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Biomedical subjects

S Frankel

Publications and source records attributed to S Frankel.

At least 73 records · Page 4Linked to original sources
PubMed1996

Birthweight, body-mass index in middle age, and incident coronary heart disease.

BACKGROUND: Several studies have shown a relation between fetal development, as shown by birthweight, and later coronary heart disease. This study investigated whether this relation is predominantly the consequence of early life exposures, or can best be explained in terms of an interaction between influences in early life and in adulthood. METHODS: This prospective study in Caerphilly, South Wales, included 1258 men, aged 45-59 at initial screening, who were able to provide birthweight data. These men are from an initial cohort of 2512 men, from whom information has been obtained in a series of examinations since 1979 on health-related behaviours, incidence of coronary heart disease, and risk factors. The main outcome measure was fatal and non-fatal coronary heart disease during 10 years of follow-up. FINDINGS: Higher birthweight was related to lower risk of coronary heart disease during the follow-up period: coronary heart disease occurred in 46 (11.6%) men in the lowest birthweight tertile, 44 (12.0%) of those in the middle tertile, and 38 (9.1%) of those in the highest tertile (p = 0.03). Stratification of the cohort by body-mass index (BMI) revealed a significant interaction such that the inverse association between birthweight and risk of coronary heart disease was restricted to men in the top tertile of BMI (interaction test p = 0.048 adjusted for age, and p = 0.012 fully adjusted). Within the top BMI tertile, coronary heart disease occurred in 19 (16.4%) of men in the lowest birthweight tertile, 13 (12.6%) of those in the middle tertile, and 13 (7.5%) of those in the highest tertile (p = 0.0005). These associations were not changed substantially by adjustment for age, father's social class, own social class, marital status, fibrinogen and cholesterol concentrations, systolic blood pressure, and smoking history. INTERPRETATION: The association between birthweight and risk of coronary heart disease cannot be explained by associations with childhood or adulthood socioeconomic status. Nor do conventional risk factors for coronary heart disease in adulthood account for the association. However, there is an important interaction between birthweight and BMI such that the increased risk of coronary heart disease associated with low birthweight is restricted to people who have high BMI in adulthood. Risk of coronary heart disease seems to be defined by the combined effect of early-life and later-life exposures.

Birth Weight↗
PubMed1996

Deprivation and cause specific morbidity: evidence from the Somerset and Avon survey of health.

OBJECTIVE: To investigate the association between cause specific morbidity and deprivation in order to inform the debates on inequalities in health and health services resource allocation. DESIGN: Cross sectional postal questionnaire survey ascertaining self reported health status, with validation of a 20% sample through general practitioner and hospital records. SETTING: Inner city, urban, and rural areas of Avon and Somerset. SUBJECTS: Stratified random sample of 28,080 people aged 35 and over from 40 general practices. MAIN OUTCOME MEASURES: Age and sex standardised prevalence of various diseases; Townsend deprivation scores were assigned by linking postcodes to enumeration districts. Relative indices of inequality were calculated to estimate the magnitude of the association between socioeconomic position and morbidity. RESULTS: The response rate was 85.3%. The prevalence of most of the conditions rose with increasing material deprivation. The relative index of inequalilty, for both sexes combined, was greater than 1 for all conditions except diabetes. The conditions most strongly associated with deprivation were diabetic eye disease (relative index of inequality 3.21; 95% confidence interval 1.84 to 5.59), emphysema (2.72; 1.67 to 4.43) and bronchitis (2.27; 1.92 to 2.68). The relative index of inequality was significantly higher in women for asthma (P < 0.05) and in men for depression (P < 0.01). The mean reporting of prevalent conditions was 1.07 for the most deprived fifth of respondents and 0.77 in the most affluent fifth (P < 0.001). CONCLUSIONS: Material deprivation is strongly linked with many common diseases. NHS resource allocation should be modified to reflect such morbidity differentials.

Adult↗
PubMed1996

Alternatives to hospital care: what are they and who should decide?

OBJECTIVE: To examine potential for alternatives to care in hospitals for acute admissions, and to compare the decisions about these alternatives made by clinicians with different backgrounds. DESIGN: Standardised tool was used to identify patients who could potentially be treated in an alternative form of care. Information about such patients was assessed by three panels of clinicians: general practitioners without experience of general practitioner beds, general practitioners with experience of general practitioner beds, and consultants. SETTING: One hospital for acute admissions in a rural area of the South and West region of England. SUBJECTS: Of 620 patients admitted to specialties of general medicine and care of the elderly, details of 112 were assessed by panels. MAIN OUTCOME MEASURES: Proportion of hospitalised patients who could have received alternative care and identification of most appropriate alternative form of care. RESULTS: Both general practitioner panels estimated that between 51 and 89 of the hospitalised patients could have received alternative care (equivalent to 8-14% of all admissions). Consultants estimated that between 25 and 55 patients could have had alternative care (5.5-9% of all admissions). General practitioner bed and urgent outpatient appointment were the main alternatives chosen by all three panels. CONCLUSION: About 10% of admissions to general hospital might be suitable for alternative forms of care. Doctors with different backgrounds made similar overall assessments of most appropriate forms of care.

Acute Disease↗
PubMed1996

Lifecourse exposure and later disease: a follow-up study based on a survey of family diet and health in pre-war Britain (1937-1939).

There is an increasing interest in the origins of adult disease in early life. The elucidation of such explanations of current morbidity and mortality must depend upon the follow-up of previously established cohorts. This paper describes the design of and background to such a follow-up of one of the richest data sources for this type of research: Sir John Boyd Orr's survey of diet and health in pre-war Britain. 1,352 families from 16 centres in England and Scotland were surveyed; 3,762 children aged up to 19 years from these families were examined. Socio-economic information and detailed one week dietary diary records are available for all families. Detailed medical examinations (including anthropometry) were undertaken on children in 14 of the centres. Most of the information is cross-sectional although 1,322 children were examined on two or more occasions one year apart to assess the effects of dietary supplementation. Dietary records were retrieved for 1,343 (99.3%) of the families. Medical examination records were found for 3,560 (94.6%) of the children who were examined in the survey and attempts have been made to trace 4,973 children who were either examined or whose family participated in the dietary survey. The data demonstrate relationships between family food expenditure and height in childhood and housing conditions. Eighty-five per cent (4211/4973) of the children have been traced and flagged on the National Health Service Central Register, Southport. The characteristics of those traced do not differ significantly from those we have been unable to trace although untraced females were slightly heavier. To date 696 (16.5%) of the cohort have died. The cohort will be used to investigate the relationship between diet, nutritional status (height, weight, cristal height), health and social circumstances in childhood, and mortality and morbidity in adulthood.

Adolescent↗
PubMed1996

Birthweight, adult risk factors and incident coronary heart disease: the Caerphilly Study.

OBJECTIVE: To determine the relationships between birthweight, the incidence of coronary heart disease, and a range of coronary heart disease risk factors that operate during adult life. DESIGN: Cohort study with a 10-year follow-up period. SETTING: The town of Caerphilly, South Wales, and five adjacent villages. SUBJECTS: 1,258 men aged 45-59 at time of recruitment between 1979 and 1983. MAIN OUTCOME MEASURES: All deaths, coronary heart disease deaths, non-fatal CHD events. RESULTS: The validity of the birthweight data was supported by the strong graded associations between birthweight and anthropometric measures in adulthood, particularly height, body mass index, triceps, skinfold thickness and percentage body fat. An inverse relationship was found between birthweight and incident fatal and non-fatal CHD, (P = 0.01), though no relationship was found between birthweight and all-cause mortality. Amongst the major CHD risk factors, only fibrinogen shows a statistically significant relationship with birthweight (P = 0.008), fibrinogen levels being lower among the men with lower birthweights. When social and biological variables are included in models relating incident CHD and birthweight, the relationship between birthweight and incident fatal and non-fatal CHD remains essentially unchanged. CONCLUSION: A graded association between low birthweight and later CHD has been demonstrated in this cohort. This inverse association cannot be explained by the measured social or behavioural variables, or by other risk factors operating in adult life.

Birth Weight↗
PubMed1996

The actin-related proteins.

A family of proteins has been discovered over the past three years whose members have clear sequence homology to actin but are distinguished from actin by their structural and functional diversity. The ranks of this family, whose members are known as the actin-related proteins (arps), are expanding rapidly. Arps are but one branch of a larger superfamily which includes the actins, hsp/hsc70s, sugar kinases and several cell cycle proteins from bacteria. The existence of the superfamily has been inferred from tertiary structural data. In the case of the arps, their identification and classification has been based upon primary structural data. Placing the arps in a functional context is proving a slower process, although genetic and biochemical analyses are converging in several cases. In the past year, different arps have been linked to functions mediated by actin filaments (arp2 and arp3), microtubules (arp1) and the structural elements of chromatin (arp4 and arp6).

Actins↗
PubMed1996

Non-melanoma skin cancer and solar keratoses. I. Methods and descriptive results of the South Wales Skin Cancer Study.

This study aimed to describe the prevalence and incidence of solar keratoses and skin cancers and the natural history of solar keratoses in a random population sample. It was a cross-sectional study, with follow-up, conducted in South Wales, and involved 1034 subjects aged 60 years and over drawn from the Family Health Services Authority register. The main outcome measures were detection of the presence of solar keratoses and skin cancers on sun-exposed skin and photographic validation of solar keratoses and biopsy confirmation of cancers wherever possible. We found that solar keratosis prevalence was 23% (95% confidence interval 19.5-26.5) and that of skin cancer (all types) 2% (95% confidence interval 1.0-3.5). The incidence rate of solar keratoses was 149 lesions per 1000 person-years and of non-melanoma skin cancer 9 per 1000 person-years. In all 21% (95% CL 16-26) of solar keratoses regressed spontaneously during follow-up. None underwent malignant change. We believe that the failure of individuals to seek medical advice and the variable under-registration of non-melanoma skin cancer makes population-based study important. The high prevalence and incidence of malignant and pre-malignant skin lesions in this random sample raise major public health concerns. The high rate of spontaneous regression of solar keratoses and the low rate of malignant change challenges conventional views about the need for routine treatment of these lesions.

Adult↗
PubMed1996

Non-melanoma skin cancer and solar keratoses II analytical results of the South Wales Skin Cancer Study.

This study aimed to identify risk markers for prevalent solar keratoses (SKs) and squamous cell carcinomata (SCC) combined, for incident SKs and for spontaneous remission of SKs and to evaluate primary preventative measures. It was a cross-sectional study, with follow-up, conducted in South Wales, and involved 1034 subjects aged 60 years and over. The main outcome measures were the presence of and changes in SKs, and presence of skin cancers, on sun-exposed skin, and risk factors for prevalent SKs/SCCs and for incidence and remission of SKs. We found that variables independently associated with prevalent SKs/SCCs were: age [80 + years vs 60-64 years, odds ratio (OR) 3.7]; sex (male vs female OR 2.2); cumulative sun exposure (top quintile vs bottom quintile OR 3.3) and skin type (skin type 1 vs 4 OR 12.4). Use of sunscreen or protective clothing was not protective after controlling for confounders. Males and those who sunbathe infrequently showed greater remission of SKs. Older subjects and those spending most time in the sun in the preceeding 2 years were most likely to develop new SKs. We conclude that the risk factors identified are consistent with results from sunnier countries. The failure of sunscreen or clothing to emerge as protective raises doubts as to whether these measures are as effective in routine use in the general population as theoretical considerations and the limited trial evidence would predict. Recently reported sun exposure appears to influence the risk of developing new SKs.

Aged↗
PubMed1996

Suppression of matrix metalloproteinase production by hCG in cultures of human luteinized granulosa cells as a model for gonadotrophin-induced luteal rescue.

Granulosa cells were isolated from follicular aspirates collected at ovum recovery for in vitro fertilization. Cells were cultured in a defined medium on artificial extracellular matrix (Matrigel) in the presence or absence of hCG as a model for corpus luteum function. Release of cells from this culture system is reduced by hCG and this effect may be mediated through an inhibition of extracellular matrix degradation. Using zymography and western blot analysis, we confirm the identity of matrix metalloproteinases-2 and -9 in culture media. Matrix metalloproteinase-9 was the predominant gelatinase in freshly prepared granulosa cells and in culture media, and also represented a major metalloproteinase component in homogenates of early and mid-luteal phase samples of corpora lutea. Quantitative analysis of matrix metalloproteinases in culture media, obtained throughout the 14 day culture period and expressed per microgram of DNA, showed that matrix metalloproteinase-2, undetectable on day 2, rose throughout the culture period and that this rise was significantly inhibited by hCG. In contrast, matrix metalloproteinase-9 was clearly detectable on day 2 and remained relatively constant throughout much of the culture (day 2 to day 12) in the presence of gonadotrophin. Significantly increased production of matrix metalloproteinase-9 (day 6 to day 12) was evident in the absence of hCG. Our results provide further evidence for the hypothesis that the rescue of the corpus luteum in early pregnancy involves the maintenance of cellular function through the stabilization of the extracellular matrix.

Blotting, Western↗
PubMed1996

Methodology for a randomised controlled trial of preschool vision screening. A new approach with the 'ALSPAC' project.

We present the methodology of a population-based Randomised Controlled Trial, comparing an intensive programme of primary preschool vision screening by orthoptists with the usual non-specialist screening. The aims of the trial are to compare the effectiveness and costs of intensive orthoptic screening with non-specialist measures. The orthoptic screening programme will be evaluated both as a composite package and in terms of the screening value of the individual tests at specific ages. This trial is nested within a large population-based longitudinal study. Additional demographic and developmental data on the children in the trial are therefore available. The results of the trial will be used to help clarify which methods of preschool ophthalmic population screening are best in terms of disease detection and cost efficiency.

Amblyopia↗
PubMed1996

Stem cell transplantation with chemoradiotherapy myeloablation and interleukin-2.

Interleukin 2 (IL-2) stimulates the proliferation of T-cells both in vitro and in vivo. When murine or human peripheral blood (PB) or bone marrow (BM) mononuclear cells are incubated with IL-2 in vitro for 24 hours, cytotoxic T-cells are generated. If these activated cells are infused into mice, the enhanced cytotoxicity continues if low dose IL-2 is administered. This combination of administering activated cells with the subsequent low dose IL-2 infusion results in enhanced tumor cell destruction and improved survival rates in mice with acute myeloid leukemia. The encouraging results of these laboratory experiments prompted the initiation of phase I clinical trials in patients with refractory/relapsed hematologic malignancies and patients with breast cancer (Stages II-IV). Results from these trials demonstrate that stem cell transplantation with IL-2 activated stem cells (either PB or BM) with or without parenteral administration of IL-2 results in hematopoietic reconstitution with mild-to-moderate toxicities. This regimen also generates cutaneous and visceral autologous graft versus host disease (AuGVHD). The majority of our patients with relapsed/refractory hematologic malignancies or breast cancer developed either clinical and/or histological evidence of AuGVHD. Further studies are being conducted to determine if patients who develop AuGVHD experience improved disease-free survival from a possible autologous graft versus tumor (GVT) effect. Current laboratory evaluations include the elucidation of the pathogenesis of AuGVHD and molecular evaluation of the purging efficacy of IL-2.

Animals↗
PubMed1996

Granulocyte-macrophage colony-stimulating factor (GM-CSF) priming of high-dose etoposide and cyclophosphamide: a pilot trial.

Given the limitations of bone marrow transplantation (BMT), alternative approaches to deliver dose-intensive regimens without stem cell support are needed. Administration of hematopoietic growth factors before high-dose chemotherapy (priming) may reduce myelosuppression directly, delaying the onset of neutropenia by expanding the mature neutrophil compartment, and shortening the duration of neutropenia by expanding progenitor cell mass. Priming may also render progenitor populations mitotically quiescent after growth factors are withdrawn, thereby making them less sensitive to the cytotoxic effects of chemotherapy. It is also possible, however, that growth factor priming may worsen aplasia when used with dose-intensive regimens by either depleting early progenitor pools or recruiting progenitor populations into cycle. To determine the safety and hematopoietic efficacy of growth factor priming, 13 patients with hematologic malignancy or breast cancer were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) (250 micrograms/m2 twice daily subcutaneously) until the white blood cell (WBC) count reached either a plateau or 100,000 cells/microL. Forty-eight hours after the last dose of GM-CSF, chemotherapy was begun using high-dose etoposide and cyclophosphamide. All patients received GM-CSF after chemotherapy. Two patients were withdrawn during GM-CSF priming because they developed urticarial rashes. The maximum median increases in WBC and absolute neutrophil count (ANC) during GM-CSF priming were 7.1- and 4.4-fold, respectively. Only one patient achieved the original target WBC of 100,000/microL. The kinetics of leukocyte expansion were slow; a median of 13 days was needed to reach the maximum WBC. Furthermore, much of the leukocyte expansion was caused by an increase in eosinophils, which would not be expected to accelerate hematopoietic recovery. GM-CSF priming did not appear to have a significant impact on hematopoietic recovery after high-dose etoposide and cyclophosphamide, as there was no significant difference in 1) recovery to an ANC > 500/microL compared to a historical control group that received no growth factor (median of 29 and 30 days, respectively; p = 0.4), 2) number of days with an ANC < 500/microL (median of 19 and 20 days, respectively; p = 0.11), and 3) number of days to an untransfused platelet count > or = 50,000/microL (median 36 and 32 days, respectively; p = 0.23). The failure of GM-CSF priming may be a result of its modest stimulation of hematopoiesis or the expansion of a committed progenitor cell population that is exquisitely sensitive to this regimen.

Adult↗
PubMed1996

Microanatomical distribution of dendritic cells in normal tonsils.

Lymphoid dendritic cells play an essential role in antigen presentation in primary immune responses and are believed to be important in normal healthy responses of the mucosal immune system. The microanatomical distribution of HLA-DR-positive/S100 antigen-positive dendritic cells was analyzed in 10 normal palatine tonsils. Tonsil biopsies were obtained from 8 normal children undergoing otolaryngological surgery for reasons completely unrelated to tonsil disease. Two samples of normal adult tonsil were also obtained. Standard immunohistochemical methods, with antigen retrieval, were used to detect cell surface markers in formalin-fixed and/or frozen tissue specimens. The clinical identification of these tonsils as normal was confirmed by their microscopic appearance. HLA-DR antigen expression was restricted to lymphocytes, macrophages and dendritic cells; all normal epithelia were negative. S100-positive dendritic cells were readily detected in surface and crypt epithelium and were rare in submucosal sites or follicles. T cells were observed as frequently as dendritic cells in epithelial sites. Dendritic cell density was highest in extrafollicular T cell areas, where CD4-positive lymphocytes were especially abundant. A significant correlation was observed between the total number of different bacterial species isolated from individual normal tonsils and the frequency of dendritic cells in both the crypt epithelium and extrafollicular T cell areas. The number of dendritic cells at the tonsil surface was not similarly related to the bacterial flora.

Child↗
PubMed1996

The role of dendritic cells in the development of chronic tonsillar disease in children.

Thirty-one children, 2.6-12.2 years (mean = 7.9 +/- 5.0) were divided into four clinical categories: normal controls (n = 7), recurrent tonsillitis (n = 8), idiopathic tonsillar hyperplasia (n = 9) and recurrent tonsillitis with hyperplasia (n = 7). Immunohistopathologic studies were performed to determine the presence and location of HLA-DR, S-100 positive antigen presenting dendritic cells (DCs) in six microanatomic compartments: surface and crypt epithelium and submucosae, extrafollicular areas and lymphoid follicles. The results were analyzed in the context of the clinical history, bacteriology, and routine histopathology. The distribution of DCs was altered significantly with disease fewer numbers of DCs were found in the surface epithelium and greater numbers in the crypts and extrafollicular areas, than in normals, p <0.01. The surface : crypt ratio of DCs was 1:1 for normal tonsils, but dropped to 1:3 in disease. Chronic cryptitis was more common in disease and correlated strongly to the presence of beta-lactamase producing microorganisms (R = 1.0). An increased total bacterial concentration was correlated with increased numbers of DCs in the surface epithelium (R = 0.5, p <0.009). In summary, the microanatomical distribution of DCs within the tonsil is significantly altered in disease. These alterations appear to be influenced by potentially pathogenic bacteria more often found in the crypts of abnormal tonsils.

Adenoids↗
PubMed1995

Profile of immunoglobulin heavy chain variable gene repertoires and highly selective detection of malignant clonotypes in acute lymphoblastic leukemia.

The predominant B cell immunoglobulin heavy chain variable gene (IgH-V) usage and the uniquely rearranged, clonotype-specific variable-diversity-joining region gene (VDJ) sequences were identified in patients with B cell acute lymphoblastic leukemia (B-ALL) using a novel DNA-based gene amplification strategy. The approach allows a thorough and sensitive determination of the number of clonal leukemic IgH rearrangements and their precise V gene usage. This strategy may be applied in the detection of minimal residual disease, in surveillance after induction of disease-free states, and in analyzing the effectiveness of purging autologous bone marrow of malignant clones. An initial primary polymerase chain reaction (PCR), directed by an IgH-J generic primer and a complement of family-specific IgH-V primers, defined the major B cell IgH-V gene usage. Use of an IgH-J generic primer supplanted the use of a constant region primer anchor and thus eliminated the need to target mRNA by the traditional RNA reverse transcription-PCR amplification method. Monoclonality of rearranged VDJ bands was further substantiated by high-resolution denaturant gel electrophoretic analysis. The predominant amplified bands were subcloned and sequenced. By sequencing through VDJ juxtaposed regions, that is, the third complementarity-determining region, clonotype-specific primers were developed and used in a secondary clonotype primer-directed PCR (CPD-PCR) to detect, with extreme sensitivity and specificity, a unique B cell clone. Analysis of the products of the CPD-PCR permitted the detection of a single malignant cell among 1 million polyclonal cells and superseded the constraints of prior studies that have provided a limited evaluation of family variable gene repertoire usage. Leukemic clonal rearrangements were detected in 100% of the eight cases of pediatric and two cases of adult B-ALL studied. Two or more clonal IgH-VDJ amplified sequences were observed in 50% of the B-ALL bone marrows analyzed. In two cases, clonotype-specific oligodeoxynucleotide primers, derived from B-ALL VDJ sequences, directed the secondary CPD-PCR, and disease activity was monitored after chemotherapy and allogeneic bone marrow transplantation.

Adult↗
PubMed1995

Analyzing finasteride data.

Published data on the safety and efficacy of finasteride in the treatment of benign prostatic hyperplasia are studied and compared with published conclusions. The need for publishing correlation studies of both the benefits and side-effects, to allow for informed physician and patient decisions, is detailed.

Enzyme Inhibitors↗
PubMed1995

Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: studies with blasts of leukaemic patients.

BACKGROUND: A clinical pilot study performed by our group showed that dacarbazine can induce a marked reduction of blast cells in patients with acute myelogenous leukaemia (AML). Leukaemic blasts (LB) from responsive patients showed low levels of O6-alkylguanine-DNA alkyltransferase (OGAT). DESIGN: An in vitro study was performed to evaluate OGAT levels and sensitivity to temozolomide (a triazene compound that spontaneously decomposes into the active metabolite of dacarbazine) in a relatively large number of LB samples. RESULTS: OGAT levels varied widely among the LB of different patients, with a mean value higher in acute lymphoblastic leukaemias than in AML. About 25% of LB obtained from patients with AML showed low OGAT activity, in the range corresponding to that observed in leukaemic patients responsive to dacarbazine in vivo. A reasonable inverse correlation was found between OGAT levels and LB sensitivity to temozolomide. CONCLUSIONS: Triazenes could have a therapeutic potential in human leukaemias. Moreover, OGAT determination could provide rapid and reliable information about a patient's susceptibility to these antitumor agents.

Adolescent↗