Biomedical subjects
Publications and source records attributed to V C Shah.
The Harlequin fetus is a distinct genetic entity with a strikingly grotesque appearance. Three siblings (two males, one female) with Harlequin Ichthyosis, a rare form of congenital disorder, born to the same parents are presented. The genetic aspects are discussed and the relevant literature is reviewed.
The precise location of the SRY gene on the human Y chromosome has been revealed through studies of sex reversal cases involving deletion, cross-linking and mutations of the SRY gene. Its DNA sequence and mechanism of action are being understood. Similarity of SRY with Sry of mice and its interaction with other genes in male sex determination are discussed.
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A 21-year-old phenotypic male with ambiguous external genitalia and hypospadias was referred for cytogenetic studies. Exploratory laparotomy revealed presence of a small atropic uterus, unilateral gonadal dysgenesis with fallopian tubes on both sides and a cryptorchid testis on the left side. No gonad could be traced on the right side. Chromosomal analysis from peripheral whole blood culture revealed a 46,XY cell line. No mosaicism was detected. Endocrine studies showed elevated levels of serum FSH and LH with low borderline testosterone level and failure to respond to HCG stimulation. The presence of fallopian tube next to testis suggests absence of anti-Mullerian hormone secretion by Sertoli cells. The absence of Wolffian duct derivatives indicates insufficient secretion of testosterone by Leydig cells.
Preaxial polydactyly was observed in up to five generations of an Indian family living in a village in the Rajkot district (Gujarat). Among the 71 affected members, 45 were males and 26 were females. All these affected members showed preaxial polydactyly manifesting as a well formed, articulated extra digit of the hand or foot. Twenty other cases were also identified with polydactyly involving triphalangeal digits replacing the thumbs or duplication of the big toe(s). To the best of our knowledge, the present family is the largest in which several members have preaxial polydactyly of different types. No other abnormalities were apparent. The present study strongly suggests that preaxial polydactyly with a well formed extra digit, triphalangeal thumbs, and duplication of the big toe can be manifestations of the same autosomal dominant gene. It is likely that other factors are modifying the expression of this gene.
In continuation of our studies on stress situations in female reproductive life span, serum lipid peroxide levels in terms of malondialdehyde (nmol/ml) have been determined in females [(n = 40) (aged between 35-40 years)] to undergo total abdominal hysterectomy (due to dysfunctional uterine bleeding). There occurred a statistically significant though within physiological limits, progressive rise in serum lipid peroxide levels right from preoperative stage 3.51, per operatively 3.56 to a maximum of 4.10 postoperative stage I with a tendency of fall at postoperative stage II 3.94 in comparison with self control on admission 2.97. It is suggestive of the balancing and protective role of scavenging enzyme system like superoxide dismutase also backed by improvement in health status of abdominal hysterectomy patients in terms of ambulation, free intake of food and behavioural positive attitude within 24 hours following operation presumably due to relief from stress of DUB. It is felt from the results of the present investigation that patients undergoing abdominal hysterectomy were free from free radical toxicity.
A 32-year-old phenotypic female with a history of nine consecutive abortions each in the first trimester was referred for cytogenetic studies. She was found to have 45,XX,t(22;22) (p11.1;q11.1) chromosomal pattern. The Ag-NOR banding technique showed that the NORs of both the acrocentrics involved in the translocation were deleted and the loss suffered from the elimination was compensated by the increased NOR activity as well as presence of dNOR on other acrocentric chromosomes.
A 5-year-old male with ambiguous external genitalia, hypospadias and microphallus without an urethral orifice was referred for cytogenetic studies. Exploratory laparotomy revealed presence of an infantile uterus and unilateral gonadal dysgenesis with both testes and fallopian tube on the right side. The metaphase cells from peripheral blood culture showed both 45,X/46,X inverted Y (p11.2q11.23) cell-lines (98:2). The inverted Y was found to be of paternal origin. Maternal chromosomal pattern was normal 46,XX. The presence of a fallopian tube next to testis suggest absence of secretion of anti-Mullerian hormone by Sertoli cells. The absence of Wolffian duct derivatives suggest insufficient secretion of testosterone by Leydig cells.
Abortion, primarily as a measure of population control, certainly continues to be an emotional, frustrating and stressful event. In continuation of our work on stressful situations in the female life span and biochemical parameters, serum lipid peroxide levels in terms of malondialdehyde (nmol/ml) have been determined in females undergoing abortion [suction curettage (n = 30), Emcredil-induced abortion (n = 30) and spontaneous abortion (n = 40)] and were compared with appropriate gestational controls. Irrespective of the type of abortion, the serum lipid peroxide levels before abortion [mean malondialdehyde concentrations (nmol/ml): suction curettage 2.67, Emcredil-induced abortion 3.22, and spontaneous abortion 3.49] were found to be significantly elevated in comparison with those after abortion (suction curettage 1.91, Emcredil 1.97 and spontaneous abortion 1.95), indicating a maximum at peak time of stress and a minimum at the end of stress. The levels of serum lipid peroxide encountered before abortion were found to be significantly elevated in case of Emcredil-induced abortion and spontaneous abortion when compared with controls (second trimester mean levels 1.82 and first trimester 2.4) whereas the levels before suction curettage were found to be nonsignificant in comparison with controls, indicating a lesser degree of stress. It is felt that monitoring of serum lipid peroxide levels in serum and tissues (placenta), backed by scavenging enzyme superoxide dismutase, can be more helpful for corroborating safety and the risk of free radical toxicity in pregnancy and abortion.
A 25-year-old phenotypic female with primary amenorrhoea was referred for chromosomal analysis. Earlier she had undergone hormonal therapy but showed no response. The secondary sex characters were of female type, with poor breast development. Laparoscopic findings revealed the presence of a very small uterus; the right ovary was found to be undeveloped and the left was absent. Cytogenetic study revealed a case of triple-X with deletion of the terminal region of the long arm of one of the X chromosomes [Xq27.3]. Among the 100 buccal mucosa cells analysed, 30 cells showed double Barr bodies. Hormonal studies using RIA technique revealed normal levels of prolactin (9.1 ng/ml), a high level of FSH and LH (135 and 61 mIU/ml) and low levels of estradiol and progesterone (12 pg/ml and 0.20 ng/ml respectively). To our knowledge, this may be the first report of a triple X with deletion of the X chromosome associated with primary amenorrhoea.
A 13-year-old boy with clinical features of Down syndrome was investigated. His karyotype was 47,X,inv(Y),+21. The proband's father and two elder brothers were also found to have the inv(Y). A spontaneous chromatid break was observed in the long arm of the X chromosome[? fra (X)] in 2% of the cells. The mother had two spontaneous abortions. This is the first case of trisomy-21 with inv(Y) in our population. This finding might be fortuitous. The frequency of inv(Y) in Down syndrome is not known.
Peripheral blood lymphocytes of 9 patients under CCNU therapy were examined for frequency of sister-chromatid exchanges (SCEs) and chromosomal aberrations (CAs). 7 out of 9 patients were treated with only CCNU, whereas the remaining 2 were treated with other chemotherapeutic agents in combination with CCNU. Compared to normal individuals, a significantly increased frequency of SCE was observed in the patients before starting anticancer therapy (P less than 0.001). Increased incidences of structural changes in chromosomes were observed in cells from all the treated patients. The most frequent aberrations were of chromatid type. After administration of a single dose of CCNU, an increase in SCE frequencies was observed which remained elevated even after 6 weeks. It was concluded that increases in SCEs and CAs in lymphocytes were caused by CCNU treatment. Further studies are needed to elucidate whether any CAs observed in the present study could participate in the induction of second neoplasm.
MeCCNU (semustine, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, NSC 95441) is successfully used in the treatment of various human malignancies. The drug was tested for its in vitro genotoxic effects on human peripheral blood lymphocytes. Several drug concentrations were studied considering mean plasma level achieved in patients after the receipt of MeCCNU therapy. Induction of chromosome aberrations and sister chromatid exchange frequency had shown dose-effect relationship. Reduced mitotic activity and prolonged average generation time was observed in MeCCNU treated cultures. The results suggest that 'therapeutic' MeCCNU concentrations have genotoxic effects on human peripheral blood lymphocytes.
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Effect of different doses of gamma-irradiation on SCE induction in unifiliarly 5-bromo 2-deoxyuridine substituted DNA was studied in various phases of cell cycle. Changes in gamma-irradiation induced SCE frequency was measured by post-irradiation treatment with antimutagen L-cysteine. Perturbation in cellular proliferation kinetics due to gamma-irradiation and gamma-irradiation plus L-cysteine was also studied. It was observed that gamma-irradiation is an efficient inducer of SCE and is most effective in S phase. L-cysteine also causes SCE induction which is slightly higher than the spontaneous level of SCEs found in HeLa cells. However, post-irradiation addition of L-cysteine reduces SCE frequency in gamma-irradiated cultures and this reduction is maximum in G1 phase irradiated cells. gamma-irradiation delayed the mitosis considerably and this delay continued to increase with increasing doses. L-cysteine reduced the delay in cell cycle caused by gamma-irradiation.
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1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (Me-CCNU) was tested for its in vitro effects on sister chromatid exchanges (SCE), cellular kinetics and chromosome aberrations in CHO cells. There was a relationship between the inhibitory activity of the drug and the cytogenetic damage, which was dose dependent. Increase in SCE values were highly significant (p less than 0.001) for all the four concentrations used. It also delayed the cell cycle progression. Inhibition of DNA synthesis results in increased frequency of chromosomal aberrations, which was highly significant for the higher concentrations, i.e. 5 micrograms and 10 micrograms Me-CCNU/ml.
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