Biomedical subjects
Publications and source records attributed to S Ahmed.
More than 80 million women in Africa and around the world have been damaged by the practice of female genital mutilation. As Somali refugees are accepted into New Zealand and others immigrate from African countries where the practice is still prevalent, health professionals need to be aware of what legal, ethical and cultural considerations are involved.
Thalassaemia is the most common inherited disorder in Pakistan and there are very inadequate treatment facilities for over 4000 homozygotes born each year. Prevention of these disorders therefore forms an essential part of the management of this enormous health problem. We have characterized 1216 beta-thalassaemia alleles from the five major ethnic groups of Pakistan. The complete spectrum comprised 19 different mutations. There are important ethnic and regional differences in the prevalence of mutations. The five most common mutations, IVSI-5 (G-C) (37.3%), Fr 8-9 (+G) (25.9%), del 619 (7.0%), Fr 41-42 (-TTCT) (6.7%) and IVSI-1 (G-T) (5.4%), constitute 82.3% of the total. Fr 8-9 (+G) is the most common mutation in Northern Pakistan (41.3%), whereas IVSI-5 (G-C) is the most frequent mutation in Southern Pakistan (52.2%). Six subjects with transfusion-dependent thalassaemia major showed only a single mutant allele. One subject with transfusion-dependent thalassaemia major showed a novel 17 bp deletion involving Cd126-131. Our findings provide a comprehensive basis for carrying out prenatal diagnosis of thalassaemia in a geographical area where it is found in high frequency.
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A novel molecular modelling study is described for the fitting of non-steroidal 1-substituted-3-[2'(4"-aminophenyl) alkyl] pyrrolidine-2,5-dione based reversible inhibitors of the Aromatase (AR) enzyme to the natural substrate androstenedione. The study suggests that the 'larger' inhibitors (such as the [2'(4"-aminophenyl)alkyl] pyrrolidine-2,5-dione based compounds), after an initial binding of the phenylamine nitrogen lone pair electrons with the Fe3+ haem of the cytochrome P-450, preferentially utilise the region of the AR active site which would normally bind C(17) = O of the substrate. It is suggested that the conformers needed for inhibition by the larger inhibitors when the C(3) carbonyl binding region is used, are too high in energy-in some cases the relative difference between the C(17) carbonyl binding conformer and the C(3) carbonyl binding conformer was found to be greater than 50 KJ mol-1. The 'smaller' inhibitors, such as Aminoglutethimide (AG) however, are found to preferentially use the C(3) = O binding region of the active site. The modelling of smaller inhibitors has suggested a new parameter, the C(10) to liganding hetero atom distance, which may be considered in the design of further inhibitors. We observe that in the potent inhibitors C(10) to liganding hetero atom distances are comparable to approximately twice the steroid C(10) to C(19) bond length, whilst in the less potent inhibitors, much larger distances are observed.
A novel molecular modelling study, involving inhibitors bound to a 'substrate-heme complex', is described for steroidal and non-steroidal inhibitors of Aromatase (AR). Results with azole compounds such as CGS-16949A, and its derivatives, agree with recently reported studies that these compounds appear to utilise the steroid C(17) carbonyl binding region of the active site as opposed to the steroid C(3) carbonyl binding region. The study of Aminoglutethimide (AG) type compounds, however, suggests that they mimic the steroid C(17) and not the C(3) carbonyl group as suggested by previous workers. However, results with inhibitors based on pyridine ligands such as 3-(4'-pyridyl)-3-ethyl piperidine-2, 6-dione (PYG), suggest that these compounds utilise the steroid C(3) carbonyl binding region and therefore agrees with previous reports. Consideration of the orientation of the R and S enantiomers of PYG is, however, found to be a reversal of that previously reported. Using inhibitors bound to the 'substrate-heme complex', and data from previous studies of derivatives of androstenedione, reasons for differences in activity of enantiomers of AG, PYG, N-octyl-3-(4'-pyridyl)-3-ethyl piperidine-2, 6-dione, and 10-thiiranylestr-4-ene-3, 17-dione, as well as other potent and less potent inhibitors, are put forward.
Establishment of loss-of-function phenotypes is often a key step in determining the biological function of a gene. We describe a procedure to obtain mutant petunia plants in which a specific gene with known sequence is inactivated by the transposable element dTph1. Leaves are collected from batches of 1000 plants with highly active dTph1 elements, pooled according to a three-dimensional matrix, and screened by PCR using a transposon- and a gene-specific primer. In this way individual plants with a dTph1 insertion can be identified by analysis of about 30 PCRs. We found insertion alleles for various genes at a frequency of about 1 in 1000 plants. The plant population can be preserved by selfing all the plants, so that it can be screened for insertions in many genes over a prolonged period.
BACKGROUND: Poor survival among African American patients with breast cancer has been attributed to low socioeconomic status and lack of access to health care. However, Hispanics of equivalent socioeconomic status and health care access exhibit much higher survival rates, almost comparable to whites. This suggests that biologic differences play a role in differences in breast cancer survival in addition to socioeconomic and health care access factors. METHODS: The authors studied clinical and molecular differences between patients with breast cancer of different ethnicity to determine biologic explanations for the observed differences in survival. Consecutive patients scheduled for breast biopsies were identified preoperatively and were interviewed. Blood was withdrawn for serum marker measurements, and tumor specimens collected at frozen section diagnosis were analyzed by flow cytometry, hormone receptor concentration, tumor grade, and Ki-67 nuclear antigen, HER-2/neu, and epidermal growth factor oncoprotein expression. RESULTS: Age, age at menarche, number of lymph nodes with metastasis, estrogen and progesterone receptor levels, ploidy status, S-phase, Ki-67, HER-2/neu expression, tumor grade, epidermal growth factor receptor expression, lipid-associated sialic acid (LASA), and carcinoembryonic antigen level were not significantly related to ethnicity. African Americans presented at a significantly more advanced stage and with significantly larger tumors. They were significantly heavier and had a significantly higher mean Quetelet's index and a significantly higher number of pregnancies and number of live births. Whites and Hispanics were significantly older at menopause. CONCLUSIONS: The molecular indices associated with breast cancer prognosis do not differ significantly among whites, African Americans, and Hispanics, suggesting that the reported differences in survival among these groups are not due to biologic differences in breast cancer among ethnic groups.
Cdc42Hs and Rac1 are members of the Ras superfamily of small molecular weight (p21) GTP binding proteins. Cdc42Hs induces filopodia formation in Swiss 3T3 fibroblasts while Rac1 induces membrane ruffling. Rac1 also activates superoxide production by the components (cytochrome b, p40phox, p67phox, and p47phox) of the neutrophil oxidase. To isolate target proteins involved in these signaling pathways, we have probed proteins from neutrophil cytosol immobilized on nitrocellulose with Cdc42Hs labeled with [gamma-32P]GTP. Cdc42Hs probe detected binding protein(s) of 66-68 kDa in neutrophil cytosol. Rac1 probe also detected the 66-68-kDa proteins, suggesting the possibility that p67phox may be a binding protein for both of these p21 proteins. Indeed, Cdc42Hs and Rac1 were found to bind specifically to purified recombinant p67phox but not the other oxidase components. A 68-kDa Cdc42Hs binding protein was purified from neutrophil cytosol and found to be related to the recently described p65pak kinase from brain. These results suggest that the p68 kinase and p67phox are targets for Cdc42Hs and Rac1 in neutrophils.
Stereoselective hydrolysis of two ester prodrugs of propranolol, isovaleryl propranolol (IV-PL) and cyclopropanoyl propranolol (CP-PL), was studied in Tris-HCl buffer (pH 7.4) containing 0.15 M KCl, skin and liver homogenates, 5% plasma in Tris-HCl buffer, skin cytosol and microsomes, and liver cytosol and microsomes. The hydrolysis rate constants of (R)-isomers of the prodrugs were 1.1-30.3 times greater than those of the respective (S)-isomers in tissue preparations. Skin showed considerable metabolic activity and very high stereoselectivity (R/S ratio: 7.3-30.3). The hydrolyzing capacities of buffer and different tissue preparations per milligram of protein content were in the following increasing order: buffer < skin homogenate < plasma < liver homogenate. The studies with microsomes and cytosol indicated that the esterases, which are responsible for the hydrolysis of prodrugs, were mainly present in the cytosolic and microsomal fractions of skin and liver, respectively. There was a good correlation between the octanol-buffer partition coefficients of propranolol and its prodrugs and the skin partition coefficient. In vitro stereoselective penetration of propranolol and the prodrugs through full-thickness hairless mouse skin was evaluated with flow-through diffusion cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Congenital cystic adenomatoid malformation of the lung (CCAM) is an uncommon developmental abnormality presenting most often in the neonatal period. We report the clinical, radiological and pathological findings in a 9-year-old boy who presented with acute chest pain.
BACKGROUND: Prognostic factors are used routinely in the management of breast cancer. However, their potential for identifying precursor malignant lesions has not been assessed. METHODS: We have examined 285 breast biopsy specimens (140 benign, 145 malignant) for DNA ploidy, S-phase fraction, Ki-67 nuclear antigen proliferative indices, and HER-2/neu and epidermal growth factor receptor oncoproteins. RESULTS: When proliferative indices were compared between the benign and malignant groups, differences were noted for DNA ploidy, S-phase fraction, and cell cycling index (p < 0.0005). When the benign nonproliferative specimens were compared with the atypical/proliferative benign specimens, proliferative indices failed to show any differences. When the specific subset of proliferative/atypical benign breast tissue was compared with the malignant specimens, DNA index, S-phase fraction, and cell cycling index showed significant differences. The mean for epidermal growth factor receptor was greater in the non-proliferative group but not statistically significant (p < 0.1). HER-2/neu oncoprotein failed to show any differences between the benign and malignant groups. Within the atypical benign group, Ki-67 correlated strongly with S-phase fraction and HER-2/neu (p < 0.01). CONCLUSIONS: We have demonstrated that proliferative indices can differentiate between benign and malignant breast tissues but not among specific subgroups. In addition, epidermal growth factor may differentiate between nonproliferative and proliferative/atypical benign biopsy results. Oncoprotein determination, ploidy, and DNA proliferative indices may be useful in defining malignant and benign breast disease but are not useful in distinguishing between benign and malignant breast disease with an increased likelihood for malignant transformation.
BACKGROUND: Many invasive breast cancers are accompanied by a variety of noninvasive components. Histological distinctions have been made between these components, but to understand their importance, it is essential to examine their molecular biology. METHODS: Proliferative indices, oncoproteins, and steroid receptor expression were compared for invasive breast cancers containing comedo-type ductal carcinoma in situ (n = 35), noncomedo-type ductal carcinoma in situ (n = 34), and pure invasive cancers (n = 49). Ploidy, S-phase fraction, Ki-67 staining, estrogen receptor (ER), progesterone receptor (PR), and the expression of HER-2/neu and epidermal growth factor receptor (EGFR) were evaluated in these tumors. RESULTS: The comedo-invasive subgroup differed significantly from the noncomedo-invasive subgroup, demonstrating significantly higher mean ploidy (1.6 vs. 1.3; p = 0.0156), S-phase fraction (7.9% vs. 4.3%; p = 0.0066), Ki-67 staining (20.3% vs. 12.0%; p = 0.0058), and HER-2/neu values (2,247 fm/mg vs. 1,014 fm/mg; p = 0.0412) and lower ER (76 fm/mg vs. 339 fm/mg; p = 0.006) and PR values (99 fm/mg vs. 265 fm/mg; p = 0.0608). A higher percentage of comedo-invasive carcinomas demonstrated aneuploidy 71%; p = 0.0158), elevated levels of S-phase fraction (75%; p = 0.0016) and Ki-67 staining (55%; p = 0.0512), overexpression of HER-2/neu oncogene (47%; p = 0.0011), and were ER negative (35%; p = 0.0148), PR negative (47%; p = 0.0073) when compared to noncomedo-invasive carcinomas. Comedo-invasive and noncomedo-invasive tumors were comparable for nodal status and tumor size, but differences were noted for tumor differentiation and percentage of tumors that were > 1 cm. Comedo-invasive tumors were predominantly poorly differentiated (60 vs. 32%) and were > 1 cm (94 vs. 77%, p < 0.05). RESULTS: Comedo-invasive cancers were comparable to pure invasive cancers for ploidy, S-phase fraction, Ki-67 staining, and ER, PR, and EGFR expression. However, comedo-invasive carcinomas had greater HER-2/neu overexpression when compared to pure invasive tumors (47 vs. 19%; p = 0.0359). CONCLUSIONS: These results are consistent with the hypothesis that comedo carcinoma is a more aggressive type of ductal carcinoma in situ and may have independent prognostic value when seen in association with infiltrating ductal carcinoma. In invasive tumors, comedo carcinomas are associated with poor prognostic factors, including higher ploidy, S-phase fractions, Ki-67 staining, negative ER and PR status, poorer differentiation, larger tumors, and presence of HER-2/neu oncogene overexpression.
Here, we review the role of total body irradiation in the treatment of children with bone marrow transplantation, as well as alternative sources of stem cells. We were unable to demonstrate any clear superiority of TBI-containing preparative regimens, but we were able to find a few definitive reports of significantly enhanced toxicity or important variations in control of the underlying primary diseases, in comparing TBI-based regimens, with those containing only chemotherapy.
Two cases in which a neourethra was constructed using a flipped anterior bladder wall tube are reported. One girl had lost her urethra secondary to a major urethrovaginal injury from blunt pelvic trauma, an in the other, the urethra had sloughed after cloacal reconstruction. Both patients had a closed bladder neck/proximal urethra and were received with a suprapubic cystostomy. A neourethra was constructed from an anterior bladder wall flap based distally. The flap was tubularized and flipped caudally to the site of the original external urethral meatus. Both girls are continent--one voids normally and the other is managed by clean intermittent catheterization. The flipped anterior bladder wall tube technique for construction of a female neourethra is suitable in patients with an absent urethra, particularly when the bladder neck/proximal urethra is closed.
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BACKGROUND: Previous studies revealed hepatic interactions of beta-carotene with alcohol in non-human primates, but bile carotenoids and alpha-tocopherol have not previously been explored in man. METHODS: To compare the plasma and biliary concentrations of carotenoids, retinoids and tocopherols among controls and patients with biliary and pancreatic diseases, these compounds were measured by high performance liquid chromatography in bile collected during 41 endoscopic retrograde cholangiopancreatographies. RESULTS: In 14 subjects with normal endoscopic retrograde cholangiopancreatography (controls), bile contained beta-carotene, alpha-carotene, lycopene, cryptoxanthin, lutein+zeaxanthin (23.9 +/- 6.6, 3.9 +/- 1.1, 39.9 +/- 21.6, 22.5 +/- 4.6, 217.1 +/- 27.8 nmol/l, respectively) with corresponding plasma values of 399.7 +/- 72.6, 88.5 +/- 18.8, 588.2 +/- 75.0, 145.1 +/- 25.9, 319.3 +/- 33.7 nmol/l. In 13 patients in whom bile duct stones impaired biliary excretion (as reflected by raised serum bilirubin), beta-carotene was significantly decreased in both plasma (199.6 +/- 35.5 nmol/l) and bile (9.4 +/- 2.0 nmol/l), with a similar trend for other carotenoids. The beta-carotene plasma/bile ratio was maintained, as well as a correlation between the two (r = 0.56; p = 0.048). Furthermore, in three subjects with complete biliary obstruction, plasma beta-carotene (35.8 +/- 20.2 nmol/l) decreased even more, probably reflecting malabsorption. In 11 patients with pancreatic diseases, plasma and bile beta-carotene were 107.9 +/- 17.8 and 6.6 +/- 2.0 nmol/l respectively, while a correlation between the two (r = 0.70; p = 0.018) again persisted, confirming the role of plasma beta-carotene in determining bile concentrations. Indeed, for the entire group (n = 41), the correlation between plasma and bile or red blood cell beta-carotene was highly significant, whereas plasma/red blood cell ratios remained unchanged. Similar findings were observed for alpha-tocopherol, with 8.4 +/- 0.9 mumol/l in control bile (vs. 23.2 +/- 1.7 mumol/l in plasma), and no significant change in the various groups. CONCLUSIONS: 1) Carotenoids and tocopherols undergo biliary excretion in man. 2) Biliary concentrations reflect plasma levels in both normal and pathologic states. 3) Decreased biliary excretion of carotenoids does not increase plasma concentrations.
A pregnant woman with a symptom-free congenital aneurysm of the internal jugular vein (IJV) is described. A color duplex scan revealed an aneurysm (2.4 cm in diameter) of the right IJV in the mid-neck without evidence of thrombus. To the authors' knowledge, this is the first reported case demonstrating that such a lesion in a pregnant woman can be safely managed without excision.
A rare case of actinomycosis presenting primarily as a mass in the vallecula is described. The patient was a healthy, 65-year-old Saudi, lady who was not immunocompromised and had no other primary pathology in the oral cavity. The clinical presentation and management of the case are discussed and the relevant literature reviewed.