OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.

OBJECTIVE: To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data. METHODS: We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and meta-analyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation. RESULTS: Core Treatments for Knee OA included arthritis education and structured land-based exercise programs with or without dietary weight management. Core Treatments for Hip and Polyarticular OA included arthritis education and structured land-based exercise programs. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were strongly recommended for individuals with Knee OA (Level 1A). For individuals with gastrointestinal comorbidities, COX-2 inhibitors were Level 1B and NSAIDs with proton pump inhibitors Level 2. For individuals with cardiovascular comorbidities or frailty, use of any oral NSAID was not recommended. Intra-articular (IA) corticosteroids, IA hyaluronic acid, and aquatic exercise were Level 1B/Level 2 treatments for Knee OA, dependent upon comorbidity status, but were not recommended for individuals with Hip or Polyarticular OA. The use of Acetaminophen/Paracetamol (APAP) was conditionally not recommended (Level 4A and 4B), and the use of oral and transdermal opioids was strongly not recommended (Level 5). A treatment algorithm was constructed in order to guide clinical decision-making for a variety of patient profiles, using recommended treatments as input for each decision node. CONCLUSION: These guidelines offer comprehensive and patient-centered treatment profiles for individuals with Knee, Hip, and Polyarticular OA. The treatment algorithm will facilitate individualized treatment decisions regarding the management of OA.

Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice.

BACKGROUND: Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. METHODS: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. RESULTS: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. CONCLUSION: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.

Web survey-based selection of controls for epidemiological analyses of a multi-prefectural outbreak of enterohaemorrhagic Escherichia coli O157 in Japan associated with consumption of self-grilled beef hanging tender.

An outbreak of enterohaemorrhagic Escherichia coli O157 occurred in multiple prefectures of Japan in November 2009. We conducted two case-control studies with trace-back and trace-forward investigations to determine the source. The case definition was met by 21 individuals; 14 (66.7%) were hospitalised, but no haemolytic uraemic syndrome, acute encephalopathy or deaths occurred. Median age was 23 (range 12-48) years and 14 cases were male (66.7%). No significant associations with food were found in a case-control study by local public health centres, but our matched case-control study using Internet surveys found that beef hanging tender (or hanger steak), derived from the diaphragm of the cattle, was significantly associated with illness (odds ratio = 15.77; 95% confidence interval, 2.00-124.11). Pulsed-field gel electrophoresis analysis of isolates from patients and the suspected food showed five different patterns: two in faecal and food samples, and another three in patient faecal samples only, although there were epidemiological links to the meat consumed at the restaurants. Trace-back investigation implicated a common food processing company from outside Japan. Examination of the logistics of the meat processing company suggested that contamination did not occur in Japan. We concluded that the source of the outbreak was imported hanging tender. This investigation revealed that Internet surveys could be useful for outbreak investigations.

Effects of pre-surgical nasoalveolar moulding on maxillary arch and nasal form in unilateral cleft lip and palate before lip surgery.

OBJECTIVES: To investigate the effects of pre-surgical nasoalveolar moulding (PNAM) on the maxillary arch and nasal form in patients with unilateral cleft lip and palate (UCLP). SETTING AND SAMPLE POPULATION: This is a retrospective case series study. The subjects were infants with complete UCLP who were treated with PNAM (n = 18) at Kagoshima University Medical and Dental Hospital (Japan) between 2006 and 2013. MATERIAL AND METHODS: Maxillary dental casts and facial photographs were taken at the time of the first visit and immediately prior to lip surgery to evaluate the maxillary arch and nasal form changes. The dental casts were scanned with a laser scanner, and changes in the 3-Dimensional coordinates of anatomical landmarks and alveolar cleft width were analysed. Moreover, we investigated the correlation between the changes in the maxillary alveolar arch and nasal form. RESULTS: Regarding the maxillary alveolar arch form, the anterior points of the major segment had moved significantly to the cleft side just prior to the time of lip repair, and the alveolar cleft width was significantly decreased. For nasal form, the inclination and displacement of the columella were significantly improved. The improvement of columella inclination was moderately correlated with the posterior movement of the anterior points of the major segment. CONCLUSIONS: These findings indicate that PNAM for infants with UCLP enhanced symmetry in the maxillary alveolar arch and nasolabial form. In addition, the posterior movement of the anterior points of the maxillary alveolar arch was correlated with the improvement of columella deformation.

Synovial mesenchymal stem cells from osteo- or rheumatoid arthritis joints exhibit good potential for cartilage repair using a scaffold-free tissue engineering approach.

OBJECTIVE: To assess whether synovial mesenchymal stem cells (SMSCs) from patients with osteoarthritis (OA) or rheumatoid arthritis (RA) can be used as an alternative cell source for cartilage repair using allogenic tissue engineered construct (TEC). METHODS: Twenty-five patients (17 female, average age 61.8 years) were divided according to their pathology (control trauma group; N = 6, OA group; N = 6) and RA patients were subdivided into two groups to evaluate the impact of biologics in accordance with whether treated with biologics [Bio(+)RA; N = 7] or not [Bio(-)RA; N = 6]. We compared the following characteristics among these groups: (1) The cell proliferation capacity of SMSCs; (2) The influence of passage number on features of SMSCs; (3) The weight and volume of TEC from the same number of SMSCs; (4) Inflammatory cytokine gene expressions levels of TEC; (5) The chondrogenic potential of TEC; and (6) Osteochondral repair using TEC in athymic nude rats. RESULTS: SMSCs from the four groups exhibited equivalent features in the above evaluation items. In in vivo studies, the TEC-treated repair tissues for all groups exhibited significantly better outcomes than those for the untreated group and no significant differences among the four TEC groups. CONCLUSION: SMSCs from OA or RA patients are no less appropriate for repairing cartilage than those from trauma patients and thus, may be an effective source for allogenic cell-based cartilage repair.

Sulforaphane reduces advanced glycation end products (AGEs)-induced inflammation in endothelial cells and rat aorta.

BACKGROUND AND AIMS: Advanced glycation end products (AGEs)-receptor RAGE interaction evokes oxidative stress and inflammatory reactions, thereby being involved in endothelial cell (EC) damage in diabetes. Sulforaphane is generated from glucoraphanin, a naturally occurring isothiocyanate found in widely consumed cruciferous vegetables, by myrosinase. Sulforaphane has been reported to protect against oxidative stress-mediated cell and tissue injury. However, effects of sulforaphane on AGEs-induced vascular damage remain unclear. METHODS AND RESULTS: In this study, we investigated whether and how sulforaphane could inhibit inflammation in AGEs-exposed human umbilical vein ECs (HUVECs) and AGEs-injected rat aorta. Sulforaphane treatment for 4 or 24 h dose-dependently inhibited the AGEs-induced increase in RAGE, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecular-1 (VCAM-1) gene expression in HUVECs. AGEs significantly stimulated MCP-1 production by, and THP-1 cell adhesion to, HUVECs, both of which were prevented by 1.6 µM sulforaphane. Sulforaphane significantly suppressed oxidative stress generation and NADPH oxidase activation evoked by AGEs in HUVECs. Furthermore, aortic RAGE, ICAM-1 and VCAM-1 expression in AGEs-injected rats were increased, which were suppressed by simultaneous infusion of sulforaphane. CONCLUSION: The present study demonstrated for the first time that sulforaphane could inhibit inflammation in AGEs-exposed HUVECs and AGEs-infused rat aorta partly by suppressing RAGE expression through its anti-oxidative properties. Inhibition of the AGEs-RAGE axis by sulforaphane might be a novel therapeutic target for vascular injury in diabetes.

Effects of lip-closing training on maximum voluntary lip-closing force during lip pursing in healthy young adults.

To investigate the effect of lip-closing training, the time-course of multidirectional lip-closing forces during training was evaluated. The subjects were healthy young adults with no systemic disease. Ten subjects each were allocated to the training and non-training (control) groups. The subjects were instructed to use a lip muscle strength fixation device (M Patakara) for lip-closing training. Regarding closing the upper and lower lips against this force for 3 min as one task, the subjects were instructed to perform three tasks a day for 4 weeks. The multidirectional lip-closing forces were measured before, during and after training every week. In the control group, the forces were measured under the same schedule without training. After the initiation of training, the total lip-closing force significantly increased at 3 and 4 weeks in the training group compared with that in the control group (P = 0·003 at 3 weeks, P < 0·001 at 4 weeks). After the completion of training, the force decreased from 1 week and no significant difference from the control group was noted. When the lip-closing force was evaluated by direction, significant increases in the upward and downward directions were noted in the training group compared with those in the control group (P = 0·034 at 3 weeks for upwards; P = 0·027 at 4 weeks for downwards). Quantitative analysis confirmed that lip-closing training enhanced the lip-closing force regionally.

First description of the neuro-anatomy of a larval coral reef fish Amphiprion ocellaris.

The present study described the neuro-anatomy of a larval coral reef fish Amphiprion ocellaris and hypothesized that morphological changes during the transition from the oceanic environment to a reef environment (i.e. recruitment) have the potential to be driven by changes to environmental conditions and associated changes to cognitive requirements. Quantitative comparisons were made of the relative development of three specific brain areas (telencephalon, mesencephalon and cerebellum) between 6 days post-hatch (dph) larvae (oceanic phase) and 11 dph (at reef recruitment). The results showed that 6 dph larvae had at least two larger structures (telencephalon and mesencephalon) than 11 dph larvae, while the size of cerebellum remained identical. These results suggest that the structure and organization of the brain may reflect the cognitive demands at every stage of development. This study initiates analysis of the relationship between behavioural ecology and neuroscience in coral reef fishes.

Direct heating of a laser-imploded core by ultraintense laser-driven ions.

A novel direct core heating fusion process is introduced, in which a preimploded core is predominantly heated by energetic ions driven by LFEX, an extremely energetic ultrashort pulse laser. Consequently, we have observed the D(d,n)^{3}He-reacted neutrons (DD beam-fusion neutrons) with the yield of 5×10^{8} n/4π sr. Examination of the beam-fusion neutrons verified that the ions directly collide with the core plasma. While the hot electrons heat the whole core volume, the energetic ions deposit their energies locally in the core, forming hot spots for fuel ignition. As evidenced in the spectrum, the process simultaneously excited thermal neutrons with the yield of 6×10^{7} n/4π sr, raising the local core temperature from 0.8 to 1.8 keV. A one-dimensional hydrocode STAR 1D explains the shell implosion dynamics including the beam fusion and thermal fusion initiated by fast deuterons and carbon ions. A two-dimensional collisional particle-in-cell code predicts the core heating due to resistive processes driven by hot electrons, and also the generation of fast ions, which could be an additional heating source when they reach the core. Since the core density is limited to 2 g/cm^{3} in the current experiment, neither hot electrons nor fast ions can efficiently deposit their energy and the neutron yield remains low. In future work, we will achieve the higher core density (>10 g/cm^{3}); then hot electrons could contribute more to the core heating via drag heating. Together with hot electrons, the ion contribution to fast ignition is indispensable for realizing high-gain fusion. By virtue of its core heating and ignition, the proposed scheme can potentially achieve high gain fusion.

Heart rate-corrected QT interval is a novel risk marker for the progression of albuminuria in people with Type 2 diabetes.

AIMS: A close association between heart rate-corrected QT interval (QTc) and albuminuria in people with Type 2 diabetes has been reported in cross sectional studies. The aim of this study was to evaluate the relationship between QTc and change in urine albumin excretion (UAE) or progression of albuminuria in people with Type 2 diabetes. METHODS: We measured QTc in 251 consecutive people at baseline. We performed a 5-year follow-up cohort study to assess the relationship between QTc and change in UAE, defined as an increase of UAE/follow-up duration (year), or progression of albuminuria, defined as an increase in the category of diabetic nephropathy. RESULTS: During follow-up, 23 of 151 people with normoalbuminuria and 13 of 73 people with microalbuminuria at baseline had progression of albuminuria. Multiple regression analysis demonstrated that QTc was independently associated with change in UAE (ß = 0.176, P = 0.0104). Logistic regression analyses showed that QTc was a risk marker for progression of albuminuria [odds ratio per 0.01-s increase in QTc 1.35, 95% confidence interval (CI) 1.11-1.66, P = 0.0024] after adjusting for confounders. According to the receiver operator characteristic (ROC) analysis, the optimal cut-off point of QTc for progression of albuminuria was 0.418 s [area under the ROC curve 0.75 (95% CI 0.66-0.82), sensitivity = 0.86, specificity = 0.56, P < 0.0001]. CONCLUSIONS: Heart rate-corrected QT interval could be a novel risk marker for progression of albuminuria in people with Type 2 diabetes.

Empagliflozin, an Inhibitor of Sodium-Glucose Cotransporter 2 Exerts Anti-Inflammatory and Antifibrotic Effects on Experimental Diabetic Nephropathy Partly by Suppressing AGEs-Receptor Axis.

Advanced glycation end products (AGEs) and receptor RAGE play a role in diabetic nephropathy. We have previously shown that increased glucose uptake into proximal tubular cells via sodium-glucose cotransporter 2 (SGLT2) stimulates oxidative stress generation and RAGE expression, thereby exacerbating the AGE-induced apoptosis in this cell type. However, the protective role of SGLT2 inhibition against the AGE-RAGE-induced renal damage in diabetic animals remains unclear. In this study, we investigated the effects of empagliflozin, SGLT2 inhibitor on AGE-RAGE axis, inflammatory and fibrotic reactions, and tubular injury in the kidney of streptozotocin-induced diabetic rats.Administration of empagliflozin for 4 weeks significantly improved hyperglycemia and HbA1c, and decreased expression levels of AGEs, RAGE, 8-hydroxydeoxyguanosine (8-OHdG), and F4/80, markers of oxidative stress and macrophages, respectively, in the diabetic kidney. Although empagliflozin did not reduce albuminuria, it significantly decreased urinary excretion levels of 8-OHdG and L-fatty acid binding protein, a marker of tubular injury. Moreover, inflammatory and fibrotic gene expression such as monocyte chemoattractant protein-1, intercellular adhesion molecule-1, plasminogen activator inhibitor-1, transforming growth factor-ß, and connective tissue growth factor was enhanced in the diabetic kidney, all of which were prevented by empagliflozin. The present study suggests that empagliflozin could inhibit oxidative, inflammatory and fibrotic reactions in the kidney of diabetic rats partly via suppression of the AGE-RAGE axis. Blockade of the increased glucose uptake into renal proximal tubular cells by empagliflozin might be a novel therapeutic target for tubulointerstitial damage in diabetic nephropathy.

DNA aptamer raised against advanced glycation end products (AGEs) improves glycemic control and decreases adipocyte size in fructose-fed rats by suppressing AGE-RAGE axis.

Advanced glycation end products (AGEs) decrease adiponectin expression and suppress insulin signaling in cultured adipocytes through the interaction with a receptor for AGEs (RAGE) via oxidative stress generation. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. This study examined the effects of AGE-aptamer on adipocyte remodeling, AGE-RAGE-oxidative stress axis, and adiponectin expression in fructose-fed rats. Although AGE-aptamer treatment by an osmotic mini pump for 8 weeks did not affect serum insulin levels, it significantly decreased average fasting blood glucose and had a tendency to inhibit body weight gain in fructose-fed rats. Furthermore, AGE-aptamer significantly suppressed the increase in adipocyte size and prevented the elevation in AGEs, RAGE, and an oxidative stress marker, 8-hydroxydeoxyguanosine (8-OHdG), levels in adipose tissues of fructose-fed rats at 14-week-old, while it restored the decrease in adiponectin mRNA levels. Our present study suggests that AGE-aptamer could improve glycemic control and prevent adipocyte remodeling in fructose-fed rats partly by suppressing the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for fructose-induced metabolic derangements.

Low serum potassium concentration is a predictor of chronic kidney disease.

AIMS: The aim of this study was to examine whether low serum potassium concentration could be a predictor of chronic kidney disease (CKD) in a community-based cohort. MATERIALS AND METHODS: We enrolled 1001 subjects, median period of 5.7 years, and evaluated the risk factors for CKD, defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), and assessed whether low serum potassium concentration could predict CKD. RESULTS: Compared with the subjects without development of CKD, age, body mass index, fasting plasma glucose, uric acid (UA), creatinine and serum sodium concentration were higher, and serum potassium concentration was lower in subjects with development of CKD. Univariate Cox regression analyses demonstrated that age, body mass index, fasting plasma glucose, UA, creatinine, serum sodium concentration and serum potassium concentration were associated with progression of CKD. Multiple Cox regression analysis revealed that age, gender, creatinine and serum potassium concentration were independent predictors of CKD after adjustment for covariates. When serum potassium concentration was below 4.0 mmol/l at baseline, hazard ratio (95% confidence interval) of developing CKD was 2.65 (2.04-3.44; p < 0.0001). CONCLUSIONS: Serum potassium concentration could be a clinically relevant risk factor for the progression of CKD, defined as eGFR < 60 ml/min/1.73 m(2) , in healthy subjects.

Fusion using fast heating of a compactly imploded CD core.

A compact fast core heating experiment is described. A 4-J 0.4-ns output of a laser-diode-pumped high-repetition laser HAMA is divided into four beams, two of which counterilluminate double-deuterated polystyrene foils separated by 100 µm for implosion. The remaining two beams, compressed to 110 fs for fast heating, illuminate the same paths. Hot electrons produced by the heating pulses heat the imploded core, emitting x-ray radiations >20 eV and yielding some 10(3) thermal neutrons.

Andropausal symptoms in men with Type 2 diabetes.

AIMS: Serum androgen concentration is reported to be low in patients with Type 2 diabetes. There have been no studies comparing andropausal symptoms such as sleep disturbance, depression, erectile dysfunction and lower urinary tract symptoms simultaneously between men with Type 2 diabetes and subjects without diabetes. METHODS: We compared andropausal symptom scores such as the Pittsburgh Sleep Quality Index, the Self-Rating Depression Scale, the International Index of Erectile Function and the International Prostate Symptom Score in 296 men with Type 2 diabetes and in 267 subjects without diabetes. Furthermore, we evaluated relationships of andropausal symptom scores to various anthropometric factors and compared andropausal symptom scores according to diabetic complications in men with Type 2 diabetes. RESULTS: Andropausal symptom scores such as the Pittsburgh Sleep Quality Index, the Self-Rating Depression Scale, the International Index of Erectile Function and the International Prostate Symptom Score were 4.2 ± 2.6 vs. 5.0 ± 3.3, P<0.01 by unpaired Student's t-test, 34.8 ± 8.2 vs. 38.4 ± 9.3, P<0.0001, 11.5 ± 6.4 vs. 9.9 ± 6.9, P<0.01 and 7.3 ± 6.7 vs. 9.0 ± 7.1, P<0.01 in subjects without diabetes and in patients with diabetes, respectively. The Pittsburgh Sleep Quality Index was higher in patients with neuropathy than without. The Self-Rating Depression Scale was higher in patients with advanced retinopathy. The International Index of Erectile Function was lower in patients with advanced retinopathy and nephropathy. The International Index of Erectile Function was lower and the International Prostate Symptom Score was higher in patients with cardiovascular disease than without. CONCLUSIONS: Our data demonstrated that men with Type 2 diabetes have higher prevalence of andropausal symptoms, especially those with diabetic complications.

Temporal Profiles of Symptom Scores After Palliative Radiotherapy for Bleeding Gastric Cancer With Adjustment for the Palliative Prognostic Index: An Exploratory Analysis of a Multicentre Prospective Observational Study (JROSG 17-3).

AIMS: Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have a negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms. MATERIALS AND METHODS: This study was an exploratory analysis of the Japanese Radiation Oncology Study Group study (JROSG 17-3). We assessed six symptom scores (nausea, anorexia, fatigue, shortness of breath, pain at the irradiated area and distress) at registration and 2, 4 and 8 weeks thereafter. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to adjust for potential bias in missing data. RESULTS: The present study analysed all 55 patients enrolled in JROSG 17-3. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain and distress (slopes, -0.26, -0.22 and -0.19, respectively). Given that the interaction terms (i.e. PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain and distress significantly improved (slope, -0.25, -0.19 and -0.17; P < 0.001, 0.002 and 0.047, respectively). An improvement in fatigue and distress was observed only in patients treated with a biologically effective dose ≤14.4 Gy. CONCLUSION: Shortness of breath, pain and distress improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect an improvement in shortness of breath, pain and distress over 8 weeks. Multiple-fraction radiotherapy might hamper the improvement in fatigue and distress by its toxicity or treatment burden.

Low serum bilirubin concentration in haemodialysis patients with Type 2 diabetes.

AIMS: Previous studies have implicated reduced serum bilirubin concentrations in the development of cardiovascular disease. The aim of this study was to examine whether bilirubin may explain the high incidence of vascular complications in haemodialysis patients with Type 2 diabetes. METHODS: We compared serum bilirubin concentrations, as well as other known aetiological risk factors for cardiovascular disease, in 206 Type 2 diabetes patients on haemodialysis with those in 741 Type 2 diabetes patients not receiving haemodialysis, and evaluated the association between serum bilirubin concentration and cardiovascular disease incidence. RESULTS: Incidences of cardiovascular disease and systolic blood pressure were higher; however, BMI and serum total cholesterol were lower in haemodialysis patients compared with those in patients without haemodialysis. Serum total (0.30 ± 0.10 vs. 0.74 ± 0.26 mg/dl, 0.005 ± 0.002 vs. 0.013 ± 0.004 mmol/l, P < 0.0001) and indirect (0.17 ± 0.08 vs. 0.70 ± 0.23 mg/dl, 0.003 ± 0.001 vs. 0.012 ± 0.004 mmol/l, P < 0.0001) bilirubin were lower in haemodialysis patients compared with those in patients without haemodialysis. Stepwise regression analysis demonstrated that age (ß = 0.109, F = 5.959, P < 0.05), duration of diabetes (ß = -0.112, F = 6.048, P < 0.05), sex (ß = -0.123, F = 8.623, P < 0.05), cardiovascular disease events (ß = -0.099, F = 5.131, P < 0.05) and presence of haemodialysis (ß = -0.626, F = 201.727, P < 0.01) were independent factors for serum total bilirubin. Logistic regression demonstrated that age (OR 1.089, 95% CI 1.044-1.136; P < 0.0001), duration of diabetes (OR 1.029, 95% CI 1.001-1.059; P = 0.0423), body mass index (OR 1.115, 95% CI 1.001-1.242; P = 0.0487), habit of smoking (OR 2.445, 95% CI 1.046-5.716; P = 0.0391) and serum total bilirubin (OR 0.192, 95% CI 0.037-0.989; P = 0.0484) were independent factors for cardiovascular disease events. CONCLUSIONS: Low serum bilirubin concentration could be one of the important factors for the high incidence of cardiovascular disease in Type 2 diabetes patients receiving haemodialysis.

Multicentric Castleman's disease representing effusion at initial clinical presentation: clinicopathological study of seven cases.

We present here seven cases of idiopathic multicentric Castleman's disease (MCD) showing effusion at the initial clinical presentation. This series includes a high proportion of middle-aged and elderly females (5/7). Various autoantibodies were detected in six cases. Anemia (Hb < 10 g/dl) was detected in four cases, leukocytosis (WBC > 10 × 10(9)/l) in three and thrombycytopenia (<100 × 10(9)/l) in five. Positivity for C-reactive protein or elevated erythrocyte sedimentation rate was recorded in all seven cases. Elevated serum IgG level (>2000 mg/dl) was recorded in only three cases. Elevated serum interleukin-6 level was recorded in all four cases examined. At the onset of disease, four cases were associated with idiopathic thrombocytic purpura. During the course of disease, one case each was diagnosed as systemic sclerosis + Sjögren's syndrome (SJS) and SJS. Histologically, five lesions exhibited a mixed type of Castleman's disease, and one case each exhibited a hyaline-vascular type and plasma cell type. The non-neoplastic nature of the B-lymphocytes was demonstrated by immunohistochemistry and polymerase chain reaction. There were no human herpes type-8 virus-positive cells in any of the seven lesions. Good responsiveness to glucocorticoid therapy has been seen in all six cases treated. From a therapeutic perspective, it is important to discriminate this subtype of MCD.

Gene transfer in utero biologically engineers a patent ductus arteriosus in lambs by arresting fibronectin-dependent neointimal formation.

Closure of the ductus arteriosus requires prenatal formation of intimal cushions, which occlude the vessel lumen at birth. Survival of newborns with severe congenital heart defects, however, depends on ductal patency. We used a gene transfer approach to create a patent ductus arteriosus by targeting the fibronectin-dependent smooth muscle cell migration required for intimal cushion formation. Fetal lamb ductus arteriosus was transfected in utero with hemagglutinating virus of Japan liposomes containing plasmid encoding 'decoy' RNA to sequester the fibronectin mRNA binding protein. Fibronectin translation was inhibited and intimal cushion formation was prevented. We thus established the essential role of fibronectin-dependent smooth muscle cell migration in intimal cushion formation in the intact animal and the feasibility of incorporating biological engineering in the management of congenital heart disease.

Fas ligand in human serum.

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-bearing cells. The membrane-bound human FasL was found to be converted to a soluble form (sFasL) by the action of a matrix metalloproteinase-like enzyme. Two neutralizing monoclonal anti-human FasL antibodies were identified, and an enzyme-linked immunosorbent assay (ELISA) for sFasL in human sera was established. Sera from healthy persons did not contain a detectable level of sFasL, whereas those from patients with large granular lymphocytic (LGL) leukemia and natural killer (NK) cell lymphoma did. These malignant cells constitutively expressed FasL, whereas peripheral NK cells from healthy persons expressed FasL only on activation. These results suggested that the systemic tissue damage seen in most patients with LGL leukemia and NK-type lymphoma is due to sFasL produced by these malignant cells. Neutralizing anti-FasL antibodies or matrix metalloproteinase inhibitors may be of use in modulating such tissue damage.