Identification of possible pathogenic pathways in Beh?et's disease using genome-wide association study data from two different populations

Behçet''s disease (BD) is a multi-system inflammatory disorder of unknown etiology. Two recent genome-wide association studies (GWASs) of BD confirmed a strong association with the MHC class I region and identified two non-HLA common genetic variations. In complex diseases, multiple factors may target different sets of genes in the same pathway and thus may cause the same disease phenotype. We therefore hypothesized that identification of disease-associated pathways is critical to elucidate mechanisms underlying BD, and those pathways may be conserved within and across populations. To identify the disease-associated pathways, we developed a novel methodology that combines nominally significant evidence of genetic association with current knowledge of biochemical pathways, protein–protein interaction networks, and functional information of selected SNPs. Using this methodology, we searched for the disease-related pathways in two BD GWASs in Turkish and Japanese case–control groups. We found that 6 of the top 10 identified pathways in both populations were overlapping, even though there were few significantly conserved SNPs/genes within and between populations. The probability of random occurrence of such an event was 2.24E−39. These shared pathways were focal adhesion, MAPK signaling, TGF-β signaling, ECM–receptor interaction, complement and coagulation cascades, and proteasome pathways. Even though each individual has a unique combination of factors involved in their disease development, the targeted pathways are expected to be mostly the same. Hence, the identification of shared pathways between the Turkish and the Japanese patients using GWAS data may help further elucidate the inflammatory mechanisms in BD pathogenesis.     

Activated leucocytes express and secrete macrophage inflammatory protein-1alpha upon interaction with synovial fibroblasts of rheumatoid arthritis via a beta2-integrin/ICAM-1 mechanism

OBJECTIVE: To examine the expression and regulation of chemotactic factor, macrophage inflammatory protein-1alpha (MIP-1alpha) by fibroblast-like synoviocytes (FLS), monocytes and polymorphonuclear neutrophils (PMN) isolated from the synovial fluid (SF) of rheumatoid arthritis (RA) patients. METHODS: Monocytes or PMN obtained from RA SF were co-cultured with unstimulated semiconfluent RA FLS. Culture supernatants were assayed for MIP-1alpha by enzyme-linked immunosorbent assay. The expression of MIP-1alpha mRNA and protein was also determined by Northern blot analyss and immunohistochemistry respectively. RESULTS: Interaction of activated leucocytes with FLS synergistically increased MIP-1alpha expression and secretion via a mechanism mediated by beta2-integrin/ intercellular adhesion molecule 1. CONCLUSION: MIP-1alpha expression within inflamed joints appears to be regulated not only by inflammatory cytokines but also by the physical interaction of activated leucocytes and FLS, and plays a crucial role in the progression and maintenance of RA synovitis.     

Effect of increasing heart rate on Doppler indices of left ventricular performance in healthy men

Objective—To investigate the effects of heart rate on the Doppler measurements of left ventricular function and to determine the normal pattern of rate dependency.

Setting—University hospital specialising in internal medicine.

Participants—14 healthy male volunteers 10 of whom were studied.

Intervention: Transoesophageal atrial pacing.

Main outcome measures—At paced rates of 70, 80, and 90 ppm the ratio of early to late peak transmitral flow velocity (E/A) was 1·97 (0·28), 1·49 (0·21), and 0·95 (0·11) respectively; the ratio of early to late time-velocity integrals of transmitral flow (Ei/Ai) was 3·03 (0·51), 2·11 (0·24), and 1·14 (0·30) respectively; and the atrial filling fraction (AFF) was 0·17 (0·03), 0·21, (0·04), and 0·24 (0·04) (mean (SD)).

Results—Heart rate showed a linear correlation with E/A (r² = 0·806), Ei/Ai (r² = 0·838), and AFF (r² = 0·343). Neither the peak aortic flow velocity or the mean aortic flow acceleration showed significant changes during pacing at rates of 70, 80, 90, and 100 ppm.

Conclusions—E/A and Ei/Ai can be expected to decrease by 0·5 and 0·9 for each increase of 10 beats/min in heart rate.

Knowledge of this relation may be useful for the development of algorithms to correct for heart rate when diastolic function is assessed.

     

Adenosquamous carcinoma of the pancreas

A 58-year-old Japanese man was admitted complaining of abdominal pain. An abdominal computed tomography examination demonstrated a tumor in the head of the pancreas and multiple calcifications. A laparotomy was performed and the tumor was removed by Whipple's operation. Histologically, the neoplasm that invaded the duodenal wall and the papilla of Vater was composed of nests of malignant squamous cells with intercellular bridges and showed the formation of keratinized pearls with a small area of concurrently neoplastic glandular and squamous elements. On the basis of these features, the diagnosis of adenosquamous carcinoma of the pancreas was made. The patient died 18 months after the operation. The neoplastic behavior of this rare primary pancreatic carcinoma is similar to that of duct cell carcinoma as well as pure squamous cell carcinoma of the pancreas. As the pancreas can be the target of metastases of squamous carcinomas from other organs it is wise to be aware of this rare entity.     

Effects of streptococcal preparation OK-432 on liver regeneration and energy status after partial hepatectomy under ischemia/reperfusion in rats

BACKGROUND/AIMS: Activation of reticuloendothelial system functions by the treatment with OK-432 has been reported to enhance liver regeneration. However, its effect on liver regeneration has not been studied after hepatectomy under ischemia/reperfusion which is in clinical use. The aim was to examine the effect of OK-432 on regeneration and energy status of the liver after hepatectomy under ischemia/reperfusion in rats. METHODOLOGY: Rats were randomly divided into two groups; OK-432 pretreatment and saline treatment (control) group. In the OK-432 group, OK-432 (2.5 mg/kg body weight) was administered intraperitoneally 24 hours before hepatectomy. In the control group, the same volume of physiological saline was administered in the same manner. Seventy percent hepatectomy was performed in both groups during the second 15-minute ischemia period after an initial 15-minute ischemia and 15-minute reperfusion periods. The survival after hepatectomy, relative liver weight, deoxyribonucleic acid synthesis rate, and hepatic adenine nucleotide and energy charge levels were examined immediately after hepatectomy and on postoperative days 1, 2, 3, and 7. Serum levels of total bilirubin, glutamic pyruvic transaminase, and hyaluronic acid were also measured. RESULTS: All rats survived and the relative liver weight and deoxyribonucleic acid synthesis rate were not significantly different in the two groups. Serum total bilirubin and glutamic pyruvic transaminase levels were not significantly different in both groups. The serum concentration of hyaluronic acid immediately after hepatectomy was significantly higher in the OK-432 group than in the control group. The pretreatment with OK-432 had no significant effect on the levels of adenine nucleotides and energy charge in the liver. CONCLUSIONS: Under ischemia/reperfusion, pretreatment with OK-432 has no significant effect on regeneration and energy status of the liver after hepatectomy.     

Clinical significance of serum autoantibodies against Ras-like GTPases,RalA, in patients with esophageal squamous cell carcinoma

Background

The Ras-like GTPases, RalA and RalB are members of the Ras superfamily of small GTPases. Aberrant activation of Ral is a major cause of human tumorigenesis induced by oncogenic Ras. Serum anti-RalA antibodies are induced in esophageal carcinoma patients. However, detailed comparisons of their pathological characteristics are unavailable, and conventional serum markers have not been well evaluated.

Methods

Serum samples of 171 patients with esophageal squamous cell carcinoma and 73 healthy individuals were analyzed using specifically developed ELISA system for serum anti-RalA antibodies. A cut-off optical density value was fixed at 0.255 (the control mean + 2 SD). Clinicopathological characteristics and positive rates of conventional tumor markers were evaluated for seropositive patients.

Results

Overall positive rate for serum anti-RalA antibodies was 18 %, which gradually increased with the tumor stages. Although the positive rate for serum anti-RalA antibodies was comparable with that of carcinoembryonic antigen (24 %) and CYFRA21-1 (21 %), it was lower than the rate for serum p53 antibodies (31 %) and squamous cell carcinoma antigen (37 %). Although serum anti-RalA antibodies were not associated with other serum markers, it was inversely associated with serum p53 antibodies. No clear association was observed between serum anti-RalA antibodies and RalA immunoreactivity.

Conclusions

Presence of serum anti-RalA antibodies is associated with tumor stages, but not with conventional tumor markers. Serum anti-RalA antibodies may be candidate serum markers in combination with other serum markers for esophageal squamous cell carcinoma.

     

Insulin resistance in nondiabetic patients is associated with expansive remodeling in coronary arterial lesions

OBJECTIVE: Insulin resistance has been implicated as an important initiating factor in coronary atherosclerosis. However, associations between insulin resistance and specific morphologic features of atherosclerotic coronary arteries remain unclear. We ultrasonographically evaluated the morphologic features of atherosclerotic coronary arteries in nondiabetic patients with insulin resistance. METHODS: Before intervention, 90 patients with 105 culprit lesions underwent intravascular ultrasound examination through which vessel area, lumen area and plaque area were evaluated. Expansive remodeling (lesion vessel area more than 5% greater than at the proximal reference segment) and constrictive remodeling (lesion vessel area more than 5% less than at the distal reference segment) were also evaluated. Insulin resistance was determined by homeostasis model assessment and defined as values above the 75th percentile (that is, 1.71). RESULTS: Insulin-resistant patients numbered 23, while nonresistant patients numbered 67. Culprit lesions in the insulin-resistant group showed larger vessel area (18.16 +/- 6.94 compared with 13.64 +/- 4.28 mm, P = 0.0001) and plaque area (16.64 +/- 6.78 compared with 12.05 +/- 4.12 mm, P = 0.0001) and more frequently showed expansive remodeling (56% compared with 14%, P < 0.0001) and calcific plaque (33% compared with 12%, P = 0.01). Multivariable logistic regression analysis identified only insulin resistance (odds ratio, 4.9, P = 0.008) as an independent predictor of expansive remodeling. CONCLUSIONS: Insulin resistance independently predicted expansive remodeling, underscoring the importance of insulin resistance in coronary atheroscrelosis.