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Biomedical subjects

S Randhawa

Publications and source records attributed to S Randhawa.

12 recordsLinked to original sources
PubMed2006

Can WHO therapy failure criteria for non-severe pneumonia be improved in children aged 2-59 months?

SETTING: In the recent past, there have been reports of rising treatment failure rates for non-severe pneumonia. It is felt that World Health Organization (WHO) criteria for therapy failure are too sensitive and that many children are unnecessarily classified as failures. We studied alternative, less sensitive therapy failure criteria. METHODS: In this nested study we followed the clinical course of non-severe pneumonia in children aged 2-59 months using alternative therapy failure criteria. All children received amoxicillin and were followed up on days 3, 5 and 14 after enrollment. On day 3, children were labelled as therapy failure only if their condition had deteriorated. These failure rates were compared with those using WHO definitions. RESULTS: During the study period, 876 children with non-severe pneumonia were followed up until day 14. On day 3, using alternative therapy failure criteria, 31 (3.5%) children were labelled as therapy failure compared to 95 (10.8%) using current WHO criteria. The difference was statistically significant (P = 0.001). CONCLUSIONS: The alternative therapy failure criteria work reasonably well, without causing any higher risk to children with non-severe pneumonia. Antibiotics should be changed only in those children who show signs of deterioration on day 3. This would prevent unnecessary changes in antibiotic treatment in many children.

Acute Disease↗
PubMed2004

Assessment and management of children aged 1-59 months presenting with wheeze, fast breathing, and/or lower chest indrawing; results of a multicentre descriptive study in Pakistan.

BACKGROUND AND AIMS: Using current WHO guidelines, children with wheezing are being over prescribed antibiotics and bronchodilators are underutilised. To improve the WHO case management guidelines, more data is needed about the clinical outcome in children with wheezing/pneumonia overlap. METHODOLOGY: In a multicentre prospective study, children aged 1-59 months with auscultatory/audible wheeze and fast breathing and/or lower chest indrawing were screened. Response to up to three cycles of inhaled salbutamol was recorded. The responders were enrolled and sent home on inhaled bronchodilators, and followed up on days 3 and 5. RESULTS: A total of 1622 children with wheeze were screened from May 2001 to April 2002, of which 1004 (61.8%) had WHO defined non-severe and 618 (38.2%) severe pneumonia. Wheeze was audible in only 595 (36.7%) of children. Of 1004 non-severe pneumonia children, 621 (61.8%) responded to up to three cycles of bronchodilator. Of 618 severe pneumonia children, only 166 (26.8%) responded. Among responders, 93 (14.9%) in the non-severe and 63 (37.9%) children in the severe pneumonia group showed subsequent deterioration on follow ups. No family history of wheeze, temperature >100 degrees F, and lower chest indrawing were identified as predictors of subsequent deterioration. CONCLUSIONS: Two third of children with wheeze are not identified by current WHO ARI (acute respiratory infections) guidelines. Antibiotics are over prescribed and bronchodilators under utilised in children with wheeze. Children with wheeze constitute a special ARI group requiring a separate management algorithm. In countries where wheeze is common it would be worthwhile to train health workers in use of the stethoscope to identify wheeze.

Bronchodilator Agents↗
PubMed2004

Comparison of clinical outcome with oral and inhaled bronchodilators in the management of wheezy children aged 1-59 months in the community: a randomised trial in Pakistan.

BACKGROUND: Wheeze is a significant problem in children. There is a gradual trend of switching from oral to inhaled bronchodilator therapy. No randomised trials have been carried out in the community to compare the clinical outcome of two modes of therapy. If outcome with oral and inhaled bronchodilators is the same in young wheezers in developing countries, it will be easier to manage them. METHODS: In a randomised multicentre trial, wheezy children aged 1-59 months with fast breathing and/or lower chest indrawing received oral or inhaled salbutamol at home after responding to up to three cycles of inhaled bronchodilators. They were re-assessed on days 3 and 5 for clinical outcome. RESULTS: From May 2001 to August 2002, 780 children were enrolled; 390 each were randomised to oral and inhaled salbutamol. On day 5, 324 (83.1%) children in the oral and 328 (84.1%) in the inhaled group were completely well. There were no differences in clinical outcome of both modes of therapy. CONCLUSIONS: The clinical outcome of children aged 1-59 months with wheeze is similar when treated with oral or inhaled salbutamol. Acute respiratory infection control programmes in developing countries should continue to use oral bronchodilators for the management of wheeze to save both time and money.

Administration, Inhalation↗
PubMed2001

CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells.

Fas-mediated mechanisms of apoptosis are thought to be involved in the bile duct loss that characterizes diseases such as primary biliary cirrhosis (PBC). We have previously shown that activation of CD40 on hepatocytes can amplify Fas-mediated apoptosis; in the present study, we investigated interactions between CD40 and Fas in biliary epithelial cells (BEC). We report that the bile ducts in PBC liver tissue frequently express increased levels of Fas, Fas ligand (FasL), and CD40 associated with apoptotic BEC. The portal mononuclear infiltrate contains CD40L+ve T cells and macrophages, thereby demonstrating a potential mechanism for CD40 engagement in vivo. Primary cultures of human BEC also expressed Fas, FasL, and CD40 but not CD40L protein or mRNA. Activation of CD40 on BEC using recombinant CD40L increased transcriptional expression of FasL and induced apoptosis, which was inhibited by neutralizing antibodies to either Fas or FasL. Thus, CD40-induced apoptosis of BEC is mediated through Fas/FasL. We then investigated the intracellular signals and transcription factors activated in BEC and found that NF-kappaB and AP-1 were both activated after CD40 ligation. Increased functional NF-kappaB was seen early after CD40 ligation, but returned to baseline levels after 4 h. In contrast, the rapid up-regulation of AP-1 was sustained over 24 h. This study provides further functional evidence of the ability of CD40 to induce Fas/FasL-dependent apoptosis of liver epithelial cells supporting the importance of cross-talk between tumor necrosis factor (TNF) receptor family members as an amplification step in apoptosis induction. Sustained activation of AP-1 in the absence of NF-kappaB signaling may be a critical factor in determining the outcome of CD40 engagement.

Apoptosis↗
PubMed2000

Apoptosis.

Apoptosis is the genetically regulated form of cell death that permits the safe disposal of cells at the point in time when they have fulfilled their intended biological function. Examples of apoptosis can be cited throughout the whole of the animal and plant kingdoms. It is a vitally important process during normal development and the adult life of many living organisms. In humans, dysregulation of apoptosis can result in inflammatory, malignant, autoimmune, and neurodegenerative diseases. In addition, infectious agents, including viruses, exploit cellular apoptosis in the host to evade the immune system. This review gives a brief historical perspective of some of the landmark discoveries in apoptosis research. The morphological and biochemical stages of apoptosis are then covered, followed by an overview of how it can be studied in the laboratory. Finally, the implications for therapeutic intervention in disease treatment are discussed.

Animals↗
PubMed1999

CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.

We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection. We detected increased hepatocyte expression of Fas, Fas ligand (FasL), and CD40 associated with dropout of centrilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expression of CD40 ligand (CD40L) was also increased but was largely restricted to CD68(+) macrophages. A functional role for CD40 and Fas in hepatocyte apoptosis was demonstrated in vitro using primary human hepatocytes and the HepG2 cell line in both of which apoptosis was induced, not only by cross-linking Fas directly but also via CD40 activation. Our data suggest that CD40 activation induces apoptosis via Fas because (a) ligation of CD40 upregulated hepatocyte FasL expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to FasL. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify Fas-dependent hepatocyte apoptosis in chronic rejection and other inflammatory liver diseases in which Fas-mediated apoptosis is involved.

Antibodies, Monoclonal↗
PubMed1999

Fas/Fas ligand interaction in human colorectal hepatic metastases: A mechanism of hepatocyte destruction to facilitate local tumor invasion.

This study demonstrates a novel role for the Fas pathway in the promotion of local tumor growth by inducing apoptotic cell death in normal hepatocytes at the tumor margin in colorectal hepatic metastases. Our results show that >85% of lymphocytes infiltrating colorectal liver cancer express high levels of Fas-ligand (Fas-L) by flow cytometry. Using immunohistochemistry of tumor tissue we showed strong Fas expression in noninvolved hepatocytes, whereas Fas-L expression was restricted to tumor cells and infiltrating lymphocytes at the tumor margin. Apoptosis was observed in 45 +/- 13% of the Fas(high) hepatocytes at the tumor margin whereas only 7 +/- 3% tumor cells were apoptotic (n = 10). In vitro, primary human hepatocytes expressed Fas receptor and crosslinking with anti-Fas antibody induced apoptosis in 44 +/- 5% of the cells compared with 4. 6 +/- 1.0% in untreated controls (P = 0.004). Both tumor-infiltrating lymphocytes (TIL) and human metastatic colon cancer cells cells are able to induce Fas-mediated apoptosis of primary human hepatocytes in coculture cytotoxic assays. TIL induced apoptosis in 47 +/- 9% hepatocytes compared with control 4.3 +/- 1. 0% (P = 0.009) and this effect was reduced by anti-human Fas-L mAb (18.7 +/- 1.3%, P = 0.009). SW620 cells induced apoptosis in 26 +/- 2% hepatocytes compared with control 5.6 +/- 1.7% (P = 0.004) and this was reduced to 11.2 +/- 1.8% (P = 0.004) in the presence of anti-human Fas-L mAb. These data suggest that the inflammatory response at the margin of colorectal liver metastases induces Fas expression in surrounding hepatocytes, allowing them to be killed by Fas-L-bearing TIL or tumor cells and facilitating the invasion of the tumor into surrounding liver tissue.

Aged↗
PubMed1998

The influence of human endotoxemia on CD95-induced apoptosis.

BACKGROUND: The responses of monocyte and neutrophil tumor necrosis factor receptor type 1 (TNFR-1) and TNFR-2 during systemic inflammation have been described previously. Several other members of the TNFR superfamily also appear to have regulatory roles in immunocyte function, including apoptosis. However, the response of these other receptor members, such as CD95, to systemic inflammation is unclear. OBJECTIVES: To compare the response of CD95 with that of TNFR during systemic inflammation and to assess the influence of the inflammatory milieu on CD95 function. SETTING: Adult clinical research center of a university hospital. SUBJECTS AND METHODS: Five healthy male subjects were administered intravenous endotoxin (2 ng/kg), and systemic response was measured by cytokine analysis and receptor expression assays during a 48-hour period. CD95 function during systemic inflammation was assessed using a Jurkat cell bioassay for degree of apoptosis. RESULTS: Monocyte and neutrophil CD95 expression exhibited changes parallel to that of TNFR following endotoxin injection. In contrast to soluble TNFR, which was transiently elevated during endotoxemia, soluble CD95 levels remained unchanged from baseline. Jurkat cells incubated in normal and post-endotoxin serum samples equally exhibited less than 10% spontaneous apoptosis. No soluble CD95 ligand was detectable in experimental human endotoxemia. CONCLUSIONS: Cell-associated CD95 exhibited changes parallel to its receptor family member TNFR following endotoxin administration. Soluble CD95 is present in human serum samples, but the levels remained unchanged following endotoxin administration. No soluble CD95 ligand activity was detectable by enzyme-linked immunosorbent assay or by functional assay. The potential protective role of soluble CD95 in human serum samples against CD95 ligand-induced apoptosis remains to be defined.

Adult↗
PubMed1996

The enteric neural network and three dimensional computer modelling of intestinal peristalsis.

A computer model of the enteric nervous system has been developed using MATLAB in order to determine the extent to which the nature of intestinal activity can be explained by our current understanding of the projections and connectivity of enteric neurons. The model is based on repeated, identical overlapping modules, each of which contains the same number of neurones and circular muscle. The connections between modules were derived from microanatomical data. This simple model explains some characteristic features of the generation of an intestinal motor pattern.

Animals↗
PubMed1991

Temperature induced changes in microsomal (Na+,K+)-ATPase and lipid composition of Candida kefyr.

Growth temperature affected both the membrane lipid composition and microsoma (Na+, K+)-ATPase activity of Candida kefyr. Higher growth, temperature (37 degrees C) increased the amount of total lipids, phospholipids and free sterol. Ratios of phosphatidylcholine to phosphatidylethanolamine as well saturated to unsaturated fatty acids increased with a rise in growth temperature. Km of the ATPase isolated from the yeast grown at 27 degrees C was minimum, suggesting that the membranes of C. kefyr grown at optimal growth temperature provide the most suitable environment for the activity of ATPase.

Candida↗