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K Snow

Publications and source records attributed to K Snow.

At least 37 records · Page 2Linked to original sources
PubMed1994

Length of uninterrupted CGG repeats determines instability in the FMR1 gene.

Analysis of 84 human X chromosomes for the presence of interrupting AGG trinucleotides within the CGG repeat tract of the FMR1 gene revealed that most alleles possess two interspersed AGGs and that the longest tract of uninterrupted CGG repeats is usually found at the 3' end. Variation in the length of the repeat appears polar. Alleles containing between 34 and 55 repeats, with documented unstable transmissions, were shown to have lost one or both AGG interruptions. These comparisons define an instability threshold of 34-38 uninterrupted CGG repeats. Analysis of premutation alleles in Fragile X syndrome carriers reveals that 70% of these alleles contain a single AGG interruption. These data suggest that the loss of an AGG is an important mutational event in the generation of unstable alleles predisposed to the Fragile X syndrome.

Base Sequence↗
PubMed1994

Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation.

This study addresses mechanism of instability of the FMR-1 (CGG)n-repeat, and investigates features which may distinguish between normal stable and fragile X unstable repeats. To achieve this, we have sequenced 178 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n-repeat at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines instability. We predict that certain sequence configurations [no AGG, and (CGG)9-11AGG(CGG) > or = 20] present in the general population, are predisposed towards replication slippage. Association between these proposed predisposing repeats and DXS548 alleles may explain the previously reported frequencies of fragile X mutations and large-size normal repeats on specific haplotype backgrounds. We propose that predisposing alleles arise in the general population by as yet undefined mechanism(s) which introduce a relatively long stretch of pure CGG repeat at the 3'-end (relative to the direction of transcription) of the FMR-1 repeat region. The 3' pure repeat may then be susceptible to further expansion by replication slippage. Slippage on these predisposing chromosomes could accumulate over many generations until a threshold size is reached, at which point the repeat is susceptible to greater instability (i.e. premutation stage). Thus, results suggest that evolution of fragile X full mutations could involve 4 definable stages: 1) ancestral events leading to the formation of predisposing alleles which have large total repeat length (e.g. between 35 to 50) but no AGG or 1 AGG; 2) gradual slippage of these predisposing alleles to small premutations (S alleles); 3) conversion from S alleles to larger premutations (Z); 4) massive expansion from a Z allele to a full mutation (L).

Alleles↗
PubMed1994

Is there a relationship between autoantibodies and silicone-gel implants?

The present study was conducted to determine if 200 patients with silicone-gel implants demonstrated elevated levels of autoantibodies, compared with a similar group of 100 age-matched control subjects without breast implants. These results were then compared with 29 patients who had demonstrated implant rupture. Differences in the frequency of autoantibody levels were determined by the chi-squared test. Differences in autoantibody titers were determined by Wilcoxon's signed rank test. Differences were considered significant with p > 0.05. The prevalence of a positive antinuclear antibody (ANA) test (dilution 1:100) in the 200 patients with breast implants was 26.5% compared with 28% in the 100 control subjects. In 29 patients with implant rupture, only 17.2% tested ANA positive. These values were not significantly different. In addition, there were no significant differences between the ANA titers of positive patients in each group. In each of the three groups, all patients who tested ANA positive were analyzed to assess the frequency and titer of other autoantibodies, including anti-DNA, anti-cardiolipin, anti-SSA, anti-SSB, anti-SM, anti-RNP, and anti-Scl-70. There were no significant differences between the frequency or titer of any of these autoantibody levels in each of the three groups of patients. These studies strengthen the concept that there is no conclusive evidence that silicone-gel implants are related to the development of connective tissue disease.

Adult↗
PubMed1993

Doctors under the knife.

With Bill Clinton's new reforms only a month away, the health-care system is on the operating table--and the doctors are under the knife. Americans have a love-hate relationship with physicians: they like the care that doctors provide but hold them to blame for the nation's health-care mess. NEWSWEEK looks at how the culture of medicine may change, assesses doctors' fears--and examines the brave new world of HMOs.

American Medical Association↗
PubMed1993

Molecular-clinical correlations in children and adults with fragile X syndrome.

INTRODUCTION: Fragile X syndrome is the most commonly known inherited form of mental retardation. The intellectual abilities range from a normal IQ with learning disabilities to severe mental retardation. In males, there is a tendency for IQ decline in childhood. The purpose of this study was to correlate variations of the molecular cytosine guanine guanine (CGG) amplification in the fragile X mental retardation-1 (FMR-1) gene with the clinical findings, including IQ and physical features. METHODS: Full-scale IQ and cytogenetic results in 116 individuals with the FMR-1 mutation were studied. The IQ testing was performed with age-appropriate standardized tests. Physical features were summarized in a physical index score for each patient. The FMR-1 results were determined with the OX1.9 probe and the following system was used: P1 indicates premutation; P2, large premutation to small full mutation; P3, full mutation; and P4, mosaic. RESULTS/CONCLUSIONS: The findings showed that those females with a small insert in the P1 range had a significantly higher IQ than other heterozygotes (P2, P3, and P4 categories). P4 males had a significantly higher IQ than P2 or P3 males. In cross-sectional age comparisons, the slope of the IQ decline was greater in P2 males than in P4 or P3 males.

Adolescent↗
PubMed1993

The polymerase chain reaction. Applications in dermatology.

Within the space of the last 5 years, application of the revolutionary in vitro method of deoxyribonucleic acid (DNA) amplification known as the polymerase chain reaction (PCR), has become ubiquitous. The rapidly increasing number of clinical and research articles utilizing this technology, both in the dermatologic and general medical literature, requires one to have at least a basic understanding of how the PCR is conducted, what it has to offer, and the potential shortcomings. Such knowledge will hopefully allow a more critical appraisal of an increasingly complex literature. This review aims to describe the methodology and medical applications of this powerful technique with special consideration to the increasing role PCR may have on dermatologic research and practice.

Genetic Diseases, Inborn↗
PubMed1993

Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population.

In this study, we have characterized a CGG repeat at the FMR-1 locus in more than 100 families (more than 500 individuals) presenting for fragile X testing and in 247 individuals from the general population. Both Southern blot and PCR-based assays were evaluated for their ability to detect premutations, full mutations, and variability in normal allele sizes. Among the Southern blot assays, the probes Ox1.9 or StB12.3 with a double restriction-enzyme digest were the most sensitive in detecting both small and large amplifications and, in addition, provided information on methylation of an adjacent CpG island. In the PCR-based assays, analysis of PCR products on denaturing DNA sequencing gels allowed the most accurate determination of CGG repeat number up to approximately 130 repeats. A combination of a Southern blot assay with a double digest and the PCR-sequencing-gel assay detected the spectrum of amplification-type mutations at the FMR-1 locus. In the patient population, a CGG repeat of 51 was the largest to be stably inherited, and a repeat of 57 was the smallest size of premutation to be unstably inherited. When premutations were transmitted by females, the size of repeat correlated with risk of expansion to a full mutation in the next generation. Full mutations (large repeats typically associated with an abnormal methylation pattern and mitotic instability) were associated with clinical and cytogenetic manifestations in males but not necessarily in females. In the control population, the CGG repeat ranged from 13 to 61, but 94% of alleles had fewer than 40 repeats. The most frequent allele (34%) was a repeat of 30. One female had an allele (61 repeats) within a range consistent with fragile X premutations, while two other individuals each had a repeat of 52. This suggests that the frequency of unstable alleles in the general population may be approximately 1%.

Blotting, Southern↗
PubMed1992

Characterization of human sperm antigens and antisperm antibodies in infertile patients.

OBJECTIVE: To identify which sperm antigens may elicit the production of functionally important antisperm antibodies. DESIGN: Immunoblot analysis was performed on 69 serum and 9 seminal plasma samples from infertile patients, using detergent extracts of pooled donor sperm as the antigen source. Serum and seminal plasma had been previously tested by an indirect immunobead binding test (IBT); 61 IBT-positive and 17 IBT-negative samples were included in the study. Proteins recognized by IBT-positive but not IBT-negative samples were most likely to be cell surface antigens, whereas proteins recognized by both IBT-positive and IBT-negative samples were probably intracellular. Antibodies directed toward surface antigens would be most likely to affect fertilization. Characterization of sperm surface proteins on both acrosome-intact and -reacted sperm used labeling of cell surface proteins with an N-hydroxysuccinimide ester of biotin, fractionation of sperm heads and tails, and lectin binding to determine glycosylation. RESULTS: Specific immunoreactivity (with respect to IBT results) was observed to 35K, 40 to 45K, 57K, 66K, and 88 to 90K MW proteins. Characterization studies identified an 88K MW glycosylated plasma membrane protein, a 66K MW inner acrosomal membrane protein, a 34K MW inner acrosomal membrane protein, and a 35K MW prominent tail protein. CONCLUSION: Immunological infertility may involve several antigens characterized in this study. Further studies are necessary to determine if antibodies to these specific proteins interfere with sperm function.

Acrosome↗
PubMed1992

Biochemical evaluation of adrenal dysfunction: the laboratory perspective.

In this study, we reviewed the diagnostic efficiency of laboratory tests that are performed for assessment of patients with Cushing's syndrome or adrenal insufficiency. Baseline laboratory data from patients subsequently diagnosed with adrenal dysfunction were analyzed for tests performed between 1987 and 1989 at our institution. Results were analyzed for 36 patients diagnosed with pituitary-dependent Cushing's syndrome, 15 with ectopic Cushing's syndrome, 12 with adrenal-dependent Cushing's syndrome, 20 with primary adrenal insufficiency, and 7 with secondary adrenal insufficiency. Tests reviewed were plasma cortisol, plasma corticotropin, urinary free cortisol, urinary 17-ketosteroids, urinary ketogenic steroids, low-dose and high-dose dexamethasone suppression, and metyrapone stimulation. Our findings suggest that a substantial proportion of diagnoses could be based on the results of three tests--plasma corticotropin, plasma cortisol, and urinary free cortisol. We present a nomogram that combines the results of plasma corticotropin and plasma cortisol testing to enhance the diagnostic efficiency of these tests.

Adolescent↗
PubMed1991

Characterisation of adriamycin- and amsacrine-resistant human leukaemic T cell lines.

Cell lines resistant to adriamycin and amsacrine were derived from cloned sublines of the human T cell line Jurkat. Most of the lines resemble atypical MDR cells (Danks et al., 1987; Beck et al., 1987). Thus, resistant Jurkat sublines were cross resistant to several topoisomerase II inhibiting drugs but had low or no resistance to other classes of drugs, resistance was not reversed by verapamil, Pgp was not overexpressed, and drug accumulation was unaltered in resistant compared to parental (control) sublines. Other findings were that anthracycline metabolism differed between resistant and parental sublines, and that resistant sublines displayed altered expression of small polypeptides (less than 20K MW) and an 85K MW protein. Drug resistant cells showed resistance to the production of drug induced cytogenetic aberrations, DNA breaks, and protein-DNA complexes. Resistance was not mediated by altered binding of drugs to DNA or by increased repair of DNA damage. Indirect evidence suggests that the resistant cells had an altered drug-DNA-topoisomerase II association. The study highlights the complex relationships between DNA breaks, cytogenetic aberrations, protein-DNA complexes and drug cytotoxicity, and shows that the relationships differ for adriamycin and amsacrine, suggesting some differences in the modes of action and/or resistance for the drugs and cell lines.

Amsacrine↗
PubMed1991

Effects of maternal diabetes on fetal rat lung ion transport. Contribution of alveolar and bronchiolar epithelial cells to Na+,K(+)-ATPase expression.

Fetuses of streptozotocin-induced diabetic rats exhibited delayed lung maturation and a 40% reduction in the steady-state level of lung Na+,K(+)-ATPase alpha 1 subunit mRNA and Na+,K(+)-ATPase activity at 21 d of gestation. In in situ hybridization experiments the signal specific for Na(+)-pump alpha 1 subunit message was strongest above columnar epithelial cells of air-conducting structures. Strong labeling was also present above cuboidal cells lining the forming alveoli, but not above mesenchymal cells. Immunocytochemical localization of the protein paralleled the distribution of the mRNA. Mesenchymal cells were more abundant in fetal lungs of diabetic mothers, and thus the decreased overall levels of Na+,K(+)-ATPase may result from the observed morphological pulmonary immaturity. One day after birth there was no apparent difference in lung morphology at the light microscopic level, in the localization or the steady-state level of Na+,K(+)-ATPase alpha 1 isoform mRNA, or in enzyme activity. Na+,K(+)-ATPase has a likely role in the active phase of fluid absorption in the airways of newborns before the onset of breathing. Decreased fluid clearance and lack of thinning of the lung's connective tissue may contribute to the increased risk for respiratory distress in infants of diabetic mothers.

Animals↗
PubMed1990

Multiple patterns of resistance of human leukemia cell sublines to amsacrine analogues.

The antileukemia drug amsacrine and seven analogues were tested for in vitro activity against five multidrug-resistant human leukemia cell sublines (two derived from each of two Jurkat parent lines and one from the K562 line) and the corresponding parent lines (Jurkat, K562, and P388 leukemia). Resistant cell lines were derived by exposure to either amsacrine or doxorubicin. The resistance factor was calculated as the ratio of the mean IC50 value for the resistant cell line to that for the parent line. IC50 was defined as the concentration of drug inhibiting cell growth to 50% of that in control (drug-free) cultures. Patterns of cross-resistance were visualized by plotting the deviations of resistance factors from the mean resistance factor, on a logarithmic scale. Considerable variations in resistance factors were noted for each cell subline as the amsacrine substituents were altered. Four main patterns were evident: a transport-related multidrug-resistance pattern (three sublines), a pattern similar to that for a murine P388 leukemia subline resistant to amsacrine, and two patterns not observed previously. Since some of the sublines tested showed evidence of altered topoisomerase II activity, it appears that changes in the resistance pattern in these lines may reflect changes in the stability of the ternary complexes formed by the drug, the altered enzyme, and the DNA. The resistance factor was reduced from more than 100-fold to about 13-fold in three of the sublines tested and from eightfold to twofold in two others. This finding suggests that appropriate drug design may overcome several forms of multidrug resistance in human leukemia and other types of cancer.

Amsacrine↗
PubMed1990

In vitro production of interferon-gamma by peripheral blood from patients with Graves' disease, Hashimoto's thyroiditis and rheumatoid arthritis.

The production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells (PBMC), CD4 cells, or CD8 cells in response to interleukin-2 (IL-2) stimulation has been studied; the samples were obtained from 12 healthy control subjects, 19 patients with Graves' disease (10 hyperthyroid and nine euthyroid), 13 patients with Hashimoto's thyroiditis (four hypothyroid and nine euthyroid), and 15 patients with rheumatoid arthritis (11 active and four inactive). A dose of IL-2 (25 U/ml) was utilized to induce IFN-gamma by PBMC from all four groups. The incremental increase in IFN-gamma values (with IL-2 stimulation minus without stimulation) was significantly less in PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis than that in PBMC from control subjects. The values from PBMC in patients with Graves' disease in a euthyroid state were below normal but greater than those from patients with Graves' disease in a hyperthyroid state. The incremental increase in IFN-gamma values from Graves' disease PBMC correlated with the serum TSH values (r = 0.622, P less than 0.01), but not with thyroid autoantibodies (anti-thyroid microsomal antibodies, anti-thyroid microsomal antibodies, nor TSH-binding inhibitory immunoglobulin activities). The incremental increase in IFN-gamma from PBMC from both control subjects and Graves' disease was correlated with that from CD4 cells (r = 0.711, P less than 0.01), but not with that from CD8 cells. The production of IFN-gamma in response to IL-2 from PBMC in Graves' disease correlated inversely with thyroid function, appearing to reflect the very effect of hyperthyroidism in this process. The precise explanation of these phenomena remains unclear. The decreased response of IFN-gamma to IL-2 stimulation by PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis seems to be a non-specific phenomenon occurring in both organ specific autoimmune disease and systemic autoimmune disease. It may be due to a down-regulation in autoimmune disease of CD4 cells in response to IL-2, a decreased level of IL-2 cellular receptors or a decreased receptor affinity, associated increased soluble IL-2 receptors, or a defect of the intra-CD4 cellular IL-2 signal to produce or release IFN-gamma in the conditions studied.

Adult↗
PubMed1990

Intrinsic pituitary interleukin-1 beta is induced by bacterial lipopolysaccharide.

Using a specific antiserum recognizing recombinant rat interleukin-1 beta (IL-1 beta), immunoreactive material was localized to cytoplasmic granules in anterior pituitary endocrine cells and colocalized with TSH in thyrotropes. Authenticity was established by Northern blot hybridization using a specific rat IL-1 beta cRNA probe, revealing a 1.8-kilobase mRNA identical to that in the spleen. The marked increase in anterior pituitary IL-1 beta message after the administration of bacterial lipopolysaccharide, raises the possibility that IL-1 beta may be involved in paracrine or autocrine regulation of pituitary function during infectious challenge.

Animals↗
PubMed1988

Reactivity of T-cells from patients with rheumatoid arthritis to anti-CD3 antibody.

The ability of an anti-CD3 monoclonal antibody (OKT3) to induce proliferation was examined in peripheral blood mononuclear cells (PBM) from 30 patients with rheumatoid arthritis (RA). Controls consisted of 10 patients with osteoarthritis, 12 patients with psoriatic arthritis, and 12 healthy subjects. The results revealed enhanced PBM reactivity in patients with active RA relative to inactive RA patients and all control groups. PBM of patients with mild/moderate clinical disease activity exhibited augmented anti-CD3 reactivity while those with severe disease demonstrated impaired reactivity. Enhanced reactivity was also observed in the active RA group using another anti-CD3 monoclonal antibody (Leu-4). Differences in anti-CD3 dose-response or time kinetics could not account for the results. Studies of enriched T-cell preparations revealed a markedly enhanced anti-CD3 reactivity of RA T-cells relative to normal control T-cells. Monocyte/T-cell mixing experiments revealed no enhanced reactivity of RA monocytes in the anti-CD3 response. RA T-cell preparations depleted of monocytes by limiting dilution reacted significantly more to anti-CD3 in the presence of IL-2 relative to controls. The enhanced reactivity could be accounted for in part by hyperreactivity of the OKT8-bearing subpopulation of T-cells.

Antibodies, Monoclonal↗
PubMed1987

Heterogeneity of a human T-lymphoblastoid cell line.

A human T-lymphoblastoid cell line (Jurkat) was cloned, and four resulting sublines were characterized in a variety of ways with the objective of gaining information on heterogeneity in cell lines. Within a few weeks of cloning, distinct cellular morphologies and growth patterns became apparent in the four sublines. Growth rate measurements made over 3 months did not show any significant differences between the sublines. Surface protein profiles obtained by radioimmunoprecipitation using antisera in conjunction with extracts from [35S]Met and 125I-labeled cells revealed differences between the sublines. Analysis of total cell DNA showed that one of the sublines possessed only half the chromosome complement of the other sublines and the parental line. Karyotyping confirmed this result and, in addition, demonstrated that chromosome numbers fluctuated around a mean value for each subline. Karyotypic variability became apparent within 2 months of cloning and tended to increase with time in culture. G-banding analysis showed that the analyzed cell populations contained distinctive cytogenetic aberrations. Properties of the cloned sublines were monitored over a 9-month period. One of the sublines that had shown heterogeneous morphology even after 6 weeks maintained the heterogeneity throughout this time. Another subline underwent a marked change in morphology (round to irregular) and growth habit (single cells to large clumps) with increasing time in culture. Interestingly, several alterations to surface proteins accompanied these growth changes. A third subline had relatively stable morphology and chromosome number throughout the 9-month period. The modal chromosome number was hypotetraploid for three sublines and the parent line, but was diploid for another subline. However, it was interesting that progression toward tetraploidy in this subline was apparent after almost 2 years of culturing. The results showed that the original cell line consisted of a heterogeneous assemblage of cell types, some of which were quite unstable. Some implications for research using cultured cell lines are discussed.

Adolescent↗
PubMed1985

Yesterday's O.R.

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Humans↗