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Biomedical subjects

V Krishnan

Publications and source records attributed to V Krishnan.

At least 19 recordsLinked to original sources
PubMed2006

The effect of drugs on orthodontic tooth movement.

OBJECTIVE: Molecules produced in various diseased tissues, or drugs and nutrients consumed regularly by patients, can reach the mechanically stressed paradental tissues through the circulation, and interact with local target cells. The combined effect of mechanical forces and one or more of these agents may be inhibitory, additive or synergistic. The objective of this review is to outline the mechanisms of action and effects of some commonly used drugs on tissue remodeling and orthodontic tooth movement. DESIGN: All the existing published literature on the effects of various drugs that are prescribed by orthodontists, which are consumed by patients for systemic diseases and those that are known to promote and retard the tooth movement process was obtained and subjected to thorough review process. RESULTS: All the drugs reviewed have therapeutic effects, as well as side effects, that may influence the cells targeted by orthodontic forces. Therefore, it is imperative that the orthodontist pays close attention to the drug consumption history of each and every patient, before and during the course of orthodontic treatment. When the use of drugs is revealed, their effects and side effects on tissue systems should be explored, to determine their potential influence on the outcome of mechanotherapy. CONCLUSION: Drug-consumption history must be an integral part of every orthodontic diagnosis and treatment plan.

Animals↗
PubMed2004

The nongenotropic synthetic ligand 4-estren-3alpha17beta-diol is a high-affinity genotropic androgen receptor agonist.

The nongenotropic ligand estren (Science 298:843-846, 2002) was evaluated for its transcriptional activity mediated by the human androgen receptor (AR). Our results show that estren can bind, translocate, transactivate, and regulate two known target genes of AR in androgen-responsive cell lines. Estren binds recombinant AR with 10-fold higher affinity than either estrogen receptor (ER)-alpha or ERbeta. Estren-bound AR can translocate AR to the nucleus and stimulate the androgen response element-luciferase reporter activity with an efficacy similar to that of androgen. Estren also increased the expression of prostate-specific antigen (PSA) in a dose-dependent manner in human LnCaP cells. Using chromatin immunoprecipitation analysis, we show that the estren-bound AR coimmunoprecipitates with a region of the PSA gene promoter. Therefore, cotreatment with an AR antagonist, bicalutamide, blocked the estren-induced increase in PSA expression. In contrast, phosphoinositol 3-kinase inhibitor wortmannin, or extracellular signal-regulated kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), and ER antagonist ICI-182780 failed to block the effects of estren. In vivo analysis of estren's action on male-orchidectomized ICR mice revealed estren's AR agonist actions on the levator ani and seminal vesicle target tissues. Taken together, our results reveal the hitherto unidentified genotropic action of estren mediated by AR in androgen-responsive cells and tissues.

Androgens↗
PubMed2001

Bone anabolic effects of sonic/indian hedgehog are mediated by bmp-2/4-dependent pathways in the neonatal rat metatarsal model.

A neonatal rat metatarsal organ culture model has been employed to study the anabolic effects of Sonic/Indian hedgehog and BMP-4. In this culture system, a significant increase in endochondral ossification is measured by an increase in length of mineralized bone, after daily treatment for 7 days with Sonic hedgehog protein (Shh-N). Previous evidence indicated that PTH related protein (PTHrP) is a critical target of hedgehog function in endochondral ossification. Using a PTHrP blocking antibody, it is shown that hedgehog mediates this activity via pathways other than through PTHrP. A dose-related increase in endochondral ossification is observed when metatarsals are treated with 25 ng/ml recombinant human bone morphogenetic protein 4 (BMP-4). However, this activity is not evident at higher doses of BMP-4 (200 ng/ml). High doses of BMP-4 resulted in increased expression of noggin messenger RNA and cotreatment of noggin and Shh-N resulted in reversal of the anabolic action of Shh-N. This observation suggests that BMP-4 signaling can influence the Shh-N mediated increase in endochondral ossification. Finally, we show that the Shh-N and BMP-4 mediated increase in endochondral ossification is reversed by treatment with antisense oligonucleotides targeted against Cbfa1. Thus, this report identifies Shh-N as an inducer of endochondral ossification that mediates its effect via BMP-4 and Cbfa1-dependent pathways.

Animals↗
PubMed2001

Osteoblast apoptosis and bone turnover.

With the discoveries of different death mechanisms, an emerging definition of apoptosis is the process of cell death associated with caspase activation or caspase-mediated cell death. This definition accepts that caspases represent the final common mechanistic pathway in apoptosis. Apoptosis may be triggered either by activation events that target mitochondria or endoplasmic reticulum or by activation of cell surface "death receptors," for example, those in the tumor necrosis factor (TNF) superfamily. In the postnatal and adult skeleton, apoptosis is integral to physiological bone turnover, repair, and regeneration. The balance of osteoblast proliferation, differentiation, and apoptosis determines the size of the osteoblast population at any given time. Although apoptosis has been recorded in many studies of bone, the selective mechanisms invoked in the different models studied rarely have been identified. This review offers a broad overview of the current general concepts and controversies in apoptosis research and then considers specific examples of osteoblast apoptosis pertinent to skeletal development and to the regulation of bone turnover. In reviewing selected work on interdigital apoptosis in the developing skeleton, we discuss the putative roles of the bone morphogenetic proteins (BMPs), Msx2, RAR-gamma, and death inducer obliterator 1 (DIO-1). In reviewing factors regulating apoptosis in the postnatal skeleton, we discuss roles of cytokines, growth factors, members of the TNF pathway, and the extracellular matrix (ECM). Finally, the paradoxical effects of parathyroid hormone (PTH) on osteoblast apoptosis in vivo are considered in the perspective of a recent hypothesis speculating that this may be a key mechanism to explain the anabolic effects of the hormone. An improved understanding of the apoptotic pathways and their functional outcomes in bone turnover and fracture healing may facilitate development of more targeted therapeutics to control bone balance in patients with osteoporosis and other skeletal diseases.

Animals↗
PubMed2001

Reactive and clonal thrombocytosis: proinflammatory and hematopoietic cytokines and acute phase proteins.

BACKGROUND: We quantitated proinflammatory and thrombopoietic cytokines in reactive thrombocytosis (RT) and clonal thrombocytosis (CT) to identify a cytokine profile that might aid in the distinction of these two disorders. METHODS: Serum levels of cytokines relevant to platelet biology--interleukins 3, 6, 11, and 1beta; thrombopoietin; tumor necrosis factor alpha; and C-reactive protein (CRP)--were measured by enzyme-linked immunosorbent assay in healthy subjects and in patients with CT and RT. RESULTS: Interleukin-6 and CRP levels were higher in RT patients than in controls or CT patients. Interleukin 1beta levels were higher in the RT group than in the CT and control groups. CONCLUSIONS: In RT, IL-6, IL-1beta, and CRP levels are elevated. In both RT and CT, IL-11 is elevated, but thrombopoietin levels are not.

Adult↗
PubMed2000

Mechanism of action of estrogens and selective estrogen receptor modulators.

Estrogen, one of several sex steroid hormones, mediates its actions through the estrogen receptor. The estrogen receptor (ER) has two subtypes, ER alpha and ER beta, each of which predominates in specific tissues and organs. Cofactor proteins interact with the ER to maximize ligand-dependent transactivation of target-gene promoters. The estrogen response element is the final step in estrogen-mediated gene regulation, and current research is focused on alternate response elements. The resulting biologic action can vary according to the specific type of ER, cofactor milieu, response element, and ligand. Selective estrogen receptor modulators (SERMs) exhibit tissue-specific estrogen agonist or antagonist activity. The SERM raloxifene, which binds to ER and targets a distinct DNA element, may distinguish agonist vs antagonist activity by ER subtype and has unique activity among other SERMs because of its molecular conformation. Phytoestrogens, a potential alternative to hormone replacement therapy and for cancer prevention, do not consistently mimic estrogen's activity. Different types of phytoestrogens have different potencies, and taking high-dose supplements after menopause may not emulate the apparent benefits of lifelong consumption of phytoestrogen-rich diets. In conclusion, the complexity of estrogen action--through different ER subtypes, with various cofactors, on alternate response element--is further enhanced by ligands with selective estrogen activity. Additional research is needed to elucidate these pathways and the resulting biological effects.

Estrogens↗
PubMed2000

Neutrophils in induced sputum arise from central airways.

A high neutrophil count is often found in induced sputum compared to bronchoalveolar lavage fluid (BALF). This study investigated whether such a high neutrophil count may be a response to inhaled hypertonic saline or that the airway compartment sampled by induced sputum has a higher concentration of neutrophils than BALF. Saliva and induced sputum samples were taken at 10 and 20 min following inhalation of 3% hypertonic saline from an ultrasonic nebulizer in 12 healthy nonsmoking subjects. Four days later the 12 subjects underwent bronchoscopy (six following inhalation with 3% saline). Tracheal, proximal bronchial secretions, bronchial washings and BALF samples were obtained. The neutrophil count (% total leukocytes) increased significantly in saliva at 10 and 20 min post nebulization with 3% saline, although there was no change in neutrophils in induced sputum at 10 and 20 min. There was no significant difference in neutrophil count in the subjects who inhaled 3% saline as compared to those who did not, in secretions from the trachea, proximal bronchi, bronchial washings and BALF. Neutrophil counts were significantly higher in the trachea, proximal bronchi and bronchial washings as compared to BALF (p<0.001). It is concluded that neutrophil counts in healthy subjects increase from the peripheral towards the proximal airways, in the absence of hypertonic saline-induced changes. This suggests that the relatively high neutrophil count in induced sputum arises from the proximal airways and is not a response to inhaled hypertonic saline during the procedure.

Adult↗
PubMed2000

Relative prevalence of hepatitis B viral markers and hepatitis C virus antibodies (anti HCV) in Madurai, south India.

(1) The positivity of HBsAg was 4% (75/1819) whereas anti HCV was present only in 0.75% (27/3574) of blood donors. (2) 5.3% (4/75) of hospital staff had HBsAg alone in their blood samples. One doctor, one Staff nurse, one Lascar and one Sanitary worker were positive for HBsAg. None of them were positive for anti HBcIgm and anti-HCV. (3) 29% (31/115) of suspected hepatitis cases were positive for any one of the viral markers or both. 21% (15/72) of males and 14% (6/43) of females were positive for HBsAg. Whereas only 4% (3/72) of males and 2% (1/43) of females were positive for anti HCW. Both HBsAg and anti HCV were found in 8% (6/72) of males only. The age group predominantly, i.e. in 29 out of 31 cases found positive for HBsAg and/or anti HCV, was above 15 years. Two remaining HBsAg positive cases belonged to the 5 to 14 years age group. 71% (84/115) of suspected hepatitis cases were negative for both HBsAg and anti HCV.

Biomarkers↗
PubMed1999

First fatty acylated dipeptides to affect muscarinic receptor ligand binding.

Fatty acylated dipeptides homologous to Gi alpha N-termini affect ligand binding to muscarinic acetylcholine receptors. Myristylglycine-serine containing dipeptides decrease antagonist binding at both M1 and M2 muscarinic receptors. Palmitate on the serine analogous to native palmitoylated cysteine affords dipeptide which selectively decreases the number of high affinity agonist binding sites at M2 but not M1 receptor.

Acylation↗
PubMed1997

Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase.

A Sonic hedgehog (Shh) response element was identified in the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) promoter that binds to a factor distinct from Gli, a gene known to mediate Shh signaling. Although this binding activity is specifically stimulated by Shh-N (amino-terminal signaling domain), it can also be unmasked with protein phosphatase treatment in the mouse cell line P19, and induction by Shh-N can be blocked by phosphatase inhibitors. Thus, Shh-N signaling may result in dephosphorylation of a target factor that is required for activation of COUP-TFII-, Islet1-, and Gli response element-dependent gene expression. This finding identifies another step in the Shh-N signaling pathway.

Animals↗
PubMed1997

Orbital floor reconstruction with autogenous mandibular symphyseal bone grafts.

PURPOSE: This article shows the usefulness of the mandibular symphysis as a source of bone graft for the reconstruction of the orbital floor. PATIENTS AND METHODS: A retrospective study was conducted on 16 patients who had isolated blowout fractures (n = 10) or orbital floor defects (n = 6) reconstructed with mandibular symphyseal bone grafts. Symphyseal bone grafts were used when the defects were less than 2 cm in diameter. Patients were examined at recall visits for any evidence of unsuccessful reconstruction by checking extraocular movements, and evidence of diplopia or enophthalmous. RESULTS: During a mean follow-up of 12 months (range, 9 to 36 months), patients had no postoperative complaints. There were no instances of infection at the surgical sites, and none of the grafts were extruded or lost. There was good restoration of the orbital floor, with no clinical evidence of enophthalmous or diplopia. Extraocular movements were intact in all patients. CONCLUSION: The mandibular symphysis is a readily available source of autogenous bone that can be harvested with minimal morbidity. Its contour is suitable for use in orbital floor reconstruction. It merits consideration when autogenous bone grafts are considered for orbital floor defects less than 2 cm in diameter.

Adult↗
PubMed1997

Identification of a novel sonic hedgehog response element in the chicken ovalbumin upstream promoter-transcription factor II promoter.

Sonic hedgehog (Shh) is a secreted morphogen that regulates dorso-ventral patterning within the neural tube during embryonic development. It is well established that Shh can induce motor-neuron differentiation that coincides with the appearance of specific motor-neuron markers including chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) and Isl1. However, the mechanism of Shh-induced signaling pathway in vertebrates is not clearly defined. In this report we have identified COUP-TFII as a target gene for Shh. In addition we have used a 1.6-kb region of the COUP-TFII promoter to identify a target element that mediates the Shh-induced activity. Extensive deletions introduced within this region have further enabled us to identify a novel sonic hedgehog response element (ShhRE) in the COUP-TFII promoter. Point mutations introduced within the ShhRE reveal some key nucleotides that are essential for protein(s)-binding activity. Finally, the ShhRE is capable of functioning as a true enhancer element and can mediate Shh-induced transactivation of reporter gene via a heterologous promoter.

Animals↗
PubMed1997

A macro approach to the explanation of physician distribution in Canada.

Physician distribution is influenced by complex factors. It is generally argued that the probability of physician increase will be greater in areas that have more to offer in the way of social and economic advantages, This study examines the effects of selected demographic, socioeconomic, and environmental factors (e.g., population size, percent university educated, and hospital bed/population ratio) on the spatial distribution of physicians, using data for "active" civilian physicians obtained from Health and Welfare Canada. The findings indicate that the variable "percentage university educated" is the most important factor influencing physician distribution, once demographic and environmental factors are controlled. The higher the educational level of the population, the higher the physician/population ratio and the higher the proportion of children under age 5, the lower the physician/population ratio. Findings provide evidence of a concentration of physicians in high-status areas. A pattern of larger relative dispersion was also observed for physician/population ratios across areas for suburban dwellers.

Canada↗
PubMed1996

Chicken ovalbumin upstream promoter-transcription factors and their regulation.

COUP-TFs are orphan members of the steroid/thyroid hormone receptor superfamily. COUP-TF homologues have been cloned in several species, from Drosophila to man. The vertebrate COUP-TFs can be classified into four subgroups according to sequence homology in their ligand-binding domain. COUP-TFs bind to AGGTCA direct repeats or palindromes with various spacings. These include the response elements of several other members of the superfamily, the vitamin D receptor, the thyroid hormone receptor, the retinoic acid receptor, the retinoid X receptor, the peroxisome proliferation activated regulator, and the hepatocyte nuclear factor-4. COUP-TF response elements have been identified in the promoters of many genes and COUP-TFs have been shown to act as negative regulators both in vitro and in vivo. They can compete with the above mentioned receptors for binding to the common response elements. The ratio of COUP-TF and the other positive regulator determines the transcriptional state of the particular gene in any given moment. COUP-TFs are expressed in the developing central nervous system of mouse and zebra-fish. In addition, they are also expressed in many organs during mouse organogenesis. The expression pattern and profile of COUP-TFs favor the hypothesis that they are involved in development and differentiation. The expression of COUP-TFs are also highly regulated. P19 embryonal carcinoma cells have been used as a model system to study COUP-TF regulation. COUP-TFs are up-regulated in retinoic acid (RA) treated P19 cells. Transient transfection assay showed that mouse COUP-TFII promoter directly responded to RA treatment, suggesting that COUP-TF expression is directly regulated by RA signaling pathway.

Animals↗
PubMed1995

Isolation, characterization, and chromosomal localization of mouse and human COUP-TF I and II genes.

Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are orphan members of the steroid/thyroid hormone receptor superfamily. COUP-TF homologues have been cloned in many species, from Drosophila to human. The protein sequences of COUP-TFs are highly homologous across species, suggesting functional conservation. Two COUP-TF genes have been cloned from human, and their genomic organizations have been characterized. To determine whether the genomic organization is conserved between human and mouse, we isolated two mouse COUP-TF genes (I and II) and characterized their genomic structures. Both genes have relatively simple structures that are similar to those of their human counterparts. In addition, we mapped mouse COUP-TF I to the distal region of chromosome 13 and COUP-TF II to the central region of chromosome 7. Furthermore, we mapped human COUP-TF I to 5q14 of chromosome 5 and COUP-TF II to 15q26 of chromosome 15. The results demonstrate that COUP-TF genes are located in chromosomal regions that are syntenic between mouse and human.

Animals↗
PubMed1995

Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds elicit diverse toxic and biochemical responses in laboratory animals and mammalian cells in culture. TCDD induces CYP1A1 gene expression and results of extensive research have delineated the molecular mechanism of this response. In target cells, TCDD initially binds to the aryl hydrocarbon (Ah) receptor which accumulates in the nucleus as an Ah-receptor:aryl hydrocarbon nuclear translocator (Arnt) protein heterodimeric complex. The nuclear Ah receptor complex acts as a ligand-induced transcription factor which binds to transacting genomic dioxin/xenobiotic responsive elements (DREs/XREs) located in the 5'-regulatory region upstream from the initiation start site and this interaction results in transactivation of gene transcription. DREs have been identified in several other genes which are induced by TCDD, including CYP1A2, aldehyde-3-dehydrogenase, NAD(P)H quinone oxidoreductase, and glutathione S transferase Ya and similar induction response pathways have been observed or proposed. However, TCDD and other Ah receptor agonists also inhibit expression of several genes and research in this laboratory has investigated inhibition of estrogen (E2)-induced genes including uterine epidermal growth factor, c-fos protooncogene, and the progesterone receptor, estrogen receptor (ER) and cathepsin D genes in human breast cancer cell lines. In MCF-7 human breast cancer cells, E2 induces cathepsin D gene expression and this is associated with formation of an ER/Sp1 complex at the sequence in the promoter region (-199/-165) of this gene. Within 30 min TCDD causes a rapid inhibition of E2-induced cathepsin D gene expression in MCF-7 cells. Moreover, using a series of synthetic oligonucleotides which include the wild-type ER/Sp1 and various mutants, it was shown by gel electromobility shift and transient transfection assays that the nuclear Ah receptor complex binds to an imperfect DRE located between the ER and Sp1 binding sequences. This interaction results in disruption of the ER/Sp1 complex and inhibition of E2-induced gene expression. These results illustrate that the nuclear Ah receptor complex also exhibits activity as a negative transcription factor via a mechanism which is similar to that reported for Ah receptor-mediated induction of gene expression.

Animals↗
PubMed1995

An ecological model of child maltreatment in a Canadian province.

The rate at which children are maltreated is one of the most sensitive measures of demographic, social, and economic conditions. Although the consequences of maltreatment and the effectiveness of treatment programs in reducing the incidence have been extensively studied, little attention has been given to identifying spatial variations in maltreatment in terms of characteristics of areas, especially demographic, social or economical. Maltreatment may differ markedly in terms of an area's socio-demographic and economic makeup and this phenomenon needs to be studied in a structural context. This study employs an ecological perspective to predict variations in the rate of maltreatment (including neglect and abuse) among children aged 0 to 19 years in Alberta, Canada in 1986. Several hypotheses are tested in a multivariate framework and the implications of the findings in assessing the effectiveness of intervention strategies are briefly discussed.

Adolescent↗