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Biomedical subjects

L Sanders

Publications and source records attributed to L Sanders.

At least 19 recordsLinked to original sources
PubMed2001

Gastric outlet obstruction secondary to pancreatic cancer: surgical vs endoscopic palliation.

BACKGROUND: Gastric outlet obstruction in patients with pancreatic cancer has a grim prognosis. Open surgical bypass is associated with high morbidity, whereas endoscopic duodenal stenting appears to provide better palliation. METHODS: We reviewed the medical records of patients with gastric outlet obstruction secondary to pancreatic carcinoma who were admitted to our clinic between 1 October 1988, and 30 September 1998. The data included stage of disease, American Society of Anesthesiologists (ASA) class, surgical interventions, complications, and survival. RESULTS: A total of 250 patients with pancreatic cancer were identified. Twenty-five of them (10%) had gastric outlet obstruction. Of these 25, 17 were treated with gastrojejunostomy, six had duodenal stenting (Wallstent), and two were resectable. There was no significant difference between the gastrojejunostomy group and the duodenal stenting group in ASA class or stage of disease. For the gastrojejunostomy group, median survival was 64 days (range, 15-167) and postoperative stay in hospital was 15 days (range, 8-39). For the duodenal stenting group, median survival was 110.5 days (range, 42-212) and postoperative stay was 4 days (range, 2-6). Ten patients (58.8%) in the gastrojejunostomy group had delayed gastric emptying. All of the patients in the duodenal stenting group were able to tolerate a soft diet the day after stent placement. Thirty-day mortality in the gastrojejunostomy group was 17.64%; in the duodenal stenting group, it was 0. CONCLUSION: In pancreatic carcinoma patients with gastric outlet obstruction, duodenal stenting results in an earlier discharge from hospital and possibly improved survival.

Aged↗
PubMed2001

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection.

BACKGROUND: Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). METHODS: Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher's exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. RESULTS: Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P=0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P=0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. CONCLUSIONS: Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.

Acute Disease↗
PubMed2001

National survey of imaging technologists in nuclear medicine 1998/99.

This survey investigated the nature of imaging staff and the distribution and structure of nuclear medicine departments in the UK. Total numbers of cameras and average per department were lower than in 1989/90 but higher than the 1992/93 survey. Total whole time equivalents, average per department and average per camera had increased. Excluding the Isle of Man, Wales had the lowest population per camera and Northern Ireland the highest. This survey identified 237 departments (90 independent, 116 integrated and 31 satellite), radiographers being the chief technologists in 64% and MTOs in 36%. Over half had one single-headed camera but one third had dual- or triple-headed cameras. Chief technologist grades ranged from Basic to Superintendent II and MTO3 to MTO5. The most common grades for other staff were Senior II or MTO3. Of the 786 technologists who provided details, 68% had initially trained as radiographers. Specific nuclear medicine qualifications were held by 67% of all technologists. In 52% of departments at least one member of staff rotated between nuclear medicine and another department or hospitals and 25% had no full-time staff. Survey returns revealed that, although 84% of imaging technologists often or occasionally attended conferences, 5% never attended.

Allied Health Personnel↗
PubMed2001

Production of biologically active equine interleukin 12 through expression of p35, p40 and single chain IL-12 in mammalian and baculovirus expression systems.

Interleukin-12 (IL-12) is a key cytokine in the development of cell-mediated immune responses. Bioactive IL-12 is a heterodimeric cytokine composed of disulphide linked p35 and p40 subunits. The aim of this study was to verify biologically activity of the products expressed from equine interleukin-12 (IL-12) p35 and p40 cDNAs and to establish whether equine IL-12 could be expressed as a p35/p40 fusion polypeptide, as has been reported for IL-12a of several mammalian species. We report production of equine IL-12 through expression of p35 and p40 subunits in mammalian and insect cells and of a p35:p40 fusion polypeptide in mammalian cells. Conditioned medium recovered from cultures transiently transfected with constructs encoding equine p35 and p40 subunits or single chain IL-12 enhanced IFN-gamma production in cells derived from equine lymph nodes. Preincubation of IFN-gamma inducing preparations with anti-p40 monoclonal antibody resulted in a significant decrease in IFN-gamma induction capacity. Medium recovered from p35 and p40-expressing baculovirus infected cultures enhanced target cell IFN-gamma production and proliferation. Experimental studies in mice and other animals have revealed a therapeutic benefit of IL-12 in cancer, inflammatory and infectious disease and an adjuvant effect in prophylactic regimes. Production of a bioactive species-specific IL-12 is a first step towards an investigation of its potential application in equine species.

Amino Acid Sequence↗
PubMed2001

Resident utilization of information technology.

OBJECTIVE: To determine if a simple educational intervention can increase resident physician literature search activity. DESIGN: Randomized controlled trial. SETTING: University hospital-based internal medicine training program. PATIENTS/PARTICIPANTS: Forty-eight medical residents rotating on the general internal medicine service. INTERVENTIONS: One-hour didactic session, the use of well-built clinical question cards, and practical sessions in clinical question building. MEASUREMENTS AND MAIN RESULTS: Objective data from the library information system that included the number of log-ons to medline, searching volume, abstracts viewed, full-text articles viewed, and time spent searching. Median search activity as measured per person per week (control vs intervention): number of log-ons to medline (2.1 vs 4.4, P <.001); total number of search sets (24.0 vs 74.2, P <.001); abstracts viewed (5.8 vs 17.7, P=.001); articles viewed (1.0 vs 2.6, P=.005); and hours spent searching (0.8 vs 2.4, P <.001). CONCLUSIONS: A simple educational intervention can markedly increase resident searching activity.

Adult↗
PubMed2000

Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons.

Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent trophic factors that have been identified for midbrain dopamine (DA) neurons. Null mutations for trophic factor genes have been used frequently for studies of the role of these important proteins in brain development. One problem with these studies has been that often only prenatal development can be studied because many of the knockout strains, such as those with GDNF null mutations, will die shortly after birth. In this study, we looked at the continued fate of specific neuronal phenotypes from trophic factor knockout mice beyond the time that these animals die. By transplanting fetal neural tissues from GDNF -/-, GDNF +/-, and wild-type (WT) mice into the brain of adult wild-type mice, we demonstrate that the continued postnatal development of ventral midbrain dopamine neurons is severely disturbed as a result of the GDNF null mutation. Ventral midbrain grafts from -/- fetuses have markedly reduced DA neuron numbers and fiber outgrowth. Moreover, DA neurons in such transplants can be "rescued" by immersion in GDNF before grafting. These findings suggest that postnatal survival and/or phenotypic expression of ventral mesencephalic DA neurons is dependent on GDNF. In addition, we present here a strategy for studies of maturation and even aging of tissues from trophic factor and other knockout animals that do not survive past birth.

Animals↗
PubMed2000

Four novel mutations in the gene encoding gp91-phox of human NADPH oxidase: consequences for oxidase assembly.

The superoxide-forming nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase of human phagocytes comprises membrane-bound and cytosolic proteins, which, upon cell activation, assemble on the plasma membrane to form the active enzyme. Patients with chronic granulomatous disease (CGD) are defective in one of the phagocyte oxidase (phox) components, p47-phox or p67-phox, which reside in the cytosol of resting phagocytes, or gp91-phox or p22-phox, which constitute the membrane-bound cytochrome b(558). In four X-linked CGD patients we have identified novel missense mutations in CYBB, the gene encoding gp91-phox. These mutations were associated with normal amounts of nonfunctional cytochrome b(558) in the patients' neutrophils. In phorbol-myristate-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, the association of p47-phox and p67-phox with the membrane fraction of the cells with Cys369-->Arg, Gly408-->Glu, and Glu568--> Lys substitutions was strongly disturbed. Only a Thr341-->Lys substitution, residing in a region of gp91-phox involved in flavin adenine dinucleotide (FAD) binding, supported a normal translocation. Thus, the introduction or reversal of charge at residues 369, 408, and 568 in gp91-phox destroys the correct binding of p47-phox and p67-phox to cytochrome b(558). Based on mutagenesis studies of structurally related flavin-dependent oxidoreductases, we propose that the Thr341-->Lys substitution results in impaired hydride transfer from NADPH to FAD. Because we found no electron transfer in solubilized neutrophil plasma membranes from any of the four patients, we conclude that all four amino acid replacements are critical for electron transfer. Apparently, an intimate relation exists between domains of gp91-phox involved in electron transfer and in p47/p67-phox binding. (Blood. 2000;95:666-673)

Amino Acid Sequence↗
PubMed1999

Expression of the dominant-negative regulator Id4 is induced during adipocyte differentiation.

Expression of the Id4 gene was investigated during differentiation of 3T3-L1 preadipocytes into mature adipocytes. Id4 is a member of a family encoding non-DNA binding helix-loop-helix proteins proposed to inhibit the activity of basic HLH (bHLH) proteins important in many developmental processes. We show here that Id4 expression is low in confluent preadipocytes and rapidly induced by treatment with the combination of hormones which causes differentiation into mature adipocytes. Id4 expression is also induced by treatment with individual hormones, especially dexamathasone. Id4 mRNA can be detected in mouse and human adipose tissue. Genes encoding E-proteins (bHLH proteins known to interact with and be regulated by Id proteins) are expressed and regulated during differentiation in 3T3-L1 cells. These data suggest that the Id4 transcriptional regulator is playing a role in adipose cell differentiation and suggest that DNA-binding HLH proteins may also be important in regulation of differentiation of these cells.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes.

Thiazolidinediones (TZDs) are a novel class of insulin-sensitizing agents used in the treatment of NIDDM and are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The thiazolidinedione BRL 49653 has been shown to promote the differentiation of the HIB-1B brown preadipocyte cell line and to increase rat interscapular brown adipose tissue (BAT) mass. Given the importance of brown fat in the control of energy metabolism in rodents, this may represent an important therapeutic effect of this class of compound. To date, however, no studies examining the effects of TZDs on human brown fat have been reported. In the present study, we have measured uncoupling protein 1 (UCP-1) mRNA, a specific marker for BAT, in isolated adipocytes and subcultured preadipocytes prepared from different adult human adipose tissue depots. Consistent with previous studies of adult human whole adipose tissue, UCP-1 mRNA was detectable in isolated human adipocytes prepared from all depots studied with a rank order of perirenal, omental, and subcutaneous. BRL 49653 treatment of subcultured human pre-adipocytes prepared from all depots resulted in increased levels of UCP-1 mRNA, compared with those of the vehicle-treated cells. When exposed to BRL 49653 for 5 days, preadipocytes from the human perirenal depot accumulated lipid, and a proportion of cells showed clear mitochondrial staining for UCP-1 protein by confocal microscopy. Thus, cells of the brown fat lineage were detectable in all human adipose depots studied, and cultured human pre-adipocytes, particularly from the perirenal depot, showed a marked increase in UCP-1 expression in response to thiazolidinediones. Given the role of brown adipocytes in the enhancement of energy expenditure, promotion of brown fat adipogenesis by thiazolidinediones could contribute to the beneficial effects of these drugs on insulin resistance in humans.

Adipocytes↗
PubMed1998

Depot-related gene expression in human subcutaneous and omental adipocytes.

Human omental adipocytes display a range of biochemical properties that distinguish them from adipocytes of subcutaneous origin. However, information about site-related gene expression in human fat cells is limited. We have previously demonstrated that leptin mRNA is markedly overexpressed in abdominal subcutaneous (SC) compared with omental (Om) adipocytes. To further investigate depot-specific differences in adipocyte gene expression, we have measured, in paired samples of isolated human adipocytes obtained from SC and Om fat depots, the expression of mRNAs encoding a number of proteins involved in the control of adipocyte metabolism. In contrast to the marked site-related expression of leptin, genes encoding lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and adipsin were not consistently differentially expressed. Of note, a highly significant inverse correlation between adipocyte PPAR-gamma expression and BMI (r = -0.7, P = 0.0005) was found. In parallel experiments, differential display was used in an attempt to identify novel and/or unexpected adipocyte genes that were expressed in a site-related manner. No transcript that was unique to one or another depot was found, but cellular inhibitor of apoptosis protein-2 (cIAP2) mRNA, which has not previously been reported in adipocytes, was expressed at higher levels in Om than SC adipocytes (Om > SC in all eight subjects; mean Om:SC ratio 1.9 +/- 0.2, P < 0.01). Because cIAP2 may be involved in the regulation of TNF-alpha signaling, this raises the possibility that depot-specific differences may exist in the regulation of adipocyte apoptosis. Thus, of the mRNAs examined to date, only leptin and cIAP2 show consistent site-related expression, suggesting that these molecules may have important roles in determining functional properties particular to individual adipose depots. Given the importance of PPAR-gamma in adipocyte development and insulin sensitivity, the inverse correlation between adipocyte PPAR-gamma mRNA levels and adiposity may represent a local regulatory mechanism restraining fat accumulation and/or may be related to the reduction of insulin sensitivity that occurs with increasing fat mass.

Adipocytes↗
PubMed1998

A cross sectional analysis of 5 different markers of collagen degradation in rheumatoid arthritis.

OBJECTIVE: To compare 5 different assays measuring collagen degradation in rheumatoid arthritis (RA). METHODS: Daily serum samples and 3 consecutive 24 h urine samples were obtained from 25 patients with RA and 20 control subjects. Levels of pyridinoline (PYD), deoxypyridinoline (DPYD), n-telopeptide (NTx), CrossLaps (XL), and carboxy-terminal peptide of type I collagen (ICTP) were determined by ELISA or radioimmunoassay. PYD, DPYD, NTx, and XL were measured in urine and expressed as a ratio of the amount of crosslink to mmoles of creatinine (Cr). ICTP was determined in serum. The day-to-day variability of urinary collagen crosslink levels and serum ICTP was assessed over 3 day hospitalization. RESULTS: Four of the 5 markers were significantly elevated in the RA cohort compared to controls: PYD (nmol)/Cr (median 33.8 vs 19.3; p = 0.0001), NTx (nmol)/Cr (median 22.5 vs 13.8; p = 0.01), XL (microg)/Cr (median 191.4 vs 126.1; p = 0.01), and ICTP (microg/l) (median 5.8 vs 3.7; p = 0.001). In the RA group, higher levels of the markers were associated with concomitant prednisone therapy. The levels of the 4 urine markers and of ICTP in serum exhibited little day-to-day variability. CONCLUSION: Biochemical evidence of increased collagen degradation can be readily observed in RA using simple quantitative assays. These measures have minimal short term, day-to-day variability and hence may be useful to assess the effect of potentially disease modifying therapies.

Amino Acids↗
PubMed1997

Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation.

Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differentiation of murine preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of insulin-sensitizing compounds effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high affinity. We have examined the effects of these compounds on the differentiation of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand) enhanced markedly the differentiation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPARgamma was expressed at similar levels in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDDM, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo insulin sensitivity.

Adipocytes↗
PubMed1997

Consequences of lost gallstone.

Laparoscopic cholecystectomy has become the treatment of choice in the management of calculus gallbladder disease. Intraperitoneal gallstone loss is not uncommon; it occurs in up to 40% of cases. Often, the stones are left unretrieved and are thought to be inconsequential. We present a series of patients who have had serious sequela from gallstones in the peritoneal cavity. We performed a retrospective study of the management of six patients with complications from intraperitoneal gallstones. The patients presented with a variety of complaints, from fevers to pneumonia to a colo-cutaneous fistula. Presentation ranged from immediately postoperatively to 18 months after surgery. Diagnosis included perihepatic abscesses and colo-biliary fistula. General anesthesia was usually necessary for removal of the stones. All patients have resolved following the removal of the gallstones. Our recommendation is to attempt to avoid spillage through careful dissection and retrieve any lost stones. The defect in the gallbladder can be closed with a clip. Whether the procedure should be converted to an open one to retrieve all the stones remains open to debate. The surgeon should be aware of the possible consequences of the lost gallstone.

Biliary Fistula↗