Early vs late intervention in twin reversed arterial perfusion sequence.

OBJECTIVE: To compare two different management approaches in prenatally diagnosed twin reversed arterial perfusion (TRAP) sequence. METHODS: Retrospective analysis of all cases with TRAP sequence diagnosed in one center over a period of 10 years. Prior to 2010, all cases were managed expectantly until 19 weeks' gestation; thereafter, patients could choose either radiofrequency ablation (RFA) or expectant management (Group A). From 2010 onward all patients were offered interstitial laser at the time of diagnosis (12 weeks at the earliest) or expectant management (Group B). RESULTS: Forty cases were included in the study. In Group A, 23 cases were diagnosed at a mean gestational age of 19.9 ± 6.3 weeks. Sixteen patients were managed expectantly (13 survivors, 81%), while six underwent RFA at the time of diagnosis and one later in pregnancy (six survivors, 86%). In Group B, 17 cases were diagnosed at a mean gestational age of 16.4 ± 4.7 weeks. Six patients chose expectant management (five survivors, 83%) and 11 had interstitial laser therapy at the time of diagnosis (eight survivors, 73%). The loss rate of the pump twin was not significantly different between Group A and Group B (three of 23 vs four of 17; P = 0.3). In Group B the rates of preterm premature rupture of membranes (PPROM) and delivery < 34 weeks were significantly lower, and gestational age at birth as well as birth weight were significantly higher than in Group A. CONCLUSION: Despite the limitations resulting from its retrospective design, our study on management of TRAP sequence adds some evidence in favor of prophylactic intervention by intrafetal laser from 12 weeks onward.

Oral health in a life-course: birth-cohorts from 1929 to 2006 in Norway.

OBJECTIVES: The purpose of the work was to study the influence of the oral health environment at age 10, of adolescent and adulthood dental behaviours and of social status on oral health of three birth-cohorts in 1983 and two of the three birth-cohorts in 2006 in Norway. METHODS: The material comprised data from random samples of three birth-cohorts living in the counties of Sør- and Nord-Trøndelag in 1983. The birth-cohorts were 1929-1938, 1939-1948 and 1959-1960. In 2006 two samples were drawn from the 1929-1938 and 1959-1960 birth-cohort. The data collection comprised standard clinical measurements and self-administered questionnaires. The early oral health environment and social status and gender were related to oral health in 1983 by multiple regressions. The impact of social status was studied in combined datafiles from 1983 and 2006. RESULTS: The oral health environment in childhood was important for adults' oral health. The attention from parents and the local environment lead to a better oral health outcome in adulthood. Social status affected choices leading to better oral health. Regular dental visits were important especially for the eldest birth-cohort. Good oral health behaviours early and during adulthood were also important for oral health. Judged by number of tooth surfaces the difference between social status groups had not increased by 2006. CONCLUSIONS: A life-course perspective provides an opportunity to understand oral health over time. The present study supports the assumption that oral health is continuously exposed to environmental and behavioural risks that lead to accumulated diseases in the dental tissues.

Positive allosteric modulation of α4ß2 nAChR agonist induced behaviour.

Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4ß2 receptors being the most abundant heteromer. The stoichiometry of α4ß2 receptors can be either (α4)(3)(ß2)(2) or (α4)(2)(ß2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4ß2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4ß2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4ß2 nAChR in rotational and analgesic responses and confirm striatal α4ß2 receptors to be of the HS form.

The oral health environment and the equal environment assumption (EEA) among 1-8-year-old twins.

AIM: The purpose of the present study was to describe the oral health environment in preschool children and to examine the extent to which paired twins experience the same oral health environment. MATERIALS AND METHODS: In collaboration with The Medical Birth Registry of Norway (MBRN) 100 twin families who participated in the Norwegian Mother and Child Cohort, were invited to take part in ongoing studies on oral health. Participating twin families lived in Oslo and the surrounding counties of the capital. The age range of the participating twins was 1-8 years. A clinical examination took place at The Institute of Clinical Dentistry, University of Oslo in 2008. The oral health environment was measured in two ways: 1) Interview. Mothers were interviewed by trained interviewers about oral health related habits of each of the twins. 2) Weekend diet log. Parents listed 84 different deserts, ice cream, sweets, cakes, cookies, fruits, snacks, and biscuits for each twin that were consumed on during the weekend. The statistical analyses comprised frequency distributions of the environmental variables and correlations between the variables within the pair of twins. RESULTS: The results showed a parental involvement in early tooth brushing and also an indication of tooth brushing not always being easy. Use of fluoride toothpaste started early, and two thirds of the children also used fluoride tablets. Use of pacifier was prevalent; the duration of use of pacifier and feeding bottle was relatively long. Nearly 75% of the parents indicated that they had no problems relatively to the twins' meals, and 53% mentioned that the twin pairs were different with regard to meals. Nearly 70% of the kindergartens had a clear health profile. The correlations varied between r = 0.45 and 1.00. CONCLUSION: The children in the present work were young, and the detailed information in this paper therefore adds to the knowledge of parental involvement in children's oral health. Generally the findings indicate a high level of involvement from the parents in the oral health environment at home. Altogether the results showed that the assumption of identical oral health environment cannot be supported by these data.

Oral health-related quality of life among adults 68-77 years old in Nord-Trøndelag, Norway.

Dental health has mostly been measured by dental staff disregarding patient's experiences. However, clinical conditions alone do not fully indicate how people feel affected by their oral status. The aim of this study was to investigate how clinical recorded dental health, self-rated dental health, satisfaction with dental health were related to oral health-related quality of life (OHRQoL) assessed by Oral Health Impact Profile (OHIP-14) in 68-77 years old. A total of 151 individuals completed a questionnaire on self-rated dental health, satisfaction with dental health and the short form of OHIP-14. Clinical examination was performed registering number of teeth and dental caries. In total 63% of the individuals rated their dental health as good, and 59% were satisfied with their dental health. Using the OHIP-14 42% reported no problems or oral discomfort at all. The proportion of individuals reporting problems or discomfort varied between 13% and 43% according to the dimensions of OHIP-14. The most frequently reported problems were physical pain (43%), psychological discomfort (28%) and psychological disability (28%). Individuals who rated their dental health as poor and those who were dissatisfied with their dental health had significantly lower OHRQoL than other individuals. The study showed relationship between self-evaluations of dental health and OHRQoL in 68-77 years old. Individuals with few teeth reported lower OHRQoL than others, but no association between clinical caries status and OHRQoL could be found.

An assessment of the feasibility of a poultry tracing scheme for smallholders in Vietnam.

Tracing movements could assist the implementation of bio-containment measures during a disease outbreak. To evaluate the potential for implementing a tracing system for a poultry supply chain in northern Vietnam, a four-month longitudinal study was conducted to identify marketing practices associated with poultry traceability. Poultry sold in batches were traced between farms and markets, and their traceability was assessed upon market arrival. A total of 315 batches were released from the farms; 37% arrived at a market, from which 57.3% were 'traceable'. The results of the multivariable analysis showed that traceability was associated with farms operating through no more than two traders (Odds ratio [OR] = 5.97, 95% CI 1.15-30.92) and batches brought to the market on the day of purchase (OR = 4.05, 95% CI 1.23-13.27). No specific incentives were provided to farmers or traders. Results suggest that there is potential for implementing a poultry traceability scheme, although the tracing methodology should be refined.

[Prevention of infections under anesthetic breathing with breathing filters: concerted recommendations of the Deutsche Gesellschaft für Krankenhaushygiene e.V. (DGKH) and the Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin e.V. (DGAI)]. / Infektionsprävention bei der Narkosebeatmung durch Einsatz von Atemsystemfiltern: Gemeinsame Empfehlung der Deutschen Gesellschaft für Krankenhaushygiene e.V. (DGKH) und der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin e.V. (DGAI).

An interdisciplinary working group from the German Society of Hospital Hygiene (DGKH) and the German Society for Anesthesiology and Intensive Care (DGAI) worked out the following recommendations for infection prevention during anesthesia by using breathing system filters (BSF). The BSF shall be changed after each patient. The filter retention efficiency for airborne particles is recommended to be >99% (II). The retention performance of BSF for liquids is recommended to be at pressures of at least 60 hPa (=60 mbar) or 20 hPa above the selected maximum ventilation pressure in the anesthetic system.The anesthesia breathing system may be used for a period of up to 7 days provided that the functional requirements of the system remain unchanged and the manufacturer states this in the instructions for use. The breathing system and the manual ventilation bag are changed immediately after the respective anesthesia if the following situation has occurred or it is suspected to have occurred: Notifiable infectious disease involving the risk of transmission via the breathing system and the manual bag, e.g. tuberculosis, acute viral hepatitis, measles, influenza virus, infection and/or colonization with a multi-resistant pathogen or upper or lower respiratory tract infections. In case of visible contamination e.g. by blood or in case of defect, it is required that the BSF and also the anesthesia breathing system is changed and the breathing gas conducting parts of the anesthesia ventilator are hygienically reprocessed.Observing of the appropriate hand disinfection is very important. All surfaces of the anesthesia equipment exposed to hand contact must be disinfected after each case.

SK3 K+ channel-deficient mice have enhanced dopamine and serotonin release and altered emotional behaviors.

SK3 K(+) channels influence neuronal excitability and are present in 5-hydroxytryptamine (5-HT) and dopamine (DA) nuclei in the brain stem. We therefore hypothesized that SK3 channels affect 5-HT and DA neurotransmission and associated behaviors. To explore this, we used doxycycline-induced conditional SK3-deficient (T/T) mice. In microdialysis, T/T mice had elevated baseline levels of striatal extracellular DA and the metabolites dihydroxyphenylacetic acid and homovanillic acid. While baseline hippocampal extracellular 5-HT was unchanged in T/T mice, the 5-HT response to the 5-HT transporter inhibitor citalopram was enhanced. Furthermore, baseline levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were elevated in T/T mice. T/T mice performed equally to wild type (WT) in most sensory and motor tests, indicating that SK3 deficiency does not lead to gross impairments. In the forced swim and tail suspension tests, the T/T mice displayed reduced immobility compared with WT, indicative of an antidepressant-like phenotype. Female T/T mice were more anxious in the zero maze. In contrast, anxiety-like behaviors in the open-field and four-plate tests were unchanged in T/T mice of both sexes. Home cage diurnal activity was also unchanged in T/T mice. However, SK3 deficiency had a complex effect on activity responses to novelty: T/T mice showed decreased, increased or unchanged activity responses to novelty, depending on sex and context. In summary, we report that SK3 deficiency leads to enhanced DA and 5-HT neurotransmission accompanied by distinct alterations in emotional behaviors.

Optimal litter size for individual growth of European rabbit pups depends on their thermal environment.

In altricial mammals and birds, the presence of a large number of litter or brood mates often affects the development of individual offspring by reducing the share of resources provided by the parents. However, sibling presence can also be favourable, conferring thermoregulatory benefits when ambient temperatures are low. Consequently, shifts in the relation between costs and benefits of sibling presence can be expected as a function of the thermal environment. In a study of a European rabbit population (Oryctolagus cuniculus) living in a field enclosure, we investigated the effects of litter size and soil temperature on pup growth over 7 years. Temperatures inside the subterranean nests were positively correlated with soil temperature and with litter size. Soil temperature varied strongly across the breeding season, ranging from 3 to 21 degrees C. Under warmer soil temperature conditions (10-15 degrees C and >15 degrees C), pup growth decreased with increasing litter size, where litters of two pups (smallest litter size considered) showed the highest growth rates. In contrast, under colder soil temperature conditions (<10 degrees C), the highest growth rates were found in litters of three pups. We also asked if such temperature-dependent differences in the optimal pup growth rates might be explained by differences in maternal characteristics, which might affect lactational performance. We assessed maternal performance using females' postpartum body mass and social rank. However, we did not find consistent differences in maternal characteristics between females giving birth to different-sized litters during different soil temperature conditions, which would have provided an alternative explanation for the observed differences in litter size-dependent pup growth. We conclude that under colder soil temperature conditions, the thermal benefits of a greater number of littermates outweigh the negative consequences of competition for milk, leading to an environment-dependent shift in the optimal litter size for individual growth in this species.

Inter-individual variation in the plaque formation rate of young individuals.

OBJECTIVES: The aim of the present study was to describe the inter-individual variation in the plaque formation rate of 38 young adults. METHODS: The plaque formation rate was estimated by employing a quantitative plaque percent index (P% index). A substantial inter-individual variation in the plaque formation rate was observed. The possible contributions of stimulated salivary flow rate, buffer capacity, diet and smoking to the variation in plaque formation were estimated by regression analysis. RESULTS: The control variables explained only 2.5% of the variance in the plaque formation rate. Neither associations nor the total model were significant. The present method of measuring plaque presented as a simple and time-effective procedure. CONCLUSIONS: It is suggested that the observed variation in the plague formation rate between the young individuals can be regarded as a biological function which is possibly an inherent individual characteristic. Studies with larger sample sizes are required to confirm the findings of the present study.

Over-winter survival in subadult European rabbits: weather effects, density dependence, and the impact of individual characteristics.

The survival probability of an individual may be limited by density-dependent mechanisms and by environmental stochasticity, but can also be modified by individual characteristics. In our study, we investigated over-winter survival of subadults of an enclosed European rabbit Oryctolagus cuniculus population in a temperate zone habitat over the period 1992-2002. We: (1) selected for appropriate models to explain individual variation in over-winter survival and the animals' autumn body mass, the latter was used as a measure of the individual pre-winter body condition; and (2) aimed to compare the sensitivity of the target variables on the realised variation of the factors considered. Model selection based on information theory revealed that individual over-winter survival was best explained by the combination of autumn body mass, winter temperature, population density and sex, where the probability of survival was higher in females than in males. According to this model, the probability of survival reacted most sensitively to variation in the autumn body mass and in winter temperature. Individual autumn body mass was best explained by the combination of the date of birth, population density, and weather conditions by means of the percentage of rainy days during the first 2 months after the animals had emerged above ground, where the autumn body mass was negatively related to the percentage of rainy days. The chosen model suggested that the autumn body mass reacted most sensitively to variation in the date of birth. Combining these models, we found that weather conditions during two different periods of time as well as population density, sex and the date of birth operated together to determine the probability of over-winter survival. In particular, the study points out the high impact of environmental stochasticity on over-winter survival: (1) by direct effects of winter temperature conditions, and (2) by the indirect action of weather conditions to which the animals were exposed during the early period of juvenile development.

Causal patterns of dental health in populations. An empirical approach.

In the present investigation we aimed to analyse causally the pattern of determinants leading to the maintenance of functional teeth in adults. Clinical and self-reported information was used. The hypothesis was that socio-economic conditions operate through psychosocial circumstances that influence lifestyle, and are thus related to oral hygiene and levels of remaining teeth. Testing of the patterns for adults residing in high- and low-fluoride areas did not reveal any principal differences in dental health, therefore further testing was combined for both fluoride areas. Further analysis also indicated that testing should be performed separately for each gender. Social structure and dental health-related lifestyle were important in an overall pattern of maintaining functional teeth, but general lifestyle and psychosocial conditions were not found to be part of the pattern influencing dental health. Gender-specific patterns were revealed. New hypotheses may be suggested for further research with regard to studying patterns of dental health in Lithuanian adults.

An "S-shaped" relationship between smoking duration and alveolar bone loss: generating a hypothesis.

BACKGROUND: A number of epidemiological studies have shown that smoking is a risk factor for periodontal disease. Little is known about the relationship between smoking duration and alveolar bone loss. The purpose of this research was to describe the prevalence of alveolar bone loss according to smoking status in Norway. A dose-response model for duration of tobacco smoking on alveolar bone loss was then developed and discussed. METHODS: The study population consisted of 812 individuals living in Norway aged 45 to 64 years old (248 current smokers, 245 former smokers and 319 non-smokers). Alveolar bone loss was measured on bite-wing radiographs. Simple descriptive statistics were used to describe the central tendency and variation in alveolar bone loss. Regression analyses were performed to study the relationship between smoking duration and alveolar bone loss. RESULTS: Mean alveolar bone loss varied between 1.51 mm and 2.64 mm depending on smoking status and age. Mean alveolar bone loss was lowest in non-smokers and highest in current smokers. Given identical smoking status, the mean alveolar bone loss increased with increasing age except for the 2 oldest age groups of current smokers. CONCLUSIONS: Our results generate the hypothesis that the relationship between smoking duration and alveolar bone loss was "S-shaped." Assuming that alveolar bone loss is irreversible after smoking cessation, it could be hypothesized that there is a threshold period for tobacco smoking after which the accumulated effect of smoking becomes clinically observable. After a certain number of years of smoking, the effect on alveolar bone loss seems to level out. To test this hypothesis, the relationship between smoking duration and alveolar bone loss should be studied in a prospective study design.

Improved outcomes from a comprehensive management system for heart failure.

AIMS: Congestive heart failure (CHF) is associated with a high readmission rate after diagnosis. We assessed the ability of a comprehensive management program (CMP) for CHF to reduce readmissions with secondary endpoints of improving quality of life, exercise capacity and targeted drug doses. METHODS AND RESULTS: Patients (pts) with: New York Heart Association Class (NYHA) III or IV CHF; left ventricular ejection fraction <40%; and stable outpatient therapy were assigned to a CMP of cardiology assessment intensive education and referral to a tailored exercise program. Forty-two pts (35 M, 7 F, mean age 54 years, S.D. 12 years) were enrolled. Two pts were transplanted, two died during follow-up and two were lost to follow-up. Hospital admissions were reduced by 87.2%, (mean 1.05, S.D. 0.98, admissions per pt to mean 0.08, S.D. 0.28, admissions per pt at 6-month follow-up; P<0.0001). ACE-inhibitor dose increased by 42% (P<0.0008) and beta-blocker dose increased by 61% (P<0.0001). NYHA Class, 6-min walk and quality of life scores all improved significantly (P<0.0001). CONCLUSION: A CMP improves QOL and exercise capacity as well as substantially reducing hospital admissions in CHF pts. This study validates the benefit of intensive outpatient care of CHF.

Utility of chest computed tomography for staging in patients with T1 extremity soft tissue sarcomas.

BACKGROUND: National Cancer Center Network (NCCN) and Society of Surgical Oncology (SSO) practice guidelines recommend chest computed tomography (CT) as part of the staging evaluation of patients with extremity soft tissue sarcoma (STS). In the current study, the authors evaluated the use and yield of chest roentgenography (CXR) and selective chest CT to screen for pulmonary metastases in patients with T1 STS. METHODS: The utility of these staging studies was evaluated retrospectively in a cohort of 125 consecutive patients who presented to a tertiary care cancer center with T1 primary (nonrecurrent) extremity STS. Two diagnostic strategies (CXR alone vs. CXR plus chest CT) were evaluated using an incremental cost-effectiveness ratio. RESULTS: The majority of tumors (70%) were high grade. The median sarcoma size was 3.0 cm; 64 of the tumors (51%) were located deep to the investing fascia of the extremity. All patients underwent staging CXR; 1 CXR (< 1%) was suspicious for metastatic disease. Fifty-one patients (41%) also underwent chest CT; 1 chest CT, performed in the patient with a suspicious CXR, revealed metastatic disease. With a median follow-up of 76 months, 19 patients (15%) developed metachronous pulmonary metastases. The relatively low yield resulted in an incremental cost-effectiveness ratio of $59,772 per case of synchronous pulmonary metastasis detected by CXR plus chest CT. CONCLUSIONS: Less than 1% of patients with T1 primary extremity STS were found to have pulmonary metastases that were detectable using a staging algorithm that employs routine CXR with the selective use of chest CT. The findings of the current study do not support current NCCN or SSO practice guidelines for patients with high-grade T1 STS.

[Postoperative nausea and vomiting--still a problem?]. / Postoperative Ubelkeit und Erbrechen--Immer noch ein Problem?

Based on a questionnaire of the General Hospital of Hamburg-Altona, we asked 738 patients about postoperative complaints such as nausea, vomiting, pain in the operating field and feeling of coldness in order to record the quality of the results of operation and anaesthesia in 1997 and 1998. The incidence of nausea and vomiting amounted to only 29% on average. One of our earlier studies of postoperative vomiting from 1995-1997 and the results gained from a control group of non-treated patients in our ondansetron study from 1995, which was conducted using information drawn from the routinely-used anaesthesia protocol and was therefore limited to data from the immediate pre- and postoperative period up to discharge of the patients from the recovery ward, showed much higher frequencies of nausea and vomiting (44 and even 66% on average, respectively). We cannot definitely evaluate whether the reduction in the average rates of nausea and vomiting in our present study is due to the additional preoperative application of 150 mg vomex supp. and 1.0-2.5 mg dehydrobenzperidol and/or 20-30 mg metoclopramid given i.v. shortly before the end of anaesthesia or to more intensive observation of non-medicinal prophylactic possibilities. But when we look at the frequency of nausea and vomiting in special groups of our present study, we can still find unacceptably high rates of nausea and vomiting, for instance 40% after cholecystectomies and abruptios and even 50% after struma operations. This shows that a satisfactory solution to this problem has not yet been found--partly due, unfortunately, to financial restrictions. Nevertheless, for 15% of the patients postoperative nausea and vomiting were of only minor importance for general satisfaction with the treatment given them. This was probably due to good premedication of amnestic after-effects of narcosis.

Caries in populations--a theoretical, causal approach.

The focus of this paper is caries in populations. Caries is assessed as a phenomenon and as it occurs in populations. It is observed that in recent literature the notion of causation of caries is restricted to the biological process on the tooth surface. This may be sufficient to explain caries as a phenomenon, but it is argued that a biological causation is insufficient in order to understand caries and its variation in populations. The understanding of the determinants of a population's oral health has been seriously impeded by the absence of a theoretical framework. A framework would be useful to the extent that it would bridge relevant categories for portraying complex causal patterns of caries in populations. An approach to a framework has therefore been outlined, and the idea of such a framework has been confronted with three critical comments. The framework is as yet pragmatic, incomplete, uncertain and fragmented. Yet, even such an approach may invite greater precision in epidemiological concepts about causes of caries than presently prevails. The framework directs attention to health effects of collective phenomena that cannot be reduced to individual attributes. The image proposed in this paper is intended to spur discussion about important aspects of the epidemiology of caries in populations.

Oral status indicators DMFT and FS-T: reflections on index selection.

Oral status in a population has traditionally been described by the DMFT index (decayed, filled, and missing teeth). There seems to be contradicting and confusing evidence in the literature with regard to the usefulness of different indices. Limitations of the DMFT are recognised, and attempts have been made to develop other indices. Two indices, DMFT and FS-T (filled and sound teeth) have been selected for analysis in the present paper. The purpose of this paper is to examine the relationship between DMFT and FS-T in different populations, and to show consequences of choice of index exemplified in analytical analysis. Data stem from the Trondelag-83 and -94 studies that were follow-up studies of the Norwegian portion of the 1973 International Collaborative Study. Sunflower scatter plots and regression analyses were used to describe the variation in DMFT and FS-T in different populations. DMFT was more suitable for describing variation in populations with low levels of disease than FS-T, while FS-T was more suitable for describing variation in populations with high levels of disease. It may be concluded that both DMFT and FS-T should be presented when describing oral status in a population. However, choice of index depends first of all on the purpose of the investigation. If there are theoretical reasons to prefer one index instead of the other, the superiority of the alternative index in terms of variation must be disregarded.

Acyl-CoA esters antagonize the effects of ligands on peroxisome proliferator-activated receptor alpha conformation, DNA binding, and interaction with Co-factors.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor and a key regulator of lipid homeostasis. Numerous fatty acids and eicosanoids serve as ligands and activators for PPARalpha. Here we demonstrate that S-hexadecyl-CoA, a nonhydrolyzable palmitoyl-CoA analog, antagonizes the effects of agonists on PPARalpha conformation and function in vitro. In electrophoretic mobility shift assays, S-hexadecyl-CoA prevented agonist-induced binding of the PPARalpha-retinoid X receptor alpha heterodimer to the acyl-CoA oxidase peroxisome proliferator response element. PPARalpha bound specifically to immobilized palmitoyl-CoA and Wy14643, but not BRL49653, abolished binding. S-Hexadecyl-CoA increased in a dose-dependent and reversible manner the sensitivity of PPARalpha to chymotrypsin digestion, and the S-hexadecyl-CoA-induced sensitivity required a functional PPARalpha ligand-binding pocket. S-Hexadecyl-CoA prevented ligand-induced interaction between the co-activator SRC-1 and PPARalpha but increased recruitment of the nuclear receptor co-repressor NCoR. In cells, the concentration of free acyl-CoA esters is kept in the low nanomolar range due to the buffering effect of high affinity acyl-CoA-binding proteins, especially the acyl-CoA-binding protein. By using PPARalpha expressed in Sf21 cells for electrophoretic mobility shift assays, we demonstrate that S-hexadecyl-CoA was able to increase the mobility of the PPARalpha-containing heterodimer even in the presence of a molar excess of acyl-CoA-binding protein, mimicking the conditions found in vivo.

Evidence for genetic associations between asthma, atopy, and bronchial hyperresponsiveness: a study of 8- to 18-yr-old twins.

We measured asthma in the last 12 mo, diagnosed by a respiratory physician at interview; atopy, defined by a positive skin prick test to any of eight common allergens; and bronchial hyperresponsiveness (BHR) to hypertonic saline, in 381 twin pairs aged 8 to 18 yr selected from the Australian Twin Registry-183 monozygous (MZ) and 198 dizygous (DZ). The associations between twins, as measured by an odds ratio, were greater in MZ pairs compared with DZ pairs for asthma: 25.6 (95% confidence interval 11.3- 57.8) versus 1.9 (1.0-3. 5); atopy: 14.6 (7.1-30.1) versus 2.5 (1.4- 4.5); and BHR: 14.1 (6. 4-31.0) versus 4.2 (2.1-8.6) (all p < 0.002). The associations between each pair of traits within an individual were slightly greater than the association between one trait in a twin and the other trait in the cotwin (cross-trait cross-pair) in MZ pairs. Further, the associations in MZ pairs were greater than in DZ pairs (p < 0.05). Under the assumptions of the classic twin model, these data suggest that the strong cross-sectional associations between these three traits are due to an overlap between the genetic factors involved in each of these three traits.