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BACKGROUND: Earthquakes and other catastrophic events frequently occurring worldwide can be considered as outliers and cause a growing and urgent need to improve our understanding of the negative effects imposed by such disasters. Earthquakes can intensively impact the birth outcomes upon psychological and morphological development of the unborn children, albeit detailed characteristics remain obscure. METHODS AND FINDINGS: We utilized the birth records at Du Jiang Yan and Peng Zhou counties to investigate the birth outcomes as a consequence of a major earthquake occurred in Wenchuan, China on May 12, 2008. Totally 13,003 of neonates were recorded, with 6638 and 6365 for pre- and post- earthquake, respectively. Significant low birthweight, high ratio of low birthweight, and low Apgar scores of post-earthquake group were observed. In contrast, the sex ratio at birth, birth length and length of gestation did not show statistical differences. The overall ratio of birth-defect in the post-earthquake (1.18%) is statistically high than that of pre-earthquake (0.99%), especially for those in the first trimester on earthquake day (1.47%). The birth-defect spectrum was dramatically altered after earthquake, with the markedly increased occurrences of ear malformations. The ratio of preterm birth post-earthquake (7.41%) is significant increased than that of pre-earthquake (5.63%). For the birth outcomes of twins, significant differences of the ratio of twins, birth weight, ratio of low birthweight and birth-defect rate were observed after earthquake. CONCLUSION: A hospital-based study of birth outcomes impacted by the Wenchuan earthquake shows that the earthquake was associated with significant effects on birth outcomes, indicating it is a major monitor for long-term pregnant outcomes.

Objective: To explore the genetic characteristics and molecular regulator of Kidney-Yang Deficiency Syndrome (KDS). Design: A typical KDS family was collected using a questionnaire of cold feeling and a 40-item scoring table of KDS based on Traditional Chinese Medicine (TCM), by single-blind method repeated annually over three years. Their transcriptomes were assayed by microarray and validated by RT-PCR and ELISA. Simultaneously, 10 healthy volunteers were recruited as controls and the same protocols were performed. Results: This typical KDS family has 35 members, of whom 11 were evaluated as having severe KDS and 6 as having common KDS. Results of the cDNA microarray revealed that there were 420 genes/expressed sequence tags differentially expressed in KDS transcriptomes, indicating a global functional impairment in the mass-energy-information carrying network of KDS patients, involving energy metabolism, signal transduction, development, cell cycle, and immunity. Pathway analysis by gene set enrichment assay (GSEA) and other tools demonstrated that mitogenic activated protein kinase (MAPK) is among the most insufficiently activated pathways, while the oxidative phosphorylation and glycolysis/gluconeogenesis pathways, the two main pathways relevant to ATP synthesis, were among the most excessively activated pathways in KDS patients. Results of RT-PCR and ELISA confirmed the status of insufficient activity of the MAPK pathway. Conclusion: KDS patients undergo overall attenuated functions in the mass-energy-information carrying network. The marked low level of energy output in KDS may be primarily attributed to the insufficient activity of the MAPK pathway, which may be a key monitor for the abnormal energy metabolism and other impaired activities in KDS. [ABSTRACT FROM AUTHOR]

Introduction: Symptoms during the onset of major depressive disorder [MDD] and bipolar disorder type II [BD-II] are similar. The difference of hippocampus subregion could be a biological marker to distinguish MDD from BD-II., Methods: We recruited 61 drug-naïve patients with a first-episode MDD and BD-II episode and 30 healthy controls (HC) to participate in a magnetic resonance imaging [MRI] study. We built a general linear model (one-way analysis of covariance) with 22 hippocampal subfields and two total hippocampal volumes as dependent variables, and the diagnosis of MDD, BD-II, and HC as independent variables. We performed pair-wise comparisons of hippocampal subfield volumes between MDD and HC, BD-II and MDD, BD-II and HC with post hoc for primary analysis., Results: We identified three regions that differed significantly in size between patients and controls. The left hippocampal fissure, the hippocampal-amygdaloid transition area (HATA), and the right subiculum body were all significantly larger in patients with MDD compared with the HC. In the onset of first-episode of MDD, the hippocampal volume increased significantly, especially on the left side comparing to HC. However, we found differences between MDD and BD-II were not statistically significant. The volume of the left HATA and right subiculum body in BD-II was larger., Conclusions: The sample size of this study is relatively small, as it is a cross-sectional comparative study. In both MDD and BD-II groups, the volume of more left subregions appeared to increase. The left subregions were severely injured in the development of depressive disorder., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cong, Zhong, Wu, Chen, Cai, Ling, Wang, Wen, Hu, Zhang, Li, Liu, Zhong, Lai, Xu and Wu.)

Background: The adolescent depression associated with childhood trauma has been confirmed, but the underlying mechanisms remain unclear. This study aims to explore the chain-mediated role of borderline personality traits and self-control in the relationship between childhood trauma and adolescent depression., Methods: A cross-sectional study was conducted on 2,664 students from a senior high school through online questionnaires from October to December 2022 in Henan, China. Childhood Trauma Questionnaire-Short Form, Borderline Personality Dimension of Personality Diagnostic Questionnaire-4, Self-Control Scale, and Children's Depression Inventory were used to measure childhood trauma, borderline personality traits, and self-control., Results: The prevalence of depression in adolescents was 21.17%, while the prevalence of borderline personality was 12.00%. childhood trauma (r = 0.50, p < 0.001) and borderline personality traits (r = 0.60, p < 0.001) were positively correlated with adolescent depressive symptoms, while self-control was negatively correlated with depressive symptoms (r = - 0.50, p < 0.001). Borderline personality traits and Self-control both play a mediating role in childhood trauma and depressive symptoms, and the mediating effect values are 0.116 (95%CI = [0.098, 0.137]), and 0.022 (95%CI = [0.012, 0.032]) respectively. The chain mediating effect of borderline personality traits and self-control on the relationship between childhood trauma and depressive symptoms was significant (effect value: 0.034, 95%CI = [0.028, 0.042])., Conclusions: Childhood trauma can predict depressive symptoms in adolescents due to the formation of borderline personality traits and the reduction of self-control. These findings are important for understanding the formation of personality traits, self-control abilities and coping strategies shaped by traumatic experiences in adolescents., (© 2024. The Author(s).)

Purpose: Postpartum depression (PPD) brings adverse and serious consequences to both new parents and newborns. Neuroticism affects PPD, which remains controversial for confounding factors and reverse causality in cross-sectional research. Therefore, mendelian randomization (MR) study has been adopted to investigate their causal relationship., Methods: This study utilized large-scale genome-wide association study genetic pooled data from three major databases: the United Kingdom Biobank, the European Bioinformatics Institute, and the FinnGen databases. The causal analysis methods used inverse variance weighting (IVW). The weighted median, MR-Egger method, MR-PRESSO test, and the leave-one-out sensitivity test have been used to examine the results' robustness, heterogeneity, and horizontal pleiotropy. The fixed effect model yielded the results of meta-analysis., Results: In the IVW model, a meta-analysis of the MR study showed that neuroticism increased the risk of PPD (OR, 1.17; 95% CI, 1.11-1.25, p < 0.01). Reverse analysis showed that PPD could not genetically predict neuroticism. There was no significant heterogeneity or horizontal pleiotropy bias in this result., Conclusion: Our study suggests neuroticism is the risk factor for PPD from a gene perspective and PPD is not the risk factor for neuroticism. This finding may provide new insights into prevention and intervention strategies for PPD according to early detection of neuroticism., (© 2024. The Author(s).)

Introduction: After decades of the one-child policy, China changed its rules to allow two children in 2016, which altered family dynamics. Few studies have examined the emotional problems and the family environment of multi-child adolescents. This study aims to explore the role of only-child status in the impact of childhood trauma and parental rearing style on depressive symptoms of adolescents in Shanghai, China., Methods: A cross-sectional study was conducted on 4,576 adolescents ( M  = 13.42 years, SD = 1.21) from seven middle schools in Shanghai, China. Childhood Trauma Questionnaire-Short Form, the Short Egna Minnen Beträffande Uppfostran, and Children's Depression Inventory were used to evaluate childhood trauma, perceived parental rearing style, and depressive symptoms of adolescents, respectively., Results: Results showed that girls and non-only children reported more depressive symptoms, while boys and non-only children perceived more childhood trauma and negative rearing styles. Emotional abuse, emotional neglect, and father's emotional warmth significantly predicted depressive symptoms in both only children and non-only children. Father's rejection and mother's overprotection were related to adolescents' depressive symptoms in only-child families, but not non-only child families., Discussion: Therefore, depressive symptoms, childhood trauma, and perceived negative rearing styles were more prevalent among adolescents in non-only child families, while negative rearing styles were especially associated with depressive symptoms in only children. These findings suggest that parents pay attention to their impacts on only children and give more emotional care to non-only children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhong, Huang, Chen, Li, Li, Chen, Cong and Xu.)

Objective: The aim of this study was to examine the effect of either conjugated equine estrogen or transdermal estradiol on vitamin D metabolism in postmenopausal women., Methods: Twenty-five women from the Kronos Early Estrogen Prevention Study who were randomized to conjugated equine estrogen 0.45 mg/d and 20 women who were treated with transdermal estradiol 50 mg/d (patch replaced weekly) were analyzed in the present study. All participants received micronized progesterone for 12 days per month., Results: There was no significant treatment effect on serum total 25-hydroxyvitamin D over 48 months in either study group, and there were no significant differences between treatment arms. In contrast, at 12 months, directly measured free 25-hydroxyvitamin D was significantly higher in the transdermal estradiol group than in the conjugated equine estrogen group. Directly measured free 25-hydroxyvitamin D subsequently increased significantly from 12 to 48 months in both treatment arms. Calculated free 25-hydroxyvitamin D was also significantly higher in the transdermal estradiol group at 36 months. Vitamin D-binding protein decreased significantly in both treatment groups from 12 to 48 months, but at 48 months, least square mean values were no different based on treatment assignment., Conclusions: Directly measured free 25-hydroxyvitamin D levels, but not serum total 25-hydroxyvitamin D levels, are different within the first 12 months of estrogen replacement depending on the preparation. However, this difference is transient, in that there were no differences at 36 or 48 months. These findings suggest that there may be a short-term benefit to prescribing transdermal estradiol for women who are either vitamin D deficient or vitamin D insufficient., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2022 by The North American Menopause Society.)

Background: Major depression is the largest single contributor to suicide, and anxiety symptoms are associated with the severity of depression and suicidality. It is important to explore biomarkers of anxiety and suicidal ideation in major depression. In this study we hypothesized that the volume of subregions of the amygdala might be indicators of anxiety and suicidal ideation in patients with major depression., Methods: We recruited 59 drug-naïve patients with first-episode depression who scored >17 on the Hamilton Rating Scale for depression, and 30 healthy controls to participate in a magnetic resonance imaging study. We examined the volume of sub-regions of the amygdala thought to be involved in processing anxious emotion in the depression and healthy control groups. We performed pair-wise comparisons of amygdala subfield volumes in patients with depression and healthy controls with an analysis of variance. We used logistic regression to test the relationship between suicidal ideation and anxious character with the volume of subregions of the amygdala., Results: 1) We found a significant difference in the volumes of the left amygdala (P = 0.003) and right amygdala (P = 0.001) between the two groups. There are significant differences in the volumes of the sub-region of the left amygdala. 2) The volume of the left lateral nucleus (P<0.001), basal nucleus (P<0.001), accessory basal nucleus (P<0.05), left Paralaminar-nucleus (P<0.001), right lateral-nucleus (P<0.05), right basal-nucleus (P<0.05), right anterior-amygdaloid area AAA (P<0.05), right paralaminar-nucleus (P<0.001) in the depression group are larger than healthy controls, however the volumes of the central-nucleus (P<0.05), medial-nucleus (P<0.001) in both sides are decreased in the major depression group. 3) There is a significantly larger volume of right medial nucleus in the suicidal ideation group comparing the hopelessness (P = 0.026), and the depressive patients without hopeless thoughts (P = 0.004). 4) We found a negative relation between the left basal nucleus and anxiety (OR: 0.940, 95%CI: 0.891-0.991), and a positive relation between the accessory basal nucleus on the left side and anxiety (OR: 1.007, 95%CI: 1.002-1.158)., Limitations: We were not able to examine the effects of gender or age. The changes of amygdala volume in patients with depression were not followed up. Our sample size was such that independent replication is needed to confirm the robustness of our results., Conclusions: The volumes of the basal nucleus in both sides are increased in depressed patients while the volumes of the central-nucleus, medial-nucleus bilaterally are reduced in the major depression group. Among the subregions, the volume of right medial nucleus might be the biomarkers for suicidal ideation in depressive patients., (Copyright © 2022. Published by Elsevier B.V.)

The narrow band gap and significant separation of photogenerated carriers are essential aspects in practical photocatalytic applications. Nitrogen doping usually narrows the band gap of semiconductor oxides, and it enhances photocatalytic activity. Nitrogen-doped Nb 2 O 5 was prepared by a multiple hydrothermal method. The non-metal element N inside the nanostructure, working as the trapping sites for the holes, which were effectively incorporated into the crystal lattice of Nb 2 O 5 semiconductor oxide, remarkably shorten the band gap (3.1 eV) to enhance the visible light response, effectively reducing the photoinduced electron-hole pair recombination and prolonging carrier lifetime. The multilayer coating structure with a gradient concentration distribution and the type of nitrogen doped is favorable for the migration of photoexcited carriers in the bulk of catalysts. The unique multi-layer coating with the micro-concentration gradient of doped nitrogen provides a fast separation channel and jump steps for the separation of electron-hole pairs.

Introduction: The purpose of this study was to investigate the prognostic utility and reproducibility of a qualitative 5-point 18-fluorodeoxyglucose (FDG)-PET primary visual score (PVS) in patients with oesophageal and gastro-oesophageal junction (GOJ) cancer., Methods: This was a retrospective review of patients with histologically proven oesophageal or GOJ cancer who received curative intent therapy. Clinical, pathological and imaging data were extracted from electronic medical records. Patients were required to have pre-treatment and post-treatment FDG-PET scans, that were evaluated with a 5-point primary visual score (prePVS, postPVS). The changes in PVS (ΔPVS) were correlated with progression-free survival and overall survival. Interobserver variability was assessed using Cohen's Kappa intraclass correlation and agreement., Results: Sixty-seven patients were retrospectively identified. Two (3%), 36 (54%) and 29 (43%) of the patients had stage I, II and III disease respectively. Twenty-five (37%) patients had squamous cell carcinoma. Thirty-seven (55%) patients proceeded onto surgical resection. postPVS was associated with both PFS (P = 0.013) and OS (P = 0.0002). ΔPVS predicted for PFS (P = 0.002) and OS (P = 0.0003). When thresholds of response were considered, agreement was 80.6% (K = 0.78) and 74.6% (K = 0.69) for postPVS and ΔPVS respectively., Conclusion: Qualitative assessment of oesophageal and GOJ cancers utilising FDG-PET is reproducible and may be able to prognosticate outcomes in patients undergoing treatment. Prospective validation is required., (© 2020 The Royal Australian and New Zealand College of Radiologists.)

Background: Robust evidence has shown that abnormal function networks, particularly the salience network (SN), are observed in depressed patients. Although white matter structural connectivity may predict time-varying functional connectivity, including symptom phenotype, in psychiatric disorders, there is still a gap in elucidating the concurrent dynamic functional and structural connectivity profiles of the SN in depressed patients., Methods: We measured static and dynamic functional connectivity (FC) of the SN using resting-state fMRI BOLD time series in 76 subjects (21 with major depressive disorder (MDD), 27 with bipolar depression (BD), and 28 healthy controls (HC)). Hamilton Depression Scale total score was used to measure depression severity. Furthermore, we investigated the concurrent structural connectivity using diffusion kurtosis imaging (DKI)-based tractography., Results: Our findings suggested that in the presence of MDD, both structural and dynamic (but not static) FC were reduced in the SN, particularly affecting the left prefronto-insular pathways (L.aPFC-L.insula). MDD patients showed decreased connectivity variability within the SN compared with HC. The aberrant dynamic FC in the prefronto-insular pathways of the SN related to severity of depressive symptoms in MDD. Furthermore, compared with BD patients, those with MDD showed significantly decreased dynamic FC in the left prefronto-parietal system (L.aPFC-lateral parietal cortex)., Limitations: The generalizability of our findings is, to some extent, constrained by the small sample size., Conclusions: The integrity of SN connectivity, particularly the prefronto-insular pathway, appears to be a crucial signature of MDD. The perturbed dynamic interaction of SN with prefrontal regions may underlie the clinical severity in depressed patients., Competing Interests: Declaration of Competing Interests There is no conflict of interest in our study., (Copyright © 2020. Published by Elsevier B.V.)

Objective: The neurophysiological mechanisms underlying cognitive dysfunction in primary hyperparathyroidism (PHPT) and the brain regions affected are not clear. We assessed neural activation during cognitive testing (matrix reasoning, paired associates, and logical memory) using functional MRI (fMRI) in 23 patients with PHPT and 23 healthy controls. A subset with PHPT was re-assessed 6 months post-parathyroidectomy (PTX)., Design: This is an observational study comparing neural activation by fMRI in patients with PHPT to normative controls. Postmenopausal women were studied at a tertiary referral center., Results: There were no between-group differences in cognitive task performance. Patients with PHPT had lower neural activation vs controls (max Z = 4.02, all P < 0.01) during matrix reasoning in brain regions involved in executive function (left frontal lobe (k = 57) and right medial frontal gyrus (k = 72)) and motor function (right precentral gyrus (k = 51)). During paired associates (verbal memory), those with PHPT had greater activation in the right inferior parietal lobule (language/mathematical operations; k = 65, P < 0.01). Greater activation in this region bilaterally correlated with higher PTH (k = 96, P < 0.01). Post-PTX, activation decreased during matrix reasoning, but in different regions than those affected pre-PTX., Conclusions: PHPT is associated with differences in task-related neural activation patterns, but no difference in cognitive performance. While this may indicate compensation to maintain the same cognitive function, there was no clear improvement in neural activation after PTX. Larger, longitudinal studies that include PHPT patients followed without surgery are needed to determine if PTX could prevent worsening of altered neural activation patterns in PHPT.

Objective: This study addresses the relationship between circulating levels of colony-stimulating factor 1 (CSF-1) and rates of postmenopausal bone loss. The purpose was to test the hypothesis that CSF-1 levels would correlate with the rate of bone loss in estrogen-deficient woman. We further hypothesized that estrogen replacement would eliminate this association., Methods: This was an ancillary study to the parent Kronos Early Estrogen Prevention Study (KEEPS)-a 4-year randomized placebo-controlled study that evaluated the effects of estrogen therapy on cardiovascular endpoints. Women between of the ages of 42 and 58, who had been amenorrheic for ≥6 months and ≤36 months, were enrolled in KEEPS. Participants were randomized to conjugated equine estrogen 0.45 mg daily, transdermal estradiol 50 micrograms weekly, or placebo., Results: There was no correlation between serum levels of CSF-1 and bone mineral density at the spine, hip, or femoral neck in estrogen-deficient women (correlation 0.0017, P = 0.99 for spine; correlation 0.0010, P = 0.0079 for hip, and correlation 0.0019, P = 0.99 for femoral neck). There was also no significant correlation in the treatment group (correlation 0.0015, P = 0.99; correlation -0.00024, P = 0.99; correlation 0.0011, P = 0.99 at spine, hip, and femoral neck respectively)., Conclusions: This study did not demonstrate a meaningful relationship between circulating levels of CSF-1 and bone mineral density in either the placebo group or estrogen-treated group. Although CSF-1 is required for osteoclastic bone resorption, our data suggest that circulating levels of the cytokine may not reflect this process.

Objective To identify serum proteome of ejaculation praecox(EP) with Shen-yang de- ficiency, and to explore its pathogenesis of EP in the protein-protein interaction ( PPI) network. Methods The serum samples were respectively collected from 4 EP with Shen-yang deficiency patients and 4 healthy controls. After the serum proteome of EP with Shen-yang deficiency was obtained, the technology of isobaric tags for relative and absolute quantitation (iTRAQ) was adopted for identification. The STRING data- base was applied to construct the PPI network whose function was analyzed through bioinformatics meth- ods. Results A group of 238 serum proteins were identified in total, of which, 162 proteins reached the strict quantitative standard. Nine proteins were differently expressed, including 1 up-regulated and 8 down-regulated. The constructed PPI network was constituted by 72 protein nodes and 283 protein couples, and could be clustered to 16 clusters, in which 10 clusters were composed of 3 or more proteins. Each cluster could be found with a core protein correspondingly. The core protein of C3,C5,C1S and MASP2 were all main constituents of complement system, whose function involves in biological process of complement ac- tivation. Conclusions The protein models in PPI network of differently expressed serum proteome about EP with Shen-yang deficiency were functional enriched in the biological process of complement activa-, tion; which indicate that a immune dysfuction dominated by abnormal process of complent activation may' be one of the main mechanisms of EP with Shen-yang deficiency.

Context: Patients with 25-hydroxyvitamin D deficiency (25OHD <20 ng/ml) and primary hyperparathyroidism (PHPT) have more severe disease reflected by higher serum PTH levels compared to those with vitamin D levels in the insufficient (20-29 ng/ml) or replete range (≥ 30 ng/ml)., Objective: To study the effect of low vitamin D in PHPT on volumetric bone mineral density (vBMD), bone microarchitecture, and bone strength., Design, Setting, and Participants: This is a cross-sectional analysis of 99 PHPT patients with and without 25OHD insufficiency and deficiency from a university hospital., Outcome Measures: Bone microarchitecture and strength were assessed with high-resolution peripheral quantitative computed tomography (HRpQCT), microfinite element analysis, and individual trabecula segmentation., Results: In this cohort, 25OHD levels were deficient in 18.1%, insufficient in 35.4% and replete in 46.5%. Those with lower 25OHD levels had higher PTH (P < .0001), were younger (P = .001) and tended to weigh more (P = .053). There were no age-, weight- and sex-adjusted between-group differences (<20 vs 20-29 vs ≥ 30 ng/ml) in any HRpQCT, microfinite element analysis, or individual trabecula segmentation indices. Because few participants had 25OHD below 20 ng/ml, we also compared those with 25OHD below 30 vs at least 30 ng/ml and found only a trend toward lower adjusted cortical vBMD (3.1%, P = .08) and higher cortical porosity (least squares mean ± SEM 7.5 ± 0.3 vs 6.6 ± 0.3%, P = .07) at the tibia but not the radius. Stiffness did not differ at either site. In multiple regression analysis, 25OHD accounted for only three of the 49.2% known variance in cortical vBMD; 25OHD was not significant in the model for cortical porosity at the tibia., Conclusion: Low 25OHD levels are associated with higher PTH levels in PHPT, but contrary to our hypothesis, these differences did not significantly affect vBMD or microarchitecture, nor did they result in lower stiffness. Low vitamin D in PHPT using current 25OHD thresholds for insufficiency and deficiency did not significantly affect skeletal integrity as assessed by HRpQCT.

Context: Seasonal variability in 25-hydroxyvitamin D [25(OH)D] and PTH levels in the general population has been associated with differences in bone turnover markers, bone density, and fracture risk. Seasonal variability in 25(OH)D and PTH levels has also been reported in primary hyperparathyroidism (PHPT)., Objective: Given the widespread use of vitamin D supplements, we sought to determine whether patients with PHPT still demonstrated seasonal variation in 25(OH)D levels., Design and Setting: This cross-sectional study was conducted at a university medical center at a Northeastern U.S. latitude (New York, NY)., Patients: One hundred patients with PHPT participated in the study., Outcome Measures: We assessed vitamin D supplement use and seasonal variation in serum 25(OH)D., Results: Patients had PHPT ([mean ± SD] calcium, 10.8 ± 1.0 mg/dL; PTH, 85 ± 48 pg/mL) with a mean 25(OH)D level of 29 ± 10 ng/mL. Although only one fifth of participants had vitamin D deficiency (19% < 20 ng/mL), more than half were either deficient or insufficient (54% < 30 ng/mL). Sun exposure varied by season, but there were no seasonal differences in levels of 25(OH)D, PTH, bone markers, or bone mineral density, or in the prevalence of 25(OH)D less than 20 or less than 30 ng/mL. Most of the participants (65%) took supplemental vitamin D (dose among users: mean, 1643 ± 1496 IU; median, 1000 IU daily), and supplement users had markedly better vitamin D status than nonusers (25(OH)D < 20 ng/mL: 8 vs 40%; P < .0001; < 30 ng/mL: 40 vs 80%; P = .0001; ≥ 30 ng/mL: 60 vs 20%; P = .0001)., Conclusions: We found no evidence of seasonal variation in 25(OH)D levels or PHPT disease severity in the Northeastern United States. This change is likely due to widespread high vitamin D supplement intake, which has resulted in better vitamin D status among supplement users and can mask the effect of season on serum 25(OH)D levels.

Context: Vitamin D (25-hydroxyvitamin D [25OHD]) deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common in primary hyperparathyroidism (PHPT), but data regarding their skeletal effects in PHPT are limited., Objective: The objective was to evaluate the association between 25OHD levels and PHPT severity., Design, Settings, and Participants: This is a cross-sectional analysis of 100 PHPT patients with and without 25OHD insufficiency and deficiency from a university hospital setting., Outcome Measures: We measured calciotropic hormones, bone turnover markers, and bone mineral density (BMD) by dual x-ray absorptiometry., Results: Lower 25OHD was associated with some (PTH: r = -0.42; P < .0001; 1,25-dihydroxyvitamin D: r = -0.27; P = .008; serum PO4: r = 0.31; P = .002) but not all (serum/urine calcium) indicators of PHPT severity. Lower 25OHD was also associated with younger age, higher body mass index, male gender, better renal function, and lower vitamin D intake. Comparison of those with deficient (<20 ng/mL; 19%) vs insufficient (20-29 ng/mL; 35%) vs replete (≥30 ng/mL; 46%) 25OHD demonstrated more severe PHPT as reflected by higher PTH (mean ± SEM, 126 ± 10 vs 81 ± 7 vs 72 ± 7 pg/mL; P < .0001) but no difference in nephrolithiasis, osteoporosis, fractures, serum or urinary calcium, bone turnover markers, or BMD after adjustment for age and weight. In women, T-scores at the 1/3 radius were lower in those with 25OHD of 20-29 ng/mL, compared to those who were vitamin D replete (P = .048). In multiple regression modeling, 25OHD (but not PTH) was an independent predictor of 1/3 radius BMD., Conclusion: Vitamin D deficiency is associated with more severe PHPT as reflected by PTH levels, but effects on BMD are limited to the cortical 1/3 radius and are quite modest. These data support international guidelines that consider PHPT patients with 25OHD <20 ng/mL to be deficient. However, in this cohort with few profoundly vitamin D-deficient patients, vitamin D status did not appear to significantly impact clinical presentation or bone density.

Background: Patients with schizophrenia using antipsychotics often develop metabolic side effects, especially with clozapine. Previous studies indicated that antipsychotics could activate the pathway of the sterol regulatory element-binding protein (SREBP). The sterol regulatory element binding transcription factor 2 (SREBF2) gene mainly regulates the cholesterol biosynthetic gene. Therefore, we hypothesized that the SREBF2 gene would be a candidate gene for interindividual variation in drug-induced metabolic syndrome (MetS). In this genetic case-control study, we examined the SREBF2 gene polymorphisms in the risk of MetS patients treated with clozapine., Methods: Ten single nucleotide polymorphisms (SNPs) of SREBF2 were genotyped in a CHB (Han Chinese in Beijing, China) population, a sample of 621 schizophrenia patients treated with clozapine. Patients were evaluated for metabolic parameters and screened for the MetS criteria., Results: The incidence of MetS among all subjects was 41.8% (260/621). Two markers of SREBF2 were associated with MetS induced by clozapine after False Discovery Rate (FDR) correction (rs1052717, corrected Pallele=0.010, corrected Pgenotype=0.022; and rs2267443, corrected Pgenotype=0.015). Patients who received clozapine and carried the A-allele of rs2267443 or rs1052717 had an increased risk of MetS (rs2267443, odds ratio (OR)=1.67, 95% confidence interval (CI): 1.20-2.34; and rs1052717, OR=1.81, 95% CI: 1.15-1.98), adjusted by logistic regression for clinical characteristics., Conclusion: The results suggest that the genetic polymorphisms of SREBF2 gene may be associated with MetS in patients treated with clozapine., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages., (Copyright © 2014 by the American Society of Nephrology.)

Osteoporotic fractures are a major public health problem worldwide, but incidence varies greatly across racial groups and geographic regions. Recent work suggests that the incidence of osteoporotic fracture is rising among Asian populations. Studies comparing areal bone mineral density and fracture across races generally indicate lower bone mineral density in Asian individuals including the Chinese, but this does not reflect their relatively low risk of non-vertebral fractures. In contrast, the Chinese have relatively high vertebral fracture rates similar to that of Caucasians. The paradoxically low risk for some types of fractures among the Chinese despite their low areal bone mineral density has been elucidated in part by recent advances in skeletal imaging. New techniques for assessing bone quality non-invasively demonstrate that the Chinese compensate for smaller bone size by differences in hip geometry and microstructural skeletal organization. Studies evaluating factors influencing racial differences in bone remodeling, as well as bone acquisition and loss, may further elucidate racial variation in bone microstructure. Advances in understanding the microstructure of the Chinese skeleton have not only helped to explain the epidemiology of fracture in the Chinese, but may also provide insight into the epidemiology of fracture in other races as well.

Context: Vitamin D (25OHD) deficiency may be a modifiable cardiovascular (CV) risk factor. 25OHD insufficiency (20-29 ng/mL) and deficiency (<20 ng/mL) are common in primary hyperparathyroidism (PHPT), but their association with CV disease in PHPT has not been systematically investigated., Objective: This study evaluated whether low 25OHD is associated with subclinical CV disease in PHPT., Design: This is a cross-sectional analysis of PHPT patients with and without low 25OHD., Settings and Participants: We studied 110 PHPT patients in a university hospital setting., Outcome Measures: We measured carotid intima-media thickness; carotid plaque presence/thickness; carotid strain and stiffness; left ventricular mass index; cardiac systolic and diastolic function; and mitral annular calcification., Results: Low 25OHD levels (<30 ng/mL) were observed in 28%, but only 9% had 25OHD deficiency (<20 ng/mL). In the whole group, 25OHD levels negatively correlated with body mass index (r = -0.33, P = .0005), PTH (r = -0.30, P = .001), calcium (r = -0.29, P = .002), renal function, and PHPT duration. CV indices were normal except for carotid intima-media thickness, stiffness, and plaque thickness, which were increased, regardless of 25OHD status. Isovolumic relaxation time was the only CV measure associated with 25OHD (r = -0.26, P = .01). Those with 25OHD less than 20 ng/mL had more severe PHPT and a higher rate of nephrolithiasis. Those with 25OHD less than 30 ng/mL were younger, had higher body mass index, had lower serum phosphate, and were more likely to be male, nonwhite, and Hispanic. Other than lower tissue Doppler e' and higher isovolumic relaxation time within normal range in those with 25OHD less than 30 vs greater than 30 ng/mL, there were no differences in CV indices using either 25OHD threshold., Conclusions: Patients with mild PHPT have subclinical carotid abnormalities, but low 25OHD is not associated with abnormal carotid or cardiac measures. To the extent that PTH levels differentiated those with 25OHD less than 20 but not 30 ng/mL, these data support a 25OHD threshold of 20 ng/mL as clinically relevant in PHPT.

Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal-recessive form of nonsyndromic steroid-resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid-resistant nephrotic syndrome before the age of 6 years and rapidly progress to end-stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype-phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database (www.lovd.nl/NPHS2) software that will allow the inclusion of future reports., (© 2013 WILEY PERIODICALS, INC.)

Background: Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set?, Method: Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression., Results: We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19-5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58-3.15), genital (OR 5.24, 95% CI 3.52-8.15) and intercourse (OR 10.65, 95% CI 5.56-23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11-2.27) and phobia (OR 1.41, 95%CI 1.09-1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20-1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02-2.02). Intercourse (OR 3.47, 95%CI 1.66-8.22), use of force and threats (OR 1.95, 95%CI 1.05-3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20-1.64) were significantly associated with recurrent MD., Conclusions: In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.

Background: Charcot-Marie-Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot-Marie-Tooth neuropathy associated with FSGS., Methods: We performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted., Results: We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2-MAL-CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42., Conclusions: INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. (Funded by the Agence Nationale de la Recherche and others.).