Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene.

Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidney's filtering system, causing serious scarring. More than half of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X-linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify two mutated genes, NXF5 and ALG13, which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population.

Suicide-risk-related factors in a psychiatric patient cohort: a cross sectional study on outpatients, inpatients, and therapeutic community patients.

BACKGROUND: Suicide constitutes a significant global health concern. Joiner's interpersonal-psychological theory of suicide focuses on three variables: Thwarted Belongingness (TB), Perceived Burdensomeness (PB) and Acquired Capability for Suicide. METHODS: A sample of 90 psychiatric patients, comprising outpatients, inpatients and individuals residing in therapeutic communities, was recruited between 2021 and 2022. Scales measuring anxiety, depression, mental pain, reasons for living, TB, PB and fearlessness about death were administered. Patients with and without suicidal ideation (SI), as well as those with and without history of suicide attempt (SA) were compared and two stepwise logistic regression models were performed. RESULTS: Both patients with SI and with SA had higher anxiety, depression, mental pain, PB, fearlessness about death and lower self-esteem. Notably, depression, PB and beliefs about coping strategies were strongly associated with SI, while higher fearlessness about death and PB were strongly linked to history of SA. Additionally, inpatients and therapeutic community patients were at higher risk of suicide and had higher levels of depression compared to outpatients. LIMITATIONS: The small sample size and the inclusion of patients with mixed psychiatric diagnoses limit the generalizability of the findings. The cross-sectional design hinders causal hypotheses about the relationship between current SI or past SA and potential risk factors. The use of self-report measures entails biases. The analyses did not include details about pharmacological treatments. CONCLUSIONS: SA history could be explained by fearlessness about death. Improving the ability to cope with suicidal thoughts constitutes a pivotal component of therapeutic interventions with suicidal patients.

The Interpersonal Psychological Theory of Suicide in Italian University Students: Validation of the INQ-15 and the ACSS-FAD.

In the frame of the interpersonal psychological theory of suicide (IPTS), Interpersonal Needs Questionnaire (INQ-15) assesses thwarted belongingness (TB) and perceived burdensomeness (PB), related to suicidal ideation (SI); Acquired Capability for Suicide Scale-Fearlessness About Death (ACSS-FAD) measures this component which contributes to lethal self-harm. The objective was to evaluate the psychometric properties of INQ-15 and ACSS-FAD in a population of Italian university students. Since the Italian INQ-15 was already validated, we translated ACSS-FAD through a multistage procedure and administered both to 1,665 Italian university students. Factor analysis confirmed a two-factor-related model of INQ-15, one factor of ACSS-FAD, and good reliability for both. We proved the association between INQ-15 and current SI and between ACSS-FAD and lifetime suicidal planning and/or suicide attempt. The convergent and discriminant validities were in line with those of previous studies. Both tools are valid and reliable to assess the constructs associated with suicide outcomes according to IPTS.

The melatonin receptor 1A (MTNR1A) gene is associated with recurrent and idiopathic calcium nephrolithiasis.

BACKGROUND: Experimental evidence indicate that melatonin regulates some renal tubular functions via specific melatonin receptors (MTNRs) located in the kidney of several avian and mammalian species, including humans. We hypothesized that single nucleotide polymorphisms (SNPs) in the melatonin receptor 1A gene (MTNR1A) might influence the risk of calcium nephrolithiasis. METHODS: We performed a systematic analysis of the MTNR1A gene in 246 recurrent calcium stone formers (136 men, 110 women; mean age 40.2 ± 12.0 years; body mass index 25.8 ± 4.5 kg/m2) and 269 healthy controls comparable for age and gender without a history of nephrolithiasis. RESULTS: Two SNPs in Intron 1 of MTNR1A were significantly associated with calcium nephrolithiasis: rs13140012 (P = 0.0004) and rs6553010 (P = 0.009). The haplotypes resulting from the two SNPs were also differently distributed between stone formers and controls, the haplotype A-T being more represented among stone formers (P = 0.00001) and the haplotype T-C being more common in healthy controls (P = 0.00001). Preliminary functional studies showed that the SNP rs13140012 could modify the binding sites for transcription factors. CONCLUSION: The results of this case-control study indicate a strong association between allelic variants of MTNR1A and recurrent calcium nephrolithiasis.

The interpersonal-psychological theory of suicide and the role of psychological pain during the COVID-19 pandemic: A network analysis.

INTRODUCTION: Among the most investigated theories explaining suicidal behavior there are the interpersonal-psychological theory of suicide (IPTS) by Thomas E. Joiner and the one focused on the construct of psychological pain (or psychache, or mental pain). OBJECTIVE: Since it remains unclear whether these two different theories correlate with each other in the explanation of suicidal risk, we used a network analysis approach to investigate the complex interplay between both IPTS and psychological pain theories and history of suicidal planning and/or suicide attempt (SP/SA). METHODS: A sample of 1,586 university students from various Italian universities was recruited between April 24th, 2020 and February 23rd, 2021, hence during the COVID-19 pandemic. To be included subjects should have been university students and aged between 18 and 35 years old. RESULTS: Within a network that included the core factors from both models (IPTS and psychological pain), higher fearlessness about death (Acquired Capability for Suicide Scale-Fearlessness About Death, ACSS-FAD) and higher psychological pain (Psychache Scale) were the variables most strongly associated with history of SP/SA. CONCLUSIONS: Considering a large number of variables, history of SP/SA was explained in particular by fearlessness about death and psychological pain in university students. Hence these aspects should be targeted in the treatment for suicide prevention.

The role of the acceptance and commitment therapy in the treatment of social anxiety: An updated scoping review.

BACKGROUND: Social Anxiety Disorder (SAD) or Social Phobia is characterized by fear and anxiety of social circumstances that negatively impact an individual's occupational and relational life. There are several treatment options for this disorder ranging from pharmacological therapy to psychotherapies. In particular, the Acceptance and Commitment Therapy (ACT), a form of cognitive-behavioral therapy that practices acceptance and awareness strategies with behavior change strategies in order to increase an individual's mental flexibility, has been found to be effective. In this review, we aimed to provide an overview of recent studies that examined ACT's efficacy in SAD, also taking into consideration the comparison with traditional Cognitive-behavioral Therapy (CBT) interventions. METHODS: A bibliographic search on PubMed, EMBASE and Scopus was conducted from inception to the 3rd of February 2022 of all studies investigating the effect of ACT in SAD individuals without any comorbidity. Among the articles retrieved, 11 met the inclusion criteria. RESULTS: From the reviewed studies, ACT may be considered a promising treatment of social phobia by improving attentional bias, awareness, emotion regulation, and safety/avoidance behaviors; however, the results have not yet demonstrated a valid alternative to the CBT. LIMITATIONS: Only four studies considered a follow-up evaluation, which is paramount to exploring the effectiveness of ACT and several studies have a very small sample size. Concerning the review itself we only considered original English articles and we did not measure the risk of publication bias and the risk of bias between studies. CONCLUSIONS: The results of this study suggest that ACT can be a promising treatment for improving selective psychological problems often observed in SAD. However, larger longitudinal studies further exploring the effectiveness of the behavioral and cognitive "third-wave" psychotherapies, based mainly on acceptance of SAD, are necessary.

A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis.

BACKGROUND: A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function have renal phosphate leak. This disorder is characterized by idiopathic hypophosphatemia and reduced renal phosphate threshold normalized for the glomerular filtration rate (TmPi/GFR). The majority of these patients harbor high or inappropriately normal circulating levels of fibroblast growth factor 23 (FGF23), a hormone regulating phosphate homeostasis. AIM: The aim of this study was to define the role of FGF23 allelic variants in the pathogenesis of hypophosphatemic nephrolithiasis. SUBJECTS AND METHODS: We sequenced the regulative and coding regions of the FGF23 gene in 106 stone formers, 17 of which had renal phosphate leak, and in 87 healthy controls. We subsequently performed in vitro studies. RESULTS: A C716T nonsynonymous change (T239M, rs7955866) in the FGF23 gene was detected in seven of the 17 stone formers with renal phosphate leak. The prevalence of the T allele and of the CT genotype in stone formers with renal phosphate leak was significantly higher compared to that observed in stone formers without renal phosphate leak and in controls (P < 0.03 in all cases). In the whole study population, FGF23(716T) subjects showed levels of serum phosphate and TmPi/GFR significantly lower compared to FGF23(716C) subjects. In vitro studies showed that the T239M change increases FGF23 secretion and that the FGF23(239M) variant induces a higher activation of the FGF receptor/ERK pathway compared to FGF23(239T). CONCLUSION: Our results highlight a novel significant association between the C716T missense variation in the FGF23 gene and calcium nephrolithiasis with renal phosphate leak.

A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease.

Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for the T575C variant, yielding an odds ratio of 1.29 (p = 0.003), with the C allele as the risk allele. Moreover, an even more significant p-value (p = 0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly, patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively; p = 0.01), as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p = 0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, cotrasfection with mutated SQSTM1 and TNFRSF11A(A192) produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11A(V192), confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations.

piR_015520 belongs to Piwi-associated RNAs regulates expression of the human melatonin receptor 1A gene.

Piwi-associated RNAs (piRNAs) are a distinct class of 24- to 30-nucleotide-long RNAs produced by a Dicer-independent mechanism, and are associated with Piwi-class Argonaute proteins. In contrast to the several hundred species of microRNAs (miRNAs) identified thus far, piRNAs consist of more than 30,000 different species in humans. Studies in flies, fish and mice implicate these piRNAs in regulating germ line development, the silencing of selfish DNA elements, and maintaining germ line DNA integrity. Most piRNAs map to unique sites in the human genome, including intergenic, intronic, and exonic sequences. However, the role of piRNAs in humans remains to be elucidated. Here, we uncover an unexpected function of the piRNA pathway in humans. We show for the first time, that the piRNA_015520, located in intron 1 of the human Melatonin receptor 1A (MTNR1A) gene, is expressed in adult human tissues (testes and brain) and in the human cell line HEK 293. Although the role of piR_015520 expression in brain tissue remains unknown, the testes-specific expression is consistent with previous findings in several species. Surprisingly, in contrast to the mechanism known for miRNA-mediated modulation of gene expression, piRNA_015520 negatively regulates MTNR1A gene expression by binding to its genomic region. This finding suggests that changes in individual piRNA levels could influence both autoregulatory gene expression and the expression of the gene in which the piRNA is located. These findings offer a new perspective for piRNAs functioning as gene regulators in humans.