ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities.

Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.

Impact of severe acute kidney injury on short-term mortality in urosepsis.

PURPOSE: To evaluate the impact of severe acute kidney injury (AKI) on short-term mortality in patients with urosepsis. METHODS: This prospective cohort study evaluated 207 patients with urosepsis. AKI was diagnosed in accordance with the Kidney Disease Improving Global Outcomes criteria, and severe AKI was defined as stage 2 or 3 AKI. Patients were divided into two groups: patients who developed severe AKI (severe AKI group) and patients who did not (control group). The primary endpoint was all-cause mortality within 30 days. The secondary endpoints were 90-day mortality and in-hospital mortality. The exploratory outcomes were the risk factors for severe AKI development. RESULTS: The median patient age was 79 years. Of the 207 patients, 56 (27%) developed severe AKI. The 30-day mortality rate in the severe AKI group was significantly higher than that in the control group (20% vs. 2.0%, respectively; P < 0.001). In the multivariable analysis, performance status and severe AKI were significantly associated with 30-day mortality. The in-hospital mortality and 90-day mortality rates in the severe AKI group were significantly higher than those in the control group (P < 0.001 and P < 0.001, respectively). In the multivariable analysis, age, urolithiasis-related sepsis, lactate values, and disseminated intravascular coagulation were significantly associated with severe AKI development. CONCLUSIONS: Severe AKI was a common complication in patients with urosepsis and contributed to high short-term mortality rates.

Necdin: A purposive integrator of molecular interaction networks for mammalian neuron vitality.

Necdin was originally found in 1991 as a hypothetical protein encoded by a neural differentiation-specific gene transcript in murine embryonal carcinoma cells. Virtually all postmitotic neurons and their precursor cells express the necdin gene (Ndn) during neuronal development. Necdin mRNA is expressed only from the paternal allele through genomic imprinting, a placental mammal-specific epigenetic mechanism. Necdin and its homologous MAGE (melanoma antigen) family, which have evolved presumedly from a subcomplex component of the SMC5/6 complex, are expressed exclusively in placental mammals. Paternal Ndn-mutated mice totally lack necdin expression and exhibit various types of neuronal abnormalities throughout the nervous system. Ndn-null neurons are vulnerable to detrimental stresses such as DNA damage. Necdin also suppresses both proliferation and apoptosis of neural stem/progenitor cells. Functional analyses using Ndn-manipulated cells reveal that necdin consistently exerts antimitotic, anti-apoptotic and prosurvival effects. Necdin interacts directly with a number of regulatory proteins including E2F1, p53, neurotrophin receptors, Sirt1 and PGC-1α, which serve as major hubs of protein-protein interaction networks for mitosis, apoptosis, differentiation, neuroprotection and energy homeostasis. This review focuses on necdin as a pleiotropic protein that integrates molecular interaction networks to promote neuronal vitality in modern placental mammals.

Associations of impaired grip strength and gait function with the severity of erectile dysfunction in men undergoing dialysis: a cross-sectional study.

OBJECTIVE: To investigate the associations of impaired muscle strength and gait function with the severity of erectile dysfunction (ED) in men undergoing dialysis. METHODS: This cross-sectional study included 63 men undergoing dialysis. ED was assessed with the Sexual Health Inventory for Men (SHIM). Patients were divided into the mild/moderate (SHIM score ≥8) and severe ED groups (SHIM score ≤7). Correlations between variables were analyzed using Spearman's rank correlation coefficient. Multivariable logistic regression analyses were performed to evaluate the impact of impaired grip strength and gait function on the severity of ED. RESULTS: The median age of the study participants was 62 years; all had ED, with 67% having severe ED. Spearman's rank correlation test demonstrated significant negative and positive correlations between gait function and SHIM score (ρ = -0.257, p = 0.042) and between grip strength and SHIM score (ρ = 0.305, p = 0.015), respectively. In the multivariable analyses, impaired grip strength was significantly associated with severe ED (odds ratio [OR]: 4.965, p = 0.017), whereas gait function was not (OR: 3.147, p = 0.064). CONCLUSION: Impaired muscle strength was significantly associated with severe ED, whereas impaired gait function had a marginal effect on this erectile condition.

Association of oxidative stress with erectile dysfunction in community-dwelling men and men on dialysis.

OBJECTIVES: To investigate the association between oxidative stress and erectile dysfunction (ED) in community-dwelling men and men on dialysis. METHODS: This cross-sectional study included 398 community-dwelling men and 42 men on dialysis. Oxidative stress was assessed using 8-hydroxy-2'-deoxyguanosine (8-OHdG). Univariable and multivariable logistic regression analyses were performed to evaluate the association between oxidative stress and ED. RESULTS: Spearman's rank correlation test showed no significant correlation between urine 8-OHdG levels and the 5-Item International Index of Erectile Function scores in community-dwelling men (ρ = -0.005, p = 0.917) and between plasma 8-OHdG levels and the Sexual Health Inventory for Men scores in men on dialysis (ρ = 0.166, p = 0.295). In community-dwelling men, univariable and multivariable analyses revealed that urine 8-OHdG level was not significantly associated with ED (odds ratio [OR]: 1.005, 95% confidence interval [CI]: 0.884-1.144, p = 0.934; OR: 0.930, 95% CI: 0.798-1.084, p = 0.353; respectively). In men on dialysis, univariable analyses revealed that plasma 8-OHdG level was not significantly associated with severe ED (OR: 0.967, 95% CI: 0.876-1.066, p = 0.498). CONCLUSIONS: Oxidative stress was not significantly associated with ED prevalence and severity in community-dwelling men and men on dialysis.

Single immediate instillation of chemotherapy is associated with decreased recurrence and progression in patients with high-risk non-muscle-invasive bladder cancer who receive adjuvant induction bacillus Calmette-Guérin therapy.

OBJECTIVES: To investigate whether a single intravesical instillation of chemotherapy is associated with improved oncological outcomes in patients with high-risk non-muscle-invasive bladder cancer who receive adjuvant induction bacillus Calmette-Guérin therapy. METHODS: This multi-institutional retrospective study included 205 patients with high-risk non-muscle-invasive bladder cancer who received adjuvant induction bacillus Calmette-Guérin therapy. Patients were divided into two groups: those who received the combined therapy of a single instillation of chemotherapy plus subsequent adjuvant induction bacillus Calmette-Guérin therapy (combined therapy group), and those who received adjuvant induction bacillus Calmette-Guérin therapy alone (bacillus Calmette-Guérin monotherapy group). Multivariable analyses using the inverse probability of treatment weighting method and Fine-Gray competing risk regression models were performed to evaluate the impact of a single instillation of chemotherapy on intravesical recurrence-free survival and muscle-invasive bladder cancer-free survival. RESULTS: Among the 205 patients, 130 (63%) and 75 (37%) were classified as the combined therapy and bacillus Calmette-Guérin monotherapy groups, respectively. Multivariable analyses using the inverse probability of treatment weighting method showed that a single instillation of chemotherapy was significantly associated with longer intravesical recurrence-free survival (hazard ratio 0.279; P < 0.001) and muscle-invasive bladder cancer-free survival (hazard ratio 0.078; P < 0.001). Fine-Gray competing risk regression model revealed that a single instillation of chemotherapy was associated with a significantly lower probability of intravesical recurrence and muscle-invasive bladder cancer progression, with an adjusted subdistribution hazard ratio of 0.477 (P = 0.008) and 0.261 (P = 0.043), respectively. CONCLUSION: A single intravesical instillation of chemotherapy may be a potential treatment option in patients with high-risk non-muscle-invasive bladder cancer who receive adjuvant induction bacillus Calmette-Guérin therapy.

Geriatric 8 screening of frailty in patients with prostate cancer.

OBJECTIVES: To evaluate the association between the score of the Geriatric 8 screening tool and treatment by disease stages in patients with prostate cancer. METHODS: Between January 2017 and June 2019, we prospectively evaluated the Geriatric 8 in 540 prostate cancer patients who were treated with robot-assisted radical prostatectomy, radiotherapy, androgen deprivation therapy alone and standard of care for metastatic hormone-naïve prostate cancer or castration-resistant prostate cancer. The primary purpose was the association between frailty (Geriatric 8 ≤14) and robot-assisted radical prostatectomy, radiotherapy, androgen deprivation therapy alone, and metastatic diseases. Secondary purposes included a comparison of the Geriatric 8 scores among the disease status and the influence of Geriatric 8 score on overall survival. RESULTS: The median age was 75 years. Geriatric 8 scores ≤14 were seen in 36% of robot-assisted radical prostatectomy (n = 78/214), 57% of radiotherapy (n = 119/209), 91% of androgen deprivation therapy alone (n = 19/21) and 70% of metastatic diseases (n = 67/96). The median Geriatric 8 score in patients treated with robot-assisted radical prostatectomy, radiotherapy, androgen deprivation therapy alone and metastatic diseases was 15.0, 14.0, 12.0 and 12.8, respectively. The median Geriatric 8 score was significantly higher in the metastatic disease than that in localized disease (14.5 vs 12.8, respectively). Robot-assisted radical prostatectomy patients had a significantly higher Geriatric 8 score than radiotherapy patients, with the cut-off value of <14.5. The overall survival was significantly different between Geriatric 8 scores ≤13 and >13 in metastatic hormone-naïve prostate cancer patients, and between Geriatric 8 scores ≤12 and >12 in castration-resistant prostate cancer patients. CONCLUSION: The Geriatric 8 score is significantly associated with treatment by disease stages in patients with prostate cancer.

Frailty is significantly associated with the type of urinary diversion in patients with muscle-invasive bladder cancer.

OBJECTIVES: To investigate the effect of frailty on the type of urinary diversion after radical cystectomy in patients with muscle-invasive bladder cancer. METHODS: Between January 2014 and January 2020, we prospectively evaluated frailty in 88 patients with localized muscle-invasive bladder cancer, who had received radical cystectomy and urinary diversion. The selection of the type of urinary diversion was determined by the operating surgeon based on performance status, comorbidities, tumor status and the patient's preference. The frailty evaluation included the Fried phenotype criteria, the modified frailty index and the frailty discriminant score. We investigated the association between frailty and type of urinary diversion, the effect of frailty on postoperative complications and the effect of frailty on overall survival. RESULTS: The median age of the selected participants was 68 years. The number of patients with an orthotopic neobladder and any postoperative complications was 54 (61%) and 46 (52%), respectively. Of the frailty assessment tools that were used, Fried phenotype criteria and frailty discriminant score were significantly associated with the selection of non-orthotopic neobladder urinary diversion. Occurrences of postoperative complications in participants were significantly associated with modified frailty index, but not with Fried phenotype criteria and frailty discriminant score. Multivariate Cox regression analysis showed that a higher frailty discriminant score was significantly associated with poor overall survival, whereas higher Fried phenotype criteria and modified frailty index were not. CONCLUSION: Frailty is significantly associated with the type of urinary diversion, and it should be considered for the selection of urinary diversion in muscle-invasive bladder cancer patients undergoing radical cystectomy.

C-reactive protein/albumin ratio is a predictive factor for prognosis in patients with metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the effect of pretreatment C-reactive protein/albumin ratio and modified Glasgow prognostic score on the prognosis in patients with metastatic renal cell carcinoma. METHODS: A retrospective study was carried out in 176 patients with metastatic renal cell carcinoma who received first-line tyrosine kinase inhibitors. The effect of adding inflammatory prognostic scores to the International Metastatic Renal Cell Carcinoma Database Consortium model (International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio and International Metastatic Renal Cell Carcinoma Database Consortium-Glasgow prognostic score models) on overall survival was evaluated using receiver operating characteristic curves. The prognostic value of inflammatory prognostic scores (C-reactive protein/albumin ratio-modified Glasgow prognostic score) was tested using the Kaplan-Meier method and Cox proportional regression models. RESULTS: Patients were stratified into two groups using the cut-off value of 0.05: C-reactive protein/albumin ratio-low (<0.05) and C-reactive protein/albumin ratio-high (≥0.05). The area under the curve was significantly higher in the International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio model (0.720) than that of the International Metastatic Renal Cell Carcinoma Database Consortium model (0.689) and the International Metastatic Renal Cell Carcinoma Database Consortium-modified Glasgow prognostic score model (0.703). Significant differences were observed in overall survival stratified by the number of risk factors in the International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio risk model between one or two and three or four factors (P < 0.001), and three or four and five or more factors (P = 0.001). For the patients in the International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk group, overall survival was significantly different between the C-reactive protein/albumin ratio-low and -high groups (P = 0.001), whereas it was not significantly different between the patients with one and two International Metastatic Renal Cell Carcinoma Database Consortium risk factors (P = 0.106). CONCLUSION: The C-reactive protein/albumin ratio is a simple and independent predictor of overall survival in patients with metastatic renal cell carcinoma. The predictive activity was significantly improved in the International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio model compared with the International Metastatic Renal Cell Carcinoma Database Consortium/International Metastatic Renal Cell Carcinoma Database Consortium-modified Glasgow prognostic score models.

Terminal differentiation of cortical neurons rapidly remodels RanGAP-mediated nuclear transport system.

Terminal differentiation of neurons is accompanied by irreversible exit from the cell cycle and expression of neuronal phenotypes. The molecular mechanism whereby committed neuronal progenitors lose their ability to reenter the cell cycle is largely unknown. Here, we report that the nuclear transport system is rapidly remodeled in primary cortical progenitor cells (CPCs) at the very beginning of neuronal terminal differentiation. High levels of Ran GTPase-activating protein 1 (RanGAP), a key regulator of the Ran GTP-GDP cycle, in primary CPCs are drastically reduced upon neuronal induction. Small ubiquitin-like modifier (SUMO)-2/3-conjugated RanGAP undergoes desumoylation and degradation in neuronally committed CPCs, where reduced RanGAP levels impede the nuclear import of nucleocytoplasmic shuttling proteins including the DNA replication initiation factor Cdc6. Furthermore, RNAi-mediated down-regulation of RanGAP expression in undifferentiated CPCs induces neuronal phenotypes including cell cycle exit. Our data suggest that remodeling of the RanGAP-mediated nuclear transport system plays a key role in cell cycle exit for terminal differentiation of cortical neurons.

Extended Production of Cortical Interneurons into the Third Trimester of Human Gestation.

In humans, the developmental origins of interneurons in the third trimester of pregnancy and the timing of completion of interneuron neurogenesis have remained unknown. Here, we show that the total and cycling Nkx2.1(+)and Dlx2(+)interneuron progenitors as well as Sox2(+)precursor cells were higher in density in the medial ganglionic eminence (MGE) compared with the lateral ganglionic eminence and cortical ventricular/subventricular zone (VZ/SVZ) of 16-35 gw subjects. The proliferation of these progenitors reduced as a function of gestational age, almost terminating by 35 gw. Proliferating Dlx2(+)cells were higher in density in the caudal ganglionic eminence (CGE) compared with the MGE, and persisted beyond 35 gw. Consistent with these findings, Sox2, Nkx2.1, Dlx2, and Mash1 protein levels were higher in the ganglionic eminences relative to the cortical VZ/SVZ. The density of gamma-aminobutyric acid-positive (GABA(+)) interneurons was higher in the cortical VZ/SVZ relative to MGE, but Nkx2.1 or Dlx2-expressing GABA(+)cells were more dense in the MGE compared with the cortical VZ/SVZ. The data suggest that the MGE and CGE are the primary source of cortical interneurons. Moreover, their generation continues nearly to the end of pregnancy, which may predispose premature infants to neurobehavioral disorders.

ß-Catenin signaling specifies progenitor cell identity in parallel with Shh signaling in the developing mammalian thalamus.

Neural progenitor cells within the developing thalamus are spatially organized into distinct populations. Their correct specification is critical for generating appropriate neuronal subtypes in specific locations during development. Secreted signaling molecules, such as sonic hedgehog (Shh) and Wnts, are required for the initial formation of the thalamic primordium. Once thalamic identity is established and neurogenesis is initiated, Shh regulates the positional identity of thalamic progenitor cells. Although Wnt/ß-catenin signaling also has differential activity within the thalamus during this stage of development, its significance has not been directly addressed. In this study, we used conditional gene manipulations in mice and explored the roles of ß-catenin signaling in the regional identity of thalamic progenitor cells. We found ß-catenin is required during thalamic neurogenesis to maintain thalamic fate while suppressing prethalamic fate, demonstrating that regulation of regional fate continues to require extrinsic signals. These roles of ß-catenin appeared to be mediated at least partly by regulating two basic helix-loop-helix (bHLH) transcription factors, Neurog1 and Neurog2. ß-Catenin and Shh signaling function in parallel to specify two progenitor domains within the thalamus, where individual transcription factors expressed in each progenitor domain were regulated differently by the two signaling pathways. We conclude that ß-catenin has multiple functions during thalamic neurogenesis and that both Shh and ß-catenin pathways are important for specifying distinct types of thalamic progenitor cells, ensuring that the appropriate neuronal subtypes are generated in the correct locations.

Necdin controls proliferation and apoptosis of embryonic neural stem cells in an oxygen tension-dependent manner.

Neural stem cells (NSCs) reside in vivo in hypoxic environments, and NSC proliferation is enhanced in vitro under hypoxic conditions. Various adaptive responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), a family of basic helix-loop-helix Per-Arnt-Sim (PAS) transcription factors. Necdin, a MAGE (melanoma antigen) family protein, is expressed abundantly in postmitotic neurons and possesses potent antimitotic and antiapoptotic activities. We here report that hypoxia induces degradation of the necdin protein in primary NSCs by HIF-mediated ubiquitin-proteasome system. Necdin was expressed in primary NSCs prepared from the ganglionic eminences of mouse embryos. Hypoxia enhanced neurosphere formation of NSCs, in which the necdin protein level was significantly reduced. Primary NSCs prepared from necdin-deficient mice exhibited higher rates of proliferation and apoptosis than those from wild-type mice in normoxia, whereas there were no significant differences in the proliferation and apoptosis rates between necdin-deficient and wild-type NSCs in hypoxia. HIF-2α was predominantly expressed in hypoxic NSCs, where expression of HIF-responsive genes was upregulated. HIF-2α interacted with necdin via its PAS domain, which enhanced necdin ubiquitination. Lentivirus-mediated expression of the PAS domain in primary NSCs promoted necdin degradation and enhanced NSC proliferation in normoxia, whereas a small-molecule inhibitor of HIF-2α translation stabilized the necdin protein and reduced NSC proliferation in hypoxia. These results suggest that oxygen tension regulates the necdin protein level in NSCs through HIF-2α-mediated proteasomal degradation to modulate their proliferation and apoptosis.

The Wnt receptor Ryk controls specification of GABAergic neurons versus oligodendrocytes during telencephalon development.

GABAergic neurons and oligodendrocytes originate from progenitors within the ventral telencephalon. However, the molecular mechanisms that control neuron-glial cell-fate segregation, especially how extrinsic factors regulate cell-fate changes, are poorly understood. We have discovered that the Wnt receptor Ryk promotes GABAergic neuron production while repressing oligodendrocyte formation in the ventral telencephalon. We demonstrate that Ryk controls the cell-fate switch by negatively regulating expression of the intrinsic oligodendrogenic factor Olig2 while inducing expression of the interneuron fate determinant Dlx2. In addition, we demonstrate that Ryk is required for GABAergic neuron induction and oligodendrogenesis inhibition caused by Wnt3a stimulation. Furthermore, we showed that the cleaved intracellular domain of Ryk is sufficient to regulate the cell-fate switch by regulating the expression of intrinsic cell-fate determinants. These results identify Ryk as a multi-functional receptor that is able to transduce extrinsic cues into progenitor cells, promote GABAergic neuron formation, and inhibit oligodendrogenesis during ventral embryonic brain development.

Early decline in progenitor diversity in the marmoset lateral ventricle.

The lateral ventricle (LV) of the adult rodent brain harbors neural stem cells (NSCs) that continue to generate new neurons throughout life. NSCs located in defined areas of the LV walls generate progenitors with distinct transcriptional profiles that are committed to specific neuronal fates. Here, we assessed if such diversity of NSCs also exist in the adult common marmoset, a widely used primate species in basic and clinical neuroscience research. We first investigated the 3D distributions of proliferative progenitors and committed neuroblasts in the marmoset forebrain. In addition to these maps, we assessed the spatial presence of divergent progenitor populations based on their expression of defined transcription factors, that is, Dlx2, Pax6, Tbr2, and Ngn2 which are differentially expressed by γ-aminobutyric acidergic versus glutamatergic progenitors in the adult rodent forebrain. In striking contrast to rodents, glutamatergic progenitors were only sparse in neonates and absent from the adult LV, whilst present in the hippocampus. Our analyses highlight major differences in the diversity of NSCs of the marmoset LV compared with rodents and emphasize the need to address NSCs diversity in evolutionary higher order mammals concomitantly to rodents.

BMP receptor 1A regulates development of hypothalamic circuits critical for feeding behavior.

Hypothalamic neural circuits are known to regulate energy homeostasis and feeding behavior, but how these circuits are established during development is not well understood. Here we report that embryonic neural progenitors that express the transcription factor OLIG1 contribute neurons to the ventral hypothalamus including the arcuate nucleus (ARH), a center that regulates feeding behavior. Ablation of bone morphogenetic protein receptor 1a (BMPR1A) in the OLIG1 lineage resulted in hypophagia, hypoglycemia, and weight loss after the second postnatal week with death by week 4. Differentiation and specification of inhibitory hypothalamic neurons contributing to melanocortin and dopaminergic systems were abnormal in the BMPR1A-deficient ARH. Although the hypophagia promoted expression of the orexigenic neuropeptide agouti related protein (AgRP) in the BMPR1A-deficient ARH, there was a profound decrease of AgRP(+) axonal terminals in the mutant ARH targets including dorsomedial and paraventricular hypothalamic nuclei. Projection of AgRP(+) neurons to these nuclei is known to be regulated by leptin. Leptin injection in neonatal mice increased bone morphogenic protein (BMP) signaling in the ventral hypothalamus, and blocking BMP signaling prevented leptin-induced neurite outgrowth in ARH explant cultures. These findings suggest that BMPR1A signaling is critical for postnatal establishment of leptin-responsive orexigenic fibers from ARH to multiple hypothalamic nuclei. More generally these observations indicate that BMPR1A signaling regulates postnatal establishment of OLIG1 lineage-derived ARH neuronal circuits that are critical for leptin-mediated feeding behavior.

Necdin controls Foxo1 acetylation in hypothalamic arcuate neurons to modulate the thyroid axis.

The forkhead transcription factor Foxo1 regulates energy homeostasis by modulating gene expression in the hypothalamus. Foxo1 undergoes post-translational modifications such as phosphorylation and acetylation, which modulate its functional activities. Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, regulates the acetylation status of Foxo1 in mammalian cells. Necdin, a pleiotropic protein required for neuronal development and survival, interacts with both Sirt1 and p53 to facilitate p53 deacetylation. The necdin gene (Ndn), an imprinted gene transcribed only from the paternal allele, is strongly expressed in hypothalamic neurons. Here, we demonstrate that necdin controls the acetylation status of Foxo1 in vivo in hypothalamic arcuate neurons to modulate the thyroid function. Necdin forms a stable ternary complex with Sirt1 and Foxo1, diminishes Foxo1 acetylation, and suppresses the transcriptional activity of Foxo1 in vitro. Paternal Ndn mutant mice express high levels of acetylated Foxo1 and mRNAs encoding agouti-related protein and neuropeptide Y in the hypothalamus in vivo during the juvenile period. The mutant mice exhibit endocrine dysfunction characteristic of hypothalamic hypothyroidism. Chemically induced hyperthyroidism and hypothyroidism lead to hypothalamic responses similar to those under necdin-deficient and excessive conditions, respectively, suggesting that thyroid hormone serves as a negative regulator of this system. These results suggest that necdin regulates Foxo1 acetylation and neuropeptide gene expression in the arcuate neurons to modulate the hypothalamic-pituitary-thyroid axis during development.

Association between Aortic Calcification Burden and the Severity of Erectile Dysfunction in Men Undergoing Dialysis: A Cross-Sectional Study.

PURPOSE: Accelerated atherosclerosis is a major complication in patients with end-stage renal disease and it plays an important role in the pathogenesis of erectile dysfunction (ED). However, the association between aortic calcification burden and the severity of ED remains unclear. The aim of the present study was to investigate this association in men undergoing dialysis. MATERIALS AND METHODS: This cross-sectional study included 71 men undergoing peritoneal dialysis and/or hemodialysis between July 2016 and May 2018 at Mutsu General Hospital. ED was assessed with the Sexual Health Inventory for Men (SHIM). Patients were divided into the mild/moderate (SHIM score ≥8) and severe ED groups (SHIM score ≤7). Aortic calcification index (ACI) was examined as a clinical indicator of abdominal aortic calcification. Multivariable logistic regression analysis was performed to identify the significant factors associated with severe ED. RESULTS: The median age of the study participants was 64 years; all had ED, with 64.8% having severe ED. In the multivariable analyses, a slight association was observed between ankle-brachial index and severe ED (odds ratio [OR], 0.058; p=0.072), whereas ACI was significantly associated with severe ED (OR, 1.022; p=0.022). CONCLUSIONS: Aortic calcification burden was independently associated with severe ED.

Can Erectile Dysfunction Severity Predict Major Adverse Cardiovascular Events in Men Undergoing Dialysis? A Prospective Cohort Study.

PURPOSE: To evaluate the impact of severe erectile dysfunction (ED) on future major adverse cardiovascular events (MACE) in men on dialysis. MATERIALS AND METHODS: This prospective cohort study included 71 men on dialysis. ED was assessed using the Sexual Health Inventory for Men (SHIM). Men were divided into the mild/moderate ED (SHIM score ≥8) and severe ED (SHIM score ≤7) groups. The primary endpoint was MACE-free survival. MACE was a composite of myocardial infarction, cardiovascular death, and stroke. The secondary endpoints were cardiac event-free survival and overall survival (OS). Moreover, the predictive abilities of severe ED for 5-year MACE, 5-year cardiac events, and 5-year overall mortality were evaluated. RESULTS: The median age and follow-up period of the included men were 64 years and 58 months, respectively. The median SHIM score was 4.0; all had a degree of ED, and 64.7% had severe ED. In the background-adjusted multivariable analyses, severe ED was not significantly associated with shorter MACE-free survival (hazard ratio [HR], 1.890; 95% confidence interval [CI], 0.533-6.706; p=0.324), cardiac event-free survival (HR, 2.081; 95% CI, 0.687-6.304; p=0.195), and OS (HR, 0.817; 95% CI, 0.358-1.863; p=0.630). Severe ED did not significantly improve the predictive abilities for 5-year MACE, 5-year cardiac events, and 5-year overall mortality (p=0.110, p=0.101, and p=0.740, respectively). CONCLUSIONS: ED severity was not associated with shorter MACE-free survival, cardiac event-free survival, or OS, and ED severity could not improve the predictive abilities for these outcomes in men undergoing dialysis.

Impact of an optimized surveillance protocol based on the European Association of Urology substratification on surveillance costs in patients with primary high-risk non-muscle-invasive bladder cancer.

OBJECTIVES: The optimal frequency and duration of surveillance in patients with high-risk non-muscle-invasive bladder cancer (NMIBC) remain unclear. The aim of the present study is to develop an optimal surveillance protocol based on the European Association of Urology (EAU) substratification in order to improve surveillance costs after transurethral resection of bladder tumor (TURBT) in patients with primary high-risk NMIBC. MATERIALS AND METHODS: We retrospectively evaluated 428 patients with primary high-risk NMIBC who underwent TURBT from November 1993 to April 2019. Patients were substratified into the highest-risk and high-risk without highest-risk groups based on the EAU guidelines. An optimized surveillance protocol that enhances cost-effectiveness was then developed using real incidences of recurrence after TURBT. A recurrence detection rate ([number of patients with recurrence / number of patients with surveillance] × 100) of ≥ 1% during a certain period indicated that routine surveillance was necessary in this period. The 10-year total surveillance cost was compared between the EAU guidelines-based protocol and the optimized surveillance protocol developed herein. RESULTS: Among the 428 patients with primary high-risk NMIBC, 97 (23%) were substratified into the highest-risk group. Patients in the highest-risk group had a significantly shorter recurrence-free survival than those in the high-risk without highest-risk group. The optimized surveillance protocol promoted a 40% reduction ($394,990) in the 10-year total surveillance cost compared to the EAU guidelines-based surveillance protocol. CONCLUSION: The optimized surveillance protocol based on the EAU substratification could potentially reduce over investigation during follow-up and improve surveillance costs after TURBT in patients with primary high-risk NMIBC.