Two-day assertive-case-management educational program for medical personnel to prevent suicide attempts: A multicenter pre-post observational study.

AIM: Suicide attempters have a high risk of repeated suicide attempts and completed suicide. There is evidence that assertive case management can reduce the incidence of recurrent suicidal behavior among suicide attempters. This study evaluated the effect of an assertive-case-management training program. METHODS: This multicenter, before-and-after study was conducted at 10 centers in Japan. Participants were 274 medical personnel. We used Japanese versions of the Attitudes to Suicide Prevention Scale, the Gatekeeper Self-Efficacy Scale, the Suicide Intervention Response Inventory (SIRI), and the Attitudes Toward Suicide Questionnaire. We evaluated the effects with one-sample t-tests, and examined prognosis factors with multivariable analysis. RESULTS: There were significant improvements between pre-training and post-training in the Attitudes to Suicide Prevention Scale (mean: -3.07, 95% confidence interval [CI]: -3.57 to -2.57, P < 0.001), the Gatekeeper Self-Efficacy Scale (mean: 10.40, 95%CI: 9.48 to 11.32, P < 0.001), SIRI-1 (appropriate responses; mean: 1.15, 95%CI: 0.89 to 1.42, P < 0.001), and SIRI-2 (different to the expert responses; mean: -4.78, 95%CI: -6.18 to -3.38, P < 0.001). Significant improvements were found on all Attitudes Toward Suicide Questionnaire subscale scores, except Unjustified Behavior. The effect of training was influenced by experience of suicide-prevention training and experience of working with suicidal patients. CONCLUSION: The training program (which was developed to implement and disseminate evidence-based suicide-prevention measures) improved attitudes, self-efficacy, and skills for suicide prevention among medical personnel. Specialized suicide-prevention training and experience with suicidal patients are valuable for enhancing positive attitudes and self-efficacy; furthermore, age and clinical experience alone are insufficient for these purposes.

Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ.

Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1ß in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases.

A comparison of the characteristics of suicide attempters with and without psychiatric consultation before their suicidal behaviours: a cross-sectional study.

BACKGROUND: Because psychiatric disorders are risk factors for suicide, psychiatric consultation should be an essential element of suicide prevention among individuals with a high risk of suicide. The aim of the present study was to compare the characteristics of individuals who had or had not received psychiatric consultation before they attempted suicide in Japan. METHODS: Clinical records were used to identify 300 consecutive persons who were admitted to the hospital for attempting suicide between April 2006 and March 2013. We divided the patients into two groups. One group consisted of patients who consulted a psychiatrist before their suicidal behaviours (the consultation group), and the other group consisted of patients who had not consulted a psychiatrist before their suicidal behaviours (the non-consultation group). Group differences were analysed with respect to gender, age, method of suicide attempts, psychiatric diagnosis (ICD-10), and duration of hospitalisation in the emergency unit. RESULTS: Females tended to be over-represented in the consultation group (73.0%), and males tended to be over-represented in the non-consultation group (59.8%). Poisoning by prescription drugs was used more frequently as a method of suicide in the consultation group than in the non-consultation group. Neuroticism and related disorders were higher in the non-consultation group (33.7%) than in the consultation group (18.9%). Mood disorders (32.6%) were nearly as common as neuroticism in the non-consultation group, and together they accounted for almost two-thirds of all diagnoses. Mood disorders were comparable between the consultation group (30.9%) and the non-consultation group (32.6%). Adult personality disorders (13.3%) and schizophrenia and related disorders (26.0%) were higher in the consultation group than in the non-consultation group. CONCLUSIONS: Measures have to be taken to encourage people with these diverse characteristics to consult psychiatrists, and psychiatrists have to regularly evaluate patients for suicide risk. Furthermore, we need further research on the relationship between psychiatric consultation and poisoning by prescribed drugs.

One-year follow up after admission to an emergency department for drug overdose in Japan.

AIM: The aim of the study was to investigate the incidence of and risk factors for repetition of suicidal behavior within a year after admission for drug overdose in Japan. METHODS: Patients admitted to the emergency department of a general public hospital in Tokyo for drug overdose of prescribed medicine and/or over-the-counter drugs between March 2008 and February 2009 were followed up after 1 year. Demographic characteristics, previous suicide attempts, and mental health state were examined by self-report questionnaire and interview at recovery from the initial attempt. Information about suicidal behavior during the follow-up period was obtained from the outpatient psychiatrists by postal questionnaire 1 year after discharge. RESULTS: Of 190 patients admitted to the emergency department, 132 patients answered the questionnaire and had the interview. Information about thefollow-up period for 66 patients was obtained. Of the 66 patients, 28 patients attempted suicide again and two patients committed suicide during the 1-year follow-up period. Psychiatric diagnosis of personality disorder and denial of suicidal intent at the time of recovery were associated with increased risk for another suicide attempt. Lethality levels of suicidal behaviors before and after admission were associated with each other. CONCLUSION: The rate of fatal and non-fatal suicide attempt within a year after admission for self-poisoning was substantial. Psychiatric diagnosis of personality disorder was a risk factor for repetition of suicide attempt. Clinicians should pay attention to the means of previous suicide attempts even though the patient denies suicidal intent at recovery.

Survey of psychiatric symptoms among inpatients with COVID-19 using the Diagnosis Procedure Combination data and medical records in Japan.

Physical symptoms such as fatigue and muscle weakness, and psychiatric symptoms like depression and anxiety are considered as complications and sequelae of COVID-19. This epidemiological study investigated the actual status of psychiatric symptoms and disorders caused by COVID-19, from four major university hospitals and five general hospitals in Fukuoka Prefecture, Japan, having a population of 5 million. We conducted a survey of psychiatric disorders associated with COVID-19 using Diagnosis Procedure Combination (DPC) data and the psychiatric records of the hospitals. In the study period from January 2019 to September 2021, 2743 COVID-19 admissions were determined from DPC data across the nine sites. These subjects had significantly more anxiety, depression, and insomnia, and were receiving higher rates of various psychotropic medications than controls influenza and respiratory infections. A review of psychiatric records revealed that the frequency of organic mental illness with insomnia and confusion was proportional to the severity of COVID-19 infection and that anxiety symptoms appeared independent of infection severity. These results indicate that COVID-19 is more likely to produce psychiatric symptoms such as anxiety and insomnia than conventional infections.

Mitogen-activated protein 3 kinase 6 mediates angiogenic and tumorigenic effects via vascular endothelial growth factor expression.

Genome-wide screening using a small interfering RNA (siRNA) library has revealed novel molecules that are involved in a wide range of physiological responses. The expression of vascular endothelial growth factor (VEGF) is increased under hypoxic conditions, and plays a crucial role in tumor angiogenesis and tissue responses to ischemia. Here, we used a siRNA expression vector library to elucidate molecules that modify VEGF expression. Screening using an siRNA library revealed that MAPKKK6 (MEKK6/MAP3K6) regulates VEGF expression under both normoxic and hypoxic conditions in vitro, although the biological function of MAP3K6 remains unknown. Attenuation of VEGF expression by MAP3K6 inhibition was demonstrated by transient transfection of double-stranded RNA as well as by stable transfection of short hairpin RNA-expressing vectors against MAP3K6. Conditioned medium of MAP3K6-knocked down cells attenuated both endothelial proliferation and capillary network formation in a VEGF-dependent manner in vitro. In addition, tumor cells with down-regulation of MAP3K6 expression showed significant suppression of tumor growth in vivo, which was accompanied by significant repression of vessel formation and VEGF expression in these tumors. The results of this study suggest that MAP3K6 regulates VEGF expression in both normoxia and hypoxia, and that regulation of VEGF by MAP3K6 may play a crucial role in both angiogenesis and tumorigenesis.

Association of advanced glycation end products with A549 cells, a human pulmonary epithelial cell line, is mediated by a receptor distinct from the scavenger receptor family and RAGE.

Cellular interactions with advanced glycation end products (AGE)-modified proteins are known to induce several biological responses, not only endocytic uptake and degradation, but also the induction of cytokines and growth factors, combined responses that may be linked to the development of diabetic vascular complications. In this study we demonstrate that A549 cells, a human pulmonary epithelial cell line, possess a specific binding site for AGE-modified bovine serum albumin (AGE-BSA) (K(d) = 27.8 nM), and additionally for EN-RAGE (extracellular newly identified RAGE binding protein) (K(d) = 118 nM). Western blot and RT-PCR analysis showed that RAGE (receptor for AGE) is highly expressed on A549 cells, while the expression of other known AGE-receptors such as galectin-3 and SR-A (class A scavenger receptor), are below the level of detection. The binding of (125)I-AGE-BSA to these cells is inhibited by unlabeled AGE-BSA, but not by EN-RAGE. In contrast, the binding of (125)I-EN-RAGE is significantly inhibited by unlabeled EN-RAGE and soluble RAGE, but not by AGE-BSA. Our results indicate that A549 cells possess at least two binding sites, one specific for EN-RAGE and the other specific for AGE-BSA. The latter receptor on A549 cells is distinct from the scavenger receptor family and RAGE.

NaPi-mediated transcellular permeation is the dominant route in intestinal inorganic phosphate absorption in rats.

Inorganic phosphate in food is absorbed two ways, the transcellular route via the brush border membrane and the paracellular route via tight junctions. NaPi, a sodium-dependent inorganic phosphate transporter, is expressed in rat and human intestine. However, the relative contribution of NaPi to total carrier-mediated transport of physiological concentrations of inorganic phosphate in rat intestine is not clear. Here, we characterized inorganic phosphate transport across the rat small intestine using a voltage-clamp analysis which allowed the diffrentiation of inorganic phosphate permeation through these two (transcellular and paracellular) routes. Results showed that, under a physiologically normal transmucosal electrical potential difference (about 2 mV), permeation of inorganic phosphate by the transcellular route was greater than that by the paracellular route. Further, transport was significantly decreased by the addition to the incubation medium of phosphonoformic acid, a sodium-dependent phosphate transporter inhibitor, and severely inhibited under sodium-free conditions. Similar results were obtained without the voltage-clamp. Together, these results suggest that NaPi-mediated transcellular permeation is the dominant route in the absorption of inorganic phosphate across the small intestine.

Interventions to prevent repeat suicidal behavior in patients admitted to an emergency department for a suicide attempt: a meta-analysis.

BACKGROUND: A huge number of patients with self-harm and suicide attempt visit emergency departments (EDs). We systematically reviewed studies and examined the effect of interventions to prevent repeat suicidal behavior in patients admitted to EDs for a suicidal attempt. METHOD: We searched the databases of MEDLINE, PsychoINFO, CINAHL, and EMBASE through August 2013. Eligible studies were randomized controlled trials assessing the effects on repeat suicidal behavior of interventions initiated in suicidal patients admitted to EDs. Interventions in each trial were classified into groups by consensus. Meta-analyses were performed to determine pooled relative risks (RRs) and 95% confidence intervals (CIs) of repetition of suicide attempt for interventions in each group. RESULTS: Out of 5390 retrieved articles, 24 trials were included and classified into four groups (11 trials in the Active contact and follow-up, nine in the Psychotherapy, one in the Pharmacotherapy, and three in the Miscellaneous). Active contact and follow-up type interventions were effective in preventing a repeat suicide within 12 months (n=5319; pooled RR=0.83; 95% CI: 0.71 to 0.97). However, the effect at 24 months was not confirmed (n=925; pooled RR=0.98; 95% CI: 0.76-1.22). The effects of the other interventions on preventing a repetition of suicidal behavior remain unclear. LIMITATION: Caution is needed regarding the heterogeneity of the effects. CONCLUSION: Interventions of active contact and follow-up are recommended to reduce the risk of a repeat suicide attempt at 12 months in patients admitted to EDs with a suicide attempt. However, the long-term effect was not confirmed.

Assertive case management versus enhanced usual care for people with mental health problems who had attempted suicide and were admitted to hospital emergency departments in Japan (ACTION-J): a multicentre, randomised controlled trial.

BACKGROUND: Non-fatal suicide attempt is the most important risk factor for later suicide. Emergency department visits for attempted suicide are increasingly recognised as opportunities for intervention. However, no strong evidence exists that any intervention is effective at preventing repeated suicide attempts. We aimed to investigate whether assertive case management can reduce repetition of suicide attempts in people with mental health problems who had attempted suicide and were admitted to emergency departments. METHODS: In this multicentre, randomised controlled trial in 17 hospital emergency departments in Japan, we randomly assigned people aged 20 years and older with mental health problems who had attempted suicide to receive either assertive case management (based on psychiatric diagnoses, social risks, and needs of the patients) or enhanced usual care (control), using an internet-based randomisation system. Interventions were provided until the end of the follow-up period (ie, at least 18 months and up to 5 years). Outcome assessors were masked to group allocation, but patients and case managers who provided the interventions were not. The primary outcome was the incidence of first recurrent suicidal behaviour (attempted suicide or completed suicide); secondary outcomes included completed suicide and all-cause mortality. This study is registered at ClinicalTrials.gov (NCT00736918) and UMIN-CTR (C000000444). FINDINGS: Between July 1, 2006, and Dec 31, 2009, 914 eligible participants were randomly assigned, 460 to the assertive case management group and 456 to the enhanced usual care group. We noted no significant difference in incidence of first recurrent suicidal behaviour between the assertive case management group and the enhanced usual care group over the full study period (log-rank p=0·258). Because the proportional hazards assumption did not hold, we did ad-hoc analyses for cumulative incidence of the primary outcome at months 1, 3, 6, 12, and 18 after randomisation, adjusting for multiplicity with the Bonferroni method. Assertive case management significantly reduced the incidence of first recurrent suicidal behaviour up to the 6-month timepoint (6-month risk ratio 0·50, 95% CI 0·32-0·80; p=0·003), but not at the later timepoints. Prespecified subgroup analyses showed that the intervention had a greater effect in women (up to 18 months), and in participants younger than 40 years and those with a history of previous suicide attempts (up to 6 months). We did not identify any differences between the intervention and control groups for completed suicide (27 [6%] of 460 vs 30 [7%] of 454, log-rank p=0·660) or all-cause mortality (46 [10%] of 460 vs 42 [9%] of 454, log-rank p=0·698). INTERPRETATION: Our results suggest that assertive case management is feasible in real-world clinical settings. Although it was not effective at reducing the incidence of repetition of suicide attempts in the long term, the results of our ad-hoc analyses suggested that it was effective for up to 6 months. This finding should be investigated in future research. FUNDING: The Ministry of Health, Labour, and Welfare of Japan.

Erythropoietin induces heme oxygenase-1 expression and attenuates oxidative stress.

Recent studies have established that erythropoietin (EPO) is a pleiotropic cytokine. In this study we investigated whether pleiotropic effects of EPO may involve regulation of heme oxygenase (HO)-1, an anti-oxidative stress protein. A stimulatory effect of EPO on HO-1 expression was demonstrated in cultured renal endothelial cells, in which EPO decreased intracellular oxidative stress and provided cytoprotection against H(2)O(2). These beneficial effects were partially reversed by a HO-1 inhibitor. We then evaluated whether EPO induces HO-1 and ameliorates renal injury in vivo. Administration of EPO to Dahl salt-sensitive (DS) rats with low salt diet, a model of chronic tubulointerstitial injury, reduced proteinuria, and renal injury including peritubular capillaries rarefaction as compared to vehicle-treated DS rats. This renoprotection was associated with up-regulation of HO-1 in the kidney. In conclusion, EPO-induced HO-1 expression is likely to provide cytoprotection against oxidative stress.

Nicotinamide prevents the development of hyperphosphataemia by suppressing intestinal sodium-dependent phosphate transporter in rats with adenine-induced renal failure.

BACKGROUND: Nicotinamide has been shown to inhibit intestinal sodium-dependent phosphate transport activity in normal rats. It was reported recently that type IIb sodium-dependent phosphate co-transporter (NaPi-2b) is a carrier of intestinal phosphate absorption, and that its expression level is regulated by serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and Pi levels in normal rats. However, in chronic renal failure (CRF), serum 1,25(OH)(2)D and Pi levels are often abnormal. In a rat model of CRF, we investigated whether short-term nicotinamide administration was effective in reducing intestinal phosphate absorption and, if so, whether the effect was mediated by intestinal NaPi-2b. METHODS: Adenine-induced CRF rats were given a single daily intrapenitoneal administration of nicotinamide or vehicle solution for 6 days, and time course changes in serum Pi, Ca, blood urea nitrogen (BUN) and creatinine levels were monitored. Intestinal phosphate absorption was examined by oral administration of radiolabelled phosphate on the final day. In addition, NaPi-2b protein content in jejunum brush border membranes was determined. RESULTS: Nicotinamide prevented the progressive increase in serum Pi associated with renal failure and significantly inhibited intestinal Pi absorption as assessed by the influx of orally administered radiolabelled phosphate into the circulation. This effect was accompanied by a decrease in NaPi-2b expression in jejunum brush border membranes. In addition, nicotinamide treatment was also associated with less marked elevations in BUN and serum creatinine and a higher creatinine clearance. CONCLUSIONS: Nicotinamide inhibited intestinal Pi absorption in a rat model of CRF, at least in part by inhibiting the expression of NaPi-2b, and appeared to protect against the deterioration of renal function.

Protection of endothelial cells by dextran sulfate in rats with thrombotic microangiopathy.

The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury in association with loss of heparan sulfate proteoglycans on the cell surface and thrombus formation, followed by subsequent ischemic tubulointerstitial damage. It therefore was hypothesized that dextran sulfate (DXS) may protect the kidney against endothelial damage in a model of TMA. TMA was induced in rats by renal artery perfusion of an antiglomerular endothelial antibody, followed by the administration of DXS or vehicle. Renal damage was assessed by histologic analysis and measurements of blood urea nitrogen and creatinine. Whereas control rats developed severe renal failure with extensive glomerular and tubular injury, administration of DXS significantly protected renal function and preserved the glomerular endothelium and peritubular capillaries. The beneficial effect of DXS could be attributed to the ability of DXS to protect endothelial cells from coagulation and complement activation, as demonstrated by the histologic analysis. In addition, binding of the administered DXS to the surface of the glomerular endothelium was confirmed in TMA rats, suggesting that DXS acts as a "repair coat" of injured glomerular endothelium. In conclusion, DXS protects the kidney from experimental TMA. This protection may be mediated by DXS's binding directly to the surface of glomerular endothelium and amelioration of coagulation, complement activation, and cellular matrix loss.

Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney.

Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, K(m) = 7.8 microM and ouabain, K(m) = 0.38 microM), thyroid hormone (triiodothyronine, K(m) = 5.9 microM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin (K(m) = 8.0 microM) and triiodothyronine (K(m) = 1.9 microM). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP4C1/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.