Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
1.
J Infect Dis ; 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39013016

ABSTRACT

BACKGROUND: Pneumococcal carriage in children has been extensively studied, but carriage in healthy adults and its relationship to invasive pneumococcal disease (IPD) is less understood. METHODS: Nasal wash samples from adults without close contact with young children (Liverpool, UK), 2011-2019, were cultured, and culture-negative samples tested by PCR. Pneumococcal carriage in adults 18-44 years was compared with carriage among PCV-vaccinated children 13-48 months (nasopharyngeal swabs, Thames Valley, UK) and IPD data for England for the same ages for 2014-2019. Age-group specific serotype invasiveness was calculated and used with national IPD data to estimate carriage serotype distributions for adults aged 65+ years. RESULTS: In total 98 isolates (97 carriers) were identified from 1,631 adults aged 18+ years (age and sex standardized carriage prevalence 6.4%), with only three identified solely by PCR. Despite different carriage and IPD serotype distributions between adults and children, serotype invasiveness was highly correlated (R=0.9). Serotypes 3, 37 and 8 represented a higher proportion of adult carriage than expected from direct low-level transmission from children to adults. The predicted carriage serotype distributions for 65+ years aligned more closely with the carriage serotype distribution for young adults than young children. CONCLUSIONS: The nasal wash technique is highly sensitive; additional benefit of PCR is limited. Comparison of carriage serotype distributions suggests some serotypes may be circulating preferentially within these specific young adults. Our data suggest that for some serotypes carried by adults 65+ years, other adults may be an important reservoir for transmission. Age groups such as older children should also be considered.

2.
Med J Malaysia ; 77(5): 597-601, 2022 09.
Article in English | MEDLINE | ID: mdl-36169072

ABSTRACT

INTRODUCTION: The elderly is at risk for traumatic brain injury (TBI), but local data on their morbidity and mortality outcomes was lacking. This study aims to assess the outcome in mortality and functional outcome, Glasgow Outcome Scale (GOS) and factors associated with poor outcomes in patients with TBI more than 60 years old. MATERIALS AND METHODS: This single centre retrospective cohort study was carried out involving patients age 60 years old and above with TBI between June 2018 to May 2021. The mortality and GOS at hospital discharge, 30th day, and 90th day of trauma were analysed. The simple logistic regression (SLR) and multiple logistic regression (MLR) were performed to determine factors associated with poor outcomes and mortality. RESULTS: A total of 248 patients were analysed. The mean age was 67.5 ± 6.31 years. 156 (62.9%), 26 (10.5%), and 66 (26.6%) had mild, moderate, and severe TBI, respectively. The overall mortality rate was 9.7% and the median(IQR) GOS score were 4(2); p<0.001 at hospital discharge, 30th day and 90th day. There was significant difference in GOS outcomes after 90 days χ2(2) = 136.76 p<0.001. Upon MLR, there was a significant association of polytrauma, Adj. OR 11.04 (2.503-48.711); p < 0.002 and TBI severity: moderate TBI, Adj. OR 71.44(13.028-391.782); p < 0.001 and severe TBI, Adj OR 2533.51 (213.050-30127.644); p<0.001 towards poor outcome. However, only severity of TBI: moderate TBI, Adj. OR 19.48 (1.899-199.094); p=0.012 and severe TBI, Adj OR 26.42 (2.864-243.722); p=0.004 is associated with mortality. CONCLUSION: Polytrauma and moderate-severe head injury are associated with poor outcomes and moderate-severe head injury is associated with high mortality.


Subject(s)
Brain Injuries, Traumatic , Multiple Trauma , Aged , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/therapy , Glasgow Coma Scale , Humans , Logistic Models , Middle Aged , Multiple Trauma/complications , Retrospective Studies
3.
Med J Malaysia ; 75(6): 666-671, 2020 11.
Article in English | MEDLINE | ID: mdl-33219175

ABSTRACT

INTRODUCTION: Chiari malformation (CM) is a disorder of mesodermal origin and is commonly associated with syringomyelia. Foramen magnum decompression is the first-line of standard treatment in symptomatic patients with a confirmed radiographic diagnosis. Magnetic resonance (MR) cine allows accurate evaluation of cerebrospinal fluid (CSF) physiology at the craniovertebral junction but often this is under-utilised in Malaysia. METHODS: In this series, we looked into nine cases of CM with syringomyelia from clinical and radiological perspective before and after surgery. The radiological parameters were herniated tonsillar length, syrinx: cord ratio, syrinx length and diameter. Flow velocity and morphologic changes in Chiari were illustrated. RESULTS: Seven patients showed either reduction in syrinx length, syrinx: cord ratio or both postoperatively. Clinical recovery somewhat varied in motor and sensory symptoms. Four patients gained better functional grade in modified Rankin scale (MRS) while the rest remained similar. The study highlighted the advantage of CSF flow dynamics information over MR anatomical radiographic improvement in addressing the neurologic and functional recovery. We also discussed the practicality of cine sequence in preoperative patient selection, syrinx analysis and postoperative flow evaluation in anticipation of clinical outcome. CONCLUSION: Phase-contrast cine MRI is a useful tool dictated by resource availability. We recommend its routine use in preoperative analysis and subsequent observational follow-up after surgery.


Subject(s)
Arnold-Chiari Malformation , Syringomyelia , Arnold-Chiari Malformation/complications , Arnold-Chiari Malformation/diagnostic imaging , Arnold-Chiari Malformation/surgery , Decompression, Surgical , Foramen Magnum/diagnostic imaging , Foramen Magnum/surgery , Humans , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Syringomyelia/complications , Syringomyelia/diagnostic imaging , Syringomyelia/surgery , Treatment Outcome
4.
Med J Malaysia ; 69(2): 86-8, 2014 Apr.
Article in English | MEDLINE | ID: mdl-25241818

ABSTRACT

Subtentorial subdural empyema is a rare and life threatening intracranial suppuration. It is usually an intracranial complication of otogenic infections. Early diagnosis and surgical drainage are the most important factors determining prognosis. The high mortality reported in the literature reflects the severity of subtentorial subdural empyema if proper management is delayed. Intracranial infections usually require between 4 to 6 weeks of intravenous antibiotics therapy. However, the prolonged duration of hospitalization as well as requirement for neurosurgically inserted indwelling devices may predispose these patients to new nosocomial infections.

5.
Int Immunopharmacol ; 10(2): 218-25, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19900583

ABSTRACT

Isatin, an endogenous indole compound, prevents atrial natriuretic peptide (ANP) from signaling through its cell-surface receptor, NPRA. Allergic airway inflammation has been linked to natriuretic peptide signaling and blocking this signaling axis in the lung prevents allergen-induced pathology. In this study we encapsulated isatin in chitosan nanoparticles and tested them in a mouse model of allergic asthma by intranasal delivery to the lung. Isatin nanocapsules reduced lung pathology by blocking ANP signaling, but surprisingly also by reducing the expression of NPRA. Ovalbumin-allergic mice were treated intranasally with isatin-containing chitosan nanocapsules either before or after allergen challenge, and lung function, cytokine levels, histopathology and cellular infiltration were determined. ANP activity was quantitated by measuring changes in intracellular cyclic GMP and changes in NPRA levels were determined. For comparison with isatin's effects, the expression of the receptor was inhibited with small interfering RNA against NPRA mRNA. Isatin nanocapsules administered locally to the lung reduced cGMP production and NPRA expression and protected allergic mice from airway hyperreactivity and lung inflammation when given either before or after allergen challenge. Leukocyte infiltration was reduced and lung cytokine profiles showed a repolarization from a Th2-like to a Th1-like phenotype. Isatin nanocapsules administered locally to the lung inhibit NPRA signaling but also are capable of lowering the expression of NPRA, thus effectively reducing inflammation in a mouse model of allergic asthma. Pharmacological intervention to reduce NPRA activity through the inflammatory natriuretic peptide axis in the lung may be a useful adjunct therapy for treating lung disease.


Subject(s)
Asthma/drug therapy , Isatin/administration & dosage , Receptors, Atrial Natriuretic Factor/antagonists & inhibitors , Administration, Intranasal , Animals , Bronchoalveolar Lavage Fluid/chemistry , Chitosan/administration & dosage , Cyclic GMP/chemistry , Cytokines/chemistry , Female , Inflammation/drug therapy , Leukocytes/chemistry , Lung/chemistry , Lung/pathology , Mice , Mice, Inbred BALB C , Nanocapsules/administration & dosage , Ovalbumin/immunology
6.
Acute Med ; 5(1): 13-6, 2006.
Article in English | MEDLINE | ID: mdl-21655500

ABSTRACT

Psoas abscess is an uncommon presentation on the acute medical take. However recognition and appropriate treatment is essential. This review is designed to highlight the clinical features, microbiology, diagnostic tests and treatment for this condition. In order to illustrate some of the pitfalls and complexities in the management of psoas abscess we have included a case history of a patient who was recently treated in our department.

7.
Anaesth Intensive Care ; 29(4): 383-7, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11512649

ABSTRACT

This randomized controlled study examined intubating conditions and haemodynamic changes following sevoflurane nitrous oxide induction in four groups: three different doses of alfentanil compared with low-dose alfentanil and suxamethonium. All patients received atropine 0.3 mg i.v. before induction of anaesthesia with vital capacity breaths of sevoflurane 8% (more than 7% in the inspiratory gas) in 60% nitrous oxide and oxygen. Patients were allocated randomly to four groups of intravenous supplements: group SA20, alfentanil 20 microg x kg(-1); group SA25, alfentanil 25 microg x kg(-1); group SA30, alfentanil 30 microg x kg(-1); group SSA, alfentanil 10 microg x kg(-1) and suxamethonium 1 mg x kg(-1). Orotracheal intubation and assessment of intubating conditions was performed by one of the investigators who was blinded to the subject's group. Intubating conditions were satisfactory or excellent in 83%, 80%, 92% and 96% of patients in groups SA20, SA25, SA30 and SSA respectively. These differences were not statistically significant. The increase in heart rate associated with laryngoscopy and tracheal intubation was effectively attenuated in all groups. Mean arterial pressure decreased significantly and similarly after induction in all groups. Two minutes after intubation the mean arterial pressure was increased significantly (P<0.05) compared to the post-induction value in group SSA. The intubating conditions obtained with sevoflurane plus alfentanil 30 microg x kg(-1) were comparable to those provided by the sevoflurane, suxamethonium and alfentanil 10 microg x kg(-1) combination.


Subject(s)
Alfentanil/administration & dosage , Anesthetics, Inhalation/administration & dosage , Anesthetics, Intravenous/administration & dosage , Intubation, Intratracheal/methods , Methyl Ethers/administration & dosage , Neuromuscular Depolarizing Agents/administration & dosage , Succinylcholine/administration & dosage , Adolescent , Adult , Aged , Blood Pressure/drug effects , Double-Blind Method , Female , Heart Rate/drug effects , Hemodynamics , Humans , Male , Middle Aged , Pulse , Sevoflurane , Vital Capacity
8.
Singapore Med J ; 41(7): 356-8, 2000 Jul.
Article in English | MEDLINE | ID: mdl-11026804

ABSTRACT

Eisenmenger's syndrome was originally described in 1897 and redefined by Wood in 1958. This syndrome includes pulmonary hypertension with reversed or bi-directional shunt associated with septal defects or a patent ductus arteriosus. A 27-year-old G2 PO with Eisenmenger's syndrome presented to the hospital for management at 17 weeks of pregnancy. She was advised termination of pregnancy but she refused. An elective caesarean section was performed successfully under general anaesthesia uneventfully at 29 weeks due to severe intrauterine growth retardation (IUGR). Patient's postoperative complications like pulmonary thromboembolism, the advantages and disadvantages of anticoagulation are discussed. Pregnancy carries substantial maternal and fetal risk for patients with pulmonary hypertension and Eisenmenger's syndrome. Although pregnancy should be discouraged in women with Eisenmenger's syndrome it can be successful.


Subject(s)
Anesthesia, General , Anesthesia, Obstetrical , Cesarean Section , Eisenmenger Complex/complications , Pregnancy Complications/physiopathology , Adult , Anesthesia, Inhalation , Anesthesia, Intravenous , Cardiotonic Agents/therapeutic use , Dopamine/therapeutic use , Eisenmenger Complex/physiopathology , Female , Fetal Growth Retardation/therapy , Humans , Hypotension/etiology , Neuromuscular Blockade , Oxygen/blood , Postoperative Complications , Pregnancy , Pregnancy Outcome , Respiration Disorders/etiology , Tachycardia/etiology
9.
FEMS Microbiol Lett ; 186(2): 239-43, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10802178

ABSTRACT

Pir proteins are unique proteins with internal repeat sequences that are reported to be present in the cell wall of Saccharomyces cerevisiae. They are covalently attached to the cell wall and can be released by mild alkali treatment. In this study the biotinylated cell wall preparations from Candida albicans and S. cerevisiae were extracted by alkali and beta-1,3 glucanase and analyzed in parallel. Among the four bands detected by streptavidin, two proteins were recognized by the antibody to the S. cerevisiae Pir protein Hsp150. The antibody also detected a high molecular mass protein secreted in the growth medium of C. albicans. Using S. cerevisiae HSP150/PIR2 gene as a probe, Southern and Northern hybridizations were performed with DNA and RNA of C. albicans. Hybridization with DNA digested with different restriction enzymes showed more than one hybridized fragment. An increased level of mRNA was found in heat shocked cells (37 degrees C for 45 min compared to 25 degrees C). Hybridization of ScHSP150 gene to mRNAs from cells grown in different media was also determined. Two transcripts of size approximately 3.5 kb and 2.0 kb were detected in mRNAs from cells grown in defined medium with glucose as carbon source or in the same medium supplemented with hemoglobin. The lower transcript of size 2.0 kb was absent in cells grown in medium with galactose as carbon source. A single band was also observed when cells were grown in rich medium. Together these results demonstrated the existence of beta1,3 glucan linked proteins in C. albicans, which are related to Pir family proteins of S. cerevisiae.


Subject(s)
Candida albicans/chemistry , Fungal Proteins/analysis , Glycoproteins/analysis , Membrane Proteins/analysis , Saccharomyces cerevisiae Proteins , Biotinylation , Blotting, Northern , Blotting, Southern , Candida albicans/genetics , Candida albicans/growth & development , Cell Wall/chemistry , Electrophoresis, Polyacrylamide Gel , Fungal Proteins/genetics , Glycoproteins/genetics , Heat-Shock Proteins/genetics , Membrane Proteins/genetics , Molecular Weight , RNA, Messenger/genetics , Saccharomyces cerevisiae/genetics
10.
Acta Anaesthesiol Scand ; 44(5): 627-9, 2000 May.
Article in English | MEDLINE | ID: mdl-10786753

ABSTRACT

Inhalational induction is one of the recognized methods for the management of difficult airway. Halothane is the usual choice of agent for this purpose. The relatively new agent sevoflurane, which is the least irritant of all the available agents, is emerging as a choice of inhalational agent for both adult and pediatric populations. There are various reports for and against the use of sevoflurane for the management of difficult airway. We describe the use of sevoflurane for the management of difficult airway in four patients presenting with airway problems.


Subject(s)
Anesthetics, Inhalation/administration & dosage , Intubation, Intratracheal , Methyl Ethers/administration & dosage , Adult , Anesthesia, General , Child , Female , Humans , Infant , Male , Middle Aged , Sevoflurane
11.
Anaesthesia ; 54(3): 271-6, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10364865

ABSTRACT

One hundred unpremedicated ASA 1 or 2 patients scheduled for elective surgery were divided equally into four groups and recruited into this prospective, randomised parallel groups study. Induction was with propofol 2.5 mg.kg-1 or vital-capacity breath induction with sevoflurane (> 7% in the inspiratory gas) in 65% nitrous oxide and oxygen, or gaseous induction with sevoflurane plus alfentanil 5 micrograms.kg-1 or propofol 2.5 mg.kg-1 and alfentanil 5 micrograms.kg-1. The conditions for laryngeal mask insertion were assessed and graded on a three-point scale using six variables. The overall condition for laryngeal mask insertion was assessed as excellent, satisfactory or poor on the basis of total score in each group. Excellent or satisfactory conditions were observed in 25 (100%) patients in the sevoflurane-alfentanil group, 22 (88%) in the propofol-alfentanil group and 16 (64%) patients each in the propofol and sevoflurane groups (p < 0.001). A sevoflurane-alfentanil combination provides better conditions for laryngeal mask insertion when compared with sevoflurane alone, or a propofol-alfentanil combination.


Subject(s)
Anesthetics, Inhalation , Anesthetics, Intravenous , Laryngeal Masks , Methyl Ethers , Propofol , Adolescent , Adult , Aged , Alfentanil , Anesthetics, Combined , Female , Hemodynamics/drug effects , Humans , Laryngeal Masks/adverse effects , Male , Middle Aged , Prospective Studies , Sevoflurane
13.
Plant Physiol ; 112(1): 79-88, 1996 Sep.
Article in English | MEDLINE | ID: mdl-12226376

ABSTRACT

The effects of ethoxyzolamide (EZ), a carbonic anhydrase inhibitor, on the active CO2 and Na+-independent and Na+-dependent HCO3- transport systems of the unicellular cyanobacterium Synechococcus sp. UTEX 625 were examined. Measurements of transport and accumulation using radiochemical, fluorometric, and mass spectrometric assays indicated that active CO2 transport and active Na+-independent HCO3- transport were inhibited by EZ. However, Na+-independent HCO3- transport was about 1 order of magnitude more sensitive to EZ inhibition than was CO2 transport (50% inhibition = 12 [mu]M versus 80 [mu]M). The data suggest that both the active CO2 (G.D. Price, M.R. Badger [1989] Plant Physiol 89: 37-43) and the Na+ -independent HCO3 - transport systems possessed carbonic anhydrase-like activity as part of their mechanism of action. In contrast, Na+-dependent HCO3- transport was only partially (50% inhibition = 230 [mu]M) and noncompetitively inhibited by EZ. The collective evidence suggested that EZ inhibition of Na+ -dependent HCO3- transport was an indirect consequence of the action of EZ on the CO2 transport system, rather than a direct effect on HCO3- transport. A model is presented in which the core of the inorganic carbon translocating system is formed by Na+-dependent HCO3- transport and the CO2 transport system. It is argued that the Na+-independent HCO3 - utilizing system was not directly involved in translocation, but converted HCO3- to CO2 for use in CO2 transport.

14.
J Biol Chem ; 271(33): 19922-7, 1996 Aug 16.
Article in English | MEDLINE | ID: mdl-8702706

ABSTRACT

Plasma membrane Na+/H+ exchanger (NHE) isoforms NHE1 and NHE3 exhibit very different sensitivities to amiloride and its 5-amino-substituted analogues, benzoyl guanidinium derivatives (e.g. (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE694)), and cimetidine. To define structural domains that confer differential sensitivity to these antagonists, unique restriction endonuclease sites were engineered into cDNAs for each isoform near the regions that encode the putative membrane-spanning domains. These new sites did not modify their pharmacological properties and allowed several chimeric Na+/H+ exchangers to be constructed by exchanging homologous segments. The modified parental (E1' and E3') and chimeric molecules were stably expressed in exchanger-deficient Chinese hamster ovary AP-1 cells and assayed for their sensitivities to amiloride, ethylisopropylamiloride, HOE694, and cimetidine. Most chimeras showed drug sensitivities corresponding to the dominant parental segment. However, interchanging a 66-amino acid segment containing the putative ninth transmembrane (M9) domain and its adjacent loops caused reciprocal alterations in the sensitivities of E1' and E3' to all antagonists. In addition, substituting the first five putative membrane-spanning domains of E3' with the corresponding region of E1' modestly reduced the transporter's sensitivity to cimetidine but not the other compounds. These data indicate that the protein segment between M8 and M10 may be a major site of interaction with these antagonists, although other regions modestly influence sensitivity to certain drugs.


Subject(s)
Sodium-Hydrogen Exchangers/antagonists & inhibitors , Amiloride/analogs & derivatives , Amiloride/pharmacology , Animals , Biological Transport , Cimetidine/pharmacology , DNA, Complementary/genetics , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Kinetics , Ligands , Membrane Glycoproteins/chemistry , Rats , Recombinant Fusion Proteins , Sodium-Hydrogen Exchanger 3 , Structure-Activity Relationship , Sulfones/pharmacology
15.
J Biol Chem ; 271(18): 10551-9, 1996 May 03.
Article in English | MEDLINE | ID: mdl-8631855

ABSTRACT

The activity of the apical membrane Na+/H+ exchanger NHE3 isoform of renal or intestinal epithelial cells is chronically regulated by a wide variety of stimuli, including acidosis, cAMP, glucocorticoids, and thyroid hormone. To understand the molecular mechanisms responsible for long term regulation of this cation transporter, we have isolated and determined the structure of this gene from a rat genomic library. The Nh3 gene spans > 40 kilobases and contains 17 exons that are flanked by typical splice donor and acceptor sequences at the exon-intron boundaries. The transcription initiation site was mapped by S1 nuclease protection analyses of mRNA from rat kidney and intestine. Multiple start sites were clustered between nucleotides -100 and -96 relative to the translation initiation codon. An atypical TATA-box and CCAAT-box are centered 30 and 147 nucleotides, respectively, upstream of the predominant transcription initiation site. Sequence analysis of approximately 1.4 kilobases of the 5'-flanking promoter region also revealed the presence of other putative cis-acting elements recognized by various transcription factors (e.g. AP-1, AP-2, C/EBP, NF-I, OCT-1/OTF-1, PEA3, Sp1, glucocorticoid, and thyroid hormone receptors), some of which may participate in the chronic regulation of this gene. The glucocorticoid responsiveness of the Nhe3 gene was assessed by fusing its 5' regulatory region to the firefly luciferase reporter gene and then by measuring the expression of the chimeric gene in transiently transfected renal epithelial OK and LLC-PK1 cells. Glucocorticoid treatment significantly increased the luciferase activity of the chimeric gene in both cell lines, thereby indicating that glucocorticoid regulation of Nhe3 is mediated primarily by a transcriptional mechanism.


Subject(s)
Glucocorticoids/pharmacology , Sodium-Hydrogen Exchangers/genetics , Transcriptional Activation/drug effects , Amino Acid Sequence , Animals , Base Sequence , Cell Line , DNA, Complementary , Humans , Kidney/cytology , Kidney/metabolism , Molecular Sequence Data , Promoter Regions, Genetic , Rats , Sequence Homology, Amino Acid , Swine
16.
J Biol Chem ; 270(49): 29209-16, 1995 Dec 08.
Article in English | MEDLINE | ID: mdl-7493949

ABSTRACT

Na+/H+ exchanger (NHE) activity is regulated by several types of receptors directly coupled to distinct classes (i.e. Gs, Gi, Gq, and G12) of heterotrimeric (alpha beta gamma) GTP-binding proteins (G proteins), which, upon activation, modulate production of various second messengers (e.g. cAMP, cGMP, diacylglycerol, inositol trisphosphate, and Ca2+). Recently, four isoforms of the rat Na+/H+ exchanger were identified by molecular cloning. To examine their intrinsic responsiveness to G protein and second messenger stimulation, three of these isoforms, NHE-1, -2, and -3, were stably expressed in mutant Chinese hamster ovary cells devoid of endogenous NHE activity (AP-1 cells). Incubation of cells with either AIF4-, a general agonist of G proteins, or cholera toxin, a selective activator of G alpha s that stimulates adenylate cyclase, accelerated the rates of amiloride-inhibitable 22Na+ influx mediated by NHE-1 and -2, whereas they inhibited that by NHE-3. Similarly, short term treatment with phorbol 12-myristate 13-acetate, which mimics diacylglycerol activation of protein kinase C (PKC), or with agents (i.e. forskolin, 8-(4-chlorophenylthio)-cAMP, and isobutylmethylxanthine) that lead to activation of cAMP-dependent protein kinase (PKA) also stimulated transport by NHE-1 and NHE-2 but depressed that by NHE-3. The effects of phorbol 12-myristate 13-acetate were blocked by depleting cells of PKC or by inhibiting PKC using chelerythrine chloride, confirming a role for PKC in modulating NHE isoform activities. Likewise, the PKA antagonist, H-89, attenuated the effects of elevated cAMPi on NHE-1, -2, and -3, further demonstrating the regulation by PKA. Unlike cAMPi, elevation of cGMPi by treatment with dibutyryl-cGMP or 8-bromo-cGMP had no influence on NHE isoform activities, thereby excluding the possibility of a role for cGMP-dependent protein kinase in these cells. These data support the concept that the NHE isoforms are differentially responsive to agonists of the PKA and PKC pathways.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/physiology , Cyclic AMP/physiology , Protein Kinase C/physiology , Sodium-Hydrogen Exchangers/physiology , Animals , CHO Cells , Colforsin/pharmacology , Cricetinae , GTP-Binding Proteins/physiology , Hydrogen-Ion Concentration , Rats , Sodium/metabolism , Sodium-Hydrogen Exchanger 3 , Tetradecanoylphorbol Acetate/pharmacology
17.
Pediatr Hematol Oncol ; 12(4): 333-41, 1995.
Article in English | MEDLINE | ID: mdl-7577385

ABSTRACT

The optimal therapy for children with Hodgkin's disease is controversial. Between 1989 and 1993, 53 children under 14 years of age with Hodgkin's disease were treated with COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisolone/adriamycin, bleomycin, vinblastine) hybrid chemotherapy. The results were analyzed with the Kaplan-Meier product limit method for survival and the Logrank test for predicting statistical significance. Ten patients (18.87%) had early-stage disease (I to IIA) and 43 (81.13%) had advanced disease. Lymphocyte-predominant histology was seen in 20 (37.5%) patients, nodular sclerosis in 8 (15%), mixed cellularity in 21 (39.6%), and lymphocyte depletion in 4 (7.56%). The male:female ratio was 3.82:1. Complete responses were seen in 51 (96.22%) patients, with 47 (92.15%) of them in sustained first remission. The event-free survival rate is 90.3% to date. COPP/ABV hybrid chemotherapy is an effective primary therapy for all stages of Hodgkin's disease in children.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hodgkin Disease/drug therapy , Bleomycin/administration & dosage , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Hodgkin Disease/mortality , Hodgkin Disease/physiopathology , Humans , Male , Neoplasm Staging , Prednisone/administration & dosage , Procarbazine/administration & dosage , Survival Analysis , Vinblastine/administration & dosage , Vincristine/administration & dosage
18.
Genomics ; 25(3): 615-22, 1995 Feb 10.
Article in English | MEDLINE | ID: mdl-7759094

ABSTRACT

A human genomic clone for a novel fifth member of the Na+/H+ exchanger (NHE) family, NHE5 (gene symbol SLC9A5), has been isolated and partially sequenced. The deduced amino acid sequence of two exons, containing 154 codons, exhibits 59-73% identity to the other members of the NHE family, with closest similarity to NHE3. Northern blot analysis demonstrated that the NHE5 gene is expressed in brain, testis, spleen, and skeletal muscle. Fluorescence in situ hybridization analysis of a cosmid containing NHE5 to human metaphase chromosomes localized the NHE5 gene to the cytogenetic interval 16q21-q22. A panel of somatic cell hybrids containing various portions of chromosome 16 was used to refine further the placement of NHE5 within band 16q22.1. A polymorphic dinucleotide (GT/CA)n repeat contained in the NHE5 cosmid was identified and developed into a microsatellite PCR marker. This was typed in a subset of the CEPH (Centre d'Etude du Polymorphisme Humain) families to place it on a genetic map of the human genome. Pairwise linkage analysis of this marker showed that it was linked to marker D16S421 with a maximal lod score of 35.21 at a recombination fraction (theta) of 0.000, in complete concordance with its chromosomal localization by physical mapping. Multipoint linkage analysis placed NHE5 between the flanking markers D16S421 and D16S512. The cloning of this new member of the sodium hydrogen exchanger family, its chromosomal localization, and the discovery of a polymorphic marker for it now make it feasible to study the possible involvement of this gene in disorders of Na+/H+ transport.


Subject(s)
Chromosomes, Human, Pair 16 , Sodium-Hydrogen Exchangers/genetics , Amino Acid Sequence , Animals , Base Sequence , Blotting, Northern , Chromosome Mapping , Cloning, Molecular , Cosmids , DNA , Exons , Genetic Markers , Humans , Introns , Mice , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Genetic , RNA, Messenger/genetics , Rats , Sequence Homology, Amino Acid
19.
J Biol Chem ; 269(38): 23544-52, 1994 Sep 23.
Article in English | MEDLINE | ID: mdl-8089122

ABSTRACT

Four distinct isoforms of the mammalian Na+/H+ exchanger (NHE) have been identified by molecular cloning. Three of these (NHE-1, NHE-2, and NHE-3) have been shown to be functionally active by heterologous expression. Their kinetic and pharmacological properties are well documented, yet comparatively little is known about their regulation. In this report, rat NHE-1, NHE-2, and NHE-3 were stably transfected into antiporter-deficient Chinese hamster ovary cells to study their role in cellular proliferation and their regulation by nucleotides and cell volume. Their ability to influence cell proliferation was assessed by measuring the growth of antiporter-deficient cells and of the different transfectants in media of varying pH. While antiporter-deficient cells were unable to grow at acidic pH levels, all three isoforms supported proliferation under these conditions. Therefore, while the epithelia-specific isoforms (NHE-2 and NHE-3) are thought to play primarily a role in transcellular ion transport, they can also contribute to intracellular pH (pHi) homeostasis and have a permissive role in cell growth. The activity of the three isoforms was markedly inhibited by depletion of cellular ATP. In the pHi 6.0-7.2 range, decreases in the affinity for internal H+ and/or the maximal rate of transport accounted for the inhibitory effect, depending on the isoform. The osmotic responsiveness of the three isoforms was also compared. As reported earlier, NHE-1 was stimulated by hypertonicity. Under similar conditions, NHE-2 was also stimulated to a comparable extent. Conversely, both isoforms were inhibited in hypotonic media. In contrast, NHE-3 was markedly inhibited by hypertonic cell shrinking but was unaffected by hypotonicity. Osmotic inhibition of NHE-3 was rapid, reversible, and apparent throughout the pH range studied. Osmotic inhibition of NHE-3 may play a role in the physiology and pathophysiology of epithelia.


Subject(s)
Sodium-Hydrogen Exchangers/metabolism , Adenosine Triphosphate/metabolism , Animals , CHO Cells , Cell Division , Cricetinae , Cytoplasm/metabolism , Hydrogen-Ion Concentration , In Vitro Techniques , Isoenzymes/chemistry , Isoenzymes/metabolism , Osmolar Concentration , Recombinant Proteins , Sodium-Hydrogen Exchangers/chemistry , Transfection
20.
Plant Physiol ; 104(4): 1419-1428, 1994 Apr.
Article in English | MEDLINE | ID: mdl-12232177

ABSTRACT

The effect of monensin, an ionophore that mediates Na+/H+ exchange, on the activity of the inorganic carbon transport systems of the cyanobacterium Synechococcus UTEX 625 was investigated using transport assays based on the measurement of chlorophyll a fluorescence emission or 14C uptake. In Synechococcus cells grown in standing culture at about 20 [mu]M CO2 + HCO3-, 50 [mu]M monensin transiently inhibited active CO2 and Na+-independent HCO3- transport, intracellular CO2 and HCO3- accumulation, and photosynthesis in the presence but not in the absence of 25 mM Na+. These activities returned to near-normal levels within 15 min. Transient inhibition was attributed to monensin-mediated intracellular alkalinization, whereas recovery may have been facilitated by cellular mechanisms involved in pH homeostasis or by monensin-mediated H+ uptake with concomitant K+ efflux. In air-grown cells grown at 200 [mu]M CO2 + HCO3- and standing culture cells, Na+-dependent HCO3- transport, intracellular HCO3- accumulation, and photosynthesis were also inhibited by monensin, but there was little recovery in activity over time. However, normal photosynthetic activity could be restored to air-grown cells by the addition of carbonic anhydrase, which increased the rate of CO2 supply to the cells. This observation indicated that of all the processes required to support photosynthesis only Na+-dependent HCO3- transport was significantly inhibited by monensin. Monensin-mediated dissipation of the Na+ chemical gradient between the medium and the cells largely accounted for the decline in the HCO3- accumulation ratio from 751 to 55. The two HCO3- transport systems were further distinguished in that Na+-dependent HCO3- transport was inhibited by Li+, whereas Na+-independent HCO3- transport was not. It is suggested that Na+-dependent HCO3- transport involves an Na+/HCO3- symport mechanism that is energized by the Na+ electrochemical potential.

SELECTION OF CITATIONS
SEARCH DETAIL