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Biomedical subjects

A Ahmed

Publications and source records attributed to A Ahmed.

At least 163 records · Page 9Linked to original sources
PubMed1999

Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: molecular evidence for "placental hyperoxia" in intrauterine growth restriction.

Early placental development occurs in an environment of relative hypoxia. Hypoxia promotes angiogenesis and up-regulates vascular endothelial growth factor (VEGF) expression while it down-regulates placenta growth factor (PIGF) that possess 53% homology with VEGF. Morphological studies show poor placental vascular development and an increase in the mitotic index of cytotrophoblasts in intrauterine growth restriction (IUGR). We hypothesized that the reported relatively high oxygen level in the intervillous space in contact with IUGR placental villi will limit angiogenesis by changes in VEGF and PIGF expression and function. Western immunoblot analysis demonstrates a diametric expression of PIGF and VEGF proteins throughout pregnancy with PIGF levels increasing and VEGF levels decreasing, consistent with placental oxygenation. In IUGR placentae, the ratio of PIGF/GAPDH mRNA was increased by 2.3-fold (p < 0.03) and PIGF protein levels were also increased, (p < 0.05) as compared with gestationally-matched normal placentae. PIGF mRNA and protein were localized to the trophoblast bilayer and villous mesenchyme of the human placenta throughout gestation. In vitro studies demonstrated that increasing oxygen tension (hyperoxia) up-regulated PIGF protein in term placental villous explants, whereas hypoxic culture of a term trophoblast choriocarcinoma cell line (BeWo) down-regulated PIGF mRNA and protein and VEGFR-1 (Flt-1) autophosphorylation. The addition of PIGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line stimulated DNA synthesis while PIGF-2 had little effect. VEGF and PIGF exert their biological actions by means of a common receptor VEGFR-1. In the first trimester trophoblast cells, PIGF-1 increased the association of phosphorylated extracellular signal-related kinase (ERK) with VEGFR-1 immunoprecipitates while both PIGF-1 and PIGF-2 also potentiated endogenous VEGF mediated association of phosphorylated extracellular related kinase (ERK) with VEGFR-2 (KDR). More importantly, the addition of PIGF-1 had little effect while PIGF-2 inhibited cell growth in cultured endothelial cells derived from human umbilical vein. Nitric oxide (NO) is reported to promote angiogenesis and PIGF-2 inhibited the basal release of NO from the first trimester trophoblast. The tissue expression and functional studies support the hypothesis of "placental hyperoxia" in early-onset IUGR because hypoxia down-regulates trophoblast PIGF levels, PIGF expression is increased in IUGR, and PIGF-2 inhibits endothelial cell growth. Taken together, these changes provide a cellular explanation for the observed poor angiogenesis in the pathogenesis of IUGR and show that the two PIGF isoforms may modulate trophoblast and endothelial cell function differently, possibly through potentiation of VEGF mediated activation of VEGF-2.

Cell Line↗
PubMed1999

VEGF via VEGF receptor-1 (Flt-1) mimics preeclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: implications in the pathogenesis of preeclampsia.

Preeclampsia is a multisystem disorder characterized by hypertension and proteinuria. There is accumulating evidence that this is a disease of the endothelium, with an as-yet unidentified circulating factor, or factors, causing the observed alteration in vascular function. We previously reported that the function of myometrial vessels is altered on exposure to plasma from women with preeclampsia. Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts via two high-affinity receptors (KDR and Flt-1), and its production is increased in preeclampsia. Here we report that VEGF and its Flt-1 receptor may play a pivotal role in the altered vascular function of preeclampsia. Myometrial resistance vessels were obtained at the time of cesarean section. Using the Mulvany wire myograph, the endothelium-dependent behavior of these vessels was studied. Incubation of vessels from pregnant women with VEGF resulted in a reduction of endothelium-dependent relaxation that mimicked the reduction induced by plasma from women with preeclampsia. The altered function that occurred upon exposure of vessels to VEGF or plasma from women with preeclampsia did not occur when plasma was incubated with antibodies to VEGF before vessel incubation. The presence of an anti-KDR receptor antibody had no effect on VEGF response. However, in the presence of an anti-Flt-1 receptor antibody, VEGF or plasma from women with preeclampsia no longer attenuated the endothelium-dependent relaxation (p < 0.05). The changes observed with VEGF and plasma from women with preeclampsia and their subsequent blockade with anti-VEGF antibody and anti-Flt-1 receptor antibody strongly suggest that VEGF acting through the Flt-1 receptor is pivotal in the pathogenesis of this disease.

Adolescent↗
PubMed1999

Equivalence of the acute phase reactants C-reactive protein, plasma viscosity, and Westergren erythrocyte sedimentation rate when used to calculate American College of Rheumatology 20% improvement criteria or the Disease Activity Score in patients with early rheumatoid arthritis. Western Consortium of Practicing Rheumatologists.

OBJECTIVE: In an additive cohort of patients with early rheumatoid arthritis (RA), to determine the effect of substituting one acute phase reactant for another on the number of patients satisfying the American College of Rheumatology (ACR) 20% preliminary criteria for improvement, and on calculated Disease Activity Scores (DAS). METHODS: A total of 251 patients with 6.4 months average disease duration had detailed clinical assessments at entry and 6, 12, and 24 months in a multicenter prospective longterm observational study. Matched erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and plasma viscosity (PV) assays were done at 366 time points. Disease modifying antirheumatic drugs were not started until after the baseline evaluation. RESULTS: After 6, 12, and 24 months, 50%, 53%, and 57% of patients were responders, as defined by the ACR 20% improvement criteria. The difference in response rates when ESR, CRP, or PV was used as the acute phase reactant ranged from 0.4% at 12 months to 3% at 24 months. Percentile distributions of the 366 matched CRP, ESR, and PV values were used to prepare a nomogram that can be used to calculate the other acute phase reactant values if the value of one is known. When the nomogram was used to impute ESR values from observed PV or CRP values, average DAS scores calculated with the actual ESR values were not different from average DAS scores calculated from the imputed ESR values. CONCLUSION: ESR, CRP, and PV are equally useful in calculating ACR 20% response rates in patients with active early RA. A nomogram can be used to impute ESR values from CRP or PV values; use of the imputed ESR values is as accurate as use of the actual ESR values to calculate average DAS.

Acute-Phase Reaction↗
PubMed1999

Q wave and non-Q wave myocardial infarction: a multivariate analysis of survival experience and clinical outcome after first diagnosis at a tertiary care hospital.

INTRODUCTION: Myocardial infarction (MI) is a well-recognized clinical entity with a worldwide distribution. In the United States alone, 1.5 million cases of MI occur per year. This study compares the in-hospital mortality, 1 year mortality and time to death following a first Q-wave or non Q-wave myocardial infarction (MI). METHODS: One thousand five hundred and ninety-six patients were admitted at the Aga Khan University Hospital with a diagnosis of MI over a period of four years of whom 420 patients met our inclusion criteria. Data was collected from the patients' medical records and on telephone using a pretested questionnaire. Logistic regression and Cox proportional hazard models were used to analyze the data. RESULTS: The mean age +/- sd of the patients was 59 +/- 10 years. Of the total patients, 151(36%) and 269(64%) suffered non-Q wave and Q-wave MI respectively. A higher in hospital mortality was observed in patients with Q-wave MI (n = 64, 23.8%) than those with non-Q wave MI [n = 16 (10.6%); adjusted OR = 2.76, 95% CI: 1.5-5.01]. Similarly, patients having Q-wave MI experienced increased 1 year mortality (n = 77, 28.6%) compared to patients suffering non-Q wave MI [n = 26 (17.2%); adjusted OR = 2.04, 95% CI: 1.21-3.43]. CONCLUSION: Patients with Q-wave MI had a worse prognosis compared with patients with non-Q-wave MI and therefore warrant a closer follow up. Further prospective studies are needed to evaluate the efficacy of early aggressive interventions in modifying the natural history of this disease.

Aged↗
PubMed1999

Dietary practices and beliefs of patients with chronic liver disease.

OBJECTIVE: To study of the dietary practices and beliefs of patients suffering from chronic liver disease. SETTING: Two private tertcary care hospitals. METHOD: Fifty patients presenting to the Gastroenterology Clinics at the Aga Khan University Hospital and Baqai Hospital, with compensated liver disease and no other co-morbid condition which required dietary modifications, were enrolled in the study. Patients were interviewed regarding their current dietary practices using an open-ended questionnaire. RESULTS: The mean age of the patients was 48 years and the majority were in relatively poor nutritional status. Four had BMI's < 18; 58% had Hb < 12 g/dl and 36% had albumin levels < 3 gm/dl. The percentage of patients avoiding various foods is as follows: meats 72%, fats and oils 64%, salt 42%, spices 34%, milk and milk products 28%, rice 20%. CONCLUSION: The most commonly cited reason for avoiding a given food was the advice of the family doctor, followed by advice by gastroenterologists, family and friends. Concepts from alternative medicine and continuation of dietary restrictions imposed during a decompensated phase also influenced intake. Compromised nutritional status is a poor predictor of clinical outcome in liver disease therefore it is important that gastroenterologists be proactive regarding nutritional counseling and both patients and their primary care physicians understand the importance of not imposing unnecessary restrictions on dietary intake.

Adolescent↗
PubMed1998

Observations on template switching during DNA replication through long inverted repeats.

The bacterial Tn5 transposon consists of a pair of long inverted repeats flanking a central region that carries genes for antibiotic resistance. An analysis of DNA replication through Tn5 by two-dimensional gel electrophoresis has revealed two interesting features: (i) a spike representing X-shaped molecules, and (ii) a spot representing a barrier on the arc of Y-shaped replication intermediates. The electrophoretic behavior of various restriction fragments derived from this region indicates that the X molecules contain two linear Tn5 fragments joined together by a cross connection (Holliday junction). However, their formation is recA independent. The junction seems to connect the right inverted repeat of one fragment to the left inverted repeat of the other. The structure of the X molecules suggests that they could be formed by template switching when synthesis of the leading strand enters the right inverted repeat. One possible mechanism is that switching occurs at the center of a transient cruciform structure. A similar switching event, occurring when synthesis of the leading strand enters the left inverted repeat, could give rise to the barrier. These results imply that the inviability of palindromic DNA, which has previously been attributed to the slowing down of replication, may actually be caused by frequent template switching.

Bacterial Proteins↗
PubMed1998

Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders.

BACKGROUND: Retroviruses have been implicated in the aetiology of various autoimmune diseases. We used immunoblots as a surrogate test to find out whether retroviruses play a part in the development of primary biliary cirrhosis. METHODS: We did western blot tests for HIV-1 and the human intracisternal A-type particle (HIAP), on serum samples from 77 patients with primary biliary cirrhosis, 126 patients with chronic liver disease, 48 patients with systemic lupus erythematosus, and 25 healthy volunteers. FINDINGS: HIV-1 p24 gag seroreactivity was found in 27 (35%) of 77 patients with primary biliary cirrhosis, 14 (29%) of 48 patients with systemic lupus erythematosus, 14 (50%) of 28 patients with chronic viral hepatitis, and nine (39%) of 23 patients with either primary sclerosing cholangitis or biliary atresia, compared with only one (4%) of 24 patients with alcohol-related liver disease or alpha1-antitrypsin-deficiency liver disease, and only one (4%) of 25 healthy volunteers (p=0.003). Western blot reactivity to more than two HIAP proteins was found in 37 (51%) of patients with primary biliary cirrhosis, in 28 (58%) of patients with systemic lupus erythematosus, in 15 (20%) of patients with chronic viral hepatitis, and in four (17%) of those with other biliary diseases. None of the 23 patients with either alcohol-related liver disease or alpha1-antitrypsin deficiency, and only one of the healthy controls showed the same reactivity to HIAP proteins (p<0.0001). Our results showed a strong association between HIAP seroreactivity and the detection of autoantibodies to double-stranded DNA. HIAP seroreactivity was also strongly associated with the detection of mitochondrial, nuclear, and extractable nuclear antigens. INTERPRETATION: The HIV-1 and HIAP antibody reactivity found in patients with primary biliary cirrhosis and other biliary disorders may be attributable either to an autoimmune response to antigenically related cellular proteins or to an immune response to uncharacterised viral proteins that share antigenic determinants with these retroviruses.

Autoantibodies↗
PubMed1998

Differential effects of Ca2+ channel blockers on Ca2+ transients and cell cycle progression in vascular smooth muscle cells.

We examined the differential effects of Ca2+ channel blockers on the elevation of the cytosolic Ca2+ concentration ([Ca2+]i) and G0/G1 transition induced by platelet-derived growth factor (PDGF) in rat aortic smooth muscle cells in primary culture. The phase of the cell cycle was determined by an immunocytochemical analysis of cell cycle-specific nuclear antigens. [Ca2+]i was monitored by fura-2 microfluorometry. The efficacy of Ca2+ channel blockers for the inhibition of [Ca2+]i elevation induced by PDGF (NiCl2 > isradipine > verapamil = diltiazem) did not parallel that for the inhibition of cell cycle progression induced by PDGF (verapamil = diltiazem > NiCl2 > isradipine). In addition, no significant correlation was observed between the extent of [Ca2+]i elevation and the extent of G0/G1 transition. We thus conclude that the inhibitory effects of Ca2+ channel blockers on the G0)/G1 transition induced by PDGF are not simply due to their inhibitory action on the [Ca2+]i elevations but instead are due to more complex unknown factors.

Animals↗
PubMed1998

Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy.

Nitric oxide was proposed as an endogenous inhibitor of myometrial contractility during pregnancy. Carbon monoxide (CO) like nitric oxide increases cGMP and is generated during the degradation of heme to biliverdin IX by hemeoxygenases (HO). Here we report that the expression of both HO-1 (inducible) and HO-2 (constitutive) were > 15-fold higher in pregnant myometrium compared to nonpregnant myometrium (n = 4, P < 0.001, P < 0.005, respectively). Moreover, the activation of the HO-CO pathway by the HO inducer, hemin (10 microM), completely inhibited spontaneous contractility (n = 3). Oxytocin-stimulated contractions (n = 5) were also significantly reduced (P < 0.05) in myometrial strips mounted for isometric recording under 2 g tension in Krebs solution. Reverse transcription-PCR analysis revealed that mRNA encoding HO-1 and HO-2 was undetected in explant cultures of nonlaboring pregnant myometrium under basal conditions, however, exposure to progesterone, but not estradiol-17beta, induced the expression of HO-1 and HO-2 mRNAs. Progesterone also significantly induced HO-1 protein synthesis (n = 4, P < 0.001) while estradiol-17beta had no effect (n = 4). In term (37-42-wk gestation) nonlaboring myometrial explants, CO production was stimulated by progesterone (10(-6) M) (n = 2) and hemin (10 microM) (n = 3) after 2 h of incubation and the effect of hemin was inhibited by 1 h of preincubation with the HO inhibitor tin protoporphyrin IX (20 microM). This study clearly demonstrates the expression of HO in the human myometrium and shows that its induction produces CO that limits uterine contractility in pregnant myometrium indicating a role for the HO-CO-cGMP pathway in the maintenance of the quiescent state of the uterus during pregnancy.

Blotting, Western↗
PubMed1998

Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.

Angiotensin II (ANG II) is a potent vasoconstrictor and growth promoter. Quantitative receptor autoradiography using the nonselective radioligand [125I]ANG II and subtype-selective competing compounds demonstrated the presence of both ANG II receptor (AT)1 and AT2 receptor recognition sites. In addition, a relatively small population of apparently non-AT1/non-AT2 sites was identified that may represent a novel high affinity ANG II recognition site in human placenta. Using placental membrane preparations, the AT2 receptor antagonist PD123177 failed to compete for [3H]ANG II binding at relevant concentrations, whereas the AT1 receptor antagonist losartan competed in a monophasic manner for all the specific binding, suggesting that the non-AT1/non-AT2 recognition site identified using autoradiography may be a cytosolic binding site. AT1 receptor binding was significantly reduced (P < 0. 02) in intraeuterine growth restriction (IUGR) pregnancies. Western blot analysis confirmed this showing a reduction in AT1 receptor protein. In situ hybridization and immunocytochemistry revealed that AT1 receptor mRNA and protein were localized throughout pregnancy in the cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast, as well as in or around the blood vessels of placental villi. The intensity of the hybridization signal for AT1 receptor mRNA over the syncytium was reduced in IUGR. ANG II evoked a rapid and concentration-dependent release of NO in first trimester cytotrophoblast-like cells that was abolished by the inclusion of the competitive NOS inhibitor NG-monomethyl-L-arginine. Neither losartan nor PD123177 alone significantly inhibited ANG II-evoked NO release, and when cells were stimulated with ANG II in the presence of losartan (10 microM) and PD123177 (10 microM) in combination, NO release was significantly inhibited (P < 0.05). These observations also suggest, for the first time, the existence of a cross-talk between AT1 or AT2 receptors in trophoblast and that the reduction in placental AT1 receptors in IUGR may, in part, account for poor placental function in this disorder.

Angiotensin II↗
PubMed1998

Amino acid transport during muscle contraction and its relevance to exercise.

The functional significance of amino acid transport in skeletal muscle has been explored by the use of a variety of techniques including work in isolated perfused organs, isolated incubated organs and tissue culture of muscle cells. The results suggest that although there is a wide variety of amino acid transport systems of different characteristics and with different responses to ionic, hormonal and nervous modulation, the amino acid glutamine (transported by system Nm) demonstrates some unusual properties not observed with amino acids transported by other systems. Glutamine is transported at very high rates in skeletal muscle and heart and both the glutamate and glutamine transporter appear to be adaptively regulated by the availability of glutamine. Glutamine appears to be involved in the regulation of a number of important metabolic processes in heart and skeletal muscle (e.g., regulation of the glutathione reduced/oxidised ratio and regulation of protein and glycogen synthesis). Furthermore, glutamine transport appears to interact with systems for regulation of volume control and many of the metabolic features attributable to changes in glutamine concentration appear to be modulated via alteration in cytoskeletal status.

Amino Acids↗
PubMed1998

Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers.

Autosomal recessive familial amyotrophic lateral sclerosis (RFALS) is a rare form of ALS that usually presents at an early age with slow progression of symptoms. RFALS is clinically and genetically heterogeneous and the locus of RFALS type 3 was mapped to 2q33 (ALS2) in a single family. We now report linkage of a more-common form of RFALS to chromosome 15q15-q22 markers (ALS5) and show further genetic locus heterogeneity in RFALS. ALS5 is the locus for most families with RFALS and appears to be present in both North African and European populations.

Age of Onset↗
PubMed1998

Ontogeny of hepatocyte growth factor (HGF) and its receptor (c-met) in human placenta: reduced HGF expression in intrauterine growth restriction.

Severe intrauterine growth restriction (IUGR) is characterized by abnormal placentation. Mouse gene knockout studies show that an absence of either hepatocyte growth factor (HGF) or its receptor, c-met, leads to intrauterine death secondary to severe IUGR with deficient placentation. In this study, immunocytochemistry localized HGF protein throughout placental villi across gestation, whereas c-met protein was localized only to the perivillous trophoblast and vascular endothelium. Within the IUGR placentae, a reduction in HGF immunostaining within the villous stroma was observed. HGF mRNA was strongly expressed in the perivascular tissue around the stem villous arteries throughout gestation, with weaker expression within the villous stroma and the terminal villi. c-met mRNA expression was limited to the perivillous trophoblast, particularly in the first trimester, with only a faint hybridization signal from the villous stroma. Placental mRNA expression was examined quantitatively using a ribonuclease protection assay: HGF and c-met mRNA expression increased from the first to the second trimester, reaching a zenith before decreasing again through the third trimester to term. HGF mRNA levels were significantly reduced in the IUGR placentae (P = 0.036), whereas c-met mRNA expression was within the normal range for gestation. These findings suggest that HGF derived from the perivascular tissue of stem villous arteries may play an important role in controlling normal villous development. Whereas reduced expression of HGF within IUGR placentae does not prove a causative link with abnormal villous development, the association lends support to this possibility.

Adult↗
PubMed1998

Why do infants make A not B errors in a search task, yet show memory for the location of hidden objects in a nonsearch task?

In 4 experiments, infants aged 8 to 12 months were tested on A not B search tasks, and nonsearch A not B tasks following the violation-of-expectation paradigm. A 1-location task and 2 control tasks were also conducted. In the nonsearch tasks, a toy was hidden in A, moved to B, and retrieved after a delay from either A (impossible) or B (possible). Results showed significantly longer looking times at impossible events, indicating some memory for where the object was hidden and an expectation of where it should be found. This effect occurred at delays at which infants made the A not B error when searching, and at a longer delay of 15 s. The results showed clearly that infants have some memory for the object's location, even at delays at which they search at the incorrect location. Discussion centers on how these results are accounted for within explanations of the A not B error.

Attention↗
PubMed1998

Molecular cloning and chromosomal localization of a prophenoloxidase cDNA from the malaria vector Anopheles gambiae.

A cDNA clone for prophenoloxidase was isolated from the most important human malaria vector, Anopheles gambiae. The clone encoded a polypeptide of 79341 Da that contains the two copper binding domains common to all invertebrate prophenoloxidases and haemocyanins. Expression of the prophenoloxidase gene was detected throughout all life stages from egg to imago in two strains of A. gambiae; however, the strongest expression was observed in developing embryos in eggs. The prophenoloxidase gene was mapped to the inversion rich region of the right arm of chromosome-2 in region 13B.

Amino Acid Sequence↗