In recent times, therapy for renal anemia has changed dramatically in that iron administration has increased and doses of erythropoiesis-stimulating agents (ESAs) have decreased. Here we used a prospective, observational, multicenter design and measured the serum ferritin and hemoglobin levels every 3 months for 2 years in 1086 patients on maintenance hemodialysis therapy. The associations of adverse events with fluctuations in ferritin and hemoglobin levels and ESA and iron doses were measured using a Cox proportional hazards model for time-dependent variables. The risks of cerebrovascular and cardiovascular disease (CCVD), infection, and hospitalization were higher among patients who failed to maintain a target-range hemoglobin level and who exhibited high-amplitude fluctuations in hemoglobin compared with patients who maintained a target-range hemoglobin level. Patients with a higher compared with a lower ferritin level had an elevated risk of CCVD and infectious disease. Moreover, the risk of death was significantly higher among patients with high-amplitude ferritin fluctuations compared with those with a low ferritin level. The risks of CCVD, infection, and hospitalization were significantly higher among patients who were treated with high weekly doses of intravenous iron compared with no intravenous iron. Thus, there is a high risk of death and/or adverse events in patients with hemoglobin levels outside the target range, in those with high-amplitude hemoglobin fluctuations, in those with consistently high serum ferritin levels, and in those with high-amplitude ferritin fluctuations.
The assembly of progenitor cells is a crucial step for organ formation during vertebrate development. Kupffer's vesicle (KV), a key organ required for the left-right asymmetric body plan in zebrafish, is generated from a cluster of ∼20 dorsal forerunner cells (DFCs). Although several genes are known to be involved in KV formation, how DFC clustering is regulated and how cluster formation then contributes to KV formation remain unclear. Here we show that positive feedback regulation of FGF signaling by Canopy1 (Cnpy1) controls DFC clustering. Cnpy1 positively regulates FGF signals within DFCs, which in turn promote Cadherin1-mediated cell adhesion between adjacent DFCs to sustain cell cluster formation. When this FGF positive feedback loop is disrupted, the DFC cluster fails to form, eventually leading to KV malformation and defects in the establishment of laterality. Our results therefore uncover both a previously unidentified role of FGF signaling during vertebrate organogenesis and a regulatory mechanism underlying cell cluster formation, which is an indispensable step for formation of a functional KV and establishment of the left-right asymmetric body plan.left-right patterning | ciliogenesis F ibroblast growth factor (FGF) signaling plays crucial roles in multiple morphogenetic processes of vertebrate development, including gastrulation movement, mesoderm formation, and leftright (LR) patterning (1-3). Because gain or loss of function of FGF signaling results in morphological changes in the embryo, some mechanism must ensure appropriate FGF signal levels in space and time for proper morphogenesis throughout development. FGF effectors acting as positive or negative regulators show a wide range of expression patterns and activities, contributing to the precise regulation of FGF signal activity (1, 4). Although most effectors identified to date act as negative regulators of FGF signaling, a few that positively regulate FGF activity have been reported (1, 4).We recently identified in zebrafish a positive regulator of FGF signaling named canopy1 (cnpy1), which is required for maintenance of the midbrain-hindbrain boundary (MHB) (5). Expression of cnpy1 was restricted to the MHB at late-somitogenesis stages, whereas cnpy1 was broadly distributed in earlier embryos (5) (SI Appendix, Fig. S1A), suggesting an additional role(s) for Cnpy1-mediated FGF signaling beyond the regulation of MHB formation. In this study, we characterize cnpy1 in detail during early zebrafish development and show that a Cnpy1-mediated positive feedback loop of FGF signaling promotes cell cluster formation between dorsal forerunner cells (DFCs) during gastrulation. We also demonstrate that the failure of DFCs to cluster when this FGF positive loop is disrupted eventually leads to Kupffer's vesicle (KV) malformation and randomization of LR asymmetric patterning. Results Positive Feedback Loop of FGF Signaling Mediated by Cnpy1 IsActivated Specifically in DFCs During Zebrafish Gastrulation. To reveal the role of Cnpy1-mediated FGF signaling in ...
Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest 349-354 DOI 10.1007/s10038-007-0122-9 mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan.
We generated transgenic silkworms that synthesized human type I collagen alpha1 chain [alpha1(I) chain] in the middle silk glands and secreted it into cocoons. The initial content of the recombinant alpha1(I) chain in the cocoons of the transgenic silkworms was 0.8%. The IE1 gene, a trans-activator from the baculovirus, was introduced into the transgenic silkworm to increase the content of the chain. We also generated silkworms homozygous for the transgenes. These manipulations increased the alpha1(I) chain content to 8.0% (4.24 mg per cocoon). The alpha1(I) chain was extracted and purified from the cocoons using a very simple method. The alpha1(I) chain contained no hydroxyprolines due to the absence of prolyl-hydroxylase activity in the silk glands. Circular dichroism analysis showed that the secondary structure of the alpha1(I) chain is similar to that of denatured type I collagen, demonstrating the absence of the triple helical structure. Human skin fibroblasts were seeded on the alpha1(I) chain-coated dishes. The cells attached and spread, although at decreased chain concentrations the spreading rate was lower than that of the collagen and gelatin. Cynomolgus monkey embryonic stem cells cultured on the alpha1(I) chain-coated dishes maintained an undifferentiated state after 30 passages, and their pluripotency was confirmed by teratoma formation in severe combined immunodeficient mice. These results show that the recombinant human alpha1(I) chain is a promising candidate biomaterial as a high-quality and safe gelatin substitute for cell culture.
Cilnidipine, an L-/N-type calcium channel blocker, dilates the efferent glomerular arterioles in an experimental model and shows a renoprotective effect, but its clinical benefits and safety have not yet been assessed in type II diabetics with albuminuria. The objective of this trial was to evaluate the effect of reducing albuminuria in type II diabetic patients with a combination therapy consisting of valsartan plus cilnidipine versus monotherapy with valsartan. An open-label, randomized controlled trial was conducted from April 2002 to October 2003 in 87 Japanese patients aged 31-90 years with type II diabetes showing albuminuria (urinary albumin/creatinine ratio: 10-300 mg/g). The patients were randomized to receive either valsartan (n=41) or valsartan plus cilnidipine (n=46) once daily for 1 year. The primary end point was the percent change in the albumin/creatinine ratio. The secondary end points were the progression/regression of albuminuria, blood pressure (BP), renal function, and safety. After 1 year, the albumin/creatinine ratio was found to have decreased more markedly in the valsartan plus cilnidipine group than in the valsartan group (reduction rate -44+/-11% (s.e.) versus -9+/-7% (s.e.); P=0.014 by analysis of covariance). Although a significant reduction was observed in the systolic and diastolic BP of both groups from baseline to 1 year (P<0.0001, respectively), there was no significant difference in the change in the BP between the two groups (systolic BP, P=0.066; diastolic BP, P=0.391). There were also no significant differences in the side effects between the two groups. Cilnidipine was thus found to show an additive effect with valsartan and thereby caused a reduction in albuminuria in type II diabetics.
Intracellular free calcium concentration [( Ca2+]i) was measured with the fluorescent Ca2+ indicator Fura 2 within individual human neutrophils during the phagocytosis of several types of particles, including serum-treated zymosan (STZ), immunoglobulin G (IgG)-coated zymosan (IGZ), C3b-coated zymosan (C3Z), nontreated zymosan (Z), and serum-treated similarly sized latex particles (STL). STZ was coated with both IgG and C3b. IGZ was coated with only IgG, and C3Z was coated with only C3b. STL was coated with only C3b but to a lesser extent than C3Z. The ingestion of particles was greatest for STZ and somewhat lower for C3Z. Ingestion of IGZ and STL was much less than ingestion of C3Z. The relative efficiencies of the particles for inducing superoxide production were as follows: STZ greater than IGZ = C3Z greater than Z = STL. [Ca2+]i significantly increased from the resting level of approximately 70 to greater than 240 nM (P less than 0.01) during phagocytosis of the particles. The increment in [Ca2+]i was greater in the paraphagosomal region than in the cell body after the ingestion of STZ or IGZ. The mean peak [Ca2+]i values in the paraphagosomal cytoplasm of neutrophils ingesting one particle of STZ, IGZ, C3Z, Z and STL were 536.1 +/- 57.6, 424.7 +/- 55.8, 373.8 +/- 62.7, 272.3 +/- 31.5, and 270.8 +/- 38.0 nM, respectively, which showed good correlation (r = 0.97) with the efficiency of the particles for inducing superoxide production. Depletion of extracellular Ca2+ by EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N,N'N'-tetraacetic acid] attenuated both [Ca2+]i increase and superoxide production induced by particles. Thus [Ca2+]i increased after ingestion of several types of particles, and the subcellular pattern of [Ca2+]i was different depending on the type of particle ingested. Greater increases in paraphagosomal [Ca2+]i were closely associated with greater increases in superoxide production by neutrophils.
We report here the first case of successful pregnancy and delivery after the blastocyst transfer of twice-vitrified embryos produced following in vitro maturation (IVM) and ICSI. The patient received 5000 IU hCG on day 12 of the treatment cycle, and oocyte retrieval was carried out 36 h after hCG injection. A total of 22 immature oocytes were obtained. Following incubation for 26 h in IVM medium, 15 oocytes (68.2%) reached metaphase II stage. In total, 13 oocytes (86.7%) were fertilized after ICSI with the husband's sperm, and 11 embryos at the pronuclear stage and two cleaved embryos on day 2 were vitrified because of thin endometrial thickness. Eight cryopreserved embryos at the pronuclear stage were warmed and cultured until the day 3 stage. Three embryos were transferred, and three embryos were twice vitrified. Unfortunately, these transferred embryos did not implant. Three twice-vitrified embryos were rewarmed and cultured until the day 5 stage, and two embryos were transferred. The second transfer attempt of twice-vitrified embryos resulted in the full-term delivery of a healthy infant. This case report demonstrates that twice-vitrified embryos, developed using an IVM protocol, retain the developmental competence for full-term, healthy infants.
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