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Biomedical subjects

J C Evans

Publications and source records attributed to J C Evans.

At least 19 recordsLinked to original sources
PubMed2006

People with MECP2 mutation-positive Rett disorder who converse.

BACKGROUND: People with useful speech after regression constitute a distinct group of those with mutation-positive Rett disorder, 6% (20/331) reported among mutation-positive people in the British Survey. We aimed to determine the physical, mental and genetic characteristics of this group and to gain insight into their experience of Rett syndrome. METHODS: Clinical and molecular data for people with Rett, aged 10 or more years at follow-up (the study group, n = 13), with the ability to converse and a MECP2 mutation are presented. They were compared with an age-matched control group (n = 110), who could not converse and had a pathogenic MECP2 mutation. RESULTS: The study group differed significantly from the control group with regard to their disease severity (P < 0.001); feeding difficulty scores (P < 0.001); health scores (P < 0.001); epilepsy (P < 0.001); head circumference (P < 0.004); age at onset of the regression period (P < 0.001) (six in the study group did not regress) and mutation frequency (C-terminal deletions P = 0.014, R133C P < 0.006). The results indicate that favourable skewing of X-inactivation is only present in a small proportion of mild cases. Speech was fragmented with a soft, breathless quality, and all but two had obviously irregular breathing. One person with an R168X mutation preferred signing to speech. All enjoyed interpersonal contact, showing affection and preferring people to objects, clearly distinguishing the condition from autism. Most were habitually anxious. Music was a source of pleasure and relaxation also providing a valuable educational asset. Even in these most able cases, understanding was severely restricted in most and little initiative was shown. CONCLUSIONS: While the Rett profile is present in these people they are commonly not classic, and the presence of speech, good head growth and lack of regression may lead to missed diagnoses. A strong association was demonstrated between this milder form of the disease and R133C and C-terminal deletions.

Adult↗
PubMed2006

Germline mosaicism for a MECP2 mutation in a man with two Rett daughters.

Rett syndrome is a severe neurodevelopmental disorder that is caused by mutations in the X-linked gene, methyl-CpG binding protein 2 (MECP2). The majority of cases are sporadic, but rarely germline mosaicism can lead to familial cases. Here, we report the first case where germline mosaicism for a MECP2 mutation has been shown in a man. He has two affected daughters who are half sisters, and both have the c.808delC mutation. We show that this mutation is present at a low level in DNA extracted from the patient's semen. This case has implications for genetic counseling, and pre-natal testing should be offered for the partners of men who have a daughter with Rett syndrome.

Base Sequence↗
PubMed2005

Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Adolescent↗
PubMed2005

Analysis of haematopoietic chimaerism by quantitative real-time polymerase chain reaction.

Allogeneic bone marrow transplantation (BMT) with marrow ablative conditioning is the treatment of choice for haematopoietic malignancies. The use of nonmyeloablative stem cell transplants has allowed the treatment of patients previously ineligible for BMT because of age or other disease. These reduced conditioning regimes allow the persistence initially of some recipient cells in the blood and bone marrow (haematopoietic chimaerism). Monitoring of the relative proportion of donor and recipient cells is required to assess the success of the procedure, to predict subsequent rejection or impending relapse and to guide the use of donor lymphocyte infusions. We present a quantitative real-time PCR approach for the measurement of haematopoietic chimaerism using the TaqMan. This approach exploits the presence of single-nucleotide polymorphisms (SNPs) to distinguish cells of patient or donor origin. We have designed and validated a panel of seven allele-specific probes to quantify the contribution of patient and donor cells in the haematopoietic population from 12 patient and donor pairs. We have compared the performance of this approach with an existing method and proved it to be superior in both accuracy and sensitivity. The use of more sensitive and accurate techniques permits earlier intervention for improved clinical outcome.

Adult↗
PubMed2004

Major resection for chronic pancreatitis in patients with vascular involvement is associated with increased postoperative mortality.

BACKGROUND: The aim was to evaluate the outcome of major resection for chronic pancreatitis in patients with and without vascular involvement. METHODS: Of 250 patients with severe chronic pancreatitis referred between 1996 and 2003, 112 underwent pancreatic resection. The outcome of 17 patients (15.2 per cent) who had major vascular involvement was compared with that of patients without vascular involvement. RESULTS: The 95 patients without vascular involvement had resections comprising Beger's operation (39 patients), Kausch-Whipple pancreatoduodenectomy (28), total pancreatectomy (25) and left pancreatectomy (three). Twenty-five major vessels were involved in the remaining 17 patients. One or more major veins were occluded and/or compressed producing generalized or segmental portal hypertension, and three patients also had major arterial involvement. Surgery in these patients comprised Beger's operation (eight), total pancreatectomy (five), Kausch-Whipple pancreatoduodenectomy (two) and left pancreatectomy (two). Perioperative mortality rates were significantly different between the groups (two of 95 versus three of 17 respectively; P = 0.024). There were similar and significant improvements in long-term outcomes in both groups. CONCLUSION: Resection for severe chronic pancreatitis in patients with vascular complications is hazardous and is associated with an increased mortality rate. Vascular assessment should be included in the routine follow-up of patients with chronic pancreatitis, to enable early identification of those likely to develop vascular involvement and prompt surgical intervention.

Adolescent↗
PubMed2003

Glutamine synthetase in tilapia gastrointestinal tract: zonation, cDNA and induction by cortisol.

Glutamine synthetase, an enzyme generally associated with ammonia detoxication in the vertebrate brain and with hepatic nitrogen turnover in mammals, shows substantial activities in the gastrointestinal tract of teleostean fishes. Enzyme activity is highest in the central area of the stomach and reveals a distinct distribution pattern in stomach and along the intestine of tilapia (Oreochromis niloticus), rainbow trout (Oncorhynchus mykiss) and copper rockfish (Sebastes caurinus). In all three species, intestinal activity peaks in the distal region of the intestine. The brain contains the highest titre of the enzyme (46 U g(-1) in tilapia brain versus 15 U g(-1) in tilapia stomach), but because of the relative mass of the stomach, the largest glutamine synthetase pool in tilapia body appears to be localized in the stomach. Activities in white and red muscle are very modest at 0.1% of the brain. Independent of distribution, peak activities of glutamine synthetase in selected areas of tilapia stomach and intestine are significantly (two- to fourfold) increased after a 5-day treatment with an intraperitoneal cortisol deposit. Cortisol also increases glutamine synthetase activity in tilapia liver, white and red muscle, while activities in brain remain unaffected. We cloned and sequenced the predominant transcript of tilapia stomach glutamine synthetase (about 1.9 kb), encoding a 371-amino acid peptide. The open reading frame shows considerable identity with glutamine synthetase in toadfish (92% at peptide level, 87% at nucleotide level), but possesses a longer 3'-untranslated region than the toadfish. The tilapia glutamine synthetase mRNA contains a remnant of a putative mitochondrial leader sequence, but without a conserved second site for initiation of translation. We also find evidence for additional transcripts of glutamine synthetase in tilapia, suggesting multiple genes. Finally, we present evidence for similar abundance of glutamine synthetase transcripts in all regions of rockfish intestine. The physiological significance of the presence of glutamine synthetase in teleostean intestine is discussed.

Amino Acid Sequence↗
PubMed2003

Minimally invasive retroperitoneal pancreatic necrosectomy.

INTRODUCTION: Open surgery for pancreatic necrosis is associated with considerable morbidity and mortality. We report the results of a recently developed minimally invasive technique that we adopted in 1998. METHODS: A descriptive explanation of the approach is given together with the results of a retrospective analysis of patients who underwent a minimally invasive retroperitoneal pancreatic necrosectomy (MIRP) between August 1998 and April 2002. PATIENTS: There were 24 patients with a median (range) age of 61 (29-75) years. The initial median (range) APACHE II score was 8 (2-21). All patients had infected pancreatic necrosis with at least 50% pancreatic necrosis. In three patients it was not possible to complete the first MIRP because of technical reasons. RESULTS: A total of 88 procedures were performed with a median (range) of 4 (0-8) per patient. Twenty-one (88%) patients developed 36 complications during the course of their illness. Five patients required an additional open procedure: 2 for subsequent distant collections, 2 for bleeding and 1 for persisting sepsis and a distant abscess. Six (25%) patients who had MIRP died. The median (range) post-operative hospital stay was 51 (5-200) days. CONCLUSIONS: MIRP is a new technique that has shown promising results, and could be preferable to open pancreatic necrosectomy in selected patients. However, unresolved issues remain to be overcome and the exact role of MIRP in the management of pancreatic necrosis has yet to be defined.

Adult↗
PubMed2002

Association of calpain-10 gene with microvascular function.

AIMS/HYPOTHESIS: Genotype could influence vascular function. In some populations, Calpain 10 gene polymorphisms increase susceptibility to diabetes or insulin resistance. Alterations in microvascular function could contribute to insulin resistance. This study investigated whether polymorphisms in the Calpain-10 gene influence microvascular function. METHODS: Skin maximum microvascular hyperaemia to local heating on the dorsum of the foot (30 min at 43 degrees C) was measured by Laser Doppler Fluximetry in 37 healthy volunteers. All were normoglycaemic according to World Health Organisation criteria, normotensive and not on any medication. Four polymorphisms in the calpain-10 gene were typed: SNP-44, SNP-43, SNP-19, SNP-63. The SNP common to all the described high risk haplotypes is the G-allele at SNP-43. This intron 3 polymorphism appears to influence gene expression. Microvascular function was examined in relation to polymorphisms at this site alone as well as the effects of the known extended high risk haplotypes using the SNP's above. RESULTS: Maximum microvascular hyperaemia was increased in the 21 subjects with G/G genotypes at SNP-43 compared to the combined group of subjects ( G/ A genotype at SNP-43 ( n=12) + A/ A genotype at SNP-43 ( n=4)), and the minimum microvascular resistance was reduced 49.4 (39.6-94.2) vs 67.5 (39.1-107.3) mmHg/V, p=0.007). Haplotype analysis of the hyperaemic response revealed no significant differences between haplotypes. The two groups did not differ in terms of anthropometric measures, blood pressure, insulin resistance or glucose. CONCLUSIONS/INTERPRETATION: The polymorphism that confers susceptibility to Type II (non-insulin-dependent) diabetes mellitus in some populations is associated in United Kingdom Caucasians with enhanced microvascular function in the presence of normoglycaemia.

Adult↗
PubMed2001

The potential size and duration of an epidemic of bovine spongiform encephalopathy in British sheep.

Because there is a theoretical possibility that the British national sheep flock is infected with bovine spongiform encephalopathy (BSE), we examined the extent of a putative epidemic. An age cohort analysis based on numbers of infected cattle, dose responses of cattle and sheep to BSE, levels of exposure to infected feed, and number of BSE-susceptible sheep in the United Kingdom showed that at the putative epidemic peak in 1990, the number of cases of BSE-infected sheep would have ranged from fewer than 10 to about 1500. The model predicts that fewer than 20 clinical cases of BSE in sheep would be expected in 2001 if maternal transmission occurred at a rate of 10%. Although there are large uncertainties in the parameter estimates, all indications are that current prevalence is low; however, a simple model of flock-to-flock BSE transmission shows that horizontal transmission, if it has occurred, could eventually cause a large epidemic.

Age Factors↗
PubMed2001

Family breast cancer history and mammography: Framingham Offspring Study.

The authors examined mammography use according to family cancer history and identified predictors of recent use (<or=2 years). Framingham Offspring Study participants in Framingham, Massachusetts, aged 40-79 years, completed a breast health questionnaire in 1996-1997. The study sample of women included 141 with a first-degree relative with breast cancer, 221 with a mother or sister(s) with other cancers, and 331 with a mother and sister(s) who participate in the Framingham Heart Study and did not report a history of cancer. Stepwise logistic regression analysis was used to identify predictors of recent mammography use. Among women with a family breast cancer history, 98% reported mammography use compared with 95% of other women. Recent mammography use was higher in women with a family breast cancer history (93%) compared with women with a family history of other cancer (80%) and women without a family history of cancer (84%) (p = 0.004). Odds ratios and 95% confidence intervals for significant predictors of recent mammography use were as follows: family history of breast cancer, 3.2 (95% confidence interval (CI): 1.4, 7.7); recent clinical breast examination, 17.4 (95% CI: 9.2, 32.8); and smoking, 0.4 (95% CI: 0.2, 0.7). Mammography use was high among women with a family breast cancer history.

Adult↗
PubMed2001

Impact of high-normal blood pressure on the risk of cardiovascular disease.

BACKGROUND: Information is limited regarding the absolute and relative risk of cardiovascular disease in persons with high-normal blood pressure (systolic pressure of 130 to 139 mm Hg, diastolic pressure of 85 to 89 mm Hg, or both). METHODS: We investigated the association between blood-pressure category at base line and the incidence of cardiovascular disease on follow-up among 6859 participants in the Framingham Heart Study who were initially free of hypertension and cardiovascular disease. RESULTS: A stepwise increase in cardiovascular event rates was noted in persons with higher baseline blood-pressure categories. The 10-year cumulative incidence of cardiovascular disease in subjects 35 to 64 years of age who had high-normal blood pressure was 4 percent (95 percent confidence interval, 2 to 5 percent) for women and 8 percent (95 percent confidence interval, 6 to 10 percent) for men; in older subjects (those 65 to 90 years old), the incidence was 18 percent (95 percent confidence interval, 12 to 23 percent) for women and 25 percent (95 percent confidence interval, 17 to 34 percent) for men. As compared with optimal blood pressure, high-normal blood pressure was associated with a risk-factor-adjusted hazard ratio for cardiovascular disease of 2.5 (95 percent confidence interval, 1.6 to 4.1) in women and 1.6 (95 percent confidence interval, 1.1 to 2.2) in men. CONCLUSIONS: High-normal blood pressure is associated with an increased risk of cardiovascular disease. Our findings emphasize the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease.

Adult↗
PubMed2001

Heritability of longitudinal change in lung function. The Framingham study.

There have been multiple reports of heritability of lung function in cross-sectional analysis, but no prior reports of heritability of rate of change in lung function. We examined heritability of rate of change of lung function in families participating in the Framingham Heart Study. Spirometric measures from two time points were used to calculate annualized rate of change in FEV(1), FVC, and FEV(1)/FVC ratio, adjusting for the effects of age, height, and weight using multiple linear regression models. Standardized residuals from these models were used as phenotypic variables in variance components analysis to assess effects of smoking and heritable factors on rate of change in lung function. Heritable factors explained a modest proportion of the population variance, with heritability estimates for change in FEV(1), FVC, and ratio of 0.05, 0.18, and 0.13, respectively. Restricting the analysis to subjects concordant for smoking status during the interval over which lung function was measured, the heritability estimates increased to 0.18, 0.39, and 0.14, respectively, among interim smokers. These data suggest that in middle-aged and older persons in the general population, genetic factors contribute modestly to the overall population variance in rate of lung function decline, and further suggest the importance of gene-environment interactions.

Adult↗
PubMed2001

Echocardiographic features of the right heart in sleep-disordered breathing: the Framingham Heart Study.

The effect of sleep-disordered breathing (SDB) on right heart structure and function is controversial. Studies of patients referred for evaluation of possible sleep apnea have yielded conflicting results, and the impact of SDB on the right heart has not been investigated in the general population. We examined the echocardiographic features of subjects with SDB at the Framingham Heart Study site of the Sleep Heart Health Study. Of 1,001 polysomnography subjects, 90 with SDB defined as a respiratory disturbance index (RDI) score > 90th percentile (mean RDI = 42) were compared with 90 low-RDI subjects (mean RDI = 5) matched for age, sex, and body mass index. Right heart measurements, made without knowledge of clinical status, were compared between groups. The majority of the subjects were male (74%). After multivariable adjustment, right ventricle (RV) wall thickness was significantly greater (p = 0.005) in subjects with SDB (0.78 +/- 0.02 cm) than in the low-RDI subjects (0.68 +/- 0.02 cm). Right atrial dimensions, RV dimensions, and RV systolic function were not found to be significantly different between subjects with SDB and the low-RDI subjects. We conclude that in this community-based study of SDB and right heart echocardiographic features, RV wall thickness was increased in subjects with SDB. Whether the RV hypertrophy observed in persons with SDB is associated with increased morbidity and mortality remains unknown.

Adult↗
PubMed2001

Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Alleles↗