flow. The findings respectively indicate: (1) disparate blood flow regulation to the brainstem and cortex; (2) cerebrovascular resistance is not solely modulated at the level of the arteriolar pial vessels; and (3) transcranial Doppler ultrasound may underestimate measurements of CBF during extreme hypoxia and/or hypercapnia.

Efficacy of bivalent fimbrial vaccines to control and eliminate intermediate forms of footrot in sheep.

OBJECTIVE: The aim of this study was to determine the efficacy of serogroup-specific bivalent fimbrial vaccines in the control and elimination of relatively mild (intermediate) forms of footrot in sheep flocks in NSW, there being some evidence that such forms are difficult to control. METHODS: Four flocks of sheep with history of footrot of intermediate virulence were selected based on clinical and bacteriological diagnoses. Dichelobacter nodosus serogroups included in bivalent vaccines at each farm were based on on-farm serogroup-prevalence data. Two doses of bivalent vaccine were administered with a 4-week interval between doses. Repeated post-vaccination inspections of all feet of between 100 and 119 animals per mob were conducted and foot swabs were collected for bacteriological testing. Blood samples were collected from 10 to 24 individually identified animals per flock at each inspection to check for agglutinating antibody responses. RESULTS: In the majority of animals, antibody levels for serogroups included in each vaccine were above the level believed to be required for protective immunity. Footrot disappeared on farm 1 prior to vaccination, but did not reappear postvaccination. Footrot was controlled but not eliminated on farms 2, 3, and 4, where the prevalence and severity of the disease and number of serogroups present were reduced. CONCLUSION: Serogroup-specific bivalent vaccines can be effective at controlling footrot caused by intermediate strains of D. nodosus.

Prognostic factors for survival after curative resection of Dukes' B colonic cancer.

AIM: Data on the prognostic factors for survival in patients with locally advanced, node-negative colon cancer are limited. This study aimed to determine which factors might predict survival in patients with Dukes' B (T3 or T4, N0) colon cancer. METHOD: One hundred and eighty (93 male; median age 75 [range, 38-96] years) consecutive patients who had resection of a primary Dukes' B (on final histopathological analysis) colonic cancer between 1998 and 2003 were studied. No patient received neoadjuvant chemotherapy. Multivariate Cox regression modelling was used to assess the prognostic value of variables. Median follow up was 85 (60-125) months. RESULTS: Thirteen (7%) patients had a perforation at presentation. The median distance from tumour to the nearest longitudinal resection margin was 6 (0.3-27) cm. One hundred and twenty-four (69%) patients had a lymph node yield of 12 or more nodes. Actual 5-year survival was 59%. On multivariate regression analysis, tumour perforation (perforation vs no perforation, 5-year survival, 23%vs 61%; hazard ratio (HR), 3.7; 95% confidence interval (CI), 1.6-8.4; P = 0.002), tumour-to-margin distance (< 5 cm vs ≥ 5 cm, 48%vs 65%; HR, 1.7; 95% CI, 1.1-2.7; P = 0.039) and older age (≥ 75 years vs < 75 years, 45%vs 72%; HR, 3; 95% CI, 1.8-5; P < 0.001) were independent significant variables. CONCLUSION: A lymph node yield of 12 or more nodes is not a significant prognostic factor for survival after resection of Dukes' B colonic cancer. Patients with tumour perforation or limited resection have worse prognosis.

The severity of footrot lesions induced by aprV2-positive strains of Dichelobacter nodosus varies between strains.

OBJECTIVES: The primary objective of this study was to evaluate the clinical virulence of aprV2-positive lesser virulent field isolates of footrot bacteria Dichelobacter nodosus in comparison with an aprV2-positive clinically virulent reference strain. Correlations between the clinical expression of the disease and the presence of aprV2 (detected using PCR tests) have been inconsistent. A second objective was to evaluate the elimination of D. nodosus following treatment of sheep as some strains of D. nodosus have been reported to be difficult to eliminate. METHODS: The virulence of three aprV2-positive field isolates of D. nodosus which had lesser virulent phenotypes, and an aprV2-positive virulent reference strain was evaluated in a sheep trial using a pasture-based experimental infection model. In the second phase of the study, treatments including footbathing and a long-acting antibiotic were administered and their efficacy in elimination of these strains was evaluated. RESULTS: Severe underrun (score 4) lesions developed in sheep infected with the aprV2-positive virulent reference strain but not in sheep infected with the field isolates; they had mild lesions (score 2 or 3). The three field isolates and the virulent reference strain of D. nodosus were eliminated by intensive foot bathing and antibiotic therapy in combination with housing the animals in dry conditions post-treatment. CONCLUSION: The results suggest that the presence of aprV2 gene in isolates of D. nodosus may not be a reliable indicator of virulence and that further investigation of the factors that determine clinical virulence is required. While the treatment regime was successful, based on a range of considerations, the use of such an intensive treatment involving antibiotics should be limited to small groups of high-value animals, such as rams.

Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein.

Susceptibility to multiple sclerosis is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 (DRB1*1501) haplotype. The structure of HLA-DR2 was determined with a bound peptide from human myelin basic protein (MBP) that is immunodominant for human MBP-specific T cells. Residues of MBP peptide that are important for T cell receptor recognition are prominent, solvent exposed residues in the crystal structure. A distinguishing feature of the HLA-DR2 peptide binding site is a large, primarily hydrophobic P4 pocket that accommodates a phenylalanine of the MBP peptide. The necessary space for this aromatic side chain is created by an alanine at the polymorphic DRbeta 71 position. These features make the P4 pocket of HLA-DR2 distinct from DR molecules associated with other autoimmune diseases.