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A Mann

Publications and source records attributed to A Mann.

At least 37 records · Page 2Linked to original sources
PubMed2001

New auxiliaries for copper-catalyzed asymmetric Michael reactions: generation of quaternary stereocenters at room temperature.

Dialkyl amides of L-valine, L-isoleucine, and L-tert-leucine (2) are excellent chiral auxiliaries for the construction of quaternary stereocenters at ambient temperature. Enaminoesters 3, prepared from these auxiliaries 2 and Michael donors 1, undergo a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone (MVK, 4) to afford products 5 in 70-90% yield and 90-99% ee (enantiomeric excess). The exclusion of moisture or oxygen is not necessary. The auxiliaries 2 are readily available by standard procedures. After workup they can be recovered almost quantitatively.

Journal Article↗
PubMed2001

Up- and down-regulation of granulocyte/macrophage-colony stimulating factor activity in murine skin increase susceptibility to skin carcinogenesis by independent mechanisms.

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in tumorigenesis is complex. On the one hand, GM-CSF can promote tumor cell growth, survival, and even metastasis. On the other hand, it can stimulate tumor cell rejection. In skin, it is early expressed after topic application of tumor-promoting agents and therefore may be responsible for changes that correlate with skin tumor promotion (e.g., epidermal hyperproliferation and inflammation). To analyze GM-CSF function in skin tumorigenesis, we generated transgenic mice epidermally overexpressing either GM-CSF or a GM-CSF antagonist. Both types of transgenic mice exhibited significantly increased numbers of benign tumors in a two-step skin carcinogenesis experiment using 7',12'-dimethylbenz[a]anthracene (DMBA) as initiator and 12-O-tetradecanoylphorbol-CSF displayed a significantly elevated carcinoma burden following a single-step carcinogenesis protocol consisting of tumor initiation only. Therefore, endogenous promotion is responsible for elevated tumor development in GM-CSF-overexpressing mice. In antagonist transgenic animals, an increased tumorigenicity of modified B16 tumor cells after cutaneous transplantation as compared with nontransgenic or GM-CSF transgenic mice was observed. Thus, the antitumor activity leading to the repression of tumor cell growth in control mice is GM-CSF dependent and is compromised in mice expressing the antagonist. We suggest that both, up-regulation and down-regulation of GM-CSF activity in skin, increase the incidence and growth of tumors via two independent mechanisms: endogenous tumor promotion in the case of increased GM-CSF activity and compromised tumor cell rejection in the case of decreased GM-CSF activity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

The designer cytokine hyper-IL-6 mediates growth inhibition and GM-CSF-dependent rejection of B16 melanoma cells.

The low immunogenic B16 melanoma cell line was transfected with a mammalian expression vector containing the complementary DNA for a sIL-6R/IL-6 fusion protein, termed Hyper-IL-6 (H-IL-6), which was shown to have biological activities at 100-1000-fold lower concentrations than IL-6 in combination with sIL-6R. The secreted p84 glycoprotein was detected in the supernatant of transfected cells and was fully active on BAF3/gp130 cells, which respond to IL-6/sIL-6R but not to IL-6 alone. Administration of recombinant H-IL-6 to C57BL/6 mice resulted in a prolonged acute phase protein gene expression indicating long systemic persistence of the fusion protein. Transfected B16 cells (B16/H-IL6 cells) showed morphological alterations in combination with a dramatic growth inhibition in vitro. Subcutaneous injection in C57BL/6 mice resulted in an almost complete rejection of B16/H-IL6 cells. This effect was partially abolished in FVB/BL/6 mice transgenic for a GM-CSF receptor antagonist, indicating a GM-CSF-dependent rejection of H-IL-6 transfected B16 cells. These results demonstrate that the anti-tumor effect of cytokines like IL-6 which are secreted by transfected melanoma cells at least in part depends on GM-CSF activity.

Animals↗
PubMed2001

Thermal sterilization of heat-sensitive products using high-temperature short-time sterilization.

High-temperature short-time (HTST) sterilization with a continuous-flow sterilizer, developed for this study, was evaluated. The evaluation was performed with respect to (a) the chemical degradation of two heat-sensitive drugs in HTST range (140-160 degrees C) and (b) the microbiological effect of HTST sterilization. Degradation kinetics of two heat-sensitive drugs showed that a high peak temperature sterilization process resulted in less chemical degradation for the same microbiological effect than a low peak temperature process. Both drugs investigated could be sterilized with acceptable degradation at HTST conditions. For the evaluation of the microbiological effect, Bacillus stearothermophilus ATCC 7953 spores were used as indicator bacteria. Indicator spore kinetics (D(T), z value, k, and E(a)), were determined in the HTST range. A comparison between the Bigelow model (z value concept) and the Arrhenius model, used to describe the temperature coefficient of the microbial inactivation, demonstrated that the Bigelow model is more accurate in prediction of D(T) values in the HTST range. The temperature coefficient decreased with increasing temperature. The influence of Ca(2+) ions and pH value on the heat resistance of the indicator spores, which is known under typical sterilization conditions, did not change under HTST conditions.

Geobacillus stearothermophilus↗
PubMed2001

Cognitive function in UK community-dwelling African Caribbean elders: normative data for a test battery.

Many 'first generation' African Caribbean residents in the UK have now reached ages where risk of cognitive impairment and dementia starts to increase. In addition, conditions which may impair cognitive function, such as hypertension, diabetes and stroke, have high prevalence rates in African Caribbean populations. However, there is a lack of normative data for cognitive tests in this ethnic group. Cognitive assessment was carried out in a south London community population of 285 African Caribbean participants aged 55-75 years. Tests were drawn principally from the consortium to establish a registry for Alzheimer's disease (CERAD) battery (Boston Naming Test, verbal fluency, word list recall, and Trailmaking Tests A and B) and also included orientation items from the Mini-Mental State Examination (MMSE) and the Clock Drawing Test. Independent effects of age, sex, education and occupation were identified on scores for most but not all cognitive tests. Compared with normative data for African American populations, lower scores on verbal fluency and the Boston Naming Test were observed but scores on memory tests were comparable. Normative data for the tests are presented, stratified by level of education.

Aged↗
PubMed2001

Life events and depression in a community sample of siblings.

BACKGROUND: The overall aim of the GENESiS project is to identify quantitative trait loci (QTLs) for anxiety/depression, and to examine the interaction between these loci and psychosocial adversity. Here we present life-events data with the aim of clarifying: (i) the aetiology of life events as inferred from sibling correlations; (ii) the relationship between life events and measures of anxiety and depression, as well as neuroticism; and (iii) the interaction between life events and neuroticism on anxiety/depression indices. METHODS: We assessed the occurrence of one network and three personal life-event categories and multiple indices of anxiety/depression including General Health Questionnaire, Anhedonic Depression, Anxious Arousal and Neuroticism in a large community-based sample of2150 sib pairs, 410 trios and 81 quads. Liability threshold models and raw ordinal maximum likelihood were used to estimate within-individual and between-sibling correlations of life events. The relationship between life events and indices of emotional states and personality were assessed by multiple linear regression and canonical correlations. RESULTS: Life events showed sibling correlations of 0-37 for network events and between 0-10 and 0.19 for personal events. Adverse life events were related to anxiety and depression and, to a less extent, neuroticism. Trait-vulnerability (as indexed by co-sib's neuroticism, anxiety and depression) accounted for 11% and life events for 3% of the variance in emotional states. There were no interaction effects. CONCLUSIONS: Life events show moderate familiality and are significantly related to symptoms of anxiety and depression in the community. Appropriate modelling of life events in linkage and association analyses should help to identify QTLs for depression and anxiety.

Adult↗
PubMed2001

The impact of personality disorder in UK primary care: a 1-year follow-up of attenders.

BACKGROUND: The usefulness of the concept of personality disorder has not been properly tested outside psychiatric services. We set out to examine this in primary care, by examining the ability of the diagnosis to predict health status and patterns of service use. METHOD: A cohort of consecutive attenders, who had previously been rated for the presence of personality disorder using a standardized assessment, was followed-up at 1 year. The participating general practitioners also rated the personalities of, and their attitudes towards, a proportion of this sample of attenders. RESULTS: After adjusting for the effects of all covariates, a rating of personality disorder (generated by the standardized assessment) was associated with frequent attendance to general practice and fewer referrals to secondary care. A GP rating of personality disorder was associated with the prescription of psychotropic medication. The level of agreement between a GP rating of personality disorder and the standardized assessment was poor. GPs rated personality disorder more frequently in participants who were perceived to be less compliant, less likeable and more stressful to deal with. Participants with a psychiatric rating of personality disorder did not attract these negative perceptions. CONCLUSIONS: Personality disorder, as rated by a research interview, is a predictor of health service usage. There is a significant disparity between a research rating of personality disorder and the diagnostic ratings made by GPs. The GP ratings of personality disorder were strongly associated with adverse perceptions of the patient's consulting behaviour.

Adult↗
PubMed2001

Correlation between c-erbB-4 receptor expression and response to gemcitabine-cisplatin chemotherapy in non-small-cell lung cancer.

BACKGROUND: While the overexpression of c-erbB gene family in several malignancies is associated with poorer prognosis, the association between the expression of the cellular markers and the response to chemotherapy is not yet clear. In this study we investigated the expression of c-erbB-4 receptor in NSCLC and correlated it with the response to gemcitabine-cisplatin combination chemotherapy. PATIENTS AND METHODS: Forty-three NSCLC patients with histologically or cytologically proven disease were treated with gemcitabine-cisplatin combination chemotherapy. Immunohistochemical stains for c-erbB-4 receptor were performed in 20 cases on paraffin sections using the avidin-biotin-peroxidase method. RESULTS: Two patients achieved complete response (5%), and 16 achieved partial response (37%) yielding an overall objective response rate of 42%. Minimal response was observed in seven patients (16%) and disease stabilization in 7%. Immunohistochemical stain was positive for the presence of c-erbB-4 receptor in 25% of patients, and negative in 75%. No response was documented in c-erbB-4 positive patients (0 of 5) while an objective response (complete, partial or minimal) was seen in 11 of 15 (73%) c-erbB-4 negative patients. Negative stain for c-erbB-4 significantly favored response to gemcitabine-cisplatin combination (P < 0.01). CONCLUSION: C-erbB-4 expression status showed no correlation with survival and cannot be accepted at this time as a guiding factor for therapeutic management. These interesting results deserve further evaluation in a large-scale prospective trial before treatment recommendations on the basis of c-erbB-4 presence can be finally made.

Adult↗
PubMed2001

Keratinocyte-derived granulocyte-macrophage colony stimulating factor accelerates wound healing: Stimulation of keratinocyte proliferation, granulation tissue formation, and vascularization.

Chronic, nonhealing wounds represent a major clinical challenge to practically all disciplines in modern medicine including dermatology, oncology, surgery, and hematology. In skin wounds, granulocyte-macrophage colony stimulating factor (GM-CSF) is secreted by keratinocytes shortly after injury and mediates epidermal cell proliferation in an autocrine manner. Many other cells involved in wound healing including macrophages, lymphocytes, fibroblasts, endothelial cells, and dendritic cells synthesize GM-CSF and/or are targets of this cytokine. Therefore, GM-CSF is a pleiotropic cytokine evoking complex processes during wound repair. Despite this complexity and the scarcity of mechanistic understanding GM-CSF has been employed in trials of clinical treatment of skin wounds with some success. In this study, we evaluated a transgenic mouse model in order to analyze the effects of an excess of keratinocyte-derived GM-CSF on excisional wound healing in the skin. Transgenic mice constitutively overexpressing GM-CSF in the basal layer of the epidermis displayed accelerated reepithelialization of full-thickness skin wounds. In the early stages of wound repair, transgenic mice exhibited significantly higher numbers of proliferating keratinocytes at the wound edges and increased formation of granulation tissue with enhanced neovascularization. As a potential mechanism of these beneficial changes, we identified the differential temporal regulation of cytokines such as transforming growth factor-beta, a known angiogenetic factor, interferon-gamma, a proinflammatory cytokine, and interleukin 6, an essential factor for reepithelialization, in transgenic mice versus controls. We propose that the beneficial effects observed in GM-CSF transgenics are due not only to direct GM-CSF action but in addition to indirect processes via the induction of secondary cytokines.

Animals↗
PubMed2001

Vascular risk and cognitive impairment in an older, British, African-Caribbean population.

OBJECTIVES: In an older, British, African-Caribbean population with high prevalence rates of hypertension and diabetes mellitus, we ascertained clinical vascular disease (stroke or ischemic heart disease) and vascular risk (including hypertension, diabetes, and lipid profile) and investigated their associations with cognitive impairment. DESIGN: Cross-sectional community-based study. SETTING: The sample was drawn from registration lists for seven primary care services in south London, United Kingdom. PARTICIPANTS: 278 individuals, age 55 to 75, who were born in a Caribbean nation. MEASUREMENTS: Participants were interviewed and examined for cardiovascular risk factors, including a blood test for lipid profile and fibrinogen. A battery of 11 psychometric tests was administered blind to medical status. Cognitive impairment was defined on the basis of a composite measure derived from individual test scores. RESULTS: Seventy-nine (28%) subjects were classified as having relative cognitive impairment and were compared with the remainder of the sample. Marked differences were seen between low and normal/high educational levels in the strength of associations between measures of vascular risk and cognitive impairment. Hypertension, diabetes, and raised triglycerides were significant factors in those with lower levels of education. Low fibrinogen (negatively associated), high cholesterol, and manual occupation were significant factors in those with normal/high levels of education. Physical exercise was negatively associated with cognitive impairment: an association that persisted after adjustment for age, occupation, depression, and physical disability and after excluding subjects with the most severe imipairment. CONCLUSION: Measures of vascular risk were associated with relative cognitive impairment in this population. These associations were modified by previous educational attainment. Physical activity was negatively associated with cognitive impairment.

Black or African American↗
PubMed2001

Stroke, vascular risk factors and depression: Cross-sectional study in a UK Caribbean-born population.

BACKGROUND: Stroke, hypertension and diabetes are common in older Caribbean-born populations in the UK who may be at risk of depression secondary to vascular disease. AIMS: We examined the association between stroke, vascular risk factors and depression in a community-based Caribbean-born population aged 55-75 years. METHOD: Vascular risk factors were identified by interview, examination and blood tests. Depression was categorised using the Geriatric Depression Scale. Disablement was assessed as a potential mediating factor. RESULTS: Physical illness and disablement were strongly associated with depression, independent of disablement. Previous stroke was associated with depression, independent of disablement. No vascular risk factors were associated with depression. CONCLUSIONS: The risk of depression associated with stroke was not explained by disablement. However, the hypothesis that vascular risk factors are important in the genesis of depression was not supported.

Age Distribution↗
PubMed2001

Depression, APOE genotype and subjective memory impairment: a cross-sectional study in an African-Caribbean population.

BACKGROUND: Subjective memory impairment (SMI) is common in older populations but its aetiology and clinical significance is uncertain. Depression has been reported to be strongly associated with SMI. Associations with objective cognitive impairment are less clear cut. Other factors suggested to be associated with SMI include poor physical health and the apolipoprotein E (APOE) epsilon4 allele. Studies of SMI have been predominantly confined to white Caucasian populations. METHOD: A community study was carried out in a UK African-Caribbean population aged 55-75, sampled from primary care lists. Twenty-three per cent were classified with SMI. Depression was defined using the 10-item Geriatric Depression Scale. Other aetiological factors investigated were education, objective cognitive function, APOE genotype, disablement and vascular disease/risk. The principal analysis was restricted to 243 participants scoring > 20 on the Mini-Mental State Examination (85%). A second analysis included all 290 participants. RESULTS: Depression, self-reported physical impairment and APOE epsilon4 were associated with SMI. The association between SMI and physical impairment was not explained by depression, vascular disease/risk, or disability/handicap. The association between epsilon4 and SMI increased as MMSE scores decreased and was particularly strong in those with depression. The epsilon4 allele was present in 69% (95% CI 41-89%) of those with depression and SMI compared with 28% (20-36%) of those with neither. CONCLUSIONS: Depression may not be a sufficient explanation for subjective memory complaints. Memory complaints in the presence of depression are associated with high prevalence of epsilon4 and therefore, presumably, a raised risk of subsequent dementia.

Aged↗
PubMed2000

Comparison of electrocardiographic-gated technetium-99m sestamibi single-photon emission computed tomographic imaging and rest-redistribution thallium-201 in the prediction of myocardial viability.

Although the combined assessment of perfusion and function using rest electrocardiographic (ECG)-gated technetium-99m (Tc-99m) sestamibi single-photon emission computed tomographic (SPECT) imaging has been shown to improve sensitivity and accuracy over perfusion alone in the prediction of myocardial viability, no data are available comparing this technique with rest-redistribution thallium-201. Thirty patients with coronary artery disease and left ventricular dysfunction (ejection fraction < or = 40%) underwent rest-redistribution thallium-201 and rest ECG-gated Tc-99m sestamibi SPECT imaging before revascularization and rest ECG-gated Tc-99m sestamibi SPECT imaging at 1 or 6 weeks after revascularization. All thallium-201 and Tc-99m sestamibi images were interpreted by a consensus agreement of 3 experienced readers without knowledge of patient identity or time of imaging with Tc-99m sestamibi (before or after revascularization) using a 17-segment model. Concordance between techniques for the prediction of viability was 89% (kappa 0.556 +/- 0.109). With rest-redistribution thallium-201, sensitivity, specificity, positive predictive value, negative predictive value, and predictive accuracy were 95%, 59%, 88%, 78%, and 86%, respectively. With rest ECG-gated Tc-99m sestamibi SPECT imaging, sensitivity, specificity, positive predictive value, negative predictive value, and predictive accuracy were 96%, 55%, 87%, 80%, and 86%, respectively (p = NS vs rest-redistribution thallium-201). Although both techniques are comparable for detecting viable myocardium, rest ECG-gated Tc-99m sestamibi SPECT imaging allows direct assessment of both myocardial perfusion and ventricular function, which may be clinically useful in patients who require assessment of myocardial viability.

Coronary Disease↗
PubMed2000

The association between APOE and dementia does not seem to be mediated by vascular factors.

OBJECTIVE: The effect of APOE on dementia may be mediated through dyslipidemia and atherogenesis through its effect on cholesterol metabolism. The authors investigated this possibility among aged survivors from the UK Medical Research Council Trial of the Treatment of Hypertension in Older Adults. DESIGN: A total of 370 of 657 survivors from an initial cohort of 1,088 recruited into the trial between 1983 and 1985 were traced in 1994 and agreed to be screened for dementia. Blood samples were analyzed for APOE genotype and serum fibrinogen. Cholesterol level, smoking behavior, blood pressure, body mass index, and EKG recordings had been measured at recruitment 10 to 12 years earlier. Odds ratios (ORs) for the association between APOE epsilon4/* and both AD and dementia were estimated and adjusted incrementally for the effect of age and premorbid intelligence, cholesterol, other risk factors for vascular disease, and EKG evidence of cardiovascular disease. RESULTS: The authors diagnosed 24 cases of National Institute of Neurological and Communicative Disorders and Stroke AD from 41 cases of dementia. The crude OR for the association between APOE epsilon4/* and AD was 3.40 (95% CI 1.30 to 8.91). APOE genotype was associated with serum cholesterol level, and there was a nonsignificant trend for an association with smoking behavior. After adjusting for these and all other vascular risk factors and vascular disease variables listed earlier, the OR for the association between APOE epsilon4/* and AD increased to 4.81 (1.60 to 14.4). CONCLUSION: Presence of APOE epsilon4/* seems to increase the risk for dementia and AD independently of its effect on dyslipidemia and atherogenesis.

Aged↗
PubMed2000

A pilot study of sibling resemblance in later life.

OBJECTIVE: Behavioural genetic studies of later life are strictly limited. We carried out a community-based pilot study of sibling resemblance with the primary aims of establishing the feasibility of such work in this population and estimating genetic influence on depression and its risk factors. METHODOLOGY: Data were collected on surviving siblings of individuals interviewed in previous phases of an epidemiological study of the elderly (the Gospel Oak survey); scales relevant to the investigation of late life depression and its risk factors were utilized. Since families tend to be geographically scattered, the interview was conducted by telephone. Comparisons were made between data relating to the siblings and those obtained on the probands. Variability in phenotypic traits and environmental measures was partitioned into between- and within-family variation, in order to distinguish familial and non-familial sources of variation. Intraclass correlations were used to estimate the strength of genetic influences on continuous measures, while pairwise concordances were calculated for dichotomous traits. RESULTS: Thirty-two siblings from 20 families were ultimately identified and interviewed. Intraclass correlations for the Depression and Dementia Diagnostic Scales and the Handicap Scale were 0, 0.27 and 0.22, respectively. Those for number of life events, number of friends in contact and number of neighbours in contact were 0.08, 0.03 and 0, respectively. Concordance for both depression caseness and dementia caseness was 0. DISCUSSION: There were difficulties carrying out this study, which are discussed. The study is the first of its kind to examine familial resemblance for the common disorders of old age. Establishing ways of engaging elderly families with research will be a challenge that future research will need to meet.

Aged↗
PubMed2000

Does depression predict cognitive outcome 9 to 12 years later? Evidence from a prospective study of elderly hypertensives.

BACKGROUND: Previous longitudinal studies of the association between depression and cognitive dysfunction have had relatively short follow-up periods. This report presents a long-term study of the association between baseline syndromal depression and cognitive outcome measured 9 to 12 years later. METHODS: Self-CARE (D) depression, cognitive function and pre-morbid intelligence were recorded on 1083 subjects on entry to the Medical Research Council trial of treatment of hypertension in older adults in 1983-5. In 1994-5, we aimed to re-interview all survivors to assess cognitive function using the MMSE. We used multivariate analysis to explore whether baseline depression predicted cognitive outcome after this long follow-up period. RESULTS: Baseline depression was crudely associated with poorer cognitive outcome at time 2. However, this long-term prospective association was no longer apparent after adjusting for baseline cognitive performance, which was associated with baseline depression and robustly predicted cognitive outcome at time 2. We found that gender modified the association between depression and poorer cognitive outcome, so that the association was statistically significant only among men. CONCLUSION: Propensity for depression and failing cognition may have common determinants that still need to be established by future neurobiological investigations in conjunction with further long-term prospective epidemiological research.

Aged↗