Biomedical subjects
Publications and source records attributed to A Ranganathan.
[figure: see text] 9-Ethyladenine forms a unique molecular complex with N-methylcyanuric acid consisting of homomeric and heteromeric hydrogen-bonding patterns. Also, the homomeric hydrogen bond pattern is different than that observed in its pure crystal structures.
BACKGROUND: Polyketides are structurally diverse natural products with a range of medically useful activities. Non-aromatic bacterial polyketides are synthesised on modular polyketide synthase multienzymes (PKSs) in which each cycle of chain extension requires a different 'module' of enzymatic activities. Attempts to design and construct modular PKSs that synthesise specified novel polyketides provide a particularly stringent test of our understanding of PKS structure and function. RESULTS: We show that the ketoreductase (KR) domains of modules 5 and 6 of the erythromycin PKS, housed in the multienzyme subunit DEBS3, exert an unexpectedly low level of stereochemical control in reducing the keto group of a synthetic analogue of the diketide intermediate. This led us to construct a hybrid triketide synthase based on DEBS3 with ketosynthase domain ketosynthase (KS)5 replaced by the loading module and KS1. The construct in vivo produced two major triketide stereoisomers, one expected and one surprising. The latter was of opposite configuration at three out of the four chiral centres: the branching alkyl centre was that produced by KS1 and, surprisingly, both hydroxyl centres produced by the reduction steps carried out by KR5 and KR6 respectively. CONCLUSIONS: These results demonstrate that the epimerising activity associated with module 1 of the erythromycin PKS can be conferred on module 5 merely by transfer of the KS1 domain. Moreover, the normally precise stereochemical control observed in modular PKSs is lost when KR5 and KR6 are challenged by an unfamiliar substrate, which is much smaller than their natural substrates. This observation demonstrates that the stereochemistry of ketoreduction is not necessarily invariant for a given KR domain and underlines the need for mechanistic understanding in designing genetically engineered PKSs to produce novel products.
BACKGROUND: Polyketides are structurally diverse natural products that have a range of medically useful activities. Nonaromatic bacterial polyketides are synthesised on modular polyketide synthase (PKS) multienzymes, in which each cycle of chain extension requires a different 'module' of enzymatic activities. Attempts to design and construct modular PKSs that synthesise specified novel polyketides provide a particularly stringent test of our understanding of PKS structure and function. RESULTS: We have constructed bimodular and trimodular PKSs based on DEBS1-TE, a derivative of the erythromycin PKS that contains only modules 1 and 2 and a thioesterase (TE), by substituting multiple domains with appropriate counterparts derived from the rapamycin PKS. Hybrid PKSs were obtained that synthesised the predicted target triketide lactones, which are simple analogues of cholesterol-lowering statins. In constructing intermodular fusions, whether between modules in the same or in different proteins, it was found advantageous to preserve intact the acyl carrier protein-ketosynthase (ACP-KS) didomain that spans the junction between successive modules. CONCLUSIONS: Relatively simple considerations govern the construction of functional hybrid PKSs. Fusion sites should be chosen either in the surface-accessible linker regions between enzymatic domains, as previously revealed, or just inside the conserved margins of domains. The interaction of an ACP domain with the adjacent KS domain, whether on the same polyketide or not, is of particular importance, both through conservation of appropriate protein-protein interactions, and through optimising molecular recognition of the altered polyketide chain in the key transfer of the acyl chain from the ACP of one module to the KS of the downstream module.
Total laryngectomy for advanced carcinoma of the larynx is effective but functionally disabling. In an effort at laryngeal preservation, 33 patients of stage III/IV carcinoma larynx were treated between 1987 and 1991 with induction chemotherapy followed by definitive radiation. Two chemotherapy protocols were administered. Group I patients received one to three cycles of cisplatin 100 mg/m2 (day 1), bleomycin 15 U/m2 (day 1), and 5-fluorouracil 1000 mg/m2/day (day 2 to 5) at three weekly intervals. This was then followed by radiotherapy. Group II received one to six weekly injections of single agent methotrexate 50 mg/m2 with or without leucocovorin rescue followed by radiotherapy. Any recurrence was salvaged by surgery. Midway through the study, Group II protocol was discontinued as the initial results were not comparable with Group I or standard treatment. The Group I protocol, however, yielded an initial locoregional control rate of 83.3 per cent With the addition of surgical salvage the locoregional control rate was 94.4 per cent and the control rate with laryngeal preservation was 88.8 per cent. The Kaplan-Meier probability of two years and five years disease-free survival was 81.9 per cent and 61.4 per cent respectively. For disease-free survival with laryngeal preservation the corresponding figures for two years and five years were 58.3 per cent and 41.7 per cent. The control group of 51 patients treated with radical surgery followed by radiotherapy yielded survival figures at two years and five years of 64.3 per cent and 57.2 per cent. The difference in the survival of Group I and the control group was not statistically significant (p value = 0.280). These initial results indicate that for stage III and for surgically resectable stage IV laryngeal carcinomas, a protocol of induction combination chemotherapy consisting of cisplatin, bleomycin and 5-fluorouracil followed by radiotherapy and combined with surgical salvage whenever required, can lead to comparable cure rates. In addition, a large proportion of patients are spared the morbidity of a total laryngectomy.
Panic disorder is a chronic and debilitating illness. In this article, we present an algorithm of the diagnosis and treatment of the illness. We place much importance upon the patient variables associated with the treatment decisions. We emphasize strong patient involvement in treatment as a way to become panic free and improve level of functioning. Panic disorder is defined in DSM-IV1 as "The presence of recurrent panic attacks followed by at least one month of persistent concern about having another panic attack, worry about the possible implications or consequences of the panic attack, or a significant behavioral change related to the attacks." A panic attack is defined as "a discrete period of intense fear or discomfort, in which four or more of the following symptoms developed abruptly and reached a peak within 10 minutes." 1) Palpitations, pounding heart or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, light-headed or faint; 9) derealization or depersonalization; 10) fear of losing control or going crazy; 11) fear of dying; 12) paresthesias; 13) chills or hot flashes. The following hypotheses have been used to conceptualize panic disorder from a psychiatrist's perspective.
Strongyloides stercoralis infection in humans continues to be a subject that has frequently inspired reviews and papers. Within the AIDS epidemic, interest gathered momentum with the inclusion of this infection in the indicator diseases list, and its subsequent removal 5 years later by the CDC. These actions have prompted a debate as to whether this infection has special significance in patients with AIDS and whether its exclusion from the CDC criteria is justified. A detailed review of the world literature reveals an increased awareness and diagnosis of this infection in patients with AIDS which takes the form of dissemination, a rapid course, and a usually fatal outcome.