Once-weekly teriparatide in hemodialysis patients with hypoparathyroidism and low bone mass: a prospective study.

UNLABELLED: Once-weekly 56.5-µg teriparatide treatment was significantly associated with the increase in lumbar spine bone mineral density at 48 weeks among hemodialysis patients with hypoparathyroidism and low bone mass; however, discontinuation of treatment because of adverse events was frequently observed. Careful monitoring for adverse events should be required. INTRODUCTION: Once-weekly 56.5-µg teriparatide is reportedly effective for treating osteoporotic patients without renal insufficiency. However, little is known about the efficacy and safety of once-weekly teriparatide in hemodialysis patients. METHODS: We conducted a 48-week prospective, observational cohort study including 22 hemodialysis patients aged 20 years or older with hypoparathyroidism and low bone mass who received once-weekly teriparatide at 56.5 µg at a tertiary care hospital between January 2013 and January 2015. Primary outcomes were within-subject percent changes of bone mineral density (BMD) at the lumbar spine, femoral neck, and distal one-third radius at 24 and 48 weeks. Secondary outcomes included percent changes of serum bone turnover markers (osteocalcin, bone-specific alkaline phosphatase (BAP), N-terminal propeptide of procollagen type 1 (P1NP), and tartrate-resistant acid phosphatase 5b (TRAP-5b)). Adverse events were evaluated. RESULTS: The BMD increased at the lumbar spine by 3.3 ± 1.9 % (mean ± SEM) and 3.0 ± 1.8 % at 24 and 48 weeks but not in the femoral neck and distal one-third radius. Serum osteocalcin, BAP, and P1NP increased significantly at 4 weeks, maintaining higher concentrations up to 48 weeks, although TRAP-5b decreased gradually during treatment. The baseline BAP was significantly associated with the 48-week percent change in lumbar spine BMD. Transient hypotension was the most common adverse event. Ten patients discontinued treatment because of adverse events. CONCLUSIONS: Once-weekly teriparatide was associated with increased lumbar spine BMD in hemodialysis patients with hypoparathyroidism and low bone mass. Careful monitoring should be required for treatment of such patients.

Bone histomorphometry in a long-term hemodialysis patient with hypoparathyroidism and sarcoidosis.

A bone biopsy specimen in a long-term hemodialysis patient with sarcoidosis coexisting with severe hypoparathyroidism has demonstrated that a persistent near physiological level of 1,25-dihydroxyvitamin D3 contributes to the preservation of bone remodeling and has the potential to retard the development of vascular calcification and atherosclerosis. Sarcoidosis-related hypercalcemia and hypoparathyroidism, which is characterized by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) overproduction, is rarely seen in hemodialysis patients. Herein, we describe a 60-year-old Japanese woman on hemodialysis for 35 years who presented with malaise and hypercalcemia. Severe hypoparathyroidism without parathyroidectomy and a preserved 1,25(OH)2D3 level were detected. Computed tomography showed bilateral axillary lymphadenopathy and minimal aortic and soft tissue calcification. The axillary node biopsy led to a definite diagnosis of sarcoidosis. A bone biopsy specimen obtained from the right iliac crest showed remodeling of normal lamellar bone with scalloped cement lines and clear double labeling by tetracycline on fluorescence microscopy. Histomorphometric analysis revealed that the bone formation rate was preserved (30.0 %/year), together with a decrease of osteoid volume (5.75 %) and fibrous volume (0 %), indicating that the patient did not have adynamic bone disease and only showed mild disease. This is the first documented case of sarcoidosis-related hypercalcemia associated with severe hypoparathyroidism in a long-term hemodialysis patient who underwent bone histomorphometry. Our findings suggest that, in hemodialysis patients with sarcoidosis coexisting with severe hypoparathyroidism, a persistent near physiological level of 1,25(OH)2D3 contributes to the preservation of bone remodeling and has the potential to retard the development of vascular calcification and atherosclerosis.

Impact of tubulointerstitial lesions on anaemia in patients with biopsy-proven diabetic nephropathy.

AIMS: To investigate the relationship between the progression of anaemia and renal pathological findings in patients with diabetic nephropathy. METHODS: A total of 223 patients with diabetes underwent renal biopsy from 1985 to 2010 and were confirmed to have pure diabetic nephropathy according to the recent classification, of whom 113 (baseline haemoglobin ≥ 11 g/dl) were enrolled in the study. Linear regression analysis was used to estimate the changes in haemoglobin levels during the follow-up period. RESULTS: In a multivariate model adjusted for clinical and histopathological variables, higher interstitial fibrosis and tubular atrophy scores were more strongly associated with a decrease in haemoglobin levels than were lower scores. Compared with an interstitial fibrosis and tubular atrophy score of 0, the standardized coefficients for interstitial fibrosis and tubular atrophy scores of 1, 2 and 3 were 0.20 (95% CI -0.31 to 0.93), 0.34 (95% CI -0.22 to 1.34) and 0.47 (95% CI 0.07 to 1.96), respectively, whereas a higher glomerular class, a higher vascular lesion score and the presence of exudative lesions were not strongly correlated with the decrease in haemoglobin. CONCLUSIONS: Tubulointerstitial lesions that are more advanced are significantly associated with the progression of anaemia in patients with diabetic nephropathy after adjustment for numerous covariates. This finding suggests that tubulointerstitial lesions may be a useful prognostic indicator for anaemia in patients with diabetic nephropathy, and that decreased erythropoietin production attributable to the progression of tubulointerstitial lesions is a major cause of anaemia in these patients.

A case of familial lecithin-cholesterol acyltransferase deficiency on hemodialysis for over 20 years.

We trace the 34-year history of a member of the first Japanese family in which lecithin-cholesterol acyltransferase (LCAT) deficiency was diagnosed. Marriage between cousins with low LCAT activity was responsible for familial LCAT deficiency (FLD). In 1976, a 27-year-old Japanese man was noted to have FLD based on proteinuria, hematuria, grayish corneal opacity and low LCAT activity (9.83%). Genetic analysis showed insertion of G-G-C coding glycine at codon 141. Total cholesterol (C) was low at 108 mg/dl and the ratio of C-ester to total C was very low (12%), while the lecithin (phosphatidylcholine) level was very high (97.3%). When his serum creatinine reached 2.6 mg/dl at the age of 41 years (in 1991), renal biopsy was performed. This showed expansion of the mesangial matrix and irregularly thickened capillary walls with a bubble-like appearance because of lipid deposits consisting of two components (partly lucent vacuolated areas and partly deeply osmiophilic areas). Magnification of the latter deposits showed curvilinear and serpiginous striated membranous structure. Hemodialysis was started in 1990 and has been continued for over 20 years until August 2010. Clinical problems have included AV shunt failure requiring 4 operations and 13 percutaneous transcatheter angioplasty procedures, as well as episodes of hemolytic anemia that subsided after infusion of fresh frozen plasma. Cardiovascular events have not yet occurred, although severe calcification of abdominal aorta has been detected by computed tomography.

Current-induced domain-wall switching in a ferromagnetic semiconductor structure.

Magnetic information storage relies on external magnetic fields to encode logical bits through magnetization reversal. But because the magnetic fields needed to operate ultradense storage devices are too high to generate, magnetization reversal by electrical currents is attracting much interest as a promising alternative encoding method. Indeed, spin-polarized currents can reverse the magnetization direction of nanometre-sized metallic structures through torque; however, the high current densities of 10(7)-10(8) A cm(-2) that are at present required exceed the threshold values tolerated by the metal interconnects of integrated circuits. Encoding magnetic information in metallic systems has also been achieved by manipulating the domain walls at the boundary between regions with different magnetization directions, but the approach again requires high current densities of about 10(7) A cm(-2). Here we demonstrate that, in a ferromagnetic semiconductor structure, magnetization reversal through domain-wall switching can be induced in the absence of a magnetic field using current pulses with densities below 10(5) A cm(-2). The slow switching speed and low ferromagnetic transition temperature of our current system are impractical. But provided these problems can be addressed, magnetic reversal through electric pulses with reduced current densities could provide a route to magnetic information storage applications.

Hepatitis C virus-related kidney disease: various histological patterns.

BACKGROUND: Although hepatitis C virus (HCV) infection is known to be associated with Type 2 cryoglobulinemic glomerulopathy (CG), only a few reports about other types of nephropathy have been published. METHODS: 68 HCV antibody positive patients in whom renal biopsy had been performed for persistent proteinuria, hematuria, and/or renal dysfunction between 1992 and 2008 at our institute were included. The histological, clinical and laboratory characteristics including the age, gender, hypertension, diabetes mellitus, liver histology (chronic hepatitis or liver cirrhosis), HCV-RNA, HCV genotype, splenomegaly, gastroesophageal varices, serum creatinine, hemoglobin, platelet count, rheumatoid factor, cryoglobulin, IgG, IgA, IgM, CH50, C3, C4, creatinine clearance, 24-h protein excretion, and hematuria, between their nephropathy with and without immune deposition were compared. RESULTS: Nephropathy was classified into two groups based on the detection of immune deposits by immunofluorescence microscopy: i.e., a positive group (n = 39) and a negative group (n = 29). The former group was further classified into three types of nephropathy: IgG dominant group (n = 10) (including membranous nephropathy (MN)), IgA dominant group (n = 20) (including IgA nephropathy (IgAN)), membranoproliferative glomerulonephritis (MPGN) (IgA type)), and IgM dominant group (n = 9) (MPGN apart from the IgA type). The latter group included diabetic nephropathy (n = 13), focal glomerular sclerosis (n = 4), and benign nephrosclerosis (n = 3), malignant nephrosclerosis (n = 1), tubulointerstitial nephritis (TIN) (n = 2), minimal change nephrotic syndrome (n = 1), cast nephropathy (n = 1), granulomatous TIN (n = 1), and others (n = 3). An increased serum IgM level, hypocomplementemia, splenomegaly, thrombocytopenia, liver cirrhosis, hematuria, and a high HCV RNA level were features of patients with MPGN of IgM dominant group (consistent with "CG"). CONCLUSIONS: Our results showed various histological patterns of HCV-related kidney disease and the specificity of CG, and revealed that a minority of HCV patients (n = 7) presented typical CG, while IgAN, MN, and diabetic nephropathy were more frequent.

Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice.

Several lines of evidence show the importance of angiotensin II (AII) in renal injuries, especially when hemodynamic abnormalities are involved. To elucidate the role of AII in immune-mediated renal injury, we studied anti-glomerular basement membrane (GBM) nephritis in AII type 1a receptor (AT1a)-deficient homozygous (AT1a-/-) and wild-type (AT1a+/+) mice. A transient activation of the renin-angiotensin system (RAS) was observed in both groups of mice at around day 1. A renal expression of monocyte chemoattractant protein-1 (MCP-1) was transiently induced at six hours in both groups, which was then downregulated at day 1. In the AT1a+/+ mice, after RAS activation, the glomerular expression of MCP-1 was exacerbated at days 7 and 14. Thereafter, severe proteinuria developed, and the renal expressions of transforming growth factor-beta1 (TGF-beta1) and collagen type I increased, resulting in severe glomerulosclerosis and interstitial fibrosis. In contrast, glomerular expression of MCP-1, proteinuria, and tissue damage were markedly ameliorated in the AT1a-/- mice. Because this amelioration is likely due to the lack of AT1a, we can conclude that AII action, mediated by AT1a, plays a pathogenic role in anti-GBM nephritis, in which AII may contribute to the exacerbation of glomerular MCP-1 expression. These results suggest the involvement of AII in immune-mediated renal injuries.

Simplified PET quantitation of myocardial glucose utilization.

UNLABELLED: The purpose of this study was to validate experimentally a simple method to quantify tissue glucose utilization with the brain reference index (BRI) using 14C-deoxyglucose and assess its clinical feasibility for myocardial PET. METHODS: To validate the BRI method, glucose utilization in myocardial and skeletal muscle was studied in rats with 14C-deoxyglucose after increasing doses of oral glucose loading. To assess clinical feasibility of the method, the BRI was applied to nine patients undergoing myocardial PET and compared to rMGU measured by the deoxyglucose model of Sokoloff et al. and by Patlak graphical analysis. The normal range of myocardial FDG uptake expressed as the BRI was estimated with four normal volunteers. RESULTS: In skeletal muscle, a dose-dependent increase of glucose utilization was observed during oral glucose loading with doses up to 4 mg/g. In the myocardium, glucose utilization increased with a glucose loading dose of up to 1 mg/g without increasing further at greater glucose doses. Ratios of maximal glucose utilization in glucose-loaded rats to 19-hr fasted rats (controls), expressed as the BRI for left and right ventricular myocardium and skeletal muscle were 4.16, 3.74 and 7.39, respectively. Glucose utilization of right ventricular myocardium was approximately 70% of left ventricular myocardium for all glucose-loaded conditions. For patients, the BRI correlated with rMGU; four of these patients had a constant plasma glucose concentration. CONCLUSION: Myocardial BRI is a sensitive indicator of rMGU that does not require dynamic data acquisition or constant plasma glucose concentrations.

Prognostic utility of myocardial blood flow assessed by N-13 ammonia positron emission tomography in patients with idiopathic dilated cardiomyopathy.

Previous studies in patients with idiopathic dilated cardiomyopathy (IDC) have suggested that myocardial perfusion is impaired and spatially heterogeneous in such cases. Our objective was to identify any association between an abnormality in myocardial perfusion and the prognosis of patients with IDC. We collected data on N-13 ammonia positron emission tomography (PET) studies performed in 26 patients with IDC (9 nonsurvivors, 17 survivors) and in 8 normal control subjects. Regional myocardial blood flow (rMBF) was quantified using N-13 ammonia positron emission tomography and the Simple flow model. The spatial heterogeneity of myocardial perfusion was assessed by calculating the coefficient of variance of rMBF. Mean rMBF of the survivors was significantly lower (0.54 +/- 0.13 ml/min/g) than that of control subjects (0.66 +/- 0.06 ml/min/g) (p = 0.03 vs control), but did not differ significantly between nonsurvivors (0.58 +/- 0.15 ml/min/g) and control subjects. The coefficient of variance of rMBF was significantly higher in nonsurvivors than in either survivors or control subjects (0.24 +/- 0.08 vs 0.15 +/- 0.08, p = 0.007, and 0.16 +/- 0.05, p = 0.03, respectively). The probability of 3-year survival (Kaplan-Meier method) was 33.0% in subjects whose coefficient of variance of rMBF was above the median compared with 90.0% in subjects whose coefficient of variance of rMBF was below the median (p = 0.01). The probability of 3-year survival did not differ among subjects whose mean rMBF was above versus below the median (61.5% vs 62.9%, respectively). The results suggest that the prognosis of patients with IDC is associated with the spatial heterogeneity of myocardial perfusion, not with initial absolute rMBF.

Nociceptin inhibits capsaicin-sensitive contraction to mesenteric nerve stimulation in the guinea-pig isolated ileum.

Mesenteric nerve stimulation (MNS) in the presence of guanethidine and hexamethonium antidromically stimulated extrinsic sensory nerve fibers and cholinergic myenteric motor neurons, resulting in longitudinal muscle contraction in the isolated guinea-pig ileum. Nociceptin (NC) is a recently discovered neuropeptide that structurally resembles an opioid peptide. The aim of the current study was to examine how NC affects the contractile responses to MNS in the isolated guinea-pig ileum, in comparison with an opiate, methionine-enkephalin. These contractions were auxotonically recorded and their amplitude was analyzed. NC (1-100 nM) and methionine-enkephalin (0.1-10 microM) concentration-dependently inhibited the response to MNS (20 Hz, 0.5 ms, supramaximal currents). Naloxone (10 microM) significantly diminished the inhibitory effect of methionine-enkephalin (0.1-10 microM), but did not antagonize the inhibitory effect of NC (1-100 nM). We conclude that NC receptors, distinct from opioid receptors, exist on the capsaicin-sensitive sensory nerve fibers and/or myenteric cholinergic motor neurons in the guinea-pig ileum and that specific antagonists for these NC receptors are not found yet.

Mantle cell lymphoma of the rectum at an early stage: a case report.

We report a very rare early-stage case of mantle cell lymphoma, which arose from the rectum. A 60-year-old man presented with a small elastically hard polypoid lesion in the rectum. The lesion was 1.2 x 1.2 cm in size. As a preoperatively barium enema and endoscopy suggested a benign tumor of the rectum, he underwent local excision of a rectal polypoid mass transanally under spinal anesthesia. However, histological examination revealed a malignant lymphoma, because the lesion was histologically characterized by solid growths of small to medium-sized round cells. Furthermore, immunohistochemical tests revealed B-cell marker positivity and CD5 positivity, but cyclin D1 negativity. Since it was reported that lymphomas with a mantle cell lymphoma morphology and CD5 expression, but without cyclin D1 overexpression, exist in about 10% of mantle cell lymphoma cases, we diagnosed his disease as mantle cell lymphoma. To our knowledge, this is the first reported case of an early-stage mantle cell lymphoma, originating from the rectum.

Low copper and brain abnormalities in fetus from triethylene tetramine dihydrochloride-treated pregnant mouse.

The effects of prenatal triethylene tetramine dihydrochloride (Trien-2HCl) exposure on fetal mice have been investigated on gestational day 19. Trien-2HCl was given throughout pregnancy at levels of 0 (control), 3,000, 6,000, or 12,000 ppm as drinking water, ad libitum. At the level of 12,000 ppm, the frequency of total resorption tended to be high and that of fetal viability tended to be low, as compared to controls. Decreased maternal weight was observed in body, but not in liver, at the level of 12,000 ppm. Fetal body and cerebrum weights significantly decreased at the levels of 6,000 and 12,000 ppm; however, fetal liver weight remained unchanged. Maternal serum copper concentration was not affected by the Trien-2HCl. Fetal copper concentrations of liver and cerebrum were significantly lower in the Trien-2HCl-treated groups than in the controls, with levels decreasing in a dose-related manner. When the copper and zinc concentrations in the group treated at 12,000 ppm were compared with those in controls, significant decreases in both metals were observed in placenta but not in maternal liver. Changes in fetal zinc concentration varied by tissues: i.e., an increase in liver and no change in cerebrum. Fetal abnormalities were frequently observed in brain, and the frequency was increased with increasing levels of the Trien-2HCl. These results suggest that fetal brain abnormalities caused by Trien-2HCl may be due in part to induction of copper deficiency, which is almost equivalent to that in brindled mutant mouse.

[Relationship between static images of 13N ammonia positron emission tomography and left ventricular wall motion in patients with coronary artery disease].

Observed myocardial activities in static image of 13N ammonia positron emission tomography (PET) contains factors about not only myocardial blood flow but also wall motion, wall thickness and glutamine synthetase activity. Those factors may help to delineate myocardial viability in 13N ammonia static image. To assess the role of 13N ammonia static image in prediction of reversibility of regional wall motion abnormalities after revascularization, we studied 20 patients with coronary artery disease. Of these patients, 15 patients underwent successful coronary revascularization (8 PTCA, 7 CABG). Regional 13N concentration before revascularization was expressed as a percent of maximal myocardial concentration and compared with regional wall motion. Wall motion was assessed by visual analysis using left ventriculography. Regional myocardial 13N concentration in normal, hypokinetic, akinetic and dyskinetic segments was 85 +/- 9.3%, 75 +/- 11%*, 71 +/- 17%* and 58 +/- 7.7%*#+, respectively (*p < 0.05 vs. normal, #p < 0.05 vs. hypokinesis, +p < 0.05 vs. akinesis). The segments with functional improvement showed significantly higher concentration of 13N than those without functional recovery (80 +/- 9.7% vs. 67 +/- 8.3%, p < 0.05). By using an optimized threshold value for normalized 13N activities, the sensitivity and specificity reached to 67% and 100%, respectively, to predict functional recovery. Our data suggested that myocardial 13N concentration in static PET image is closely related to the left ventricular wall motion in the patients with coronary artery disease and that it has a possible value of prediction of myocardial viability.

[A case report of left atrial free-floating ball thrombus in a patient without mitral valve disease].

A 77-year-old man who had a left atrial free-floating ball thrombus without mitral valve disease was operated. His electrocardiogram showed atrial fibrillation. Transesophageal echocardiography showed free-floating mass in dilated left atrium and intact mitral valve. Transesophageal echocardiogram was also useful for intra-operative management. At the operation, the mass proved to be a free-floating ball thrombus in the left atrium and the intact mitral valve was confirmed. The thrombus was removed, but we could not wean the patient from extra-corporeal circulation due to intra-operative myocardial infarction. Autopsy showed left ventricular hypertrophy and the focus of acute myocardial infarction in lateral wall and posterior wall of left ventricle. Furthermore, large organized thrombi were found in aorta and right main pulmonary artery. It was suggested that the patient had abnormal coagulative system or fibrolytic system preoperatively.

Depinning probability of a magnetic domain wall in nanowires by spin-polarized currents.

Current-induced magnetic domain wall motion is attractive for manipulating magnetization direction in spintronics devices, which open a new era of electronics. Up to now, in spite of a crucial significance to applications, investigation on a current-induced domain wall depinning probability, especially in sub-nano to a-few-nanosecond range has been lacking. Here we report on the probability of the depinning in perpendicularly magnetized Co/Ni nanowires in this timescale. A high depinning probability was obtained even for 2-ns pulses with a current density of less than 10¹² A m⁻². A one-dimensional Landau-Lifshitz-Gilbert calculation taking into account thermal fluctuations reproduces well the experimental results. We also calculate the depinning probability as functions of various parameters and found that parameters other than the coercive field do not affect the transition width of the probability. These findings will allow one to design high-speed and reliable magnetic devices based on the domain wall motion.