Experimental Studies on Bilirubin and Haem Biosynthesis

It has recently been shown that patients with unconjugated hyperbilirubinaemia due to Gilbert's syndrome have reduced activity of the enzyme protoporphyrinogen oxidase in circulating leucocytes. This may be explained by the further observation that unconjugated bilirubin competes with protoporphyrinogen for binding to protoporphyrinogen oxidase. In order to further investigate the effect of unconjugated hyperbilirubinaemia on porphyrin metabolism and haem biosynthesis studies have been performed in the Gunn rat which has unconjugated hyperbil irubinaemia and raised plasma bilirubin concentrations. Protoporphyrinogen oxidase activity was found to be reduced in the liver of the Gunn rat compared to heterozygous controls with normal plasma bilirubin concentrations. This reduction of protoporphyrinogen oxidase activity was not accompanied by any increase in the activity of the initial and rate-controlling enzyme of the pathway delta-aminolaevulinic acid synthase. In contrast to hepatic tissue, the activities of both protoporphyrinogen oxidase and delta-aminolaevulinic acid synthase were normal in renal tissue of the Gunn rat. Porphyrin excretion was reduced in the Gunn rat compared to that in heterozygous controls. Further studies were performed to investigate the effects of unconjugated hyperbilirubinaemia on haem biosynthesis in the brain of the Gunn rat. This was studied as the major effect of hyperbilirubinaemia is brain damage and the mechanism by which it occurs is unknown. Inherited partial enzyme deficiencies in haem biosynthesis are known to produce neurological damage. Therefore the possibility that bilirubin induced brain damage might be due to inhibition of protoporphryinogen oxidase activity and hence deficient neuronal haem synthesis, was investigated. Optimal conditions for the measurement of protoporphyrinogen oxidase activity were determined in the brain and found to be identical to those which provided optimal activity in hepatic tissue. The activity of protoporphyrinogen oxidase in brain tissue homogenates from Gunn rats was similar to that in heterozygous rats with normal bilirubin concentrations. This was also the case in neonatal Gunn rats in whom kernicterus had been induced by the displacement of bilirubin into the brain by sulphonamide treatment. Delta-aminolaevulinic acid synthase activities were also similar in the homozygous Gunn rat and heterozygous controls. These findings make it unlikely that the brain damage induced by hyperbilirubinaemia is due to inhibition of protoporphyrinogen oxidase activity and impaired neuronal haem biosynthesis. The above studies concerned the effect of disturbed haem catabolism on haem biosynthesis. The latter part of the studies extended the theme of the investigation by examining the effect of the administration of Tin-protoporphyrin, an inhibitor of haem biosynthesis, on haem biosynthesis in acute porphyria. The effect of administering Tin-protoporphyrin and haem arginate alone and in combination on succinyl acetone induced porphyria in rats was studied. This animal model proved to be unsatisfactory as the haem arginate given alone did not significantly reduce the over-production of the porphyrin precursor, delta-aminolaevulinate. This may be explained by inhibition of aminolaevulinic acid dehydratase by succinyl acetone so increasing aminolaevulinic acid overproduction in most body tissues. The effect of the haem arginate is largely confined to the liver. Studies in 1 patient during clinical attacks proved more encouraging. They showed that the coadministration of Tin-protoporphyrin with haem arginate prolonged both the biochemical response and clinical remission induced by haem arginate therapy. These findings indicate that co-administration of Tin-protoporphyrin and haem arginate may be used as prophylactic therapy in patients experiencing recurrent attacks of acute porphyria

Incidence and severity of respiratory syncytial virus pneumonia in rural Kenyan children identified through hospital surveillance

Background.Although necessary for developing a rationale for vaccination, the burden of severe respiratory syncytial virus (RSV) disease in children in resource‐poor settings remains poorly defined. Methods.We conducted prospective surveillance of severe and very severe pneumonia in children aged <5 years admitted from 2002 through 2007 to Kilifi district hospital in coastal Kenya. Nasal specimens were screened for RSV antigen by immunofluorescence. Incidence rates were estimated for the well‐defined population. Results.Of 25,149 hospital admissions, 7359 patients (29%) had severe or very severe pneumonia, of whom 6026 (82%) were enrolled. RSV prevalence was 15% (20% among infants) and 27% during epidemics (32% among infants). The proportion of case patients aged 3 months was 65%, and the proportion aged 6 months was 43%. Average annual hospitalization rates were 293 hospitalizations per 100,000 children aged <5 years (95% confidence interval, 271–371 hospitalizations per 100,000 children aged <5 years) and 1107 hospitalizations per 100,000 infants (95% confidence interval, 1012–1211 hospitalizations per 100,000 infants). Hospital admission rates were double in the region close to the hospital. Few patients with RSV infection had life‐threatening clinical features or concurrent serious illnesses, and the associated mortality was 2.2%. Conclusions.In this low‐income setting, rates of hospital admission with RSV‐associated pneumonia are substantial; they are comparable to estimates from the United States but considerably underestimate the burden in the full community. An effective vaccine for children aged >2 months (outside the age group of poor responders) could prevent a large portion of RSV disease. Severity data suggest that the justification for RSV vaccination will be based on the prevention of morbidity, not mortality

Sexual function in 16- to 21-year-olds in Britain

Purpose: Concern about young people's sexuality is focused on the need to prevent harmful outcomes such as sexually transmitted infections and unplanned pregnancy. Although the benefit of a broader perspective is recognized, data on other aspects of sexuality, particularly sexual function, are scant. We sought to address this gap by measuring the population prevalence of sexual function problems, help seeking, and avoidance of sex in young people. Methods: A cross-sectional stratified probability sample survey (Natsal-3) of 15,162 women and men in Britain (response rate: 57.7%), using computer-assisted self-interviews. Data come from 1875 (71.9%) sexually active, and 517 sexually inactive (18.7%), participants aged 16–21 years. Measures were single items from a validated measure of sexual function (the Natsal-SF). Results: Among sexually active 16- to 21-year-old participants, 9.1% of men and 13.4% of women reported a distressing sexual problem lasting 3 months or more in the last year. Most common among men was reaching a climax too quickly (4.5%), and among women was difficulty in reaching climax (6.3%). Just over a third (35.5%) of men and 42.3% of women reporting a problem had sought help, but rarely from professional sources. Among those who had not had sex in the last year, just &gt;10% of young men and women said they had avoided sex because of sexual difficulties. Conclusions: Distressing sexual function problems are reported by a sizeable minority of sexually active young people. Education is required, and counseling should be available, to prevent lack of knowledge, anxiety, and shame progressing into lifelong sexual difficulties

Conceptualisations of children’s wellbeing at school: the contribution of recognition theory

A large study in Australian schools aimed to elucidate understandings of ‘wellbeing’ and of factors in school life that contribute to it. Students and teachers understood wellbeing primarily, and holistically, in terms of interpersonal relationships, in contrast to policy documents which mainly focused on ‘problem areas’ such as mental health. The study also drew on recognition theory as developed by the social philosopher Axel Honneth. Results indicate that recognition theory may be useful in understanding wellbeing in schools, and that empirical research in schools may give rise to further questions regarding theory

RELIABILITY OF JUMP AND PERFORMANCE MEASURES IN RUGBY UNION PLAYERS

The current study examined the reliability of countermovement (CMJ), squat (SJ), and rebound jumps (RBJ) to sprint and estimated 1RM back squat (SQ) of sub-elite Rugby Union players drawn from two teams of similar competitive level. Comparisons of mean performance on all tests were made via Student t-tests. The three trial reliability of jump height for the SJ, CMJ, RBJ, contact time (CT) and Reactive Strength Index for the RBJ, T-Test agility run (TA-Test), 30 and 36.58 m (40 yd) sprint times were estimated via ICC and ReANOVA. All variables displayed Average measures ICC &#8805; .900; and except for the TA-Test, the three trials did not differ from each other. The performance of the two teams was found to be similar on all tests except the 30 m and 40 yd sprint tests. All the studied performance measures could be reliably assessed with one trial, except the TA-test

Study to determine the likely accuracy of pH testing to confirm nasogastric tube placement

Objective To establish the likely accuracy of pH testing to identify gastric aspirates at different pH cut-offs to confirm nasogastric tube placement.Methods This prospective observational study included a convenience sample of adult patients who had two (one fresh and one frozen) gastric and oesophageal samples taken during gastroscopy or two bronchial and saliva samples taken during bronchoscopy. The degree of observer agreement for the pH of fresh and frozen samples was indicted by kappa (k) statistics. The sensitivities and specificities at pH ≤5.5 and the area under the receiver operating characteristics (ROC) curve at different pH cut-offs were calculated to identify gastric and non-gastric aspirates.Results Ninety-seven patients had a gastroscopy, 106 a bronchoscopy. There was complete agreement between observers in 57/92 (62%) of the paired fresh and frozen gastric samples (k=0.496, 95% CI 0.364 to 0.627). The sensitivity of a pH ≤5.5 to correctly identify gastric samples was 68% (95% CI 57 to 77) and the specificity was 79% (95% CI 74 to 84). The overall accuracy to correctly classify samples was between 76% and 77%, regardless of whether patients were taking antacids or not. The area under the ROC curve at different pH cut-offs was 0.74.Conclusion The diagnostic accuracy of pH ≤5.5 to differentiate gastric from non-gastric samples was low, regardless of whether patients were taking antacids or not. Due to the limited accuracy of the pH sticks and the operators’ ability to differentiate colorimetric results, there is an urgent need to identify more accurate and safer methods to confirm correct placement of nasogastric tubes

Analysis of enzyme-responsive peptide surfaces by Raman spectroscopy

We report on the use of Raman spectroscopy as a tool to characterise model peptide functionalised surfaces. By taking advantage of Raman reporters built into the peptide sequence, the enzymatic hydrolysis of these peptides could be determined

Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2

Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis