Biomedical subjects
Publications and source records attributed to K Ramachandran.
Primary osteosarcoma of the skull is rare. Osteosarcoma arising from the sellar region is extremely uncommon. The case of a 38-year-old man with osteosarcoma of the sella is described, and the literature is reviewed. The patient was treated with surgery followed by aggressive chemotherapy and radiotherapy. Currently he is in remission at 12 months.
Involvement of the central nervous system in epithelial ovarian carcinoma is rare. A 46-year-old woman with ovarian carcinoma relapsing with brain metastasis is described. She received radiotherapy for the metastasis and survived for 18 months.
Multiple myeloma, a disease of the elderly, is extremely rare in those below 30 years of age. Two patients with multiple myeloma diagnosed at 20 years and 18 years are described. Both presented with extradural cord compression, lytic bone lesions and bone marrow plasmacytosis. One patient received combination chemotherapy and radiotherapy and survived for 14 years. A literature review is presented.
Metastatic tumours of the eye commonly occur from primaries of the breast or lung. The prognosis is poor and the mean life expectancy is 6.5 months from diagnosis. Although metastatic tumours of the eye are not a rarity, ocular metastasis from choriocarcinoma has not been reported previously. We report a case of gestational choriocarcinoma with ocular metastasis.
Forced hyperventilation is simple, safe to perform, and can be used as a provocative test for coronary vasospasm. This study assesses whether a vasospastic component of angina might be detected in patients with angiographically "nonobstructive" coronary artery disease by posthyperventilation technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) cardiac imaging. Eleven patients with angiographically nonobstructive coronary artery disease underwent Tc-99m sestamibi SPECT imaging at rest and after forced hyperventilation. Vessel diameters were measured by quantitative angiography before and after forced hyperventilation, and posthyperventilation SPECT images were compared with dipyridamole Tc-99m sestamibi stress images. Forced hyperventilation resulted in a 15% reduction in coronary artery diameter in stenotic segments (p <0.01), and a 17% reduction in adjacent nonstenotic segments (p <0.001). Myocardial uptake of Tc-99m sestamibi in segments perfused by vessels with angiographically nonobstructive stenoses was reduced by 24% following forced hyperventilation (p <0.001) compared with only 4% following dipyridamole (p <0.02). These findings suggest that posthyperventilation Tc-99m sestamibi SPECT imaging in patients with angina pectoris and nonobstructive coronary artery disease may be useful in identifying a vasospastic component of angina.
Methodology for the production of recombinant active cynomolgus monkey (Macaca fascicularis) cathepsin K (EC 3.4.22.38) was elucidated. The cDNA encoding the cathepsin K was cloned from female M. cynomolgus monkey mRNA. The deduced amino acid sequence of M. cynomolgus preprocathepsin K from the cDNA sequence showed 94.2% identity to human preprocathepsin K. Sequence differences occurred only in the prepro- domains; the mature domains were identical. The recombinant M. cynomolgus cathepsin K was expressed as a secreted proenzyme using baculovirus-infected SF21 insect cells having the predicted N-terminus (LYPEEILDTH ellipsis ), indicating proper cleavage of the secretion sequence. Purified monkey procathepsin K was activated under autocatalytic conditions at pH 4.0. The mature enzyme was composed of mixture of enzymes having N-termini of Gly113 and Arg114. The molecular weight was determined to be 23,668.3 Da by MALDI-TOF-MS which is consistent with the absence of carbohydrate on the mature enzyme. These results indicate that monkey procathepsin K is able to autoactivate and produces a mature enzyme which is identical to that of human cathepsin K. Since the sequence of monkey and human mature cathepsin K are identical and the in vitro activation mechanisms appear to be indistinguishable, monkeys are predicted to be a good animal model for evaluating cathepsin K inhibitors in vivo as therapeutic agents for diseases characterized by excessive bone loss, such as osteoporosis.
To help elucidate the mechanisms involved in spontaneous mutagenesis, DNA sequencing has been applied to characterize the types of mutation whose rates are increased or decreased in mutator or antimutator strains, respectively. Increased spontaneous mutation rates point to malfunctions in genes that normally act to reduce spontaneous mutation, whereas decreased rates are associated with defects in genes whose products are necessary for spontaneous mutagenesis. In this article, we survey and discuss the mutational specificities conferred by mutator and antimutator genes in the budding yeast Saccharomyces cerevisiae. The implications of selected aspects of the data are considered with respect to the mechanisms of spontaneous mutagenesis.
Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.
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Considerable evidence now indicates that DNA is the receptor site for dicationic benzimidazole anti-opportunistic infections agents (Bell, C.A.; Dykstra, C.C.; Naiman N.A.I.; Cory, M.; Fairley, T.A.; Tidwell, R.R. Antimicrob. Agents Chemother. 1993, 37, 2668-2673. Tidwell R.R.; Jones, S.K.; Naiman, N.A.; Berger, I.C.; Brake, W.R.; Dykstra, C.C.; Hall, J.E. Antimicrob. Agents Chemother. 1993, 37, 1713-1716). To obtain additional information on benzimidazole-receptor complexes, the syntheses and DNA interactions of series of symmetric benzimidazole cations, linked by alkyl or alkenyl groups, have been evaluated. Biophysical techniques, thermal denaturation measurement (deltaTm), kinetics, and circular dichroism (CD) have been used in conjunction with NMR and molecular modeling to evaluate the affinities, binding mode, and structure of complexes formed between these compounds and DNA. All the compounds bind strongly to DNA samples with four or more consecutive AT base pairs, and they bind negligibly to GC rich DNA or to RNA. Spectral and kinetics characteristics of the benzimidazole complexes indicate that the compounds bind in the DNA minor groove at AT sequences. NMR and molecular modeling of the complex formed between an ethylene-linked benzimidazole derivative, 5, and the self-complementary oligomer d(GCGAATTCGC) have been used to establish structural details for the minor groove complex. These results have been used as a starting point for molecular mechanics calculations to refine the model of the minor groove-benzimidazole complex and to draw conclusions regarding the molecular basis for the effects of substituent changes on benzimidazole-DNA affinities.
RAD3 functions in DNA repair and transcription in Saccharomyces cerevisiae and particular rad3 alleles confer a mutator phenotype, possibly as a consequence of defective mismatch correction. We assessed the potential involvement of the Rad3 protein in mismatch correction by comparing heteroduplex repair in isogenic rad3-1 and wild-type strains. The rad3-1 allele increased the spontaneous mutation rate but did not prevent heteroduplex repair or bias its directionality. Instead, the efficiency of mismatch correction was enhanced in the rad3-1 strain. This surprising result prompted us to examine expression of yeast mismatch repair genes. We determined that MSH2, but not MLH1, is transcriptionally regulated during the cell-cycle like PMS1, and that rad3-1 does not increase the transcript levels for these genes in log phase cells. These observations suggest that the rad3-1 mutation gives rise to an enhanced efficiency of mismatch correction via a process that does not involve transcriptional regulation of mismatch repair. Interestingly, mismatch repair also was more efficient when error-editing by yeast DNA polymerase delta was eliminated. We discuss our results in relation to possible mechanisms that may link the rad3-1 mutation to mismatch correction efficiency.
The antimutator phenotype, reportedly conferred by disruption of the Saccharomyces cerevisiae DDR48 gene, was suggested to affect only a specific spontaneous mutational pathway. We attempted to identify the types of mutation that are DDR48-dependent by determining the specificity of the ddr48 antimutator. However, disruption of DDR48 did not decrease the rates of spontaneous forward mutation in a plasmid-borne copy of the yeast SUP4-o gene, the reversion or suppression of the lys2-1 allele, or forward mutation at the CAN1 locus. Interestingly, the latter gene had been reported previously to be subject to the antimutator effect. DNA sequence analysis of spontaneous SUP4-o mutations arising in DDR48 and ddr48 backgrounds provided no evidence for a reduction in the rates of individual mutational classes. Thus, we were unable to verify that disruption of DDR48 causes an antimutator phenotype.
Mucins are produced by both benign and malignant gastric epithelium. In general, mucins can be classified into neutral and acidic mucins. The latter are of 2 major types, sulphated (sulphomucins) and carboxylated (sialomucins). A retrospective study was initiated at the Department of Pathology, University Hospital, Kuala Lumpur to histochemically study the mucin profiles of cases of intestinal (IGC) and diffuse (DGC) types of gastric carcinoma in Malaysian patients to determine whether a significant change of mucin type occurs in the event of malignant transformation. 42 IGC and 37 DGC were subjected to alcian blue-periodic acid Schiff and high iron diamine-alcian blue histochemical staining. In addition, 18 cases of gastrectomies performed for benign lesions in the stomach served as normal controls. The number of cases of IGC and DGC which exhibited sulphomucin production was significantly increased (p < 0.001) compared to normal controls. Also, the number of cases of DGC which produced neutral mucin were significantly less (p < 0.05) than the control group. However, there was no significant difference between the number of IGC and DGC cases which demonstrated sialomucin production and normal controls. It appears that while not pathognomonic, a lack of neutral mucin production should alert the pathologist to the possibility of a gastric malignancy, in particular DGC. The likelihood of a malignant lesion would be further supported if there is an increased sulphomucin production.
OBJECTIVES: To determine the acid secretory status of patients operated on for perforated duodenal ulcer, with or without prior history suggestive of acid-peptic disease. METHOD: Basal and peak acid output were measured in 48 patients with perforated duodenal ulcer who were treated by simple closure alone, 10 patients with uncomplicated chronic duodenal ulcer and 30 normal controls. Patients operated on for perforated duodenal ulcer were analyzed according to presence (or absence) and duration of prior history of acid-peptic disease. RESULTS: Peak acid output was similar in controls and patients with perforated duodenal ulcer with no prior symptoms. However, patients with prior symptoms had significantly higher peak acid output, similar to those with uncomplicated duodenal ulcer. CONCLUSION: Patients with perforated duodenal ulcer with no antecedent history of acid-peptic disease have normal gastric acid output. These patients may therefore have other etiological factors for their ulcers.
Eventhough neuroblastoma presents with wide spread tumour dissemination, metastasis to testes had rarely been reported. We report a case of Stage IV neuroblastoma who developed metastasis to both testes. He had massive infra-diaphragmatic disease with involvement of left supraclavicular lymph node at presentation. Treatment received by him was not adequate and five months later he developed metastasis to both testes. Hematogenous spread might have been the possibility in this case.
Spin lattice relaxation times of water protons have been reported to correlate with the water contents of malignant as well as benign tissues. In order to investigate whether such a correlation exists in keloid and hypertrophic scars, T1 values of keloid and hypertrophic scars were measured using Magnetic Resonance Imaging and compared with that of normal skin. A linear correlation of the T1 values of the scars with their age was observed. Even though both the scars exhibited higher T1 values in the early stages of lesion, a faster return to the steady state level was observed in hypertrophic scars compared to keloids. It is suggested that the measurement of T1 values could serve to differentiate the two abnormal wound healing situations.
A follow-up study of coronary heart disease (CHD) was carried out among adults in Delhi 3 years after an initial community-based epidemiological survey of the same population. A total of 575 of the 814 cases of CHD detected clinically and by electrocardiogram (ECG) in the initial survey took part. On re-examination of the original cohort of 4151 adults who were free of CHD both clinically and by ECG in the initial survey, 245 new cases of CHD were detected - 73 on a clinical basis (21 with myocardial infarction and 52 with angina pectoris) and 172 by ECG (13 with myocardial infarction and 159 with probable CHD based on ST and T changes). The overall incidence of CHD was 19.7 per 1000 (males, 17.3 per 1000; females, 21.0 per 1000). The incidence on a clinical basis was 5.9 per 1000 (males, 6.5 per 1000; females, 5.5 per 1000) compared with 13.8 per 1000 by ECG (males, 10.8 per 1000; females, 15.5 per 1000). Although the incidence of myocardial infarction was higher in men (3.6 per 1000) than women (2.2 per 1000), the incidence of angina pectoris was 36.5% higher in women (18.7 per 1000) than in men (13.7 per 1000). Hypercholesterolaemia and systemic hypertension were the commonest risk factors in the 245 new cases.
A prospective randomized study was conducted to compare the efficacy of long-term endoscopic sclerotherapy vs. propranolol in Child class B and C patients with variceal bleeds within the 30 days before the study. Forty-five and 46 patients were randomized to receive sclerotherapy and propranolol, respectively, after preentry stratification for Child scores. Sclerotherapy was administered with 1% polidocanol at 10-day intervals until obliteration of varices was achieved. Propranolol was administered to achieve a reduction in resting pulse rate of 25%. Rebleeding occurred in 19 patients undergoing sclerotherapy and in 31 receiving propranolol (p less than 0.05). The number of episodes of rebleeding was higher (p less than 0.05) in the propranolol group (n = 64) than in the sclerotherapy group (n = 35). The mean bleeding risk factor, number of hospitalizations for rebleeding and blood transfusion requirement were also significantly higher in the propranolol-treated patients. The median bleed-free period was more than 36 mo in the sclerotherapy group and 2.5 mo in the propranolol group (p less than 0.01). The median survival time was significantly longer in the sclerotherapy group (greater than 36 mo) than in the propranolol group (greater than 24 mo). We conclude that in decompensated cirrhotic patients, long-term endoscopic sclerotherapy is superior to propranolol in preventing rebleeding and improving survival.