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Biomedical subjects

M G Butler

Publications and source records attributed to M G Butler.

At least 55 records · Page 3Linked to original sources
PubMed1998

Microsatellite instability in malignant melanoma.

Defective mismatch repair has been detected in human colorectal and endometrial carcinomas which exhibit microsatellite instability (MIN). The purpose of this study was to search for MIN in melanoma. Paraffin-embedded neoplastic and non-neoplastic control cells were obtained from 20 untreated individuals with cutaneous malignant melanoma. Breslow thickness ranged from 0.2-7.4 mm (mean 1.4). Cells were carefully scraped from glass slides so that tumor and control DNA could be isolated and then amplified by polymerase chain reaction (PCR) at seven separate microsatellites localized to specific chromosome regions: 1p22 (D1S187), 5q11.2-13.3 (D5S107), 6q21-23.3 (D6S357), 9p21 (IFNA), 11p15.2 (D11S861), 17p13.1 (D17S786), and 18q11 (D18S34). Heterozygosity indices were > or = 0.70. Loci from these chromosome regions were chosen because of cytogenetic abnormalities reported in melanoma (1p, 6q, 9p), location of common oncogenes (11p-HRAS, 17p-TP53), or use in other MIN studies (5q, 18q). Five individuals (25%) demonstrated MIN. There was no correlation with tissue thickness. One individual demonstrated MIN at two loci and one individual demonstrated loss of heterozygosity. The results indicate that MIN occurs in melanoma, albeit less frequently than reported in carcinomas.

Adult↗
PubMed1998

Molecular cytogenetic analysis of patients with holoprosencephaly and structural rearrangements of 7q.

The holoprosencephaly (HPE) sequence is a malformation complex with abnormal midline cleavage of the embryonic forebrain. HPE is genetically heterogeneous with at least 6 different chromosome regions containing genes involved in the expression of the phenotype. HPE3, recently identified as the human Sonic hedgehog gene, is localized to 7q36. We have used fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) amplification in 5 cell lines from patients with HPE (3 cases), HPE and sacral agenesis (1 case), and microcephaly (1 case) to further define the structural rearrangements of the long arm of chromosome 7 in each case. All cell lines demonstrated loss of material in the critical region of HPE3 at band 7q36, which includes the Sonic hedgehog gene. We report here the analysis of these patient cell lines.

Cell Line↗
PubMed1998

Comparison of leptin protein levels in Prader-Willi syndrome and control individuals.

Prader-Willi syndrome (PWS) is characterized by early childhood obesity, mental deficiency, hypogonadism, hypotonia, hypopigmentation, short stature, small hands and feet, and a characteristic face. It is the most common genetic cause of obesity and obesity is the most significant health problem for PWS patients. Ob protein (leptin), which is produced by adipose tissue, is thought to play a significant role in obesity; thus, unusually low plasma leptin levels, or relative loss of sensitivity to leptin in PWS subjects, could be an important factor in their obesity. We measured plasma leptin levels in 19 obese and 14 non-obese PWS patients [mean body mass index (BMI) 37.2 and 22.0, respectively] and compared these levels to those of 28 obese controls (mean BMI 35.5) and 16 non-obese control individuals (mean BMI 21.6). The mean plasma leptin concentration (ng/ml) for obese PWS subjects was 33.4 and 23.6 for non-obese PWS subjects. Obese control leptin was 36.2 ng/ml and non-obese control was 9.9. Among the control groups, leptin levels in females were significantly higher than those in males; the obese males and females had significantly higher leptin than their respective non-obese counterparts. These differences did not hold true for the PWS subjects. Leptin levels in obese PWS males and females were similar, and the same was true of the non-obese PWS males and females. The differences between obese and non-obese PWS subjects of both sexes were small and not significant. Comparing control groups with their PWS counterparts revealed no significant differences, with one exception: circulating plasma leptin levels in non-obese PWS males were nearly five times higher than in non-obese control males with similar BMI. This difference may reflect a more female pattern of fat distribution and hypogonadism, which are characteristic of PWS males. Leptin levels in PWS patients were not obviously correlated with the chromosome 15 finding seen in the patients.

Adolescent↗
PubMed1998

Microsatellite instability in sarcomas.

BACKGROUND: Microsatellite instability (MIN) has been studied in a variety of carcinomas and gynecologic sarcomas, but never in musculoskeletal sarcomas. METHODS: We evaluated 16 skeletal and soft tissue sarcomas at nine genetic loci from chromosomal regions 1q, 5q, 7q, 12p, 13q, 17p, 19q, and two at 11p--all potential regions of interest regarding musculoskeletal sarcomas. RESULTS: MIN was identified at one or more loci in seven of the cancers studied (44%). Three tumors had more than one locus with MIN and one tumor, a high-grade osteogenic sarcoma, had five of nine loci positive for MIN. CONCLUSION: These results indicate that musculoskeletal sarcomas show instability in areas inside and outside the loci of known oncogenes. Areas of mismatch repair, as heralded by MIN, may contribute to the vast heterogeneity of these neoplasms.

Adolescent↗
PubMed1998

Clear cell sarcoma or malignant melanoma of soft parts: molecular analysis of microsatellite instability with clinical correlation.

Malignant melanoma of soft parts, also termed clear cell sarcoma (CCS), is a rare malignancy of neural crest origin which is different from cutaneous malignant melanoma. Although a translocation involving chromosomes 12 and 22 is characteristic of clear cell sarcoma and not malignant melanoma, there are a paucity of methods to differentiate the two. Therefore, a study of microsatellite instability (MIN) was undertaken to determine if mechanisms of DNA mismatch repair can differentiate these malignancies. MIN has been described in a variety of malignancies including 25% of malignant melanomas. Paraffin-embedded neoplastic and non-neoplastic cells were obtained from 11 individuals (five males; six females; age range from seven to 60 years) with CCS. Isolated DNA was PCR amplified at 17 separate microsatellite loci using radioactive-labeled primers. Tumor tissue was compared to normal tissue for each analysis. No MIN was detected. Loss of heterozygosity was detected in only one patient at a single locus (IFNA). The lack of MIN in clear cell sarcoma further defines the distinction between this tumor and malignant melanoma. Clinically, local recurrence and metastasis were indicators of poor outcome. The size of the tumor was not a significant prognostic indicator. Local recurrence, satellitosis, or nodal metastasis was not proven to be uniformly fatal. Utilization of chemotherapy and/or radiation demonstrated no obvious survival advantage. The histologic parameters of mitotic rate and the presence of necrosis were not prognostic. Limb-preserving surgical procedures were as effective as amputation for local disease control. The actuarial survival rate was calculated to be 48% at five years.

Adolescent↗
PubMed1998

Comparison of chromosome telomere integrity in multiple tissues from subjects at different ages.

Telomere DNA, at the ends of each chromosome, is conserved in nature and required for chromosome replication and stability. Reduction in telomere length has been observed in several malignancies as well as in leukocytes from healthy persons with advancing age. There is a paucity of data regarding telomere length and the effects of in vivo aging in different tissues. These data could be helpful in interpreting telomere length and understanding the role of telomere integrity and telomerase activity in malignant cells. We report telomeric DNA integrity studies of blood and skin collected from eight Caucasians of both sexes representing each decade of life from the fetus to 72 years of age without exposure to chemotherapy or radiation. In addition, telomeric data from 15 other tissues from the fetus and 8 other tissues from the 72-year-old male were examined. No significant differences were found in the shortest telomere size, the average telomere size, or telomere size variation between blood and skin from subjects at different ages. The average telomere size was 11.7 +/- 2.2 kb for blood and 12.8 +/- 3.7 for skin in all subjects studied. The shortest telomere length was 5.4 +/- 1.9 kb for blood and 4.3 +/- 0.9 kb for skin. Significant differences (P < 0.001) were found in the overall length of the DNA hybridization signal representing the shortest telomere size and the length of the DNA peak migration hybridization signal representing variation in telomere size between the 20-week fetus and the 72-year-old male. The 72-year-old male showed the shortest telomeres and the most variation (heterogeneity) in telomere size for all tissues studied, but the greatest differences were observed in blood compared with other tissues (e.g., average telomere length was 12.2 kb in the fetus and 7.2 kb in the 72-year-old male). The size of the telomere was negatively correlated with age for all tissues studied.

Adolescent↗
PubMed1998

The latent variable structure of the Compulsive Behaviour Checklist in people with Prader-Willi syndrome.

The presence and severity of compulsive behaviours may be evaluated via the Compulsive Behaviour Checklist (CBC) and this instrument has been successfully employed in people with intellectual disability. However, the applicability of the overall CBC scoring system, which entails tallying the number of behavioural categories represented (i.e. five) as well as the number of individual behaviours endorsed (i.e. 25), is not known in the population with Prader-Willi syndrome (PWS). The present investigation examined the latent variable structure of the CBC in people with PWS in order to identify possible population-specific scoring and interpretation considerations. The 25 behaviour-specific items of the CBC were analysed for 75 people with PWS (44 females and 31 males) aged between 4 and 41 years (mean +/- SD = 11.4+/-9.4) via factor analysis with principal component extraction and equamax rotation. The most suitable solution was determined on the basis of multiple empirical criteria: (1) the scree test; (2) eigenvalues >1.00; (3) salient loadings >0.30; (4) the clarity of item assignment to a single latent dimension; (5) the internal consistency of the latent dimension(s) (coefficient alpha > or = 0.70); and (6) item-total correlations between 0.20 and 0.79. In addition, solutions were examined with respect to psychological theory and previous research. A 'general factor' (i.e. single latent dimension) solution which adhered to all a priori criteria was indicated. Twenty-four out of 25 items achieved salient loadings ranging from 0.46 to 0.80 on the general factor. The single item which failed to achieve salience, 'deviant grooming-skin picking', exhibited both substantial unique variance (0.997) and moderate reliability (r = 0.59, P<0.001). The internal consistency of the general factor was strong (alpha = 0.93) and all salient items were suitably correlated with the unit-weighted total score (r(item-total) = 0.41-0.77). The traditional CBC scoring system, which includes tallying the number of categories represented, would not be relevant in this PWS sample. In addition, the recommended tallying of the number of individual behaviours endorsed does not reflect the empirically indicated notion of compulsive behaviour in this special population. These findings indicate that the 24 salient items should be scored as a unit-weighted composite and that the score on the substantially unique item (skin picking) should be considered a separate measure when evaluating compulsive behaviours via the CBC in people with PWS.

Adolescent↗
PubMed1998

Photoanthropometric study of craniofacial traits in individuals with Prader-Willi syndrome on short-term growth hormone therapy.

An objective photoanthropometric method, useful for delineating craniofacial characteristics, was performed on 20 individuals with Prader-Willi syndrome (PWS; 14 males and 6 females) under 12 years of age and on growth hormone therapy (e.g. for 3-12 months) to determine the effects of therapy on craniofacial features in PWS. Facial parameters were measured from strict frontal and profile photographic 35 mm slides and compared with other facial measurements from the same face (e.g. palpebral fissure width to bizygomatic diameter). We studied 16 photoanthropometric craniofacial indices following previously established protocols. Our photoanthropometric data on 20 PWS subjects meeting diagnostic criteria further supported previous findings of a high midface, a broad interalar distance, a prominent high chin and broad ears in PWS patients without growth hormone therapy. In addition, while on growth hormone therapy, the high midface, broad interalar distance and prominent high chin appeared to accentuate over time in relationship to untreated PWS patients. Conversely, broad appearing ears were not accentuated by growth hormone therapy in the PWS subjects analyzed in this study.

Anthropometry↗
PubMed1998

Genetic variants of the human obesity (OB) gene in subjects with and without Prader-Willi syndrome: comparison with body mass index and weight.

We investigated whether an association exists between genetic variants of the human obesity (OB or leptin) gene and body mass index (BMI) or weight in subjects with Prader Willi syndrome (PWS) and in age- and gender-matched lean and obese subjects without PWS. The study included 51 subjects with PWS (mean age = 17.7 +/- 9.5 years, BMI = 29.7 +/- 8.3 kg/m2); 50 non-PWS obese subjects (mean age = 18.2 +/- 10.8 years, BMI = 33.3 +/- 9.5 kg/m2); and 53 non-PWS lean subjects (mean age = 17.8 +/- 9.5 years, BMI = 19.5 +/- 2.9 kg/m2). Allele sizes were determined via standard polymerase chain reaction of the D7S1875 locus, a dinucleotide repeat polymorphism close to the OB gene and classified as trichotomous (homozygous < 208 bp, heterozygous < 208/ > or = 208 bp, homozygous > or = 208 bp) or dichotomous (homozygous < 208 bp or not). Non-PWS males showed a marked decrease in weight with larger alleles while females did not (interaction effect, p < 0.05). Comparable effects were not observed among the PWS subjects. Associations between BMI and genotype were statistically significant (r = 0.22, one-tailed p < 0.05) and comparable to previous research among the non-PWS subjects < 18 years, but not the adults (r = 0.05, one-tailed p = 0.38). Correlations were not statistically significant among either the adult or non-adult PWS subjects.

Adult↗
PubMed1997

Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele.

The Prader-Willi syndrome (PWS) usually results from a paternal deletion of 15q11-q13 or maternal disomy for chromosome 15. Reduced pigmentation of skin, hair, and eyes is common in PWS and was suggested previously to be associated with the 15q11-q13 deletion. The P gene, located in this same region, is associated with OCA2, an autosomal recessive disorder that is the most frequent form of tyrosinase-positive oculocutaneous albinism. We studied 28 individuals with PWS and found that hemizygosity for the P gene was significantly correlated with the occurrence of hypopigmentation among PWS patients. However, we found little or no relationship between the occurrence of hypopigmentation and the polymorphism haplotype of the intact P allele. Thus, our results indicate that hypopigmentation is likely the result of deletion of the P gene in the context of PWS but do not support the linked hypothesis that hypopigmentation results from hemizygosity for variant P alleles with reduced function.

Alleles↗
PubMed1997

Photoanthropometric study of craniofacial traits in individuals with Williams syndrome.

A photoanthropometric method, which enables an objective description of facial structures, was used to better delineate the craniofacial characteristics of 29 individuals with Williams syndrome (WS; 18 males and 11 females) between the ages of 0 to 10 years, with an average age of 4.0 years. Facial parameters were measured from strict frontal and profile photographic 35-mm slides and compared with other facial measurements from the same face (e.g., palpebral fissure width to bizygomatic diameter). Sixteen photoanthropometric craniofacial indices were developed from 20 measurements (3 from the frontal face, 2 from the eye region, 3 from the nose region, 2 from the mouth region, 4 from the profile face, and 6 from the ear region). Based on our measurements of 29 Williams syndrome individuals, two parameters (e.g. nose length to midface height and palpebral fissure width to bizygomatic diameter) were outside the normal range when compared with photoanthropometric index standards for age established by Stengel-Rutkowski et al. from white control children. Overall, our data supported a high midface height, broad palpebral fissure width, broad interalar distance, short length of back of nose, prominent ears with long narrow conchae, increased chin height, increased inclination of the ears and a narrow bizygomatic diameter in WS patients. These craniofacial parameters (many not previously evaluated in WS patients) may become useful for early detection, and aid in the diagnosis and study of the development of the characteristic face in Williams syndrome subjects.

Age Factors↗
PubMed1997

Elevated plasma gamma-aminobutyric acid (GABA) levels in individuals with either Prader-Willi syndrome or Angelman syndrome.

Plasma gamma-aminobutyric acid (GABA) levels were measured in 14 subjects with Prader-Willi syndrome, 9 subjects with Angelman syndrome, and matched control subjects. Mean levels in both patient groups were 2 to 3 times higher than in nonretarded moderately obese or retarded nonobese control subjects. Levels in each patient group differed significantly from both control groups. Neither the two patient groups nor the two control groups differed. GABA levels seemed unrelated to genetic status (chromosome 15 deletion or disomy). These preliminary findings of elevated plasma GABA levels possibly represent a compensatory increase in presynaptic GABA release in response to hyposensitivity of a subset of GABA receptors and could produce increased postsynaptic activation of other normal GABA receptor subtypes, resulting in complex alterations of GABAergic function throughout the brain.

Adolescent↗