Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14

Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year-old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia. His gait was wide-based but he did not require a walking stick. Limb muscle strength was intact. Deep tendon reflexes were normal or slightly reduced. Pathological reflexes were absent. He demonstrated mildly impaired vibration sense in the lower limbs. There was no urinary dysfunction. Brain MRI showed cerebellar atrophy without brainstem involvement. We first confirmed the absence of repeat expansion in genes known to be responsible for SCAs 1–3, 6–8, 10, 12, 17, 36 and dentatorubral-pallidoluysian atrophy. By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A>T; Lys177X) in exon 4 of the FGF14 gene. This variant is expected to generate a truncated FGF14 protein lacking the heparin binding sites, those are likely to modify the activity of FGF14. We confirmed the absence of the variant in 502 healthy Japanese individuals by Sanger sequencing. There is no record of the variant in public databases. We conclude that the novel variation in FGF14 is causative for SCA27 in this patient.     

Correspondence of cue activity to reward activity in the macaque orbitofrontal cortex

It has been reported that neurons in the orbitofrontal cortex (OFC) respond to emotionally significant events such as reward-predicting cues and/or the reward itself. The responses to reward-predicting cues are considered to carry the information of the predicted reward. However, few studies have focused on the relationship of the neuronal activity during a cue period with that during a reward period. We can infer that the cue responses of OFC neurons are correlated to the reward responses if they carry the information of the predicted reward. In this study, we focused on neurons that showed responses during both the cue and reward periods, and compared the response characteristics between these periods. We found 94 of 369 OFC neurons showed significant responses during both the cue and reward periods, and 43 of which preserved their selectivity between these periods. Furthermore, population analysis showed that stronger cue responses corresponded to stronger reward responses, and stronger reward responses corresponded to stronger cue responses. These results suggest that individual neurons in the OFC associate visual information with reward information, and contribute to the prediction of future rewards by forming reward representations.     

Vinyl polymerization with dimethylaniline/cupric nitrate system

A study of vinyl polymerizations initiated with the system of dimethylaniline (DMA) and cupric [Cu(II)] nitrate has been made. This initiator system was found to induce the polymerization of vinyl monomers having an electron-attracting substituent such as methyl methacrylate (MMA) and acrylonitrile, but it does not initiate the styrene and vinyl acetate polymerizations. The rate of polymerization (R_p) of MMA with this system was expressed by the following Eqs., depending upon the Cu(II) concentration used: The apparent activation energy for this polymerization was found to be 16.5 and 14.4 kcal/mole for the above two Cu(II) concn. ranges, respectively. The polymer of MMA obtained by this system was found to contain an endgroup similar to dimethylaniline, probably a methylanilinomethyl group, from the determination of its UV spectrum.     

Gastric juvenile polyposis associated with germline SMAD4 mutation

We treated a 39-year-old woman with hypoproteinemia and anemia who had profuse gastric polyposis. Radiographic and endoscopic examination showed numerous polyps restricted to the stomach. The patient had pulmonary arteriovenous malformations in the left lung. Histological examination of the resected stomach revealed the gastric polyposis to be composed of cystic dilatation of the glands with small areas of adenocarcinoma. These findings were compatible with gastric juvenile polyposis (GJP) accompanied by gastric cancer. Analysis of genomic DNA revealed that the patient had truncating mutation of SMAD4, a responsible gene for juvenile polyposis (JP). Our case suggests that SMAD4 is possibly a responsible gene for GJP.     

Metal-containing initiator systems, 34. Polymerization of vinyl monomers initiated by the binary system cobaltocene/bis(ethyl acetoacetato)copper (II)

The effect of some metallocenes such as ferrocene (Fe(C₅H₅)₂), nickelocene (Ni(C₅H₅)₂), and cobaltocene (Co(C₅H₅)₂), on the vinyl polymerization initiated with bis(ethyl acetoacetato)-copper(II) (Cu(eacac)₂) was investigated. Co(C₅H₅)₂ was found to exert a markedly accelerating effect on the polymerization of methyl methacrylate (MMA) with Cu(eacac)₂. The polymerization of MMA with the system Co(C₅H₅)₂/Cu(eacac)₂ at 50°C was found to be fairly affected by the solvent used. The results of copolymerization of MMA with styrene (St) and the effect of hydroquinone (HQ) on the polymerization of MMA with Co(C₅H₅)₂/Cu(eacac)₂ showed that the polymerization proceeds via a radical mechanism. The polymerization of MMA with Co(C₅H₅)₂/Cu(eacac)₂ was studied kinetically in acetone. The overall activation energy of the polymerization was calculated to be 86,3 kJ/mol (20,6 kcal/mol). This value was somewhat higher than that (17,6 kcal/mol) obtained for the polymerization of MMA with Cu(eacac)₂ alone. The polymerization rate (R_p) is represented by the following equation: R_p = k[Co(C₅H₅)₂]^0,5 [Cu(eacac)₂]^0,2 [MMA]^1,3. The high order in monomer concentration suggests a participation of the monomer in the initiation process of this polymerization. This is supported by the examination of the ESR spectrum of the system Co(C₅H₅)₂/Cu(eacac)₂/MMA/acetone, where reduction of Cu(II) to Cu(I) occurs. To elucidate the initiation mechanism, the spin trapping technique was applied to the system Co(C₅H₅)₂/Cu(eacac)₂/methyl acrylate. From these results, an initiation mechanism for the binary initiator system Co(C₅H₅)₂/Cu(eacac)₂ is proposed and discussed.     

Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals

A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, p < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both p < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.     

Importance of Hydrostatic Pressure and Irrigation for Hemostasis in Neuroendoscopic Surgery

Recently neurosurgical operations have been carried out with water irrigation such as endoscopic third ventriculostomy and tumor resections in ventricles. Water irrigation is one of several published methods that promote hemostasis; however, not enough experimental evidence exists on its efficacy. In this study, we investigate whether hydrostatic pressure and persistent irrigation promote hemostasis in neuroendoscopic surgery. We dissected tails of 12–16-week-old C57BL/6 male mice at 5 mm proximal from the tip and checked for bleeding times under dry and wet conditions at pressures of 0 cmH₂O, 10 cmH₂O, 15 H₂O, and 20 cmH₂O without persistent irrigation to bleeding point and 10 cmH₂O with persistent irrigation. We then examined the dissected edge with hematoxylin–eosin staining and measured the size of vessels. The average bleeding time of each group is as follows: dry: 203.4 sec, wet: 164.4 sec, 5 cmH₂O: 138.6 sec, 10 cmH₂O: 104.6 sec (P <0.001), 20 cmH₂O: 56 sec (P <0.001), and 10 cmH₂O with persistent irrigation: 72.8 sec (P <0.01 compared to 10 cmH₂O without persistent irrigation). The maximum caliber of mice’s tail artery was 50–60 μm. Hydrostatic pressure and irrigation are important factors contributing to hemostasis.     

Pig kidney xenotransplantation: Progress toward clinical trials

Pig organ xenotransplantation offers a solution to the shortage of deceased human organs for transplantation. The pathobiological response to a pig xenograft is complex, involving antibody, complement, coagulation, inflammatory, and cellular responses. To overcome these barriers, genetic manipulation of the organ‐source pigs has largely been directed to two major aims—(a) deletion of expression of the known carbohydrate xenoantigens against which humans have natural (preformed) antibodies, and (b) transgenic expression of human protective proteins, for example, complement‐ and coagulation‐regulatory proteins. Conventional (FDA‐approved) immunosuppressive therapy is unsuccessful in preventing an adaptive immune response to pig cells, but blockade of the CD40:CD154 costimulation pathway is successful. Survival of genetically engineered pig kidneys in immunosuppressed nonhuman primates can now be measured in months. Non‐immunological aspects, for example, pig renal function, a hypovolemia syndrome, and rapid growth of the pig kidney after transplantation, are briefly discussed. We suggest that patients on the wait‐list for a deceased human kidney graft who are unlikely to receive one due to long waiting times are those for whom kidney xenotransplantation might first be considered. The potential risk of infection, public attitudes to xenotransplantation, and ethical, regulatory, and financial aspects are briefly addressed.     

Iron,coronary artery calcification,and mortality in patients undergoing hemodialysis

ObjectiveA high coronary artery calcification score (CACS) may be associated with high mortality in patients undergoing hemodialysis (HD). Recently, effects of iron on vascular smooth muscle cell calcification have been described. We aimed to investigate the relationships between iron, CACS, and mortality in HD patients.MethodsWe studied 173 consecutive patients who were undergoing maintenance HD. Laboratory data and Agatston’s CACS were obtained at baseline for two groups of patients: those with CACS ≥400 (n = 109) and those with CACS <400 (n = 64). Logistic regression analyses for CACS ≥400 and Cox proportional hazard analyses for mortality were conducted.ResultsThe median (interquartile range) age and duration of dialysis of the participants were 67 (60–75) years and 73 (37–138) months, respectively. Serum iron (Fe) and transferrin saturation (TSAT) levels were significantly lower in participants with CACS ≥400 than in those with CACS <400, although the serum ferritin concentration did not differ between the groups. TSAT ≥21% was significantly associated with CACS ≥400 (odds ratio 0.46, p<0.05). TSAT ≥17%, Fe ≥63 µg/dL, and ferritin ≥200 ng/mL appear to protect against 5-year all-cause mortality in HD patients, independent of conventional risk factors of all-cause mortality (p < 0.05).ConclusionWe have identified associations between iron, CACS, and mortality in HD patients. Lower TSAT was found to be an independent predictor of CACS ≥400, and iron deficiency (low TSAT, iron, or ferritin) was a significant predictor of 5-year all-cause mortality in HD patients.