Structural abnormalities of the nervous system in Crohn's disease and ulcerative colitis.
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Animals↗
Biomedical subjects
S Collins
Publications and source records attributed to S Collins.
Dietary treatment of severe malnutrition in adults.
The aim of this study was to compare the effects of two diets, differing primarily in protein content, on the nutritional rehabilitation of severely malnourished adults. The study took place in the Concern Worldwide Adult Therapeutic Feeding Centre in Baidoa, the town at the epicenter of the 1992 famine in Somalia. The response to treatment in 573 patients admitted to the center between November 1992 and March 1993 was studied. Mortality, appetite, rates of edema loss, and weight gain in 2 groups of patients receiving either a higher-protein (16.4% of energy from protein) or lower-protein (8.5% of energy from protein) diet were compared. Among edematous patients, the use of the lower-protein diet during the initial phase of treatment was associated with a threefold decrease in mortality (P < 0.05) and accelerated resolution of edema (P < 0.05). Among marasmic patients, no differences in mortality or rate of weight gain were observed. The large reduction in mortality associated with the use of the lower-protein diet in edematous patients appeared to be due to the lower amount of dietary protein. However, differences in the 2 diets other than or in addition to the protein content may have contributed. Notwithstanding, the data obtained suggest strongly that severely malnourished adults, particularly those with edema, recover more successfully with a diet of lower protein content than usually recommended. The lower-protein diet used in this study was much cheaper and more easily obtained than the conventional higher-protein diets in Baidoa.
Adult↗
Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.
Blood samples from 125 unrelated families with classical type 2 neurofibromatosis (NF2) with bilateral vestibular schwannomas have been analysed for mutations in the NF2 gene. A further 17 families fulfilling modified criteria for NF2 have also been analysed. Causative mutations have been identified in 54 (43%) classical families and six (35%) of those fulfilling modified criteria. Forty-two cases from 38 families with truncating mutations had an average age at onset of symptoms of 19 years and diagnosis at 22.4 years. Fifty-one cases from 16 families with splice site mutations (15 from six), missense mutations (18 from six), and large deletions (18 from five) had an average age of onset of 27.8 years and at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to have symptoms before 20 years of age (p<0.001) and to develop at least two symptomatic CNS tumours in addition to vestibular schwannoma before 30 years (p<0.001). There were also significantly fewer multigenerational families with truncating mutations. Four further truncating mutations were in mosaic form and were associated with milder disease than other similar mutations. This large study has confirmed the previous impression that truncating mutations are associated with severe disease, but caution has to be exercised in using mutation type to predict disease course.
Adult↗
Sex and electroencephalographic synchronization after photic stimulation predict signal changes in the visual cortex on functional MR images.
PURPOSE: We evaluated factors that influence MR signal changes during photic stimulation of the visual cortex. We also tested the hypothesis that functional MR imaging response corresponds to electroencephalographic (EEG) synchronization after photic stimulation. METHODS: Thirty-eight healthy subjects, 20 men and 18 women, underwent photic stimulation of the visual cortex. They were studied with a 1.5-T MR unit, and photic stimulation was induced via 8-Hz LED goggles. Seven subjects with and seven without detectable functional MR imaging response to photic stimulation underwent further studies with 16-channel EEG after 2- to 30-Hz stroboscopic stimulation. RESULTS: Thirteen men and 18 women had a significant increase in MR signal in the visual cortex; seven men showed no visual cortex activation during more than two repeated studies. Six of seven volunteers with increased functional MR imaging signal after photic stimulation also showed signs of EEG synchronization when an 8-Hz stroboscopic flash was used; six of seven subjects with no functional MR imaging lacked EEG synchronization at 8-Hz stimulation. CONCLUSIONS: Men were more likely than women to have undetectable MR signal changes after photic stimulation. This finding should be considered when interpreting results of functional MR imaging studies. EEG with stroboscopic examination is a good predictor of functional MR imaging sensitivity to changes in regional cerebral blood flow induced by sensory stimulation.
Adult↗
The national asthma audit. Bridging the gap between guidelines and practice.
OBJECTIVE: This pilot study was undertaken to assess the need and acceptability of a theoretically based audit model to assist GPs improve their asthma care. METHOD: Seventeen GPs from two GP divisions conducted a chart audit and patient survey of asthma patients presenting during the 8 week audit period. Audit results were discussed at a workshop providing a forum for GP peer groups to review their asthma care against current guidelines. This workshop allowed the GPs to develop strategies to improve their asthma care in the context of the resources of their individual practice, GP division, local community and health services. RESULTS: Of the 243 asthma patients audited 177 (72.8%) had a review of their asthma recorded in the past 12 months, 138 (56.8%) were prescribed regular preventive therapy and 118 (48.2%) had been given an asthma action plan. Despite the time commitment required to participate in the activity, 16 respondents who answered the audit evaluation questionnaire reported that the audit was a useful process and 15 (93.8%) stated that it had motivated them to change their practice. CONCLUSION: The results confirmed the need for improved asthma care in general practice and demonstrated the feasibility of the GP-peer led, regionally coordinated, audit-workshop model.
Adult↗
Up-regulation of UCP-2 gene expression by PPAR agonists in preadipose and adipose cells.
UCP-2 is a member of the emerging family of UCP homologues. Upon high-fat feeding, UCP-2 mRNA levels are increased in epididymal fat pads of A/J mice, suggesting that the flux of fatty acids entering adipose tissue may regulate UCP-2 gene expression. Since fatty acids act as positive transcriptional regulators of lipid-related genes by means of peroxisome proliferator-activated receptors (PPARs), the regulation of UCP-2 gene expression by PPAR agonists (carbacyclin, alpha-bromopalmitate, BRL49653) has been examined in mouse preadipose and adipose cells in primary cultures or from clonal lines (Ob1771, 3T3-F442A, 1B8). In preadipose cells, carbacyclin and alpha-bromopalmitate are active and BRL49653 shows no effect, whereas all these ligands are active in adipose cells. The stimulatory effect of PPAR agonists is potentiated by RXR agonists in adipose cells. In contrast to the UCP-1 gene, norepinephrine as a cAMP-elevating agent does not enhance the expression of UCP-2 gene. Altogether, the data favor a predominant role of PPARdelta in preadipose cells and the involvement of PPARgamma2 in adipose cells in up-regulating UCP-2 gene expression. Thus, a potential link between fatty acid metabolism and thermogenesis may exist in PPAR-expressing tissues.
Adipocytes↗
Discharge summaries. Map reading.
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Aftercare↗
Involvement of retinoic acid receptor-alpha-mediated signaling pathway in induction of CD38 cell-surface antigen.
Human leukocyte antigen CD38, a 45-kD single-chain, transmembrane glycoprotein, is a bifunctional ectoenzyme that participates in signal transduction pathways involved in the regulation of cell growth and differentiation. In this study, we demonstrate the nature of retinoid receptors involved in retinoic acid-induced expression of CD38 protein in the human myeloblastic leukemia cell line HL-60. We used a variant HL-60 cell line, HL-60R, in which retinoid receptor function has been abrogated by a trans-dominant negative mutation. We introduced the normal retinoic acid receptors (RAR)-alpha, -beta, and -gamma or retinoid X receptor (RXR)-alpha into HL-60R cells by retroviral vector-mediated gene transfer. Based on experiments using these cell lines and receptor-specific synthetic retinoids that preferentially bind to one of the RARs or RXRs, we conclude that RAR-alpha is involved in retinoid-induced CD38 expression in HL-60 cells. Further evidence included our demonstration that blocking of RAR-alpha with the antagonist Ro 41-5253 completely suppressed the retinoid-induced expression of CD38 mRNA transcript and the production of CD38 protein in HL-60 cells. Various tissues from transgenic mice that expressed an antisense construct of RAR-alpha lacked or produced very low levels of CD38. As expected, the tissues from transgenic mice contained 50% to 80% reduced levels of RAR-alpha. These results suggest that regulation of CD38 expression, both in vitro and in vivo, is under the direct control of RAR-alpha retinoid receptors.
ADP-ribosyl Cyclase↗
Volitional control of anticipatory ocular smooth pursuit after viewing, but not pursuing, a moving target: evidence for a re-afferent velocity store.
Although human subjects cannot normally initiate smooth eye movements in the absence of a moving target, previous experiments have established that such movements can be evoked if the subject is required to pursue a regularly repeated, transient target motion stimulus. We sought to determine whether active pursuit was necessary to evoke such an anticipatory response or whether it could be induced after merely viewing the target motion. Subjects were presented with a succession of ramp target motion stimuli of identical velocity and alternating direction in the horizontal axis. In initial experiments, the target was exposed for only 120 ms as it passed through centre, with a constant interval between presentations. Ramp velocity was varied from +/- 9 to 45 degrees/s in one set of trials; the interval between ramp presentations was varied from 640 to 1920 ms in another. Subjects were instructed either to pursue the moving target from the first presentation or to hold fixation on another, stationary target during the first one, two or three presentations of the moving display. Without fixation, the first smooth movement was initiated with a mean latency of 95 ms after target onset, but with repeated presentations anticipatory smooth movements started to build up before target onset. In contrast, when the subjects fixated the stationary target for three presentations of the moving target, the first movement they made was already anticipatory and had a peak velocity that was significantly greater than that of the first response without prior fixation. The conditions of experiment 1 were repeated in experiment 3 with a longer duration of target exposure (480 ms), to allow higher eye velocities to build up. Again, after three prior fixations, the anticipatory velocity measured at 100 ms after target onset (when visual feedback would be expected to start) was not significantly different to that evoked after the subjects had made three active pursuit responses to the same target motion, reaching a mean of 20 degrees/s for a 50 degrees/s target movement. In a further experiment, we determined whether subjects could use stored information from prior active pursuit to generate anticipatory pursuit in darkness if there was a high expectancy that the target would reappear with identical velocity. Subjects made one predictive response immediately after target disappearance, but very little response thereafter until the time at which they expected the target to reappear, when they were again able to re-vitalize the anticipatory response before target appearance. The findings of these experiments provide evidence that information related to target velocity can be stored and used to generate future anticipatory responses even in the absence of eye movement. This suggests that information for storage is probably derived from a common pre-motor drive signal that is inhibited during fixation, rather than an efference copy of eye movement itself. Furthermore, a high level of expectancy of target appearance can facilitate the release of this stored information in darkness.
Afferent Pathways↗
Paracetamol with and without codeine in acute pain: a quantitative systematic review.
In order to assess the analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in postoperative pain, we conducted a systematic review of randomised controlled trials. We found 31 trials of paracetamol against placebo with 2515 patients, 19 trials of paracetamol plus codeine against placebo with 1204 patients and 13 trials of paracetamol plus codeine against the same dose of paracetamol with 874 patients. Pain relief information was extracted, and converted into dichotomous information (number of patients with at least 50% pain relief). Wide variations in responses to placebo (0-72%) and active drug (3-89%) were observed. In postoperative pain states paracetamol 1000 mg alone against placebo had an number-needed-to-treat (NNT) of 3.6 (3.0-4.4) and paracetamol 600/650 mg alone an NNT of 5.0 (4.1-6.9). Paracetamol 600/650 mg plus codeine 60 mg against placebo had a better NNT of 3.1 (2.6-3.8), with no overlap of 95% confidence intervals with paracetamol 600/650 mg alone. In direct comparisons of paracetamol plus codeine with paracetamol alone the additional analgesic effect of 60 mg of codeine added to paracetamol was 12 extra patients in every 100 achieving at least 50% pain relief. In indirect comparisons of each with placebo it was 14 extra patients per 100. This was an NNT for adding codeine 60 mg of 9.1 (5.8-24). The results confirm that paracetamol is an effective analgesic, and that codeine 60 mg added to paracetamol produces worthwhile additional pain relief even in single oral doses.
Acetaminophen↗
Factors predisposing to suspected offending by adults with self-reported learning disabilities.
BACKGROUND: This study investigated factors contributing to suspected offending behaviour by adults with a history of learning disabilities taken into custody at a city police station. METHODS: Adults charged with offences, and/or leaving custody, during a defined period, were identified as having a possible learning disability using a four-item questionnaire (Lyall et al. 1995 a). A comparison group, of similar age, sex and IQ, was identified from a database of young people with learning difficulties. Information was obtained on interview about each individual's medical, psychiatric, social and family histories and psychological assessments were undertaken. RESULTS: In contrast to the comparison group, those in the 'offending' group were more likely to have a history of the following: losing contact with their father, forensic contact in one or more family members, past homelessness, illicit drug use, experiencing an excess of recent life events, self-reported behavioural problems at school, truancy, childhood police contact and contact with probation services. All had histories of repeated offending. There was also an increased rate of drug/alcohol dependence. Only two subjects in the study group had a full-scale IQ below 70. CONCLUSIONS: These differences would suggest that the presence of childhood behavioural problems, offending behaviour by other family members, family separation and other social disruption and the development of drug and alcohol related problems are potentially the most important factors in trying to understand why one group engaged in criminal behaviour. The offending group had many characteristics in common with general offending populations.
Adult↗
Risk of subsequent primary cancers in patients with carcinoma of the Ampulla of Vater.
Data were collected on subsequent primary cancers occurring in 194 individuals diagnosed with ampullary carcinoma during 1979-92 in the north western region of England, UK. Four cancers were identified compared with 6.62 expected (relative risk 0.60), suggesting that individuals with ampullary carcinoma are not at increased risk of developing subsequent primary cancers.
Adult↗
Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia.
A mitochondrial protein called uncoupling protein (UCP1) plays an important role in generating heat and burning calories by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy-consuming process. This pathway has been implicated in the regulation of body temperature, body composition and glucose metabolism. However, UCP1-containing brown adipose tissue is unlikely to be involved in weight regulation in adult large-size animals and humans living in a thermoneutral environment (one where an animal does not have to increase oxygen consumption or energy expenditure to lose or gain heat to maintain body temperature), as there is little brown adipose tissue present. We now report the discovery of a gene that codes for a novel uncoupling protein, designated UCP2, which has 59% amino-acid identity to UCP1, and describe properties consistent with a role in diabetes and obesity. In comparison with UCP1, UCP2 has a greater effect on mitochondrial membrane potential when expressed in yeast. Compared to UCP1, the gene is widely expressed in adult human tissues, including tissues rich in macrophages, and it is upregulated in white fat in response to fat feeding. Finally, UCP2 maps to regions of human chromosome 11 and mouse chromosome 7 that have been linked to hyperinsulinaemia and obesity. Our findings suggest that UCP2 has a unique role in energy balance, body weight regulation and thermoregulation and their responses to inflammatory stimuli.
Adipose Tissue↗
RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient beta-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice.
OBJECTIVE: To investigate the role of hypercorticism in the development of compromised beta-adrenergic signalling in adipocytes of mature C57BL/6J-ob/ob mice. DESIGN AND EXPERIMENTAL UNITS: Mature male ob/ob mice and their lean littermates were treated with vehicle or the specific glucocorticoid receptor (GR) antagonist, RU-486 (30 mg/kg bw/d) for 21 d. MEASUREMENTS: Blood glucose, serum insulin, adipocyte Glut-4 expression, adipocyte Gs alpha expression, adenylylcyclase activation by beta-adrenergic receptor (beta-AR) agonists in adipocyte membranes and mRNA levels for beta 1-, beta 2- and beta 3-adrenergic receptor subtypes in adipocytes. RESULTS: RU-486 reduced blood glucose levels in ob/ob mice to levels that were not different from lean mice. RU-486 also reduced serum insulin by approximately 50% in ob/ob mice, but failed to restore depressed Gs alpha or GLUT-4 expression in adipocytes of ob/ob mice. RU-486 produced a two-fold increase in beta 3-AR mRNA in ob/ob mice and a small but significant improvement in isoprenaline-mediated adenylylcyclase activation. CONCLUSIONS: The present results indicate that glucocorticoid antagonism ameliorates diabetic symptoms of the mature ob/ob mouse, but does not lessen their obesity or fully reverse deficient expression and function of components of the adipocyte beta-adrenergic signalling cascade.
Adenylyl Cyclases↗
What changes in the organisation of cancer services will improve the outcome for women with ovarian cancer?
OBJECTIVE: To examine the influence of operator specialty, volume of work and referral to an oncologist on the survival of women with ovarian cancer. DESIGN: Population-based retrospective cohort study, using hospital records and Cancer Registry data. SETTING: The North Western Region, UK. POPULATION: Six hundred and ninety-one women undergoing laparotomy for histologically confirmed ovarian malignancy during 1991 to 1992. METHODS: Univariate and multivariate survival analyses. MAIN OUTCOME MEASURES: Univariate survival estimates. Relative risks, derived from Cox's proportional hazards model, describing the effect on survival of surgeons vs gynaecologists as baseline, high volume vs low volume operators and referral vs nonreferral to an oncologist. RESULTS: After adjusting for woman and disease-related prognostic factors, operation by a surgeon was shown to have an adverse impact on survival (RR = 1.58, 95% CI 1.19 to 2.10). Regardless of how a high volume operator was defined (in terms of the number of laparotomies performed), no survival advantage over low volume operators could be demonstrated. Women referred to an oncologist had significantly better survival than women not referred (RR = 0.54, 95% CI 0.43 to 0.68). CONCLUSIONS: All women undergoing surgery for ovarian cancer should have access to a gynaecological opinion and postoperatively should be referred for a nonsurgical oncological opinion.
Adolescent↗
Strain-specific response to beta 3-adrenergic receptor agonist treatment of diet-induced obesity in mice.
Fat intake has long been associated with the development of obesity. The studies described herein show that fat adversely affects adipocyte adrenergic receptor (AR) expression and function. As beta 3AR agonists have been shown to acutely reduce adipose tissue mass and improve thermogenesis in genetically obese rodents, we examined whether chronic supplementation of a high fat diet with a highly selective beta 3AR agonist, CL316,243 could prevent diet-induced obesity, and whether the effect could be sustained over prolonged treatment. C57BL/6J and A/J mice were weaned onto one of three diets: low fat (10.5% calories from fat), high fat (58% calories from fat), or high fat supplemented with 0.001% CL316,243. B/6J mice gained more weight on the high fat diet than A/J mice (at 16 weeks: B/6J, 36.6 +/- 1.4 g; A/J, 32.9 +/- 0.8 g; P < 0.002; n = 10), whereas weights on the low fat diets were similar (B/6J, 29.5 +/- 0.5 g; A/J, 28.8 +/- 0.6 g; P > 0.05; n = 10). CL316,243 prevented the development of diet-induced obesity in A/J animals, but not in B/6J animals. A/J mice weighed 26.0 +/- 0.5 g at 16 weeks, whereas B/6J animals on the same diet weighed 34.1 +/- 0.8 g (P < 0.00001; n = 10), but food intake was not different between the strains throughout the study. beta-Adrenergic stimulation of adenylyl cyclase in obese B/6J mice was decreased by more than 75% in white adipose tissue and by more than 90% in brown adipose tissue (BAT). In contrast, in fat-fed A/J mice, beta-agonist-stimulated adenylyl cyclase was decreased in white adipose tissue by about 10%, whereas the activity in interscapular BAT was decreased by 50%, indicating significant retention of beta AR-stimulated activity in A/J mice compared to B/6J mice. High fat feeding was associated with decreased expression of beta 3AR and beta 1AR in white adipose tissue of both strains. However, chronic CL316,243 treatment prevented both the obesity and the decline in beta 3AR and beta 1AR messenger RNA levels in all adipose depots from A/J mice, but not B/6J mice. As CL316,243-treated A/J mice, but not B/6J mice, also showed marked uncoupling protein expression in white adipose depots, the ability of chronic CL316,243 treatment to prevent diet-induced obesity is dependent upon the elaboration of functional BAT in these regions.
Adipocytes↗
Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice.
Despite the fact that mutations resulting in the absence of leptin or its receptor have been associated with severe obesity and diabetes, such mutations do not appear to be responsible for most human obesity. Indeed, diet-induced obesity in animals and humans has been characterized by hyperleptinemia. This has been interpreted as evidence for leptin resistance. However, no careful longitudinal studies evaluating the role of leptin in the development of obesity exist. We report a series of studies in A/J and C57BL/6J (B/6) mice that demonstrate a direct relationship between the ability to increase plasma leptin levels in response to a high-fat diet and resistance to the subsequent development of obesity and diabetes. While leptin levels are similar in lean, low-fat-fed A/J and B/6 mice, the effects of a high-fat diet on plasma leptin differ dramatically between the two strains. After 4 weeks of high-fat feeding, leptin levels in A/J mice increased 10-fold, and this elevated level was maintained independent of weight gain throughout a 14-week feeding period. However, in B/6 mice, leptin levels remained at least twofold lower and only rose very gradually along with a significant increase in adiposity, hyperglycemia, and hyperinsulinemia. These differences in the response of leptin to diet are independent of food intake and plasma insulin levels during the 1st month of feeding. Further, we demonstrated that leptin administration did not influence the expression of the novel uncoupling protein UCP2, which also responds to dietary fat. From these results, we suggest that the response of leptin to fat feeding may be an important predictor of the development of subsequent obesity.
Animals↗
Renal cryotherapy in a sheep model; a feasibility study.
PURPOSE: This study was designed to evaluate the safety and efficacy of renal cryotherapy as a possible treatment of renal malignancy with preservation of renal parenchyma. MATERIALS AND METHODS: Ten Merino sheep were anaesthetised and the right kidney was exposed through a retro-peritoneal approach. A 5 mm. cryotherapy probe (LCS 3000 Cryotec UK) was inserted into the lower pole of the kidney and freezing was undertaken to form an iceball 5 cm. in diameter. RESULTS: There was no mortality and no complications were observed. A transient rise in creatinine was observed post-operatively. The sheep were euthenased at 4 weeks and at necropsy macroscopic examination revealed a contracted, fibrotic wedge shaped lesion of 3 cm in diameter. Histological examination of the "cryolesion" revealed a central area of coagulative necrosis and a 5 mm rim of partial necrosis with preservation of renal tubules. CONCLUSION: We conclude that renal cryotherapy is safe and can achieve effective renal necrosis in the sheep model.
Animals↗