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Biomedical subjects

A M Goldstein

Publications and source records attributed to A M Goldstein.

At least 73 records · Page 4Linked to original sources
PubMed1997

Sib-pair linkage analyses of nuclear family data: quantitative versus dichotomous disease classification.

Model-free sib-pair linkage analysis was used to screen 367 highly polymorphic markers for evidence of linkage to a disease, defined either quantitatively (Q1) or dichotomously (AF). Five individual replicates, plus a case family data set containing all families in these replicates with at least one individual with AF, were analyzed. Sib-pair linkage results for Q1 and AF varied considerably among the five replicates and did not consistently detect any of the three underlying major loci, MG1, MG2, and MG3. For the pooled case families, linkage analyses of Q1, but not AF, detected the flanking markers for MG1 and MG2 at the 0.05 and 0.01 levels, respectively. Overall, type 1 error rates were not elevated. The ability to analyze the disease quantitatively (Q1) and construct a data set more appropriate for linkage analysis (case families) enhanced the power to detect at least some of the major loci underlying the disease.

Genetic Diseases, Inborn↗
PubMed1997

Femoral venous access is safe in burned children: an analysis of 224 catheters.

OBJECTIVE: To document the incidence of septic and mechanical complications associated with femoral venous catheters in a subgroup of patients thought to be at particularly high risk of both: young children with large burns. DESIGN: An analysis of data collected prospectively on all femoral venous catheters placed during a 4-year period at a regional pediatric burn facility. RESULTS: There were 224 femoral catheters placed in 86 children with an average age of 5.3 +/- 5.1 years and an average burn size of 38% +/- 23%. Catheters were left in place for a mean duration of 5.7 days. Catheter-related sepsis occurred with 4.9% of the catheters, and mechanical complications occurred in 3.5% of the patients. There was no statistically significant association between the risk of catheter sepsis and the placement of catheters through burned versus unburned skin. Similarly, the risk of sepsis was equivalent between lines placed over a guide wire and those placed of a new site. CONCLUSION: Femoral venous catheters are safe in burned children and are associated with a low incidence of infectious and mechanical complications.

Burns↗
PubMed1997

The genetics of melanoma.

OBJECTIVES: To review the current status and recent advances of genetic epidemiology research in familial melanoma, and the implications for primary and secondary prevention of melanoma. DATA SOURCES: Research studies, review articles, and book chapters pertaining to melanoma susceptibility factors. CONCLUSION: Molecular genetic studies examining candidate genes for melanoma are being pursued vigorously. Considering the complexities and heterogeneity in the genetics of familial melanoma, predictive testing is not currently recommended as an established method for identifying individuals with a genetic predisposition to melanoma. IMPLICATIONS FOR NURSING PRACTICE: An understanding of the genetics of melanoma will help oncology nurses in translating the appropriate clinical implications for primary and secondary prevention related to melanoma.

Humans↗
PubMed1997

Second cancers after medulloblastoma: population-based results from the United States and Sweden.

Medulloblastoma, one of the most common central nervous system (CNS) tumors in children, requires aggressive multimodality therapy including surgery, radiation therapy, and occasionally chemotherapy. Given its intensive treatment regimen and improved survival during the past 20 years, it is likely that a cohort of survivors will result who may incur consequences of therapy, including a second cancer. We used population-based data from the United States and Sweden to estimate risks of second neoplasms in patients with histologically confirmed medulloblastoma (n = 1,262). Overall, there was a 5.4-fold excess of second neoplasms (95 percent confidence interval = 3.3-8.4) based on 20 observed and 3.7 expected cancers. The second cancers occurred eight to 432 months after initial diagnosis (median, 73 months) with significantly elevated ratios for all intervals examined except for less than one year after initial diagnosis. Significantly elevated risks were seen for cancers of the salivary glands, cervix uteri, brain and CNS, thyroid gland, and acute lymphoblastic leukemia. Of the 15 second cancers with treatment data, seven occurred in the radiation field or within areas of scatter while two others may have been radiation-related. Although based on small numbers of second cancers, the results suggest that as survival increases, some patients with medulloblastoma will have an increased risk of a second cancer, particularly a radiation-related cancer. Thus, as survival improves, late-occurring consequences of diagnosis and treatment will need to be carefully assessed. Identification of patients hypersensitive to radiation therapy, such as those with Gorlin Syndrome, should also be attempted in order to reduce the sequelae from intensive radiation exposure.

Adolescent↗
PubMed1997

Affected members of melanoma-prone families with linkage to 9p21 but lacking mutations in CDKN2A do not harbor mutations in the coding regions of either CDKN2B or p19ARF.

Mutations in the gene encoding the cell cycle inhibitor CDKN2A have been identified in some melanoma kindreds linked to 9p21. However, many such families show no evidence of mutations in the coding regions of CDKN2A. In this study, we examined whether two other potential tumor suppressors, CDKN2B and p19ARF, which also map within the 9p21 region, play a role in the development of familial melanoma. We found no mutations in the coding regions of either gene in melanoma-prone families with evidence of linkage to 9p21. We conclude either that another melanoma susceptibility gene exists within this chromosomal area or that mutations in noncoding regions of CDKN2A, CDKN2B, or p19ARF predispose to melanoma.

Carrier Proteins↗
PubMed1996

Mutations in the human homologue of the Drosophila patched gene in Caucasian and African-American nevoid basal cell carcinoma syndrome patients.

The nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin syndrome, is a multisystem autosomal dominant disorder. The salient features of this syndrome include multiple basal cell carcinomas, palmar and/or plantar pits, odontogenic keratocysts, skeletal and developmental anomalies, and ectopic calcification. Other features include such tumors as ovarian fibromas and medulloblastomas. There is extensive interfamilial as well as intrafamilial variability with respect to the manifestation and severity of the phenotype. Alterations in the human homologue (PTCH) of the Drosophila segment polarity gene patched have been identified in NBCCS patients as well as tumors associated with this syndrome. We report several mutations in this gene in NBCCS patients and present the clinical phenotypes of the individuals in whom these mutations were identified.

Basal Cell Nevus Syndrome↗
PubMed1996

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

Alleles↗
PubMed1996

DR2/DQw1 inheritance and haplotype sharing in affected siblings from multiple sclerosis families.

Although the human leukocyte antigen DR2/DQw1 allele has been associated with multiple sclerosis, studies of DR2/DQw1 inheritance in multiple sclerosis multiplex families have yielded conflicting results. We examined this question in "high-incidence" families, defined as families with more than 50% of siblings affected. DR2/DQw1 allele frequencies were significantly increased, particularly in mothers and affected siblings (p < 0.0001). The transmission of DR2/DQw1 from both parents was more frequent in affected offspring (p = 0.005). While evidence for segregation of disease with a particular parental allele was lacking in most families, the frequency of haplotype sharing was higher in affected sib pairs (p < 0.01).

Alleles↗
PubMed1996

Localization of the gene for Cowden disease to chromosome 10q22-23.

Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.

Breast Neoplasms↗
PubMed1996

Use of relatives of cases as controls to identify risk factors when an interaction between environmental and genetic factors exists.

BACKGROUND: The difficulty in detecting relevant risk factors for chronic diseases (such as breast and colon cancer) may be due to heterogeneity in the populations of studied cases, and one source of heterogeneity may be differential genetic susceptibility predisposing to differential environmental sensitivity. METHODS: The purpose of this investigation is to determine whether the estimates of odds ratios are modified by using relatives as controls when risk factors interact with an underlying genetic factor. RESULTS: We demonstrate that using relative controls in matched case-control studies produces odds ratios different from population-based odds ratios. This difference is dependent on the amount of interaction between the genetic and environmental factors and on the genetic correlation between relatives. CONCLUSIONS: In the case of a common disease, the use of relatives as controls could be helpful in detecting interaction between an exposure and an underlying genetic factor when the genetic factor is common.

Case-Control Studies↗
PubMed1996

Apparent anticipation in familial melanoma.

Genetic anticipation refers to progressively earlier age at diagnosis (AAD) and/or increasing severity of a disorder in successive generations. Previous examination of 23 familial melanoma kindreds revealed evidence for a dramatic reduction in AAD in successive generations. To further evaluate evidence for anticipation, we examined the AAD, number of tumours, and tumour thickness in affected parent-offspring (P-O) pairs from these 23 kindreds. Number of tumours and tumour thickness were also evaluated by generation. There were statistically significant intergenerational differences for AAD and number of tumours in the 47 affected P-O pairs. Median AAD decreased from 48 years to 28 years. The median AAD in the offspring (AADo) of a parent with CMM (median 28, mean 29.3 +/- 10.1 years, n = 51) was significantly different from the median AADo of a parent without CMM (42, 42.3 +/- 13.9 years, n = 55) (P < 0.001). In addition, parents with AAD less than the median of 48 years had offspring with a median AAD (26, 25.8 +/- 8.5 years, n = 21) significantly different from those of parents with AAD > or = 48 years (32, 34.5 +/- 10.2 years, n = 26) (P = 0.005). Ninety-four percent (44/47) of the P-O pairs showed positive anticipation, with 62% showing anticipation of > 15 years. There was little difference based on the affected parent's sex. In the 106 CMM cases there were no significant differences in tumour number (P = 0.08) or tumour thickness (P = 0.85) by generation. Number of tumours was however significantly different in cases with AAD < 34 years (n = 52, median 1.5, mean 2.3 +/- 2.4) vs cases with AAD > or = 34 years (n = 54, 1.0, 1.6 +/- 1.7) (P < 0.001). Thus these 23 familial melanoma kindreds showed evidence for anticipation as defined by a decrease in AAD in successive generations. Although increased surveillance may partly explain the results, additional studies should evaluate melanoma risk factors, genetic and/or environmental, across generations to examine the reasons for the apparent anticipation.

Age of Onset↗
PubMed1996

Two-locus linkage analysis of cutaneous malignant melanoma/dysplastic nevi.

Previous linkage analyses of 19 cutaneous malignant melanoma/dysplastic nevi (CMM/DN) kindreds showed significant evidence of linkage and heterogeneity to both chromosomes 1p and 9p. Five kindreds also showed evidence of linkage (Z>0.7) to both regions. To further examine these findings, we conducted two-trait-locus, two-marker-locus linkage analysis. We examined one homogeneity and one heterogeneity single-locus model (SL-Hom and SL-Het), and two-locus (2L) models: an epistatic model (Ep), in which CMM was treated as a genuine 2L disease, and a heterogeneity model (Het), in which CMM could result from disease alleles at either locus. Both loci were modeled as autosomal dominant. The LOD scores for CMM alone were highest using the SL-Het model (Z = 8.48, theta = .0). There was much stronger evidence of linkage to chromosome 9p than to 1p for CMM alone; the LOD scores were approximately two times greater on 9p than on 1p. The change in LOD scores from an evaluation of CMM alone to CMM/DN suggested that a chromosome 1p locus (or loci) contributed to both CMM and CMM/DN, whereas a 9p locus contributed more to CMM alone. For both 2L models, the LOD scores from 1p were greater for CMM/DN than for CMM alone (Ep: Z=4.63 vs. 3.83; Het: 4.94 vs. 3.80, respectively). In contrast, for 9p, the LOD scores were substantially lower with CMM/DN than with CMM alone (Ep: 4.64 vs. 7.06; Het: 5.38 vs. 7.99, respectively). After conditioning on linkage to the other locus, only the 9p locus consistently showed significant evidence for linkage to CMM alone. Thus, the application of 2L models may be useful to help unravel the complexities of familial melanoma.

Adult↗
PubMed1995

Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.

BACKGROUND: A gene on chromosome 9p, p16INK4, has been implicated in the pathogenesis of cutaneous malignant melanoma in 19 melanoma-prone families. In 10 of these kindreds mutations that impaired the function of the p16INK4 protein (p16M alleles) cosegregated with the disease. By contrast, in the other nine kindreds the mutation did not alter the function of p16INK4 (p16W alleles). We looked for differences in clinical and genetic epidemiologic features in these two groups of families. METHODS: We compared the median ages at diagnosis of melanoma, number of melanomas, thickness of the tumors, and number of nevi in the kindreds. We estimated prospectively the risks of melanoma or other cancers in families followed for 6 to 18 years and the risks of other cancers since 1925 (the entire period) by comparing the number of cancer cases observed with the number expected. RESULTS: The risk of invasive melanoma was increased by a factor of 75 in kindreds with p16M alleles and a factor of 38 in kindreds with p16W alleles. Although this difference was not significant (P = 0.14), there was a striking difference in the risk of other tumors. In kindreds with p16M alleles, the risk of pancreatic cancer was increased by a factor of 13 in the prospective period (2 cases observed, 0.15 expected; standardized incidence ratio, 13.1; 95 percent confidence interval, 1.5 to 47.4) and by a factor of 22 in the entire period (7 cases observed, 0.32 expected; standardized incidence ratio, 21.8; 95 percent confidence interval, 8.7 to 44.8). In contrast, we found no cases of pancreatic cancer in kindred with p16W alleles. CONCLUSIONS: The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic factors, such as the kind of mutation found in p16INK4, may explain the inconsistent occurrence of other cancers in these kindreds.

Adult↗
PubMed1995

Mutations associated with familial melanoma impair p16INK4 function.

Cell division is controlled by a series of positive and negative regulators which act at sequential points throughout the cell cycle. Disturbance of these checks could contribute to cancer by allowing excessive cell proliferation. The point in G1 at which cells irrevocably commit to DNA synthesis is controlled by protein complexes consisting of cyclin-dependent kinases (CDK4 or CDK6) and cyclins (D1, D2 or D3). These complexes are inhibited by low molecular weight proteins, such as p16INK4 (refs 1,2), p15INK4B (ref. 3) and p18 (ref. 4). Deletion or mutation of these CDK-inhibitors could lead to unchecked cell growth, suggesting that members of the p16INK4 family may be tumour suppressor genes. The recent detection of p16INK4 (MTS1) mutations in familial melanoma kindreds, many human tumour cell lines, and primary tumours is consistent with this idea. Previously, we described eight germline p16INK4 substitutions in 18 familial melanoma kindreds. Genetic analyses suggested that five mutations predisposed carriers to melanoma, whereas two missense mutations had no phenotypic effect. We now describe biochemical analyses of the missense germline mutations and a single somatic mutation detected in these families. Only the melanoma-predisposing mutants were impaired in their ability to inhibit the catalytic activity of the cyclin D1/CDK4 and cyclin D1/CDK6 complexes in vitro. Our data provide a biochemical rationale for the hypothesis that carriers of certain p16INK4 mutations are at increased risk of developing melanoma.

Animals↗
PubMed1995

Prospectives for cutaneous malignant melanoma. Considerations of the precursor state and heritability.

Each of the discoveries through the years has begotten a series of Gordian knots. We must patiently inspect our new collection of mysteries and focus on those where our efforts may well change the course of the disease to the benefit of affected patients. The proper management of the precursor state, the beginning of the disease, and the patient exploration of the complexities of heritability would seem to be appropriate beginnings.

Disease Susceptibility↗
PubMed1995

Parenchymal-stromal interactions in neoplasia. Theoretical considerations and observations in melanocytic neoplasia.

The paper briefly reviews the reciprocal and continuous reciprocal interactions between epithelia, mesenchyme, and extracellular matrix in the development and maintenance of organismal form in multicellular organisms in the animal kingdom and describes the progressive changes in parenchymalstromal interactions in melanocytic neoplastic development and progression. In addition to the parenchymal stromal form in non-lesional skin seven different and unique stromal patterns are described. These have been termed: 1) The stroma (diff-regress) of programmed differentiation leading to lesional regression characteristic of common nevi; 2) concentric eosinophilic fibroplasia (cef), the hallmark of precursor nevi (dyplastic nevi) with and without melanocytic nuclear atypia; 3) Fibroplasia with angiogenesis (fa) commonly seen in superficial spreading melanoma without metastic competence (SSM); 4) Lamellar fibroplasia (lf) seen in precursor nevi and melanomas with and without metastatic competence; 5) Diffuse fibroplasia with angiogenesis (dfa), 6) Narrow, uniform concentric eosinophilic fibroplasia (nucef), 7) No parenchymal-stromal interaction (nopsi); the last three being seen in the heterogeneous stroma of melanomas of the superficial spreading type with metastatic competence. The changes in neoplastic stroma proceed in concert with the changes in the parenchyma characteristic of melanocytic tumor progression.

Animals↗