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Biomedical subjects

B Saxena

Publications and source records attributed to B Saxena.

At least 19 recordsLinked to original sources
PubMed1995

Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis.

Evidence suggests that transforming growth factor beta (TGF-beta) may play a central role in a variety of fibroproliferative disorders via the induction of extracellular matrix accumulation. The three mammalian TGF-beta isoforms are present in the normal lung, but very little is known about their expression during lung injury and repair. To more fully understand the role of TGF-beta in lung repair, we investigated the expression of the TGF-beta 1, TGF-beta 2, and TGF-beta 3 isoforms in a bleomycin-induced model of pulmonary fibrosis using immunohistochemical and in situ hybridization techniques. We found expression of the three TGF-beta isoforms, in an identical pattern, widely distributed throughout the normal rat lung: in airways, blood vessels, lung parenchyma, and alveolar macrophages. In general, the distribution of TGF-beta mRNA and protein coincided; however, bronchial epithelial cells were a notable exception, exhibiting immunoreactivity but no mRNA expression. During the "inflammatory" phase (days 1 and 3) of bleomycin-induced injury there was an increase in the mRNA and protein expression of all three TGF-beta isoforms in the injured areas, most prominently in parenchymal cells and alveolar macrophages. There was a further increase in TGF-beta isoform expression in the areas of developing fibrosis during the later reparative phase (days 7 and 14), and the bronchial epithelium, previously not expressing TGF-beta mRNA, showed strong expression of mRNA for the three isoforms concomitant with increased immunoreactivity. These findings implicate the three mammalian TGF-beta isoforms in the dysregulated repair process that results in pulmonary fibrosis. Furthermore, the pattern of TGF-beta mRNA and protein expression by the bronchial epithelium suggests that a transition may occur at this site from a paracrine mode of action in the normal lung to an autocrine mode of action during the "reparative" phase of fibrosis.

Animals↗
PubMed1994

Increased expression of transforming growth factor beta isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium: evidence for paracrine and autocrine action.

Endometrial carcinoma is associated with antecedent simple and complex hyperplasia, and the endometrium is a target tissue for the action of cytokines and growth factors. Transforming growth factor (TGF)-beta s are potent cellular growth and differentiation regulatory factors. Therefore, we investigated the potential role for TGF-beta s in the normal proliferative endometrium and its possible involvement in the transition to complex hyperplasia and progression to endometrial carcinoma. The angiogenic and mitogenic growth factor, basic fibroblast growth factor, was used for comparison. Differential TGF-beta isoform-specific immunoreactivity was observed in the normal endometrium, which is composed of glandular and stromal cells. There was an increase in TGF-beta 3 but not TGF-beta 1 or TGF-beta 2 in the glandular epithelium from the proliferative to the secretory phase of the menstrual cycle. Immunostaining for TGF-beta 2 was more intense in the stroma than the glands. In contrast, TGF-beta 1 and TGF-beta 3 were near equal intensity in these two endometrial compartments, TGF-beta 3 being the most intense. The glandular epithelium demonstrated a statistically significant stepwise increase in the expression of all three TGF-beta s progressing from the normal proliferative endometrium to simple hyperplasia and on to complex hyperplasia. However, the stromal cells maintained approximately the same level of immunoreactivity for TGF-beta in all these samples. In comparing proliferative endometrium with complex hyperplasia, there was a 5.1-, 3.4-, and 2.6-fold increase in immunostaining in the glands for TGF-beta 1, TGF-beta 2, and TGF-beta 3, respectively (P < or = 0.001). There was no further increase in immunoreactivity with progression from preneoplastic complex hyperplasia to carcinoma. Immunoreactive basic fibroblast growth factor was slight in normal endometrium and simple hyperplasia. There was a 4.6- and 4.2-fold increase in immunostaining observed in complex hyperplasia compared with proliferative endometrium in the glandular (P < or = 0.0054) and stromal (P < or = 0.0053) cells, respectively, with no further increase in carcinoma. By in situ hybridization, an increase in mRNA for all TGF-beta isoforms paralleled TGF-beta immunoreactivity. However, in contrast to the increased immunostaining in the glands in complex hyperplasia, there was remarkably more mRNA in the stromal cell compartment. The discordant expression of mRNA and protein was only observed in the pathological endometrium since both were more highly expressed in the stromal cells in normal proliferative endometrium.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1994

Neutrophil chemotaxis in response to TGF-beta isoforms (TGF-beta 1, TGF-beta 2, TGF-beta 3) is mediated by fibronectin.

TGF-beta isoforms regulate numerous cellular functions including cell growth and differentiation, the cellular synthesis and secretion of extracellular matrix proteins, such as fibronectin (Fn), and the immune response. We have previously shown that TGF-beta 1 is the most potent chemoattractant described for human peripheral blood neutrophils (PMNs), suggesting that TGF-beta s may play a role in the recruitment of PMNs during the initial phase of the inflammatory response. In our current studies, we demonstrate that the maximal chemotactic response was attained near 40 fM for all mammalian TGF-beta isoforms. However, there was a statistically significant difference in migratory distance of the PMNs: TGF-beta 2 (556 microM) > TGF-beta 3 (463 microM) > TGF-beta 1 (380 microM) (beta 2: beta 3, p < or = 0.010; beta 3: beta 1, p < or = 0.04; beta 2: beta 1, p < or = 0.0012). A mAb to the cell binding domain (CBD) of Fn inhibited the chemotactic response to TGF-beta 1 and TGF-beta 3 by 63% and to TGF-beta 2 by 70%, whereas the response to FMLP, a classic chemoattractant, was only inhibited by 18%. In contrast, a mAb to a C-terminal epitope of Fn did not retard migration (< 1.5%). The Arg-gly-Asp-ser tetrapeptide inhibited chemotaxis by approximately the same extent as the anti-CBD (52 to 83%). Furthermore, a mAb against the VLA-5 integrin (VLA-5; Fn receptor) also inhibited TGF-beta-induced chemotaxis. These results indicate that chemotaxis of PMNs in response to TGF-beta isoforms is mediated by the interaction of the Arg-gly-Asp-ser sequence in the CBD of Fn with an integrin on the PMN cell surface, primarily the VLA-5 integrin. TGF-beta isoforms also elicited the release of cellular Fn from PMNs; we observed a 2.3-fold increase in Fn (389 to 401 ng/ml) in the supernatants of TGF-beta-stimulated PMNs compared with unstimulated cells (173.6 ng/ml). The concentration of TGF-beta required to cause maximal release of Fn from PMNs (4000 fM) is a concentration at which TGF-beta is no longer chemotactic, suggesting that PMNs only use Fn that is constitutively expressed for migration. At higher concentrations of TGF-beta, the Fn released may accumulate basal to the cell, ultimately retarding cellular migration and modulating the chemotactic response.

Amino Acid Sequence↗
PubMed1993

Studies on the mechanisms by which transforming growth factor-beta (TGF-beta) protects against allergic encephalomyelitis. Antagonism between TGF-beta and tumor necrosis factor.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease in which peripheral lymphoid cells are activated by immunization with myelin proteins and become effector cells that traverse the central nervous system (CNS) capillaries and initiate inflammatory demyelinating lesions. The administration of transforming growth factor-beta (TGF-beta) has been shown previously to decrease the incidence and severity of EAE. In our studies we have determined: 1) the effects of TGF-beta injected at different intervals after the EAE-inducing immunization; 2) the effect of TGF-beta on the development of sensitized T cells, as assayed by the proliferative responses of T cells from lymph nodes and peripheral blood; 3) the extent of lymphoid cell infiltration in CNS of TGF-beta-treated and control mice; and 4) the role of endogenous TGF-beta and TNF in determining the severity of both acute and relapsing EAE. The onset of acute-EAE in SJL mice, induced by immunization with spinal cord homogenate in CFA and pertussigen, is on days 10 to 15. Although daily i.p. injections of 0.2 to 2 micrograms TGF-beta 1 or TGF-beta 2 on days 5 to 9 after immunization are highly protective, injections on days 1 to 5 or 9 to 13 are not. Moreover, anti-TGF-beta accelerates and aggrevates EAE when given on days 5 and 9, but not on day 12. Anti-TNF, injected on days 5 and 9, provides a comparable degree of protection as does TGF-beta. Similarly, in relapsing EAE, anti-TGF-beta increases, whereas anti-TNF decreases the incidence and severity of relapses. TGF-beta treatment on days 5 to 9 does not influence the appearance of sensitized cells in peripheral blood and lymph nodes, but does prevent the accumulation of T cells in brain and spinal cord, as assayed on days 15 to 20. It is concluded that the protective effect of TGF-beta is exerted at the level of the target organ, CNS and/or its vascular endothelium, rather than through a direct effect on lymphoid cells, and that there is a small window of 4 days in which TGF-beta exerts its protective effect.

Acute Disease↗
PubMed1991

Serotonergic interhemispheric asymmetry: neurochemical and pharmaco-EEG evidence.

1. Postmortem neurochemical investigations revealed interhemispheric asymmetry in the mediofrontal region of human brain. Significantly higher right hemisphere serotonin metabolite (5HIAA) content as well as increased maximal imipramine binding (IB) were found in the right hemisphere than in the left side. 2. IB did not show a gender difference in the mediofrontal area. However, women had higher IB in the right orbital frontal cortex than did men. 3. In vivo pharmaco-EEG results tend to support the postmortem neurochemical data. Intravenous chlorimipramine resulted in an asymmetric topographic distribution of the P300 auditory evoked potential, peak amplitudes were shifted to the right hemisphere.

Adult↗
PubMed1991

Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development.

Isoform-specific antibodies to TGF beta 1, TGF beta 2, and TGF beta 3 proteins were generated and have been used to examine the expression of these factors in the developing mouse embryo from 12.5-18.5 d post coitum (d.p.c.). These studies demonstrate the initial characterization of both TGF beta 2 and beta 3 in mammalian embryogenesis and are compared with TGF beta 1. Expression of one or all three TGF beta proteins was observed in many tissues, e.g., cartilage, bone, teeth, muscle, heart, blood vessels, lung, kidney, gut, liver, eye, ear, skin, and nervous tissue. Furthermore, all three TGF beta proteins demonstrated discrete cell-specific patterns of expression at various stages of development and the wide variety of tissues expressing TGF beta proteins represent all three primary embryonic germ layers. For example, specific localization of TGF beta 1 was observed in the lens fibers of the eye (ectoderm), TGF beta 2 in the cortex of the adrenal gland (mesoderm), and TGF beta 3 in the cochlear epithelium of the inner ear (endoderm). Compared to the expression of TGF beta mRNA transcripts in a given embryonic tissue, TGF beta proteins were frequently colocalized within the same cell type as the mRNA, but in some cases were observed to localize to different cells than the mRNA, thereby indicating that a complex pattern of transcription, translation, and secretion for TGF beta s 1-3 exists in the mouse embryo. This also indicates that TGF beta 1, beta 2, and beta 3 act through both paracrine and autocrine mechanisms during mammalian embryogenesis.

Animals↗
PubMed1990

A controlled dose-ranging study of remoxipride and haloperidol in schizophrenia--a Canadian multicentre trial.

The efficacy and side-effect profile for three dose ranges of remoxipride were compared with haloperidol in 242 schizophrenic inpatients in 13 centres. All patients were in a productive phase of schizophrenia according to DSM-III criteria. Relative efficacy of low dose (30-90 mg daily) vs middle dose (120-240 mg daily) vs high dose (300-600 mg daily) was compared with the standard dose of haloperidol (15-45 mg daily), as were the side effects. It was concluded that the therapeutic efficacy of remoxipride was comparable to that of haloperidol for acute episodes of schizophrenia; that the low dose range was significantly less effective than the higher ranges; that there was a clear advantage of remoxipride over haloperidol with respect to incidence and severity of extrapyramidal symptoms. The general safety profile of remoxipride as assessed from clinical chemistry, haematology, and cardiovascular variables suggests that remoxipride in the dose ranges studied can be used safely for the treatment of schizophrenic patients.

Acute Disease↗
PubMed1988

The effect of lithium administration on LH response in healthy volunteers.

1. As part of a systematic investigation of the effects of lithium administration on neuroendocrine function we investigated the luteinizing hormone (LH) response to luteinizing hormone releasing hormone (LHRH) of healthy males. 2. In healthy volunteers after 3 weeks of therapeutic doses of lithium the LH response to LHRH was significantly increased in comparison with the responses prior to lithium administration. 3. An attempt is made to explain these findings by underlying neurotransmitter changes.

Adult↗
PubMed1984

Effects of lithium, nortriptyline and dexamethasone on insulin sensitivity.

The effects of lithium, dexamethasone, nortriptyline and their combinations on insulin sensitivity, expressed as a drop of plasma glucose in response to insulin challenge, were investigated in healthy volunteers. Short-term (three weeks) lithium treatment did not appear to exert any influence on the insulin sensitivity. Dexamethasone administered alone (2 mg given 57 hours prior to the test) had no effect on the insulin sensitivity of drug-free healthy subjects. However, after three weeks of lithium treatment the dexamethasone premedication resulted in slight flattening of glucose response to insulin in the same persons. Nortriptyline administered for three weeks to healthy volunteers, pretreated with dexamethasone, increased insulin sensitivity. These findings may have clinical implications regarding the treatment of depressed diabetic patients, and may provide information about the regulation of insulin sensitivity.

Adult↗
PubMed1983

A comparative study of bupropion and amitriptyline in depressed outpatients.

A double-blind controlled trial comparing a standard antidepressant drug, amitriptyline, with a new compound, bupropion, was conducted at six centers. There was a placebo washout, after which patients were assigned in a randomized fashion to one of the two treatments. No significant difference was found in therapeutic response to the two drugs after 4 weeks of treatment. Anticholinergic and cardiovascular side effects were less common in the bupropion-treated patients.

Adolescent↗
PubMed1980

Long-term lithium treatment and the kidney. Interim report on fifty patients.

This is a report on the first part of our study of the effects of long-term lithium treatment on the kidney. Creatinine clearance, maximum urinary osmolality and 24 hour urine volume have been tested in 50 affectively ill patients who have been on long-term lithium for more than one year. These findings have been compared with norms and with values of the same tests from screening prior to lithium, available for most of our patients. No evidence was found for any reduction of glomerular filtration during lithium treatment. Low clearance values found in several patients could be accounted for by their age and their pre-lithium values. Urinary concentration defect appeared frequent but the extent of the impairment is difficult to assess because of the uncertainty about the norms applicable to this group of patients. The concentration defect appeared reversible, at least in part. Polyuria above 3 litres/24 hours was found in 10% of patients. An attempt is made to draw practical conclusions from the preliminary findings.

Adult↗
PubMed1978

Fluphenazine decanoate and fluphenazine enanthate in the out-patient management of chronic schizophrenia.

39 chronic schizophrenic out-patients were given either fluphenazine decanoate or enanthate for a 1-year double-blind trial. Doses of 25 mg were given for the first 6 months and 37.5 mg for the last 6 months. For both agents the intervals between treatments lengthened significantly over the course of the trial. Fluphenazine decanoate showed a non-significant trend for a longer duration of action coupled with a significantly lower incidence of extrapyramidal side effects.

Adult↗
PubMed1978

Primary intracranial HCG-producing germinoma in a boy with congenital adrenal hyperplasia.

A primary intracranial HCG-producing tumour was studied in an 8 year old boy with congenital adrenal hyperplasia. The case provided a unique opportunity to study the sequential changes in serum and urinary androgens and HCG as measured by radioreceptor assay for HCG and by radioimmunoassay for HCG using antisera raised against the hormone specific for the beta subunit of HCG. Plasma concentrations of HCG, measured by the radioreceptor assay, closely correlated with the biologic activity of his tumour, as measured by serum testosterone concentration. This case demonstrates that precocious puberty in any child, including one with a known androgen disorder such as congenital adrenal hyperplasia, warrants through investigation.

Adrenal Hyperplasia, Congenital↗
PubMed1977

Dopaminergic agonist nomifensine compared with amitriptyline: a double-blind clinical trial in acute primary depressions.

1. Nomifensine (8-amino-2-methyl-4-phenyl-1,2,3,4,-tetrahydroisoquinoline) is a new antidepressant which displays an interesting pharmacological profile and acts as a potent dopaminergic agonist. 2. In a double-blind clinical trialnomifensine was compared with a standard and widely tested antidepressant amitriptyline. A total of 24 patients with primary acute depressions, defined by research criteria, were treated for 8 weeks and their clinical condition and laboratory values monitored at regular intervals. The dosage schedule was a flexible one, with a daily dose range from 50-200 mg for nomifensine and 50-225 mg for amitriptyline. 3. Nomifensine and amitriptyline were found to be equivalent in their antidepressant efficacy. Nomifensine, however, showed a trend towards more rapid effect and was relatively free of side-effects. 4. As nomifensine combined antidepressant activity with low frequency of adverse effects, it would seem to be suitable for wider use in the treatment of primary depressions. The results of our study have to be generalized with caution because of the limited sample size.

Adult↗
PubMed1976

Bioavailabiltity and side effects of different lithium carbonate products.

Among the three lithium preparations tested, no significant difference was found in the bioavailability, as expressed in serum and erythrocyte lithium concentrations and urinary lithium output. The side effect reports, however, varied significantly among the types of lithium under study. The slower the absorption of a particular preparation, the fewer the side effects. The results of this study support the view that preference should be given to lithium preparations with slow-release properites, particularly in side-effect-prone subjects.

Adult↗