The Jab1/COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression

Jab1 is a multifunctional protein associated with the signaling pathway, cell-cycle regulation, and development, and acts as a key subunit of COP9 signalosome (CSN). Jab1 promotes degradation of the cyclin-dependent kinase inhibitor p27(Kip1) by transportation from the nucleus to the cytoplasm. However, there has been no clear evidence for whether and how Jab1 contributes to malignant transformation in human cancers. Here we show that Bcr-Abl tyrosine kinase facilitates the down-regulation of p27 by modulating complex formation of Jab1/CSN through the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3 (PI3) kinase signaling pathways. Nearly half of the chronic myelogenous leukemia cell lines and the murine hematopoietic precursor cells expressing Bcr-Abl exhibited a marked increase in the small loose Jab1 complex located in the cytoplasm. Inhibition of Bcr-Abl kinase by STI571 induced G1 arrest and caused a recovery of the p27 level with reduction of the small Jab1 complex from the cytoplasm. Either blockade of the MAP kinase and PI3 kinase pathways by specific inhibitors or Jab1 knockdown by small interfering RNA (siRNA) prevented p27 down-regulation as well as formation of the small complex. Thus, regulation of p27 via modulation of the Jab1 subcomplex is a novel mechanism whereby Bcr-Abl oncogenic signals accelerate abnormal cell proliferation.     

Nicorandil, a potent cardioprotective agent, reduces QT dispersion during coronary angioplasty

BACKGROUND: Previous studies have found that ST-segment elevation and QT dispersion are smaller in second coronary occlusions than in first occlusions, a trend that suggests ischemic preconditioning. It has not been established whether nicorandil reduces ST-segment elevation and QT dispersion during coronary angioplasty. METHODS AND RESULTS: Thirty patients with stable angina undergoing coronary angioplasty in the proximal left anterior descending artery were randomly assigned to one of two groups, receiving either 5 mg oral nicorandil 3 times daily (n = 15) or placebo (n = 15). In the control patients, the total ST-segment elevation decreased from 14 +/- 3 mm during the first inflation to 7 +/- 2 mm during the second inflation (P < .01). In contrast, in the nicorandil-treated patients, the total ST-segment elevation during the second inflation was roughly equivalent to that during the first inflation (8 +/- 3 mm vs 8 +/- 3 mm, P = not significant). After the first reperfusion, a significantly smaller increase in QT dispersion was observed in the nicorandil-treated patients than in the control patients (43 +/- 15 ms vs 54 +/- 15 ms, P < .001). However, after the second reperfusion, QT dispersion was similar for the two groups (32 +/- 15 ms vs 34 +/- 13 ms, P = not significant). CONCLUSIONS: Nicorandil may precondition the myocardium and may prevent the occurrence of ventricular arrhythmias after coronary reperfusion by suppressing the increase in QT dispersion.     

The prevalence of Eustachian tube dysfunction symptoms in patients with chronic rhinosinusitis

Background

While Eustachian tube dysfunction (ETD) is a known comorbidity of chronic rhinosinusitis (CRS), the prevalence of ETD symptoms in the CRS population is poorly understood. We sought to determine the cross‐sectional prevalence of ETD in patients with CRS using the validated Eustachian Tube Dysfunction Questionnaire (ETDQ‐7) and to correlate ETDQ‐7 scores with 22‐item Sino‐Nasal Outcome Test (SNOT‐22) scores, endoscopy scores, and computed tomography (CT) scores.

Methods

A total of 101 patients with confirmed CRS completed the ETDQ‐7 and SNOT‐22 at their initial visit to our rhinology clinic. Lund‐Mackay CT and Lund‐Kennedy endoscopy scores were also obtained. Spearman's correlation coefficient (ρ) was calculated.

Results

Among the 101 patients, 49 patients (48.5%) had an ETDQ‐7 score of ≥14.5, signifying clinically significant ETD. The mean ± standard deviation (SD) ETDQ‐7 score of the entire cohort was 17.8 ± 10.1. There was a moderately strong correlation between ETDQ‐7 and the SNOT‐22 ear subdomain (ρ = 0.691, p < 0.001). The correlation coefficient between ETDQ‐7 and total SNOT‐22 scores was ρ = 0.491 (p < 0.001), indicating moderate correlation. ETDQ‐7 scores were poorly correlated to objective measures of sinonasal disease, including Lund‐Mackay CT score (ρ = ?0.055, p = 0.594) and Lund‐Kennedy endoscopy score (ρ = ?0.099, p = 0.334).

Conclusion

Symptoms of ETD are highly prevalent among patients with CRS as documented by patient‐reported outcome measures. The correlation between ETDQ‐7 scores and SNOT‐22 ear subdomain scores is moderately strong, while the correlation between ETDQ‐7 scores and SNOT‐22 scores is moderate. ETD severity does not correlate with CT score or nasal endoscopy score.

     

The role of Ia positive T cells in patients with rheumatoid arthritis

Summary In peripheral blood and synovial fluid of patients with rheumatoid arthritis (RA), increased levels of Ia antigen-positive (Ia+) T cells have been demonstrated. Therefore, we examined these Ia+ T cells in vitro to identify their role in the production of rheumatoid factor (RF) and to study the immunologic abnormalities of RA. When Ia+ T cells from peripheral blood of RA patients were added to pokeweed mitogen (PWM)-non-stimulated autologous B cells, the amount of IgM-RF production was 25.8±6.4 (mean±SE) (p<0.001) as compared to 16.0±4.6 ng/ml (mean±SE) in the presence of Ia^– T cells. When Ia^– OKT4+ cell fractions, obtained by excluding Ia+ T cells from OKT4+ cells, were added to B cells, the increase in IgM-RF production was markedly lower than that obtained with the OKT4+ cell fraction. These results indicate that the helper T cells which induce the production of IgM-RF may derive from the Ia+ OKT4+ cell fraction. B cells from rheumatoid synovial fluid produced IgM-RF levels as high as 102.7±19.2 ng/ml (mean±SE) even without stimulation. When T cells from autologous synovial fluid were added, IgM-RF production was not increased. These data suggest that B cells from RA synovial fluid had already been activated. When synovial fluid T cells were added to B cells from autologous peripheral blood, larger amounts of IgM-RF were produced as compared to experiments in which T cells from peripheral blood were added, suggesting that T cells from synovial fluid induce an enhanced IgM-RF production by B cells. The presence or absence of Ia antigen on the surface of synovial fluid T cells did not affect the level of IgM-RF production. Our results indicate that Ia+ T cells from the peripheral blood of RA patients induce the production of IgM-RF by autologous B cells.     

Rotavirus gastroenteritis‐associated urinary ammonium acid urate crystals

Although ammonium acid urate (AAU) calculi are extremely rare renal stone components, it was recently found that many urinary tract calculi that cause post‐renal renal failure in rotavirus (RV) gastroenteritis are AAU calculi. The mechanism of AAU calculi development in RV gastroenteritis has not been fully elucidated. We analyzed data from eight RV gastroenteritis patients who transiently had AAU crystals in their urinary sediment. In these patients, formation of AAU crystals occurred earlier than the formation of AAU calculi. No difference was observed in serum and urine uric acid levels between RV gastroenteritis patients with or without AAU crystals. Interestingly, fractional excretion of sodium was extremely low among patients with AAU crystals. These results suggest that the formation of AAU crystals might not be due to excretion of uric acid, but excretion of sodium.     

Study of posterior left atrial wall motion by echocardiography and its clinical application.

Echocardiographic tracings of posterior left atrial wall motion were examined in 30 normal subjects, 17 patients of mitral stenosis with sinus rhythm and 31 coronary patients with elevated left ventricular end-diastolic pressure. Because of the plane of the posterior left atrial wall motion and the angle of the sound beam, usually the postero-inferior portion of the left atrial wall was recorded. In normal subjects, there were 3 positive waves (A,C,V waves) and 2 negative waves (X and Y waves). The A wave during atrial contraction period occurred in the closing motion of the mitral valve and was initiated by a slight negative wave. The fourth heart sound was consistent with the ascending limb of the A wave. The C wave coincided with the first heart sound followed by the pronounced negative depression (X wave). The X trough coincided with the beginning of the mitral valve opening in early diastole and was the deepest point in the motion curve. The V wave was a peaked anterior motion during rapid filling period and followed by the third heart sound. The Y wave was a slight negative depression following the V wave, and its trough occurred when the both leaflets of the mitral valve assumed a semiclosed position. In both mitral stenosis and coronary artery disease, significant increase (p less than 0.01) of the A wave excursion and significant decrease (p less than 0.01) of the V wave excursion were observed, resulting in marked increase (p less than 0.01) of the A/V ratio. The slope of the ascending limb of the V wave was also decreased apparently in both conditions. These findings might reflect increased resistance to left atrial emptying in mitral stenosis and decreased left ventricular filling rate in coronary artery disease. This study shows that echocardiographic examination of the posterior left atrial wall motion is feasible and useful in estimating the presence of either mitral stenosis or decreased left ventricular filling rate.     

Detection and partial sequencing of hepatitis C virus RNA in the liver.

To detect hepatitis C virus RNA, total RNA was extracted from liver tissue, reverse transcribed to complementary DNA, and amplified by polymerase chain reaction. The reaction products were analyzed by ethidium bromide staining in acrylamide gel and hybridization with a radiolabeled probe. Hepatitis C virus RNA was thereby detected in 17 of 27 (63%) liver tissue specimens obtained from patients with non-A, non-B chronic liver diseases. Of these 27 patients, viral RNA was detected in 12 of 17 (71%) liver tissues from anti-hepatitis C virus-positive patients and in 5 of 10 (50%) liver tissues from anti-hepatitis C virus-negative patients. Direct sequencing of amplified complementary DNA (35 nucleotides) of the 17 RNA-positive samples showed only 66% to 77% homology to the reported hepatitis C virus complementary DNA sequence. These results indicate that the majority of anti-hepatitis C virus-positive patients are currently infected with hepatitis C virus, and some of the anti-hepatitis C virus-negative patients with non-A, non-B hepatitis are harboring hepatitis C virus in the liver. Detection of hepatitis C virus RNA appears to provide a useful indicator in the study of hepatitis C virus infection.     

Acute and chronic effects of domperidone on gastric emptying in diabetic autonomic neuropathy

Gastric emptying was studied with a double radioisotopic method in 12 patients with insulin-dependent diabetes mellitus complicated by autonomic neuropathy and in 22 control subjects. In the diabetics, the acute and chronic effects of oral domperidone on gastric emptying, symptoms of gastroparesis, and glycemic control were assessed. Gastric emptying of solid and liquid was slower in diabetics than controls (P<0.001). Acute administration of domperidone increased the rate of both solid and liquid emptying (P<0.005). Domperidone was most effective in those patients with the greatest delay in gastric emptying. After chronic administration (35–51 days), domperidone had no significant effect on solid emptying (P>0.05), but was still effective in increasing liquid emptying (P<0.025). Symptoms of gastroparesis were less after domperidone (P<0.001).Dr. M. Horowitz was supported by a grant from the National Health and Medical Research Council of Australia.