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Biomedical subjects

S Akhtar

Publications and source records attributed to S Akhtar.

At least 127 records · Page 7Linked to original sources
PubMed1996

Dynamic and steady state response of heart rate to orthostatic stress in normotensive and hypertensive pregnant women.

We determined the dynamic and steady state responses of heart rate (HR) to orthostatic stress (standing up) in normotensive and hypertensive pregnant women. Using a continuous recording with servo-photosphygmography, HR response to change in posture from left lateral recumbent position to standing was analysed. The subjects were divided into five groups comprising: Groups I, II and III: normotensive pregnant women in each of the three trimesters of pregnancy (total n = 77); Group IV: women with gestational proteinuric hypertension (GPH) in the third trimester (n = 16); Group V: age-matched non-pregnant normotensive controls (n = 15). The HR reacted with a typical overshoot response to this orthostatic change with HR rising to a peak and then settling to a new but higher steady state. Change in steady state HR from lying to standing (delta HR), rate of rise of HR in response to standing (i.e. the acceleration slope (HRon)), and rate of fall of HR after reaching the peak (i.e. deceleration slope (HRoff)) were evaluated from standing heart rate time curves. HRon in response to standing showed a downward trend with gestation (ANOVA, P < 0.05) in normotensive gravida. The deceleration slope (HRoff) showed a distinct gestational age-related decrease from first to third trimester in normotensive women (ANOVA, P < 0.01). The most striking observation was that the slope of HRoff for the GPH group was significantly steeper than that of normotensive women of comparable gestational age (unpaired t-test P < 0.01) and approximated to that of the non-pregnant group. The difference in HR response between normotensive women and those with GPH in the third trimester suggests it may have potential as a new marker for pre-eclampsia.

Adult↗
PubMed1996

Interactions of phosphodiester and phosphorothioate oligonucleotides with intestinal epithelial Caco-2 cells.

PURPOSE: Oral bioavailability for antisense oligonucleotides has recently been reported but the mechanistic details are not known. The proposed oral delivery of nucleic acids will, therefore, require an understanding of the membrane binding interactions, cell uptake and transport of oligonucleotides across the human gastro-intestinal epithelium. In this initial study, we report on the cell-surface interactions of oligonucleotides with human intestinal cells. METHODS: We have used the Caco-2 cell line as an in vitro model of the human intestinal epithelium to investigate the membrane binding interactions of 20-mer phosphodiester (PO) and phosphorothioate (PS) oligonucleotides. RESULTS: The cellular association of both an internally [3H]-labelled and a 5'end [32P]-labelled PS oligonucleotide (3.0% at 0.4 microM extracellular concentration) was similar and was an order of magnitude greater than that of the 5'end [32P]-labelled PO oligonucleotide (0.2%) after 15 minutes incubation in these intestinal cells. The cellular association of PS was highly saturable with association being reduced to 0.9% at 5 microM whereas that of PO was less susceptible to competition (0.2% at 5 microM, 0.1% at 200 microM). Differential temperature-dependence was demonstrated; PS interactions were temperature-independent whereas the cellular association of PO decreased by 75% from 37 degrees C to 17 degrees C. Cell association of oligonucleotides was length and pH-dependent. A decrease in pH from 7.2 to 5.0 resulted in a 2- to 3-fold increase in cell-association for both backbone types. This enhanced association was not due to changes in lipophilicity as the octanol:aqueous buffer distribution coefficients remained constant over this pH range. The ability of NaCl washes to remove surface-bound PS oligonucleotides in a concentration-dependent manner suggests their binding may involve ionic interactions at the cell surface. Cell-surface washing with the proteolytic enzyme, Pronase, removed approximately 50% of the cell-associated oligonucleotide for both backbone types. CONCLUSIONS: Binding to surface proteins seems a major pathway for binding and internalization for both oligonucleotide chemistries and appear consistent with receptor (binding protein)-mediated endocytosis. Whether this binding protein-mediated entry of oligonucleotides can result in efficient transepithelial transport, however, requires further study.

Azides↗
PubMed1996

The influence of polarized epithelial (Caco-2) cell differentiation on the cellular binding of phosphodiester and phosphorothioate oligonucleotides.

Cell aging and the degree of cellular differentiation are thought to be important variables governing uptake of oligonucleotides but remain poorly understood. The Caco-2 colon carcinoma cell line has the ability to spontaneously differentiate into enterocytes in vitro and serves as a useful model to further investigate the effect of differentiation on oligonucleotide binding and uptake. In this study, we report that the extent of oligonucleotide association and the expression of cell surface binding proteins are governed by the age and thus the degree of differentiation of Caco-2 epithelial cells in culture. Cellular association (normalized for cell number) of an all phosphodiester (PO), all phosphorothioate (PS), and a phosphodiester oligonucleotide containing two terminal phosphorothioate internucleotide linkages at the 3' end (EC-PO) gradually increased from day 3 to around day 17 of the culture, followed by a plateau, or slight decrease, up to day 21 of the cell aging study. Overall, a threefold to fourfold increase in binding was observed from day 3 to day 17. Oligonucleotide binding was temperature and pH dependent, but the magnitude of the effect was influenced by cell aging and the degree of differentiation. PS oligonucleotides exhibited greater binding (up to threefold) at the basolateral surface compared with the apical surface within the pH range 5-7. These findings could be directly correlated with the expression levels of cell surface oligonucleotide binding proteins during the aging study. A Caco-2 cell surface protein binding complex of around 46 kDa was identified as the major site of binding for both PO and PS oligonucleotides, although the latter also bound to several other proteins, especially at low pH.

Caco-2 Cells↗
PubMed1996

Antisense therapy.

The sequence specificity of the antisense technique makes it an attractive basis for novel molecular therapeutics. Inhibition of gene expression by antisense in cell culture models has provided a strong rationale for identification and validation of disease targets. Analogues modified from normal phosphodiester oligodeoxynucleotides have entered clinical trials of diseases including AIDS, cancer, and inflammation. It is becoming increasingly apparent that these drugs act by means of a complex mechanism of action, and some of their effects can be sequence independent. Nevertheless, these oligodeoxynucleotides offer considerable promise as novel molecular drugs. Harnessing the therapeutic potential of this powerful technique depends on elucidation of the complex mechanism of action so that effective and meaningful therapeutic modalities can be realized.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Blood cultures in adult patients released from an urban emergency department: a 15-month experience.

OBJECTIVE: To determine the frequency of positive blood cultures obtained from adult patients with potential occult bacteremia released from an urban ED and how often these positive cultures alter the subsequent patient course or management. METHODS: This retrospective case series study was conducted at the ED of a large, urban teaching hospital. The study population consisted of a convenience sample of adult patients who presented to the ED with evidence of fever or other clinical conditions suggesting the possibility of bacteremia. The records of all patients who had blood cultures done and who were not admitted to an inpatient service were reviewed. Follow-up was obtained for all patients for whom culture results were positive. A substantial influence on the medical management or clinical course by a (noncontaminant) positive blood culture result was defined as a positive result that directly led to: further diagnostic testing, hospital admission, initiation or alteration of antibiotic therapy, or a different diagnosis. Culture-positive patients who were noncompliant with requested ED follow-up were included in this estimate. An estimate of the laboratory charges per diagnosis of bacteremia also was derived. RESULTS: Only 24 of 1,350 patients (1.8% of the study population; 95% CI 1.1-2.5%) had true-positive blood cultures. Only 7 patients (0.52% of the population; 95% CI 0.14-0.90%) potentially had their medical management affected by the positive blood culture results. Based on the laboratory charges associated with all blood cultures for this patient group, the cost per clinically significant positive blood culture result was $ 11,570. CONCLUSIONS: The prevalence of bacteremia was 1.8% among the released patients who had blood cultures obtained in the ED. Furthermore, only 0.52% of the patients had positive blood cultures that potentially affected their medical management. Further study is warranted to identify specific criteria for selecting ambulatory patients for whom the use of blood cultures may be cost-effective.

Adult↗
PubMed1996

"Someday ..." and "if only ..." fantasies: pathological optimism and inordinate nostalgia as related forms of idealization.

Fantasies whose core is constituted by the notions of "someday" and "if only" are ubiquitous in human psyche. In severe character pathology, however, these fantasies have a particularly tenacious, defensive, and ego-depleting quality. The "someday" fantasy idealizes the future and fosters optimism, and the "if only" fantasy idealizes the past and lays the groundwork for nostalgia. The two fantasies originate in the narcissistic disequilibrium consequent upon the early mother-child separation experiences, though the oedipal conflict also contributes to them. Both can be employed as defenses against defective self and object constancy as well as later narclssistic and oedipal traumas. This paper attempts to highlight the metapsychology and behavioral consequences of these fantasies as well as their unfolding in the treatment situation. It suggests six tasks to be especially important for analytic work with such patients: (1) providing and sustaining a meaningful "holding environment"; (2) employing "affirmative interventions"; (3) helping the patient unmask these fantasies and interpreting their defensive, narcissistic and sadomasochistic aspects; (4) rupturing the patient's excessive hope, analyzing the effects of such rupture, and facilitating the resultant mourning; (5) reconstructing the early scenarios underlying the need for excessive hope; and (6) paying careful attention to countertransference feelings throughout such work.

Countertransference↗
PubMed1996

A nonantisense sequence-selective effect of a phosphorothioate oligodeoxynucleotide directed against the epidermal growth factor receptor in A431 cells.

The overexpression of epidermal growth factor receptor (EGFr) has been implicated as a causative factor and a poor prognostic marker in a number of carcinomas. Therefore, strategies that down-regulate EGFr expression may be therapeutically useful. We designed antisense ODNs complementary to the initiation codon region of the EGFr mRNA and evaluated their efficacy in several tumor-derived cells, including the A431 cell line, that express amplified levels of EGFr. A 15-mer phosphorothioate (PS) antisense ODN (erbB1AS15) induced a concentration-dependent reduction in proliferation that was accompanied by a change in the morphology of A431 cells into more tightly clustered and discrete colonies. A 15-mer sense (PS) control oligodeoxynucleotide (ODN) and a phosphodiester (PO) version of erbB1AS15 had little or no effect on cell number of morphology, and erbB1AS15 (PS) did not induce these effects in control cell lines expressing lower levels of EGFr. The effects of erbB1AS15 (PS) on A431 cells were not mediated by a true antisense mechanism in that there was no reduction in the level of EGFr mRNA or protein over a 24-hr period, as determined by Northern and Western blotting, respectively. However, autophosphorylation of the receptor was significantly reduced by erbB1AS15 (PS) and not by control ODNs. The results of further studies suggested that this effect was mediated by a direct, dose-dependent inhibition of the EGFr tyrosine kinase enzyme and was not due to impairment of either ligand-binding or receptor dimerization. These data suggest that erbB1AS15 (PS) can inhibit proliferation and alter the morphology of A431 cells by a sequence-selective, but nonantisense, mechanism affecting receptor tyrosine kinase activity.

Base Sequence↗
PubMed1996

Rhinomanometric evaluation of the improved mechanical therapeutic nasal dilator in patients with anterior nasal obstruction.

The effectiveness of the Improved Mechanical Therapeutic Nasal Dilator (IMTND) was evaluated rhinomanometrically in 33 patients (mean age: 26 years; range 18-68 years) with anterior nasal obstruction. Using anterior rhinomanometry the patients were observed to have a mean total resistance of 0.376 Pa/cm3/s (range: 0.16-0.87 Pa/cm3/s). There was a significant drop in the inspiratory nasal resistance by 26% after the insertion of the IMTND in the nostrils (p < 0.001). Following decongestion with 1% phenylephrine the resistance decreased by 41%. This difference was statistically significant (p < 0.001). Insertion of the IMTND in the decongested nostrils resulted in even higher and significant decrease in the nasal resistance by 59% (p < 0.001).

Administration, Intranasal↗
PubMed1996

Hemorrheologic effects of pyrimido-pyrimidine derivatives.

A series of pyrimido-pyrimidine derivatives were tested for their effect on membrane fluidity-deformability of human red blood cells and on human platelet aggregation. These agents were also tested for their intracellular cAMP increasing activity and proliferation inhibitory activity in neoplastic cells. The order of activity was established and clinical implications discussed. Several derivatives are under study as antineoplastic agents.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Endogenous and exogenous nitric oxide protect against intracoronary thrombosis and reocclusion after thrombolysis.

BACKGROUND: Nitric oxide (NO), an endothelium-derived relaxing factor, plays an important role in regulating platelet activation. We evaluated the effect of NO in a canine model of intracoronary thrombosis, thrombolysis, and reocclusion. METHODS AND RESULTS: Before thrombosis was induced, 34 anesthetized dogs were treated with a continuous intracoronary infusion of saline (n = 8); NG-nitro-L-arginine (L-NNA, n = 8), an inhibitor of NO synthetase; L-arginine (n = 7), the precursor for NO; or sodium nitroprusside (SNP, n = 11), an NO donor. Ten minutes after the infusion was begun, an electric current of 150 microA was applied to the endothelium of coronary arteries to induce thrombosis. Occlusive thrombi developed in all dogs in the saline group (38 +/- 4 minutes) and the L-NNA group (30 +/- 6 minutes), in 6 of 7 dogs in the L-arginine group (81 +/- 18 minutes), and in 6 of 11 dogs in the SNP group (102 +/- 21 minutes) (P < .01). The time to thrombus was prolonged by L-arginine (P < .05) and SNP (P < .01). After 3 hours of thrombus formation in coronary arteries, tissue plasminogen activator and heparin were administered intravenously. Thrombi were lysed in 4 (of 8) dogs in the saline group (71 +/- 8 minutes), in 4 (of 8) dogs in the L-NNA group (72 +/- 8 minutes), in 4 (of 6) dogs in the L-arginine group (50 +/- 14 minutes), and in 4 (of 6) dogs in the SNP group (49 +/- 11 minutes) (P > .05). After thrombolysis, coronary artery reocclusion developed in all reperfused dogs in the saline group (30 +/- 8 minutes) and in the L-NNA group (48 +/- 12 minutes), in 3 (of 4) reperfused dogs in the L-arginine group (123 +/- 26 minutes), and in 3 (of 4) reperfused dogs in the SNP group (128 +/- 19 minutes) (P < .01). The ex vivo platelet aggregation induced by collagen was inhibited after in vivo treatment with L-arginine or SNP. CONCLUSIONS: Increasing NO production or giving an NO donor may inhibit platelet aggregation and delay intracoronary thrombus formation and reocclusion after thrombolysis.

Animals↗
PubMed1995

Lateral spread of the aetiologic agent(s) of hydropericardium syndrome in broiler chickens.

The rate of lateral spread of the agent(s) of hydropericardium syndrome was investigated in three controlled experimental trials, (1, 2 and 3), in which groups of 60, 50 and 70 birds had five, three and seven birds infected deliberately and were then maintained at stocking densities of 0.83, 1.00 and 0.71 square feet/bird. In each trial a control group of birds was reared at the same time. The non-parametric survival functions (Kaplan-Meier product limit) were fitted to the data and compared by the Mantel-Cox and Breslow tests. In trials 1, 2 and 3 the hydropericardium syndrome occurred with a median latent period of 9.5, 13.0 and 14.5 days, respectively, the median daily mortality rates were 3.4, 4.5 and 4.5 per cent and the cumulative mortalities were 40, 54 and 55.7 per cent. These results were not significantly different.

Animals↗