Biomedical subjects
J Young
Publications and source records attributed to J Young.
Factor XIII--circulating levels and Val34Leu polymorphism in relatives of South Asian patients with ischemic stroke.
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The postprandial state does not impair endothelial function in women with type 2 diabetes irrespective of glycaemic control.
AIMS/HYPOTHESIS: The postprandial state has been shown to be associated with endothelial dysfunction, a predictor of cardiovascular morbidity. In type 2 diabetes, postprandial metabolic excursions are prolonged and exaggerated, but less pronounced if glycaemic control is optimised. We investigated the impact of improved glycaemic control on endothelial function in the postprandial state. METHODS: We studied 19 postmenopausal women with type 2 diabetes and ten non-diabetic subjects. Participants with diabetes were re-studied 3 months after intensive glucose regulation. We measured forearm blood flow by strain gauge plethysmography during rest, during acetylcholine infusion and post ischaemia in the fasting state, and again 3 hours after a mixed meal (660 kcal, 55% fat). RESULTS: Endothelium-dependent vasodilation was impaired in the diabetic group (p<0.005) and improved following an HbA1c reduction of 0.96% (p<0.05 for high-dose acetylcholine infusion). Postprandial metabolic excursions were higher in the diabetic group (p<0.001, p<0.01 and p<0.05 for glucose, insulin and triglycerides respectively). Resting forearm blood flow increased in all groups after the meal (p<0.005). There was no difference in fasting and postprandial endothelium-dependent vasodilation before and after improved glucose regulation in either group. CONCLUSIONS/INTERPRETATION: The postprandial state does not impair endothelial function in non-diabetic women and does not make pre-existing endothelial dysfunction worse in women with type 2 diabetes, irrespective of glycaemic control.
Combined anterior and posterior inguinal hernia repair: intermediate recurrence rates with three groups of surgeons.
BACKGROUND: Use of a bilayer polypropylene mesh device (BPMD) for inguinal hernia repair began in 1998. Intermediate follow-up is now available for patients undergoing repair by three groups of surgeons. METHODS: Surgeons whose practice is dedicated to hernia repair trained preceptors who, in turn, assisted in the training of other surgeons in this new technique. All three groups provided information regarding their recurrence rates with this technique. RESULTS: Recurrence rates were similar for all three groups. Hernia specialists reported three recurrences out of 4,801 repairs. Preceptors reported one recurrence in 3,780 repairs. Other surgeons reported one failure in 3,369 repairs. CONCLUSIONS: Use of the BPMD (Prolene Hernia System) provides reliable results in the hands of hernia specialists, as well as general surgeons whose practices are not concentrated on the management of hernias.
Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer.
BACKGROUND: Colorectal cancers resulting from defective DNA mismatch repair can occur in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting. They are characterised by a high level of microsatellite instability (MSI-H) and superficially resemble each other in that they are frequently located in the proximal colon and share features such as circumscribed tumour margins and tumour-infiltrating lymphocytes. However, significant differences can be demonstrated at the molecular level including widespread promoter hypermethylation and BRAF -activating mutations which occur significantly less often in HNPCC. AIMS: In this study, we sought to determine whether the presence of widespread promoter hypermethylation and BRAF mutations would exclude HNPCC. MATERIALS AND METHODS: We investigated the methylation status of four methylated in tumour markers (MINTs 1,2,12 and 31), and the promoter regions of 5 genes hMLH1, HPP1, MGMT, p16INK4A and p14ARF, in 21 sporadic MSI-H colorectal cancers and compared these with 18 cancers from HNPCC patients. The methylation status of CpG islands were determined by either methylation specific PCR (MSP) or combined bisulfite restricton analysis (COBRA). In addition we considered the BRAF mutation status of 18 HNPCC tumours and 19 sporadic MSI-H cancers which had been previously determined by RFLP analysis and confirmatory sequencing. RESULTS: Methylation of the promoter regions in target genes occurred less frequently within the HNPCC tumours (27% of analyses), compared with the sporadic MSI-H tumours (59% of analyses) (P < 0.001). Methylation of MINTs 1, 2, 12 and 31 occurred in 4% of analyses for HNPCC tumours contrasted with 73% for sporadic MSI-H tumours (P < 0.001). BRAF mutations were detected in 74% of sporadic tumours but none of the HNPCC cancers tested. CONCLUSIONS: The total number of genes and MINTs methylated in HNPCC was lower than in MSI-H colorectal tumours. No HNPCC tumour showed evidence of widespread promoter hypermethylation or BRAF mutation suggesting this feature could be used as a discriminator between familial and sporadic cases.
Suicidal behaviour in early psychosis.
OBJECTIVE: This was to determine the prevalence of suicidal behaviours prior to and during the first year of treatment in a comprehensive early psychosis program (EPP) and to identify predictors of suicidal behaviour. METHOD: In a cohort study of 238 subjects, patients were assessed at initial presentation to an EPP and 1 year later. Measures included a range of demographic variables, suicide attempts, depression, positive and negative symptoms, social functioning and substance misuse. RESULTS: Although 15.1% attempted suicide prior to program entry, only 2.9% made an attempt in the year after program entry and 0.4% completed suicide. No further attempts were seen in those with previous parasuicide. These rates are lower than other published rates for first-episode patients. CONCLUSION: It is possible that specifically designed first-episode programs can reduce the suicidal behaviour in this high-risk population. The low prevalence of attempted suicide makes modeling predictors difficult.
Paradoxical inhibitory effect of serotonin on cortisol production from adrenocortical lesions causing Cushing's syndrome.
In the human adrenal gland, serotonin (5-HT) stimulates cortisol production through a paracrine mechanism involving 5-HT4 receptors positively-coupled to adenylyl cyclase. A hyperresponsiveness of adrenocortical tissue to 5-HT has also been described in several cases of ACTH-independent bilateral macronodular adrenal hyperplasias (AIMAHs) and adenomas causing Cushing's syndrome. In the present study, we report two cases of cortisol-producing adrenocortical lesions, i.e., one AIMAH (case 1) and one adenoma (case 2), whose secretory activity was inhibited in vitro by 5-HT. The potencies (pIC50) and efficacies (Emax) of 5-HT to inhibit cortisol secretion were 8.2 +/- 0.4 and -64.1% +/- 7.5% in case 1, and 9.2 +/- 0.5 and -32.3% +/- 3.8% in case 2. The specific 5-HT4 antagonist GR 113808 failed to influence the 5-HT-induced decrease in cortisol production by the two tissues, indicating that the paradoxical inhibitory effect of 5-HT could not be accounted for by activation of eutopic 5-HT4 receptors. These results suggest that the tissues expressed aberrant 5-HT receptors. In conclusion, the present study provides the first evidence for an inhibitory effect of 5-HT on cortisol secretion in adrenocortical lesions causing Cushing's syndrome. Our data also suggest that expression of illegitimate membrane receptors by cortisol-producing adrenal hyperplasias and/or adenomas may convert a paracrine stimulatory factor into an inhibitory signal.
Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer.
AIM: Hyperplastic polyps (HP) of the colorectum have traditionally been regarded as non-neoplastic lesions. Recent data implicate HP in the pathogenesis of colorectal cancers (CRC) characterised by extensive DNA methylation and microsatellite instability. The aim of this study was to identify morphological and molecular features that may characterise subtypes of HP with potential for neoplastic progression. MATERIALS AND METHODS: HP (22) clustering around distal CRC (group I) were compared with HP (58) in subjects with hyperplastic polyposis (group II). DNA methylation was tested in methylated in tumour (MINT) loci (1, 2, 12, 31) and genes HPP1, MGMT, p14ARF, p16INK4a, and hMLH1. RESULTS: Group II HP showed significantly more methylation than group I HP at all loci except MINT1 and MGMT. Group I showed the lowest frequency of DNA methylation but the highest frequency of K-ras mutation. Group II HP (termed HP variant) had the morphological features of the recently described "sessile serrated adenomas". Methylation of hMLH1 was found most frequently in group II polyps that included foci of dysplasia (7/10) and in no group I lesions. CONCLUSION: The findings support the existence of morphological and molecular heterogeneity among HP and highlight a subset that is likely to have significant malignant potential.
BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.
BACKGROUND AND AIMS: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). METHODS: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for BRAF activating mutations. RESULTS: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). CONCLUSIONS: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this "serrated" pathway.
An unusual presentation of group B streptococcal sepsis.
This paper describes the devastating outcome of a neonate who presented with severe late onset group B beta-haemolytic streptococcal (GBS) disease. There were extensive infarcts of the brain and gangrene of the toes. The purpose of this report is to alert healthcare workers of the unusual presentation and that fatal late onset group B beta-haemolytic streptococcal disease may occur despite early and effective management.
Differential expression profiling of head and neck squamous cell carcinoma (HNSCC).
Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer in men with an incidence of about 780000 new cases per year worldwide and a poor rate of survival. There is a need for a better understanding of HNSCC, for the development of rational targeted interventions and to define new prognostic or diagnostic markers. To address these needs, we performed a large-scale differential display comparison of hypopharyngeal HNSCCs against histologically normal tissue from the same patients. We have identified 70 genes that exhibit a striking difference in expression between tumours and normal tissues. There is only a limited overlap with other HNSCC gene expression studies that have used other techniques and more heterogeneous tumour samples. Our results provide new insights into the understanding of HNSCC. At the genome level, a series of differentially expressed genes cluster at 12p12-13 and 1q21, two hotspots of genome disruption. The known genes share functional relationships in keratinocyte differentiation, angiogenesis, immunology, detoxification, and cell surface receptors. Of particular interest are the 13 'unknown' genes that exist only in EST, theoretical cDNA and protein databases, or as chromosomal locations. The differentially expressed genes that we have identified are potential new markers and therapeutic targets.
Dentine-lead levels and dental caries in First Nation children from the western James Bay region of northern Ontario, Canada.
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Staphylococcal species in the oral cavity from patients in a regional burns unit.
The aim of this study was to perform a quantitative and qualitative analysis of oral carriage of staphylococci in a range of oral specimens from patients admitted to a regional burns unit. The study recruited 28 patients and reasons for admittance were: burns (46%), skin grafting (39%), lacerations (7%), scalding (4%) and necrotizing fasciitis (4%). No patient had smoke inhalation injuries or trauma to the oro-pharynx. There were five patients from whom methicillin-sensitive S. aureus (MRSA) could be detected in oral specimens. For three patients only the wound and oral specimens were positive for MRSA. In one patient only the oral specimens were positive for MRSA. There were five patients from whom methicillin-sensitive S. aureus (MRSA) could be detected in the oral specimens. In one patient only the oral specimens were positive for MSSA. Staphylococci could be recovered from the dental plaque, denture and toothbrush specimens with a mean count of 1.1 x 10(4)cfu/mL (range 20-5.3 x 10(4)), 5.4 x 10(3) (range 40-2.1 x 10(4)) and 264 cfu/mL (range 20-500), respectively. Both MSSA and MRSA could be recovered from these specimen types. In one patient only the toothbrush was positive for MRSA and all other oral specimens were negative. This study suggests that staphylococci are not infrequent colonizers of the oral cavity, and that this site may serve as a potential reservoir for transmission to other body sites.
Social outcome in early psychosis.
BACKGROUND: It has been demonstrated that patients experiencing their first-episode of psychosis have social functioning deficits that are equivalent to those seen in patients with a more chronic course of illness. The purpose of this study is to examine social functioning over the course of the first year after admission to an early psychosis programme. METHOD: The social functioning of 177 first-episode subjects was assessed on admission and 1 year later and compared with that of 40 non-psychiatric controls. Assessment measures included the Quality of Life Scale (QLS). RESULTS: At the 1-year follow-up there was significant improvement in quality of life. However, even those first-episode patients experiencing a remission from positive symptoms had lower QLS scores than the non-psychiatric controls. CONCLUSIONS: These results are encouraging and supportive of early intervention. There is room for more improvement in the application and development of psychological interventions for these young patients.
Outcome, tolerability and compliance of compassionate use interferon and ribavirin for hepatitis C infection in a shared care hospital clinic.
BACKGROUND AND AIMS: To determine response rate, side-effects and compliance in patients with chronic hepatitis C virus (HCV) infection following treatment with interferon-alpha-2b and ribavirin in a 'shared care' hospital clinic. METHODS: Data were collected prospectively on 81 patients treated with combination therapy for chronic HCV infection between 1999 and 2001. All had biochemical and virological evidence of active infection. All patients had undergone liver biopsy except haemophiliac patients. Patients infected with genotype 1 were treated for 12 months. Patients infected with genotypes 2 and 3 were treated for 6 months. Patient care was shared with the referring general practitioner. Intention to treat, end of treatment and sustained virological response (SVR) rates, side-effects and compliance were assessed. RESULTS: Eighty-one patients with chronic HCV infection were treated with combination therapy. The majority of HCV patients were genotype 1 (n = 46; 57%). There were 12 patients (15%) with cirrhosis. SVR rates were: (i) 24% for genotype 1, (ii) 58% for genotype 3 and (iii) 75% for genotype 2. SVR was achieved in three (23%) cirrhotic patients. Compliance with the treatment regimen was 98%. Seven per cent of patients were withdrawn from therapy prematurely because of side-effects. CONCLUSIONS: These 'shared care' clinic results compare well with controlled clinical trials using combination therapy for chronic HCV infection. Outcomes were poorer in genotype 1 patients and in patients with cirrhosis. Compliance with therapy was excellent because of the 'Shared Care Programme' with participation of general practitioners, psychiatrists and hepatitis C nurse practitioners in the management protocol.
Stop those anti-platelet drugs before surgery!
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Erythema multiforme-like eruption as a result of 'Solaraze' treatment.
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Dexamphetamine treatment in stroke.
Reducing disability and dependency after a stroke is an important clinical objective. We examine what is known about the use of dexamphetamine in patients recovering from an acute stroke, and consider whether further clinical studies should be undertaken. Dexamphetamine has repeatedly been shown to enhance recovery after experimental brain injury in animals, the best effects being seen when dexamphetamine is combined with lesion-specific motor training or sensory stimulation. Postulated mechanisms for these beneficial effects in animals are in keeping with contemporary theories of neurophysiological rehabilitation in man. There have been few clinical studies of dexamphetamine during rehabilitation after an acute stroke. Four controlled trials demonstrated a tendency to an improved outcome when dexamphetamine was paired with therapy and administered 3-30 days after an ischaemic stroke. However, clinical studies to date have been small, included only highly selected patients, and have not addressed possible confounding effects of the drug on mood and untreated depression. Dexamphetamine has previously been used under supervision in medically ill patients and appears to be safe and well-tolerated. There is a need for well-designed studies to assess further the safety and efficacy of dexamphetamine in rehabilitation after stroke.