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Biomedical subjects

S Sheikh

Publications and source records attributed to S Sheikh.

At least 37 records · Page 2Linked to original sources
PubMed1999

Gastroesophageal reflux in infants with wheezing.

The relation between silent gastroesophageal reflux (GER) and respiratory problems such as persistent wheezing in infants is not well-established. Between January 1994 and June 1997, we evaluated the incidence of GER in 84 otherwise healthy infants referred to the Pediatric Pulmonary Medicine Division at Kosair Children's Hospital for evaluation of daily wheezing, and we followed their clinical course for 18 months. All underwent 24-hr esophageal pH studies to evaluate GER. The pH probe study was performed at a mean age of 8.74 +/- 4.6 months. Infants with a positive GER study were treated with an H2 receptor antagonist (H2RA) and a prokinetic agent for a mean of 5.6 +/- 2.4 months. At first follow-up visit 3 weeks after esophageal pH studies infants treated with an H2RA and those who did not have GER but continued with daily wheezing were started on flunisolide nasal solution (0.025%) delivered by nebulizer (125 mcg t.i.d.). Infants in both groups were followed every 1-2 months for a mean of 18 months and if clinically improved, attempts to decrease their daily asthma medications were made. Fifty-four of 84 (64%) had positive esophageal pH studies (GER-positive group), and 24 of them (44%) had no gastrointestinal symptoms suggestive of GER. Thirty patients had normal esophageal pH studies (GER-negative group). Twenty-two of these 30 (73%) infants without GER required nebulized flunisolide, compared to 13 of 54 (24%) infants with GER (P < 0.0005). Thirty-five of 54 (64.8%) infants with GER were able to discontinue all daily asthma medications within 3 months of starting antireflux therapy, while none of the infants without GER were able to discontinue daily asthma medications during the follow-up period (P < 0.0005). We conclude that silent GER is common in infants with daily wheezing, and controlling GER improves morbidity and decreases the need for daily asthma medications.

Anti-Asthmatic Agents↗
PubMed1999

Comparison of the efficacy of inhaled fluticasone propionate, 880 microg/day, with flunisolide, 1500 microg/day, in moderate-to-severe persistent asthma.

BACKGROUND: Inhaled corticosteroids have become the mainstay of asthma therapy. Few studies however, have compared inhaled steroids in children. We compared the efficacy of inhaled fluticasone propionate (FP), 880 microg/day (2 puffs of 220 microg/puff, BID) with inhaled flunisolide (FLU), 1500 microg/day (3 puffs of 250 microg/puff, BID). METHODS: Thirty children with moderate to severe asthma, mean age 12.7 years (range 10 to 17 years), mean duration of asthma 8.4 years, initially received flunisolide 1500 microg/day for 1 year, and then were switched to fluticasone propionate 880 microg/day and followed for an additional year. Pulmonary function tests (PFTs) were monitored and analyzed before and after the switch for the duration of study. Mean percent predicted for age values for FVC, FEV1, FEF25-75%, and FEFR were compared at 1 month, 2 to 6-month intervals, and 7 to 12-month intervals and during the same season of the year. Pulmonary function tests within 3 weeks of an exacerbation were not included in the study. The number of asthma exacerbations, emergency room visits, hospital admissions, and number of school days lost were also compared. RESULTS: There was significant improvement in mean asthma exacerbations/patient/year (1.7 +/- 1.66 SD) versus (4 +/- 2.6) (P < .0002); mean emergency room visits/patient/year (0.23 +/- 0.62) versus (1.2 +/- 1.74) (P = .004); mean hospital admissions for asthma/patient/year (0.2 +/- 0.61) versus (1.13 +/- 1.45) (P < .0002); and number of school days lost/patient/year (1.4 +/- 2.38) versus (7.93 +/- 6.7) (P < .0002) while patients were receiving fluticasone propionate as compared with flunisolide. Also, the mean percent values predicted for age in all time-periods (at 1 month, 2 to 6 months, and 7 to 12 months) revealed significant improvement in FEV1 and FEF25-75% (P < .05 for both parameters). As PFT can be affected by seasonal changes, PFT parameters were compared during the same season of the year and significant improvement in FVC and FEV1 was observed in all seasons while patients were receiving fluticasone propionate (FP) compared with flunisolide (FLU) (P < .05 for all parameters). Significant improvement in PEFR and FEF25-75% was observed only in spring and summer season. CONCLUSION: Fluticasone propionate 880 microg/day improved lung function and quality of life in adolescents with moderate-to-severe asthma when compared with flunisolide 1500 microg/day.

Absenteeism↗
PubMed1999

Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice.

Recent reports indicate an association between second trimester human influenza viral infection and later development of schizophrenia. Postmortem human brain studies also provide evidence for reduction in Reelin mRNA (an important secretory protein responsible for normal lamination of the brain) in schizophrenic brains. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of reelin in day 0 neonatal brains. Prenatally-infected murine brains from postnatal day 0 showed significant reductions in reelin-positive cell counts in layer I of neocortex and other cortical and hippocampal layers when compared to controls. Whereas layer I Cajal-Retzius cells produced significantly less Reelin in infected animals, the same cells showed normal production of calretinin and nNOS when compared to control brains. Moreover, prenatal viral infection caused decreases in neocortical and hippocampal thickness. These results implicate a potential role of prenatal viral infection in causation of neuronal migration abnormalities via reduction in Reelin production in neonatal brains.

Animals↗
PubMed1999

Comparison of lung function in infants exposed to maternal smoking and in infants with a family history of asthma.

STUDY OBJECTIVE: To compare lung function in infants exposed to maternal smoking with lung function in infants with a family history of asthma. There are no published studies comparing lung function in both groups. DESIGN: Cross-sectional study. SETTING: A tertiary pulmonary care center at a children's hospital. PATIENTS: One hundred five infants with daily wheezing. Thirty-five infants had persistent exposure to maternal smoking, and 70 had a family history of asthma in parents or siblings. MEASUREMENTS: Infant pulmonary function tests were compared between the two groups. The ratio of terminal to peak expiratory flow at tidal breathing at 25% of the previous expiration remaining and the ratio of terminal to peak expiratory flow with forced expiration at 25% of the previous expiration remaining (FEF25/PFEF) were used to evaluate peripheral airflow. A > 25% improvement in FEF25/PFEF after a bronchodilator challenge test was considered a positive response. RESULTS: Most infants in both groups had evidence of peripheral airflow obstruction with forced expiration. In infants exposed to maternal smoking, only 4 of 35 (11.4%) responded to a bronchodilator, compared to 51 of 70 (72.9%) in the group with a family history of asthma (p < 0.0005). There was no statistically significant difference in total respiratory system compliance, total respiratory system resistance, tidal volume, and degree of peripheral airflow obstruction at tidal breathing or after forced expiration in both groups. CONCLUSION: Infants with exposure to maternal smoking and infants with a family history of asthma have altered lung function, and a positive response to a bronchodilator is one variable that seems to differentiate the two groups.

Airway Resistance↗
PubMed1999

An adolescent case of sulfhemoglobinemia associated with high-dose metoclopramide and N-acetylcysteine.

We describe the case of an adolescent girl who received high-dose metoclopramide in combination with oral N-acetylcysteine therapy for acute acetaminophen toxicity. Whole blood-sample analysis for abnormal hemoglobin pigments established the diagnosis of sulfhemoglobinemia. Metoclopramide has been shown to cause sulfhemoglobinemia, particularly when used in repeated high doses. Although N-acetylcysteine alone has not been associated as the cause, we suggest that sulfhemoglobine-mia is a potential complication in patients treated with metoclopramide for the nausea that often accompanies oral N-acetylcysteine therapy for acetaminophen toxicity. Cyanosis without respiratory distress should suggest this diagnosis.

Acetaminophen↗
PubMed1998

Identification and characterization of the Nudix hydrolase from the Archaeon, Methanococcus jannaschii, as a highly specific ADP-ribose pyrophosphatase.

The MJ1149 gene from the Archaeon, Methanococcus jannaschii, has been cloned and expressed in Escherichia coli. The 19-kDa protein containing the Nudix box, GX5EX7REUXEEXGU, has been purified and identified as a highly specific enzyme catalyzing the Mg2+-dependent hydrolysis of ADP-ribose according to the equation: ADP-ribose + H2O --> AMP + ribose-5-phosphate. The enzyme retains full activity when heated to 80 degreesC, and the rate of hydrolysis is 15-fold higher at 75 degreesC than at 37 degreesC in keeping with the thermophilicity of the organism. This is the first Nudix hydrolase identified from the Archaea, indicating that the family of enzymes containing the Nudix signature sequence is represented in all three kingdoms.

Adenosine Diphosphate Ribose↗
PubMed1998

Treatment of neutrophils with cytochalasins converts rolling to stationary adhesion on P-selectin.

We investigated how disruption of the actin cytoskeleton with cytochalasins modified adhesion of neutrophils rolling on a platelet monolayer in vitro at 37 degrees C. When perfused at a wall shear stress of 0.1 Pa over rolling cells, cytochalasin B, cytochalasin D and dihydro-cytochalasin B each induced dose-dependent (approximately 1-10 microg/ml) conversion to stationary attachment over minutes. Stopping was associated with cell elongation to a teardrop shape. Increased deformability of cytochalasin-treated cells was independently evidenced by more rapid entry into a micropipette. Spherical shape and rolling were reestablished concurrently on washout of the cytochalasins, while increasing the shear stress in the range 0.2 to 1.0 Pa induced tear-drop-shaped cells to restart rolling even in the continued presence of cytochalasin. When cells were pretreated with cytochalasin B, they attached efficiently at 0.1 Pa, rolled initially and only stopped after approximately 30 seconds when elongation had been established. Adhesion was selectin-mediated in the presence or absence of cytochalasin B, as judged by inhibition of attachment by antibody against P-selectin and failure of antibody against beta2-integrin CD18 to influence adhesion. Cessation of rolling is unlikely to have arisen from an increase in adhesive contact area induced by deformation because stopped cells were found to be attached only at their pointed end. Failure of adhesive bonds to peel may have arisen because selectin ligands freed of cytoskeletal restraint were dragged into this tethered region and clustered there, and because force applied to bonds was influenced by the change in cell shape. These results suggest that cytoskeletal structure is an important modulator of dynamic adhesive responses of leukocytes, via effects on adhesion receptors and cellular mechanics.

Cell Adhesion↗
PubMed1998

Improved morbidity with the use of nasal continuous positive airway pressure in I-cell disease.

Patients with I-cell disease (mucolipidosis II) present with progressive morbidity failure to thrive, cardiomegaly, and recurrent respiratory tract infections leading to progressive deterioration and early death. We evaluated use of nasal continuous positive airway pressure (NCPAP) for 6 months in a 2-year-old girl with I-cell disease, obstructive sleep apnea (OSA), and craniofacial anomalies. We observed a marked decrease in hospitalizations for respiratory problems and a marked improvement in arterial blood gases with the use of NCPAP. In patients with I-cell disease, anatomical defects with superimposed upper respiratory tract infections cause worsening of OSA, and OSA contributes significantly to morbidity. In such patients NCPAP can lessen morbidity and can improve the quality of life.

Carbon Dioxide↗
PubMed1998

Activation of coagulation and fibrinolysis during cardiothoracic operations.

BACKGROUND: During open cardiac operations using cardiopulmonary bypass, there is activation of coagulation and fibrinolysis. We assessed the separate contributions of the surgical procedure itself and cardiopulmonary bypass to this, by studying sequential samples from patients undergoing routine open cardiac operations or thoracic operations without cardiopulmonary bypass. METHODS: Activation of coagulation and the extent of fibrinolysis were measured from sequential samples obtained before the operation to 48 hours after the operation for 7 thoracic patients and 8 cardiac patients. RESULTS: In the thoracic group operation length was shorter (p = 0.002), and there was no significant increase in thrombin-antithrombin III complexes or D-dimers until 24 hours postoperatively. In contrast, there was a highly significant increase in thrombin-antithrombin III complexes (p = 0.0043) and D-dimer levels (p = 0.009) during cardiopulmonary bypass. The increase in fibrinolytic activity was caused by an increase in tissue plasminogen activator (p = 0.013). At 48 hours postoperatively, the cardiac patients had a more hypercoagulable state than thoracic patients with significantly higher levels of thrombin-antithrombin III complexes (p = 0.041) and plasminogen activator inhibitor-1 activity (p = 0.0033). CONCLUSIONS: This study suggests the major activation of coagulation and fibrinolysis seen during cardiac operations is caused by the use of cardiopulmonary bypass.

Adolescent↗
PubMed1998

Complement activation during major surgery: the effect of extracorporeal circuits and high-dose aprotinin.

OBJECTIVE: To assess the in vivo contribution to complement activation of an extracorporeal circuit and the use of high-dose aprotinin during major surgery. DESIGN: Sequential samples were obtained from 8 patients undergoing thoracic surgery, 20 patients undergoing orthotopic liver transplantation (OLT) using venovenous bypass, and 19 patients undergoing cardiac surgery using cardiopulmonary bypass (CPB). INTERVENTION: The latter two groups were part of a randomized controlled trial of high-dose aprotinin. MEASUREMENTS: Total complement activation was measured with the hemolytic complement activity and the C3 activation-specific marker, C3d antigen. MAIN RESULTS: Complement activation did not occur during thoracic surgery. During OLT, C3d antigen levels, expressed as mean +/- standard deviation (SD), were elevated from baseline at skin closure (8.6 +/- 2.5 v 13.0 +/- 5.2 mg/L; p = 0.0082). During cardiac surgery, C3d antigen levels increased 10 minutes after the start of CPB (pre-CPB, 8.0 +/- 1.9 v 14.2 +/- 3.1 mg/L; p = 0.0001) and remained at greater than baseline values postoperatively (8.0 +/- 1.9 v 11.8 +/- 2.3 mg/L; p = 0.002). There was no difference in complement activation in those receiving high-dose aprotinin during OLT or cardiac surgery. Complement activation during cardiac surgery using extracorporeal circulation occurred to a greater extent than during OLT and thoracic surgery. Complement activation during cardiac surgery or OLT was not attenuated by the use of high-dose aprotinin.

Adolescent↗
PubMed1997

Bronchiectasis in pediatric AIDS.

OBJECTIVES: There are several reports of the pulmonary findings in children with HIV disease; however, the occurrence of bronchiectasis rarely has been noted. We evaluated occurrence of bronchiectasis in a large group of children referred to us with AIDS pneumopathy. METHODS: From January 1984 to April 1996, 203 children with AIDS and respiratory problems were referred to the pediatric pulmonary division at Children's Medical Center of Brooklyn. Medical records for 164 of these children were available and retrospectively reviewed. RESULTS: Uncomplicated pneumonia was present in 75, 24 had recurrent pneumonia, and 18 had unresolved pneumonia; lymphocytic interstitial pneumonitis (LIP) was diagnosed in 47 patients, worsening with time in all patients. Bronchiectasis was observed in 26 patients (26/164, 15.8%), diagnosed by chest radiograph in 26 (26/26, 100%), confirmed by CT scan of chest in 10 (10/26, 38.4%), and by histology in three (3/26, 11.5%). Median age at time of diagnosis of bronchiectasis was 7.5 years (range, 1 to 16 years). Sixteen children with LIP developed bronchiectasis (16/47, 34.0%). Three patients with recurrent pneumonia (3/24, 12.5%) developed bronchiectasis. Five patients with unresolved pneumonia (5/18, 27.7%) developed bronchiectasis. One infant developed bronchiectasis after Pneumocystis carinii pneumonia; another child developed bronchiectasis after P. carinii and Mycobacterium tuberculosis pneumonia. The CD4+ T-cell counts measured within 6 months of diagnosis of bronchiectasis were available in 23/26 patients and, all were < 100 cells per cubic millimeter. CONCLUSION: We conclude, from our experience, that there is a significant occurrence of bronchiectasis in children with AIDS and pulmonary disease, especially in children developing LIP, recurrent pneumonia and unresolved pneumonia, and CD4+ T-cell counts < 100 cells per cubic millimeter.

AIDS-Related Opportunistic Infections↗
PubMed1997

Actin polymerisation regulates integrin-mediated adhesion as well as rigidity of neutrophils.

Activation of adherent neutrophils causes them to convert from selectin-mediated rolling to integrin-mediated immobilisation and migration. Migration is known to depend on formation and redistribution of filamentous (F) actin, but although immobilisation in seconds parallels early cortical actin polymerisation, no link has been proven. We tested the effect of the actin-polymerising agent jasplakinolide (10 microM) on adhesive and mechanical properties of neutrophils. Pretreated cells were able to adhere and roll on immobilised platelets in a flow-based adhesion assay, but whereas untreated rolling cells became immobilised in seconds when chemotactic formyl peptide (fMLP, 0.1 microM) was superfused over them, the cells treated with jasplakinolide continued rolling. Pretreatment with jasplakinolide also blocked de novo expression of integrin CD11b and shape change which otherwise occurred in minutes after treatment with fMLP. Jasplakinolide directly caused actin polymerisation within neutrophils, evidenced by a marked increase in rigidity (resistance to aspiration into a 5 microm micropipette) and increase in association of actin with the Triton-insoluble cytoskeleton. These results indicate that rearrangement of the actin cytoskeleton regulates integrin-mediated adhesion of activated neutrophils, as well as their migration and mechanical properties.

Actins↗
PubMed1997

The potential roles of the conserved amino acids in human liver mitochondrial aldehyde dehydrogenase.

The sequence alignment of all known aldehyde dehydrogenases showed that only 23 residues were completely conserved (Hempel, J., Nicholas, H., and Lindahl, R. (1993) Protein Sci. 2, 1890-1900). Of these 14 were glycines and prolines. Site-directed mutagenesis showed that Cys302 was the essential nucleophile and that Glu268 was the general base necessary to activate Cys302 for both the dehydrogenase and esterase reaction. Here we report the mutational analysis of other conserved residues possessing reactive side chains Arg84, Lys192, Thr384, Glu399, and Ser471, along with partially conserved Glu398 and Lys489, to determine their involvement in the catalytic process and correlate these finding with the known structure of mitochondrial ALDH (Steinmetz, C. G., Xie, P.-G., Weiner, H., and Hurley, T. D. (1997) Structure 5, 701-711). No residue was found to be absolutely essential, but all the mutations caused a decrease in the specific activity of the enzyme. None of the mutations affected the Km for aldehyde significantly, although k3, the rate constant calculated for aldehyde binding was decreased. The Km and dissociation constant (Kia) for NAD+ increased significantly for K192Q and S471A compared with the native enzyme. Mutations of only Lys192 and Glu399, both NAD+-ribose binding residues, led to a change in the rate-limiting step such that hydride transfer became rate-limiting, not deacylation. Esterase activity of all mutants decreased even though mutations affected different catalytic steps in the dehydrogenase reaction.

Aldehyde Dehydrogenase↗
PubMed1997

Involvement of glutamate 399 and lysine 192 in the mechanism of human liver mitochondrial aldehyde dehydrogenase.

Mutation to the conserved Glu399 or Lys192 caused the rate-limiting step of human liver mitochondrial aldehyde dehydrogenase (ALDH2) to change from deacylation to hydride transfer (Sheikh, S., Ni, L., Hurley, T. D., and Weiner, H. (1997) J. Biol. Chem. 272, 18817-18822). Here we further investigated the role of these two NAD+-ribose-binding residues. The E399Q/K/H/D and K192Q mutants had lower dehydrogenase activity when compared with the native enzyme. No pre-steady state burst of NADH formation was found with the E399Q/K and K192Q enzymes when propionaldehyde was used as the substrate; furthermore, each mutant oxidized chloroacetaldehyde slower than propionaldehyde, and a primary isotope effect was observed for each mutant when [2H]acetaldehyde was used as a substrate. However, no isotope effect was observed for each mutant when alpha-[2H]benzaldehyde was the substrate. A pre-steady state burst of NADH formation was observed for the E399Q/K and K192Q mutants with benzaldehyde, and p-nitrobenzaldehyde was oxidized faster than benzaldehyde. Hence, when aromatic aldehydes were used as substrates, the rate-limiting step remained deacylation for all these mutants. The rate-limiting step remained deacylation for the E399H/D mutants when either aliphatic or aromatic aldehydes were used as substrates. The K192Q mutant displayed a change in substrate specificity, with aromatic aldehydes becoming better substrates than aliphatic aldehydes.

Acetaldehyde↗
PubMed1997

Allosteric inhibition of human liver aldehyde dehydrogenase by the isoflavone prunetin.

Isoflavonoid derivatives including prunetin (4',5-dihydroxy-7-methoxyisoflavone) were shown to be potent inhibitors of human aldehyde dehydrogenases (Keung W-M and Vallee BL, Proc Natl Acad Sci USA 90: 1247-1251, 1993). The inhibition reaction was reinvestigated using recombinantly expressed human aldehyde dehydrogenases. The kinetic analyses showed that prunetin inhibits competitively against both NAD and propionaldehyde with the mitochondrial and cytoplasmic enzymes. The Ki value for the mitochondrial enzyme was much lower than for the cytoplasmicenzyme. A mixed pattern of inhibition was obtaiend with the mitochondrial enzyme in the presence of Mg2+. Only one mole of prunetin binds per mole of tetrameric mitochondrial enzyme, which remains unaltered in the presence of Mg2+. Prunetin did not displace NADH from the enzyme-NADH complex. Propionaldehyde did not reverse the loss of fluorescence obtained due to enzyme-prunetin complex formation, indicating that prunetin may not be interacting at the substrate site. The esterase activity of the mitochondrial enzyme was also inhibited by prunetin in a competitive manner. The replacement of lysine 192 by glutamine resulted in a mutant with a 20% kcat and a 100-fold increase in the Km for NAI) compared with the native enzyme. However, the Ki value of prunetin against NAD was similar to that observed with the native enzyme. Prunetin, even at a very high concentration, was not an inhibitor of alcohol and malate dehydrogenase. It was concluded that prunetin may act as an allosteric inhibitor of aldehyde dehydrogenase.

Aldehyde Dehydrogenase↗