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Biomedical subjects

M A Siddiqui

Publications and source records attributed to M A Siddiqui.

At least 19 recordsLinked to original sources
PubMed2006

Caudal anesthesia in pediatric surgical practice.

Prospective study was carried out on 100 patients since May 2005 in my private practice and in the department of pediatric surgery of MMCH. Under caudal anesthesia along with or without ketaminie induction and gas inhalation all the patients underwent different surgical procedure namely anorectal surgery (eg. anoplasty, rectal polyp), urogenital surgery (Circumcision, hypospadias, meatotomy), groin surgery (hernia, hydrocele) and foot & leg surgery. Calculated dose schedule of drugs used in anesthesia and volume were maintained. Time of giving anesthesia and time of starting analgesia were recorded. Per-operative and postoperative analgesia were evaluated. Every parent was explained regarding the merit of caudal anesthesia calculated and compared with that of general anesthesia. Application of caudal anesthesia with or without ketamine & diazepam induction can be used safely and cost effectively and may be put into protocol in many of the pediatric surgical practice both in institute and also in private practice.

Anesthesia, Caudal↗
PubMed2004

Treatment of non union of humerus using G. A. Ilizarov technique.

The management of the non union of humerus is one of the most challenging problems that the surgeon confronts in his practice. The procedures traditionally used are: I.M. Nailing, interlocking, plating, transplantation of allograft. In our series, 36 cases with non union has been treated by G.A. Ilizarov technique. The age range were: 21-62 years with an average of 32 years. The initial treatment were done by DCP, rush nails & plates with screw fixation. The duration of treatment ranged from 5-11 months (average 8 months). With the application of Ilizarov fixator a good range of elbow & shoulder motion were achieved. The average follow up period was 5 years with a range of 1-8 years. Union was achieved in all the 36 cases.

Adult↗
PubMed2002

Predominance of the DEN-3 genotype during the recent dengue outbreak in Bangladesh.

A recent outbreak of dengue in Bangladesh was marked by many fatal complications. As clinical virulence varies among the genotypes of dengue virus, a study was conducted to investigate the molecular genotypes of dengue in Bangladesh. Reverse transcription polymerase chain reaction was used to determine viral genotypes using oligonucleotide generic primers that produce a 511 bp product. The resulting product was typed by nested PCR with strain-specific primers, yielding 482 (DEN-1), 119 (DEN-2), 290 (DEN-3) and 392 (DEN-4), visualized on UV transilluminator after electrophoresis on 2% agarose gel stained with ethidium bromide. Of 45 clinically diagnosed dengue patients (mean age 28 years; male/female 30/15), 19 (42.2%) had detectable viral RNA in their blood. However, during the first 5 days of fever in 30 patients, the frequency was 60% (18/30), implying that the sooner serum is drawn after the fever, the greater the chances of detecting viral RNA. DEN-3 was detected in all except 2 patients who were infected with DEN-2. DEN-2 (two cases) and DEN-4 (one case) were present as co-infections with DEN-3. All of the patients presented with fever, anorexia and vomiting; many had headache and general body ache; a few had a rash. About a quarter had suffered episodes of bleeding, while ascites, pleural effusion and CNS symptoms were found in a few patients Patients positive for viral RNA were also positive for anti-dengue IgM (p=0.007) in subsequent sampling. The study suggests the predominance of DEN-3 infection with occasional co-infection with other types, during the recent outbreak of dengue in Bangladesh.

Adolescent↗
PubMed2002

Effect of prenatal doxycycline administration on skeletal differentiation in long bones of Albino rat.

OBJECTIVE: To study the teratogenic risk of Doxycycline administration during gestation on skeletal differentiation. DESIGN: An animal study carried out on experimental Albino rat. SETTING: The study was carried out in the Department of Anatomy Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre (JPMC), Karachi from June 1999 to May 2000. METHODS: Doxycycline was given to pregnant female Albino rats in a dose of 8 mg/kg intraperitoneally from day 8th to 19th of gestation. The intact rat fetuses were isolated on days 15th to 19th of gestation and pups on 1st postnatal day. These animals were then killed by deep ether anesthesia and fixed in 80% alcohol. They were then bulk stained with alizarin red S and alcian blue. Finally they were cleared in 4% KOH and stored in glycerin. The fore and hind limbs were disarticulated from the axial skeleton and observed under stereomicroscope for evidence of skeletal differentiation in the form of presence of primary ossification centers in long bones. The time of appearance of these centers were noted and compared statistically with those in the control animals. RESULTS: The study revealed that the skeletal differentiation in long bones was delayed in experimental animals as compared with controls. CONCLUSION: Doxycycline administration during pregnancy presents a risk to skeletal differentiation and therefore to its growth.

Animals↗
PubMed2001

Novel bicyclic lactam inhibitors of thrombin: potency and selectivity optimization through P1 residues.

Peptidomimetic inhibitors of thrombin lacking the important Ser195-carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.

Animals↗
PubMed2001

Response to hypoxia involves transforming growth factor-beta2 and Smad proteins in human endothelial cells.

Oxygen deprivation (hypoxia) is a consistent component of ischemia that induces an inflammatory and prothrombotic response in the endothelium. In this report, it is demonstrated that exposure of endothelial cells to hypoxia (1% O(2)) increases messenger RNA and protein levels of transforming growth factor-beta2 (TGF-beta2), a cytokine with potent regulatory effects on vascular inflammatory responses. Messenger RNA levels of the TGF-beta2 type II membrane receptor, which is a serine threonine kinase, also increased. The stimulatory effect of hypoxia was found to occur at the level of transcription of the TGF-beta2 gene and involves Smad proteins, a class of intracellular signaling proteins that mediates the downstream effects of TGF-beta receptors. Transient transfection studies showed that the region spanning -77 and -40 base pairs within the TGF-beta2 promoter (harboring a Smad-binding "CAGA box") is activated in hypoxic cells compared with nonhypoxic controls (P <.01). Hypoxia also stimulated transcription from another promoter, 3TP-Lux, a reporter construct responsive to Smads and TGF-beta. In addition, specific binding to a Smad-binding oligonucleotide was observed with nuclear extracts from hypoxic endothelial cells but not from nonhypoxic cells. It is concluded that Smad proteins, which can regulate endothelial responses to mechanical and inflammatory stress, also may play an important role in vascular responses to hypoxia and ischemia.

Binding Sites↗
PubMed2001

JAK/STAT signaling is associated with cardiac dysfunction during ischemia and reperfusion.

BACKGROUND: Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium. METHODS AND RESULTS: We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 micromol/L), an AT(1) blocker, or with tyrphostin AG490 (5 micromol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium. CONCLUSIONS: These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function.

Angiotensinogen↗
PubMed2001

Early developmental expression pattern of retinoblastoma tumor suppressor mRNA indicates a role in the epithelial-to-mesenchyme transformation of endocardial cushion cells.

The earliest stages of embryonic development are characterized by the generation of precursor cell populations that differentiate and coalesce into tissue and organ primordia. To provide sufficient numbers of differentiated cells for tissue and organ formation, the differentiative as well as the proliferative processes of cells must be controlled and coordinated. Potential regulators of the proliferative process include molecules that control the cell cycle, in particular, the tumor suppressor proteins. To begin to understand the role such molecules can play in development, we have studied the expression of the retinoblastoma tumor suppressor (Rb) gene in early chicken development. Our studies in early chicken embryos show that Rb is encoded by a single gene that gives rise to several Rb mRNA isoforms through alternative splicing of a primary transcript. These mRNA isoforms potentially encode Rb proteins that differ with respect to the number of sequence motifs known to target cyclin-dependent kinases to Rb, suggesting dynamic control of Rb phosphorylation and function during development. This complex expression pattern of Rb mRNA begins as early as the blastoderm stage of chicken development (stage 3) and continues through stage 18, the latest stage examined. Despite this early embryonic expression of Rb mRNA as detected by reverse transcription polymerase chain reaction, Rb mRNA levels sufficient to be detected by in situ hybridization were not expressed until after stage 14 of development. Rb mRNA was found to be localized to cells of the endocardial cushions of the early heart tube, cells of the epicardium, and myogenic cells of the somitic myotome. Interestingly, each of these cell types undergoes an epithelial-to-mesenchyme transformation to form a migratory and/or invasive population of mesenchymal cells. We have focused our studies on the expression of Rb mRNA in endocardial cells of the early heart tube, because the transition of these cells to mesenchyme initiates the important process of septation, an early step in the formation of heart valves.

Animals↗
PubMed2001

Anabolic-androgenic steroids induce apoptotic cell death in adult rat ventricular myocytes.

We tested whether exposure to anabolic-androgenic steroids (AASs) would induce apoptosis in adult rat ventricular myocytes in vitro. Myocytes were exposed to stanozolol (STZ), testosterone enanthate (TE) and testosterone (T) (0.1 micromol/L, 1 micromol/L, 10 micromol/L, and 100 micromol/L) for 20 h. The percentage of myocytes undergoing apoptosis was determined by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and was found to be increased when compared to control myocytes at STZ 10 micromol/L 12 +/- 2% (mean +/- SD), STZ 100 micromol/L 42 +/- 3%; TE 1 micromol/L 11 +/- 2%, TE 10 micromol/L 21 +/- 3%, TE 100 micromol/L 62 +/- 2%; T 10 micromol/L 11 +/- 2%, T 100 micromol/L 40 +/- 3% (P < 0.001 vs. CTL 2 +/- 2%). The STZ-, TE- and T-induced dose-dependent apoptotic cell death was corroborated by a significantly increased DNA laddering in myocytes exposed to STZ and T > or = 10 micromol/L and TE > or = 1 micromol/L. Notably, STZ, TE, and T exposure markedly increased the expression of the pro-apoptotic oncogene Bax-alpha, as assessed by reverse transcription-polymerase chain reaction. Taken together, these results clearly show for the first time that AASs induce apoptotic cell death in a dose-dependent manner. This finding may have important implications in understanding the pathogenesis of ventricular remodeling, cardiomyopathy, and sudden cardiac death associated with AAS abuse.

Anabolic Agents↗
PubMed2001

Role of STAT3 in ischemic preconditioning.

We recently demonstrated that ischemic preconditioning (IPC) induced by cyclic episodes of short durations of ischemia and reperfusion potentiates a signal transduction cascade involving protein tyrosine kinases and MAP kinases. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STAT6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in classical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor tyrphostin AG490 (5 microm) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibitor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated cardioprotection by altering the IPC-mediated survival signal into death signal. Thus, IPC-induced upregulation of antiapoptotic gene bcl-2 and downregulation of pro-apoptotic gene bax are decreased and increased, respectively, in the AG490 treated hearts. The results suggest that early phase of IPC potentiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium.

Animals↗
PubMed2001

Modulation of MLC-2v gene expression by AP-1: complex regulatory role of Jun in cardiac myocytes.

Hypertrophic stimulation of cardiac myocytes results in rapid induction of a number of transcription factors, including members of the AP-1 family, which is followed by a programmed alteration in the pattern of gene expression. In the ventricular cardiocytes there is re-expression of the fetal atrial natriuretic factor (ANF) gene and upregulation of its myosin light chain-2 (MLC-2v). The mechanism(s) by which the induction ofAP-1 is coupled to the promoters of these target genes is largely unknown. In this report, we demonstrate that in transient co-transfection assay, c-Jun inhibited while Jun B stimulated the MLC-2v promoter activity. Mutant c-Jun recombinants, in which the activation domains were deleted, still remained inhibitory, but a specific mutation in the leucine zipper, which changes the alignment of Jun with its dimerization partner, caused a reversal of its effect on the target MLC-2v promoter. Based on these findings, we propose that in chicken cardiac myocytes, the regulation of MLC-2v promoter by Jun may occur via its interaction with other proteins, possibly of the leucine zipper family.

Animals↗
PubMed2001

Ventricular myosin light chain-2 gene expression in developing heart of chicken embryos.

Recent gene knock-out studies in mice have suggested that ventricular myosin light chain-2 (vMLC2) has a role in the regulation of cardiogenic development and that perturbation in expression of vMLC2 is linked to the onset of dilated cardiomyopathy. In an attempt to develop an avian model for such studies, we examined the expression pattern of vMLC2 in chicken embryos at various stages and analyzed the effect of antisense oligonucleotide-mediated interference of vMLC2 function in cultures of whole embryos. Our results showed vMLC2 to be a specific marker for ventricular chamber throughout chicken embryonic development and antisense vMLC2 treatment of primitive streak stage (stage 4) embryos to produce pronounced dilation of heart tube with severe deficiency in formation of striated myofibrils. Further studies with antisense mRNA techniques of whole embryo cultures should, therefore, be useful to evaluate the role of vMLC2 and other putative regulatory factors in cardiac myofibrillogenesis.

Animals↗
PubMed2001

Differential effects of doxorubicin on atrial natriuretic peptide expression in vivo and in vitro.

Doxorubicin (Dox) is a potent anti-cancer agent with cardiotoxic side-effects but the mechanism of its cardiotoxicity and its effect on expression of the vasoactive atrial natriuretic peptide (ANP), an important marker for cardiac hypertrophy, are little understood. The present study examined Dox-induced changes in vivo in hearts of 6 mongrel dogs and 5 Sprague-Dawley rats and in vitro in cardiac cultures of neonatal rats. Quantitative RT-PCR analysis using gamma 32-p labeled primers for beta-actin, phospholamban (PLB) and ANP showed a selective 5-fold increase of ANP mRNA in Dox-treated dog hearts in comparison to controls. Similarly, northern analysis of GAPD, beta-actin, cardiac alpha-actin and ANP gave a selective 4.5-fold increase in ANP transcripts in Dox-treated rat hearts. On the other hand, there was a selective decrease (approximately 39%) of ANP transcripts in Dox-treated cardiac cultures relative to controls. Immunohistochemistry localized the ANP changes both in tissue sections and in cultures to the cardiomyocytes. The data clearly showed that Dox selectively increases ANP expression in dog and rat hearts in absence of cardiocyte hypertrophy but selectively decreases it in cardiac cultures. This differential effect of Dox on cardiocytes in vivo and in vitro should be a useful parameter for studies of transcriptional control of ANP expression.

Animals↗
PubMed2001

Interventional therapy for acute myocardial infarction.

Percutaneous transluminal coronary angioplasty has proven to be more effective and safer than thrombolytic therapy for the treatment of acute ST elevation myocardial infarction. Coronary intervention decreases early mortality and the incidence of intracerebral hemorrhage when performed by an experienced interventional team in a timely fashion. After failed fibrinolytic therapy for myocardial infarction, percutaneous transluminal coronary angioplasty is indicated for signs of ischemia and is very effective in restoring vessel patency and reducing mortality when used as a rescue procedure. The glycoprotein IIb-IIIa inhibitors improve outcomes in percutaneous transluminal coronary angioplasty, particularly in patients undergoing stent placement. Percutaneous interventional therapy in acute myocardial infarction is particularly beneficial in patients with cardiogenic shock and effective for saphenous vein graft occlusions, patients with diabetes mellitus, and in the elderly. New devices and drugs are currently being tested for acute myocardial infarction and provide hope for even better interventional therapies in the near future.

Angioplasty, Balloon, Coronary↗
PubMed2000

Parallel synthesis of isatin-based serine protease inhibitors.

The synthesis of N-functionalised isatins using parallel, solution synthesis is described. Functionalised polymers were employed as stoichiometric and catalytic reagents as well as purification media in the exercise, and the derivatives were screened against a panel of serine proteases; high percentage inhibition was observed in several cases.

Isatin↗
PubMed2000

In vitro and in vivo properties of bicyclic lactam inhibitors: a novel class of low molecular weight peptidomimetic thrombin inhibitors.

We have developed potent and selective thrombin inhibitors with a novel non-peptidic structure. A bicyclic lactam was used as the scaffold on which various P1 and P3 motifs were substituted. Herein, we report the in vitro and in vivo properties of four representatives of this novel class of inhibitors. Their Ki values were less than 10 nM, they inhibited equally both free and clot-bound thrombin, and they displayed high level of specificity for thrombin over other serine proteases (trypsin, factor Xa, activated Protein C, and plasmin). They prolonged the clotting time of human plasma to twice the control value in coagulation assays (TT, APTT, and PT) at a concentration below 3 microM. Their anticoagulant activities using rat plasma were similar to, although slightly weaker, than with human plasma. Furthermore, they inhibited thrombin-induced platelet aggregation (human and rat) at concentrations close to their Ki values for thrombin. These molecules demonstrated similar dose response antithrombotic efficacy in rat arterial and venous thrombosis models when given as i.v. bolus followed by infusion. Antithrombotic efficacy of 85% and greater was observed at a dose of 5-7 microM/kg/hour in each model. Bicyclic lactam inhibitor 3, at a dose which caused a complete inhibition of visible thrombus formation in the venous and arterial models of thrombosis, showed a 1.9-2.1 and a 4.0-4.8-fold shift in APTT and TT, respectively. Unfortunately, the bicyclic lactam inhibitors exhibited low oral bioavailability in rats. Therefore, this novel class of bicyclic lactam thrombin inhibitor has the potential to be promising intravenous antithrombotic agents for the treatment of arterial as well as venous thrombosis and warrants further investigation.

Animals↗