Renal-protective effect of T-and L-type calcium channel blockers in hypertensive patients: an Amlodipine-to-Benidipine Changeover (ABC) study.

Both strict blood pressure control and efferent artery dilatation are critical in reducing proteinuria, which in turn helps to regulate blood pressure. Benidipine, an L- and T-type calcium channel blocker, has the potential for increased effectiveness compared with L-type-dominant calcium channel blockers such as amlodipine. Therefore, we evaluated blood pressure and proteinuria after changeover from amlodipine to benidipine in poorly controlled hypertensive patients. Fifty-eight hypertensive outpatients undergoing amlodipine treatment and unable to achieve optimal blood pressure as determined by Japanese Society of Hypertension Guidelines for the Management of Hypertention (JSH 2004) were changed over to benidipine treatment. We measured blood pressure and pulse rate and assessed urinary protein excretion before and after changeover. Systolic and diastolic blood pressure dropped from 151/90 mmHg to 140/81 mmHg (p<0.0001). Mean blood pressure (p<0.0001) and pulse pressure (p=0.0069) were also reduced, but pulse rate increased from 75 bpm to 78 bpm (p=0.0047). Urinary protein excretion adjusted for urinary creatinine was reduced from 0.35 +/- 0.82 to 0.22 +/- 0.55 g/g creatinine (p=0.0119). The urinary protein reduction was observed only in patients with renin-angiotensin inhibition (p=0.0216). By switching from amlodipine to benidipine treatment, more than 80% of patients reduced their blood pressure, and more than 40% achieved optimal blood pressure. Higher urinary protein excretion (p<0.0001), lower glomerular filtration rate (p=0.0011) and presence of diabetes (p=0.0284) were correlated with reduction of urinary proteins during changeover. Taken together, our results suggest that benidipine may have greater efficacy than amlodipine in reducing blood pressure and proteinuria.     

Different changes of bone mineral density and nutritional status after hospitalization between vascular dementia and Alzheimer's disease in elderly female patients

Background:   Bone fractures strongly influence morbidity and mortality in elderly patients with dementia. The goal of this study was to examine whether difference in the type of dementia affects changes of bone mineral density (BMD) during hospitalization with rehabilitation programs.
Methods:   Ninety-four Japanese elderly female patients were enrolled. BMD, Mini-Mental State Examination (MMSE) scores, and levels of serum albumin, calcium-related factors and urinary calcium excretion were measured.
Results:   Multivariable analyses indicated that serum albumin levels and MMSE scores were positively correlated with changes in BMD after 2 years hospitalization. Significant reduction of BMD levels after hospitalization were observed in patients with severe dementia (MMSE scores, <10) or with severe malnutrition (serum albumin, <2.0). We next classified our subjects into three groups according to the 4th edn of the Diagnostic and Statistical Manual criteria: non-dementia (ND), Alzheimer's disease (AD) and vascular dementia (VaD). Although there were no significant differences in age and physical activities among the groups; the levels of BMD were maintained in AD as well as ND but not in VaD. Notably, calcium excretion levels were significantly decreased after hospitalization in AD as well as ND but not in VaD. Serum 25(OH)D levels were also restored in AD but not in VaD. In addition, the nutritional status significantly improved in AD but not in VaD.
Conclusion:   The levels of BMD were maintained and the nutritional status was improved in AD but not in VaD for 2 years hospitalization with rehabilitation programs. These results suggest that different programs including nutritional support may be necessary for maintaining BMD levels in VaD as compared with AD during hospitalization.     

Methods and timing of biliary drainage for acute cholangitis: Tokyo Guidelines

Biliary drainage is a radical method to relieve cholestasis, a cause of acute cholangitis, and takes a central part in the treatment of acute cholangitis. Emergent drainage is essential for severe cases, whereas patients with moderate and mild disease should also receive drainage as soon as possible if they do not respond to conservative treatment, and their condition has not improved. Biliary drainage can be achieved via three different routes/procedures: endoscopic, percutaneous transhepatic, and open methods. The clinical value of both endoscopic and percutaneous transhepatic drainage is well known. Endoscopic drainage is associated with a low morbidity rate and shorter duration of hospitalization; therefore, this approach is advocated whenever it is applicable. In endoscopic drainage, either endoscopic nasobiliary drainage (ENBD) or tube stent placement can be used. There is no significant difference in the success rate, effectiveness, and morbidity between the two procedures. The decision to perform endoscopic sphincterotomy (EST) is made based on the patient’s condition and the number and diameter of common bile duct stones. Open drainage, on the other hand, should be applied only in patients for whom endoscopic or percutaneous transhepatic drainage is contraindicated or has not been successfully performed. Cholecystectomy is recommended in patients with gallbladder stones, following the resolution of acute cholangitis with medical treatment, unless the patient has poor operative risk factors or declines surgery.     

X-Linked Lymphoproliferative Disease in an Adult

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic vasculitis.The causative gene for XLP was identified as SH2D1A/DSHP/SLAM-associated protein (SAP) in 1998, and genetic analysis has been used for the definite diagnosis of XLP. Diagnosis for most patients occurs at ages younger than 10 years, and there are few adult patients. Here we describe a 23-year-old man with hypogammaglobulinemia and EBV-associated hemophagocytic lymphohistiocytosis and a diagnosis of XLP. In addition, the patient showed type 1 helper T-cell (Th1) skewing, as has been described in Sap knock-out mice. Th1/Th2 imbalance in humans, as well as in mice, may play an important role in the pathogenesis of XLP.     

Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells

Although the cellular and molecular mechanisms governing angiogenesis are only beginning to be understood, signaling through endothelial-restricted receptors, particularly receptor tyrosine kinases, has been shown to play a pivotal role in these events. Recent reports show that EphB receptor tyrosine kinases and their transmembrane-type ephrin-B2 ligands play essential roles in the embryonic vasculature. These studies suggest that cell-to-cell repellent effects due to bidirectional EphB/ephrin-B2 signaling may be crucial for vascular development, similar to the mechanism described for neuronal development. To test this hypothesis, we disrupted the precise expression pattern of EphB/ephrin-B2 in vivo by generating transgenic (CAGp-ephrin-B2 Tg) mice that express ephrin-B2 under the control of a ubiquitous and constitutive promoter, CMV enhancer-beta-actin promoter-beta-globin splicing acceptor (CAG). These mice displayed an abnormal segmental arrangement of intersomitic vessels, while such anomalies were not observed in Tie-2p-ephrin-B2 Tg mice in which ephrin-B2 was overexpressed in only vascular endothelial cells (ECs). This finding suggests that non-ECs expressing ephrin-B2 alter the migration of ECs expressing EphB receptors into the intersomitic region where ephrin-B2 expression is normally absent. CAGp-ephrin-B2 Tg mice show sudden death at neonatal stages from aortic dissecting aneurysms due to defective recruitment of vascular smooth muscle cells to the ascending aorta. EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells plays an essential role in vasculogenesis, angiogenesis, and vessel maturation.     

Movements of truncated kinesin fragments with a short or an artificial flexible neck

To investigate the role of the neck domain of kinesin, we used optical trapping nanometry to perform high-resolution measurements of the movements and forces produced by recombinant kinesin fragments in which the neck domains were shortened or replaced by an artificial random coil. Truncated kinesin fragments (K351) that contain a motor domain consisting of ≈340 aa and a short neck domain consisting of ≈11 aa showed fast movement (800 nm/s) and 8-nm steps. Such behavior was similar to that of recombinant fragments containing the full-length neck domain (K411) and to that of native kinesin. Kinesin fragments lacking the short neck domain (K340), however, showed very slow movement (<50 nm/s), as previously reported. Joining an artificial 11-aa sequence that was expected to form a flexible random chain to the motor domain (K340–chain) produced normal fast (≈700 nm/s) and stepwise movement. The results suggest that the neck domain does not act as a rigid lever arm to magnify the structural change at the catalytic domain as has been believed for myosin, but it does act as a flexible joint to guarantee the mobility of the motor domain.     

The role and therapeutic targeting of IL-6 in rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is an autoimmune chronic disease with joint and systemic inflammation and it has been found that interleukin-6 (IL-6) plays a key role in RA. Indeed, various clinical studies have proved that the first-in-class IL-6 inhibitor, tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed outstanding efficacy in RA.

Areas covered: We review here the role of IL-6 in the inflammatory conditions and how IL-6 contributes to pathogenesis of RA, what induces IL-6 and how IL-6 expression is regulated. Furthermore, clinical studies of tocilizumab for RA are summarized,

Expert commentary: We review and discuss the prospects for future applications of IL-6 targeting therapy and new therapeutic strategies targeting IL-6. Finally, we discuss relevant issues with regard to the clinical management of IL-6 blockade in RA.     

First molecular detection and characterization of Hepatozoon and Sarcocystis spp. in field mice and voles from Japan

Sarcocystis and Hepatozoon species are protozoan parasites that are frequently detected in domestic and wild animals. Rodents are considered common intermediate and paratenic hosts for several Sarcocystis and Hepatozoon species. Here, blood DNA samples from a total of six rodents, including one Myodes rutilus, one Myodes rufocanus, and four Apodemus speciosus, collected from Hokkaido, Japan, were shown by conventional PCR of the 18S ribosomal RNA (rRNA) gene to contain Sarcocystis and Hepatozoon DNA. Sequencing of the DNA detected one Sarcocystis sp. in the M. rufocanus sample and two different Hepatozoon spp. in the M. rutilus and A. speciosus samples. Phylogenetic analysis showed that the detected Sarcocystis sp. sequence grouped with GenBank Sarcocystis sequences from rodents, snakes, and raccoons from Japan and China. The 18S rRNA partial gene sequences of both detected Hepatozoon spp. clustered with GenBank Hepatozoon sequences from snakes, geckos and voles in Europe, Africa, and Asia. This study provides evidence that wild rodents have a role in the maintenance of Sarcocystis and Hepatozoon species on the island of Hokkaido.

     

Leptin upregulation in advanced multiple system atrophy with hypocholesterolemia and unexpected fat accumulation

Advanced multiple system atrophy (MSA) patients exhibit malnutrition with hypocholesterolemia and hypoalbuminemia, similar to patients with other neurodegenerative disorders, but also display unexpected fat accumulation. To understand this paradox, we herein examined the relationship between fat accumulation, measured by triceps skinfold thickness (TSF), and plasma leptin in 29 MSA patients at three clinical stages: activities of daily living (ADL) 1: ambulatory with/without wheelchair; ADL2: bedridden/communicable; and ADL3: bedridden/non-communicable. TSF and leptin were higher while cholesterol and albumin were lower in advanced stage ADL3 than in ADL1 or ADL2. Although a correlation was observed between leptin and TSF, a stepwise regression analysis identified the first significant positive predictor of leptin as the duration of autonomic symptoms (p < 0.005) rather than TSF. Leptin/TSF strongly correlated with the duration of autonomic symptoms (p < 0.001). These results implicate leptin resistance through autonomic dysfunction in the paradoxical fat accumulation observed in patients with advanced MSA, but not to be seen in the cholesterol metabolism.