Weight loss and catabolic changes are increasingly recognized as factors that influence outcomes in patients with amyotrophic lateral sclerosis (ALS). An association between disease progression and ...low BMI has been reported in ALS; however, it remains unknown whether low BMI occurs across all forms of ALS and whether BMI changes with the development of cognitive impairment across the spectrum between ALS and frontotemporal dementia (FTD). One hundred and three ALS patients (56 limb predominant, 18 bulbar predominant, 13 ALS plus, 16 ALSFTD) were recruited and compared to 19 behavioral variant FTD (bvFTD) patients and a group of age-matched healthy controls. BMI was measured at the initial clinical visit. Patients were characterized as underweight, normal, overweight or obese, based on the current World Health Organization (WHO) guidelines. Limb and bulbar ALS patients had significantly lower BMI than ALS plus, ALSFTD, and bvFTD patient groups. When BMI was categorized using WHO guidelines the majority of the limb and bulbar ALS patients were either underweight or normal weight, whilst the majority of the ALS plus, ALSFTD and bvFTD patients were either overweight or obese. On follow-up BMI assessment the limb and bulbar groups tended to decline whilst ALS plus, ALSFTD and bvFTD groups remained stable or increased. BMI is significantly higher in ALS individuals with cognitive deficits. The present findings have prognostic implications for disease progression and may help delineate the metabolic profile across the ALSFTD spectrum.
Summary
Background Antilaminin‐332 mucous membrane pemphigoid (MMP) is a chronic autoimmune bullous disease that is often associated with internal malignancy. IgG autoantibodies against laminin‐332 ...in patients with MMP are well documented; however, IgA and IgE autoantibodies against laminin‐332 have not yet been described.
Objectives To characterize IgA and IgE autoantibodies binding to laminin‐332 in sera from patients with antilaminin‐332 MMP.
Methods Sera and skin samples from four patients who met the following criteria were used: (i) subepidermal blistering lesions present on the mucous membranes; (ii) in vivo deposition of IgG along the epidermal basement membrane zone of sampled skin; (iii) circulating IgG antibasement membrane zone antibodies that react with the dermal side of salt‐split normal human skin; and (iv) circulating IgG autoantibodies that do not show positivity against type VII collagen or 200‐kDa protein (p200 antigen) in immunoblot analysis using dermal extracts. Circulating IgG/IgA/IgE class autoantibodies against laminin‐332 were determined by immunoblotting.
Results Circulating IgG autoantibodies against the γ2, α3/γ2, α3 and α3/β3/γ2 subunits of laminin‐332 were demonstrated in sera from four patients, respectively. Serum from one of the four patients showed IgA reactivity with the α3/β3/γ2 subunits of laminin‐332. Serum from one of the four patients showed IgE reactivity with the γ2 subunit of laminin‐332. The control sera failed to display IgG/IgA/IgE reactivity to laminin‐332.
Conclusions In addition to IgG autoantibodies, circulating IgA and IgE autoantibodies against laminin‐332 are detectable in a subset of patients with antilaminin‐332 MMP.
A use of bulk high-temperature superconductors (HTSs) for an undulator is attractive since a high magnetic field can be generated at low-temperatures. While potential for generation of the high ...magnetic field is high, in-situ magnetization of the bulk HTSs for periodic field generation is challenging issue. Recently, we proposed a new type of undulator using bulk high-Tc superconductors (HTS) and a solenoid magnet. The undulator, named Bulk HTSC staggered array undulator (Bulk HTSC SAU), consists of a stacked array of bulk HTSs and copper insulators and a solenoid magnet. A proof of principle experiment at 77 K using liquid nitrogen has been carried out. The estimated performance at about 30 K was estimated using results of property measurements for the HTS used for the Bulk HTSC SAU. The expected undulator peak field reaches to 1.08 T for undulator period length of 9.9 mm for the undulator gap of 4.0 mm. This performance is about 2 times higher than that of existing technologies.
In the male monkey, luteinising hormone (LH) secretion is regulated by a negative feedback action of testicular testosterone that is exerted indirectly at the hypothalamic level to decelerate ...pulsatile gonadotrophin‐releasing hormone release (GnRH). The purpose of the present experiment was to investigate whether the kisspeptin–G protein‐coupled receptor 54 (GPR54) signalling pathway is involved in mediating the action of testosterone to suppress GnRH release in the monkey, as has been indicated by studies of nonprimates. To this end, 12 castrated adult male rhesus monkeys were implanted with either testosterone containing or empty Silastic capsules. Testosterone treatment produced a square wave increment in circulating testosterone levels within the physiologic range. After suppression of LH and follicle‐stimulating hormone secretion was established at 5–6 weeks of testosterone exposure, the animals were killed and expression of the genes encoding for kisspeptin, GPR54 and GnRH determined in the mediobasal hypothalamus and preoptic area of both treated and control animals using RNase protection assays. The suppression in pituitary gonadotrophin secretion was associated with a reduction in kisspeptin mRNA levels in the mediobasal hypothalamus, but not the preoptic area. GPR54 mRNA levels, on the other hand, were not influenced by testosterone treatment. These results are consistent with those previously reported for the rodent, and suggest that the neurobiology of the negative feedback action of testicular testosterone on LH secretion in the monkey, a representative higher primate, may be mediated by kisspeptinergic neurones upstream to the GnRH network.
Microstructural changes during the formation of White Etching Area (WEA) were investigated using a rolling/sliding contact fatigue test machine. In particular, interfaces between WEA and retained ...austenite or spherodized carbide in a high carbon chromium bearing steel have been observed. Fatigue tests were carried out by means of a disk on roller-type equipment. It was found that acicular structures are formed at an initial stage of the WEA formation process. Plastic deformations of spherodized carbides were caused by shear stress in the initial stage of this process as well. Additionally, micro voids were found near the interfaces. Furthermore, amorphous-like structures were found in the WEA. It was suggested that WEA formation is caused by the local plastic deformation of the material. The shear stress was caused by slipping between the roller and the disk. As a result, it was suggested that martensite forms an amorphous-like phase and then changes into a WEA. Cracks developed in the amorphous-like structure/the granular area interface in the WEA and in the Matrix/WEA interface.
We study the dynamical instability against bar-mode deformation of differentially rotating stars. We performed numerical simulation and linear perturbation analysis adopting polytropic equations of ...state with the polytropic index n= 1. It is found that rotating stars of a high degree of differential rotation are dynamically unstable even for the ratio of the kinetic energy to the gravitational potential energy of O(0.01). Gravitational waves from the final non-axisymmetric quasi-stationary states are calculated in the quadrupole formula. For rotating stars of mass 1.4 M⊙ and radius several 10 km, gravitational waves have frequency several 100 Hz and effective amplitude ∼5 × 10−22 at a distance of ∼100 Mpc.
We sought to clarify the involvement of caspase-12, a representative molecule related to endoplasmic reticulum (ER) stress-induced cell-death signaling pathways, in neuronal death resulting from ...ischemia/reperfusion in mice. Transient focal cerebral ischemia (1 h) was produced by intraluminal occlusion of the middle cerebral artery (MCA). We assessed the expression patterns of caspase-12, Bip/GRP78, an ER-resident molecular chaperone whose expression serves as a good marker of ER stress, and caspase-7 by Western blotting and/or immunohistochemistry. Double-fluorescent staining of caspase-12 immunohistochemistry and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) method was performed to clarify the involvement of caspase-12 in cell death. We confirmed that ER stress was induced during reperfusion in our model, as witnessed by up-regulated Bip/GRP78 expression in the MCA territory. Western blot analysis revealed that caspase-12 activation occurred at 5-23 h of reperfusion, and immunoreactivity for caspase-12 was enhanced mainly in striatal neurons on the ischemic side at the same time points. We found the co-localization of caspase-12 immunoreactivity and DNA fragmentation detectable by the TUNEL method. We did not detect the presence of caspase-7 in the ER fraction at the period of caspase-12 cleavage. Our results imply that cerebral ischemia/reperfusion induces ER stress and that caspase-12 activation concurred with ER stress. Caspase-12 seems to be involved in neuronal death induced by ischemia/reperfusion. Caspase-7 is not likely to contribute to the cleavage of caspase-12 in our experimental model.
We present analyses to determine the fundamental parameters of the Galaxy based on VLBI astrometry of 52 Galactic maser sources obtained with VERA, VLBA, and EVN. We model the Galaxy's structure with ...a set of parameters, including the Galaxy center distance
$ R_0$
, the angular rotation velocity at the LSR
$ \Omega_0$
, the mean peculiar motion of the sources with respect to Galactic rotation (
$ U_{\rm src}$
,
$ V_{\rm src}$
,
$ W_{\rm src}$
), the rotation-curve shape index, and the
$ V$
component of the Solar peculiar motions,
$ V_\odot $
. Based on a Markov chain Monte-Carlo method, we find that the Galaxy center distance is constrained at a 5% level to be
$ R_0$
$ =$
8.05
$ \pm$
0.45 kpc, where the error bar includes both statistical and systematic errors. We also find that the two components of the source peculiar motion
$ U_{\rm src}$
and
$ W_{\rm src}$
are fairly small compared to the Galactic rotation velocity, being
$ U_{\rm src}$
$ =$
1.0
$ \pm$
1.5 km s
$ ^{-1}$
and
$ W_{\rm src}$
$ =$
$-$
1.4
$ \pm$
1.2 km s
$ ^{-1}$
. Also, the rotation curve shape is found to be basically flat between Galacto-centric radii of 4 and 13 kpc. On the other hand, we find a linear relation between
$ V_{\rm src}$
and
$ V_\odot $
as
$ V_{\rm src}$
$ =$
$ V_\odot $
$-$
19 (
$ \pm$
2) km s
$ ^{-1}$
, suggesting that the value of
$ V_{\rm src}$
is fully dependent on the adopted value of
$ V_\odot $
. Regarding the rotation speed in the vicinity of the Sun, we also find a strong correlation between
$ \Omega_0$
and
$ V_\odot $
. We find that the angular velocity of the Sun,
$ \Omega_{\odot}$
, which is defined as
$ \Omega_\odot$
$ \equiv$
$ \Omega_0$
$ +$
$ V_\odot/R_0$
, can be well constrained with the best estimate of
$ \Omega_\odot$
$ =$
31.09
$ \pm$
0.78 km s
$ ^{-1}$
kpc
$ ^{-1}$
. This corresponds to
$ \Theta_0$
$ =$
238
$ \pm$
14 km s
$ ^{-1}$
if one adopts the above value of
$ R_0$
and recent determination of
$ V_\odot $
$ \sim$
12 km s
$ ^{-1}$
.
Loss-of-function mutations of RUNX1 have been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Although several reports have suggested roles for RUNX1 as a tumor ...suppressor, its precise function remains unknown. Because gene alterations of RUNX1 by themselves do not lead to the development of leukemia in mouse models, additional mutation(s) would be required for leukemia development. Here, we report that the C-terminal deletion mutant of RUNX1, RUNX1dC, attenuates DNA-damage repair responses in hematopoietic stem/progenitor cells. γH2AX foci, which indicate the presence of DNA double-strand breaks, were more abundantly accumulated in RUNX1dC-transduced lineage(-)Sca1(+)c-kit(+) (LSK) cells than in mock-transduced LSK cells both in a steady state and after γ-ray treatment. Expression profiling by real-time -PCR array revealed RUNX1dC represses the expression of Gadd45a, a sensor of DNA stress. Furthermore, bone marrow cells from MDS/AML patients harboring the RUNX1-C-terminal mutation showed significantly lower levels of GADD45A expression compared with those from MDS/AML patients with wild-type RUNX1. As for this mechanism, we found that RUNX1 directly regulates the transcription of GADD45A and that RUNX1 and p53 synergistically activate the GADD45A transcription. Together, these results suggest Gadd45a dysfunction due to RUNX1 mutations can cause additional mutation(s) required for multi-step leukemogenesis.
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