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Biomedical subjects

P Krishnan

Publications and source records attributed to P Krishnan.

At least 19 recordsLinked to original sources
PubMed2003

Characterisation of germinating and non-germinating wheat seeds by nuclear magnetic resonance (NMR) spectroscopy.

Experiments were conducted to characterise the changes, especially of water status in germinating and non-germinating wheat seeds by nuclear magnetic resonance (NMR) spectroscopy. NMR relaxation time ( T(2)) measurements showed tri-phasic or bi-phasic characteristics during different stages of hydration, depending on the seed's ability to germinate. Component analysis of T(2) data revealed the existence of only two components, bound and bulk water, in dry seeds. In contrast, both the germinating and non-germinating wheat seeds had a three-component water proton system (bound, bulk and free water) in phase I of hydration. During the lag phase (phase II) of hydration, bulk water component of non-germinating seeds disappeared completely, resulting in a two component water proton system. Nevertheless, the three component water proton system was observed in the germinating seeds in phase II. Following phase II, rapid hydration (phase III) was observed in germinating seeds only. Water protons were re-organised and there were increases in bulk and free water but decreases in bound water concomitantly. Comparison of the physical state of water in these seeds by NMR spectroscopy with that of tissue leachate conductivity measurement suggests that the seed membrane system was affected more evidently in non-germinating seeds, leading to the disorganised cell structure. The present study provides evidence that the reorganisation of physical state of water in germinating wheat seeds during hydration is essential for its subsequent event of germination.

Biophysical Phenomena↗
PubMed2002

Neuroleptic malignant syndrome presenting as pulmonary edema and severe bronchorrhea.

Neuroleptic malignant syndrome is a rare (incidence, 0.02%-3.2%) but dangerous complication following the use of neuroleptic drugs. When not promptly recognized, this disease carries a high mortality (10%-20%) and morbidity rate. We report an unusual case of neuroleptic malignant syndrome that presented predominantly with autonomic instability in the form of recurrent episodes of respiratory distress. The respiratory distress was initially caused by pulmonary edema and later was caused by severe bronchorrhea. We propose that aspiration pneumonia resulting in respiratory failure, the leading cause of death in neuroleptic malignant syndrome, may be a result of a combination of altered mental status and bronchorrhea. This has therapeutic implications because early institution of bromocriptine/dantrolene can prevent aspiration pneumonia and, hence, mortality from respiratory failure.

Amantadine↗
PubMed2002

Renal failure in a patient with primary antiphospholipid syndrome.

Antiphospholipid antibody syndrome (APLA) is a syndrome complex characterized by recurrent arterial or venous thrombosis, recurrent fetal wastage, thrombocytopenia and presence in serum of antibodies against negatively charged phospholipids like lupus anticoagulant (LA), anticardiolipin antibody (ACLA) and subgroups. These are classified further as primary (wherein this occurs in isolation) and secondary (associated with infection, drugs and malignancies). It is uncommon to find both LA and ACLA in primary APLA syndrome (unlike as in the secondary form). Renal manifestations which include renal arterial and venous occlusion and infarction and thrombotic microangiopathy have also been infrequently described. We hereby present a case of primary APLA syndrome with unusual features of LA and ACLA occurring together and also the presence of renal failure due to left renal artery thrombosis and right renal artery occlusion.

Antiphospholipid Syndrome↗
PubMed2001

Novel mechanism of cellular DNA topoisomerase II inhibition by the pyranonaphthoquinone derivatives alpha-lapachone and beta-lapachone.

PURPOSE: The mechanisms of intracellular topoisomerase II inhibition by the pyranonaphthoquinone derivatives alpha-lapachone and beta-lapachone were studied. METHODS: Cell-based mechanistic studies were designed based on the in vitro mechanisms [17] and primarily involved the use of cultured KB (nasopharyngeal tumor cells) cells and the etoposide-resistant sub-line KB-7d. RESULTS: The KB-7d cells exhibited collateral sensitivity to alpha-lapachone; this supports the possibility of catalytic inhibition of topoisomerase II in the cells. Interestingly, both compounds induced an increase (two- to threefold) in reversible double-stranded DNA breaks in cell lines with a reduced expression of topoisomerase II. However, these drug-induced DNA breaks became irreversible at treatment times greater than 1 h. Studies showed that DNA breaks in KB-7d cells were not caused by endonucleases. Use of antioxidants abolished the appearance of cellular DNA breaks; this suggests involvement of the oxidation-reduction cycle of pyranonaphthoquinones in topoisomerase II inhibition; however, irreversible DNA breaks were not a result of drug-induced oxidative stress. CONCLUSIONS: On the basis of the findings, it is proposed that the compounds, on longer incubation with cells, induce abortive dissociation of topoisomerase II from the DNA, leading to an irreversible accumulation of high molecular weight DNA fragments. In addition to establishing topoisomerase II as an intracellular target of alpha-lapachone, the results suggest that both compounds can be classified as neither typical poisons nor as typical catalytic inhibitors of the enzyme. In summary, both compounds are members of a new inhibitor class, and alpha-lapachone, in particular, can be considered a potential lead for the development of drugs to treat multidrug-resistant cell lines with lower expression of topoisomerase II.

Colony-Forming Units Assay↗
PubMed2001

Congenital aortocaval fistula to the superior vena cava.

Aortocaval fistula is a rare cause of left-to-right shunt. Common causes are congenital, traumatic, and dissecting aneurysm. We report a case of congenital aortocaval fistula to the superior vena cava, the proximal end of which was in close relation to the ostium of the right coronary artery.

Adolescent↗
PubMed2001

Human truncated Smad 6 (Smad 6s) inhibits the BMP pathway in Xenopus laevis.

A previously identified truncated form of the human Smad 6 gene containing a unique 12 amino acid motif at its N-terminus was studied. We have named this truncated form of the gene Smad 6s, for 'short-form', to distinguish it from the full-length form (Smad 6fl). Reverse transcription-polymerase chain reaction and immunohistochemistry revealed that Smad 6s has a unique pattern of expression in human coronary tissue and is upregulated in diseased heart tissue. We used the expression of human Smad 6s in Xenopus laevis as a model system to assess Smad 6s function. Injection of Smad 6fl RNA (4-cell embryos, 2 x ventral) produced tadpoles with partial secondary axes. In contrast, Smad 6s RNA injected in a similar manner produced tadpoles with a severe 'head-only' phenotype with no morphological appearance of a secondary axis. Mutant Smad 6s RNA lacking the unique 12 amino acids at the N-terminus of the Smad 6s isoform produced no embryonic phenotype, suggesting that this region is important in conferring biological activity. Ectodermal explant assays show that Smad 6s has activity consistent with being a BMP antagonist and can synergize with and enhance the activities of the activin and fibroblast growth factor pathways, all of which are novel findings in this study.

Animals↗
PubMed2000

Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives-eleutherin, alpha lapachone, and beta lapachone.

Pyranonaphthoquinones have diverse biological activities against Gram-positive bacteria, fungi, and mycoplasms, and, recently, there has also been an increasing interest in their anti-cancer activity. This study includes three derivatives: eleutherin (compound 1), beta lapachone (compound 2), and its structural isomer, alpha lapachone (compound 3). The mechanism of topoisomerase II inhibition by the three derivatives was examined systematically with respect to the steps of the catalytic cycle of the enzyme. Etoposide, the prototypical enzyme poison, was used as a control and in combination with compounds 1-3 to localize their mechanism of action. The study revealed that eleutherin (1) and beta lapachone (2) inhibited topoisomerase II by inducing religation and dissociation of the enzyme from DNA in the presence of ATP. Whereas compound 2 was an "irreversible" inhibitor of topoisomerase II, compound 1 merely slowed the catalytic cycle of the enzyme. alpha Lapachone (3), on the other hand, inhibited initial non-covalent binding of topoisomerase II to DNA and, in addition, induced religation of DNA breaks (even in pre-established ternary complexes) before dissociating the enzyme from DNA. Compound 3 was an "irreversible" inhibitor of topoisomerase II. The diverse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoquinone derivatives reveal novel ways to target the enzyme with potential for anti-cancer drug design.

Adenosine Triphosphate↗
PubMed2000

Characterization of human lung cancer cells resistant to 4'-O-demethyl-4beta-(2"-nitro-4"-fluoroanilino)-4-desoxypodophyllotoxin , a unique compound in the epipodophyllotoxin antitumor class.

A new semi-synthetic podophyllotoxin derivative, 4'-O-demethyl-4beta-2"-nitro-4"-fluoroanilino)-4-desoxypo dophyllotoxin (compound 1), an analog of GL-331 (compound 2), is a potent and broad-spectrum inhibitor of cultured human cancer and drug-resistant cell growth. In general, 4'-demethylepipodophyllotoxin analogs, including 2, exert anti-tumor activity by targeting the nuclear enzyme DNA topoisomerase II, but 1 is not an enzyme inhibitor. Unlike the cytotoxic activity of compound 2, cell killing by 1 is dose-limiting and a significant fraction of cells (30-40%) survive treatment. As an approach to investigate mechanism of action, 1-resistant A549 (human lung cancer) sub-lines were selected and characterized. Results of the work show that 1-resistant cells: (i) are moderately cross-resistant (2- to 3-fold) to various cytotoxic drugs via a P-glycoprotein-independent mechanism, (ii) have an altered growth habit, (iii) are deficient in normal attachment on plastic and collagen substrata, and (iv) have an altered plasma membrane protein composition including several proteins in the 140->200 kDa molecular mass range and a doublet of phosphoserine-containing proteins of about 135 kDa. Since 1 treatment of cells affects neither cellular attachment or membrane-protein phosphorylation, the changes observed in 1-resistant cells are interpreted as a survival response to drug action.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition.

A current model suggests that the intercalative and minor groove binding components of protoberberines and related compounds are important for DNA topoisomerase I and/or II inhibition. The significance of the 9-substituent in berberine on drug-topoisomerase II interactions is reported here and is based on a comparison of 9-ethoxycarbonyl berberine (compound 1), 9-N,N-dimethylcarbamoyl berberine (compound 2) and 12-bromo berberine (methoxy group at 9-position; compound 3) as enzyme inhibitors. Compound 1 selectively inhibited topoisomerase II and stabilized cleavage complexes predominantly at unique sites and some background sites (depending on the concentration). This agent also allowed partial dissociation of enzyme from the DNA in the absence of religation, indicating unique interactions between 1, enzyme and DNA in the ternary complexes. Compound 2, which had similar DNA binding properties to 1, was not a topoisomerase II poison in the tested concentration range. In contrast, compound 3 was a stronger DNA binding agent but a much weaker enzyme poison both in vitro and in cell-based assays. The results show that the proposed drug domain for DNA intercalation is not a major determinant of enzyme inhibition for simple berberine analogs. Rather, the 9-substituent within the domain has a major influence, presumably by facilitating drug interaction with enzyme and/or enzyme-DNA complexes.

Berberine↗
PubMed1999

Distinct secondary structures of the leucine-rich repeat proteoglycans decorin and biglycan. Glycosylation-dependent conformational stability.

Biglycan and decorin have been overexpressed in eukaryotic cells and two major glycoforms isolated under native conditions: a proteoglycan substituted with glycosaminoglycan chains; and a core protein form secreted devoid of glycosaminoglycans (Hocking, A. M., Strugnell, R. A., Ramamurthy, P., and McQuillan, D. J. (1996) J. Biol. Chem. 271, 19571-19577; Ramamurthy, P., Hocking, A. M., and McQuillan, D. J. (1996) J. Biol. Chem. 271, 19578-19584). Far-UV CD spectroscopy of decorin and biglycan proteoglycans indicates that, although they are predominantly beta-sheet, biglycan has a significantly higher content of alpha-helical structure. Decorin proteoglycan and core protein are very similar, whereas the biglycan core protein exhibits closer similarity to the decorin glycoforms than to the biglycan proteoglycan form. However, enzymatic removal of the chondroitin sulfate chains from biglycan proteoglycan does not induce a shift to the core protein structure, suggesting that the final form is influenced by polysaccharide addition only during biosynthesis. Fluorescence emission spectroscopy demonstrated that the single tryptophan residue, which is at a conserved position at the C-terminal domain of both biglycan and decorin, is found in similar microenvironments. This indicates that in this specific domain the different glycoforms do exhibit apparent conservation of structure. Exposure of decorin and biglycan to 10 M urea resulted in an increase in fluorescent intensity, which indicates that the emission from tryptophan in the native state is quenched. Comparison of urea-induced protein unfolding curves provide further evidence that decorin and biglycan assume different structures in solution. Decorin proteoglycan and core protein unfold in a manner similar to a classic two-state model, in which there is a steep transition to an unfolded state between 1 and 2 M urea. The biglycan core protein also shows a similar steep transition. However, biglycan proteoglycan shows a broad unfolding transition between 1 and 6 M urea, probably indicating the presence of stable unfolding intermediates.

Amino Acid Sequence↗
PubMed1998

Survey on health status of heavy vehicle drivers in Klang valley.

A survey was carried out using a medical examination format that was prepared by the Malaysian Medical Association. The findings of the survey show that of the 266 cases surveyed, 64 drivers (24% of cases surveyed) are either totally unfit to drive or temporarily unfit to drive heavy goods and passenger vehicles. This is clear indication that the current format that is being used by the Road Transport Department is inadequate and needs to be reviewed. It must also be stressed that all the above 64 drivers have been certified fit using the existing Road Transport Department format and are currently driving in our highways and roads. Heavy vehicle goods and passenger vehicle drivers if not properly examined and medically certified are not only be endangering their own lives but also that of others. It is therefore recommended that based on the data available from this survey, the Road Transport Department should seriously consider adopting the medical examination format that was formalised by the Malaysian Medical Association and used in this survey.

Automobile Driver Examination↗
PubMed1996

Wavelength dependence of cell cloning efficiency after optical trapping.

A study on clonal growth in Chinese hamster ovary (CHO) cells was conducted after exposure to optical trapping wavelengths using Nd:YAG (1064 nm) and tunable titanium-sapphire (700-990 nm) laser microbeam optical traps. The nuclei of cells were exposed to optical trapping forces at various wavelengths, power densities, and durations of exposure. Clonal growth generally decreased as the power density and the duration of laser exposure increased. A wavelength dependence of clonal growth was observed, with maximum clonability at 950-990 nm and least clonability at 740-760 nm and 900 nm. Moreover, the most commonly used trapping wavelength, 1064 nm from the Nd:YAG laser, strongly reduced clonability, depending upon the power density and exposure time. The present study demonstrates that a variety of optical parameters must be considered when applying optical traps to the study of biological problems, especially when survival and viability are important factors. The ability of the optical trap to alter either the structure or biochemistry of the process being probed with the trapping beam must be seriously considered when interpreting experimental results.

Animals↗
PubMed1994

Generalized Lotka distribution incorporating migration.

"This paper proposes to introduce the migration component into the stable population model and examine the stability of the age distribution. The analysis [is restricted] to one sex as [has been] done by others." The model is applied to Canadian data.

Age Distribution↗
PubMed1993

A statistical model of infant mortality.

"We have developed here a statistical model for describing infant deaths. Even though the model is tested with Canadian data, it will be a good approximation of the relationship between infant deaths and age in any population. The model needs improvement when high risk populations are studied."

Age Factors↗