Study protocol for the implementation and evaluation of the Self-harm Assessment and Management for General Hospitals programme in Ireland (SAMAGH).

BACKGROUND: Previous self-harm is one of the strongest predictors of future self-harm and suicide. Increased risk of repeated self-harm and suicide exists amongst patients presenting to hospital with high-risk self-harm and major self-harm repeaters. However, so far evidence-based training in the management of self-harm for mental health professionals is limited. Within this context, we aim to develop, implement and evaluate a training programme, SAMAGH, Self-harm Assessment and Management Programme for General Hospitals in Ireland. SAMAGH aims to (a) reduce hospital-based self-harm repetition rates and (b) increase rates of mental health assessments being conducted with self-harm patients. We also aim to evaluate the training on self-harm knowledge, attitudes, and skills related outcomes of healthcare professionals involved in the training. METHODS/DESIGN: The study will be conducted in three phases. First, the SAMAGH Training Programme has been developed, which comprises two parts: 1) E-learning Programme and 2) Simulation Training. Second, SAMAGH will be delivered to healthcare professionals from general hospitals in Ireland. Third, an outcome and process evaluation will be conducted using a pre-post design. The outcome evaluation will be conducted using aggregated data from the National Self-Harm Registry Ireland (NSHRI) on self-harm repetition rates from all 27 public hospitals in Ireland. Aggregated data based on the 3-year average (2016, 2017, 2018) self-harm repetition rates prior to the implementation of the SAMAGH will be used as baseline data, and NSHRI data from 6 and 12 months after the implementation of SAMAGH will be used as follow-up. For the process evaluation, questionnaires and focus groups will be administered and conducted with healthcare professionals who completed the training. DISCUSSION: This study will contribute to the evidence base regarding the effectiveness of an evidence informed training programme that aims to reduce repeated hospital self-harm presentations and to improve compliance with self-harm assessment and management. This study is also expected to contribute to self-harm and suicide training with the possibility of being translated to other settings. Its feasibility will be evaluated through a process evaluation.

Increased constrictor tone induced by ouabain treatment in rats.

Ouabain (Oua)-induced hypertension in rodents provides a model to study cardiovascular changes associated with human hypertension. We examined vascular function in rats after a long-term treatment with Oua. Systolic blood pressure was measured by tail-cuff plethysmography in male Sprague-Dawley rats treated with Oua (≈ 25 µg/d) or placebo for 8 weeks. Blood pressure increased in Oua-treated animals, reaching 30% above baseline systolic blood pressure after 7 weeks. At the end of treatment, vascular responses were studied in mesenteric resistance arteries (MRAs) by wire myography. Contraction to potassium chloride in intact and denuded arteries showed greater sensitivity in Oua-treated animals. Contraction to phenylephrine and relaxation to acetylcholine were similar between groups with a lower response to sodium nitroprusside in Oua-treated arteries. Sensitivity to endothelin-1 was higher in Oua-treated arteries. Na⁺-K⁺ ATPase activity was decreased in MRAs from Oua-treated animals, whereas protein expression of the Na⁺-K⁺ ATPase α2 isoform was increased in heart and unchanged in mesenteric artery. Preincubation with indomethacin (10⁻5 M) or Nω-nitro-L-arginine methyl ester (10⁻4 M) abolished the differences in potassium chloride response and Na⁺-K⁺ ATPase activity. Changes in MRAs are consistent with enhanced vascular smooth muscle cell reactivity, a contributor to the increased vascular tone observed in this model of hypertension.

Physical and mental illness comorbidity among individuals with frequent self-harm episodes: A mixed-methods study.

Background: Research has indicated an increased risk of self-harm repetition and suicide among individuals with frequent self-harm episodes. Co-occurring physical and mental illness further increases the risk of self-harm and suicide. However, the association between this co-occurrence and frequent self-harm episodes is not well understood. The objectives of the study were (a) to examine the sociodemographic and clinical profile of individuals with frequent self-harm (regardless of suicidal intent) episodes and, (b) the association between physical and mental illness comorbidity, self-harm repetition, highly lethal self-harm methods, and suicide intent. Methods: The study included consecutive patients with five or more self-harm presentations to Emergency Departments across three general hospitals in the Republic of Ireland. The study included file reviews (n = 183) and semi-structured interviews (n = 36). Multivariate logistic regression models and independent samples t-tests were used to test the association between the sociodemographic and physical and mental disorders comorbidity on highly lethal self-harm methods and suicidal intent, respectively. Thematic analysis was applied to identify themes related to physical and mental illness comorbidity and frequent self-harm repetition. Findings: The majority of individuals with frequent self-harm episodes were female (59.6%), single (56.1%), and unemployed (57.4%). The predominant current self-harm method was drug overdose (60%). Almost 90% of the participants had history of a mental or behavioral disorder, and 56.8% had recent physical illness. The most common psychiatric diagnoses were alcohol use disorders (51.1%), borderline personality disorder (44.0%), and major depressive disorder (37.8%). Male gender (OR = 2.89) and alcohol abuse (OR = 2.64) predicted the risk of a highly lethal self-harm method. Suicide intent was significantly higher among those with a diagnosis of major depressive disorder (t = 2.43; p = 0.020). Major qualitative themes were (a) the functional meaning of self-harm (b) self-harm comorbidity (c) family psychiatric history and (d) contacts with mental health services. Participants described experiencing an uncontrollable self-harm urge, and self-harm was referred to as a way to get relief from emotional pain or self-punishment to cope with anger and stressors. Conclusion: Physical and mental illness comorbidity was high among individuals with frequent self-harm episodes. Male gender and alcohol abuse were associated with highly lethal self-harm methods. The mental and physical illness comorbidity of individuals with frequent self-harm episodes should be addressed via a biopsychosocial assessment and subsequent indicated treatment interventions.

Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms.

BACKGROUND: Suicidal behaviour is known to aggregate in families. Patients with psychiatric disorders are at higher risk for suicide attempts (SA), however protective and risk genetic variants for suicide appear to be independent of underlying psychiatric disorders. Here we investigate genetic variants in genes important for neurobiological pathways linked to suicidal behaviour and/or associated endophenotypes, for association with SA among patients with co-existing psychiatric illness. Selected gene-gene and gene-environment interactions were also tested. METHODS: DNA was obtained from bloods of 159 patients (76 suicide attempters and 83 non-attempters), who were profiled for DSM-IV Axis I psychiatric diagnosis. Twenty-eight single nucleotide polymorphisms (SNPs) from 18 candidate genes (COMT, 5-HT2A, 5-HT1A, 5-HTR1B, TPH1, MAO-A, TPH2, DBH, CNR1, BDNF, ABCG1, GABRA5, GABRG2, GABRB2, SLC1A2, SLC1A3, NTRK2, CRHR1) were genotyped. Genotyping was performed by KBioscience. Tests of association between genetic variants and SA were conducted using Chi squared and Armitage Trend tests. Binary logistical regression analyses were performed to evaluate the contribution of individual genetic variants to the prediction of SA, and to examine SNPs for potential gene-gene and gene-environment interactions. RESULTS: Our analysis identified 4 SNPs (rs4755404, rs2269272, rs6296 and rs1659400), which showed evidence of association with SA compared to a non-attempter control group. We provide evidence of a 3-locus gene-gene interaction, and a putative gene-environment interaction, whereby genetic variation at the NTRK2 locus may moderate the risk associated with history of childhood abuse. CONCLUSION: Preliminary findings suggest that allelic variability in SLC1A2/3, 5-HTR1B and NTRK2 may be relevant to the underlying diathesis for suicidal acts.

Investigating the relationship between childhood sexual abuse, self-harm repetition and suicidal intent: mixed-methods study.

BACKGROUND: Research into the association between childhood sexual abuse (CSA) and self-harm repetition is limited. AIMS: We aimed to examine the association between self-harm repetition, mental health conditions, suicidal intent and CSA experiences among people who frequently self-harm. METHOD: A mixed-methods study was conducted including consecutive patients aged ≥18 years, with five or more self-harm presentations, in three Irish hospitals. Information was extracted from psychiatric records and patients were invited to participate in a semi-structured interview. Data was collected and analysed with a mixed-methods, convergent parallel design. In tandem, the association between CSA and self-harm repetition, suicidal intent and mental health conditions was examined with logistic regression models and independent sample t-test, with psychiatric records data. Thematic analysis was conducted with interview data, to explore CSA experiences and self-harm repetition. RESULTS: Between March 2016 and July 2019, information was obtained on 188 consecutive participants, with 36 participants completing an interview. CSA was recorded in 42% of the total sample and 72.2% of those interviewed. CSA was positively associated with self-harm repetition (odds ratio 6.26, 95% CI 3.94-9.94, P = 0.00). Three themes emerged when exploring participants' CSA experiences: CSA as a precipitating factor for self-harm, secrecy of CSA accentuating shame, and loss experiences linked to CSA and self-harm. CONCLUSIONS: CSA was frequently reported among people who frequently self-harm, and associated with self-harm repetition. Identification of patients at risk of repetition is key for suicide prevention. This is an at-risk group with particular characteristics that must be considered; comprehensive patient histories can help inform and tailor treatment pathways.

Evaluation of the impact and implementation of a national clinical programme for the management of self-harm in hospital emergency departments: study protocol for a natural experiment.

BACKGROUND: A National Clinical Programme for the Management of Hospital-Presenting Self-Harm (NCP-SH) was introduced in Ireland in 2014. This involved the development of a model of care to standardise the management of self-harm in emergency departments, to be delivered by dedicated clinical nurse specialists. The core components of the programme were to: ensure an empathic and timely response, conduct a biopsychosocial assessment, involve family members in assessment and discharge planning, and provide a bridge to next care. The overall aim of the programme was to reduce the rate of repeat self-harm. This multistage study will evaluate the impact of the NCP-SH on hospital-presenting self-harm and to identify determinants influencing its implementation. METHODS: Employing a sequential mixed methods design, the first stage will use data from the National Self-Harm Registry Ireland to examine the impact of the NCP-SH on self-harm repetition, along with other aspects of care, including provision of psychosocial assessments and changes in admissions and postdischarge referrals. A cost-effectiveness analysis will assess the cost per repeat self-harm attendance avoided as a result of the NCP-SH. The second stage will identify the influences of implementation fidelity-adherence to the programme's core components-using a combination of document analysis and semistructured interviews with staff of the programme, guided by the Consolidated Framework for Implementation Research. ETHICS AND DISSEMINATION: This study has received full ethical approval and will run until August 2023. This study is novel in that it will identify important factors influencing successful implementation of complex programmes. It is expected that the findings will provide important learnings for the integration of mental health services in general hospital settings and will be disseminated via peer-review publications along with reports for clinicians and policy-makers.

Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin.

Nitrite reacts with deoxyhemoglobin to form nitric oxide (NO) and methemoglobin. Though this reaction is experimentally associated with NO generation and vasodilation, kinetic analysis suggests that NO should not be able to escape inactivation in the erythrocyte. We have discovered that products of the nitrite-hemoglobin reaction generate dinitrogen trioxide (N2O3) via a novel reaction of NO and nitrite-bound methemoglobin. The oxygen-bound form of nitrite-methemoglobin shows a degree of ferrous nitrogen dioxide (Fe(II)-NO2*) character, so it may rapidly react with NO to form N2O3. N2O3 partitions in lipid, homolyzes to NO and readily nitrosates thiols, all of which are common pathways for NO escape from the erythrocyte. These results reveal a fundamental heme globin- and nitrite-catalyzed chemical reaction pathway to N2O3, NO and S-nitrosothiol that could form the basis of in vivo nitrite-dependent signaling. Because the reaction redox-cycles (that is, regenerates ferrous heme) and the nitrite-methemoglobin intermediate is not observable by electron paramagnetic resonance spectroscopy, this reaction has been 'invisible' to experimentalists over the last 100 years.

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin.

Release of hemoglobin from the erythrocyte during intravascular hemolysis contributes to the pathology of a variety of diseased states. This effect is partially due to the enhanced ability of cell-free plasma hemoglobin, which is primarily found in the ferrous, oxygenated state, to scavenge nitric oxide. Oxidation of the cell-free hemoglobin to methemoglobin, which does not effectively scavenge nitric oxide, using inhaled nitric oxide has been shown to be effective in limiting pulmonary and systemic vasoconstriction. However, the ferric heme species may be reduced back to ferrous hemoglobin in plasma and has the potential to drive injurious redox chemistry. We propose that compounds that selectively convert cell-free hemoglobin to ferric, and ideally iron-nitrosylated heme species that do not actively scavenge nitric oxide, would effectively treat intravascular hemolysis. We show here that nitroxyl generated by Angeli's salt (sodium alpha-oxyhyponitrite, Na2N2O3) preferentially reacts with cell-free hemoglobin compared to that encapsulated in the red blood cell under physiologically relevant conditions. Nitroxyl oxidizes oxygenated ferrous hemoglobin to methemoglobin and can convert the methemoglobin to a more stable, less toxic species, iron-nitrosyl hemoglobin. These results support the notion that Angeli's salt or a similar compound could be used to effectively treat conditions associated with intravascular hemolysis.

Rate of nitric oxide scavenging by hemoglobin bound to haptoglobin.

Cell-free hemoglobin, released from the red cell, may play a major role in regulating the bioavailability of nitric oxide. The abundant serum protein haptoglobin, rapidly binds to free hemoglobin forming a stable complex accelerating its clearance. The haptoglobin gene is polymorphic with two classes of alleles denoted 1 and 2. We have previously demonstrated that the haptoglobin 1 protein-hemoglobin complex is cleared twice as fast as the haptoglobin 2 protein-hemoglobin complex. In this report, we explored whether haptoglobin binding to hemoglobin reduces the rate of nitric oxide scavenging using time-resolved absorption spectroscopy. We found that both the haptoglobin 1 and haptoglobin 2 protein complexes react with nitric oxide at the same rate as unbound cell-free hemoglobin. To confirm these results we developed a novel assay where free hemoglobin and hemoglobin bound to haptoglobin competed in the reaction with NO. The relative rate of the NO reaction was then determined by examining the amount of reacted species using analytical ultracentrifugation. Since complexation of hemoglobin with haptoglobin does not reduce NO scavenging, we propose that the haptoglobin genotype may influence nitric oxide bioavailability by determining the clearance rate of the haptoglobin-hemoglobin complex. We provide computer simulations showing that a twofold difference in the rate of uptake of the haptoglobin-hemoglobin complex by macrophages significantly affects nitric oxide bioavailability thereby providing a plausible explanation for why there is more vasospasm after subarachnoid hemorrhage in individuals and transgenic mice homozygous for the Hp 2 allele.

The variation of macro- and micro-minerals of tissues in diabetic and non-diabetic rats.

This study determined the levels of Ca, Mg, Fe, Zn, Cu, and Na in various tissues samples (liver, brain, kidney, intestines, muscle and hair) of diabetic and non-diabetic rats by flame atomic absorption spectroscopy, in order to assess the role of element levels during T2DM. The ratios of Ca/Mg, Zn/Cu, Ca/Zn, and Mg/Zn in diabetic and non-diabetic rat tissues were also calculated. The determined element levels were further subjected to a student-t test statistical analysis and multiple-linear-regression in order to evaluate similarities, differences, and an inter-element association in tissues of diabetic and non-diabetic rats. The results of the study showed high variability in element levels and Ca/Mg Zn/Cu Mg/Zn Ca/Zn ratios in the tissues of diabetic and non-diabetic rats, but are tissue- and element-dependent, suggesting differences in the accumulation of the elements in tissues of diabetics and non-diabetics. The obtained significant differences in the levels of elements and Ca/Mg Zn/Cu Mg/Zn Ca/Zn ratios in several tissues of diabetic and non-diabetic rats in this study suggest that the investigated elements play considerable roles in the T2DM disease process. Strong inter-element associations (R2≥0.9) were observed for some elements in tissues of diabetic and non-diabetics rats. However, poor inter-elemental associations were obtained for some elements in the tissues of diabetic and non-diabetic rats.

Computation of plasma hemoglobin nitric oxide scavenging in hemolytic anemias.

Intravascular hemoglobin limits the amount of endothelial-derived nitric oxide (NO) available for vasodilation. Cell-free hemoglobin scavenges NO more efficiently than red blood cell-encapsulated hemoglobin. Hemolysis has recently been suggested to contribute to endothelial dysfunction based on a mechanism of NO scavenging by cell-free hemoglobin. Although experimental evidence for this phenomenon has been presented, support from a theoretical approach has, until now, been missing. Indeed, due to the low amounts of cell-free hemoglobin present in these pathological conditions, the role of cell-free hemoglobin scavenging of NO in disease has been questioned. In this study, we model the effects of cell-free hemoglobin on NO bioavailability, focusing on conditions that closely mimic those under known pathological conditions. We find that as little as 1 microM cell-free intraluminal hemoglobin (heme concentration) can significantly reduce NO bioavailability. In addition, extravasation of hemoglobin out of the lumen has an even greater effect. We also find that low hematocrit associated with anemia increases NO bioavailability but also leads to increased susceptibility to NO scavenging by cell-free hemoglobin. These results support the paradigm that cell-free hemoglobin released into plasma during intravascular hemolysis in human disease contributes to the experimentally observed reduction in NO bioavailability and endothelial dysfunction.

The borderlines of bipolar affective disorder.

This paper provides an overview of the major studies of bipolar affective disorder (BAD) and borderline personality disorder (BPD), and assesses whether the disorders might be better understood as variants of the same basic disorder. There is a shortage of research that delineates the features of both disorders within their representative samples. As a consequence the symptomatic overlap of the disorders, detected by categorical assessment instruments, is often misconstrued as an indication of the disorders' high rates of comorbidity (up to 81%). In paying particular attention to features of both disorders, eg. affective instability and impulsivity, the paper provides evidence that BPD attenuates bipolar disorder along the spectrum of affective disorders, from non-classical bipolar presentation through to severe BAD with borderline features. The paper cites clinical, research and pharmacologic support of the contention that BPD, rather than representing a distinct disorder, is merely an attenuation of Axis I disorders, most especially bipolar affective disorder. Borderline personality is evident across the bipolar spectrum and exacerbates symptomatology and leads to poorer recovery prognosis.

'Recovery' - towards integration into an Irish community mental health team.

OBJECTIVES: We aimed to further our understanding of the concept of recovery by analysing comments made in small group discussions that occurred on a planning Away Day held by a community mental health team along-side service users and carers, which had recovery as its theme. The purpose of this was to reshape the structure and workings of the team. METHOD: Five small groups, of approximately 10 individuals each, comprised of service-users, carers, representatives from voluntary organisations and mental health professionals were asked to discuss three questions related to Recovery. RESULTS: The commentary reflected previous qualitative research on the philosophy of recovery. Issues that were raised included defining wellness as independent to illness, constructive risk taking, the importance of social factors, medication issues and the importance of self-management and optimism. The comments subsequently went on to shape community mental health team service delivery. CONCLUSION: Discussion and reflection between mental health professionals, service users and carers can lead to a change in attitude and practice in a well-resourced, fully multi-disciplinary community mental health team, within which both the biological and non-biological aspects of mental illness are accepted. The result has been an introduction of service changes which have helped develop a team that is more accessible and increasingly collaborative.

Hemoglobin mediated nitrite activation of soluble guanylyl cyclase.

Nitrite has long been known to be vasoactive when present at large concentrations but it was thought to be inactive under physiological conditions. Surprisingly, we have recently shown that supraphysiological and near physiological concentrations of nitrite cause vasodilation in the human circulation. These effects appeared to result from reduction of nitrite by deoxygenated hemoglobin. Thus, nitrite was proposed to play a role in hypoxic vasodilation. We now discuss these results in the context of nitrite reacting with hemoglobin and effecting vasodilation and present new data modeling the nitric oxide (NO) export from the red blood cell and measurements of soluble guanylate cyclase (sGC) activation. We conclude that NO generated within the interior of the red blood cell is not likely to be effectively exported directly as nitric oxide. Thus, an intermediate species must be formed by the nitrite/deoxyhemoglobin reaction that escapes the red cell and effects vasodilation.