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1.  Can Technical Factors Explain the Volume-Outcome Relationship in Gastric Bypass Surgery? 
The existence of a relationship between surgeon volume and patient outcome has been demonstrated for different complex surgical operations. This relationship has also been confirmed for patients undergoing Roux-en-Y gastric bypass (RYGB) in the Longitudinal Assessment of Bariatric Surgery (LABS) study. Despite multiple studies demonstrating volume-outcome relationships, fewer studies investigate the causes of this relationship.
The purpose of the present study is to understand possible explanations for the volume-outcome relationship in LABS.
Multiple Clinical Centers – University and Private Practice, United States.
LABS includes a 10-center, prospective study examining 30-day outcomes following bariatric surgery. The relationship between surgeon annual RYGB volume and incidence of a composite endpoint (CE) has been published previously. Technical aspects of RYGB surgery were compared between high and low volume surgeons. The previously published model was adjusted for select technical factors.
High volume surgeons (>100 RYGBs/year) were more likely to perform a linear stapled gastrojejunostomy, use fibrin sealant and place a drain at the gastrojejunostomy compared to low volume surgeons (<25 RYGBs/year), and less likely to perform an intraoperative leak test. After adjusting for the newly identified technical factors, the relative risk of CE was 0.93 per 10 RYGB/year increase in volume, compared to 0.90 for clinical risk adjustment alone.
High volume surgeons exhibited certain differences in technique when compared to low volume surgeons. After adjusting for these differences, the strength of the volume-outcome relationship previously found was reduced only slightly, suggesting that other factors are also involved.
PMCID: PMC3630240  PMID: 23274125
Bariatric surgery; RYGB; volume-outcome relationship
2.  Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(8):992-999.
To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA).
Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co‐localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy.
The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid‐ and plasmacytoid‐type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon α and γ.
The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.
PMCID: PMC1954703  PMID: 17223651
rheumatoid arthritis; myeloid dendritic cells; plasmacytoid dendritic cells; IL12; interferon alpha; interferon gamma
3.  Assessment of axial bone rigidity in rats with metabolic diseases using CT-based structural rigidity analysis 
Bone & Joint Research  2012;1(2):13-19.
This study aims to assess the correlation of CT-based structural rigidity analysis with mechanically determined axial rigidity in normal and metabolically diseased rat bone.
A total of 30 rats were divided equally into normal, ovariectomized, and partially nephrectomized groups. Cortical and trabecular bone segments from each animal underwent micro-CT to assess their average and minimum axial rigidities using structural rigidity analysis. Following imaging, all specimens were subjected to uniaxial compression and assessment of mechanically-derived axial rigidity.
The average structural rigidity-based axial rigidity was well correlated with the average mechanically-derived axial rigidity results (R2 = 0.74). This correlation improved significantly (p < 0.0001) when the CT-based Structural Rigidity Analysis (CTRA) minimum axial rigidity was correlated to the mechanically-derived minimum axial rigidity results (R2 = 0.84). Tests of slopes in the mixed model regression analysis indicated a significantly steeper slope for the average axial rigidity compared with the minimum axial rigidity (p = 0.028) and a significant difference in the intercepts (p = 0.022). The CTRA average and minimum axial rigidities were correlated with the mechanically-derived average and minimum axial rigidities using paired t-test analysis (p = 0.37 and p = 0.18, respectively).
In summary, the results of this study suggest that structural rigidity analysis of micro-CT data can be used to accurately and quantitatively measure the axial rigidity of bones with metabolic pathologies in an experimental rat model. It appears that minimum axial rigidity is a better model for measuring bone rigidity than average axial rigidity.
PMCID: PMC3626191  PMID: 23610665
Fracture risk; Bone; Structural rigidity; Metabolic bone disease; Computed tomography; Rat model; CTRA
4.  Standardisation of synovial tissue infiltrate analysis: how far have we come? how much further do we need to go? 
Annals of the Rheumatic Diseases  2005;65(1):93-100.
Changes in cellular infiltrate and expression of cytokines, chemokines, and cell adhesion molecules as a result of therapeutic interventions in rheumatoid arthritis can be demonstrated in the synovial membrane. However, before synovial tissue analysis can be used as an outcome measure in such studies, standardisation of the site and method of synovial tissue acquisition, methods of tissue processing, and appropriate methods of detection and measurement of cell lineage specific markers and relevant biological proteins is needed.
PMCID: PMC1797968  PMID: 15975970
immunohistochemistry; inflammatory arthritis; standardisation; synovial tissue
5.  Changes in synovial tissue Jak‐STAT expression in rheumatoid arthritis in response to successful DMARD treatment 
Annals of the Rheumatic Diseases  2006;65(12):1558-1564.
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA).
To examine the effect of successful disease‐modifying antirheumatic drug (DMARD) treatment on the expression of Jak‐STAT in a cohort of patients with active rheumatoid arthritis.
Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry.
Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation.
Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up‐regulation of inhibitory pathways, or suppressing inflammatory paths.
PMCID: PMC1798468  PMID: 16760256
7.  Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis 
Annals of the Rheumatic Diseases  2005;65(2):149-156.
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis.
To document Jak‐STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue.
Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3‐STAT4 were assessed.
STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6.
CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro‐apoptotic and anti‐inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti‐inflammatory effects.
PMCID: PMC1798020  PMID: 16096332
dendritic cells; rheumatoid arthritis; transcription factors
9.  Latex agglutination for rapid detection of Pseudomonas pseudomallei antigen in urine of patients with melioidosis. 
Journal of Clinical Pathology  1995;48(2):174-176.
A latex agglutination test for the detection of Pseudomonas pseudomallei antigen in urine was evaluated for the rapid diagnosis of melioidosis. With unconcentrated urine, antigen was detected in only 18% of patients with melioidosis overall. However, when urine was concentrated 100-fold, antigen was detected in 47% overall and in 67% of patients with septicaemia or disseminated infection, in whom a rapid diagnosis is most important. The specificity of the test was 100%. These results compared favourably with an enzyme immunoassay. This latex agglutination test is a simple, rapid and highly specific method of diagnosing melioidosis, and will be particularly useful in areas with limited laboratory facilities.
PMCID: PMC502402  PMID: 7538150
10.  Latex agglutination test for identification of Pseudomonas pseudomallei. 
Journal of Clinical Pathology  1993;46(4):374-375.
A latex agglutination test was developed and evaluated for the rapid presumptive identification of Pseudomonas pseudomallei, the causative organism of melioidosis. The test was 100% sensitive for 52 isolates of Ps pseudomallei and 100% specific when tested with other medically important Pseudomonas species and Enterobacteriaceae. A subsequent field trial, with clinical specimens from patients with suspected melioidosis, confirmed the sensitivity and specificity of the test.
PMCID: PMC501225  PMID: 7684405
11.  Immunofluorescence microscopy for the rapid diagnosis of melioidosis. 
Journal of Clinical Pathology  1994;47(4):377-379.
A direct immunofluorescent antibody test (DIF) was developed for the rapid diagnosis of melioidosis, a potentially fatal infection caused by Pseudomonas pseudomallei. In a clinical evaluation of 369 sputum, pus, or urine specimens from 272 patients with suspected melioidosis, the DIF had a sensitivity of 73% and a specificity of 99% compared with culture. Using this DIF, a confident diagnosis of melioidosis can now be made within two hours of admission to hospital, compared with the delay of two to four days required for culture results. Consequent early institution of specific antimicrobial therapy may help to save lives.
PMCID: PMC501950  PMID: 8027383
13.  Diagnosis of Streptococcus pneumoniae pneumonia by quantitative enzyme linked immunosorbent assay of C-polysaccharide antigen. 
Journal of Clinical Pathology  1994;47(8):749-751.
AIMS--To evaluate the use of a quantitative enzyme linked immunosorbent assay (ELISA) detecting C-polysaccharide (PnC) antigen in sputum for the diagnosis of Streptococcus pneumoniae infection. METHODS--Specimens of sputum from 60 patients with acute community and hospital acquired pneumonia and infective exacerbations of obstructive airways disease were examined by semiquantitative culture and antigen ELISA. RESULTS--Using a cutoff value of 1 microgram/ml PnC antigen for a positive result, the sensitivity of this assay was 90.3%, specificity 93.1%, predictive value of a positive result was 93.5%, and the predictive value of a negative result 89.6%. CONCLUSIONS--Quantitation of C-polysaccharide antigen in sputum by ELISA distinguishes between carriage of oral bacteria which express PnC-like antigen and infection with S pneumoniae and compares favourably with other diagnostic methods.
PMCID: PMC502151  PMID: 7962631
14.  Detection of C-polysaccharide in serum of patients with Streptococcus pneumoniae bacteraemia. 
Journal of Clinical Pathology  1995;48(9):803-806.
AIM--To investigate the fate of Streptococcus pneumoniae C-polysaccharide antigen in serum in patients with S pneumoniae bacteraemia. METHOD--In vitro dissociation experiments were performed to demonstrate that C-polysaccharide was masked by ligands in normal and acute phase serum. Serum samples from 22 patients with S pneumoniae bacteraemia were treated to dissociate immune complexes and then tested for C-polysaccharide by enzyme linked immunosorbent assay (ELISA). RESULTS--C-polysaccharide antigen was masked in normal and acute phase serum but could be released by EDTA treatment and detected by ELISA. Antigen was found in six patients ranging in concentration from 2.5 to 200 ng/ml. Patients with detectable antigen were more likely to die than those in whom antigen was not detected. CONCLUSION--This study demonstrates that C-polysaccharide antigen commonly circulates in patients with S pneumoniae bacteraemia but its presence is masked by ligands present in serum.
PMCID: PMC502865  PMID: 7490310
15.  Does steroid pulsing influence the efficacy and toxicity of chrysotherapy? A double blind, placebo controlled study. 
Annals of the Rheumatic Diseases  1990;49(6):370-372.
To test the hypothesis that early steroid pulsing augments the efficacy and decreases the toxicity of chrysotherapy 40 patients with rheumatoid arthritis were studied in a double blind, placebo controlled study. During the first three months of gold treatment group 1 received monthly intravenous methylprednisolone pulsing (steroid group) while group 2 received placebo (placebo group). All patients were assessed clinically and serologically over a 24 week period. Twelve patients were withdrawn before completion of the study and all but one of the remaining 28 patients reported clinical and serological improvements. Two patients in the steroid group were withdrawn owing to gold induced side effects while four were withdrawn in the placebo group. These small numbers were not significantly different. Minor side effects occurred more commonly in the placebo group. The clinical response was clearly better in the steroid group with statistical significance almost being achieved. In an endeavour to obtain a significant conclusion further patients will now be entered into this study.
PMCID: PMC1004102  PMID: 2116773
16.  The N-terminal domain unique to the long form of the Brn-3a transcription factor is essential to protect neuronal cells from apoptosis and for the activation of Bbcl-2 gene expression. 
Nucleic Acids Research  1998;26(18):4100-4107.
The ability of the POU family transcription factor Brn-3a to stimulate neurite outgrowth and the expression of the genes encoding neuronal proteins such as the neurofilaments and SNAP-25 has previously been shown to be dependent upon the C-terminal POU domain which can mediate both DNA binding and transcriptional activation. We show here, however, that the ability of Brn-3a to activate Bcl-2 expression and protect neuronal cells from apoptosis (programmed cell death) requires a distinct N-terminal activation domain. Bcl-2 gene activation and protection from apoptosis are thus produced only by the long form of Brn-3a which contains this domain and not by a naturally occurring short form lacking this domain or by the isolated POU domain, although all these forms of Brn-3a can stimulate neurite outgrowth. Hence Brn-3a is a multi-functional transcription factor with different regions of the factor mediating its different effects and two distinct forms with different properties being generated by alternative splicing.
PMCID: PMC147830  PMID: 9722627
20.  Diagnosis of Penicillium marneffei Infection by Quantitation of Urinary Antigen by Using an Enzyme Immunoassay 
Journal of Clinical Microbiology  1999;37(1):117-121.
Penicillium marneffei is a major cause of opportunistic infection in patients with AIDS in north and northeastern Thailand. A method for the quantitation of P. marneffei antigen in urine was developed by using fluorescein isothiocyanate-labelled purified rabbit hyperimmune immunoglobulin G in an enzyme-linked immunosorbent assay. This method was evaluated with 33 patients with culture-proven penicilliosis and 300 controls (52 healthy subjects, 248 hospitalized patients without penicilliosis) from the same area in which penicilliosis is endemic. Urinary antigen was found in all 33 (100%) patients with penicilliosis, with a median titer of 1:20,480. With undiluted samples, 67 (27%) of 248 hospital patients and 3 (6%) of 52 healthy controls were reactive. At a cutoff titer of 1:40, the urine antigen detection assay had a diagnostic sensitivity of 97% and specificity of 98% (positive predictive value, 84%; negative predictive value, 99.7%). This test offers a valuable and rapid method for the diagnosis of penicilliosis in patients with AIDS and could be a useful addition to conventional diagnostic methods in areas in which penicilliosis is endemic.
PMCID: PMC84182  PMID: 9854074
22.  Arabinose assimilation defines a nonvirulent biotype of Burkholderia pseudomallei. 
Infection and Immunity  1997;65(10):4319-4321.
Two distinct types of Burkholderia pseudomallei, differentiated by the ability to assimilate L-arabinose but with similar morphologies and antigenicities, can be isolated from soil in Thailand. Approximately 25% of soil isolates from northeast Thailand were arabinose assimilators (Ara+), but in 1,200 sequentially studied patients, only arabinose "nonassimilators" (Ara-) caused melioidosis (P < 0.0001). In a murine model, there was a striking difference in virulence between Ara- and Ara+ B. pseudomallei. The mean (standard deviation) 50% lethal dose (LD[50]) inoculum for Ara- isolates was 182 (111) CFU/mouse compared with approximately 10(9) CFU/mouse for Ara+ soil isolates. There was no significant difference between the LD(50)s for clinical and soil Ara- isolates. All attempts to convert the biochemical phenotype by selective culture failed, which suggests that the biotype is stable.
PMCID: PMC175618  PMID: 9317042
23.  Specificity and functional activity of anti-Burkholderia pseudomallei polysaccharide antibodies. 
Infection and Immunity  1997;65(9):3648-3653.
The lipopolysaccharide (LPS) of Burkholderia pseudomallei, the causative agent of melioidosis, consists of two O-antigenic polysaccharides designated O-PS I and O-PS II. In this study, the O-PS specificity and functional activity of a protective polyclonal antiserum and an immunoglobulin M (IgM) monoclonal antibody were determined. The polyclonal antiserum recognized both O-PS I and O-PS II, while the monoclonal antibody was O-PS II specific. Both mediated phagocytic killing of B. pseudomallei by polymorphonuclear leukocytes. Patients acutely infected with B. pseudomallei also produced antibodies to the two O-PSs, but these antibodies were not produced by asymptomatic individuals from an area of endemicity who were seropositive by an indirect hemagglutination test using sonicated heat-killed whole organisms as antigen. IgM antibodies were detected only in patients with localized infection. IgG antibodies were detected in all acutely infected patients, but there was no significant difference in antibody levels among patients with localized infection, patients who survived septicemic illness, and patients who died from septicemic illness. Further analysis of the IgG response revealed production of IgG1 and IgG2 antibodies by all patient groups, while an IgG3 response was seen only in survivors of septicemic infection. IgG4 was not detectable even when a fivefold-lower serum dilution was used. Patient sera also mediated phagocytic killing by polymorphonuclear leukocytes, and the killing effect was enhanced by complement. These results suggest that antibodies to the LPS O-polysaccharides of B. pseudomallei are protective by promoting phagocytic killing. The antibodies develop during human infection and may facilitate clearance of the organisms, as seen in a diabetic rat model of B. pseudomallei infection.
PMCID: PMC175519  PMID: 9284132
24.  The Brn-3a transcription factor induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins. 
Molecular and Cellular Biology  1997;17(1):345-354.
The Brn-3a POU family transcription factor is expressed only in posmitotic neurons in the central nervous system and identifies the first differentiated neurons to appear in the midbrain, hindbrain, and spinal cord during development. This factor is also induced when undifferentiated proliferating ND7 cells cease dividing and differentiate to a mature neuronal-like phenotype bearing numerous neurite processes. We show that overexpression of Brn-3a in undifferentiated ND7 cells induces a mature neuronal phenotype characterized by process outgrowth and the induction of genes encoding synaptic proteins, although the cells continue to proliferate. In contrast, the closely related factors Brn-3b and Brn-3c do not have this effect. Although the N-terminal activation domain of Brn-3a is required for maximum induction of neurite outgrowth and gene expression, these effects are primarily dependent on the DNA binding POU domain, which also acts as an activation domain. Overexpression of the isolated POU domain of Brn-3a is sufficient to induce neurite outgrowth, while the ability of full-length Brn-3a to do so is abolished by mutating a single amino acid in the Brn-3a POU homeodomain to its equivalent in Brn-3b. Thus, Brn-3a appears to play a critical role in the specification of the mature neuronal phenotype, acting by stimulating the expression of genes whose products are required for process outgrowth and synapse formation.
PMCID: PMC231759  PMID: 8972215
25.  Postantibiotic effects and Burkholderia (Pseudomonas) pseudomallei: evaluation of current treatment. 
Antimicrobial Agents and Chemotherapy  1995;39(10):2356-2358.
The postantibiotic effects (PAEs) OF 16 antibiotics or antibiotic combinations currently used against Burkholderia (Pseudomonas) pseudomallei were determined. The beta-lactams had zero PAEs, while the carbapenems and ciprofloxacin induced median PAEs of 1 and 5 h, respectively. These results emphasize the need to maintain antibiotic levels above inhibitory concentrations in blood throughout the dosing interval in cases of severe melioidosis.
PMCID: PMC162945  PMID: 8619598

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