Neurofilament light mutation causes hereditary motor and sensory neuropathy with pyramidal signs

To identify novel mutations causing hereditary motor and sensory neuropathy (HMSN) with pyramidal signs, a variant of Charcot‐Marie‐Tooth disease (CMT), we screened 28 CMT and related genes in four members of an affected Japanese family. Clinical features included weakness of distal lower limb muscles, foot deformity, and mild sensory loss, then late onset of progressive spasticity. Electrophysiological studies revealed widespread neuropathy. Electron microscopic analysis showed abnormal mitochondria and mitochondrial accumulation in the neurons and Schwann cells. Brain magnetic resonance imaging (MRI) revealed an abnormally thin corpus callosum. In all four, microarrays detected a novel heterozygous missense mutation c.1166A>G (p.Y389C) in the gene encoding the light‐chain neurofilament protein (NEFL), indicating that NEFL mutations can result in a HMSN with pyramidal signs phenotype.     

Elevated Fibroblast Growth Factor 23 Exerts Its Effects on Placenta and Regulates Vitamin D Metabolism in Pregnancy of Hyp Mice

Fibroblast growth factor 23 (FGF23) functions in an endocrine fashion and requires α‐Klotho to exert its effects on the target organs. We have recently demonstrated that the human placenta also expresses α‐Klotho, which led us to hypothesize that FGF23 may exert effects on the placenta. Immunohistochemical analysis demonstrated the expression of FGF receptor 1 (FGFR1) as well as that of α‐Klotho in the feto‐maternal interface of both mouse and human normal‐term placentas, which suggested that these areas might be receptive to FGF23. Therefore, we next investigated whether FGF23 has some roles in the placenta using Hyp mice with high levels of circulating FGF23. Hyp and wild‐type (WT) females were mated with WT males, and the mothers and their male fetuses were analyzed. FGF23 levels in Hyp mothers were elevated. FGF23 levels were about 20‐fold higher in Hyp fetuses than in Hyp mothers, whereas WT fetuses from Hyp mothers exhibited low levels of FGF23, as did fetuses from WT mothers. We analyzed the placental gene expression and found that the expression of Cyp24a1 encoding 25OHD‐24‐hydroxylase, a target gene for FGF23 in the kidney, was increased in the placentas of fetuses from Hyp mothers compared with fetuses from WT mothers. In an organ culture of WT placentas, treatment with plasma from Hyp mothers markedly increased the expression of Cyp24a1, which was abolished by the simultaneous addition of anti‐FGF23 neutralizing antibody. The direct injection of recombinant FGF23 into WT placentas induced the expression of Cyp24a1. The increase in the placental expression of Cyp24a1 in fetuses from Hyp mothers resulted in decreased plasma 25‐hydroxyvitamin D levels. These results suggest that increased levels of circulating FGF23 in pathological conditions such as Hyp mice exerts direct effects on the placenta and affects fetal vitamin D metabolism via the regulation of Cyp24a1 expression. © 2014 American Society for Bone and Mineral Research.     

Glucocorticoid receptor and serum‐ and glucocorticoid‐induced kinase‐1 in esophageal adenocarcinoma and adjacent Barrett's esophagus

Barrett's esophagus (BE) is a consequence of gastroesophageal reflux disease and is predisposed to esophageal adenocarcinoma (EAC). EAC is an exemplar model of inflammation‐associated cancer. Glucocorticoids suppress inflammation through glucocorticoid receptor (GR) and serum‐ and glucocorticoid‐induced kinase‐1 (Sgk1) expressions. Therefore, we immunolocalized GR and Sgk1 in EAC and the adjacent BE tissues and studied their association with clinical disease course in 87 patients with EAC who underwent surgical resection (N = 58) or endoscopic submucosal dissection (N = 29). Low GR and Sgk1 expressions in adjacent BE tissues were associated with adverse clinical outcomes (P = 0.0008 and 0.034, respectively). Patients with low Sgk1 expression in EAC cells exhibited worse overall survival (P = 0.0018). In multivariate Cox regression analysis, low GR expression in the adjacent nonmalignant BE tissues was significantly associated with worse overall survival (P = 0.023). The present study indicated that evaluation of GR and Sgk1 expressions in both the EAC cells and adjacent nonmalignant BE tissues could help to predict clinical outcomes following endoscopic and surgical treatments. In particular, the GR status in BE tissues adjacent to EAC was an independent prognostic factor.     

Enhanced heat shock protein 25 immunoreactivity in cranial nerve motoneurons and their related fiber tracts in rats prenatally‐exposed to X‐irradiation

Alterations in histoarchitecture of the brainstem were examined immunohistochemically in 4‐week‐old rats with a single whole body X‐irradiation at a dose of 0.5, 1.0, or 1.5 Gy on embryonic day (ED) 15 using anti‐heat shock protein 25 (HSP25). HSP25 immunostaining was seen in the neuronal perikarya of cranial nerve motoneurons, that is, the motor and mesencephalic nuclei of the trigeminal nerve, facial nucleus, abducens nucleus and accessory facial nucleus in the pons, and the ambiguous nucleus, dorsal nucleus of vagus nerve and hypoglossus nucleus in the medulla oblongata of intact controls. In 0.5 to 1.5 Gy‐irradiated rats, HSP25 immunostaining in those neurons was more intense than in controls, while the most intense immunostaining was marked in 1.5 Gy‐irradiated rats. HSP25 immunostaining was also apparent in the spinal tract of the trigeminal nerve and facial nerve tracts in 0.5 to 1.5 Gy‐irradiated rats, but was faint in controls. Interestingly, HSP25 immunostaining was aberrantly enhanced in dendritic arbors in the magnocellular region of medial vestibular nucleus of 0.5–1.5 Gy‐irradiated rats. Those arbors were identified as excitatory secondary vestibulo‐ocular neurons by double immunofluorescence for HSP25 and SMI‐32. The results suggest an increase of HSP25 expression in cranial nerve motoneurons and their related fiber tracts from prenatal exposure to ionizing irradiation. This may be an adaptive response to chronic hypoxia due to malformed brain arteries caused by prenatal ionizing irradiation.     

Phorbol-ester-stimulated human lymphoid cell lines produce a plasminogen activator modulator inducing cell-bound urokinase-type plasminogen activator in malignant tumor cell lines

The importance of cell-associated plasminogen activation in tumor invasion and metastasis is becoming increasingly evident. To clarify the modulators of cell-associated plasminogen activation in malignant states, we have recently established an assay system utilizing endogenous plasminogen activators on the cell surface. In the present study using the assay system, we found that the conditioned medium from phorbol 12-myristate 13-acetate (PMA)-stimulated human lymphoid cell lines, HUT 78 and Raji, strongly enhanced plasminogen activator (PA) activity on the surface of human malignant tumor cell lines (WI-38 VA13 2RA, A431, A549 and HT-1080). The enhancing effect was inhibited by the addition of actinomycin D. By gel filtration, the active substances in PMA-stimulated HUT 78- and Raji-conditioned media were eluted in similar fractions corresponding to molecular weights of 60 to 80 kDa. The active substance was heat-labile. The enhanced PA activities were completely inhibited by anti-urokinase-type plasminogen activator (uPA) IgG. Moreover, the active substance was found to increase in cell-bound uPA antigen. These findings suggest that a population of activated lymphocytes produces a plasminogen activator modulator that induces uPA on the surface of malignant tumor cells. © 1996 Wiley-Liss, Inc.     

Leadless cardiac pacemaker implantations after infected pacemaker system removals in octogenarians

BackgroundManagement of pacemaker (PM) infections among advanced aged patients possesses particular clinical challenges due to higher rates of concurrent cardiovascular disease and medical comorbidities. Novel leadless cardiac pacemakers (LCPs) may provide new opportunities for better management options in this population, however, there is limited data especially in Asian populations to guide the decision making.MethodsWe reviewed 11 octogenarians (median age: 86 [minimum 82–maximum 90] years; male: 73%; median body mass index (BMI): 20.1 kg/m²) who received Micra Transcatheter Pacing System (Medtronic Inc, Minneapolis, MN) implantations following transvenous lead extractions (TLEs) for PM infections. ResultsAll patients had more than two medical comorbidities (average 3.7 comorbidities). The indications for LCP implantations were atrioventricular block in four patients, atrial fibrillation bradycardia in five, and sinus node dysfunction in two. Eight patients (73%) were bridged with temporary pacing using active fixation leads (median interval of 14.0 days), while one with severe dementia underwent a concomitant LCP implantation and TLE during the same procedure. Successful TLEs and LCP implantations were successfully accomplished in all without any complications. The median time from the TLE procedure to discharge was 22 days (minimum 7–maximum 136). All patients remained free of infections during a mean follow-up period of 17.2 ± 6.5 months.ConclusionsLCP implantations were safe and effective after removing the entire infectious PM system in all octogenarians. The novel LCP technology may offer an alternative option for considering a re-implantation strategy after transvenous PM infections in elderly patients, particularly those with severe frailty and PM dependency.

The incidence of cardiac pacemaker (PM) infections among patients with an advanced age has been increasing owing to the continually widening indications and growing number of generator replacements.^[1–3] In current clinical practice, there is a class l indication for removing all hardware in the case of a proven or suspected device infection, and after a recovery window, a new conventional PM is implanted in PM dependent patients.^[1,4,5] However, this management for the elderly population is one of the most sensitive issues, since they possess particular clinical challenges due to higher rates of concurrent cardiovascular disease and medical comorbidities.^[6–10]Recently, the implantation of a Micra Transcatheter Pacing System (Medtronic Inc, Minneapolis, MN) has emerged as a new option for PM re-implantations after the removal of infectious PMs.^[11–17] Without the use of leads and a device pocket, this leadless cardiac pacemaker (LCP) potentially reduces the risk of pocket infections and lead associated endocarditis.^[16,17] However, there have not been enough data supporting the feasibility of leadless PM implantations following the removal of infectious PMs in people with an older age, particularly in octogenarians. Furthermore, there has been no data regarding those therapeutic strategies in Asian populations who have a low body mass index (BMI) and are at a higher risk of a transvenous lead extraction (TLE) procedure. Therefore, in this case series, we sought to characterize the procedure for LCP implantations following TLEs of infected PMs in octogenarians at 2 Japanese high-volume centers.     

Delayed DNA Synthesis Induced by 3-Aminobenzamide in Partially Hepatectomized Liver of Rats

The possibility of poly(ADP-ribosyl)ation playing a role during liver regeneration induced by partial hepatectomy (PH) in vivo was examined. When rats were given an i.p. injection of 3-antinobenzamide (ABA) at a dose of 600 mg/kg body weight 12 h after PH, the levels of DNA synthesis at 20 h after PH were significantly reduced. The time course of DNA synthesis in regenerating liver was significantly delayed in the ABA-treated group. Enzymatic assay revealed the activity of poly-(ADP-ribose)polymerase (PADPRP) in controls to be increased in parallel with the increase of DNA synthesis induced by PH. This increase in PADPRP activity was delayed and very much weaker after ABA treatment. The results thus suggested that poly (AUP-ribosyl)ation might play an important role in DNA synthesis during liver regeneration in vivo.