Biomedical subjects

A Ryan

Publications and source records attributed to A Ryan.

At least 37 records · Page 2Linked to original sources

PubMed2000

Survey of dietetic provision for patients with diabetes.

AIMS: To survey dietitians involved in diabetes care regarding the provisions for patients with diabetes. METHODS: A national survey of 512 dietitians known to be engaged in provision of diabetes care was conducted in 1997 and 391 (76%) responded. RESULTS: Nationally the median provision of dietetic care for diabetes reported was 10.7 h per 100,000 general population per week, but the provision was uneven ranging from 2.0 to 27.6 h per 100,000. Eighty-five per cent of dietitians worked in areas where the provision was less than 22 h per 100,000 general population per week (the current recommended minimum standard). Dietetic provision was greater in secondary care (median 9.1 h per 100,000 general population per week) than in general practice, residential homes and other locations (median 4.4 h per 100,000 general population per week). Provision was greater in those areas in which a designated dietitian had responsibility for co-ordinating the dietetic service for diabetes than in areas where the co-ordinator was not a dietitian or where there was no co-ordinator. Over 90% of dietitians reported following British Diabetic Association (BDA) recommendations regarding advice on carbohydrate, sugar, fat and fibre consumption, but only one-third routinely advised on salt restriction. Of the 17% of dietitians who continue to use carbohydrate exchanges, all combine this method with other approaches. Of the recommendations made by the Clinical Standards Group, only 69% of dietitians reported seeing more than half of newly diagnosed adult patients within four weeks, and less than 50% reported offering half or more of their patients an annual review. Amongst the literature in current use, 98% of dietitians use BDA literature for teaching patients and 90% use BDA publications in their own education. Seventy-six per cent of dietitians believed that there was a role for commercial slimming organizations in weight management of people with diabetes. CONCLUSIONS: Given the proven value of dietetic input in diabetes management, there would be advantages to correcting the regional inequalities in dietetic provision for diabetes care in the UK.

Adult↗

PubMed2000

p53 codon 72 polymorphism in vulval cancer and vulval intraepithelial neoplasia.

p53 codon 72 polymorphism was analysed in UK women with human papillomavirus (HPV)-associated vulval intraepithelial neoplasia and vulval squamous cell carcinoma. Arginine homozygotes were significantly less common in either group compared with controls. We conclude that the arginine polymorphism may confer protection against the development of HPV-associated vulval neoplasia.

Adult↗

PubMed2000

Improved functional outcomes following exercise rehabilitation in patients with intermittent claudication.

BACKGROUND: The purposes of this study were to identify predictors of increased claudication distances following exercise rehabilitation in peripheral arterial occlusive disease (PAOD) patients with intermittent claudication and determine whether improved claudication distances translated into increased free-living daily physical activity in the community setting. METHODS: Sixty-three patients were recruited (age, 68+/-1 years, mean +/- standard error). Patients were characterized on treadmill claudication distances, walking economy, peripheral circulation, cardiopulmonary function, self-perceived ambulatory function, body composition, baseline comorbidities, and free-living daily physical activity before and after a 6-month treadmill exercise program. RESULTS: Exercise rehabilitation increased distance to onset of claudication pain by 115% (178+/-22 m to 383+/-34 m; p < .001) and distance to maximal claudication pain by 65% (389+/-29 m to 641+/-34 m; p < .001). The increased distance to onset of pain was independently related to a 27% increase in calf blood flow (r = .42, p < .001) and to baseline age (r = -.26, p < .05), and the increased distance to maximal pain was predicted by a 10% increase in peak oxygen uptake (r = .41, p < .001) and by a 10% improvement in walking economy (r = -.34, p < .05). Free-living daily physical activity increased 31% (337+/-29 kcal/day to 443+/-37 kcal/day; p < .001) and was related to the increases in treadmill distances to onset (r = .24, p < .05) and to maximal pain (r = .45, p < .001). CONCLUSIONS: Increased claudication distances following exercise rehabilitation are mediated through improvements in peripheral circulation, walking economy, and cardiopulmonary function, with younger patients having the greatest absolute ambulatory gains. Furthermore, improved symptomatology translated into enhanced community-based ambulation.

Aged↗

PubMed2000

Profile of men randomized to the prostate cancer prevention trial: baseline health-related quality of life, urinary and sexual functioning, and health behaviors.

PURPOSE: To describe men who agreed to be randomized to the Prostate Cancer Prevention Trial (PCPT), a 7-year, double-blind placebo-controlled study of the efficacy of finasteride in preventing prostate cancer. METHODS: Comprehensive health-related quality-of-life data are presented for 18,882 randomized PCPT participants. RESULTS: PCPT participants are highly educated, middle to upper income, and primarily white (92%). Participants reported healthy lifestyles. The mean American Urological Association Symptom Index score was well below the maximum entry score of less than 19; existing urinary symptoms were generally not bothersome. The scores for two sexual functioning scales could range from 0 to 100, with higher scores reflecting worse sexual functioning. The mean score for the Sexual Problem Scale was 19.2 out of 100, and the mean Sexual Activities Scale was 44.1 out of 100. Scores for seven of the eight Medical Outcomes Study 36-item Short-Form Health Survey scales (higher scores are better) were 10 to 20 points higher than those reported by a general population sample and differed minimally by race but not by age. Previously reported associations between sexual dysfunction and hypertension, diabetes, and depression were also observed. Men who never smoked reported less sexual dysfunction than did those who either had quit or still smoked. CONCLUSION: Individuals who are likely to enroll in primary prevention trials have a high socioeconomic status, healthy lifestyle behaviors, and better health than the general population. These data help oncologists design chemoprevention trials with respect to the selection of health-related quality-of-life assessments and recruitment strategies.

Aged↗

PubMed2000

Methylation of hMLH1 in a population-based series of endometrial carcinomas.

Microsatellite instability (MSI) is a characteristic feature of hereditary nonpolyposis colorectal cancer and is also observed in sporadic colorectal and endometrial cancers. Alterations in the mismatch repair genes hMLH1 and hMSH2 are important for the development of MSI. It has recently been demonstrated that hypermethylation of the hMLH1 promoter region is associated with MSI and appears to be a common mechanism for gene inactivation. For endometrial carcinoma, however, previous studies have been relatively small and have not been population based. We therefore wanted to assess the frequency and prognostic significance of hypermethylation of the hMLH1 and hMSH2 genes in conjunction with hMLH1 protein expression in a prospective and population-based series of endometrial carcinoma patients with known MSI status and complete follow-up. A total of 138 patients were studied, and methylation of hMLH1 was found in 23% of tumors with conclusive results, whereas methylation of hMSH2 was seen in only 1% of tumors. Methylation of hMLH1 was significantly correlated with MSI (P < 0.001). Loss of nuclear staining of hMLH1 protein was seen in 14% of the cases and was significantly correlated with hMLH1 methylation and MSI (P < 0.001). Normal expression of hMLH1 was seen in all of the unmethylated tumors (100%). Of the 14 MSI-positive tumors that were also methylated, all but 1 (93%) showed a loss of nuclear expression of hMLH1. None of the tumors with loss of hMLH1 expression or hMLH1 methylation were aneuploid (P for both < or = 0.05), and loss of hMLH1 expression and hMLH1 methylation was significantly correlated with lack of p53 overexpression (P for both < or = 0.05). Nuclear hMLH1 staining and hMLH1 methylation did not significantly influence survival. In conclusion, hMLH1 methylation was common and was significantly correlated with loss of hMLH1 protein expression, MSI, diploid tumors, and lack of p53 overexpression. In contrast, hMSH2 methylation was infrequent in this prospective and population-based series of endometrial carcinomas.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Multistep signaling and transcriptional requirements for pituitary organogenesis in vivo.

During development of the mammalian pituitary gland, specific hormone-producing cell types, critical in maintaining homeostasis, emerge in a spatially and temporally specific fashion from an ectodermal primordium. We have investigated the molecular basis of generating diverse cell phenotypes from a common precursor, providing in vivo and in vitro evidence that development of these cell types involves at least four sequential phases of signaling events and the action of a gradient at an ectodermal boundary. In the first phase, we hypothesize that this notochord induces invagination of Rathke's pouch from the oral ectoderm. This is followed by appearance of an ectodermal boundary, formed with exclusion of Shh from the nascent pouch. Next, signals from the ventral diencephalon--expressing BMP4, Wnt5a, FGF10, and FGF8--in concert with Shh represent critical in vivo signals for pituitary determination. Subsequently, a dorsal-ventral BMP2 signal gradient emanates from a ventral pituitary organizing center, forming at the boundary to oral ectoderm region from which Shh expression is selectively excluded. In concert with a dorsal FGF8 signal, this creates opposing gradients that generate overlapping patterns of specific transcription factors that underlie cell lineage specification events. The mechanisms by which these transient gradients of signaling molecules lead to the appearance of four ventral pituitary cell types appear to involve the reciprocal interactions of two transcription factors, Pit-1 and GATA-2, which are epistatic to the remainder of the cell type-specific transcription programs and serve as a molecular memory of the transient signaling events. Unexpectedly, this program includes a DNA-binding-independent function of Pit-1, suppressing the ventral GATA-2-dependent gonadotrope program by inhibiting GATA-2 binding to gonadotrope- but not thyrotrope-specific genes. This indicates that both DNA-binding-dependent and-independent actions of abundant determining factors contribute to generate distinct cell phenotypes. In the fourth phase, temporally specific loss of the BMP2 signal is required to allow terminal differentiation. The consequence of these sequential organ and cellular determination events is that each of the pituitary cell types--gonadotropes, thyrotropes, somatotropes, lactotropes, corticotropes, and melanotropes appears to be determined, in a ventral to dorsal gradient, respectively, apparently based on a combinatorial code of transcription factors induced by the gradient of specific signaling molecules.

Animals↗

PubMed1999

Effects of leptin on spinally projecting neurons in the PVN of the hypothalamus.

The study examined whether intravenous (i.v.) leptin increased Fos-production in spinally projecting neurons in the hypothalamic paraventricular nucleus (PVN). We combined (i) rhodamine tagged microspheres injected into the upper thoracic spinal cord and (ii) Fos (marker of neuronal activation) immunohistochemistry. Effects of recombinant murine leptin were compared to vehicle (containing lipopolysaccharide a contaminant present in the leptin solution). Following leptin, 10% of the spinally projecting neurons contained Fos. However, vehicle elicited similar effects and there was no significant difference between the groups.

Animals↗

PubMed1999

Carey-Fineman-Ziter (CFZ) syndrome: report on affected sibs.

We describe a sib pair with craniofacial anomalies, micrognathia, Mobius sequence, generalised myopathy, relative macrocephaly, and developmental delay. They appear to have the Carey-Fineman-Ziter syndrome (MIM 254940), which has been reported in only four children, a sib pair and two sporadic cases. This report on an additional affected brother and sister pair supports autosomal inheritance as the likely cause. These cases also confirm that scoliosis, talipes equinovarus, and a non-specific primary myopathy are important manifestations of Carey-Fineman-Ziter syndrome.

Abnormalities, Multiple↗

PubMed1999

Characterization of photosensitivity in the Smith-Lemli-Opitz syndrome: a new congenital photosensitivity syndrome.

Photosensitivity has recently been reported as a feature of the Smith-Lemli-Opitz syndrome (SLO). The aim of this study was to establish the photobiological features of this disorder and to examine the hypothesis that the photosensitivity is caused by the high levels of 7-dehydrocholesterol found in SLO. All known cases of SLO in the U.K. were reviewed and clinical details of photosensitivity were recorded in detail. The action spectrum of the photosensitive eruption was defined by monochromator light testing. Thirteen of the 23 subjects (57%) had severe photosensitivity, and in 10 there was no photosensitivity. No correlation was identified between levels of 7-dehydrocholesterol and severity of photosensitivity, suggesting that the photosensitivity in SLO is not caused by a direct phototoxic effect mediated by 7-dehydrocholesterol. A novel pattern of photosensitivity was observed, with onset of a sunburn-like erythema on sun-exposed skin within minutes of sun exposure, which persisted in most cases for up to 24-48 h before fading. Monochromator light testing in three subjects showed an ultraviolet (UV) A-mediated photosensitivity eruption with greatest photosensitivity at 350 nm. Photosensitivity is a common and prominent feature of SLO and appears to be UVA-mediated. Elucidation of its biochemical basis may provide insight into normal cutaneous protective mechanisms against UVA-induced photodamage, and also sun sensitivity in general.

Adolescent↗

PubMed1999

Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse.

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.

Age Factors↗

PubMed1999

Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations.

BACKGROUND: Mutations in the BRCA1 or BRCA2 genes are responsible for up to 95% of hereditary ovarian cancer cases. Both genes function as tumour suppressor genes, and development of a cancer is thought to require an accumulation of somatic genetic events in addition to the inherited germline predisposition. It is unknown whether these somatic events in BRCA associated ovarian cancer are similar to or distinct from those in sporadic cases. The most frequent somatic genetic event in ovarian cancer is a mutation of the p53 gene. AIM: To study the role of p53 in hereditary ovarian cancer, by analysing accumulation of the p53 protein in ovarian cancers which occurred in BRCA1 or BRCA2 germline mutation carriers and comparing the results with a panel of ovarian cancers from patients who tested negative for both BRCA1 and BRCA2. METHODS: The study group consisted of 39 ovarian cancer patients in whom a BRCA mutation had been confirmed previously. p53 Immunohistochemistry was performed on archival tissue using a standard microwave antigen retrieval technique. The rate of p53 accumulation was compared with 40 ovarian cancer cases who tested negative for BRCA1 and BRCA2 germline mutations. RESULTS: P53 Accumulation was similar in BRCA related ovarian cancers and BRCA negative controls. Overall 27 of 39 BRCA1 or BRCA2 positive cases (69%) had evidence of p53 accumulation, compared with 24 of 40 invasive ovarian cancer cases (60%) which tested negative for BRCA1 and BRCA2 germline mutations. BRCA1 related ovarian cancers showed p53 accumulation in 22 of 30 cases (73%); p53 accumulation was present in five of nine BRCA2 related ovarian cancers. CONCLUSIONS: In addition to germline BRCA1 and BRCA2 mutations, somatic p53 alterations leading to p53 accumulation are an important event in hereditary ovarian cancer and are as frequent as in non-BRCA-related ovarian cancer.

BRCA2 Protein↗

PubMed1999

Volume expansion does not activate neuronal projections from the NTS or depressor VLM to the RVLM.

We investigated whether a monosynaptic connection from the nucleus tractus solitarius (NTS) or the depressor ventrolateral medulla (VLM) to the pressor region of the rostral VLM (RVLM) constituted part of the reflex pathway activated by cardiopulmonary baroreceptors. Volume expansion in the conscious rabbit, which elicits renal nerve inhibition predominantly via cardiac mechanoreceptors, was used as the stimulus. The protein Fos was used as a marker of neuronal activation. The retrogradely transported tracer rhodamine-tagged microspheres, previously injected into the pressor region of the RVLM, identified medullary neurons that projected to that region. Volume expansion significantly increased the number of Fos-positive cell nuclei in the NTS and in the depressor VLM. Neurons that projected to the RVLM were found throughout the depressor region of the VLM and in the NTS but were not activated by volume expansion. Thus, although the central reflex pathways activated by volume expansion include the NTS and the depressor region of the VLM, we could not find evidence for a monosynaptic connection between those regions and the RVLM.

Animals↗

PubMed1999

Mucin Hypersecreting Intraductal Papillary Neoplasm of the pancreas.

Mucin Hypersecreting Intraductal Papillary Neoplasm is a rare neoplasm that arises from ductal epithelial cells. This entity is distinct from the more commonly known Mucinous Cystadenoma or Mucinous Cystadenocarcinoma. Despite this distinction, it has been erroneously categorized with these more common cystic neoplasms. Characteristic clinical presentation, radiographic, and endoscopic findings help distinguish this neoplasm from the cystadenomas and cystadenocarcinomas. Histopathologic identification is not crucial to the preoperative diagnosis. This neoplasm is considered to represent a premalignant condition and, therefore, surgical resection is warranted. Prognosis, following resection, is felt to be curative for the majority of patients. We present two cases of Mucin Hypersecreting Intraductal Papillary Neoplasm and discuss their diagnosis and surgical therapy.

Adenocarcinoma, Papillary↗

PubMed1999

Two brothers with varying combinations of severe developmental delay, epilepsy, microcephaly, tetralogy of Fallot and hydronephrosis.

We report on a sib pair who manifest a pattern of anomalies which appears to be unique and for which we are unable to provide a cytogenetic or molecular genetic explanation. While a number of their physical features are distinct, their overall appearance and pattern of neurological impairment suggest they suffer from the same genetic disorder.

Abnormalities, Multiple↗

PubMed1998

Characterization of two patched receptors for the vertebrate hedgehog protein family.

The multitransmembrane protein Patched (PTCH) is the receptor for Sonic Hedgehog (Shh), a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. According to this model, the inhibition of SMO signaling is relieved after mutational inactivation of PTCH in the basal cell nevus syndrome. Recently, PTCH2, a molecule with sequence homology to PTCH, has been identified. To characterize both PTCH molecules with respect to the various Hedgehog proteins, we have isolated the human PTCH2 gene. Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. However, the expression patterns of PTCH and PTCH2 do not fully overlap. While PTCH is expressed throughout the mouse embryo, PTCH2 is found at high levels in the skin and in spermatocytes. Because Desert Hedgehog (Dhh) is expressed specifically in the testis and is required for germ cell development, it is likely that PTCH2 mediates its activity in vivo. Chromosomal localization of PTCH2 places it on chromosome 1p33-34, a region deleted in some germ cell tumors, raising the possibility that PTCH2 may be a tumor suppressor in Dhh target cells.

Amino Acid Sequence↗

PubMed1998

p53 codon 72 polymorphism and risk of cervical cancer in UK.

BACKGROUND: A polymorphism at codon 72 of the human tumour-suppressor gene, p53, results in translation to either arginine or proline. A recent report suggested that the risk of human-papillomavirus-associated cervical cancer in white women is higher for those homozygous for the arginine allele than for those who are heterozygous. We examined a similar number of cervical cancers and a larger control group for their p53 codon 72 polymorphism status to see if we could confirm this result. METHODS: Three different groups of UK white women were studied: 96 who had volunteered to take part in a trial of ovarian-cancer screening; 150 attending for routine antenatal care in the Oxford region; and 50 women with cervical cancer. DNA from peripheral blood samples and from archival tissue samples was examined by PCR with allele-specific primers. FINDINGS: The proportions of individuals homozygous for the arginine allele, homozygous for the proline allele, and heterozygous for the two alleles were 59%, 4%, and 36% among women screened for ovarian cancer; 65%, 8%, and 27% among the antenatal-care group; and 54%, 6%, and 40% in women with cervical cancer. Chi2 analysis showed no significant differences in these proportions. INTERPRETATION: In the population studied, individuals homozygous for the arginine variant of codon 72 of the p53 gene were not at increased risk of cervical cancer.

Amino Acid Sequence↗

PubMed1998

Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat.

The hypothalamic paraventricular nucleus (PVN) projects to the rostral ventrolateral medulla (RVLM) and to the intermediolateral cell column (IML) of the spinal cord. The present study determined whether the same neurons can innervate both regions. In each rat, two retrogradely-transported tracers, microspheres tagged with fluorescein or rhodamine, were injected into the left lower thoracic/upper lumbar IML (fluorescein) and into the pressor region of the left RVLM (rhodamine). In the PVN over 90% of the neurons labelled with either tracer were found ipsilateral to the injection site. Double labelled cells averaged almost one-third of the spinally-projecting cells in four of the five animals. In the remaining animal, there were few double-labelled cells. The results suggest that a population of PVN neurons innervates both the lower-thoracic/upper lumbar IML and the RVLM.

Animals↗

PubMed1998

Development of the mouse inner ear and origin of its sensory organs.

The molecular mechanisms dictating the morphogenesis and differentiation of the mammalian inner ear are largely unknown. To better elucidate the normal development of this organ, two approaches were taken. First, the membranous labyrinths of mouse inner ears ranging from 10.25 to 17 d postcoitum (dpc) were filled with paint to reveal their gross development. Particular attention was focused on the developing utricle, saccule, and cochlea. Second, we used bone morphogenetic protein 4 (BMP4) and lunatic fringe (Fng) as molecular markers to identify the origin of the sensory structures. Our data showed that BMP4 was an early marker for the superior, lateral, and posterior cristae, whereas Fng served as an early marker for the macula utriculi, macula sacculi, and the sensory portion of the cochlea. The posterior crista was the first organ to appear at 11.5 dpc and was followed by the superior crista, the lateral crista, and the macula utriculi at 12 dpc. The macula sacculi and the cochlea were present at 12 dpc but became distinguishable from each other by 13 dpc. Based on the gene expression patterns, the anterior and lateral cristae may share a common origin. Similarly, three sensory organs, the macula utriculi, macula sacculi, and cochlea, seem to arise from a single region of the otocyst.

Animals↗