Risk of tuberculosis comparison in new users of antitumour necrosis factor-α and with existing disease-modifying antirheumatic drug therapy.

WHAT IS KNOWN AND OBJECTIVE: Patients with rheumatic disease are at risk for infections. Evaluating antitumour necrosis factor (anti-TNF) drug-associated risk of infections requires justification of baseline risk in the population at high risk of infection. We examined the incidence of active tuberculosis (TB) and its risk factors in patients with rheumatic disease started with anti-TNF-α therapy or with existing disease-modifying antirheumatic drug (DMARD) therapy. METHODS: A retrospective cohort study of anti-TNF-α therapy new users (anti-TNF-α group) and those starting with a DMARD after the failure of at least one other DMARD or who had added to existing DMARD treatment (DMARD group) for rheumatic disease in the largest medical setting in Taiwan from 1 January 2005 through 31 November 2013 was conducted to determine relative risk of TB between patient groups. Patients in the DMARD group were stratified into "mild" and "severe" disease severity as proxies for low and high background risk of infection. RESULTS AND DISCUSSION: A total of 3640 patients were enrolled (anti-TNF: 955; DMARD: 2685). The incidence of TB was 903.9/100 000 patient-years for anti-TNF-α new users and 391.7/100 000 patient-years for DMARD switchers. In Cox regression model, adjusted HR for TB in the anti-TNF-α group was higher than for the entire DMARD group (aHR, 2.41; 95% confidence interval [CI], 1.2-4.85), subgroup with mild disease (2.91; 1.31-6.47) and subgroup with severe disease (1.65; 0.68-4.03). Significant independent risk factors for TB were being male, age ≥60 years, history of respiratory disease, glucocorticoids dose >7.5 mg/d and living in a TB-prevalent region. WHAT IS NEW AND CONCLUSION: Anti-TNF-α therapy was independently associated with increased risk of TB in patients with mild disease, but it was not significantly correlated in patients with severe disease after adjusting for confounders.

A retrospective analysis of the factors associated with hypercalcaemia in patients with advanced cancer.

Hypercalcaemia, a common complication of advanced cancer, causes multiple clinical symptoms, deteriorates patients' quality of life, and is associated with poor prognoses. This study aimed to identify the factors that may be associated with hypercalcaemia in advanced cancer by retrospectively reviewing the medical records of patients (n = 404) admitted to the palliative ward of the Kaohsiung Medical University Hospital, Taiwan, from 2006 to 2008. Patients' demographics, clinical data and symptoms were recorded. Seventy-nine of 404 patients had hypercalcaemia (19.6%), predominant in cases of head-and-neck cancer and haematological malignancies (P < 0.05), but not in those of bone metastases. Hypercalcaemia was associated with consciousness disturbances and leucocytosis (P < 0.05). We recommend that ionised (corrected) calcium levels be monitored clinically in patients with advanced cancer especially when consciousness disturbances are noted, or when head-and-neck or haematological malignancies are present. Testing of free calcium levels is also recommended in patients with leucocytosis.

Possible association of nicotinic acetylcholine receptor gene (CHRNA4 and CHRNB2) polymorphisms with nicotine dependence in Japanese males: an exploratory study.

INTRODUCTION: Smoking is a leading global cause of avoidable mortality. It has been reported that the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2) genes might be associated with smoking behavior in several ethnic populations. However, no study between the 2 genes and nicotine dependence (ND) using a Japanese population has been reported. METHODS: We examined the association between ND and 5 single nucleotide polymorphisms (SNPs) within the CHRNA4 and 3 SNPs within the CHRNB2 using a well characterized sample of 558 Japanese healthy male workers with a relatively homogeneous background. The Fagerström test for nicotine dependence (FTND) was used to quantify the degree of ND. Additionally, we explored the effect of gene-gene interactions of the 2 genes on ND. RESULTS: We found CHRNB2 rs4845652 genotypes to be associated with FTND scores under an additive genetic model: rs4845652 T-allele carriers had lower ND levels (p=0.038; when adjusted for smoking duration: p=0.052). Furthermore, we demonstrated a possible gene-gene interaction of CHRNA4 and CHRNB2 on ND in a dose-dependent manner: those smokers with CHRNA4 rs1044397 GG or GA genotypes along with CHRNB2 rs4845652 CC genotype are likely to demonstrate higher ND scores. DISCUSSION: These findings suggest that CHRNB2 rs4845652 T-allele carriers may be associated with lower levels of ND, and that certain allelic combinations of CHRNA4 and CHRNB2 might be correlated with higher ND levels. This preliminary study has certain limitations (issues such as sample size/power and multiple testing) that need to be taken into account, and the present work thus has an experimental nature.

Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide ß-endorphin, via STAT3/calcium axis in atopic dermatitis.

BACKGROUND: Itch is the cardinal symptom of atopic dermatitis (AD). ß-Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and ß-endorphin interact in AD skin remains elusive. OBJECTIVES: To investigate the mechanistic interaction of IL-31 and ß-endorphin in AD. METHODS: This was a prospective cross-sectional study. We recruited adult patients with AD and controls according to Hanifin's AD criteria. Serum levels of IL-31 and ß-endorphin were measured by enzyme-linked immunosorbent assay. Expressions of IL-31 receptor A (IL-31RA) and ß-endorphin in the skin were assessed by immunohistochemistry. Their expression in the skin and blood was compared and correlated in patients with AD and in controls. We also treated primary keratinocytes with IL-31 and measured calcium influx, ß-endorphin production and signalling pathways to define their mechanistic interactions. RESULTS: ß-Endorphin was increased in the supernatant from IL-31-treated keratinocytes. IL-31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of ß-endorphin. Notably, either replacement of extracellular calcium or treatment with 2-aminoethoxydiphenyl borate, an inhibitor for the store-operated channel, blocked STAT3 activation. We found higher levels of blood ß-endorphin and IL-31, which were significantly correlated, in patients with AD. Moreover, IL-31RA and ß-endorphin were increased and colocalized both in AD human skin and TPA-painted mouse skin. CONCLUSIONS: IL-31 receptor activation in keratinocytes induces calcium influx and STAT3-dependent production of ß-endorphin. These results might contribute to an understanding of the regulatory mechanisms underlying peripheral itch.

Lifetime exposure to cigarette smoking and the development of adult-onset atopic dermatitis.

BACKGROUND: Adult-onset atopic dermatitis (AD) has recently been recognized as a distinct disease entity, but its risk factors have not yet been clearly defined. Although gestational and perinatal exposure to tobacco smoking may be associated with the development of classic AD, the association between active/passive smoking and adult-onset AD remains controversial. OBJECTIVES: To determine if exposure to smoking, including environmental tobacco smoke (ETS), is associated with the risk of adult-onset AD. METHODS: Tobacco smoking and exposure to ETS were measured in a case-control association analysis in 83 patients with physician-diagnosed adult-onset AD and 142 age- and sex-matched controls. RESULTS: Multiple logistic regression analyses showed that, among the potential environmental risk factors, both current and ever smoking were significant risk factors for adult-onset AD [odds ratio (OR) 4·994 and 3·619, respectively], compared with never smoking. Also, packs per year was significantly associated with adult-onset AD (OR 1·058, 95% confidence interval 1·028-1·089), suggesting a lifelong cumulative risk in current smokers. Moreover, nonsmokers with adult-onset AD reported significantly more exposure to ETS. CONCLUSIONS: Early and/or current exposure to cigarette smoking may contribute cumulatively to the development of adult-onset AD. Exposure to ETS in childhood is associated with the development of adult-onset AD. Adults should be discouraged from smoking to prevent adult-onset AD in themselves and their family members.

Prognostic Impact of Delirium in Older People With/Without Dementia: A Retrospective Cohort Study in Taiwan.

OBJECTIVES: To elucidate the hypothetically different interactions between delirium and post-discharge prognostic indicators in elderly hospital inpatients with versus without dementia. DESIGN: Retrospective cohort study of claims data by Taiwan National Health Insurance beneficiaries between 2002-2013. SETTING: Records of public hospital admissions in the Taiwan National Health Insurance Research database. PARTICIPANTS: Propensity-score matched subgroups of patients with delirium superimposed on dementia (n = 922) versus dementia alone (n = 922), delirium alone (n = 680) versus neither delirium nor dementia (n = 680). MEASUREMENTS: Mortality, emergency department visits, readmissions, and psychotropic drug use, within 30, 180, and 365 days of discharge, were analyzed using multivariate proportional hazards or logistic regression analyses. RESULTS: Delirium superimposed on dementia was not associated with increased post-discharge mortality, or emergency department visits, but significantly increased the risk of readmissions at 365-day follow-up (adjusted HR, 95% CI: 1.26, 1.01-1.56). However, delirium without dementia was significantly associated with increased post-discharge mortality, emergency department visits and readmissions at 180 days and 365 days (respective adjusted HRs: mortality, 1.63 and 1.79; adjusted ORs: emergency department visits, 1.89 and 1.81; readmissions, 1.47 and 1.53). Delirium in patients both with dementia and without, was associated with six-fold higher likelihood of in-hospital psychotropic drug use, and doubled post-discharge psychotropic drug usage. CONCLUSIONS: The obvious association between in-hospital delirium and worsened long-term prognosis, irrespective of dementia, raises awareness to warrants proactive and multimodal prevention and intervention strategies. Furthermore, the mechanisms about different influence of delirium for patients with/without dementia need to be further explored.

Factors influencing women's quality of life in the later half of life.

BACKGROUND: Among older women in East Asia, and Taiwan in particular, there is little research on quality of life and the health care they receive to address the symptoms of menopause. This study evaluated factors which influence quality of life among post middle-age women in Taiwan. METHODS: This cross-sectional study recruited 1250 women between 43 and 77 years of age during the year 2002. The factors investigated were demographics, menstruation status, menopausal symptoms, osteoporosis status, and use of hormone replacement therapy (HRT). SF-36 was used to assess the health-related quality of life of these women. Correlation, multiple regression and path analysis were used to test for direct and indirect relationships among the variables. RESULTS: There are statistical significances between menopause symptoms and quality of life across different age groups. Path analysis shows a direct positive effect of HRT and a direct negative effect of climacteric symptoms on both physical and mental components of quality of life. Age, marital status, education and osteoporosis also have direct and indirect effects, some positive and others negative, on the components of quality of life. CONCLUSIONS: When developing programs to enhance health in post middle-age women, consideration should be given to symptom relief as well as quality of life.

Acute effect of ionic high osmolar contrast medium on renal antioxidant enzyme activity in streptozotocin-induced diabetic rats.

Acute contrast medium-induced nephrotoxicity was estimated in 3%-12% of patients receiving cardiac angiography, especially in advanced age, renal insufficiency and diabetic patients. As intrinsic renal antioxidant enzyme activities may play a crucial role in defence against renal oxidant injury, this study was designed to investigate the acute effect of ionic high osmolar diatrizoate meglumine/diatrizoate sodium on renal antioxidant activities in normal or streptozotocin (STZ)-induced diabetic rats at two time points (1 h and 24 h). A total of 40 Wistar rats were separated to normal and STZ-induced diabetic groups. Ten of each group were injected with diatrizoate (10 ml/kg) via tail vein and 10 with 10 ml/kg of 0.9% NaCl as control. This study shows that diabetic rats had higher renal glutathione peroxidase (GPx) activities than those of normal rats. GPx activities decreased significantly after diatrizoate injection at the first hour (717.4+/-104.0 to 578.6+/-92.1 mU/mg in the diabetic group, 466.4+/-30.6 to 371.4+/-75.5 mU/mg in the normal group, all P=0.032) but the difference faded 24 h later. The increase of superoxide dismutase (SOD) activities was enhanced (673.5+/-100.2 to 750.4+/-129.8 U/mg, P=0.04) in the normal group, but not in the diabetic group (624.1+/-156.6 to 671.1+/-136.7 U/mg, P=0.15) after diatrizoate injection at the first hour. At 24 h, renal SOD activities were still significantly higher in the diatrizoate injection group. In summary, intrinsic renal antioxidant activities are adapted in STZ-induced diabetes and ionic high osmolar diatrizoate could modify their activities. Furthermore, diabetics have abnormal response of renal antioxidant activities by contrast media and are at risk for contrast-mediated nephrotoxicity.

The subcellular distribution and partial characterization of cholinesterase activities of canine platelets.

The multiple cholinesterase activities in canine platelets have been investigated. Platelets were homogenized by rapid decompression under nitrogen, glass tube/Teflon pestle, and glycerol lysis techniques. Rapid decompression under nitrogen technique was found to be the most efficient and gentle method for cell disruption. Homogenates were subfractionated using sodium diatrizoate density gradients. Marker enzyme assays and pulse labeling experiments with 5-hydroxyl[14C] tryptamine and [125I] thrombin on prepared subcellular fractions confirmed that the soluble, plasma membrane and the granule-1 fractions were all in reasonably pure form. Furthermore, labeling of the plasma membrane with [125I] thrombin is cited as the first successful attempt at attaining significantly bound marker for this structure. Cholinesterase activity distributions measured in these fractions indicated that about 30% of the activity was present in the plasma membrane, 50% in granule-1 and 5% in soluble fractions. Kinetic data of cholinesterase activities obtained from intact platelets, plasma membrane preparations and platelet release supernatants indicated that they are strikingly similar.

Color Doppler ultrasound detection and classification of the tangential hepatic vein before laparoscopic cholecystectomy.

BACKGROUND: Unexpected fatal bleeding from the gallbladder bed during laparoscopic cholecystectomy is often associated with injury to the middle hepatic vein. This paper studies whether preoperative color Doppler ultrasound is effective in reducing the risk of injury. Also a venous classification is suggested. METHODS: Between June 1999 and February 2004, 2,146 patients undergoing laparoscopic cholecystectomy by standard method received preoperative color Doppler ultrasound examinations. The closest distance between the hepatic vein and the gallbladder was studied. Also, cases of liver cirrhosis, number of conversions to open cholecystectomy, intraoperative blood loss, operative time, complications, and hospital stay were recorded (group D). At the end of the study, we retrospectively reviewed the same parameter of another 2,146 patients who received laparoscopic cholecystectomy without preoperative color Doppler ultrasound between the period of March 1995 and June 1999 (group ND). RESULTS: In group D, 108 patients had cirrhosis. Four hundred and ninety-six patients (27 cases of cirrhosis) had a closest distance of 1 mm or less between the vein and the gallbladder. There were two conversions to open cholecystectomy, but none related to gallbladder bed bleeding. In group ND, there were five conversions, including four cases of gallbladder bed bleeding from the middle hepatic vein and one case of severe adhesion. The conversion rate was significantly higher. In group ND, the mean intraoperative blood loss in the cases of liver cirrhosis was significantly greater. Also, the operative time of patients with the closest vein and gallbladder distance of 1 mm or less in group D was significantly longer. CONCLUSIONS: Color Doppler ultrasound is an effective method for detecting the presence of potential bleeders. Although the operative time will be a bit longer, the operation can be done under meticulous care and complete preparation, so that the conversion rate and the risk of fatal hemorrhage can be reduced, especially in patients with liver cirrhosis.

An unusual case of organophosphate intoxication of a worker in a plastic bottle recycling plant: an important reminder.

A young man was sent to our emergency unit because he had suffered from vomiting and cold sweating for 2 days. At the time he was admitted, he had no acute abdominal pains or gastrointestinal symptoms, and a physical examination revealed nothing but a faster heart rate and moist, flushing skin. The patient had worked for 6 years at a plastic bottle-recycling factory, but none of his co-workers had the same symptoms. Nevertheless, because the plant also recycled pesticide bottles, we suspected organophosphate pesticide intoxication. The patient's plasma acetylcholinesterase level was checked, revealing 1498.6 microU/L (normal range: 2,000-5, 000) on the first day and 1,379 microU/L on the second day. Upon questioning, the patient recalled that one of his shoe soles had been damaged and that his foot had been wet from walking all day in rain collected on the factory floor on the day that his symptoms first occurred. We conducted a study in the change of preshift and postshift acetylcholinesterase levels among six of his co-workers on a rainy day. We used the Wilcoxon signed rank test to compare the preshift and postshift plasma acetylcholinesterase levels; no significant difference was revealed (p = 0.600), leaving contamination via the damaged shoe sole suspect. We reviewed the literature on organophosphate intoxication; pesticide bottle-recycling factories were reported to be at a low risk of organophosphate toxicity in the working environment. However, because the potential risk of intoxication is still present, protective equipment such as clothing, gloves, and water-proof shoes should be worn, and employees should be educated on the potential risks.

Interrelations of lead levels in bone, venous blood, and umbilical cord blood with exogenous lead exposure through maternal plasma lead in peripartum women.

Recent research has raised the possibility that fetal lead exposure is not estimated adequately by measuring lead content in maternal whole blood lead because of the variable partitioning of lead in whole blood between plasma and red blood cells. Lead in maternal plasma may derive in large part from maternal bone lead stores. In this study we aimed to estimate the contribution of maternal whole blood lead, maternal bone lead levels, and environmental lead to umbilical cord blood lead levels (as a measure of fetal lead exposure). In the model, we assumed that lead from all of these sources reaches the fetus through the maternal plasma lead pathway. In 1994-1995, we recruited 615 pregnant women for a study of lead exposure and reproductive outcomes in Mexico City. We gathered maternal and umbilical cord blood samples within 12 hr of each infant's delivery and measured maternal lead levels in cortical bone and trabecular bone by a K-X-ray fluorescence (K-XRF) instrument within 1 month after delivery. We administered a questionnaire to assess use of lead-glazed ceramics (LGC) to cook food and we obtained data on regional air lead levels during the 2 months before delivery. We used structural equation models (SEMs) to estimate plasma lead as the unmeasured (latent) variable and to quantify the interrelations of plasma lead, the other lead biomarkers, and environmental lead exposure. In the SEM analysis, a model that allowed plasma lead to vary freely from whole blood lead explained the variance of cord blood lead (as reflected by a total model R(2); R(2) = 0.79) better than did a model without plasma lead (r(2) = 0.67). Cortical bone lead, trabecular bone lead, use of LGC, and mean air lead level contributed significantly to plasma lead. The exchange of lead between plasma and red blood cells was mostly in the direction of plasma to cells. According to the final model, an increase in trabecular bone lead and cortical bone lead was associated with increases in cord blood lead of 0.65 and 0.25 microg/dL, respectively. An increase of 0.1 microg/m(3) in air lead was associated with an increase in the mean level of fetal cord blood lead by 0.67 microg/dL. With one additional day of LCG use per week in the peripartum period, the mean fetal blood lead level increased by 0.27 microg/dL. Our analyses suggested that maternal plasma lead varies independently from maternal whole blood lead and that the greatest influences on maternal plasma lead are maternal bone lead stores, air lead exposures, and recent cooking with LGC. The contributions from endogenous (bone) and exogenous (environmental) sources were relatively equal. Measurement of plasma and bone lead may be important in accurately assessing fetal lead exposure and its major sources, particularly if exogenous exposures decline.

Fiber-optic bronchoscopic classification of inhalation injury: prediction of acute lung injury.

BACKGROUND: Fiber-optic bronchoscopy is widely used for the early diagnosis of inhalation injury. However, there is no current bronchoscopic classification of inhalation injury for the prediction of acute lung injury (ALI). Our goal was to devise such a classification. METHODS: Between February 1993 and January 2002, 167 patients with highly suspicious inhalation injuries were collected. All patients received fiber-optic bronchoscopy within 24 h after their accident. In total, 108 patients were diagnosed as positive under direct inspection. The patients were divided into three groups (G(1), G(2), and G(3)) according to the depth of mucosal damage. Six patients were found to be positive by biopsy and were assigned to group Gb. Of these 114 positive cases, 27 developed ALI. Meanwhile, 53 patients were diagnosed as negative; these patients were assigned to group G(0). RESULTS: After analysis, the following results were noted: G(0) (n = 53), two ALI (3.8%); G(1) (n = 49), two ALI (4%); G(2) (n = 46), 15 ALI (33%); G(3)(n = 13),10 ALI (77%); Gb (n = 6), no ALI. We discovered that the deeper the mucosal injuries, the higher the rate of ALI. There were no deaths related to the procedure. CONCLUSIONS: Fiber-optic bronchoscopy is a safe and effective method for the early diagnosis of inhalation injuries. Also, it is a good predictor of ALL. We hope that in the near future, this classification will serve as a treatment guideline for the early prevention of ALI. The more severe the damage, the more alert clinicians need to be to improve the patient's chances for survival.

The endothelium: roles in thrombosis and hemostasis.

The renewed interest in endothelial function is based partly on success with tissue culture of endothelial cells. Endothelium functions primarily in the control of blood vessel wall permeability and in the provision of a blood-compatible lining surface. Recent findings indicate that endothelial cells are active metabolically in ways that may help prevent thrombosis. Endothelium actively degrades several different vasoactive compounds that circulate in blood and that can serve as platelet-aggregating agents. Endothelium also contains an inhibitor of platelet function and an activator of plasminogen, both of which can be released from the cell in response to appropriate stimuli. While intact endothelium functions primarily in prevention of thrombosis, damaged endothelium can contribute greatly to thrombus formation. Release of prostaglandins, adenine nucleotides, and other intracellular components from damaged endothelium can enhance platelet aggregation. Damaged endothelium may not function effectively in removal of vasoactive agents and may not release effective quantities of the inhibitor of platelet function or the activator of plasminogen. Altered endothelium exhibits tissue-factor activity, which can activate the extrinsic blood coagulation-system cascade. Finally, altered endothelial cells may contract and expose basement membrane to blood, thus enhancing thrombosis.

Adsorption and reactivity of human fibrinogen and immunoglobulin G on two types of hemodialysis membranes.

Phase contrast microscopic examination of Cuprophane and polyacrylonitrile. After clinical ex vivo use by uremic patients revealed extensive cellular deposition of erythrocytes, platelets, and leukocytes on Cuprophane but not on polyacrylonitrile. In vitro studies with 125I-labeled human fibrinogen or immunoglobulin G (IgG) showed that the adsorption of fibrinogen or IgG was greater on polyacrylonitrile than on Cuprophane. Further studies on the reactivity of fibrinogen adsorbed on polyacrylonitrile surface indicated that the absorbed fibrinogen: (a) was not desorbed readily from the surface, (b) was not appreciably displaced by other plasma proteins such as albumin, IgG, and fibrinogen, (c) was not readily accessible for reaction with 125I-antifibrinogen-IgG, and (d) did not promote the adhesion of 51Cr-labeled platelets. IgG adsorbed on the surface produced essentially no effect on platelet adhesion to polyacrylonitrile and promoted only slightly on the adhesion of granulocytes to the same material. On the other hand, fibrinogen and IgG augmented greatly the platelet adhesion to Cuprophane and IgG enhanced the granulocyte adhesion moderately. These data indicate that fibrinogen and IgG, though at high concentration on polyacrylonitrile, may adsorb in a biologically inactive form. Our observations suggest that the thrombogenicity of an artificial surface may not be assessed entirely by the types and amount of the various protein species adsorbed but is likely determined by the reactivity of the specific protein species adsorbed on the material.

Targeted therapy with fatty acid synthase inhibitors in a human prostate carcinoma LNCaP/tk-luc-bearing animal model.

BACKGROUND: Fatty acid synthase (FASN) is highly upregulated in human prostate carcinomas. Inhibition of FASN could arrest cell cycle and trigger apoptosis rapidly, implying the reliance of cancer cell survival on FASN. However, little is known about the effect of C75, a FASN inhibitor, and siFASN (that is, small interfering RNA targeted at FASN) on prostate cancer in living subjects. METHODS: We used C75 and siFASN to mediate the endogenous fatty acid metabolism in LNCaP human prostate cancer cells stably expressing herpes simplex virus type 1 thymidine kinase (HSV1-tk) and luciferase (luc) reporter genes, and assessed the effect of FASN blockade with different schedules of administration on tumor growth using noninvasive molecular imaging. RESULTS: FASN blockade exhibited the proliferative inhibition and induced G1-phase cell cycle arrest of LNCaP cells. For in vivo studies, the tumor growth inhibition by C75 (total 120 mgkg(-1); 30 mgkg(-1) once a week or 15 mgkg(-1) twice a week for 4 weeks) and siFASN (1.4 mgkg(-1) every alternate day up to 16 days) treatments were 80% and 70%, respectively, compared with that of the control. CONCLUSION: The results suggest that C75 may be superior to siFASN in anticancer effect on prostate cancer.