Copy number variation of the SELENBP1 gene in schizophrenia

Background  

Schizophrenia is associated with rare copy-number (CN) mutations. Screening for such alleles genome-wide, though comprehensive, cannot study in-depth the causality of particular loci, therefore cannot provide the functional interpretation for the disease etiology. We hypothesized that CN mutations in the SELENBP1 locus could associate with the disorder and that these mutations could alter the gene product's activity in patients.     

Distal Revascularisation with Interval Ligation (DRIL): An Experience

INTRODUCTION

The global increase of chronic renal failure has resulted in a growing number of patients on haemodialysis using arteriovenous fistulas (AVFs). By virtue of their very function, AVFs at times shunt blood away from regions distally, resulting in an ischaemic steal syndrome. Distal revascularisation with interval ligation (DRIL) has been described as a procedure to treat symptomatic ischaemic steal. We present our experience in the management of this complication.

PATIENTS AND METHODS

Six patients with severe ischaemic steal were treated using a DRIL procedure between May 2004 and June 2007. There were three males and three females, all with elbow brachiocephalic AVFs. Symptoms ranged from severe rest pain to digital gangrene. Published results from international studies of 135 DRIL procedures were also reviewed.

RESULTS

Vascular access was maintained along with the elimination of ischaemic symptoms in the six patients using an ipsilateral reversed basilic vein graft. Interval ligation of the distal brachial artery was performed at the same time. All patients showed immediate and sustained clinical improvement of symptoms with a demonstrable increase in digital pulse oximetry.

CONCLUSIONS

DRIL is a beneficial treatment option that has proven successful at alleviating ischemic steal symptoms and preserving vascular access. This avoids placement of central lines, its associated risks, and the need to create an alternative sited fistula.     

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit

Background and purpose:

Alcohol produces its behavioural effects in part due to inhibition of N-methyl-d-aspartate (NMDA) receptors in the CNS. Previous studies have identified amino acid residues in membrane-associated domains 3 (M3) and 4 (M4) of the NMDA receptor that influence ethanol sensitivity. In addition, in other alcohol-sensitive ion channels, sedative-hypnotic agents have in some cases been shown to act at sites distinct from the sites of ethanol action. In this study, we compared the influence of mutations at these sites on sensitivity to ethanol and trichloroethanol, a sedative-hypnotic agent that is a structural analogue of ethanol.

Experimental approach:

We constructed panels of mutants at ethanol-sensitive positions in the GluN2A (NR2A) NMDA receptor subunit and transiently expressed these mutants in human embryonic kidney 293 cells. We used whole-cell patch-clamp recording to assess the actions of ethanol and trichloroethanol in these mutant NMDA receptors.

Key results:

Ethanol sensitivity of mutants at GluN2A(Ala825) was not correlated with any physicochemical measures tested. Trichloroethanol sensitivity was altered in two of three ethanol-insensitive mutant GluN2A subunits: GluN2A(Phe637Trp) in M3 and GluN2A(Ala825Trp) in M4, but not GluN2A(Met823Trp). Trichloroethanol sensitivity decreased with increasing molecular volume at Phe637 or increasing hydrophobicity at Ala825 and was correlated with ethanol sensitivity at both sites.

Conclusions and implications:

Evidence obtained to date is consistent with a role of GluN2A(Ala825) as a modulatory site for ethanol and trichloroethanol sensitivity, but not as a binding site. Trichloroethanol appears to inhibit the NMDA receptor in a manner similar, but not identical to, that of ethanol.     

Sarcomas in the groin and inguinal canal �C often missed and difficult to manage

INTRODUCTION

This is a 7-year retrospective review summarising the North of England Bone and Soft Tissue Tumour Service''s experience of managing 13 cases of groin sarcoma requiring soft tissue flap reconstruction. This study was performed to try to identify where national referral guidelines in sarcoma management had been followed and reasons for any delays. The study also includes outcome data relating to these patients.

PATIENTS AND METHODS

A retrospective, case-note review was undertaken using the local sarcoma database to identify approriate patients.

RESULTS

In nine patients, national referral guidelines were not followed. This resulted in a mean delay of presentation to the multidisciplinary team of 4.4 months. Ten patients had unplanned excision or exploration of tumours before referral. There were no lower limb amputations. All patients with narrow margins or high grade tumours were referred for radiotherapy. Four patients died; three as a result of distant metastases and one as a result of local recurrence.

CONCLUSIONS

Despite delays in referral, treatment by wide excision and plastic surgical reconstruction allowed for local control of these tumours with functional limb salvage. Implementation of National Institute for Health and Clinical Excellence (NICE) guidelines and local strategies could improve the expedient management of these patients.     

The impact of body build on the relationship between body mass index and percent body fat.

OBJECTIVE: The objective of the study was to test the hypothesis that differences in the relationship between percent body fat (%BF) and body mass index (BMI) between populations can be explained (in part) by differences in body build. DESIGN: Cross-sectional, comparative study. SUBJECTS: 120 age, gender and BMI matched Singapore Chinese, Beijing Chinese and Dutch (Wageningen) Caucasians. MEASUREMENTS: From body weight and body height, BMI was calculated. Relative sitting height (sitting height/height) was used as a measure of relative leg length. Body fat was determined using densitometry (underwater weighing) in Beijing and Wageningen and using a three-compartment model based on densitometry and hydrometry in Singapore. Wrist and knee widths were measured as indicators for frame size and skeletal mass was calculated based on height, wrist and knee width. In addition, a slenderness index (height/sum of wrist and knee width) was calculated. RESULTS: For the same BMI, Singapore Chinese had the highest %BF followed by Beijing Chinese and the Dutch Caucasians. Singaporean Chinese had a more slender frame than Beijing Chinese and Dutch Caucasians. Predicted %BF from BMI, using a Caucasian prediction formula, was not different from measured %BF in Wageningen and in Beijing, but in Singapore the formula underpredicted %BF by 4.0 +/- 0.8% (mean +/- s.e.m.) compared to Wageningen. The difference between measured and predicted %BF (bias) was related to the level of %BF and with measures of body build, especially slenderness. Correction for differences in %BF, slenderness and relative sitting height, decreased the differences between measured and predicted values compared to the Dutch group from 1.4 +/- 0.8 (not statistically significant, NS) to -0.2 +/- 0.5 (NS) in Beijing and from 4.0 +/- 0.8 (P < 0.05) to 0.3 +/- 0.5 (NS) in Singapore (all values mean +/- s.e.m.). CONCLUSIONS: The study results confirm the hypothesis that differences in body build are at least partly responsible for a different relationship between BMI and %BF among different (ethnic) groups.     

Paediatric continuous ambulatory peritoneal dialysis

Ten children in end-stage renal failure were treated by continuous ambulatory peritoneal dialysis (CAPD). This represents a total of 3.4 patient years. Biochemical control was good, and parent and patient acceptability high. Peritonitis was the chief complication, but after the institution of a specific CAPD education and training programme the incidence declined 10-fold. We regard CAPD as an effective short- and medium-term treatment for children with end-stage renal failure as part of an integrated dialysis and transplant programme, but it requires a devoted and enthusiastic trained staff to ensure success.     

Validation of skinfold thickness and hand-held impedance measurements for estimation of body fat percentage among Singaporean Chinese, Malay and Indian subjects

Body fat percentage (BF%) was measured in 298 Singaporean Chinese, Malay and Indian men and women using a chemical four-compartment model consisting of fat, water, protein and mineral (BF%4C). In addition, weight, height, skinfold thickness and segmental impedance (from hand to hand) was measured. Body fat percentage was predicted using prediction equations from the literature (for skinfolds BF%SKFD) and using the manufacturer's software for the hand-held impedance analyser (BF%IMP). The subjects ranged in age from 18-70 years and in body mass index from 16.0 to 40.2 kg/m2. Body fat ranged from 6.5 to 53.3%. The biases for skinfold prediction (BF%4C-BF%SKFD, mean +/- SD) were -0.4+/-3.9, 2.3+/-4.1 and 3.1+/-4.2 in Chinese, Malay and Indian women, respectively, the Chinese being different from the Malays and Indians. The differences were significant from zero (P < 0.05) in the Malays and Indians. For the men, the biases were 0.5+/-3.8, 0.0+/-4.8 and 0.9+/-4.0 in Chinese, Malays and Indians, respectively. These biases were not significantly different from zero and not different among the ethnic groups. The biases for hand-held impedance BF% were -0.7+/-4.5, 1.5+/-4.4 and 0.4+/-3.8 in Chinese, Malay and Indian women. These biases were not significantly different from zero but the bias in the Chinese was significantly different from the biases in the Malays and Indians. In the Chinese, Malay and Indian men, the biases of BF%IMP were 0.7+/-4.6, 1.9+/-4.8 and 2.0+/-4.4, respectively. These biases in Malay and Indian men were significantly different from zero and significantly different from the bias in Chinese men. The biases were correlated with level of body fat and age, and also with relative arm span (arm span/height) for impedance. After correction, the differences in bias among the ethnic groups disappeared. The study shows that the biases in predicted BF% differ between ethnic groups, differences that can be explained by differences in body composition and differences in body build. This information is important and should be taken into account when comparing body composition across ethnic groups using predictive methods.     

Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline-DNA adducts by indole-3-carbinol: dose-response studies in the rat colon

Indole-3-carbinol (I3C) inhibits the formation of colonic aberrant crypt foci and DNA adducts in rats given heterocyclic amine colon carcinogens, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Mechanism studies indicate that I3C induces cytochromes P4501A1 and 1A2 (CYP1A1 and CYP1A2), isozymes that respectively metabolize IQ via ring hydroxylation or activate the carcinogen by N-hydroxylation. The present study examined the dose-response for induction of CYP1A1 versus CYP1A2 by I3C, and compared the profiles of induction with the dose- response for inhibition of IQ-DNA adducts in the colon of the F344 rat. Dietary equivalent doses of I3C in the range 100-1000 p.p.m. increased in a dose-related manner both ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) activities in the liver and colonic mucosa, and Western blots showed a corresponding induction of CYP1A1 and CYP1A2 proteins. However, dietary equivalent doses of I3C in the range 10-25 p.p.m. (i) reduced hepatic EROD and MROD activities and CYP1A protein levels compared with controls, (ii) increased the ratio of CYP1A2 versus CYP1A1, and (iii) activated IQ to a more potent mutagen when liver microsomes from rats given I3C were used for metabolic activation in the Salmonella assay. Rats given a single oral dose of I3C shortly before administering IQ (5 mg/kg body wt, p.o.) exhibited dose-related inhibition of colonic IQ-DNA adducts in the range 25-100 p.p.m. I3C, reaching 95% inhibition at doses > or = 100 p.p.m. I3C, but IQ-DNA adducts were elevated slightly at the lowest I3C dose as compared with the controls. The possible significance of the low versus high dose effects of I3C are discussed in the context of human dietary exposures to I3C and the reported chemopreventive mechanisms of I3C in vivo.      

Changes in serum total cholesterol levels over 18 years in a cohort of men and women: The Nijmegen Cohort Study

BACKGROUND: This study aimed to investigate to what extent cholesterol levels change in individuals in different age groups over an 18-year period. Factors that contribute to the changes, with respect to prevention of cardiovascular disease, were taken into account. METHODS: In 1977 serum cholesterol, systolic and diastolic blood pressures, body mass index, and smoking habits were measured in a cohort of 7,092 patients (men and women from 20 to 50 years of age) from six general practices in The Netherlands. In 1995, a sample of 2,600 of these same patients were invited to take part in a similar screening program; 2,335 patients, consisting of 1,171 men and 1,164 women, agreed to participate. Patients were derived from both high-risk and low- to normal-risk category in 1977. The differences in cholesterol between 1977 and 1995 were calculated and cholesterol levels were tracked over the study period by determining Pearson correlation coefficients. A multiple linear regression analysis was performed to investigate the determinants influencing the changes in cholesterol level. RESULTS: The mean cholesterol levels rose during the study period in all age groups. The highest mean increase in men was 1.23 mmol/L, or 20%, in the youngest age group (20-24 years), and in women the maximum mean increase was 1.12 mmol/L, or 17%, in the age group 40-44 years. Correlation coefficients between the 1977 and 1995 readings varied from 0.63 in the youngest age group to 0.41 in the oldest. Body weight change during the study period, more than initial body weight, was found to have influenced the rise in serum cholesterol. At basic screening, 19.2% of the men and 12.4% of the women had cholesterol levels of 6. 5 mmol/L or higher, as against 35.8 and 36.8%, respectively, in 1995. CONCLUSIONS: Over an 18-year period cholesterol level increased in most subjects, at a younger age in men than in women. The highest increase in women took place during the menopausal period. Weight gain, more than baseline weight, had a positive influence on the increase in cholesterol.     

No association between the K variant of the butyrylcholinesterase gene and pathologically confirmed Alzheimer's disease

The polymorphic K variant of the butyrylcholinesterase ( BCHE-K ) gene recently has been demonstrated to have an elevated frequency in Alzheimer's disease (AD) patients carrying the epsilon4 allele of the apolipoprotein (APO E) gene when compared with a control population. We therefore genotyped a large series of pathologically confirmed AD patients and controls to confirm this association. We found no change in the frequency of this genetic variant, either in the AD group as a whole or in early- or late-onset patients when compared with age- matched controls. Stratification of these groups with reference to the APO E epsilon4 allele also showed no difference between AD and control groups. To determine if a biological effect were present, we also looked at senile plaque and neurofibrillary tangle densities in the frontal, temporal, parietal and occipital cortices in AD patients either carrying or not carrying a copy of the K variant. We found no difference in plaque or tangle load between these two groups in either the total, late-onset or early-onset AD subjects. Stratification of the total AD group in terms of APO E epsilon4 allele possession, and further comparison of plaque and tangle load between carriers and non- carriers of BCHE-K still failed to disclose a relationship between BCHE- K and AD. We conclude that in the population studied here there is no association between BCHE-K and AD, or that if such a relationship exists it is precluded by another, as yet unknown factor.