Identification and functional characterization of mouse TPO1 as a myelin membrane protein

TPO1 is a member of the AIGP family, a unique group of proteins that contains 11 putative transmembrane domains. Expression of the rat TPO1 gene is upregulated in cultured oligodendrocytes (OLs) during development from pro-oligodendroblasts to postmitotic OLs. However, the distribution of native TPO1 protein in cultured OLs and in the brain has not been elucidated. We investigated the distribution and cellular function of TPO1 in myelinating cells of the nervous system. In mice, TPO1 gene expression was detected in the central (CNS) and peripheral (PNS) nervous systems and was markedly upregulated at postnatal days 10-20, an early phase of myelination in the mouse brain. To investigate TPO1 localization, we generated affinity-purified antibodies to synthetic peptides derived from mouse TPO1. Immunohistochemical analysis showed that TPO1 was expressed in OLs and Schwann cells but not in neurons and astrocytes. Schwann cells from trembler mice, which lack PNS myelin, had significantly decreased TPO1 expression and an altered localization pattern, suggesting that TPO1 is a functional myelin membrane protein. In OL lineage cell cultures, TPO1 was detected in A2B5+ bipolar early progenitors, A2B5+ multipolar Pro-OLs, GalC+ immature OLs and MBP+ mature OLs. The subcellular localization of TPO1 in OL lineage cells was mapped to the GM130+ Golgi in cell bodies and Fyn+ cell processes and myelin-like sheets. Furthermore, TPO1 selectively colocalized with non-phosphorylated Fyn and promoted Fyn autophosphorylation in COS7 cells, suggesting that TPO1 may play a role in myelin formation via Fyn kinase activation in the PNS and CNS.     

Epidemiology of hip fractures in Okinawa,Japan

This study investigated the current incidence of hip fractures in Okinawa prefecture and compared the data with those obtained in our previous study, which was conducted using similar methods in 1987/1988. All patients, aged 50 years or older and residing in Okinawa, admitted to Okinawa hospitals in 2004 for a fresh hip fracture were identified from hospital registries. Details were obtained from the medical records and radiographs of all patients and classified according to fracture type (cervical or trochanteric), age, sex, and fracture location. Subtrochanteric fractures and pathological fractures were excluded. A total of 1,349 patients (242 men and 1,107 women) were admitted for a fresh hip fracture in 2004. Their average age was 76.9 years for men and 82.4 years for women. There were 671 cervical fractures, 654 trochanteric fractures, and 24 unclassified proximal femoral fractures. Comparing the data from 1987/1988 to those from 2004, the total number of hip fractures increased by 188%, from 469 to 1,349. The age-adjusted incidence rates per 100,000, standardized to the 2000 US population, were 75.7 and 296.1 in 1987/1988 and 123.6 and 420 in 2004 for men and women, respectively. The incidence rates in all age groups (at 5-year intervals) were higher in 2004 than in 1987/1988, indicating that people 50 years of age or older became more susceptible to hip fractures. Accordingly, the accretion of the hip fracture incidence rate was greater than that which could be explained purely by changes in population size and structure.     

Clear Cell Carcinoma of Palatal Minor Salivary Gland Harboring a Novel EWSR1-ATF1 Fusion Gene: Report of a Case and Review of the Literature

Clear cell carcinoma (CCC) is a rare low-grade malignant salivary gland carcinoma. EWSR1-ATF1 fusion has been characterized as a consistent finding in CCC, with breakpoints described between EWSR1 exon 11 and ATF1 exon 3. So far, over 100 cases of CCC harboring EWSR1 rearrangement arising from salivary gland of the oral cavity have been reported. Although EWSR1 involvement in these cases was confirmed by EWSR1 break-apart FISH indicating the translocation, sequence analysis for EWSR1-ATF1 fusion type has been reported only in three cases of CCC so far. Herein, we report a CCC case with novel EWSR1-ATF1 fusion (EWSR1 exon 15 and ATF1 exon 5) arising in minor salivary gland and review the role of the chimeric variants in some malignancies with EWSR1-ATF1 rearrangement. Current tumor was composed of the small nests of clear tumor cells and hyalized fibrous stroma. Immunohistochemically, the tumor was positive for AE1/AE3, CK5/6 and p63, negative for S100, Melan-A, SMA and CD10. After 8 months of follow-up, there are no evidence of recurrence.     

Indication of Liver Transplantation in the Treatment of Newly Categorized Acute-on-Chronic Liver Failure In Japan

AimThis study aims to validate Japanese diagnostic criteria for acute-on-chronic liver failure (ACLF) and confirm the feasibility of performing transplantation.MethodsWe included 60 patients with acute liver injury. Demographic and clinical features were retrospectively collected, and the primary outcome was compared among 4 types: acute liver failure (ALF) with hepatic coma (n = 23), ALF without hepatic coma (n = 12), acute liver injury (n = 20), and ACLF (n = 5). Moreover, 80 transplanted patients were enrolled to compare the difficulty of transplantation between ALF (n = 8) vs non-ALF (n = 72) patients.ResultsSeven patients in the ALF with hepatic coma group and 1 patient in the ACLF with hepatic coma group were transplanted. Ten patients who could not be registered for transplantation died. In univariate analysis, liver failure type (P < .0001), total bilirubin level (P = .05), and prothrombin time internationalized ratio (P < .0001) were associated with patient survival. In multivariate analysis, liver failure type was associated with patient survival (P < .0001). The respective 1-, 3-, and 5-year patient survival rates were 45.9%, 45.9%, and 45.9% for ALF patients with hepatic coma; 100.0%, 100.0%, and 100.0% for ALF patients without hepatic coma and acute liver injury; and 80.0%, 80.0%, and 80.0% for ACLF patients (P < .0001). Chronic liver disease did not affect operation time (P = .46) and bleeding volume (P = .49).ConclusionPatients diagnosed with ACLF via Japanese criteria presented significantly higher survival rates than ALF patients with hepatic coma.     

The impact of switching once-weekly teriparatide to denosumab in osteoporosis patients

Background

It has been reported that switching from daily (d) teriparatide (TPTD) to denosumab (DMAb) is effective for severe osteoporosis patients. However, there have been no reports about switching from weekly (w) TPTD to DMAb in patients with osteoporosis. Once-weekly 56.5-μg TPTD treatment increases bone mineral density (BMD) and reduces fracture events. The objective of the current retrospective study was to elucidate the impact of switching w-TPTD to DMAb in patients with osteoporosis.

Shared and distinct contributions of rostrolateral prefrontal cortex to analogical reasoning and episodic memory retrieval

Rostrolateral prefrontal cortex (RLPFC) is widely appreciated to support higher cognitive functions, including analogical reasoning and episodic memory retrieval. However, these tasks have typically been studied in isolation, and thus it is unclear whether they involve common or distinct RLPFC mechanisms. Here, we introduce a novel functional magnetic resonance imaging (fMRI) task paradigm to compare brain activity during reasoning and memory tasks while holding bottom‐up perceptual stimulation and response demands constant. Univariate analyses on fMRI data from twenty participants identified a large swath of left lateral prefrontal cortex, including RLPFC, that showed common engagement on reasoning trials with valid analogies and memory trials with accurately retrieved source details. Despite broadly overlapping recruitment, multi‐voxel activity patterns within left RLPFC reliably differentiated these two trial types, highlighting the presence of at least partially distinct information processing modes. Functional connectivity analyses demonstrated that while left RLPFC showed consistent coupling with the fronto‐parietal control network across tasks, its coupling with other cortical areas varied in a task‐dependent manner. During the memory task, this region strengthened its connectivity with the default mode and memory retrieval networks, whereas during the reasoning task it coupled more strongly with a nearby left prefrontal region (BA 45) associated with semantic processing, as well as with a superior parietal region associated with visuospatial processing. Taken together, these data suggest a domain‐general role for left RLPFC in monitoring and/or integrating task‐relevant knowledge representations and showcase how its function cannot solely be attributed to episodic memory or analogical reasoning computations. Hum Brain Mapp 37:896–912, 2016. © 2015 Wiley Periodicals, Inc .     

Overweight and obesity accelerate the progression of IgA nephropathy: prognostic utility of a combination of BMI and histopathological parameters

Background

Although more than 40?years have passed since IgA nephropathy (IgAN) was first reported, predicting the renal outcome of individual IgAN patients remains difficult. Emerging epidemiologic evidence indicates that overweight and obesity are risk factors for end-stage renal disease. We aimed to elucidate the outcome of overweight IgAN patients and improve our ability to predict the progression of IgAN based on a combination of body mass index (BMI) and histopathological parameters, including maximal glomerular area (Max GA).

Methods

Forty-three adult IgAN patients whose estimated glomerular filtration rate was ≥50?ml/min/1.73?m² were enrolled in this study. Renal biopsy specimens were evaluated according to the Oxford classification of IgAN. A Kaplan–Meier analysis and the multivariate Cox proportional hazards method were used to evaluate 10-year kidney survival and the impact of covariates. The ability of factors to predict the progression of IgAN was evaluated by their diagnostic odds ratio (DOR).

Results

A BMI ≥25?kg/m² was found to be an independent predictor of a ≥1.5-fold increase in serum creatinine value (DOR 7.4). The combination of BMI ≥25?kg/m², Max GA ≥42,900?μm², and presence of mesangial hypercellularity (Oxford M1) optimally raised predictive power for disease progression of IgAN (DOR 26.0).

Conclusion

A combination of BMI ≥25?kg/m², the Oxford classification M1, and a Max GA ≥42,900?μm² can serve as a predictor of long-term renal outcome of IgAN.     

Adrenomedullin inhibits pressure-induced mesangial MCP-1 expression through activation of protein kinase A

BACKGROUND: In glomerular hypertension, monocyte chemoattractant protein-1 (MCP-1) has been implicated in glomerulosclerosis progression. High-pressure load and stretch on mesangial cells (MC) are two major effects of increased glomerular pressure. We previously reported that pressure per se could induce MCP-1 expression in cultured MC, suggesting the involvement of glomerular hypertension in renal disease progression through MCP-1 expression in MC. We also showed that adrenomedullin (AM) inhibited pressure-induced MC proliferation; however, it is not clear whether AM alters pressure-induced mesangial MCP-1 expression. In this study, we examined the effect of AM on pressure-induced MCP-1 expression in cultured rat MC and the mechanism of such action. Using compressed helium, pressure was applied to MC placed in a sealed chamber. AM inhibited pressure-induced MCP-1 mRNA expression, measured by reverse transcribed-polymerase chain reaction (RT-PCR), in a dose-dependent manner. This inhibition was in parallel to an increase in cellular cyclic AMP (cAMP) levels evoked by AM. The effects of forskolin and dibutyryl cAMP mimicked those of AM. Protein kinase A (PKA) inhibitor H-89 significantly weakened the effects of AM. AM significantly reduced the pressure-induced increase in MCP-1 protein in supernatants of cultured MC, measured by enzyme-linked immunosorbent assay (ELISA). Our results suggested that AM inhibits pressure-induced mesangial MCP-1 expression through PKA activation.