ABSTRACT
BACKGROUND: Despite the established knowledge that recurrent copy number variants (CNVs) at the 16p11.2 locus BP4-BP5 confer risk for behavioural and language difficulties, limited research has been conducted on the association between behavioural and social-communicative profiles. The current study aims to further delineate the prevalence, nature and severity of, and the association between, behavioural and social-communicative features of school-aged children with 16p11.2 deletion syndrome (16p11.2DS) and 16p11.2 duplication (16p11.2Dup). METHODS: A total of 68 individuals (n = 47 16p11.2DS and n = 21 16p11.2Dup) aged 6-17 years participated. Standardised intelligence tests were administered, and behavioural and social-communicative skills were assessed by standardised questionnaires. Scores of both groups were compared with population norms and across CNVs. The influence of confounding factors was investigated, and correlation analyses were performed. RESULTS: Compared with the normative sample, children with 16p11.2DS showed high rates of social responsiveness (67%) and communicative problems (69%), while approximately half (52%) of the patients displayed behavioural problems. Children with 16p11.2Dup demonstrated even higher rates of social-communicative problems (80-90%) with statistically significantly more externalising and overall behavioural challenges (89%). In both CNV groups, there was a strong positive correlation between behavioural and social-communicative skills. CONCLUSIONS: School-aged children with 16p11.2 CNVs show high rates of behavioural, social responsiveness and communicative problems compared with the normative sample. These findings point to the high prevalence of autistic traits and diagnoses in these CNV populations. Moreover, there is a high comorbidity between behavioural and social-communicative problems. Patients with difficulties in both domains are vulnerable and need closer clinical follow-up and care.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 16 , Intellectual Disability , Humans , Child , Male , Female , Adolescent , Chromosomes, Human, Pair 16/genetics , Intellectual Disability/genetics , DNA Copy Number Variations , Social Skills , Smith-Magenis Syndrome/genetics , Social Behavior , Chromosome Duplication , Autistic Disorder , Chromosome DisordersABSTRACT
Gram-negative bacteria of the human gastrointestinal (GI) tract microbiome: (i) are capable of generating a broad-spectrum of highly neurotoxic, pro-inflammatory and potentially pathogenic molecules; and (ii) these include a highly immunogenic class of amphipathic surface glycolipids known as lipopolysaccharide (LPS). Bacteroides fragilis (B. fragilis), a commensal, Gram negative, non-motile, non-spore forming obligatory anaerobic bacillus, and one of the most abundant bacteria found in the human GI tract, produces a particularly pro-inflammatory and neurotoxic LPS (BF-LPS). BF-LPS: (i) is known to be secreted from the B. fragilis outer membrane into the external-medium; (ii) can damage biophysiological barriers via cleavage of zonula adherens cell-cell adhesion proteins, thereby disrupting both the GI-tract barrier and the blood-brain barrier (BBB); (iii) is able to transit GI-tract barriers into the systemic circulation and cross the BBB into the human CNS; and (iv) accumulates within CNS neurons in neurodegenerative disorders such as Alzheimer's disease (AD). This short communication provides evidence that the incubation of B. fragilis with aluminum sulfate [Al2(SO4)3] is a potent inducer of BF-LPS. The results suggest for the first time that the pro-inflammatory properties of aluminum may not only be propagated by aluminum itself, but by a stimulation in the production of microbiome-derived BF-LPS and other pro-inflammatory pathogenic microbial products normally secreted from human GI-tract-resident microorganisms.
Subject(s)
Alum Compounds/pharmacology , Bacteroides fragilis/drug effects , Lipopolysaccharides/metabolism , Bacteroides fragilis/metabolismABSTRACT
PURPOSE: Patients with obstructive sleep apnea (OSA) are at increased risk of cardiovascular and cerebrovascular disease (CVD) but it is unclear who are at greatest risk. We determined whether the inflammatory marker, C-reactive protein (CRP), could be a useful prognostic biomarker. METHODS: Adult patients referred for polysomnography (PSG) with OSA were studied. Serum CRP levels were measured using ELISA the morning after PSG. Validated CV events within 4 years of PSG were ascertained by linking to provincial research datasets. RESULTS: 155 patients with OSA (AHI ≥ 5/h) had CRP measured. Median age was 53 and median AHI was 21/h. 10 patients (7.1%) suffered at least one event, but rates varied substantially by CRP (0/35 patients in the lowest quartile, and 7/39 in the highest CRP quartile). In the unadjusted analysis, patients in the highest CRP quartile (≥ 2.38 mg/L) were significantly more likely to suffer an event (odds ratio = 9.72 (95% CI 2.43-38.84), p = 0.001). CRP continued to be a significant predictor after controlling for multiple confounders. OSA severity and desaturation were not significantly associated with prospective events. CONCLUSIONS: In this small preliminary study, OSA patients with an elevated CRP were significantly more likely to suffer a CVD event in the 4 years after PSG. Although these findings need to be confirmed in larger prospective cohorts, CRP may be useful in risk stratifying OSA patients to guide therapy or to identify patients that might be most appropriate for clinical trials of CVD prevention.
Subject(s)
C-Reactive Protein/analysis , Cardiovascular Diseases/epidemiology , Cerebrovascular Disorders/epidemiology , Inflammation Mediators/blood , Sleep Apnea, Obstructive/blood , Biomarkers/blood , British Columbia/epidemiology , Cardiovascular Diseases/diagnosis , Cerebrovascular Disorders/diagnosis , Databases, Factual , Female , Humans , Incidence , Male , Middle Aged , Predictive Value of Tests , Prognosis , Prospective Studies , Risk Assessment , Risk Factors , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/epidemiology , Time Factors , Up-RegulationABSTRACT
The heterotrimeric G-protein binding site on G-protein coupled receptors remains relatively unexplored regarding its potential as a new target of therapeutic intervention or as a secondary site of action by the existing drugs. Tauroursodeoxycholic acid bears structural resemblance to several compounds that were previously identified to specifically bind to the light-activated form of the visual receptor rhodopsin and to inhibit its activation of transducin. We show that TUDCA stabilizes the active form of rhodopsin, metarhodopsin II, and does not display the detergent-like effects of common amphiphilic compounds that share the cholesterol scaffold structure, such as deoxycholic acid. Computer docking of TUDCA to the model of light-activated rhodopsin revealed that it interacts using similar mode of binding to the C-terminal domain of transducin alpha subunit. The ring regions of TUDCA made hydrophobic contacts with loop 3 region of rhodopsin, while the tail of TUDCA is exposed to solvent. The results show that TUDCA interacts specifically with rhodopsin, which may contribute to its wide-ranging effects on retina physiology and as a potential therapeutic compound for retina degenerative diseases.
Subject(s)
Cholagogues and Choleretics/metabolism , GTP-Binding Proteins/metabolism , Light , Rhodopsin/radiation effects , Taurochenodeoxycholic Acid/metabolism , Animals , Cattle , Opsins/chemistry , Protein Binding , Protein Structure, Secondary , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Rhodopsin/chemistry , Rhodopsin/metabolism , Signal TransductionABSTRACT
There is a large corpus of brain imaging studies examining the dorsal visual pathway, especially area V5/MT during visual motion perception. However, despite evidence suggesting a protracted development of the dorsal visual stream, and a role of this pathway in neurodevelopmental disorders, V5/MT has not been characterized developmentally. Further, experiential factors such as reading acquisition may play a modulating role in any age-dependent changes. Here we used a coherent visual motion detection task to examine V5/MT activity and connectivity in typical participants in two studies: a Cross- Sectional Study comparing adults and children; and a Longitudinal Study of 2nd graders followed into 3rd grade. In the Cross-Sectional Study, a whole-brain analysis revealed no differences between the two groups, whereas a region of interest (ROI) approach identified greater activation in left (right trending) V5/MT in adults compared to children. However, when we measured V5/MT activation individually for each participant, children and adults showed no difference in the location or intensity of activation, although children did exhibit relatively larger extent of V5/MT activation bilaterally. There was also relatively greater functional connectivity in the children between left and right occipitotemporal cortex, including V5/MT. The Longitudinal Study revealed no changes in V5/MT activation for any measures of activation or functional connectivity from 2nd to 3rd grade. Finally, there was no evidence of an association between reading and V5/MT over time, nor predictive power of V5/MT activity for later reading. Together, our results indicate similar V5/MT activity across age groups, with relatively greater extent of V5/MT activation and functional connectivity in children relative to adults, bilaterally. These differences were not apparent over the time course of one year, suggesting that these developmental changes occur over a more protracted period.
Subject(s)
Motion Perception/physiology , Visual Cortex/growth & development , Visual Cortex/physiology , Adolescent , Adult , Brain Mapping/methods , Child , Cross-Sectional Studies , Female , Humans , Longitudinal Studies , Magnetic Resonance Imaging/methods , Male , Visual Pathways/growth & development , Visual Pathways/physiology , Young AdultABSTRACT
Functional complementation assay (FCA) is an in vivo assay that is widely used to elucidate the function/role of genes/enzymes. This technique is very common in biochemistry, genetics and many other disciplines. A comprehensive overview of the technique to supplement the teaching of biochemical pathways pertaining to amino acids, peptidoglycan and the bacterial stringent response is reported in this manuscript. Two cDNAs from the model plant organism Arabidopsis thaliana that are involved in the metabolism of lysine (L,L-diaminopimelate aminotransferase (dapL) and tyrosine aminotransferase (tyrB) involved in the metabolism of tyrosine and phenylalanine are highlighted. In addition, the bacterial peptidoglycan anabolic pathway is highlighted through the analysis of the UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-meso-2,6-diaminopimelate ligase (murE) gene from the bacterium Verrucomicrobium spinosum involved in the cross-linking of peptidoglycan. The bacterial stringent response is also reported through the analysis of the rsh (relA/spoT homolog) bifunctional gene responsible for a hyper-mucoid phenotype in the bacterium Novosphingobium sp. Four examples of FCA are presented. The video will focus on three of them, namely lysine, peptidoglycan and the stringent response.
Subject(s)
Biochemical Phenomena , Diaminopimelic Acid , Glutamic Acid , Lysine , PeptidoglycanABSTRACT
Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression.
ABSTRACT
OBJECTIVE: To study the associations of prenatal blood lead levels (B-Pb) with pregnancy outcomes in a large cohort of mother-child pairs in the UK. DESIGN: Prospective birth cohort study. SETTING: Avon area of Bristol, UK. POPULATION: Pregnant women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS: Whole blood samples were collected and analysed by inductively coupled plasma dynamic reaction cell mass spectrometry (n = 4285). Data collected on the infants included anthropometric variables and gestational age at delivery. Linear regression models for continuous outcomes and logistic regression models for categorical outcomes were adjusted for covariates including maternal height, smoking, parity, sex of the baby and gestational age. MAIN OUTCOME MEASURES: Birthweight, head circumference and crown-heel length, preterm delivery and low birthweight. RESULTS: The mean blood lead level (B-Pb) was 3.67 ± 1.47 µg/dl. B-Pb ≥ 5 µg/dl significantly increased the risk of preterm delivery (adjusted odds ratio [OR] 2.00 95% confidence interval [95% CI] 1.35-3.00) but not of having a low birthweight baby (adjusted OR 1.37, 95% CI 0.86-2.18) in multivariable binary logistic models. Increasing B-Pb was significantly associated with reductions in birth weight (ß -13.23, 95% CI -23.75 to -2.70), head circumference (ß -0.04, 95% CI -0.07 to -0.06) and crown-heel length (ß -0.05, 95% CI -0.10 to -0.00) in multivariable linear regression models. CONCLUSIONS: There was evidence for adverse effects of maternal B-Pb on the incidence of preterm delivery, birthweight, head circumference and crown-heel length, but not on the incidence of low birthweight, in this group of women.
Subject(s)
Environmental Pollutants/blood , Lead Poisoning/epidemiology , Lead/blood , Maternal Exposure/adverse effects , Pregnancy Complications/epidemiology , Prenatal Exposure Delayed Effects/epidemiology , Adult , Birth Weight , Cohort Studies , Environmental Pollutants/adverse effects , Female , Fetal Growth Retardation/chemically induced , Fetal Growth Retardation/epidemiology , Gene-Environment Interaction , Humans , Infant, Newborn , Lead/toxicity , Lead Poisoning/complications , Longitudinal Studies , Male , Maternal Exposure/statistics & numerical data , Mothers , Pregnancy , Pregnancy Complications/chemically induced , Premature Birth/chemically induced , Premature Birth/epidemiology , Prospective Studies , Risk Assessment , Risk Factors , Surveys and Questionnaires , United Kingdom/epidemiologyABSTRACT
For heavy metals that have any degree of transfer though the placenta to the fetus, it is unlikely that there are safe limits for maternal blood levels. The only means of reducing fetal exposure is to minimise maternal exposure. There are few recommendations for levels of concern. With the exception of US recommendations for maternal Pb levels, but there are no international levels of concern or cut-off levels specifically for pregnancy for heavy metals, so that comparisons can generally only be made with national reference values relating to similar physiological statuses or age groups. These include recommendations for Cd levels by Germany (reference value for non-smoking adults aged 18-69 years, 1 µg/l) and for Hg by Germany (reference value for adults age 18-60 years with fish intake < or =3 times per month, 2.0 µg/l) and the USA (cut-off level for women, 5.8 µg/dl). To illustrate the lack of cohesion, we present data on blood Pb, Cd and Hg levels from pregnant women enroled in the UK Avon Longitudinal Study of Parents and Children study and compare the values with present levels of concern and recommended cut-off values. We also compare the levels with those found in other groups of pregnant women worldwide to strengthen the database for the development of levels of concern in pregnancy. The need for clarity of terminology in describing levels of concern is discussed. There is a pressing need for international consensus on levels of concern for all age groups and physiological statuses, particularly for pregnancy.
Subject(s)
Cadmium/blood , Lead/blood , Maternal Exposure/legislation & jurisprudence , Mercury/blood , Prenatal Exposure Delayed Effects/epidemiology , Female , Humans , Pregnancy , Reference ValuesABSTRACT
The aim of this study was to evaluate the effect of prenatal exposure to lead, cadmium and mercury levels on the secondary sex ratio. Whole blood samples were collected from pregnant women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study at a median gestational age of 11 weeks and were analyzed for lead, cadmium and mercury. Regression analysis was used to identify associations between maternal lead, cadmium and mercury levels and the secondary sex ratio with adjustment for confounders. There was no evidence for associations between maternal lead, cadmium or mercury levels and the secondary sex ratio in this sample. It appears unlikely that alterations in the secondary sex ratio are influenced by exposure to heavy metals, but further work should be done in large cohorts in other countries to confirm these findings.
Subject(s)
Cadmium/blood , Lead/blood , Mercury/blood , Prenatal Exposure Delayed Effects/physiopathology , Sex Ratio , Adult , Female , Humans , Longitudinal Studies , Maternal Exposure , Pregnancy , United Kingdom/epidemiologyABSTRACT
Better regulation seeks to extend existing policy and regulatory outcomes at less burden for the actors involved. No single intervention will deliver all environmental outcomes. There is a paucity of evidence on what works why, when and with whom. We examine how a sample (n=33) of policy makers select policy and regulatory instruments, through a case study of the Department for Environment, Food and Rural Affairs (Defra), UK. Policy makers have a wide range of instruments at their disposal and are seeking ways to harness the influence of non-governmental resources to encourage good environmental behaviour. The relevance of each influence varies as risk and industry characteristics vary between policy areas. A recent typology of policy and regulatory instruments has been refined. Direct regulation is considered necessary in many areas, to reduce environmental risks with confidence and to tackle poor environmental performance. Co-regulatory approaches may provide important advantages to help accommodate uncertainty for emerging policy problems, providing a mechanism to develop trusted evidence and to refine objectives as problems are better understood.
Subject(s)
Administrative Personnel , Environmental Policy/legislation & jurisprudence , Environmental Policy/trends , Humans , Risk Factors , United KingdomABSTRACT
Vegetation affects precipitation patterns by mediating moisture, energy and trace-gas fluxes between the surface and atmosphere. When forests are replaced by pasture or crops, evapotranspiration of moisture from soil and vegetation is often diminished, leading to reduced atmospheric humidity and potentially suppressing precipitation. Climate models predict that large-scale tropical deforestation causes reduced regional precipitation, although the magnitude of the effect is model and resolution dependent. In contrast, observational studies have linked deforestation to increased precipitation locally but have been unable to explore the impact of large-scale deforestation. Here we use satellite remote-sensing data of tropical precipitation and vegetation, combined with simulated atmospheric transport patterns, to assess the pan-tropical effect of forests on tropical rainfall. We find that for more than 60 per cent of the tropical land surface (latitudes 30 degrees south to 30 degrees north), air that has passed over extensive vegetation in the preceding few days produces at least twice as much rain as air that has passed over little vegetation. We demonstrate that this empirical correlation is consistent with evapotranspiration maintaining atmospheric moisture in air that passes over extensive vegetation. We combine these empirical relationships with current trends of Amazonian deforestation to estimate reductions of 12 and 21 per cent in wet-season and dry-season precipitation respectively across the Amazon basin by 2050, due to less-efficient moisture recycling. Our observation-based results complement similar estimates from climate models, in which the physical mechanisms and feedbacks at work could be explored in more detail.
Subject(s)
Air/analysis , Atmosphere/chemistry , Rain , Trees/metabolism , Tropical Climate , Brazil , Feedback , Forestry , Humidity , Seasons , Steam/analysis , Trees/growth & developmentABSTRACT
Atypical hemolytic uremic syndrome (aHUS) is associated with mutations in the gene CFH encoding the complement regulator factor H (CFH). We previously reported a family, in which three individuals had partial CFH deficiency but only one was affected by aHUS. We have investigated this family further to show that the partial CFH deficiency is associated with a heterozygous CFH mutation (c.2768T>G, p.Tyr899Asp). We used the polymorphic CFH variant p.His402Tyr to track expression of p.Tyr899Asp, and found that this mutant was expressed in minimal quantities in serum. In the one affected individual we found a second CFH mutation (c.3581G>A, p.Gly1194Asp) on the other allele which was expressed normally. We showed that this mutant, which has been described previously in aHUS, has impaired regulation of cell surface complement activation. The affected individual in this family is therefore a compound heterozygote for two functionally significant CFH mutations. Two individuals (mother and male sib) in the pedigree carried only c.2768T>G, p.Tyr899Asp and one (father) carried only c.3581G>A, p.Gly1194Asp, and all three were asymptomatic. Thus, further investigation of this family has enabled us to clarify the genotype-phenotype correlation.
Subject(s)
Complement Factor H/genetics , Hemolytic-Uremic Syndrome/genetics , Heterozygote , Animals , Complement Factor H/chemistry , Complement Factor H/deficiency , Complement Factor H/metabolism , Female , Hemolytic-Uremic Syndrome/blood , Humans , Male , Models, Molecular , Mutation , Pedigree , Protein Structure, Tertiary , SheepABSTRACT
BACKGROUND: 5-HT(2B) receptors are localized within the myenteric nervous system, but their functions on motor/sensory neurons are unclear. To explore the role of these receptors, we further characterized the 5-HT(2B) receptor antagonist RS-127445 and studied its effects on peristalsis and defecation. EXPERIMENTAL APPROACH: Although reported as a selective 5-HT(2B) receptor antagonist, any interactions of RS-127445 with 5-HT(4) receptors are unknown; this was examined using the recombinant receptor and Biomolecular Interaction Detection technology. Mouse isolated colon was mounted in tissue baths for isometric recording of neuronal contractions evoked by electrical field stimulation (EFS), or under an intraluminal pressure gradient to induce peristalsis; the effects of RS-127445 on EFS-induced and on peristaltic contractions were measured. Faecal output of rats in grid-bottom cages was measured over 3 h following i.p. RS-127445 and separately, validation of the effective doses was achieved by determining the free, unbound fraction of RS-127445 in blood and brain. KEY RESULTS: RS-127445 (up to 1 micromol x L(-1)) did not interact with the 5-HT(4) receptor. RS-127445 (0.001-1 micromol x L(-1)) did not affect EFS-induced contractions of the colon, although at 10 micromol x L(-1) the contractions were reduced (to 36 +/- 8% of control, n= 4). RS-127445 (0.1-10 micromol x L(-1)) concentration-dependently reduced peristaltic frequency (n= 4). RS-127445 (1-30 mg x kg(-1)), dose-dependently reduced faecal output, reaching significance at 10 and 30 mg x kg(-1) (n= 6-11). In blood and brain, >98% of RS-127445 was protein-bound. CONCLUSIONS AND IMPLICATIONS: High-protein binding of RS-127445 indicates that relatively high doses are required for efficacy. The results suggest that 5-HT(2B) receptors tonically regulate colonic motility.
Subject(s)
Colon/physiology , Defecation/physiology , Gastrointestinal Motility/physiology , Pyrimidines/pharmacology , Receptor, Serotonin, 5-HT2B/physiology , Serotonin 5-HT2 Receptor Antagonists , Animals , Cell Line , Colon/drug effects , Defecation/drug effects , Gastrointestinal Motility/drug effects , Humans , In Vitro Techniques , Intestine, Large/drug effects , Intestine, Large/physiology , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: To describe the presentation, management, and outcome of 43 cases of pneumococcal-associated hemolytic uremic syndrome (P-HUS). An increased incidence of P-HUS has been noted in the United Kingdom between January 1998 and May 2005. STUDY DESIGN: Cases with microangiopathic hemolytic anemia (Hb <10 g/dL with fragmented RBCs), thrombocytopenia (platelet count < 130 x 10(9)/L), acute renal impairment with oliguria and elevated plasma creatinine for age, confirmed or suspected pneumococcal infection and/or T-activation were included. RESULTS: The median age at presentation was 13 months (range, 5-39 months). Pneumococcus was identified in 34 of 43 cases; T-activation was identified in 36 of 37 cases. Twelve strains were serotyped: serotypes 3 (n = 2), 6A (n = 2), 12F (n = 1), 14 (n = 1), 19A (n = 6). Empyema was present in 23 of 35 pneumonia cases; 13 cases had confirmed (9) or suspected (4) pneumococcal meningitis; 36 cases required dialysis (median, 10 days; range, 2-240 days). The mortality rate was 11%, comprising 3 cases of meningitis, 1 case of sepsis and 1 case of pulmonary embolism at 8 months follow up while on dialysis. Follow-up data were available for 35 of 38 patients who survived (median follow-up period, 9 months; range, 1-63 months); of these, 10 patients had renal dysfunction, 1 patient was dialysis-dependent, 5 patients had hypertension and 8 patients had at least 1+ proteinuria on urinalysis. CONCLUSION: P-HUS has increased compared with historic surveys (0/288 in 1985-1988; 8/413 in 1997-2001, 43/315 in 1998-May 2005). Early mortality remains high (8-fold that of VTEC-induced HUS). Ten of 12 strains identified would not be covered by the PCV7 vaccine.
Subject(s)
Hemolytic-Uremic Syndrome/diagnosis , Hemolytic-Uremic Syndrome/epidemiology , Pneumonia, Pneumococcal/diagnosis , Pneumonia, Pneumococcal/epidemiology , Age Distribution , Anti-Bacterial Agents/therapeutic use , Child, Preschool , Cohort Studies , Comorbidity , Female , Hemolytic-Uremic Syndrome/therapy , Humans , Incidence , Infant , Male , Pneumococcal Infections/diagnosis , Pneumococcal Infections/drug therapy , Pneumococcal Infections/epidemiology , Pneumonia, Pneumococcal/drug therapy , Probability , Risk Assessment , Severity of Illness Index , Sex Distribution , Survival Rate , United Kingdom/epidemiologyABSTRACT
Obstructive events during sleep in patients with obstructive sleep apnoea (OSA) cause large alterations in blood pressure, and this may lead to changes in baroreflex function with implications for long-term blood pressure control. This study examined the daytime variations in the responses to carotid baroreceptor stimulation in OSA patients. We determined the cardiac and vascular responses every 3 h between 09.00 and 21.00 h in 20 patients with OSA, using graded suctions and pressures applied to a neck collar. These responses were plotted against estimated carotid sinus pressures and, from these plots, baroreflex sensitivities and operating points were taken as the maximal slopes and the corresponding carotid sinus pressures, respectively. We found that at 09.00 h, sensitivity for the control of vascular resistance was at its lowest (--1.2 +/- 0.2% mmHg(-1), compared with --1.9 +/- 0.3% mmHg(-1) at 12.00 h, P < 0.02) and operating point for control of mean arterial pressure was at its highest (101.1 +/- 5.8 mmHg, compared with 94.1 +/- 5.8 mmHg at 12.00 h, P < 0.05). This is in contrast to previous data from normal subjects, in whom sensitivity was highest and operating point lowest at 09.00 h. We suggest that the higher baroreflex sensitivity and lower operating point seen in the mornings in normal subjects may provide a protective mechanism against hypertension and that this protection is absent in patients with OSA. It is possible that the reduced reflex sensitivity and increased operating point in the mornings may actually promote hypertension.
Subject(s)
Baroreflex , Blood Pressure , Circadian Rhythm , Hypertension/etiology , Hypertension/physiopathology , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/physiopathology , Adult , Carotid Sinus , Female , Heart Rate , Humans , Male , Middle Aged , Pressure , Pulse , Vascular ResistanceABSTRACT
The G protein-coupled receptors, GPR41 and GPR43, are activated by short-chain fatty acids (SCFAs), with distinct rank order potencies. This study investigated the possibility that SCFAs modulate intestinal motility via these receptors. Luminal SCFA concentrations within the rat intestine were greatest in the caecum (c. 115 mmol L(-1)) and proximal colon. Using similar concentrations (0.1-100 mmol L(-1)), SCFAs were found to inhibit electrically evoked, neuronally mediated contractions of rat distal colon, possibly via a prejunctional site of action; this activity was independent of the presence or absence of the mucosa. By contrast, SCFAs reduced the amplitude but also reduced the threshold and increased the frequency of peristaltic contractions in guinea-pig terminal ileum. In each model, the rank-order of activity was acetate (C2) approximately propionate (C3) approximately butyrate (C4) > pentanoate (C5) approximately formate (C1), consistent with activity at the GPR43 receptor. GPR43 mRNA was expressed throughout the rat gut, with highest levels in the colon. However, the ability of SCFAs to inhibit neuronally mediated contractions of the colon was similar in tissues from wild-type and GPR43 gene knockout mice, with identical rank-orders of potency. In conclusion, SCFAs can modulate intestinal motility, but these effects can be independent of the GPR43 receptor.
Subject(s)
Fatty Acids/pharmacology , Gastrointestinal Motility/drug effects , Receptors, G-Protein-Coupled/drug effects , Receptors, G-Protein-Coupled/genetics , Animals , Carboxylic Acids/pharmacology , Central Nervous System/metabolism , Electric Stimulation , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Male , Mice , Mice, Knockout , Peristalsis/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVES: This study was undertaken in 2001 in order to investigate the dental health status of 5-year-olds in an urban community within Attica County in Greece and the views of the carers of this age group. METHODS: Three hundred and forty-five nursery children were examined, using the WHO methods and criteria. Parents' views were recorded in a questionnaire. RESULTS: Overall, 48.4% had some experience of dental decay. The mean dmft of the whole study population was 2.6, whereas the mean dmft of the subjects with active decay was 5.4; in these cases untreated decay was the highest component (mean dt = 5.0). A questionnaire using phone calls to the children's homes achieved a 100% response rate. Ninety-five per cent of parents thought that a child should visit the dentist at this early age and 79.5% of responders answered that they had already visited the dentist with their child for different reasons. Three-quarters (75.4%) of parents had received information about fluoride, whereas 72.5% answered that did not use any type of fluoride for their child at home. It was reported that 63.5% of children ate snacks, sweets, cakes, biscuits, and gums between the main meals of the day and 31% of the subjects more than once per day. CONCLUSIONS: Caries indicies were higher from the National 2003-4 survey and were attributed to the increasing number of immigrants in some areas. The population under investigation had the appropriate information for the prevention of dental decay but they appear to maintain unhealthy behaviours in their everyday living.
Subject(s)
Attitude to Health , Dental Care for Children/psychology , Oral Health , Parents/psychology , Child, Preschool , DMF Index , Dental Care for Children/statistics & numerical data , Dental Caries/epidemiology , Female , Greece/epidemiology , Health Status , Humans , Male , Surveys and QuestionnairesSubject(s)
Shock, Septic , Shoes , Soccer , Staphylococcal Infections , Adolescent , Blister/complications , Child , Female , Friction , Humans , Male , Shock, Septic/diagnosis , Shock, Septic/drug therapy , Shock, Septic/etiology , Staphylococcal Infections/diagnosis , Staphylococcal Infections/drug therapy , Staphylococcal Infections/etiologyABSTRACT
The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.