Immunological and molecular analysis of B lymphocytes in low-grade MALT lymphoma of the stomach. Are there any useful markers for predicting outcome after Helicobacter pylori eradication?

Background: Background: Although Helicobacter pylori eradication is effective in treating low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the condition in some patients deteriorates even after the eradication. Therefore, it is important to predict the disease outcome before starting H. pylori eradication. We investigated the usefulness of flow cytometry, quantifying CD19- and CD20-positive B lymphocytes in MALT lymphoma tissue, for predicting the disease outcome after H. pylori eradication. Methods: Tissue specimens from 14 patients with H. pylori-positive low-grade gastric MALT lymphoma were examined by histology, Southern blotting, and flow cytometry before therapy. Serum levels of soluble interleukin (IL)-2 receptor were also measured. The relationship between the data and the prognosis after H. pylori eradication was analyzed. Results: Remission occurred in 10 of the 14 patients. The condition in the 4 remaining patients deteriorated even after H. pylori eradication. The percentages of CD19- and CD20-positive cells in MALT lymphoma tissue from the patients in remission were both significantly lower than those in the tissue from patients not in remission. Indeed, 4 of the 5 patients in whom both CD19- and CD20-positive cells accounted for more than 50% of the total number of lymphocytes had gastrectomy, whereas all patients in whom both CD19- and CD20-positive cells accounted for less than 50% of the total number of lymphocytes achieved remission. Although immunoglobulin gene rearrangement was present in all patients operated on, there were also 6 patients whose MALT lymphoma was ameliorated in spite of the presence of gene rearrangement. The serum level of soluble IL-2 receptor was in the normal range in all patients tested. Conclusions: Analysis of mature B-cell markers in MALT lymphoma tissue is more useful than the examination of immunoglobulin gene rearrangement or serum levels of soluble IL-2 receptor in predicting the outcome of low-grade gastric MALT lymphoma after H. pylori eradication. Received: January 5, 2001 / Accepted: November 2, 2001     

Left ventricular filling measured by Doppler echocar diography during dynamic exercise in patients with myocardial infarction

Summary To assess left ventricular diastolic properties in response to dynamic exercise, mitral inflow velocity integrals were measured by pulsed-wave Doppler echocardiography in ten patients with myocardial infarction and in ten normal subjects, and simultaneous left ventricular pressure was obtained with micromanometry in the patients. Early filling velocity integrals were maintained in the patients during exercise. Late filling velocity integrals were not augmented during exercise in the patients, but were increased in the normal subjects. In the patients, there was an increase in mitral valve opening pressure, left ventricular end-diastolic pressure, and the time constant of left ventricular isovolumic pressure decay. The lowest diastolic pressure and the number of time constants that had elapsed before the lowest diastolic pressure remained unchanged. These results show that in patients with myocardial infarction, early filling is maintained by an increase in driving pressure during exercise, despite incomplete relaxation. Augmentation of late filling, seen in normal subjects, is impaired in patients with myocardial infarction, probably due to an increase in left ventricular stiffness.     

Mirabegron causes vesical and urethral relaxation in rats with spinal cord injury

The effects of solifenacin and mirabegron on vesical and urethral function were compared in rats with or without spinal cord injury (SCI). Isovolumetric cystometry and urethral pressure recording were initially performed in intact rats. Then, the bladder neck was ligated under urethane anesthesia, after which a catheter was inserted through the bladder dome for isovolumetric cystometry and another catheter was inserted into the urethra to measure urethral pressure. Solifenacin (0.03–3 mg/kg) or mirabegron (0.03–3 mg/kg) was injected intravenously, and bladder and urethral activity were recorded. To create rats with SCI, the spinal cord was transected at the lower thoracic level under isoflurane anesthesia. After 2 weeks, a catheter was inserted through the bladder dome for single cystometry and bladder activity was recorded without anesthesia following intravenous injection of solifenacin or mirabegron. Isovolumetric cystometry revealed a larger decrease in maximum bladder contraction pressure after injection of solifenacin, whereas prolongation of the interval between bladder contractions was greater with mirabegron. In SCI rats, single cystometry showed that solifenacin and mirabegron both increased bladder volume at the first non‐voiding bladder contraction and decreased the maximum bladder contraction pressure. Mirabegron also increased the voided volume and decreased the percentage residual volume without altering bladder capacity. Solifenacin and mirabegron both inhibited bladder contractility, and mirabegron possibly also induced urethral relaxation. Mirabegron may be suitable for patients with overactive bladder and residual urine.     

Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization

Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.Angiogenesis plays a central role in many diseases, including age-related macular degeneration (AMD), a leading cause of blindness. Advanced AMD exists in two forms, “atrophic” and “neovascular,” which are defined by the absence or presence of choroidal neovascularization (CNV), respectively (1). Neovascular AMD is characterized by the formation of abnormal blood vessels that grow from the choroidal vasculature, through breaks in Bruch’s membrane, toward the outer retina (1). These vessels generally are immature in nature and leak fluid below or within the retina (2). Although growth factors are thought to play an important role in the late stage of neovascular AMD progression, they likely do not contribute to the underlying cause of the disease. The current standard of care for individuals with neovascular AMD is based on the targeting of VEGF, which promotes both angiogenesis and vascular permeability (3). However, although VEGF-targeted therapy attenuates angiogenesis and vascular permeability, it does not lead to complete vascular regression or disease resolution (3).The ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two classes of dietary lipids that are essential fatty acids and have opposing physiological effects. The ω-6 LCPUFA, arachidonic acid (AA), and its cytochrome P450 (CYP)-generated metabolites (epoxyeicosatrienoic acids, EETs) recently have attracted much attention as a result of increasing evidence that they play a role in cancer as well as in cardiovascular disease (4–9). EETs are part of the VEGF-activated signaling cascade leading to angiogenesis (10) and promote tumor growth and metastasis (11). The major dietary ω-3 LCPUFAs are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are highly enriched in the central nervous system including the retina (12). The ω-3 LCPUFAs have antithrombotic, antiangiogenic, and anti-inflammatory properties, and they compete with ω-6 LCPUFAs as substrates for synthesis of downstream metabolites by CYP enzymes, cyclooxygenases (COX), and lipoxygenases (LOX) (6, 13–15). Moreover, dietary enrichment with ω-3 LCPUFAs has been shown to protect against pathological angiogenesis-associated cancer and retinopathy (2, 16–19). Of the three main pathways (COX, LOX, and CYP) involved in eicosanoid biosynthesis, the lipid mediators derived from the CYP branch are the most susceptible to changes in dietary fatty acid composition (20–23). The ω-3 double bond that distinguishes DHA and EPA from their ω-6 counterparts provides a preferred epoxidation site for specific CYP family members (20, 22). In fact, most CYP isoforms can metabolize EPA and DHA with significantly higher catalytic efficiency than AA, making them uniquely susceptible to variations in the availability of these lipids (19–22). CYP epoxygenases target the ω-3 double bond, resulting in an accumulation of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) derived from EPA and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from DHA (20, 22). Very recently, it was recognized that19,20-EDP inhibits angiogenesis, tumor growth, and metastasis (24). Thus, it appears that the CYP–epoxygenase pathway has the capacity to produce proangiogenic metabolites from ω-6 LCPUFAs (10, 11) and antiangiogenic metabolites from ω-3 LCPUFAs (24). This unique feature of the CYP enzymes may provide a previously unidentified mechanistic link between the ω-6/ω-3 ratio of dietary LCPUFAs and pathological angiogenesis; however, their roles in ocular angiogenesis have been largely unexplored to date.We now show that dietary enrichment with ω-3 LCPUFAs suppresses CNV, vascular leakage, and immune cell recruitment to the lesion site in a mouse model of laser-induced CNV. We characterized the CYP-dependent pathway by which dietary ω-3 LCPUFAs promote resolution of choroidal neovessels in this model and identified CYP-generated metabolites 17,18-EEQ and 19,20-EDP as mediators of disease resolution. Furthermore, we show that expression of adhesion molecules at the CNV site was down-regulated in association with inhibition of leukocyte recruitment in mice receiving ω-3 LCPUFAs.     

Skin Autofluorescence Predicts Cardiovascular Mortality in Patients on Chronic Hemodialysis

Tissue accumulation of advanced glycation end products (AGE) is thought to contribute to the progression of cardiovascular disease (CVD). Skin autofluorescence, a non‐invasive measure of AGE accumulation using autofluorescence of the skin under ultraviolet light, has been reported to be an independent predictor of mortality associated with CVD in Caucasian patients on chronic hemodialysis. The aim of this study was to assess the predictive value of skin autofluorescence on all‐cause and cardiovascular mortality in non‐Caucasian (Japanese) patients on chronic hemodialysis. Baseline skin autofluorescence was measured with an autofluorescence reader in 128 non‐Caucasian (Japanese) patients on chronic hemodialysis. All‐cause and cardiovascular mortality was monitored prospectively during a period of 6 years. During the follow‐up period, 42 of the 128 patients died; 19 of those patients died of CVD. Skin autofluorescence did not have a significant effect on all‐cause mortality. However, age, carotid artery intima‐media thickness (IMT), serum albumin, high‐sensitivity C‐reactive protein (hsCRP), skin autofluorescence and pre‐existing CVD were significantly correlated with cardiovascular mortality. Multivariate Cox regression analysis showed skin autofluorescence (adjusted hazard ratio [HR] 3.97; 95% confidence interval [CI]1.67–9.43), serum albumin (adjusted HR 0.05; 95% CI 0.01–0.32), and hsCRP (adjusted HR 1.55; 95% CI 1.18–2.05) to be independent predictors of cardiovascular mortality. The present study suggests that skin autofluorescence is an independent predictor of cardiovascular mortality in non‐Caucasian (Japanese) patients on chronic hemodialysis.     

Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case

We report a rare case with pheochromocytoma as the first manifestation of multiple endocrine neoplasia type 2A with RET mutation S891A. Bilateral pheochromocytomas were identified in a 54-year-old woman. Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain. This mutation was previously recognized as one of the mutations only in cases manifesting solely medullary thyroid carcinomas (MTCs). Since calcitonin stimulation test indicated positive result, total thyroidectomy was performed 1 year after the bilateral adrenalectomy, and C-cell hyperplasia was diagnosed by histopathological examination. Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma. In addition, it is indicated that calcitonin stimulation test should be performed even in the unaffected elder cases with S891A mutation although the mutation is classified as lowest risk group on MTC in guidelines.     

Prevalence and risk factor analysis of nephrosclerosis and ischemic nephropathy in the Japanese general population

Background

Nephrosclerosis/ischemic nephropathy (NS/IN) ranks third among renal diseases requiring dialysis in Japan. Although it is an important renal disease in terms of frequency, its prevalence, new incidence, and risk factors are not fully elucidated.

Methods

We analyzed the prevalence, incidence, concurrent diseases, and risk factors of NS/IN by using data from specific health checkups of Kumamoto citizens between 2008 and 2010.

Results

Although the prevalence of NS/IN was 1?2 % in people in their 40s, it increased sharply with age, reaching 17.6 % in people aged 70–74 years. The incidence of new NS/IN was 0.4?0.5 % per year. In multivariate logistic regression analysis, factors such as age, male gender, body mass index (BMI), hyperuricemia, hypertension, and dyslipidemia correlated with NS/IN. When risk factors associated with NS/IN progress were evaluated by multivariate logistic regression analysis, four factors—male gender, hypertension, BMI, and current smoking—significantly correlated.

Conclusion

The analysis of Kumamoto citizens aged 40–74 years receiving specific health checkups showed that in addition to hypertension and age that were considered important, male gender and obesity are also risk factors for NS/IS independent from hypertension.     

Long-term renoprotective effect of combination therapy with prostaglandin E1 and angiotensin-converting enzyme inhibitor in patients with chronic renal failure.

Angiotensin-converting enzyme inhibitors (ACE-I) have a renoprotective effect in patients with chronic renal failure. Prostaglandins (PGs) have also been shown to ameliorate renal impairment. Although these two have different mechanisms-ACE-I reduces intraglomerular pressure by dilating the efferent arterioles, while it is thought that PGs may increase intraglomerular pressure--coadministration of these drugs may have an additive effect. Administration of a PG with an ACE-I might have an additive effect on chronic renal failure. However, there have been no studies on the efficacy of such a combination therapy. This study was conducted to determine whether combination therapy with PGE1 and an ACE-I might have a long-term benefit on chronic renal failure. Sixty patients with chronic renal disease receiving an ACE-I in advance were assigned to receive an ACE-I alone or an ACE-I plus PGE1. Blood pressure, blood chemistry, urinary protein excretion, and the changes in the reciprocal of serum creatinine (delta1/Cr) were monitored once monthly for an average of 36.5 months. In patients treated only with an ACE-I, the progression of renal failure did not change with time. In contrast, the decline of renal function was significantly reduced with the combination therapy. The renoprotective effect of the combination therapy was not exerted by reduced proteinuria or by decreased blood pressure. PGE1 may reinforce the renoprotective effects of ACE-I to prevent the progression of chronic renal failure.