Biomedical subjects
Publications and source records attributed to J Green.
Alopecia areata is a common disorder with a genetic predisposition where interaction with environmental factors leads to episodes of terminal hair loss. In this review article, we examine the evidence for a genetic basis to this disorder and discuss the prospects for future research into genetic susceptibility areas and the problems that are likely to be encountered in such research.
BACKGROUND: Chronic metabolic acidosis (CMA) adversely affects bone metabolism and skeletal growth. Given the cardinal role played by the local growth hormone (GH)/insulin-like growth factor-I (IGF-I) in promoting cell proliferation and differentiation in growth plates, we tested the effect of CMA on the GH/IGF-I axis in a skeletal growth center. METHODS: We employed an in vitro organ culture system using the murine mandibular condyle as a model for endochondral active growth center. Condyles from six-day-old ICR mice were cultured in BGJb medium of either neutral pH (pH approximately 7.4) or acidic pH (pH approximately 7.15). After 24, 48, 72, and 96 hours of culture, the condyles were washed, fixed in formaldehyde, and processed for paraffin embedding. We assessed histologic markers of the growth center. In addition, the protein level and mRNA expression for the different components of the GH/IGF-I axis were evaluated by immunohistochemistry and in situ hybridization, respectively. Finally, we evaluated the effect of acidosis on the biological functions mediated by GH and IGF-I (namely, proliferation and differentiation of cartilage cells in the active growth center). RESULTS: Following three to four days in acidic conditions, there was a marked reduction in the size of young chondrocytic population, suggesting a defect in the process of endochondral differentiation. Immunohistochemistry and in situ hybridization analyses revealed a marked reduction in the expression of the IGF-I receptor, as well as in the GH receptor. These changes were already evident after 48 hours of incubation in acidic conditions. At 48 hours of acidosis, there was also a marked reduction in the expression of IGF-I both under basal conditions (nonstimulated) and following stimulation with GH. The expression of IGF binding protein 2 (IGFBP-2) and IGFBP-4, which serve as negative modulators of IGF-I, was enhanced in CMA. IGF-I markedly stimulated chondrocytic proliferation (assessed by BrdU incorporation into DNA) and differentiation (assessed as cartilage specific proteoglycan expression). These responses were markedly attenuated in acidic conditions. CONCLUSION: CMA exerts an anti-anabolic effect in bone growth centers, which is partly related to a state of resistance to GH and IGF-I, created by CMA. This phenomenon may underlie the disturbance in longitudinal bone growth in CMA (that is, renal tubular acidosis) and may contribute to renal osteodystrophy in patients suffering from chronic renal failure.
Genetic polymorphism of the carcinogen metabolizing enzyme N-acetyl transferase 2 (NAT2) may influence susceptibility to bladder cancers related to smoking or to occupational exposure to arylamine carcinogens. This article reviews the results of 21 published case-control studies of NAT2 polymorphism and bladder-cancer risk, with a total of 2700 cases and 3426 controls. The published evidence suggests that NAT2 slow acetylator phenotype or genotype may be associated with a small increase in bladder cancer risk. However, given the possibility of selective publication of results from studies that found an excess risk, the current evidence is not sufficient to conclude that there is a real increase in risk. Only five of the 21 studies reported results separately for the effect of NAT2 on bladder cancer risk in smokers and non-smokers. Although the results suggest that the effect may be greater in smokers than in non-smokers, the possibility of publication bias makes these results difficult to interpret. There was insufficient evidence to assess the joint effect of NAT2 and occupational exposure to arylamines on bladder cancer risk. Even if estimates of the effect of NAT2 from published data are correct, studies with around 3000-5000 cases will be needed to confirm them.
We describe a new instrument, using a doll-play vignette completion method, which applies concepts and methodologies from infant and adult attachment research to enable identification and detailed classification of internal representations of attachment relationships in young school-age children. Validation of the Manchester Child Attachment Story Task (MCAST) in a normal population (N = 53) shows good interrater reliability and content validity. Patterns of attachment representation identified show stability over time. Comparisons are made with existing methodologies, and potential applications of the instrument and directions for future research are discussed.
The Manchester Attachment Story Task (MCAST) is a new method for eliciting the internal working model (IWM) of attachment representations in children between 5 and 7 years. The instrument is described in the companion paper, 'A New Method of Evaluating Attachment Representations'. This paper reports initial findings on a non-clinical sample comparing the MCAST with concurrent maternal attachment representation, measures of child temperament and behaviour, and concurrent ratings on the Separation Anxiety Test (SAT). Ratings of disorganized attachment on the MCAST show association with Unresolved status on concurrent maternal Adult Attachment Interview (AAI) and with independent teacher ratings of classroom behaviour. Child temperament shows an effect on the style of engagement with the interview but not the attachment ratings. Possible alternative explanations for the phenomena seen are discussed, along with potential applications of the instrument and directions for future research.
Hereditary nonpolyposis colon cancer (HNPCC) has been shown to be caused by mutations in the mismatch repair genes hMSH2, hMLH1, hPMS1, and hPMS2. Recent evidence has demonstrated that mutations in mismatch repair genes disrupt meiosis in mice. A large HNPCC kindred in Newfoundland, Canada, has an hMSH2 mutation-an A-->T transversion at the +3 position of the splice-donor site of exon 5. We have studied sperm from men with this hMSH2 mutation, since it is possible that mismatch repair mutations in humans might also have an effect on meiosis and normal segregation of chromosomes. The frequencies of aneuploid and diploid sperm were determined in 10 men with the hMSH2 mutation, by use of multicolor FISH analysis for chromosomes 13, 21, X, and Y. A minimum of 10,000 sperm per man was studied per chromosome probe. Control individuals consisted of men in the same kindred with HNPCC who did not carry the mutation and of other normal men from Newfoundland. A total of 321,663 sperm were analyzed: 200,905 sperm were from men carrying the hMSH2 mutation and 120,758 sperm were from control men. There was a significantly increased frequency of disomy 13, disomy 21, XX, and diploidy in mutation carriers compared with control men. These results suggest that the hMSH2 mutation may affect meiosis in humans.
The application of molecular technologies, such as the expression of viral proteins in baculovirus, has provided a powerful approach to the diagnosis of human calicivirus (HuCV) infections. The baculovirus-expressed HuCV capsid protein self-assembles into virus-like particles, providing excellent reagents for immunologic assays, such as enzyme immunoassays (EIAs). Following the expression of the capsid protein of Norwalk virus, the capsid proteins of 8 other HuCV strains have been expressed in baculovirus. The unlimited supply of baculovirus-produced reagents for HuCVs allows these EIAs to be applied in large-scale clinical and epidemiological studies. Both the antigen and antibody-detection EIAs are highly sensitive. The antigen-detection EIAs are highly specific, but the antibody-detection EIAs are more broadly reactive. This article reviews baculovirus expression techniques used to produce HuCV capsid antigens, development of EIAs using these antigens, and application of these EIAs in studies of HuCV infection and illness.
OBJECTIVES: The aim of this study was to describe the psychometric properties of the General Practice Assessment Survey (GPAS) and its acceptability to patients in the UK. GPAS comprises seven multiple item scales and two single item scales addressing nine key areas of primary care activity (access, technical care, communication, inter-personal care, trust, knowledge of patient, nursing care, receptionists and continuity of care). A further four single items relate to patients' perceptions of the GP's role in referral and co-ordination of care, their willingness to recommend their GP and their overall satisfaction with care received. METHODS: Two hundred consecutive patients attending routine consulting sessions at 55 inner London practices were invited to complete the GPAS questionnaire. The acceptability, reliability and validity of GPAS was assessed using standard psychometric techniques. RESULTS: Out of 11 000 patients, 7247 (66%) completed a questionnaire in a GP surgery. Fifty-five out of a separate sample of 77 patients attending one practice completed a second questionnaire mailed to them 1 week following their attendance. GPAS was acceptable to patients as evidenced by low proportions of missing data for all items, and a full range of possible scores for all but one of the nine scales. Reliability of the instrument was good. Multiple item scales had excellent internal consistency, high item-total correlations, and test-retest reliability. Scaling assumptions were confirmed, with six of the seven scales achieving 100% scaling success (convergent and discriminant validity). Construct validity was evident, although this requires further evaluation against external measures. CONCLUSIONS: GPAS is a useful instrument for assessing several important dimensions of primary care. It is acceptable, reliable and valid, and has the potential for versatility in mode of administration. It will be a useful instrument for practices, primary care groups and primary care researchers evaluating key areas of primary care activity. Further work is required to evaluate its performance in non-inner-city settings and to evaluate further its validity against external criteria.
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The G and P types of 2,912 rotavirus-positive fecal specimens collected from eight geographical areas of the United Kingdom between 1995 and 1998 were determined by reverse transcription-PCR. Although 15 different G-P combinations were identified, G1P[8], G2P[4], G3P[8], and G4P[8] strains constituted 95% of all the rotaviruses typed. Other genotypes included G9P[6] and G9P[8], which were first identified in the United Kingdom in 1995, or other uncommon G and/or P types of strains that may have had an animal origin. Unusual combinations of G1 or G4 with P[4] and G2 with P[8] which may have arisen by reassortment between human strains were also identified. G1P[8] was the genotype most frequently found (57 to 87%) in each season, followed by G2P[4] in the 1995-1996 (18%) and 1997-1998 (16%) seasons, although the incidence of infection with this virus decreased significantly to 2% during the 1996-1997 season. Significant differences were seen in the distributions of G1P[8], G2P[4], and G9P[8] strains between children and adults, in the temporal distributions of G4P[8] and G9P[8] strains within a season, and in the geographical distributions of each of the four most common genotypes from one season to the next.
A degenerate version (1T1-D) of the rotavirus P[8]-specific primer (1T-1) allowed strains previously untypeable due to the accumulation of point mutations at the primer binding site to be P typed by reverse transcription-PCR. Sequencing of the cDNA followed by sequence alignment and phylogenetic analysis identified lineages and sublineages within the rotavirus P[8] types, while the use of 1T-1 or 1T-1D primers did not yield viral clusters in any particular lineage.
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OBJECTIVE: To investigate whether the Australian National Sub-acute and Non-acute Patient Casemix Classification (SNAP) and Functional Independence Measure and Functional Related Group (Version 2) (FIM-FRG2) casemix systems can be used to predict functional outcome, and reduce the variance of length of stay (LOS) of patients undergoing rehabilitation after strokes. DESIGN AND SETTING: The study comprised a retrospective analysis of the records of patients admitted to the Cedar Court Healthsouth Rehabilitation Hospital for rehabilitation after stroke. SUBJECTS: The sample included 547 patients (83.3% of those admitted with stroke during this period). Patient data were stratified for analysis into the five SNAP or nine FIM-FRG2 groups, on the basis of the admission FIM scores and age. MAIN OUTCOMES: The AN-SNAP classification accounted for a 30.7% reduction of the variance of LOS, and 44.2% of motor FIM, and the FIM-FRG2 accounts for 33.5% and 56.4% reduction respectively. Comparison of the Cedar Court with the national AN-SNAP data showed differences in the LOS and functional outcomes of older, severely disabled patients. Intensive rehabilitation in selected patients of this type appears to have positive effects, albeit with a slightly longer period of inpatient rehabilitation. CONCLUSIONS: Casemix classifications can be powerful management tools. Although FIM-FRG2 accounts for more reduction in variance than SNAP, division into nine groups meant that some contained few subjects. This paper supports the introduction of AN-SNAP as the standard casemix tool for rehabilitation in Australia, which will hopefully lead to rational, adequate funding of the rehabilitation phase of care.
The Runt related transcription factors RUNX (AML/CBF(alpha)/PEBP2(alpha)) are key regulators of hematopoiesis and osteogenesis. Using co-transfection experiments with four natural promoters, including those of the osteocalcin (OC), multi drug resistance (MDR), Rous Sarcoma Virus long terminal repeat (LTR), and bone sialoprotein (BSP) genes, we show that each of these promoters responds differently to the forced expression of RUNX proteins. However, the three RUNX subtypes (i.e. AML1, AML2, and AML3) regulate each promoter in a similar manner. Although the OC promoter is activated in a C terminus dependent manner, the MDR, LTR and BSP promoters are repressed by three distinct mechanisms, either independent of or involving the AML C terminus, or requiring only the conserved C-terminal pentapeptide VWRPY. Using yeast two hybrid assays we find that the C terminus of AML1 interacts with a Groucho/TLE/R-esp repressor protein. Co-expression assays reveal that TLE proteins repress AML dependent activation of OC gene transcription. Western and northern blot analyses suggest that TLE expression is regulated reciprocally with the levels of OC gene expression during osteoblast differentiation. Digital immunofluorescence microscopy results show that TLE1 and TLE2 are both associated with the nuclear matrix, and that a significant subset of each colocalizes with AML transcription factors. This co-localization of TLE and AML proteins is lost upon removing the C terminus of AML family members. Our findings indicate that suppression of AML-dependent gene activation by TLE proteins involves functional interactions with the C terminus of AML at the nuclear matrix in situ. Our data are consistent with the concept that the C termini of AML proteins support activation or repression of cell-type specific genes depending on the regulatory organization of the target promoter and subnuclear localization.
We aimed to identify determinants of condom usage and unsafe sex in women having sex with a new partner. One hundred women attending either a genitourinary medicine (GUM) clinic or a family planning clinic participated in the study. Respondents were interviewed about last 3 new male partners, from the beginning of the sexual relationship through its development, if any. Data analysis was primarily qualitative, quantitative analysis was conducted where appropriate. Alternative contraceptive use was the most commonly reported determinant of condom usage overall. The most commonly reported determinant of condom use for prophylaxis was the woman's perception of her partner and the risks he presented. Models of risky sexual behaviour have focused on the individual's generalized estimation of risks of acquiring STDs. Existing models are poor predictors of risky sexual behaviour. We propose that it is the perceived risk presented by a particular individual partner, not global risk, which influences behaviour. An individual risk model is put forward.
BACKGROUND: Since the introduction of prostate-specific antigen (PSA) screening for the detection of prostatic adenocarcinoma (PCA), there has been an increase in the incidence of stage T1c PCA. The purpose of this study was to compare the frequency of incidental PCA found in transurethral resection of prostate (TURP) specimens for a 14-month period during 1989-1990 (before PSA screening was available) with the incidence of PCA for a 32-month period during 1997-1999 (after PSA screening became available). DESIGN: Consecutive TURP specimens from the 2 time periods were reviewed to identify incidental PCA, prostatic intraepithelial neoplasia (PIN), and atypical adenomatous hyperplasia (AAH). Cases of TURP for palliative treatment of known advanced PCA were excluded from the study. All TURP specimens were fixed in 10% buffered formalin and were processed according to the same protocol. RESULTS: We reviewed 533 and 449 TURP specimens for the time periods 1989-1990 and 1997-1999, respectively. Comparison of the results for these 2 time periods revealed that the combined prevalence of T1a and T1b PCA decreased over time from 12.9% to 8.0% (P =.06) with the introduction of PSA screening. A new group of T1c PCA was established in the post-PSA screening period of 1997-1999. There were no statistically significant differences in the incidences of T1a PCA, PIN, and AAH in TURP specimens for the 2 time periods. CONCLUSION: The decreased incidence of T1b PCA in TURP specimens for the 1997-1999 period represents a shift in PCA staging. Some PCAs previously staged as T1b are now staged as T2 carcinomas, as a result of PSA screening and earlier clinical detection. The introduction of PSA screening has had no influence on the incidence of T1a PCA, PIN, or AAH in TURP specimens.
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A 63-year-old man presented to our department with dyspnea and peripheral edema. A cystic mass in the right upper abdomen, consistent with echinococcal disease was discovered. Proteinuria was also present, and a nephrotic syndrome was diagnosed. The kidney biopsy revealed minimal change glomerulonephritis. Treatment with the antiechinococcal drug albendazole induced complete remission of the nephrotic syndrome, suggesting an etiopathogenic role for a hydatid antigen in the development of an immune-mediated glomerulonephritis.