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D M Parry

Publications and source records attributed to D M Parry.

At least 37 records · Page 2Linked to original sources
PubMed1998

Genetic variation in the 3' untranslated region of the neurofibromatosis 1 gene: application to unequal allelic expression.

Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by inactivation of neurofibromin, a protein capable of modulating signal transduction by activating Ras-GTPase activity. We have used cDNA cloning and Northern blot analysis to confirm the NF1 gene produces alternatively polyadenylated mRNAs with 3' untranslated regions (3' UTR) that show striking evolutionary conservation. Scanning of the 3'UTRs for genetic variation revealed three common sequence polymorphisms (> 30% heterozygosity), one less informative polymorphism (approximately 5% heterozygosity) and one rare variant (1/144 chromosomes). These differences were used to examine relative levels of expression of normal and mutant NF1 alleles in lymphoblast cell lines and in one case, autopsy tissue, from patients with NF1. Unequal allelic expression (up to 4-fold) was observed in a subset of both sporadic and familial NF1 cases. Where linkage phase could be determined, the allele segregating with the disorder displayed a relative reduction in expression. However, the magnitude of this effect was variable suggesting the operation of additional, non-genetic factors in determining the degree of relative expression of the mutant allele.

3' Untranslated Regions↗
PubMed1997

Transcutaneous bilirubinometry: its role in the assessment of neonatal jaundice.

OBJECTIVE: To review the literature on transcutaneous bilirubinometry so that its exact role in the prevention of kernicterus or bilirubin encephalopathy could be determined. DESIGN AND METHODS: Literature searches were done in Medline and Current Contents. RESULTS: It is estimated that about 50% of newborns have an episode of jaundice in the first few days of life. Six percent of newborns may develop hyperbilirubinemia (> 220 mumol/L), which can potentially cause bilirubin encephalopathy or kernicterus, a severe neonatal disease. In the past, serum bilirubin (SB) has been the preferred method of detecting hyperbilirubinemia in newborns. The ordering of SB in neonates is based on visual evaluation by either physicians or nursing staff. Skin puncture collection of blood exposes the neonate to trauma and risk of infection. A noninvasive device for predicting serum bilirubin levels in newborns diminishes the need to do skin punctures. One such device that has been very extensively studied is the Minolta AirShields Jaundice Meter. It is a portable light-weight instrument that uses reflectance measurements on the skin to determine the amount of yellow color present in the skin, namely transcutaneous bilirubin (TcB). Although the TcB measurements correlate well with serum bilirubin (SB) levels, they cannot accurately predict serum bilirubin because of error related to a variety of factors. CONCLUSIONS: TcB cannot be used directly to make decisions about transfusions or phototherapy in neonates. It is a good tool for screening neonates to determine when a laboratory measurement of serum bilirubin is needed. Such a practice requires careful selection of the decision level so that false-negative TcB values do not prevent appropriate serum bilirubin tests from being done.

Bilirubin↗
PubMed1997

Immunocytochemical localization of GnRH precursor in the hypothalamus of European starlings during sexual maturation and photorefractoriness.

Immunocytochemistry with quantitative image analysis, for both GnRH and its precursor proGnRH-GAP, was used in male European starlings (Sturnus vulgaris) to investigate four stages of a photoperiodically-induced reproductive cycle. Four different groups of birds were examined: photosensitive buy sexually immature, sexually mature, undergoing gonadal regression, and after the completion of regression and fully photorefractory. The size of cells staining for GnRH and proGnRH-GAP increased during gonadal maturation. A reduction in the number of cells staining for GnRH and the size of cells staining for both GnRH and proGnRH-GAP occurred during gonadal regression, though staining for GnRH and proGnRH-GAP in the median eminence remained high at this stage. Birds examined after completion of regression showed significantly reduced staining for both GnRH and its precursor. These observations suggest that photorefractoriness is promoted by a reduction in proGnRH-GAP production and in GnRH synthesis, rather than requiring inhibition of release of GnRH at the median eminence.

Animals↗
PubMed1996

Multiple schwannomas and meningiomas associated with irradiation in childhood.

OBJECTIVE: To determine the pattern of neural tumors (schwannomas, vestibular schwannomas [acoustic neuromas], and meningiomas) that developed in 3013 people who received radiation treatment with x-ray beam therapy for benign conditions of the head and neck area before their 16th birthday. METHODS: The surgical and pathology reports and pathology slides were reviewed for all neural tumors in the cohort. Patients with more than 1 neural tumor were compared with those with 1 neural tumor and those with no neural tumors. RESULTS: There were 7 patients with multiple neural tumors and 63 with single neural tumors. The distribution of tumors in these 2 groups differed. The group with multiple tumors had more spinal nerve root schwannomas, while the group with single tumors had more cranial nerve schwannomas. Six of the 7 patients did not meet the diagnostic criteria for neurofibromatosis type 2. CONCLUSIONS: Our findings suggest that host factors that increase susceptibility to radiation may be involved in the development of the multiple neural tumors. Clinically, patients with multiple neural tumors who do not meet the diagnostic criteria for neurofibromatosis type 2 should be questioned about radiation exposure. If exposure is confirmed, then screening for other radiation-related tumors should be initiated.

Adult↗
PubMed1996

Glutamatergic projections from the rostral hypothalamus to the periaqueductal grey.

Retrograde transport of fluorescent latex microspheres was combined with immunocytochemistry for glutamate to determine the organization of the projections from glutamate-containing neurones in the rostral hypothalamus to the different subdivisions of the periaqueductal grey (PAG). Double-labelled neurones, i.e. neurones immunoreactive for glutamate and projecting to the PAG, were found throughout the rostral hypothalamus. There were no apparent differences, however, in the origins of presumed glutamatergic projections from the rostral hypothalamus to the different subdivisions of the PAG.

Animals↗
PubMed1996

A point mutation associated with a severe phenotype of neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other nonmalignant tumors of the brain, spinal cord, and peripheral nerves. Although the average age of onset of NF2 is 20 years, some individuals may become symptomatic in childhood. We studied 5 unrelated NF2 patients who became symptomatic before age 13. All 5 had multiple tumors in addition to vestibular schwannoma, and none had a positive family history. Sequence analysis of the NF2 gene revealed identical nonsense mutation of exon 6 in 3 patients. Because this mutation destroys a restriction enzyme recognition site, genomic DNA from the 2 other children was directly tested for this change and identical alterations were detected. Although the work of our laboratory and others has not, in general, detected identical mutations in unrelated patients, this mutation seems to occur particularly frequently in the pediatric population and thus may be associated with an especially severe phenotype. Restriction analysis in children with NF2 may be a cost effective way of identifying their mutation. Further work is needed to characterize the effects of this change on the NF2 protein product and its relationship to this severe phenotype.

Adolescent↗
PubMed1996

Clinical impact of transcutaneous bilirubinometry as an adjunctive screen for hyperbilirubinemia.

OBJECTIVE: To determine what the clinical impact would be of implementing a jaundice meter for use in a busy neonatal service as an adjunctive screening tool for hyperbilirubinemia. DESIGN AND METHODS: Test utilization data was collected for a 6-month period to determine how neonatal bilirubin was utilized in this hospital. The jaundice meter was evaluated in a study population of healthy term infants. The performance characteristics of the meter and the test utilization data were used to predict the clinical impact a meter could have on screening for hyperbilirubinemia. RESULTS: Utilization data indicated that about 60% of all single bilirubin neonatal testing (i.e., bilirubin only ordered) was done by normal nurseries. A jaundice meter cutoff decision reading of 17 was shown to have a sensitivity of 100% and a specificity of 68% for hyperbilirubinemia (> 260 mumol/L) in a study population of healthy term infants. From this data, it was estimated that use of a jaundice meter could eliminate 43% of the single (i.e., not combined with other tests) bilirubin tests done on healthy term neonates with no prior exposure to phototherapy. This constitutes an overall 20% reduction in bilirubin testing in normal nurseries when testing done on babies exposed to phototherapy and combined bilirubin testing are taken into consideration. Additionally, it was shown that there would be an improvement of 9% in the prediction of hyperbilirubinemia without loss of 100% sensitivity. CONCLUSION: Use of a jaundice meter in normal nurseries as an adjunctive screening tool enhances patient care by reducing the overall blood procurement rate in normal nurseries by 20% and increasing screening efficiency for significant hyperbilirubinemia by 5%.

Bilirubin↗
PubMed1996

Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities.

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P < or = .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study.

Adolescent↗
PubMed1995

Lymphangiosarcoma in late-onset hereditary lymphedema: case report and nosological implications.

Hereditary lymphedemas that are not associated with other malformations usually affect the lower limbs and are inherited in an autosomal dominant fashion. These non-syndromic hereditary lymphedemas are categorized by their age of onset, being either congenital (Milroy disease) or having an onset in childhood or around puberty (Meige disease). We describe a family in which three individuals in three generations had unusually late onset of lymphedema in their mid-twenties or thirties. The proband additionally developed a very rare lymphangiosarcoma. This tumor, usually associated with post-mastectomy lymphedema, has not been described in late-onset hereditary lymphedema. Because of an unusually high incidence of multiple primary tumors in association with lymphangiosarcoma in the literature (approximately 10%) and the proband's own familial cancer background, we speculate that an inherited predisposition to malignancy may underlie the development of lymphedema-associated lymphangiosarcoma.

Adult↗
PubMed1995

Survival after retinoblastoma: long-term consequences and family history of cancer.

Retinoblastoma (Rb) is a rare childhood tumor of the eye. In the heritable form, tumors are often bilateral and survivors have a greatly increased risk both for a second malignancy and for having children with Rb. Familial patterns of both cancer and birth defects are poorly understood in families with a heritable cancer, and little is known of the ways that a heritable cancer affects the lives of long-term survivors. To find out more about these and other issues in the lives of long-term survivors of childhood and adolescent cancer, we interviewed 56 adult survivors of retinoblastoma (15 with the heritable form) and 84 brothers and sisters as controls, who formed part of a large retrospective cohort study. Rb survivors were interviewed between 1980 and 1983, when they were 30 years old on average. Types of employment and health problems did not differ between survivors and controls, regardless of sight, but the income of blind survivors was considerably less than that of partially sighted survivors. Despite similar marriage rates, fewer survivors than controls reported a pregnancy (RR = 0.45; 95% CI; 0.24-0.83 for both sexes combined). Parents of children with heritable Rb seemed more likely to have had cancer than parents in families with nonheritable Rb (P = 0.06), and mothers were more likely than fathers to be affected (P = 0.01). This small series suggests that having retinoblastoma may have many long-term consequences, reaching beyond genetic and physical effects to touch family life and income attainment and the health of other family members. Follow-up of more modern cohorts and the use of molecular tools will clarify the long-term consequences of more recent therapies, and patterns of familiar cancer.

Achievement↗
PubMed1994

Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity.

To determine the spectrum of manifestations in neurofibromatosis 2 (NF2) and to assess possible heterogeneity, we evaluated 63 affected individuals from 32 families. Work-up included skin and neurologic examinations, audiometry, a complete ophthalmology examination with slit-lamp biomicroscopy of the lens and fundus, and gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean age-at-onset in 58 individuals was 20.3 years; initial symptoms resulted from vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Five asymptomatic individuals were diagnosed through screening. Vestibular schwannomas were documented in 62 individuals (98.4%); other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). Usually, clinical manifestations and course were similar within families but differed among families. To assess possible heterogeneity, we assigned affected individuals to three proposed subtypes (representing mild, intermediate, and severe NF2) based on age-at-onset, presence or absence of CNS tumors other than vestibular schwannomas, and presence or absence of retinal hamartomas. Comparisons among the three subtypes for many clinical parameters demonstrated that patients in the mild subtype differed from those in the other two subtypes for most parameters, but that none of the parameters distinguished patients in the intermediate subtype from those in the severe subtype. Thus, there are likely two rather than three subtypes of NF2. Classification of patients to subtype may aid in counseling about long-term prognosis and in formulating individualized guidelines for medical surveillance.

Adolescent↗
PubMed1993

A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by the occurrence of bilateral vestibular schwannomas and other central nervous system tumors including multiple meningiomas. Genetic linkage studies and investigations of both sporadic and familial tumors suggest that NF2 is caused by inactivation of a tumor suppressor gene in chromosome 22q12. We have identified a candidate gene for the NF2 tumor suppressor that has suffered nonoverlapping deletions in DNA from two independent NF2 families and alterations in meningiomas from two unrelated NF2 patients. The candidate gene encodes a 587 amino acid protein with striking similarity to several members of a family of proteins proposed to link cytoskeletal components with proteins in the cell membrane. The NF2 gene may therefore constitute a novel class of tumor suppressor gene.

Amino Acid Sequence↗
PubMed1993

Ultrastructural evidence for changes in synaptic input to the hypothalamic luteinizing hormone-releasing hormone neurons in photosensitive and photorefractory starlings.

Neural input to the hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons was investigated in male starlings (Sturnus vulgaris) using electron microscopy combined with immunocytochemistry. Birds (4 to 6 in each group) were sampled at four stages of a photoperiodically induced reproductive cycle: (a) sexually immature but photosensitive, under short days; (b) during sexual maturation after 7 to 25 long days; (c) during gonadal regression after 35 to 50 long days; and (d) when fully photorefractory after 11 months exposure to long days. The length of the perikaryal membrane, the number and length of axo-somatic terminals in contact with it and the number and length of synaptic modifications within the terminals were measured for a minimum of six LHRH neurons in each brain. The number of axo-somatic terminals per neuron and the number per unit length of perikaryal membrane did not differ in birds of groups (a), (b) and (c), but was significantly greater (P < 0.05) in the fully refractory birds (group d). Similarly, the number of synaptic modifications was significantly greater (P < 0.05) in group (d) than in the other groups. These results are consistent with increased neural input to the LHRH perikarya in photorefractory birds after prolonged exposure to long days, although there was no indication of a change in input at the time of gonadal regression.

Animals↗
PubMed1993

Lens opacities in neurofibromatosis 2: further significant correlations.

This prospective study of 96 individuals from 29 families with neurofibromatosis 2, 49 of whom were affected, confirms in an extended series the previously reported association between posterior subcapsular/capsular cataract and neurofibromatosis 2. Posterior subcapsular/capsular cataracts were found in 36 (80%) of the 45 affected individuals (four individuals were excluded from statistical analyses). In addition, the association of peripheral cortical lens opacities with neurofibromatosis 2 was found to be statistically significant. Seventeen of the patients with neurofibromatosis 2 (37.8%) had peripheral cortical cataracts in comparison with none of the unaffected family members (p < 0.0001). In three patients peripheral cortical opacities were present despite the absence of posterior subcapsular/capsular cataracts. These findings support the inclusion of cortical cataracts of early onset, in addition to posterior subcapsular/capsular cataracts, in the diagnostic criteria of neurofibromatosis 2.

Adolescent↗