The Model for End-stage Liver Disease score is potentially a useful predictor of hyperkalemia occurrence among hospitalized angiotensin receptor blocker users.

WHAT IS KNOWN AND OBJECTIVE: Angiotensin receptor blockers (ARBs) are medications commonly used for treating conditions such as hypertension. However, ARBs are frequently associated with hyperkalemia, a potentially critical adverse event, in high-risk patients. Although both the liver and the kidney are major elimination routes of ARBs, the relationship between hepatorenal function and ARB-related hyperkalemia has not yet been investigated. The purpose of this study was to evaluate the risk of hyperkalemia, in terms of various hepatorenal functions, for hospitalized patients newly initiated on ARB treatment. METHODS: We evaluated ARB-related hyperkalemia in a cohort of 5530 hospitalized patients, who had not previously used ARBs, between 12 April 2004 and 31 May 2012. Hepatorenal function was assessed by the Model for End-stage Liver Disease (MELD) score. Hyperkalemia risk was assessed by hepatorenal function, risks were categorized into the four MELD scoring groups, and the groups were compared with one another. RESULTS AND DISCUSSION: The MELD score was significantly different between the hyperkalemic and non-hyperkalemic groups (independent t-test, P < 0.001). The MELD score 10-14, 15-19 and ≥ 20 groups showed higher risks of hyperkalemia than the lowest MELD score group {log-rank test, P < 0.001; multiple Cox proportional hazard model, hazard ratios 1.478 (P = 0.003), 2.285 (P < 0.001) and 3.024 (P < 0.001), respectively}. WHAT IS NEW AND CONCLUSION: The MELD score showed a stronger predictive performance for hyperkalemia than either serum creatinine or estimated glomerular filtration rate alone. Furthermore, the MELD score showed good predictive performance for ARB-related hyperkalemia among hospitalized patients. The clinical implications and reasons for these findings merit future investigation.

Onset time of hyperkalaemia after angiotensin receptor blocker initiation: when should we start serum potassium monitoring?

WHAT IS KNOWN AND OBJECTIVE: Angiotensin receptor blockers (ARBs) frequently induce hyperkalaemia in high-risk patients. Early detection of hyperkalaemia can reduce the subsequent harmful effects. This study was performed to examine the onset time of hyperkalaemia after ARB therapy. METHODS: We carried out a retrospective analysis to determine the onset time of hyperkalaemia (serum potassium >5·5 mm) among hospitalized patients newly starting ARB therapy between 2004 and 2012, in a tertiary teaching hospital. Predefined possible risk factors and concomitant medications were evaluated. RESULTS AND DISCUSSION: During the 97-month study period, a total of 4267 hospitalized patients started ARBs as new drugs and 225 patients showed hyperkalaemia. A significantly increased risk of hyperkalaemia was detected among patients with a high baseline potassium [odds ratio (OR) 6·0] and those who took non-potassium-sparing diuretics (OR 2·2) or potassium supplements (OR 1·6). A high glomerular filtration rate (GFR) was associated with a lower risk of hyperkalaemia (OR 0·992). Fifty-two percentage of hyperkalaemic events occurred within the first week after initiation of ARB therapy. The highest frequency of hyperkalaemia occurred on the first day after initiation of ARBs. Hyperkalaemia occurred earlier in patients with a high baseline serum potassium level, reduced GFR, diabetes and in those without heart failure. WHAT IS NEW AND CONCLUSION: Hyperkalaemia occurs most frequently at the beginning of ARB therapy in hospitalized patients. Monitoring of serum potassium and estimated GFR after initiation of ARBs should be started within a few days or not later than 1 week, especially in patients with risk factors.

Airflow limitation as a risk factor for vascular stiffness.

BACKGROUND: Cardiovascular disease is one of the main causes of mortality in patients with chronic obstructive pulmonary disease (COPD), and atherosclerosis is a cause of cardiac comorbidities in COPD. However, it is not clear whether airflow limitation is associated with atherosclerosis irrespective of smoking.OBJECTIVE: To investigate whether airflow limitation is independently associated with vascular stiffness.METHODS: We enrolled 18 893 participants (male 70.5%; mean age 47.5 ± 9.8 years; never smokers 44.2%) who underwent spirometry and brachial-ankle pulse wave velocity (baPWV) as part of a standard health examination at Ajou University Hospital, Suwon, South Korea, from January 2010 to December 2015.We defined vascular peripheral atherosclerosis as baPWV ≥ 1400 cm/s and airflow limitation as pre-bronchodilator ratio of forced expiratory volume in 1 sec (FEV1) to forced vital capacity (FVC) <70%.RESULTS: Mean baPWV was higher in subjects with airflow limitation (1477.6 ± 331.7 cm/sec, n = 638) than in those without airflow limitation (1344.1 ± 231.8 cm/sec, n = 18255, P < 0.001). In multivariate logistic regression analysis, the following were independent predictors associated with peripheral atherosclerosis (P < 0.05): age, male sex, fasting serum glucose, mean blood pressure, serum leukocyte count, serum low density lipoprotein level and FEV1.CONCLUSION: Airflow limitation was an independent predictor of vascular stiffness irrespective of smoking history, which suggests that airflow limitation is linked with atherosclerosis.

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor.

Rapid phagocytic clearance of apoptotic cells is crucial for the prevention of both inflammation and autoimmune responses. Phosphatidylserine (PS) at the external surface of the plasma membrane has been proposed to function as a general 'eat me' signal for apoptotic cells. Although several soluble bridging molecules have been suggested for the recognition of PS, the PS-specific membrane receptor that binds directly to the exposed PS and provides a tickling signal has yet to be definitively identified. In this study, we provide evidence that stabilin-2 is a novel PS receptor, which performs a key function in the rapid clearance of cell corpses. It recognizes PS on aged red blood cells and apoptotic cells, and mediates their engulfment. The downregulation of stabilin-2 expression in macrophages significantly inhibits phagocytosis, and anti-stabilin-2 monoclonal antibody provokes the release of the anti-inflammatory cytokine, transforming growth factor-beta. Furthermore, the results of time-lapse video analyses indicate that stabilin-2 performs a crucial function in the rapid clearance of aged and apoptotic cells. These data indicate that stabilin-2 is the first of the membrane PS receptors to provide tethering and tickling signals, and may also be involved in the resolution of inflammation and the prevention of autoimmunity.

Regulation of type I collagen genes expression.

Type I collagen, the most abundant protein of the body, is preferentially synthesized in bone, dermis, and tendons by two cell types, the osteoblast and the fibroblast. The expression of type I collagen is increased in the various forms of fibrosis such as lung, liver, bone marrow fibrosis and scleroderma. Type I collagen is a heterotrimer molecule consisting of two alpha 1(I) chains and one alpha 2(I) chain. The two polypeptide chains are synthesized in a 2:1 stoichiometry. The same 2:1 ratio is observed for the rate of synthesis of the corresponding mRNAs. One hypothesis that would explain how this coregulation occurs at the transcriptional level is that common cis-acting elements are present on both genes. These common regulatory elements would bind identical transcription factors displaying the same function. The characterization of the various regulatory elements present in these genes would foster our understanding of the molecular mechanisms controlling type I collagen gene expression in normal and in pathological situations. Over the past few years, several laboratories have identified cis-acting elements in the promoters of the COL1A1 and COL1A2 genes. At least, two of these cis-acting elements are common to both promoters. One is centered by a pentanucleotide CCAAT and binds a ubiquitously expressed heteromeric CCAAT binding factor. A second one is centered by a G-rich region and it binds a new transcription factor called C-Krox.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of fibronectin gene expression by cyclic AMP and phorbol myristate acetate in HT-1080 human fibrosarcoma cells.

We studied the regulation of fibronectin (FN) gene expression by cAMP and phorbol-12-myristate-13-acetate (PMA) in HT-1080 human fibrosarcoma cells. Dibutyryl cAMP increased FN synthesis and mRNA levels, while PMA inhibited the cAMP-induced FN synthesis. In transient transfection assays, cAMP increased FN promoter activity, while PMA paradoxically enhanced the cAMP-induced promoter activity. Stable transfection experiments, however, showed that neither cAMP or PMA alone nor together affected FN promoter activity. These results suggest that PMA antagonizes the cAMP-induced FN gene expression and that both the action of cAMP and the inhibition of its action by PMA may occur at the posttranscriptional level in HT-1080 cells.

Induction of fibronectin gene expression by inhibitors of protein phosphatase type 2B in normal and transformed fibroblasts.

Two intracellular signal pathways mediated by cAMP and protein kinase C (PKC) were involved in the regulation of FN gene expression (Lee et al., Exp. Mol. Med. 30: 240, 1998). In this study, a possible involvement of protein phosphatase-dependent pathways in the regulation of FN gene expression was investigated by using protein phosphatase type 2B (PP2B) inhibitors, cyclosporin A and ascomycin. Both cyclosporin A and ascomycin increased the levels of FN mRNA in WI-38 human lung fibroblasts and the SV40-transformed WI-38 cells but not in MC3T3-E1 osteoblasts. The expression of FN appears to increase from six hours up to 48 hours after treatment suggesting that it is not an immediate effect. In addition, this effect required a new protein synthesis. Neither cyclosporin A nor ascomycin affects the phorbol myristate acetate (PMA)-induced stimulation of FN gene expression and the same result occurred in vice versa suggesting the mechanism of PMA and cyclosporin A/ascomycin in the regulation of FN gene expression may share a common downstream pathway. Taken together, this study suggests that PP2B is involved in the regulation of FN gene expression in normal and transformed fibroblasts but not in osteoblasts.

Transcriptional repression of type I procollagen genes during adipocyte differentiation.

Adipocyte differentiation is a very complex process in which whole-cell changes are accompanied. Among them, type I procollagen gene has been shown to specifically decrease during adipocyte differentiation; however, little is known about the molecular mechanism. To examine how type I procollagen gene expression is regulated at the level of transcription during adipocyte differentiation, 3T3-L1 preadipocyte cell line was used as an in vitro model. Northern blot analysis demonstrated that mRNA expression of type I procollagen gene was dramatically reduced during adipocyte differentiation. Time-course analysis indicated that decrease in mRNA expression occurred at early stage of differentiation. Studies on several stable cell lines showed that transcriptional activities of both alpha1 and alpha2 promoters decreased significantly during adipocyte differentiation. Despite extensive deletion-promoter analyses, however, we could not identify the cis-element responsible for the switch-off of type I procollagen gene during adipocyte differentiation, suggesting that the transcriptional repression of this gene occur through general transcription machinery rather than a specific cis-element. In conclusion, down-regulation of type I procollagen mRNA expression during adipocyte differentiation is due to repression of its promoter activity through general transcription machinery.

The isolation and nature of campylobacters (microaerophilic vibrios) from laboratory and wild rodents.

Faeces voided by eight species of laboratory or feral rodents were cultured for campylobacters by means of selective methods. Campylobacters were isolated from bank voles and from rats, but not from rabbits, laboratory mice, hamsters, guinea-pigs, field mice or field voles. In routine biochemical tests isolates from bank voles resembled a type of Campylobacter fetus that causes infectious infertility in cattle; isolates from rats resembled Campylobacter coli associated with swine dysentery. Electrophoretograms of acid plus phenol soluble proteins revealed striking differences between isolates from rodents, C. fetus and C coli. It is concluded that campylobacters are more widespread in rodents than hitherto realised, and that routine methods for differentiating campylobacters do not allow an adequate correlation with pathogenicity or habitat.

The effect of the nitroimidazole drug dimetridazole on microaerophilic campylobacters.

Dimetridazole, a nitroimidazole drug reported to act only on obligately anaerobic micro-organisms, is widely used for the prevention and treatment of swine dysentery. Forty-four strains of the microaerophilic bacterium Campylobacter coli isolated from either healthy or diseased pigs, and a strain of Campylobacter fetus, were all sensitive to dimetridazole. The sensitivities (minimal inhibitory concentration less than 10 microng per ml) were similar to those of anaerobic bacteria. Dimetridazole inhibited growth of campylobacters in a shaken culture in air, but did not inhibit uptake of oxygen. Inhibition of growth appeared to result from an inhibition of nucleic-acid synthesis and does not seem to depend upon interference with electron transport in the catabolism of pyruvate.

Serotyping of campylobacters by co-agglutination on the basis of heat-stable antigens.

A new and simple method of serotyping campylobacters has been developed which utilises co-agglutination to detect the presence of heat-stable antigens. Campylobacters are heated at 75 degrees C for 30 min to destroy antigenic protein and allowed to react on a glass slide with staphylococci coated with antibody. Of 74 isolates, 67 gave the same result by co-agglutination and the previously described passive haemagglutination method. The co-agglutination technique may be used as a rapid screening test before serotyping by passive haemagglutination.

The effect of early therapeutic electrical stimulation on bone mineral density in the paralyzed limbs of the rabbit.

The purpose of this animal experiment was to evaluate the changes of bone mineral density in paralyzed limbs, and to assess the effects of electrically stimulating muscle contraction upon bone mineral density (BMD) in paralyzed limbs during the four week period immediately following spinal cord injury (SCI). Ten rabbits were used for the study, spinal cords were totally transected at the T11 spine level. The paralyzed quadriceps femoris of one limb was contracted by electrical stimulation for 60-minutes daily, while the other side was not stimulated as a control. The BMD of each lower limb was measured by Dual Photon Absorptiometry before and four weeks after acute SCI. BMD of both limbs decreased in all rabbits four weeks after SCI. The decrease in BMD for stimulated and non-stimulated limbs was 6.130 +/- 3.212% and 9.098 +/- 3.831%, respectively during the four-week period after SCI. The BMD of stimulated limbs decreased significantly less than that of the non-stimulated limbs. Electrically induced muscular contraction reduced bone mineral loss in the paralyzed limb during the early stage of SCI in the rabbit.

A case of nephrogenic diabetes insipidus caused by obstructive uropathy due to prostate cancer.

Nephrogenic diabetes insipidus (DI) secondary to chronic urinary tract obstruction is a rare disease. The exact cause is unknown but it is likely that increased collecting duct pressures cause damage to the tubular epithelium, resulting in insensitivity to the action of arginine-vasopressin (AVP). A 77-year-old man complaining of polyuria and polydipsia was treated with alpha glucosidase inhibitor under the impression of polyuria due to diabetes mellitus. But his symptoms did not improve. Water deprivation and AVP administration study revealed that the patient had nephrogenic DI. Urinary tract obstruction due to an enlarged prostate was suggested as a principal cause of nephrogenic DI. The patient underwent transurethral resection of the prostate and bilateral subcapsular orchiectomy. After surgery, the urine osmolarity was normalized and the patient became symptom-free. We report a case of nephrogenic DI due to obstructive uropathy which was cured by surgery eliminating obstruction.

Detection of adverse drug reaction signals using an electronic health records database: Comparison of the Laboratory Extreme Abnormality Ratio (CLEAR) algorithm.

Electronic health records (EHRs) are expected to be a good source of data for pharmacovigilance. However, current quantitative methods are not applicable to EHR data. We propose a novel quantitative postmarketing surveillance algorithm, the Comparison of Laboratory Extreme Abnormality Ratio (CLEAR), for detecting adverse drug reaction (ADR) signals from EHR data. The methodology involves calculating the odds ratio of laboratory abnormalities between a specific drug-exposed group and a matched unexposed group. Using a 10-year EHR data set, we applied the algorithm to test 470 randomly selected drug-event pairs. It was found possible to analyze a single drug-event pair in just 109 ± 159 seconds. In total, 120 of the 150 detected signals corresponded with previously reported ADRs (positive predictive value (PPV) = 0.837 ± 0.113, negative predictive value (NPV) = 0.659 ± 0.180). By quickly and efficiently identifying ADR signals from EHR data, the CLEAR algorithm can significantly contribute to the utilization of EHR data for pharmacovigilance.

Construction of an open-access QT database for detecting the proarrhythmia potential of marketed drugs: ECG-ViEW.

Information about the QT interval from surface electrocardiograms (ECGs) is essential for surveillance of the proarrhythmia potential of marketed drugs. However, ECG records obtained in daily practice cannot be easily used for this purpose without labor-intensive manual effort. This study was aimed at constructing an open-access QT database, the Electrocardiogram Vigilance with Electronic Data Warehouse (ECG-ViEW). This longitudinal observational database contains 710,369 measurements of QT and associated clinical data from 371,401 patients. The de-identified database is freely available at http://www.ecgview.org.

Rectal culture screening for vancomycin-resistant enterococcus in chronic haemodialysis patients: false-negative rates and duration of colonisation.

Infection or colonisation with vancomycin-resistant enterococci (VRE) is common in chronic haemodialysis (HD) patients. However, there is limited information on the duration of VRE colonisation or on the reliability of consecutive negative rectal cultures to determine the clearance of VRE in chronic HD patients. Chronic HD patients from whom VRE was isolated were examined retrospectively. Rectal cultures were collected more than three times, at least one week apart, between 1 June 2003 and 1 March 2010. The results of the sequential VRE cultures and patients' data were analysed. Among 812 patients from whom VRE was isolated, 89 were chronic HD patients and 92 had three consecutive negative cultures. It took 60.7 ± 183.9 and 111.4 ± 155.4 days to collect three consecutive negative cultures in the 83 non-chronic haemodialysis patients and nine chronic HD patients, respectively (P = 0.011). The independent risk factors for more than three negative sequential rectal cultures were glycopeptide usage [odds ratio (OR): 2.155; P = 0.003] and length of hospital stay (OR: 1.009; P = 0.001). After three consecutive negative rectal cultures, two of six chronic HD patients and 10 of 36 non-HD patients were culture positive again. In conclusion, a significant proportion of patients colonised with VRE cannot be detected by three-weekly rectal cultures, and the duration of VRE colonisation in chronic haemodialysis patients tends to be prolonged. These results may be contributing to the continued increase in the prevalence of VRE.

Acute diarrheal syndromic surveillance: effects of weather and holidays.

OBJECTIVE: In an effort to identify and characterize the environmental factors that affect the number of patients with acute diarrheal (AD) syndrome, we developed and tested two regional surveillance models including holiday and weather information in addition to visitor records, at emergency medical facilities in the Seoul metropolitan area of Korea. METHODS: With 1,328,686 emergency department visitor records from the National Emergency Department Information system (NEDIS) and the holiday and weather information, two seasonal ARIMA models were constructed: (1) The simple model (only with total patient number), (2) the environmental factor-added model. The stationary R-squared was utilized as an in-sample model goodness-of-fit statistic for the constructed models, and the cumulative mean of the Mean Absolute Percentage Error (MAPE) was used to measure post-sample forecast accuracy over the next 1 month. RESULTS: The (1,0,1)(0,1,1)7 ARIMA model resulted in an adequate model fit for the daily number of AD patient visits over 12 months for both cases. Among various features, the total number of patient visits was selected as a commonly influential independent variable. Additionally, for the environmental factor-added model, holidays and daily precipitation were selected as features that statistically significantly affected model fitting. Stationary R-squared values were changed in a range of 0.651-0.828 (simple), and 0.805-0.844 (environmental factor-added) with p<0.05. In terms of prediction, the MAPE values changed within 0.090-0.120 and 0.089-0.114, respectively. CONCLUSION: The environmental factor-added model yielded better MAPE values. Holiday and weather information appear to be crucial for the construction of an accurate syndromic surveillance model for AD, in addition to the visitor and assessment records.

Development of a Decision Support Model for Screening Attention-deficit Hyperactivity Disorder with Actigraph-based Measurements of Classroom Activity.

OBJECTIVE: Questionnaire-based ADHD screening tests may not always be objective or accurate, owing to both subjectivity and prejudice. Despite attempts to develop objective measures to characterize ADHD, no widely applicable index currently exists. The principal aim of this study was to develop a decision support model for ADHD screening by monitoring children's school activities using a 3-axial actigraph. METHODS: Actigraphs were placed on the non-dominant wrists of 153 children for 3 hours, while they were at school. Children who scored high on the questionnaires were clinically examined by child psychiatrists, who then confirmed ADHD. Mean, variance, and ratios of low-level (0.5-1.0G) and high-level (1.6-3.2G) activity were extracted as activity features from 142 children (10 ADHD, 132 non-ADHD). Two decision-tree models were constructed using the C5.0 algorithm: [A] from whole hours (class + playtime) and [B] during classes. Accuracy, sensitivity, and specificity were evaluated. PPV, NPV, likelihood ratio, and AUC were also calculated for evaluation. RESULTS: [Model A] One child without ADHD was misclassified, resulting in an accuracy score of 99.30%. Sensitivity and NPV were 1.0000. Specificity and PPV were 0.992 and 0.803-0.909, respectively. [Model B] Two children without ADHD were misclassified, resulting in an accuracy score of 98.59%. Specificity and PPV were scored at 0.985 and 0.671-0.832, respectively. CONCLUSION: The selected features were consistent with the findings of previous studies. Objective screening of latent patients with ADHD can be accomplished with a simple watch-like sensor, which is worn for just a few hours while the child attends school. The model proposed herein can be applied to a great many children without heavy cost in time and manpower cost, and would generate valuable results from a public health perspective.

Mesenteric vascular occlusion and varices complicating midgut malrotation.

Long-standing complete obstruction of the superior mesenteric artery and vein and recurrent gastrointestinal bleeding from varices within the bowel were encountered in a child as a complication of midgut malrotation and volvulus. This condition is unusual, but should be considered in cases of gastrointestinal bleeding, or when small bowel biopsy is contemplated for the evaluation of diarrhea or malabsorption in cases of malrotation.