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Background: Low-intensity repetitive transcranial magnetic stimulation (rTMS), delivered as a daily intermittent theta burst stimulation (iTBS) for four consecutive weeks, increased the number of new oligodendrocytes in the adult mouse brain. Therefore, rTMS holds potential as a remyelinating intervention for people with multiple sclerosis (MS). Objective: Primarily to determine the safety and tolerability of our rTMS protocol in people with MS. Secondary objectives include feasibility, blinding and an exploration of changes in magnetic resonance imaging (MRI) metrics, patient-reported outcome measures (PROMs) and cognitive or motor performance. Methods: A randomised (2:1), placebo controlled, single blind, parallel group, phase 1 trial of 20 rTMS sessions (600 iTBS pulses per hemisphere; 25% maximum stimulator output), delivered over 4-5 weeks. Twenty participants were randomly assigned to 'sham' (n = 7) or active rTMS (n = 13), with the coil positioned at 90° or 0°, respectively. Results: Five adverse events (AEs) including one serious AE reported. None were related to treatment. Protocol compliance was high (85%) and blinding successful. Within participant MRI metrics, PROMs and cognitive or motor performance were unchanged over time. Conclusion: Twenty sessions of rTMS is safe and well tolerated in a small group of people with MS. The study protocol and procedures are feasible. Improvement of sham is warranted before further investigating safety and efficacy.
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Receptor tyrosine kinase inhibitors (RTKIs) suppress tumour growth by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) which is an important mediator of angiogenesis. Here, we demonstrate that two potent RTKIs, axitinib and lenvatinib, are associated with hypertensive side effects. Doppler flowmetry was used to evaluate regional haemodynamic profiles of axitinib and lenvatinib. Male Sprague Dawley rats (350-500 g) were instrumented with Doppler flow probes (renal and mesenteric arteries and descending abdominal aorta) and catheters (jugular vein and distal abdominal aorta, via the caudal artery). Rats were dosed daily with axitinib (3 or 6 mg.kg-1) or lenvatinib (1 or 3 mg.kg-1) and regional haemodynamics were recorded over a maximum of 4 days. Both RTKIs caused significant (p < 0.05) increases in mean arterial pressure (MAP), which was accompanied by significant (p < 0.05) vasoconstriction in both the mesenteric and hindquarters vascular beds. To gain insight into the involvement of endothelin-1 (ET-1) in RTKI-mediated hypertension, we also monitored heart rate (HR) and MAP in response to axitinib or lenvatinib in animals treated with the ETA receptor selective antagonist sitaxentan (5 mg.kg-1) or the mixed ETA/ETB receptor antagonist bosentan (15 mg.kg-1) over two days. Co-treatment with bosentan or sitaxentan markedly reduced the MAP effects mediated by both RTKIs (p < 0.05). Bosentan, but not sitaxentan, also attenuated ET-1 mediated increases in HR. These data suggest that selective antagonists of ETA receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib.
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INTRODUCTION: Telepractice has the potential to align with the directive to reduce inequalities by United Nations Sustainable Development Goal 10. Telepractice additionally addresses a national digital health strategic plan for accessible digitally enabled models of care. To plan improvements, it is essential to understand the experience of telepractice for people with disability, which may be achieved through an approach such as journey mapping. The current article provides both a disability-specific case study and a methodological guide for the inclusion of customers and clinicians in the meaningful redevelopment of services. The Perth, Australia-based case study aimed to gain insights into the experience of telepractice for people with disability. The methodological aim describes using co-design to produce a journey map in collaboration with customers and clinicians, for potential replication in a wide range of health and social care contexts. METHOD: Interview transcripts gathered from a cohort of customer participants (n = 17) were used to inform the journey map. A group of customers (n = 5) and clinicians plus one manager (n = 5) distributed the findings onto a customer experience journey map during a co-design workshop. The journey map describes the emotional experience and actions taken, along five phases of a timeline through telepractice service interactions: (1) before, (2) selecting telepractice, (3) telepractice preparation, (4) during telepractice sessions and (5) after. RESULTS: A journey map visualisation of customer experiences was produced that identified strengths of telepractice service delivery (flexibility) while noting challenges (with technology) as opportunities for improvement. The consensus of participants was the desire to have access to telepractice currently and in the future, in addition to in-person delivery. CONCLUSION: These findings are valuable in the context of advocating for the incorporation of customers and clinicians through co-design workshops in the content analysis and creation of a journey map that is representative of the lived experience of accessing telepractice services. PATIENT OR PUBLIC CONTRIBUTION: The paper forms part of a larger co-design process that included customer participants throughout the design and planning of the project, inclusion of a peer researcher and the co-designers in the workshops, journey map and this article production.
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The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs).
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COVID-19 , Miocardite , Humanos , COVID-19/complicações , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2 , Miocardite/etiologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Receptores Toll-LikeRESUMO
Animal models are essential for assessing cardiovascular responses to novel therapeutics. Cardiovascular safety liabilities represent a leading cause of drug attrition and better preclinical measurements are essential to predict drug-related toxicities. Presently, radiotelemetric approaches recording blood pressure are routinely used in preclinical in vivo haemodynamic assessments, providing valuable information on therapy-associated cardiovascular effects. Nonetheless, this technique is chiefly limited to the monitoring of blood pressure and heart rate alone. Alongside these measurements, Doppler flowmetry can provide additional information on the vasculature by simultaneously measuring changes in blood flow in multiple different regional vascular beds. However, due to the time-consuming and expensive nature of this approach, it is not widely used in the industry. Currently, analysis of waveform data obtained from telemetry and Doppler flowmetry typically examines averages or peak values of waveforms. Subtle changes in the morphology and variability of physiological waveforms have previously been shown to be early markers of toxicity and pathology. Therefore, a detailed analysis of pressure and flowmetry waveforms could enhance the understanding of toxicological mechanisms and the ability to translate these preclinical observations to clinical outcomes. In this review, we give an overview of the different approaches to monitor the effects of drugs on cardiovascular parameters (particularly regional blood flow, heart rate and blood pressure) and suggest that further development of waveform analysis could enhance our understanding of safety pharmacology, providing valuable information without increasing the number of in vivo studies needed.
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A2A and A2B adenosine receptors produce regionally selective regulation of vascular tone and elicit differing effects on mean arterial pressure (MAP), whilst inducing tachycardia. The tachycardia induced by the stimulation of A2A or A2B receptors has been suggested to be mediated by a reflex increase in sympathetic activity. Here, we have investigated the role of ß1 - and ß2 -adrenoceptors in mediating the different cardiovascular responses to selective A2A and A2B receptor stimulation. Hemodynamic variables were measured in conscious male Sprague-Dawley rats (350-450 g) via pulsed Doppler flowmetry. The effect of intravenous infusion (3 min per dose) of the A2A -selective agonist CGS 21680 (0.1, 0.3, 1.0 µg.kg-1 .min-1 ) or the A2B -selective agonist BAY 60-6583 (4.0, 13.3, 40.0 µg.kg-1 .min-1 ) in the absence or following pre-treatment with the non-selective ß-antagonist propranolol (1.0 mg.kg-1 ), the selective ß1 -antagonist CGP 20712A (200 µg.kg-1 ), or the selective ß2 -antagonist ICI 118,551 (2.0 mg.kg-1 ) was investigated (maintenance doses also administered). CGP 20712A and propranolol significantly reduced the tachycardic response to CGS 21680, with no change in the effect on MAP. ICI 118,551 increased BAY 60-6583-mediated renal and mesenteric flows, but did not affect the heart rate response. CGP 20712A attenuated the BAY 60-6583-induced tachycardia. These data imply a direct stimulation of the sympathetic activity via cardiac ß1 -adrenoceptors as a mechanism for the A2A - and A2B -induced tachycardia. However, the regionally selective effects of A2B agonists on vascular conductance were independent of sympathetic activity and may be exploitable for the treatment of acute kidney injury and mesenteric ischemia.
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Antagonistas Adrenérgicos beta , Propranolol , Adenosina/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Pressão Sanguínea , Masculino , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/fisiologia , Taquicardia/induzido quimicamenteRESUMO
Adenosine is a local mediator that regulates changes in the cardiovascular system via activation of four G protein-coupled receptors (A1 , A2A , A2B , A3 ). Here, we have investigated the effect of A2A and A2B -selective agonists on vasodilatation in three distinct vascular beds of the rat cardiovascular system. NanoBRET ligand binding studies were used to confirm receptor selectivity. The regional hemodynamic effects of adenosine A2A and A2B selective agonists were investigated in conscious rats. Male Sprague-Dawley rats (350-450 g) were chronically implanted with pulsed Doppler flow probes on the renal artery, mesenteric artery, and the descending abdominal aorta. Cardiovascular responses were measured following intravenous infusion (3 min for each dose) of the A2A -selective agonist CGS 21680 (0.1, 0.3, 1 µg kg-1 min-1 ) or the A2B -selective agonist BAY 60-6583 (4,13.3, 40 µg kg-1 min-1 ) following predosing with the A2A -selective antagonist SCH 58261 (0.1 or 1 mg kg-1 min-1 ), the A2B /A2A antagonist PSB 1115 (10 mg kg-1 min-1 ) or vehicle. The A2A -selective agonist CGS 21680 produced a striking increase in heart rate (HR) and hindquarters vascular conductance (VC) that was accompanied by a significant decrease in mean arterial pressure (MAP) in conscious rats. In marked contrast, the A2B -selective agonist BAY 60-6583 significantly increased HR and VC in the renal and mesenteric vascular beds, but not in the hindquarters. Taken together, these data indicate that A2A and A2B receptors are regionally selective in their regulation of vascular tone. These results suggest that the development of A2B receptor agonists to induce vasodilatation in the kidney may provide a good therapeutic approach for the treatment of acute kidney injury.
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Agonistas do Receptor A2 de Adenosina/farmacologia , Hemodinâmica/efeitos dos fármacos , Receptor A2A de Adenosina/fisiologia , Receptor A2B de Adenosina/fisiologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Aminopiridinas/farmacologia , Animais , Células HEK293 , Humanos , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Masculino , Fenetilaminas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Triazóis/farmacologia , Vasodilatação/efeitos dos fármacos , Xantinas/farmacologiaRESUMO
INTRODUCTION: Little is known regarding long-term mortality outcomes after non-fatal suicide attempts among Veterans Health Administration (VHA) patients, which may inform services delivery and program evaluation. METHODS: For 4,601,081 Veterans with 2005 VHA encounters, we assessed unadjusted and age-adjusted all-cause and cause-specific mortality through 2017, overall and for Veterans with (N = 8243) versus without (N = 4,592,838) 2005 VHA suicide attempt documentation. Standardized mortality ratios compared mortality rates by suicide attempt status. Multivariable proportional hazards regression models assessed age- and gender-adjusted mortality risk. RESULTS: Among Veteran VHA users with non-fatal suicide attempt diagnoses, 1.6% died of suicide, 4.6% of non-suicide external causes, and 30.7% of any cause. In age- and gender-adjusted analyses, Veterans who attempted suicide had increased suicide (hazard ratio [HR] = 4.52, 95% confidence interval [CI] = 3.82-5.36), non-suicide external cause (HR = 3.75, 95% CI = 3.38-4.17), and all-cause (separate due to non-proportional hazards: 2006, HR = 2.05, 95% CI = 1.81-2.31; 2007-2017, HR = 1.72, 95% CI = 1.65-1.80) mortality through 2017. CONCLUSION: Over 12 years, Veteran VHA patients with non-fatal suicide attempt diagnoses had increased risk of suicide, non-suicide external cause, and all-cause mortality. Over 98% of Veteran VHA users who had a diagnosed non-fatal attempt did not die by suicide, highlighting additional program evaluation outcomes and opportunities to support physical and mental health.
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Tentativa de Suicídio , Veteranos , Humanos , Saúde Mental , Modelos de Riscos Proporcionais , Estados Unidos/epidemiologia , United States Department of Veterans Affairs , Veteranos/psicologia , Saúde dos VeteranosRESUMO
Importance: The Veterans Health Administration (VHA) implemented a national clinical program using a suicide risk prediction algorithm, Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET), in which clinicians facilitate care enhancements for individuals identified in local top 0.1% suicide risk tiers. Evaluation studies are needed. Objective: To determine associations with treatment engagement, health care utilization, suicide attempts, safety plan documentation, and 6-month mortality. Design, Setting, and Participants: This cohort study used triple differences analyses comparing 6-month changes in outcomes after vs before program entry for individuals entering the REACH VET program (March 2017-December 2018) vs a similarly identified top 0.1% suicide risk tier cohort from prior to program initiation (March 2014-December 2015), adjusting for trends across subthreshold cohorts. Subcohort analyses (including individuals from March 2017-June 2018) evaluated difference-in-differences for cause-specific mortality using death certificate data. The subthreshold cohorts included individuals in the top 0.3% to 0.1% suicide risk tier, below the threshold for REACH VET eligibility, from the concurrent REACH VET period and from the pre-REACH VET period. Data were analyzed from December 2019 through September 2021. Exposures: REACH VET-designated clinicians treatment reevaluation and outreach for care enhancements, including safety planning, increased monitoring, and interventions to enhance coping. Main Outcomes and Measures: Process outcomes included VHA scheduled, completed, and missed appointments; mental health visits; and safety plan documentation and documentation within 6 months for individuals without plans within the prior 2 years. Clinical outcomes included mental health admissions, emergency department visits, nonfatal suicide attempts, and all-cause, suicide, and nonsuicide external-cause mortality. Results: A total of 173â¯313 individuals (mean [SD] age, 51.0 [14.7] years; 161â¯264 [93.1%] men and 12â¯049 [7.0%] women) were included in analyses, including 40â¯816 individuals eligible for REACH VET care and 36â¯604 individuals from the pre-REACH VET period in the top 0.1% of suicide risk. The REACH VET intervention was associated with significant increases in completed outpatient appointments (adjusted triple difference [ATD], 0.31; 95% CI, 0.06 to 0.55) and proportion of individuals with new safety plans (ATD, 0.08; 95% CI, 0.06 to 0.10) and reductions in mental health admissions (ATD, -0.08; 95% CI, -0.10 to -0.05), emergency department visits (ADT, -0.03; 95% CI, -0.06 to -0.01), and suicide attempts (ADT, -0.05; 95% CI, -0.06 to -0.03). Subcohort analyses did not identify differences in suicide or all-cause mortality (eg, age-and-sex-adjusted difference-in-difference for suicide mortality, 0.0007; 95% CI, -0.0006 to 0.0019). Conclusions and Relevance: These findings suggest that REACH VET implementation was associated with greater treatment engagement and new safety plan documentation and fewer mental health admissions, emergency department visits, and suicide attempts. Clinical programs using risk modeling may be effective tools to support care enhancements and risk reduction.
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Prevenção do Suicídio , Veteranos/estatística & dados numéricos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Programas e Projetos de Saúde/métodos , Avaliação de Programas e Projetos de Saúde/estatística & dados numéricos , Suicídio/psicologia , Suicídio/estatística & dados numéricos , Estados Unidos , United States Department of Veterans Affairs/organização & administração , United States Department of Veterans Affairs/estatística & dados numéricos , Veteranos/psicologiaRESUMO
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin-Angiotensin-Aldosterone System (RAAS) and Kinin-Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.
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COVID-19/complicações , Doenças Cardiovasculares/etiologia , Sistema Calicreína-Cinina , Sistema Renina-Angiotensina , Enzima de Conversão de Angiotensina 2/metabolismo , Bradicinina/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/metabolismo , Humanos , Síndrome de COVID-19 Pós-Aguda , Tratamento Farmacológico da COVID-19RESUMO
INTRODUCTION: Veterans who receive Veterans Health Administration (VHA) Home Based Primary Care (HBPC) services and those discharged from VHA Community Living Centers (CLC) may be at increased risk of suicide. No studies to date have assessed suicide risks among HBPC patients. This study examined suicide risks among recipients of VHA HBPC services and following discharge from VHA CLCs, as compared to other Veteran VHA users. METHODS: We identified three cohorts of 2013 Veteran VHA patients: 47,842 HBPC users, 17,725 with live discharges from CLCs, and 5,554,635 other VHA users. Using proportional hazards regression, we assessed risk of suicide through 2016. RESULTS: Overall, HBPC recipients did not differ from the other cohorts in suicide risk. Although in unadjusted analyses CLC discharged patients had greater suicide risk than the general VHA patient cohort (hazard ratio (HR) = 1.73, 95% confidence interval = 1.25-2.41), this became nonsignificant when controlling for diagnoses. CONCLUSIONS: Overall findings did not identify differential suicide risk among VHA HBPC recipients in 2013, when compared to other Veteran VHA patient cohorts. Veterans discharged from VHA CLCs have increased mental health morbidity, which was associated with increased suicide risk.
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Suicídio , Veteranos , Humanos , Alta do Paciente , Suicídio/psicologia , Estados Unidos , United States Department of Veterans Affairs , Veteranos/psicologia , Saúde dos VeteranosRESUMO
In analyses conducted for program planning, the Veterans Health Administration evaluated associations between self-reports of suicidal ideation and behavior using the Columbia Scale obtained on two occasions separated by three months and clinical or administrative records of suicide attempts over the subsequent three months., Combining information from the two assessments improved prediction of suicidal behavior and found that risk was greater when ideation was reported on both assessments, than when it was first reported at follow-up. The absence of reported ideation at the second assessment was not associated with a clinically relevant reduction in risk. These findings confirm recent reports from the Mental Health Research Network (MHRN).
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Ideação Suicida , Tentativa de Suicídio , Humanos , Estudos Longitudinais , Saúde Mental , Fatores de RiscoRESUMO
Importance: Suicide rates are higher among veterans compared with nonveterans, and the prevalence of posttraumatic stress disorder (PTSD) is higher among veterans compared with the general adult population in the US. To date, no study has examined the association between PTSD screening results and suicide mortality among veterans. Objective: To examine whether veterans receiving care in the US Veterans Health Administration (VHA) health system who had positive results on the Primary Care-Posttraumatic Stress Disorder Screen (PC-PTSD) had a greater risk of suicide mortality compared with those who had negative results and to assess whether such risk decreased over time. Design, Setting, and Participants: Multivariable proportional hazards regression models were used to evaluate suicide mortality risk through December 31, 2016, among a cohort of veterans who received the PC-PTSD in the VHA health system. The VHA administers the PC-PTSD to patients nationwide, and screening results are routinely documented in the VHA Corporate Data Warehouse. The PC-PTSD includes 4 questions regarding PTSD symptoms, to which patients respond with either a positive (yes) or negative (no) answer. All patients who completed the PC-PTSD in 2014 and who did not have a diagnosis of PTSD in the year before screening were included in the analysis. A score of 3 or 4 on the PC-PTSD indicated a positive result, and a score of 0, 1, or 2 indicated a negative result. Data collection and analyses were performed from November 13, 2018, to June 18, 2019. Exposures: Primary Care-Posttraumatic Stress Disorder Screen (PC-PTSD). Main Outcomes and Measures: Suicide mortality risk, as assessed through data obtained from the US Veterans Affairs/Department of Defense Mortality Data Repository. Results: A total of 1â¯693â¯449 PC-PTSDs were completed by 1â¯552â¯581 individual veteran patients in 2014. Most of the patients were White (73.9%), married (52.2%), male (91.1%), 55 years or older (62.5%), and had completed only 1 PC-PTSD (92.1%). In multivariable analyses, positive PC-PTSD results (ie, total scores of 3 or 4) were associated with a 58% increase in the risk of suicide mortality at 1 day after screening (hazard ratio [HR], 1.58; 95% CI, 1.19-2.10) and a 26% increase in the risk of suicide mortality at 1 year after screening (HR, 1.26; 95% CI, 1.07-1.48). A positive response on item 4 ("felt numb or detached from others, activities, or your surroundings") of the PC-PTSD was associated with a 70% increase in suicide mortality risk at 1 day after screening (HR, 1.70; 95% CI, 1.27-2.28). Conclusions and Relevance: Positive PC-PTSD results, and specifically reports of feeling numb or detached, were associated with increases in the risk of suicide mortality. These associations decreased over time. The findings of this study can inform interpretation of PC-PTSD responses and suggest the importance of recent improvements made to the VHA suicide risk assessment.
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Programas de Rastreamento , Medição de Risco/estatística & dados numéricos , Transtornos de Estresse Pós-Traumáticos , Prevenção do Suicídio , Suicídio , Correlação de Dados , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/normas , Pessoa de Meia-Idade , Mortalidade , Psiquiatria Preventiva/métodos , Psiquiatria Preventiva/normas , Melhoria de Qualidade , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Suicídio/psicologia , Suicídio/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: To evaluate the associations of self-reports of suicidal ideation and behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS) in a survey of patients receiving mental health services in the Veterans Health Administration (VHA) with reports of attempts documented in medical records and administrative data. METHOD: The C-SSRS was administered to 15,373 Veterans in the Veterans Outcome Assessment (VOA) survey. Concurrent validity was evaluated by comparing self-reports from the past 3 months with VHA records. Predictive validity was evaluated by logistic regression models using attempts over the subsequent 3 months as the outcome. RESULTS: Tests of concurrent validity found strong associations between self-reports and attempts documented in VHA records, but there were substantial numbers of discordant responses. In tests of predictive validity, area under the ROC curve for predicting future attempts was >0.8. There were differences in the distribution of responses and of psychometric properties across VHA mental health programs. CONCLUSIONS: Findings support the value of screening and the validity of the self-reports based on the C-SSRS, but limitations in concordance with medical records and variability across programs suggest the need for clinical judgment in interpreting responses.
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Serviços de Saúde Mental , Ideação Suicida , Tentativa de Suicídio/psicologia , Suicídio/psicologia , Saúde dos Veteranos , Veteranos/psicologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND PURPOSE: Adenosine is a local mediator that regulates physiological and pathological processes via activation of four GPCRs (A1 , A2A , A2B , and A3 ). We have investigated the effect of two A1 -receptor-selective agonists and the novel A1 -receptor bitopic ligand VCP746 on the rat cardiovascular system. EXPERIMENTAL APPROACH: The regional haemodynamic responses of these agonist was investigated in conscious rats. Male Sprague-Dawley rats (350-450 g) were chronically implanted with pulsed Doppler flow probes on the renal, mesenteric arteries and the descending abdominal aorta and the jugular vein and caudal artery catheterized. Cardiovascular responses were measured following intravenous infusion (3 min each dose) of CCPA (120, 400, and 1,200 ng·kg-1 ·min-1 ), capadenoson or adenosine (30, 100, and 300 µg·kg-1 ·min-1 ), or VCP746 (6, 20, and 60 µg·kg-1 ·min-1 ) following pre-dosing with DPCPX (0.1 mg·kg-1 , i.v.) or vehicle. KEY RESULTS: CCPA produced a significant A1 -receptor-mediated decrease in heart rate that was accompanied by vasoconstrictions in the renal and mesenteric vascular beds but an increase in hindquarters vascular conductance. The partial agonist capadenoson also produced an A1 -receptor-mediated bradycardia. In contrast, VCP746 produced increases in heart rate and renal and mesenteric vascular conductance that were not mediated by A1 -receptors. In vitro studies confirmed that VCP746 had potent agonist activity at both A2A - and A2B -receptors. CONCLUSIONS AND IMPLICATIONS: These results suggest VCP746 mediates its cardiovascular effects via activation of A2 rather than A1 adenosine receptors. This has implications for the design of future bitopic ligands that incorporate A1 allosteric ligand moieties.
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Agonistas do Receptor A1 de Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Adenosina/análogos & derivados , Sistema Cardiovascular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Receptor A1 de Adenosina/efeitos dos fármacos , Tiofenos/farmacologia , Adenosina/farmacologia , Aminopiridinas/farmacologia , Animais , Sistema Cardiovascular/metabolismo , Estado de Consciência , Agonismo Parcial de Drogas , Frequência Cardíaca/efeitos dos fármacos , Ligantes , Masculino , Ratos Sprague-Dawley , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/efeitos dos fármacos , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/efeitos dos fármacos , Receptor A2B de Adenosina/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Tiazóis/farmacologiaRESUMO
Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Short-term VEGF receptor inhibition is associated with hypertension in 15%-60% of patients, which may limit the use of these anticancer therapies over the longer term. To evaluate the longer-term cardiovascular implications of treatment, we investigated the "on"-treatment (21 days) and "off"-treatment (10 days) effects following daily administration of vandetanib, pazopanib, or vehicle, in conscious rats. Cardiovascular variables were monitored in unrestrained Sprague-Dawley rats instrumented with radiotelemetric devices. In Study 1, rats were randomly assigned to receive either daily intraperitoneal injections of vehicle (volume 0.5 mL; n = 5) or vandetanib 25 mg/kg/day (volume 0.5 mL; n = 6). In Study 2, rats received either vehicle (volume 0.5 mL; n = 4) or pazopanib 30 mg/kg/day (volume 0.5 mL; n = 7), dosed once every 24 hours for 21 days. All solutions were in 2% Tween, 5% propylene glycol in 0.9% saline solution. Vandetanib caused sustained increases in mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to baseline and vehicle. Vandetanib also significantly altered the circadian cycling of MAP, SBP, and DBP. Elevations in SBP were detectable 162 hours after the last dose of vandetanib. Pazopanib also caused increases in MAP, SBP, and DBP. However, compared to vandetanib, these increases were of slower onset and a smaller magnitude. These data suggest that the cardiovascular consequences of vandetanib and pazopanib treatment are sustained, even after prolonged cessation of drug treatment.
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Hipertensão/induzido quimicamente , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Quinazolinas/efeitos adversos , Sulfonamidas/efeitos adversos , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Humanos , Indazóis , Masculino , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagemRESUMO
Detecting mutations in the plasma of patients with solid tumors is becoming a valuable method of diagnosing and monitoring cancer. The TERT promoter is mutated at high frequencies in multiple cancer types, most commonly at positions -124 and -146 (designated C228T and C250T, respectively). Detection of these mutations has been challenging because of the high GC content of this region (approximately 80%). We describe development of novel probe-based droplet digital PCR assays that specifically detect and quantify these two mutations, along with the less common 242-243 CC>TT mutation, and demonstrate their application using human tumor and plasma samples from melanoma patients. Assay designs and running conditions were optimized using cancer cell line genomic DNAs with the C228T or C250T mutations. The limits of detection were 0.062% and 0.051% mutant allele fraction for the C228T and C250T assays, respectively. Concordance of 100% was observed between droplet digital PCR and sequencing-based orthogonal methods in the detection of TERT mutant DNA in 32 formalin-fixed, paraffin-embedded melanoma tumors. TERTmutant DNA was also identified in 21 of 27 plasma samples (78%) from patients with TERTmutant tumors, with plasma mutant allele fractions ranging from 0.06% to 15.3%. There were no false positives in plasma. These data demonstrate the potential of these assays to specifically detect and quantify TERTmutant DNA in tumors and plasma of cancer patients.
Assuntos
Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas/genética , Telomerase/genética , Humanos , Mutação/genéticaRESUMO
BACKGROUND AND PURPOSE: Adenosine is a local mediator that regulates a number of physiological and pathological processes via activation of adenosine A1 -receptors. The activity of adenosine can be regulated at the level of its target receptor via drugs that bind to an allosteric site on the A1 -receptor. Here, we have investigated the species and probe dependence of two allosteric modulators on the binding characteristics of fluorescent and nonfluorescent A1 -receptor agonists. EXPERIMENTAL APPROACH: A Nano-luciferase (Nluc) BRET (NanoBRET) methodology was used. This used N-terminal Nluc-tagged A1 -receptors expressed in HEK293T cells in conjunction with both fluorescent A1 -receptor agonists (adenosine and NECA analogues) and a fluorescent antagonist CA200645. KEY RESULTS: PD 81,723 and VCP171 elicited positive allosteric effects on the binding affinity of orthosteric agonists at both the rat and human A1 -receptors that showed clear probe dependence. Thus, the allosteric effect on the highly selective partial agonist capadenoson was much less marked than for the full agonists NECA, adenosine, and CCPA in both species. VCP171 and, to a lesser extent, PD 81,723, also increased the specific binding of three fluorescent A1 -receptor agonists in a species-dependent manner that involved increases in Bmax and pKD . CONCLUSIONS AND IMPLICATIONS: These results demonstrate the power of the NanoBRET ligand-binding approach to study the effect of allosteric ligands on the binding of fluorescent agonists to the adenosine A1 -receptor in intact living cells. Furthermore, our studies suggest that VCP171 and PD 81,723 may switch a proportion of A1 -receptors to an active agonist conformation (R*).
Assuntos
Agonistas do Receptor Purinérgico P1/farmacologia , Receptor A1 de Adenosina/metabolismo , Regulação Alostérica , Animais , Células HEK293 , Humanos , Ligantes , Agonistas do Receptor Purinérgico P1/química , Ratos , Receptor A1 de Adenosina/química , Receptor A1 de Adenosina/genéticaRESUMO
Anti-cancer drug Sunitinib is linked to adverse cardiovascular events, which have shown to involve mitogen activated kinase kinase 7 (MKK7) pathway. Sunitinib-induced cardiotoxicity in 3, 12 and 24 months old male Sprague-Dawley rats and MKK7 expression and activation was investigated using the Langendorff perfused heart model followed by Western blot analysis. Cardiac function and infarct size were measured during/after 125 min of Sunitinib treatment. Left ventricular cardiac samples were analysed by qRT-PCR for expression of MKK7 mRNA and cardiac injury associated microRNAs. Infarct size was increased in all Sunitinib treated age groups. Haemodynamic alterations were observed following Sunitinib administration. Left ventricular developed pressure (LVDP) was decreased in all age groups, while heart rate (HR) was decreased in 3 and 12 months groups. Sunitinib treatment decreased the expression of miR-27a in all age groups, while miR-133a and miR-133b levels were increased in 3 months and decreased in 24 months groups. MKK7 mRNA and p-MKK7 levels were decreased in the 3 months group after Sunitinib treatment. MKK7 mRNA level was increased in 24 months group and p-MKK7 levels were increased in 12 months group following Sunitinib treatment. This study highlights the importance and impact of ageing and anti-cancer therapy-induced cardiotoxicity.
Assuntos
Envelhecimento/fisiologia , Antineoplásicos/toxicidade , Cardiotoxinas/toxicidade , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sunitinibe/toxicidade , Animais , Testes de Função Cardíaca , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Masculino , MicroRNAs , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Purpose: Children with dyslexia often have related writing difficulties. In the simple view of writing model, high-quality writing depends on good transcription skills, working memory, and executive function-all of which can be difficult for children with dyslexia and result in poor spelling and low overall writing quality. In this article, we describe the challenges of children with dyslexia in terms of the simple view of writing and instructional strategies to increase spelling and overall writing quality in children with dyslexia. Method: For spelling strategies, we conducted systematic searches across 2 databases for studies examining the effectiveness of spelling interventions for students with dyslexia as well as including studies from 2 meta-analyses. To locate other instructional practices to increase writing quality (e.g., handwriting and executive function), we examined recent meta-analyses of writing and supplemented that by conducting forward searches. Results: Through the search, we found evidence of effective remedial and compensatory intervention strategies in spelling, transcription, executive function, and working memory. Some strategies included spelling using sound-spellings and morphemes and overall quality using text structure, sentence combining, and self-regulated strategy development. Conclusions: Many students with dyslexia experience writing difficulty in multiple areas. However, their writing (and even reading) skills can improve with the instructional strategies identified in this article. We describe instructional procedures and provide links to resources throughout the article.