Rosemary Greenwood

Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial

Background: Pyoderma gangrenosum (PG) is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease. There have been a number of reports of PG responding to infliximab, a monoclonal antibody against tumour necrosis factor α. Aim: In the first randomised placebo controlled trial of any drug for the treatment of PG, we have studied the role of infliximab in this disorder. Subjects: Patients 18 years of age or older with a clinical diagnosis of PG were invited to take part. Methods: Patients were randomised to receive an infusion of infliximab at 5 mg/kg or placebo at week 0. Patients were then assessed at week 2 and non-responders were offered open labelled infliximab. The primary end point was clinical improvement at week 2, with secondary end points being remission and improvement at week 6. Results: Thirty patients were entered into the study. After randomisation, 13 patients received infliximab and 17 patients received placebo. At week 2, significantly more patients in the infliximab group had improved (46% (6/13)) compared with the placebo group (6% (1/17); p = 0.025). Overall, 29 patients received infliximab with 69% (20/29) demonstrating a beneficial clinical response. Remission rate at week 6 was 21% (6/29). There was no response in 31% (9/29) of patients. Conclusions: This study has demonstrated that infliximab at a dose of 5 mg/kg is superior to placebo in the treatment of PG. Open label treatment with infliximab also produced promising results. Infliximab treatment should be considered in patients with PG.

Psychological well‐being in patients on ‘adequate’ doses of l‐thyroxine: results of a large, controlled community‐based questionnaire study

objective Over 1% of the UK population is receiving thyroid hormone replacement with l‐thyroxine (T4). However, many patients complain of persistent lethargy and related symptoms on T4 even with normal TSH levels. To date there has been no large study to determine whether this is related to thyroxine replacement or coincidental psychological morbidity. We have therefore attempted to address this issue using a large, community‐based study.

Childhood cancer, intramuscular vitamin K and pethidine given during labour

OBJECTIVE--To assess unexpected associations between childhood cancer and pethidine given in labour and the neonatal administration of vitamin K that had emerged in a study performed in the 1970 national birth cohort. DESIGN AND SETTING--195 children with cancer diagnosed in 1971-March 1991 and born in the two major Bristol maternity hospitals in 1965-87 were compared with 558 controls identified from the delivery books for the use of pethidine during labour and administration of vitamin K. MAIN OUTCOME MEASURES--Odds ratios for cancer in the presence of administration of pethidine or of intramuscular vitamin K. Both logistic regression and Mantel-Haenszel techniques were used for statistical analyses. RESULTS--Children of mothers given pethidine in labour were not at increased risk of cancer (odds ratio 1.05, 95% confidence interval 0.7 to 1.5) after allowing for year and hospital of delivery, but there was a significant association (p = 0.002) with intramuscular vitamin K (odds ratio 1.97, 95% confidence interval 1.3 to 3.0) when compared with oral vitamin K or no vitamin K. There was no significantly increased risk for children who had been given oral vitamin K when compared with no vitamin K (odds ratio 1.15, 95% confidence interval 0.5 to 2.7). These results could not be accounted for by other factors associated with administration of intramuscular vitamin K, such as type of delivery or admission to a special care baby unit. CONCLUSIONS--The only two studies so far to have examined the relation between childhood cancer and intramuscular vitamin K have shown similar results, and the relation is biologically plausible. The prophylactic benefits against haemorrhagic disease are unlikely to exceed the potential adverse effects from intramuscular vitamin K. Since oral vitamin K has major benefits but no obvious adverse effects this could be the prophylaxis of choice.

Fecal Microbiome and Volatile Organic Compound Metabolome in Obese Humans With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS The histopathology of nonalcoholic fatty liver disease (NAFLD) is similar to that of alcoholic liver disease. Colonic bacteria are a source of many metabolic products, including ethanol and other volatile organic compounds (VOC) that may have toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. Recent data suggest that the composition of the gut microbiota in obese human beings is different from that of healthy-weight individuals. The aim of this study was to compare the colonic microbiome and VOC metabolome of obese NAFLD patients (n = 30) with healthy controls (n = 30). METHODS Multitag pyrosequencing was used to characterize the fecal microbiota. Fecal VOC profiles were measured by gas chromatography-mass spectrometry. RESULTS There were statistically significant differences in liver biochemistry and metabolic parameters in NAFLD. Deep sequencing of the fecal microbiome revealed over-representation of Lactobacillus species and selected members of phylum Firmicutes (Lachnospiraceae; genera, Dorea, Robinsoniella, and Roseburia) in NAFLD patients, which was statistically significant. One member of phylum Firmicutes was under-represented significantly in the fecal microbiome of NAFLD patients (Ruminococcaceae; genus, Oscillibacter). Fecal VOC profiles of the 2 patient groups were different, with a significant increase in fecal ester compounds observed in NAFLD patients. CONCLUSIONS A significant increase in fecal ester VOC is associated with compositional shifts in the microbiome of obese NAFLD patients. These novel bacterial metabolomic and metagenomic factors are implicated in the etiology and complications of obesity.

Leg length, insulin resistance, and coronary heart disease risk: The Caerphilly Study

BACKGROUND Adult height has been inversely associated with coronary heart disease risk in several studies. The mechanism for this association is not well understood, however, and this was investigated by examining components of stature, cardiovascular disease risk factors and subsequent coronary heart disease in a prospective study. METHODS All men aged 45–59 years living in the town of Caerphilly, South Wales were approached, and 2512 (89%) responded and underwent a detailed examination, which included measurement of height and sitting height (from which an estimate of leg length was derived). Participants were followed up through repeat examinations and the cumulative incidence of coronary heart disease—both fatal and non-fatal—over a 15 year follow up period is the end point in this report. RESULTS Cross sectional associations between cardiovascular risk factors and components of stature (total height, leg length and trunk length) demonstrated that factors related to the insulin resistance syndrome—the homeostasis model assessment of insulin resistance, fasting triglyceride levels and total to HDL cholesterol ratio—were less favourable in men with shorter legs, while showing reverse or no associations with trunk length. Fibrinogen levels were inversely associated with leg length and showed a weaker association with trunk length. Forced expiratory volume in one second was unrelated to leg length but strongly positively associated to trunk length. Other risk factors showed little association with components of stature. The risk of coronary heart disease was inversely related to leg length but showed little association with trunk length. CONCLUSION Leg length is the component of stature related to insulin resistance and coronary heart disease risk. As leg length is unrelated to lung function measures it is unlikely that these can explain the association in this cohort. Factors that influence leg length in adulthood—including nutrition, other influences on growth in early life, genetic and epigenetic influences—merit further investigation in this regard. The reported associations suggest that pre-adult influences are important in the aetiology of coronary heart disease and insulin resistance.

LONG-TERM INTELLECTUAL AND BEHAVIORAL OUTCOMES OF CHILDREN WITH FEBRILE CONVULSIONS

BACKGROUND Hospital-based studies have reported that children with febrile convulsions have subsequent mental retardation and behavior problems. In contrast, population-based studies have reported a better outcome. METHODS We identified 398 children with febrile convulsions among 14,676 children enrolled in the Child Health and Education Study, a national population-based study in the United Kingdom of children born in one week in April 1970. The children were comprehensively assessed at the age of 10. After excluding 16 children who had neurodevelopmental problems before their first febrile convulsion and 1 child whose case was atypical, we studied 381 children, 287 with simple febrile convulsions and 94 with complex febrile convulsions. We compared them with the rest of the cohort using measures of academic progress, intelligence, and behavior that included questionnaires, standardized tests, and formal tests. RESULTS At the 10-year assessment, only 4 of 102 measures of academic progress, intelligence, and behavior differed significantly between the entire group of children with febrile convulsions and the group without febrile convulsions -- no more than would be expected by chance. Similar results were found when children with simple febrile convulsions and those with complex febrile convulsions were analyzed separately. The children with recurrent episodes of febrile convulsions had outcomes similar to those of the children with only one episode each. Special schooling was required for more children who had febrile convulsions in the first year of life than for those who had had them later in life (5 of 67, or 7.5 percent, vs. 4 of 265, or 1.5 percent; P=0.02), but these numbers were small. CONCLUSION Children who had febrile convulsions performed as well as other children in terms of their academic progress, intellect, and behavior at 10 years of age.

Twins as a natural experiment to study the causes of mild language delay: I: Design; twin-singleton differences in language, and obstetric risks.

BACKGROUND Twins tend to lag behind singletons in their language development, but the causes were unknown. The possibilities suggested include obstetric complications, twin-specific features, and postnatal differences in family interaction. The present study was designed to pit these alternatives against one another as possible causal influences. METHOD The Avon Longitudinal Study of Parents and Children (ALSPAC) was used to identify the 116 twin pairs (of whom 96 participated) and 114 pairs of singletons (of whom 98 participated) whose ages were no more than 30 months apart. The McArthur Communicative Development Inventory was completed at 20 months, and the Pre-School Language Scales (PLS-3), and the McCarthy Scales of Childrens Abilities at 36 months. Obstetric and perinatal complications were assessed on the basis of detailed systematic parental reports, together with a systematic coded abstraction of all medical records dealing with pregnancy and the neonatal period. Family background details were assessed from parental reports, and the primary carers verbal functioning was assessed by the Mill Hill Vocabulary Scale. Congenital anomalies were assessed using the method of Waldrop and Halverson. RESULTS The language of twins was 1.7 months below that of singletons at 20 months and 3.1 months at 3 years. The verbal cognitive score of twins was about half a standard deviation lower than that of singletons. The twin-singleton differences in language level were found tobe unassociated with obstetric/perinatal features as assessed from both parental reports and medical records, to birthweight or gestation, to birthweight discrepancy within the twin pair, or to congenital anomalies. CONCLUSION It is concluded that obstetric/perinatal features do not account for the slower language development in twins as compared with singletons, within a sample born after at least 33 weeks gestation.

Twins as a natural experiment to study the causes of mild language delay: II: Family interaction risk factors

BACKGROUND Twins tend to lag behind singletons in their language development, but the causes were unknown. METHOD Ninety-six twin pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC), for whom birth was after at least 33 weeks of gestation, were compared with 98 pairs of singletons, no more than 30 months apart in age. Parental qualities and family interaction were assessed through standardised questionnaires and interviews and both structured and unstructured observations in the home at 20 months and 36 months. The possible causal role of postnatal family influences was assessed through five criteria: i) the feature had to differ between twins and singletons; ii) individual differences in that feature had to relate to individual differences in language level within the sample of singletons and of twins; iii) the feature as measured at 20 months had to predict language as assessed at 36 months; iv) that had to apply after controlling for language level at 20 months; and v) introduction of the predictive feature into an overall model had to obliterate the twin-singleton difference in language level. RESULTS Patterns of parent-child interaction and communication met these five criteria. The maternal factors all concerned aspects of interaction that were broadly concerned with communication: encouraging the child to speak, providing elaborating comments, engaging in reading to the child and talking about the story and its illustrations. The HOME inventory findings provided similar findings with respect to responsiveness, involvement and level of experiences involved. Family features that might have been influential, but which were not, included parental depression, breast-feeding, family size, and style of sibling interaction. CONCLUSION Patterns of parent-child interaction and communication within the normal range have environmentally mediated effects on language and account for twin-singleton differences in language developmently. The results indicate the value of a natural experiment in testing competing causal hypotheses, and show the role of environmental factors as influences on language variations within the normal range, for both twins and singletons.

Referral patterns, cancer diagnoses, and waiting times after introduction of two week wait rule for breast cancer: prospective cohort study.

Objective To investigate the long term impact of the two week wait rule for breast cancer on referral patterns, cancer diagnoses, and waiting times. Design Prospective cohort study. Setting A specialist breast clinic in a teaching hospital in Bristol. Participants All patients referred to breast clinic from primary care between 1999 and 2005. Main outcome measures Number, route, and outcome of referrals from primary care and waiting times for urgent and routine appointments. Results The annual number of referrals increased by 9% over the seven years from 3499 in 1999 to 3821 in 2005. Routine referrals decreased by 24% (from 1748 to 1331), but two week wait referrals increased by 42% (from 1751 to 2490) during this time. The percentage of patients diagnosed with cancer in the two week wait group decreased from 12.8% (224/1751) in 1999 to 7.7% (191/2490) in 2005 (P<0.001), while the number of cancers detected in the “routine” group increased from 2.5% (43/1748) to 5.3% (70/1331) (P<0.001) over the same period. About 27% (70/261) of people with cancer are currently referred in the non-urgent group. Waiting times for routine referrals have increased with time. Conclusion The two week wait rule for breast cancer is failing patients. The number of cancers detected in the two week wait population is decreasing, and an unacceptable proportion is now being referred via the routine route. If breast cancer services are to be improved, the two week wait rule should be reviewed urgently.

An investigation of fecal volatile organic metabolites in irritable bowel syndrome.

Diagnosing irritable bowel syndrome (IBS) can be a challenge; many clinicians resort to invasive investigations in order to rule out other diseases and reassure their patients. Volatile organic metabolites (VOMs) are emitted from feces; understanding changes in the patterns of these VOMs could aid our understanding of the etiology of the disease and the development of biomarkers, which can assist in the diagnosis of IBS. We report the first comprehensive study of the fecal VOMs patterns in patients with diarrhea-predominant IBS (IBS-D), active Crohns disease (CD), ulcerative colitis (UC) and healthy controls. 30 patients with IBS-D, 62 with CD, 48 with UC and 109 healthy controls were studied. Diagnosis of IBS-D was made using the Manning criteria and all patients with CD and UC met endoscopic, histologic and/or radiologic criteria. Fecal VOMs were extracted by solid phase microextraction (SPME) and analyzed by gas chromatography-mass spectrometry (GC-MS). 240 VOMs were identified. Univariate analysis showed that esters of short chain fatty acids, cyclohexanecarboxylic acid and its ester derivatives were associated with IBS-D (p<0.05), while aldehydes were more abundant in IBD (p<0.05). A predictive model, developed by multivariate analysis, separated IBS-D from active CD, UC and healthy controls with a sensitivity of 94%, 96% and 90%; and a specificity of 82%, 80% and 80% respectively (p<0.05). The understanding of the derivation of these VOMs may cast light on the etiology of IBS-D and IBD. These data show that fecal VOMs analyses could contribute to the diagnosis of IBS-D, for which there is no laboratory test, as well as IBD.