Genetic manipulation of blood group carbohydrates alters development and pathfinding of primary sensory axons of the olfactory systems

Primary sensory neurons in the vertebrate olfactory systems are characterised by the differential expression of distinct cell surface carbohydrates. We show here that the histo-blood group H carbohydrate is expressed by primary sensory neurons in both the main and accessory olfactory systems while the blood group A carbohydrate is expressed by a subset of vomeronasal neurons in the developing accessory olfactory system. We have used both loss-of-function and gain-of-function approaches to manipulate expression of these carbohydrates in the olfactory system. In null mutant mice lacking the alpha(1,2)fucosyltransferase FUT1, the absence of blood group H carbohydrate resulted in the delayed maturation of the glomerular layer of the main olfactory bulb. In addition, ubiquitous expression of blood group A on olfactory axons in gain-of-function transgenic mice caused mis-routing of axons in the glomerular layer of the main olfactory bulb and led to exuberant growth of vomeronasal axons in the accessory olfactory bulb. These results provide in vivo evidence for a role of specific cell surface carbohydrates during development of the olfactory nerve pathways. (c) 2006 Elsevier Inc. All rights reserved.

Expression and role of complex carbohydrates in axon guidance in the olfactory system

Primary sensory neurons in the vertebrate olfactory systems are characterised by the differential expression of distinct cell surface carbohydrates. We show here that the histo-blood groups Sda (or CT1 antigen) and H are expressed by primary sensory neurons in the olfactory system, while the blood group A carbohydrate is expressed by a subset of vomeronasal neurons only in the developing accessory olfactory system. We have used both loss-of-function and gain-of-function approaches to manipulate expression of these carbohydrates in the olfactory system. In null mutant mice lacking the alpha(1,2)fucosyltransferase FUT1, the blood group H and A carbohydrates were not expressed in the olfactory systems which caused delayed development of the nerve fibre and glomerular layers in the main olfactory bulb. In contrast, ubiquitous expression of blood group A on olfactory axons in gain-of-function transgenic mice perturbed the ability of vomeronasal axons to terminate in the accessory olfactory bulb and affected the selective targeting of axons in the main olfactory bulb. During regeneration following bulbectomy, vomeronasal axons were unable to effectively sort out from the main olfactory axons when blood group A was misexpressed. These results provide in vivo evidence for a role of specific cell surface carbohydrates during development and regeneration of the olfactory nerve pathways.

Temperature dependence of the thrombin-catalyzed proteolysis of prothrombin

Measurement of the temperature-dependence of thrombin-catalyzed cleavage of the Arg(155)-Ser(156) and Arg(284)-Thr(285) peptide bonds in prothrombin and prothrombin-derived substrates has yielded Arrhenius parameters that are far too large for classical mechanistic interpretation in terms of a simple hydrolytic reaction. Such a difference from the kinetic behavior exhibited in trypsin- and chymotrypsin-catalyzed proteolysis of peptide bonds is attributed to contributions by enzyme exosite interactions as well as enzyme conformational equilibria to the magnitudes of the experimentally determined Arrhenius parameters. Although the pre-exponential factor and the energy of activation deduced from the temperature-dependence of rate constants for proteolysis by thrombin cannot be accorded the usual mechanistic significance, their evaluation serves a valuable role by highlighting the existence of contributions other than those emanating from simple peptide hydrolysis to the kinetics of proteolysis by thrombin and presumably other enzymes of the blood coagulation system. (C) 2004 Elsevier B.V. All rights reserved.

Remodeling of extracellular matrix at ovulation of the bovine ovarian follicle

Using immunohistochemistry and RNA analyses we examined the fate of components of a newly identified matrix that develops between granulosa cells (focimatrix, abbreviated from focal intraepithelial matrix) and of the follicular basal lamina in ovulating bovine ovarian follicles. Pre- and postovulatory follicles were generated by treatment with estradiol (Day 1), progesterone (Days 1-10), and prostaglandin analogue (Day 9) with either no further treatment (Group 1, n = 6) and or with 25 mg porcine LH (Day 11, Group 2, n = 8 or Day 10, Group 3, n = 8) and ovariectomy on Day 12 (12-14 hr post LH in Group 2, 38-40.5 hr in Group 3). In the time frame examined no loss of follicular basal lamina laminin chains beta 2 and gamma 1 or nidogen 1 was observed. In the follicular basal lamina collagen type IV alpha 1 and perlecan were present prior to ovulation; after ovulation collagen type IV alpha 1 was discontinuously distributed and perlecan was absent. Versican in the theca interna adjacent to the follicular basal lamina in preovulatory follicles was not observed post ovulation, however, the granulosa cells then showed strong cytoplasmic staining for versican. Expression of versican isoforms V0, V1, and V3 was detected at all stages. Focimatrix was observed in preovulatory follicles. It contained collagen type IV alpha 1, laminins beta 2 and gamma 1, nidogen 1 and perlecan and underwent changes in composition similar to that of the follicular basal lamina. In conclusion focimatrix and the follicular basal lamina are degraded at ovulation. Individual components are lost at different times.

Relations between physiologic parameters and pulse transit time during loaded breathing

Pulse transit time (PTT) is a non-invasive measure, defined as time taken for the pulse pressure waves to travel from the R-wave of electrocardiogram to a selected peripheral site. Baseline PTT value is known to be influenced by physiologic variables like heart rate (HR), blood pressure (BP) and arterial compliance (AC). However, few quantitative data are available describing the factors which can influence PTT measurements in a child during breathing. The aim of this study was to investigate the effects of changes in breathing efforts on PTT baseline and fluctuations. Two different inspiratory resistive loading (IRL) devices were used to simulate loaded breathing in order to induce these effects. It is known that HR can influence the normative PTT value however the effect of HR variability (HRV) is not well-studied. Two groups of 3 healthy children ( 0.05) HR changes during all test activities. Results showed that HRV is not the sole contributor to PTT variations and suggest that changes in other physiologic parameters are also equally important. Hence, monitoring PTT measurement can be indicative of these associated changes during tidal or increased breathing efforts in healthy children.

Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives

Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease-free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study ( untreated blood pressure 169/88 +/- 12/ 8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease-free survival ( hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure >= 81 versus < 81 mm Hg; P = 0.01), no such relation was found for carotid augmentation index ( HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance ( HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.

The prognostic value of a nomogram for exercise capacity in women

BACKGROUND: Recent studies have demonstrated that exercise capacity is an independent predictor of mortality in women. Normative values of exercise capacity for age in women have not been well established. Our objectives were to construct a nomogram to permit determination of predicted exercise capacity for age in women and to assess the predictive value of the nomogram with respect to survival. METHODS: A total of 5721 asymptomatic women underwent a symptom-limited, maximal stress test. Exercise capacity was measured in metabolic equivalents (MET). Linear regression was used to estimate the mean MET achieved for age. A nomogram was established to allow the percentage of predicted exercise capacity to be estimated on the basis of age and the exercise capacity achieved. The nomogram was then used to determine the percentage of predicted exercise capacity for both the original cohort and a referral population of 4471 women with cardiovascular symptoms who underwent a symptom-limited stress test. Survival data were obtained for both cohorts, and Cox survival analysis was used to estimate the rates of death from any cause and from cardiac causes in each group. RESULTS: The linear regression equation for predicted exercise capacity (in MET) on the basis of age in the cohort of asymptomatic women was as follows: predicted MET = 14.7 - (0.13 x age). The risk of death among asymptomatic women whose exercise capacity was less than 85 percent of the predicted value for age was twice that among women whose exercise capacity was at least 85 percent of the age-predicted value (P<0.001). Results were similar in the cohort of symptomatic women. CONCLUSIONS: We have established a nomogram for predicted exercise capacity on the basis of age that is predictive of survival among both asymptomatic and symptomatic women. These findings could be incorporated into the interpretation of exercise stress tests, providing additional prognostic information for risk stratification.

Smoking and elevated blood pressure are the most important risk factors for subarachnoid hemorrhage in the Asia-Pacific region - An overview of 26 cohorts involving 306,620 participants

Background and Purpose - The cause of subarachnoid hemorrhage ( SAH) is poorly understood and there are few large cohort studies of risk factors for SAH. We investigated the risk of SAH mortality and morbidity associated with common cardiovascular risk factors in the Asia-Pacific region and examined whether the strengths of these associations were different in Asian and Australasian ( predominantly white) populations. Methods - Cohort studies were identified from Internet electronic databases, searches of proceedings of meetings, and personal communication. Hazard ratios (HRs) for systolic blood pressure (SBP), current smoking, total serum cholesterol, body mass index (BMI), and alcohol drinking were calculated from Cox models that were stratified by sex and cohort and adjusted for age at risk. Results - Individual participant data from 26 prospective cohort studies ( total number of participants 306 620) that reported incident cases of SAH ( fatal and/or nonfatal) were available for analysis. During the median follow-up period of 8.2 years, a total of 236 incident cases of SAH were observed. Current smoking (HR, 2.4; 95% CI, 1.8 to 3.4) and SBP > 140 mm Hg ( HR, 2.0; 95% CI, 1.5 to 2.7) were significant and independent risk factors for SAH. Attributable risks of SAH associated with current smoking and elevated SBP ( similar to 140 mm Hg) were 29% and 19%, respectively. There were no significant associations between the risk of SAH and cholesterol, BMI, or drinking alcohol. The strength of the associations of the common cardiovascular risk factors with the risk of SAH did not differ much between Asian and Australasian regions. Conclusions - Cigarette smoking and SBP are the most important risk factors for SAH in the Asia-Pacific region.

Strength and endurance training lead to different post exercise glucose profiles in diabetic participants using a continuous subcutaneous glucose monitoring system

Background Although both strength training (ST) and endurance training (ET) seem to be beneficial in type 2 diabetes mellitus (T2D), little is known about post-exercise glucose profiles. The objective of the study was to report changes in blood glucose (BG) values after a 4-month ET and ST programme now that a device for continuous glucose monitoring has become available. Materials and methods Fifteen participants, comprising four men age 56.5 +/- 0.9 years and 11 women age 57.4 +/- 0.9 years with T2D, were monitored with the MiniMed (Northridge, CA, USA) continuous glucose monitoring system (CGMS) for 48 h before and after 4 months of ET or ST. The ST consisted of three sets at the beginning, increasing to six sets per week at the end of the training period, including all major muscle groups and ET performed with an intensity of maximal oxygen uptake of 60% and a volume beginning at 15 min and advancing to a maximum of 30 min three times a week. Results A total of 17 549 single BG measurements pretraining (619.7 +/- 39.8) and post-training (550.3 +/- 30.1) were recorded, correlating to an average of 585 +/- 25.3 potential measurements per participant at the beginning and at the end of the study. The change in BG-value between the beginning (132 mg dL(-1)) and the end (118 mg dL(-1)) for all participants was significant (P = 0.028). The improvement in BG-value for the ST programme was significant (P = 0.02) but for the ET no significant change was measured (P = 0.48). Glycaemic control improved in the ST group and the mean BG was reduced by 15.6% (Cl 3-25%). Conclusion In conclusion, the CGMS may be a useful tool in monitoring improvements in glycaemic control after different exercise programmes. Additionally, the CGMS may help to identify asymptomatic hypoglycaemia or hyperglycaemia after training programmes.

Synthesis and immunological evaluation of M protein targeted tetra-valent and tri-valent group A streptococcal vaccine candidates based on the lipid-core peptide system

Group A streptococcus (GAS) is responsible for causing many clinical complications including the relatively benign streptococcal pharyngitis and impetigo. However. if left untreated. these conditions may lead to more severe diseases such as rheumatic fever (RF) and rheumatic heart disease (RHD). These diseases exhibit high morbidity and mortality, Particularly in developing countries and in indigenous populations of affluent countries. Only ever occur following GAS infection, a vaccine offers Promise for their Prevention. As stich, we have investigated the Use of the lipid-core peptide (LCP) system for the development of multi-valent Prophylactic GAS vaccines. The current study has investigated the capacity of this system to adjuvant LIP to four different GAS peptide epitopes. Presented are the synthesis and immunological assessment of tetra-valent and tri-valent GAS LCP systems. We demonstrated their capacity to elicit systemic IgG antibody responses in B10.BR mice to all GAS peptide epitopes. The data also showed that the LCP systems Were self-adjuvanting. These findings are particularly encouraging for the development of multi-valent LCP-based GAS vaccines.

Reduced nephron number and glomerulomegaly in Australian Aborigines: A group at high risk for renal disease and hypertension

Aborigines in remote areas of Australia have much higher rates of renal disease, as well as hypertension and cardiovascular disease, than non-Aboriginal Australians. We compared kidney findings in Aboriginal and non-Aboriginal people in one remote region. Glomerular number and mean glomerular volume were estimated with the disector/fractionator combination in the right kidney of 19 Aborigines and 24 non-Aboriginal people undergoing forensic autopsy for sudden or unexpected death in the Top End of the Northern Territory. Aborigines had 30% fewer glomeruli than non-Aborigines-202000 fewer glomeruli per kidney, or an estimated 404000 fewer per person (P=0.036). Their mean glomerular volume was 27% larger (P=0.016). Glomerular number was significantly correlated with adult height, inferring a relationship with birthweight, which, on average, is much lower in Aboriginal than non-Aboriginal people. Aboriginal people with a history of hypertension had 30% fewer glomeruli than those without-250000 fewer per kidney (P=0.03), or 500000 fewer per person, and their mean glomerular volume was about 25% larger. The lower nephron number in Aboriginal people is compatible with their susceptibility to renal failure. The additional nephron deficit associated with hypertension is compatible with other reports. Lower nephron numbers are probably due in part to reduced nephron endowment, which is related to a suboptimal intrauterine environment. Compensatory glomerular hypertrophy in people with fewer nephrons, while minimizing loss of total filtering surface area, might be exacerbating nephron loss. Optimization of fetal growth should ultimately reduce the florid epidemic of renal disease, hypertension, and cardiovascular disease.