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Biomedical subjects

S Kotecha

Publications and source records attributed to S Kotecha.

At least 19 recordsLinked to original sources
PubMed2003

Pilot investigation of hypothermia in neonates receiving extracorporeal membrane oxygenation.

BACKGROUND: Infants requiring extracorporeal membrane oxygenation (ECMO) support represent a high risk group in terms of cerebral injury. Mild hypothermia both during and after cerebral hypoxic ischaemia appears to be a promising strategy for offering neuroprotection. OBJECTIVE: To investigate whether mild hypothermia was both feasible and safe in infants receiving ECMO as a prelude to any formal assessment of this approach in a randomised trial. METHODS: Twenty infants (body weight less than 5 kg) with severe cardiopulmonary insufficiency, referred for ECMO support at Glenfield Hospital, Leicester, were enrolled in this study. Twenty consecutive infants (compromising four groups of five) were studied. Baseline data were obtained from a control group who were run throughout their course at 37 degrees C. The patients in the next group were managed with a core temperature of 36 degrees C for the first 12 hours of their ECMO run, before being warmed up to 37 degrees C. After successful completion, the next group of five were cared for at 35 degrees C for the first 12 hours, and, there having been no previous complications, the final group were cared for at 34 degrees C for the first 12 hours. Patients were assessed clinically and biologically. In addition to routine laboratory tests, cytokines (interleukin 6, interleukin 8, tumour necrosis factor alpha, and C reactive protein) were measured and coagulation tests (D-dimer, thrombin-antithrombin III complex, plasmin-alpha(2)-antiplasmin complex) were performed serially for five days. RESULTS: There were no significant differences among the four groups in gestational age, birth weight, age at the time of ECMO, Apgar scores at one and five minutes, pH before cannulation, oxygenation index, duration of ECMO, and survival rate to discharge from hospital. No adverse effects of mild hypothermia were found on patient management during ECMO. Laboratory data for up to five days of ECMO also showed no difference among the four groups. CONCLUSION: Mild hypothermia (34 degrees C) for the initial 12 hours of an ECMO run is feasible.

Blood Cell Count↗
PubMed2002

Antenatal inflammation and infection in chronic lung disease of prematurity.

In spite of improved neonatal care, chronic lung disease of prematurity (CLD) remains a major cause of morbidity and mortality in extremely preterm infants. Our current understanding is that antenatal infection can trigger intra-uterine inflammation which then promotes preterm labour. Recent studies suggest that antenatal infection and inflammation can also increase the preterm infant's susceptibility to develop CLD. It may be that exposure of the fetal lung to high concentrations of pro-inflammatory cytokines is the cause of this increased susceptibility. One candidate for initiating intra-uterine inflammation is ascending infection by the vaginal commensal Ureaplasma urealyticum (Uu). Antibiotics administered to mothers prior to delivery appear to improve the neonatal outcome in cases of preterm prolonged rupture of membranes, but not in cases of preterm labour with intact membranes. Uu can be transmitted vertically to the airways of the preterm infant, but the role of Uu in causing CLD remains uncertain. Small trials of antibiotics given to preterm infants after delivery have not shown any consistent benefit in reducing CLD. Although CLD remains a significant problem for the extremely preterm infant, it is likely that molecular biology techniques, such as the polymerase chain reaction, will enhance the detection of antenatal infection and further our understanding of the pathogenesis of CLD.

Anti-Bacterial Agents↗
PubMed2002

Fibroblast mitogenic activity of lung lavage fluid from infants with chronic lung disease of prematurity.

BACKGROUND: Lung fibrosis is thought to be important in chronic lung disease of prematurity (CLD). METHODS: Fibroblast proliferative activity was assessed in 207 bronchoalveolar lavage fluid (BALF) samples from 43 infants. Sixteen developed CLD (birth weight 765 g (630-1230), gestation 26.5 weeks (23-29)), 18 developed respiratory distress syndrome (RDS) (birth weight 1415 g (430-4160), gestation 31 weeks (23-39)), and nine control infants (birth weight 2110 g (900-3720), gestation 32 weeks (26-41)) received mechanical ventilation for non-pulmonary reasons. RESULTS: The fibroblast proliferative activity relative to 10% fetal calf serum was 64-75% in infants with CLD, 55-86% in the RDS group, and 42-68% in control infants during the first 5 weeks of life. Only at day 3 was there a difference between the groups (CLD 72% v control 42%, p < 0.01; RDS 63% v control 42%, p < 0.05). With the use of neutralising antibodies, platelet derived growth factor BB (PDGF-BB) and epidermal growth factor were undetectable, and insulin-like growth factor I (IGF-I) accounted for 14% (p < 0.05) and 11% (p < 0.005) of BALF mitogenic activity from the RDS and CLD groups respectively. CONCLUSIONS: The mitogenic activity of BALF was similar in the three groups studied and was only partially accounted for by IGF-I. Growth factors other than PDGF-BB and IGF-I contribute significantly to this process.

Bronchoalveolar Lavage Fluid↗
PubMed2002

Oxygen therapy for infants with chronic lung disease.

Supplemental oxygen is a safe and effective treatment for infants with established chronic lung disease who are not at risk of further progression of retinopathy of prematurity (ROP). Oxygen saturations of < 92% should be avoided and a target range of at least 94-96% aimed for. The saturation target range for very preterm infants at risk of developing ROP is more controversial, but the therapeutic index is probably considerably narrower.

Chronic Disease↗
PubMed2002

Management issues in CLD of prematurity.

CLD is one of the major problems in neonatal medicine. Clinicians struggle to provide optimal care because of limited evidence. Many questions still need to be answered; meanwhile many aspects of management will remain best practice rather than evidence based.

Chronic Disease↗
PubMed2001

Ascorbate acid concentration in airways lining fluid from infants who develop chronic lung disease of prematurity.

Chronic lung disease of prematurity (CLD) remains a common cause of morbidity and mortality in preterm infants. Oxygen toxicity remains a major risk factor for the development of CLD and as a consequence the antioxidant status of CLD babies is a major focus of interest. In the present study, we determined whether ascorbate, urate, and total glutathione concentrations were decreased in infants who developed CLD when compared to those who did not. From 34 preterm infants, 141 serial bronchoalveolar lavage fluid (BALF) and plasma samples were collected: 12 developed CLD (median gestation 26 weeks, range 23-28 weeks, median birth weight 780 g, range 630-1070 g), 16 developed and recovered from respiratory distress syndrome (RDS) (median gestation 31 weeks, range 26-39 weeks, median birth weight 1820 g, range 840-4160 g), and six were ventilated for non-respiratory reasons, (median gestation 35 weeks, range 32-38 weeks, median birth weight 2180 g, range 1100-2860 g). Following birth, the concentration of BALF ascorbate, urate and glutathione decreased over the 1st week in all three groups. Thereafter, BALF ascorbate increased in RDS and control infants during the 2nd week but this increase was delayed by 2 weeks in the CLD infants. No differences were noted between the RDS and CLD groups for urate and total glutathione in BALF or urate in plasma. BALF protein concentration was similar in all three groups except for a rise at day 7 in the CLD group but this did not reach statistical significance. Conclusion. A delayed increase in bronchoalveolar lavage fluid ascorbate concentration might be associated with an increased risk of developing chronic lung disease of prematurity.

Analysis of Variance↗
PubMed2001

Repeatability of cellular constituents and cytokine concentration in fluid obtained by non-bronchoscopic bronchoalveolar lavage of infants receiving extracorporeal oxygenation.

BACKGROUND: Since few studies have assessed the repeatability of non-bronchoscopic bronchoalveolar lavage (NB-BAL), we compared cellular counts and cytokine concentrations in fluid obtained by standardised NB-BAL from each side of 20 intubated infants receiving extracorporeal membrane oxygenation (ECMO). METHODS: Total cell counts were obtained from 95 paired lavages and 77 pairs were suitable for differential counts and measurement of cytokine concentrations. RESULTS: Moderate correlation was noted between the two sides for most cell types including total cell counts and percentages of neutrophils and macrophages (R=0.70-0.84) and for cytokine concentrations (IL-8 R=0.78, IL-6 R=0.75, TNF-alpha R=0.64, all p< or =0.001). Using Bland-Altman analysis the mean difference between the two sides approached zero for cellular constituents (total cell counts mean difference 1.7, limits of agreement -187.5 to +190.9 x 10(4)/ml; percentage neutrophils -3.9%, -41.5% to +33.6%; percentage macrophages 3.9%, -33.8% to +41.6%) but tended to be greater on the right for logarithmically transformed cytokine measurements (IL-8: left/right ratio 0.74, limits of agreement 0.12 to 5.45, IL-6: 0.93, 0.09 to 5.87, and TNF-alpha: 0.93, 0.27 to 3.16). Using linear regression with random effects to assess the variability, only the infant's age appeared to influence the cellular results but, for cytokines, only the volume retrieved affected the variability. The magnitude of the measurements, the underlying disease, the operator's experience, days on ECMO, or survival did not affect the variability. CONCLUSION: Measurements obtained by NB-BAL need to be interpreted with caution and strongly suggest that normalisation for the dilutional effects of saline is essential.

Age Factors↗
PubMed2001

Epidermal growth factor in the lungs of infants developing chronic lung disease.

Growth factors important to lung growth and fibrosis have been poorly studied in chronic lung disease (CLD) of prematurity. Epidermal growth factor (EGF) promotes epithelial cell maturation, and vascular endothelial growth factor (VEGF) is important in angiogenesis. The concentration of these growth factors was determined in 111 bronchoalveolar lavage fluid (BALF) samples from 35 ventilated infants: 13 developed CLD (median gestation 27 weeks, birthweight 820 g), 16 developed and recovered from respiratory distress syndrome (RDS) (31 weeks, 1,415 g) and six control infants (33 weeks, 2,075 g) were ventilated for nonpulmonary reasons. At birth, EGF in BALF from the CLD and RDS infants was lower than in the control infants (control versus CLD, 7.3 versus 0.0 pg x mL(-1), p<0.01; control versus RDS, 7.3 versus 5.0, p=0.08). EGF increased in all groups with a more rapid increase in control infants. A close relationship was noted between BALF EGF and gestational age (R=0.73). VEGF was undetectable at birth but increased at a similar rate in all three groups and did not correlate with gestation. In conclusion, these data suggest that epidermal growth factor is closely correlated to gestation and that it may predispose preterm infants to develop chronic lung disease.

Bronchoalveolar Lavage Fluid↗
PubMed2001

Chronic lung disease of prematurity: clinical and pathophysiological correlates.

Chronic lung disease of prematurity (CLD) is largely confined to preterm infants who require mechanical ventilation in the newborn period. Its development is associated with preterm labour and pulmonary inflammation secondary to oxidant stress, barotrauma of mechanical ventilation and antenatally--or postnatally--acquired respiratory tract infection. Pathological studies have shown that infants dying of established CLD have airway wall thickening secondary to increased airway wall smooth muscle mass, alveolar hypoplasia and pulmonary vascular re-modelling. These structural abnormalities are likely to account for the clinical problems of arterial hypoxemia and hypercapnia, tachypnea, recurrent wheezing and decreased exercise tolerance. Severity of the structural components may account for the clinical variation that is observed in a particular child. Management of CLD is aimed at decreasing the effects of hypoxemia and in maximising somatic, and by implication lung, growth. Low flow domiciliary oxygen and bronchodilators are used for arterial hypoxemia and recurrent wheezing. Systemic and inhaled corticosteroids may be beneficial but it is unclear if such treatment alters the natural history of CLD in the developing lung. Gastro-esophageal reflux should be sought in these infants and they should receive immunizations or immunoprophylaxis against respiratory tract pathogens. There is considerable concern that survivors of CLD may develop respiratory failure in early--or late--middle age.

Bronchopulmonary Dysplasia↗
PubMed2000

Regulation of the tinman homologues in Xenopus embryos.

Vertebrate homologues of the Drosophila tinman transcription factor have been implicated in the processes of specification and differentiation of cardiac mesoderm. In Xenopus three members of this family have been isolated to date. Here we show that the XNkx2-3, Xnkx2-5, and XNkx2-10 genes are expressed in increasingly distinctive patterns in endodermal and mesodermal germ layers through early development, suggesting that their protein products (either individually or in different combinations) perform distinct functions. Using amphibian transgenesis, we find that the expression pattern of one of these genes, XNkx2-5, can be reproduced using transgenes containing only 4.3 kb of promoter sequence. Sequence analysis reveals remarkable conservation between the distalmost 300 bp of the Xenopus promoter and a portion of the AR2 element upstream of the mouse and human Nkx2-5 genes. Interestingly, only the 3' half of this evolutionarily conserved sequence element is required for correct transgene expression in frog embryos. Mutation of conserved GATA sites or a motif resembling the dpp-response element in the Drosophila tinman tinD enhancer dramatically reduces the levels of transgene expression. Finally we show that, despite its activity in Xenopus embryos, in transgenic mice the Xenopus Nkx2-5 promoter is able to drive reporter gene expression only in a limited subset of cells expressing the endogenous gene. This intriguing result suggests that despite evolutionary conservation of some cis-regulatory sequences, the regulatory controls on Nkx2-5 expression have diverged between mammals and amphibians.

Animals↗
PubMed2000

Xenopus Hand2 expression marks anterior vascular progenitors but not the developing heart.

We have isolated cDNAs encoding the bHLH protein Hand2 in the amphibian Xenopus laevis and analysed Hand2 expression in early development from the onset of gastrulation to feeding tadpole stages. XHand2 is expressed in the branchial arch mesenchyme and also in small bilateral populations of cells in the anterior, ventrolateral region of early tailbud embryos. At later stages, these punctate Hand2-expressing cells are located at the sites of the forming common cardinal veins, suggesting that they may constitute progenitors of vascular smooth muscle cells. Other Hand2-expressing cells are also associated with further components of the forming anterior vasculature but are not detected in mature blood vessels. Interestingly, no myocardial expression of XHand2 can be detected in the developing tadpole heart, in marked contrast to results obtained with chick and mouse embryos.

Amino Acid Sequence↗
PubMed1999

MEF-2 function is modified by a novel co-repressor, MITR.

The MEF-2 proteins are a family of transcriptional activators that have been detected in a wide variety of cell types. In skeletal muscle cells, MEF-2 proteins interact with members of the MyoD family of transcriptional activators to synergistically activate gene expression. Similar interactions with tissue or lineage-specific cofactors may also underlie MEF-2 function in other cell types. In order to screen for such cofactors, we have used a transcriptionally inactive mutant of Xenopus MEF2D in a yeast two-hybrid screen. This approach has identified a novel protein expressed in the early embryo that binds to XMEF2D and XMEF2A. The MEF-2 interacting transcription repressor (MITR) protein binds to the N-terminal MADS/MEF-2 region of the MEF-2 proteins but does not bind to the related Xenopus MADS protein serum response factor. In the early embryo, MITR expression commences at the neurula stage within the mature somites and is subsequently restricted to the myotomal muscle. In functional assays, MITR negatively regulates MEF-2-dependent transcription and we show that this repression is mediated by direct binding of MITR to the histone deacetylase HDAC1. Thus, we propose that MITR acts as a co-repressor, recruiting a specific deacetylase to downregulate MEF-2 activity.

Amino Acid Sequence↗
PubMed1999

Concentration of nitric oxide products in bronchoalveolar fluid obtained from infants who develop chronic lung disease of prematurity.

AIMS: To determine if nitric oxide (NO) products (nitrate and nitrite) are increased in bronchoalveolar lavage (BAL) fluid obtained from infants who develop chronic lung disease of prematurity (CLD). METHODS: One hundred and thirty six serial bronchoalveolar lavages were performed on 37 ventilated infants (12 with CLD, 18 with respiratory distress syndrome (RDS), and seven control infants) who did not receive inhaled NO. RESULTS: During the first week of life nitrate concentration was between 25-31 micromol/l in all three groups. Thereafter, the concentration of BAL fluid nitrate decreased to 14 micromol/l and 5.5 micromol/l, respectively in the RDS and control groups by 14 days of age. In contrast, nitrate in the CLD infants remained constant until 28 days of age (31.3 micromol/l at day 14; p<0.05). In all BAL fluid samples the mean concentration of nitrite was <1.2 micromol/l throughout the first 28 days with no significant differences noted among the three groups. CONCLUSION: The similar concentration of BAL fluid nitrate in all groups during the first week of life suggest that NO may be important in the adaptation of the pulmonary circulation after birth. However, persistence of nitrate in the BAL fluid of infants with CLD during the second week may reflect pulmonary maladaptation, or, more likely, persisting pulmonary inflammation.

Bronchoalveolar Lavage Fluid↗
PubMed1999

Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors.

To determine a potential role for the renin-angiotensin system in the growth of human pulmonary artery (PA) smooth muscle, we studied the localization of angiotensin (ANG) II-receptor subtypes by autoradiography in sections of human PA and in cultured PA smooth muscle cells (PASMCs) and examined the growth responses to ANG II in vitro. Specific 125I-labeled [Sar1,Ile8]ANG II binding was demonstrated within the pulmonary arterial media, but binding to cultured cells varied between isolates. Binding in tissues and cells was inhibited by the ANG II type 1 (AT1) receptor antagonist losartan but not by the type 2 (AT2) receptor antagonist PD-123319. Microautoradiographic studies indicated that cultured PASMCs exhibit heterogeneity with regard to ANG II binding sites. Addition of ANG II to serum-deprived PASMCs, exhibiting a relatively high level of 125I-[Sar1,Ile8]ANG II binding, led to a dose-dependent stimulation of DNA synthesis at 24 h and protein synthesis at 48 h. ANG II led to an increase in cell size without an increase in cell number. These effects were inhibited by losartan but not by PD-123319. In addition, ANG II led to rapid activation of mitogen-activated protein kinase (MAPK), and ANG II-stimulated DNA synthesis was inhibited by the specific inhibitor of MAPK PD-98059. We conclude that the AT1 receptor is expressed by human PASMCs in vivo and in vitro and is coupled to activation of MAPK and increased DNA and protein synthesis in vitro. These results are consistent with the hypothesis that ANG II may be involved in human pulmonary vascular remodeling.

Angiotensin II↗