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M Skolnick

Publications and source records attributed to M Skolnick.

At least 19 recordsLinked to original sources
PubMed1991

Cytologic identification of clinically occult proliferative breast disease in women with a family history of breast cancer.

A cytologic method for sampling the normal breast by fine-needle aspiration (FNA) was used to determine the frequency of clinically inapparent proliferative breast disease (PBD) in women with family histories of breast cancer. The authors attempted to obtain specimens from each quadrant of both breasts in 51 female first-degree relatives of breast cancer patients. The study group had no detectable masses by physical examination or mammography. Samples were prepared on membrane filters, Papanicolaou stained, and evaluated cytomorphologically. Three hundred seventy-eight of 408 (92.6%) possible quadrants were sampled; cellular material was obtained from 290 (76.7%) quadrants. PBD was identified in 20 of the 51 women (39.2%). When epithelium was obtained, nuclear area, perimeter, and diameter were measured with the use of computerized image analysis. Nuclei in samples containing atypical hyperplasia showed significant differences in these parameters when compared with cells from samples containing normal epithelium or benign hyperplasia. The authors' findings indicate that FNA sampling and computerized image analysis are useful in the detection and characterization of clinically inapparent PBD.

Adipose Tissue↗
PubMed1991

Focal dorsal raphe stimulation and pinnal electrical stimulation modulate spontaneous and noxious evoked responses in thalamic neurons.

This study investigated the nocieceptive responses of single neurons within the nucleus parafascicularis (PF) thalami of the rat following two modes of electrical stimulation known to induce analgesia. It was found that both focal electrical dorsal raphe stimulation (DRS) and bilateral pinnal (ear) electrical stimulation (PES) converge on the same PF neurons, affecting both the spontaneous discharges and the noxious evoked responses toward these neurons. The effects of different stimulus current intensity, frequency and pulse duration were also examined. It was found that for both DRS and PES at pulse frequency of 10 Hz and current amplitude of 10 microA are the optimal parameters to modulate both the spontaneous and the noxious evoked responses. These stimuli produced prolonged effects related to the duration of stimulation. The external (PES) low current stimulation which was delivered below the sensory threshold was as effective in modulating noxious responses as the invasive DRS in intact animals and in animals with bilateral dorsolateral-funiculus ablation. It was observed that dorsal lateral funiculus ablation (DLFx) did not modify the DRS and the PES effects. These observations further support the existence of an ascending pain modulation pathway.

Animals↗
PubMed1990

Serotonin involvement in analgesia induced by transcranial electrostimulation.

The experiments described here were intended to investigate whether serotonin (5HT) may be involved in analgesia induced by low current transcranial electrostimulation (TE). The TE stimulus is a 10 mu-ampere, 10 Hz, pulsed current transmitted via electrodes in the pinnae. Combinations of the following were given as intraperitoneal injections: 300 mg/kg p-chlorophenylalanine (pCPA) 48 hours before testing, 100 mg/kg 5-hydroxytryptophan (5HTP) 30 min before testing and the saline vehicle for these drugs. Rats were tested prior to and 30 minutes after TE or sham TE. Testing for analgesia consisted of putting progressively increasing pressure on the rat tail 1/4 inch from the tip with a pneumatically driven, right angle wedge. The amount of pressure at which the rat moved its tail was measured both before and after TE, or sham TE, and recorded as the difference in tolerated peak pressure (DTPP). TE produced analgesia as manifested by a 613 percent increase in DTPP compared with sham TE treatment values. Among TE treated rats, pretreatment with pCPA decreased DTPP 91.5 percent compared with saline control values, indicating 5HT involvement. 5HTP restored TE induced analgesia in pCPA treated rats to the level of saline treated control animals, confirming 5HT involvement.

5-Hydroxytryptophan↗
PubMed1988

Dorsal raphe and external electrical stimulation modulate noxious input to single neurons in nucleus parafascicularis thalami.

Spontaneous discharges and nociceptive responses of 47 parafascicularis thalami (PF) neurons were recorded extracellularly and comparisons were made between the effects of these discharges following focal dorsal raphe stimulation (DRS) and bilateral pinnal electrical stimulation (PES). Eighty-three percent of PF neurons (N = 39) responded to noxious stimulus, about 69% of the PF responsive cells (N = 27) were excited during noxious stimuli and thus categorized as "nociceptive-on" cells. The remaining 31% (N = 12) were suppressed by the noxious stimuli, and were categorized as "nociceptive-off" cells. DRS and PES attenuated the spontaneous activity of the "nociceptive-on" neurons as well as the noxious input to these cells, while the spontaneous activity of the "nociceptive-off" cells was suppressed only following DRS and not following PES. Moreover, PES displayed disinhibiting properties, namely, it reduced the suppression effects elicited by noxious input. In conclusion, it was demonstrated that both focal DRS and noninvasive PES were effective in modulating pain input to single neurons in the PF.

Animals↗
PubMed1988

A mapped set of DNA markers for human chromosome 17.

We have developed and mapped by genetic linkage a primary set of markers for chromosome 17. The map consists of 21 loci derived from 27 probe/enzyme systems, including eight highly informative markers at loci containing a variable number of tandemly repeated DNA sequences (VNTRs). The map is continuous from the telomeric region of the short arm to the telomeric region of the long arm, covering estimated genetic distances of 218 cM in males and 279 cM in females. The average heterozygosity among all 21 loci in the population sample analyzed is 58%; 77% heterozygosity was observed among the eight VNTR markers that were highly informative. This map will make it possible to detect by linkage the location of genetic defects associated with chromosome 17 and will also provide anchor points for a high-resolution map of this chromosome.

Algorithms↗
PubMed1988

Insulin gene in familial NIDDM. Lack of linkage in Utah Mormon pedigrees.

Although non-insulin-dependent diabetes mellitus (NIDDM) is well recognized to be an inherited disease, the genetic lesion responsible remains to be determined. Several pedigrees have been reported in which defects of the insulin gene result in glucose intolerance or diabetes in affected members, but the role of insulin gene mutations in NIDDM is unknown. To evaluate this role, we ascertained 23 Caucasian pedigrees for a diabetic individual with at least one diabetic family member, sampled the unaffected individuals by a 75-g glucose tolerance test, and prepared leukocyte DNA on all family members. Included in the pedigrees ascertained were those with both predominantly lean and predominantly obese diabetic members and four pedigrees included as insulin-dependent diabetic individual. Insulin gene involvement was evaluated via previously described restriction-fragment-length polymorphisms (RFLPs) for the insulin gene and the nearby c-Ha-Ras oncogene (HRAS). Combination of these RFLPs resulted in the ability to trace the insulin alleles in all pedigrees studied. Analysis of individual pedigrees for sharing of insulin alleles was possible in 12 pedigrees, and lack of linkage was demonstrated in 6 of them. Neither linkage nor lack of linkage could be proved in the remaining pedigrees. Analysis of the pooled pedigree data failed to demonstrate linkage under several models, including autosomal-dominant and -recessive inheritance with different sporadic frequencies of diabetes and different prevalence figures. These results show that mutations of the insulin gene and the immediately surrounding area, including regulatory regions of the insulin gene, are unlikely to account for a significant subset of NIDDM in Caucasian individuals.

Diabetes Mellitus, Type 2↗
PubMed1988

Mapping of Alport syndrome to the long arm of the X chromosome.

Five X-chromosome DNA markers were typed on 261 members of three large kindreds with Alport syndrome (hereditary glomerulonephritis). Lod scores greater than 3.0 for linkage between the disease locus and two of the markers confirmed X-linked inheritance of the disease. A decreasing gradient in the estimated recombination fractions observed when the markers were ordered on the basis of their map locations suggested that the disease locus is on the long arm distal to all the markers typed in this study. Using three-locus analysis we rejected all but three map orders for the six loci (the disease locus and five markers). In all three the Alport syndrome locus was on the long arm of the X chromosome distal to all the markers. Two types of Alport syndrome were represented in the three kindreds. Affected males in one kindred developed deafness in addition to nephritis; deafness did not occur in members of the other two kindreds. Although larger recombination-fraction estimates were obtained for all five markers in the kindreds without deafness, the difference was significant for only one marker. Evidence of heterogeneity was not found in tests using two markers. Markers distal to the disease locus are needed to determine whether two loci are responsible for the two types of Alport syndrome.

Chromosome Mapping↗
PubMed1987

Detection of human somatic cell structural gene mutations by two-dimensional electrophoresis.

The feasibility of detecting human somatic structural gene mutations by two dimensional electrophoresis has been investigated. A lymphoblastoid cell line was grown as a mass culture in the presence of ethylnitrosourea, after which cells were regrown as single cell clones. A total of 257 polypeptide spots were analyzed in gels derived from 186 clones. Four structural mutations were detected by visual analysis of the gels. Computer analysis of gels corresponding to the mutant clones was also undertaken. At a spot size threshold of 200 spots to be matched using a computer algorithm, all four mutant polypeptides were detected. These results indicate the usefulness of the two-dimensional approach for mutagenesis studies at the protein level.

Clone Cells↗
PubMed1987

Tightly linked markers for the neurofibromatosis type 1 gene.

Relationships among genetic markers in the region of the neurofibromatosis type 1 (NF1) gene on chromosome 17 were investigated by linkage studies in a large sample set of affected families and in a panel of 58 normal families. A new marker, pHHH202 (D17S33), was included along with two markers known to be closely linked to NF. The maximum likelihood estimate of the recombination rate between the pHHH202 and NF1 loci was found to be O. Multilocus analysis suggested the following marker order: pA10-41-(p3-6, pHHH202); the NF1 gene fell with equal likelihood between either pA10-41-p3-6 or p3-6-pHHH202. The odds against NF1 being outside this cluster of tightly linked markers were greater than 15:1.

Chromosome Mapping↗
PubMed1986

The genetic aspects of neurofibromatosis.

Although the genetic pattern in NF has been definitely established as autosomal dominant, more precise data regarding penetrance, natural history, prevalence, and heterogeneity are needed for the counseling of families. NF is the prototypic disorder for the study of the biologic mechanisms of variable expressivity. The widely cited prevalence figure of Crowe is probably too high; thus the mutation ratio estimation in NF is among the highest in man but close to other common Mendelian disorders. With the existing data on frequency of Lisch nodules and with future prospective date on café-au-lait spot development, an age-of-onset penetrance curve for NF could be constructed for genetic counseling purposes. The segmental form of NF is of interest as cases of this presentation may be helpful in studying the hypothesis of human somatic mutation when DNA analysis is available. Guidelines for routine evaluation and ongoing health supervision of individuals with neurofibromatosis need to be developed; multidisciplinary NF clinics and collaborative study groups are appropriate settings for this undertaking. Neurofibromatosis is an important disorder for the study of the psychodynamic processes that families experience in dealing with uncertainty.

Adolescent↗
PubMed1985

Insulin gene analysis in a family with maturity-onset diabetes of the young.

The insulin gene locus has been studied in a large kindred with maturity-onset diabetes of the young (MODY) characterized by hypoinsulinemia. DNA was isolated from peripheral leukocytes of 42 family members and 5 spouses. A highly polymorphic region in the 5'-flanking portion of the human insulin gene provided an opportunity for linkage analysis. The presence of three different length polymorphisms of + 1600 base pairs (bp), - 50 bp, and - 150 bp different from the common size allele allowed haplotype assignment of insulin alleles. The hypothesis of linkage was tested by calculating the log of the ratio of the likelihood of the hypothesis of linkage to that of the hypothesis of nonlinkage (LOD score) at a given recombination distance between the insulin polymorphism and the diabetes locus. At a recombination frequency of 0.0, the LOD score was - 14.50 and, therefore, the hypothesis of tight linkage can be strongly rejected. This report is the third study of the relationship between the insulin locus and MODY; however, it is the first report in which a formal linkage analysis indicates with a high degree of probability no linkage between the insulin locus and hypoinsulinemia in a family. Because MODY is a heterogeneous disorder, it may be that different genotypes result in a composite phenotype. The lack of linkage between an insulin allele and MODY in a total of four families studied, however, suggests that the insulin locus is probably not a marker for the MODY phenotype. These results do not exclude the possibility that the insulin locus may be involved in the etiology of other forms of NIDDM.

Adolescent↗
PubMed1985

Hyperproinsulinemia in a family with a proposed defect in conversion is linked to the insulin gene.

Two previously described pedigrees with familial hyperproinsulinemia have elevated proinsulin conversion intermediates resulting from amino acid substitutions in the proinsulin molecule. In contrast, a third family with elevated levels of an apparently normal proinsulin molecule may have a defect in the converting process. To determine if the defect in this family lies in the insulin gene region, we used restriction fragment length polymorphisms adjacent to the insulin gene to examine cosegregation with hyperproinsulinemia. We demonstrate linkage of hyperproinsulinemia and the insulin gene in this family with a LOD score of 1.8, suggesting that the defect lies in or near the insulin gene. This method has wide applicability in determining whether hyperproinsulinemia or hyperinsulinemia is the result of defects at the insulin gene, and should permit the detection of new defects at or near this locus.

Alleles↗
PubMed1984

A general autosomal/X-linked model.

This paper describes a general genetic model which encompasses both autosomal and X-linked inheritance as submodels. It allows one to test for X-linked inheritance of a trait by comparing the likelihood of X-linked inheritance to the likelihood of the general genetic model. The general model is formulated as two loci, the first representing the trait locus and the second representing the sex chromosomes. The test for X-linked inheritance is a test of linkage between the two loci. Three data sets were analyzed using this approach. Each was also analyzed using a variant of a model introduced by Demenais and Elston [1981], which treats the transmission probabilities as estimable parameters. Similar conclusions were reached using either model.

Alleles↗
PubMed1983

The inheritance of immunoglobulin E: genetic linkage analysis.

Linkage analyses between 21 genetic markers including HLA-A, B, and the postulated locus for determining total serum IgE levels were done to try to clarify the inheritance of total IgE levels and to map the locus. A total of 316 individuals from five Mormon kindreds were studied, and data from an additional 204 Amish individuals from 11 families were analyzed for possible HLA linkage. Segregation analyses of both data sets did not give clear definition of the mode of inheritance of total IgE levels, but purely environmental models were rejected. Linkage analyses gave significant evidence against HLA linkage with the codominant, recessive, or dominant model of inheritance for total IgE levels. No significant evidence for linkage with any of the genetic markers was obtained. Since total serum IgE levels are correlated with allergies, understanding the genetics of total IgE levels is important to understanding the genetics of allergic disease in man.

Blood Group Antigens↗