Biomedical subjects

A Ryan

Publications and source records attributed to A Ryan.

At least 55 records · Page 3Linked to original sources

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↗

PubMed1998

Activating Smoothened mutations in sporadic basal-cell carcinoma.

Basal-cell carcinomas (BCCs) are the commonest human cancer. Insight into their genesis came from identification of mutations in the PATCHED gene (PTCH) in patients with the basal-cell nevus syndrome, a hereditary disease characterized by multiple BCCs and by developmental abnormalities. The binding of Sonic hedgehog (SHH) to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of Smoothened (SMO), a seven-span transmembrane protein. According to this model, the inhibition of SMO signalling is relieved following mutational inactivation of PTCH in basal-cell nevus syndrome. We report here the identification of activating somatic missense mutations in the SMO gene itself in sporadic BCCs from three patients. Mutant SMO, unlike wild type, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture. Furthermore, skin abnormalities similar to BCCs developed in transgenic murine skin overexpressing mutant SMO. These findings support the role of SMO as a signalling component of the SHH-receptor complex and provide direct evidence that mutated SMO can function as an oncogene in BCCs.

Adenovirus E1A Proteins↗

PubMed1998

No evidence exists for methylation inactivation of the p16 tumor suppressor gene in ovarian carcinogenesis.

The p16ink4/CDKN2/MTS1 tumor suppressor gene encodes a cyclin-dependent kinase inhibitor which plays an important role in regulation of the G1/S phase cell cycle checkpoint. Loss of heterozygosity (LOH) at the p16 locus, 9p21, has been documented in a wide variety of tumors including ovarian carcinoma. However, inactivating mutations of the remaining allele and homozygous deletions are relatively infrequent events in primary tumors, even in cases where expression of p16 at the mRNA and protein level is clearly absent. These findings initially cast doubt on the role of p16 as a tumor suppressor gene in vivo. Recently, an alternative mechanism of p16 inactivation involving methylation of the CpG island in the 5' region of the gene has been demonstrated in a number of malignancies and cell lines. In this study we have analyzed the methylation status of four CpG dinucleotides in a panel of 23 ovarian tumors using a multiplex PCR approach to correlate our findings with the LOH data in this region. Using the microsatellite markers D9S171 and D9S1679 LOH was demonstrated in 4/22 (18%) informative cases. All 23 tumors showed no evidence of methylation at the p16 locus including the 4 tumors demonstrating LOH at 9p21. These results suggest that methylation inactivation of the p16 gene does not play an important role in ovarian carcinogenesis.

Alleles↗

PubMed1998

Indications for surgical resection of metastatic ocular melanoma. A case report and review of the literature.

CONCLUSIONS: Ocular melanoma can metastasize to the gallbladder and porta hepatic nodes and mimic pancreatic carcinoma. If one suspects metastatic disease, a complete metastatic work-up must be done prior to surgery to prevent unnecessary surgery. If no distant disease is present or the patient is symptomatic, metastatic disease should be resected. PURPOSE: To review the literature pertaining to the spread of ocular melanoma and to determine if distant disease should be resected. PATIENTS AND METHODS: A 44-yr-old Egyptian male presented to an outside institution with mid-epigastric and right upper quadrant abdominal pain. His past medical history was significant for a left orbital enucleation for uveal melanoma in 1982. On physical examination, there was no supraclavicular adenopathy and no skin lesions were noted. There was a mass in the right upper quadrant. The total bilirubin was 4.8 mg/dL. A computed tomography showed a mass in the head of the pancreas and portal vein involvement could not be determined. RESULTS: The patient was taken to the operating room and a pancreatico-duodenectomy was performed for a cystic mass in the head of the pancreas. Final pathology revealed metastatic melanoma in the gallbladder and an enlarged, cystic lymph node growing into the head of the pancreas replaced with metastatic melanoma. The patient did well post-operatively and was discharged home on the eighth post-operative day.

Adult↗

PubMed1998

Myoepithelial hamartoma of the duodenal wall.

A rare case of myoepithelial hamartoma of the duodenal wall is presented, and previous case reports found in the literature are reviewed. Myoepithelial hamartomas are thought to arise from displaced pancreatic anlage present along the gastrointestinal tract during embryogenesis, which can differentiate into various pancreatic elements; the most highly differentiated form is heterotopic pancreas. An alternative theory is pancreatic metaplasia of endodermal tissues. We describe a 41-year-old man who presented with abdominal pain and vomiting. CT scanning revealed a mass at the head of the pancreas. A pancreaticoduodenectomy was performed for presumed cystadenoma. Histology of the mass revealed a disorderly arrangement of smooth muscle, dilated and nondilated ducts, pancreatic acinar tissue and mucus glands. The relationship of myoepithelial hamartomas involving the small bowel to similar lesions in the stomach, bile ducts and gallbladder is discussed.

Adult↗

PubMed1998

Spontaneous lower arch changes with and without second molar extractions.

This study describes the spontaneous changes that occurred in the lower arches of 41 children in whom orthodontic treatment was restricted to the upper arch only. In one group, lower second molars were extracted (n = 18), whereas in the other, these teeth remained in situ (n = 23). A two-phase treatment involved distal movement of the buccal segments with an "en masse" appliance and extraoral traction, followed by edgewise mechanics to retract or align the anterior teeth. Only study casts were examined. The occlusal aspects of the lower casts were recorded with the reflex microscope. Models were examined at the start of treatment, at the completion of buccal segment retraction, and when active appliance therapy was complete. The following arch measurements were recorded: intercanine and intermolar width, arch length and perimeter, and the degree of crowding in both the labial segment and the arch as a whole. In the extraction sample, upper buccal segment retraction was associated with increases in all lower arch dimensions and a reduction of crowding. In the nonextraction group, the response was inconsistent. Although arch length and perimeter reduced, intercanine and intermolar dimensions enlarged with minimal alteration in the labial segment crowding. During the second stage of therapy, dimensions generally decreased: arch length, perimeter, and the intercanine width returned to their pretreatment values in the extraction group and were further reduced in the nonextraction sample. However, both arch length and perimeter remained significantly longer in the extraction group. Intermolar width remained stable in both groups, whereas crowding increased. Over the 2-year observation period, arch length, arch perimeter, and crowding exhibited statistically significant differences in behavior between the two groups.

Adolescent↗

PubMed1998

Differences between African American and Caucasian men participating in a community-based prostate cancer screening program.

Prostate cancer is a major contributor to morbidity and mortality in the male population, but public awareness of the cancer has been reported as minimal. We evaluated the effectiveness of an educational prostate cancer screening program on 944 men in a midwest urban community. Digital rectal examinations and PSA blood tests were provided at no charge to participants with a grant from the Michigan Department of Community Health. An educational intervention that stressed the importance of prostate cancer early detection and treatment was conducted before screenings. A brief questionnaire administered before and after the videotape and screenings, targeted both knowledge and attitudes concerning prostate cancer. Pre-test results revealed that African American men were significantly (t = 3.7, P = .00) less likely then white men to correctly identify early symptoms of prostate cancer and the basic components of a prostate checkup. Following program involvement, scores significantly improved in all areas and differences were no longer significant between the races. Racial differences were also found for screening preferences and modes of reaching men to participate in screening. African American men were twice as likely as white men to choose private appointments over mass screening (OR = 2.2, P = .00). Radio reached the most African Americans (25%) while newspaper reached the most Caucasians (34%). The decreased level of knowledge among African Americans regarding prostate etiology and clinical factors highlights the need for educational programs to target minority populations. The need for discretion also applies by providing minority-favored access with screening through private appointments.

Adult↗