Remote mental health care interventions during the COVID-19 pandemic: An umbrella review.

Mitigating the COVID-19 related disruptions in mental health care services is crucial in a time of increased mental health disorders. Numerous reviews have been conducted on the process of implementing technology-based mental health care during the pandemic. The research question of this umbrella review was to examine what the impact of COVID-19 was on access and delivery of mental health services and how mental health services have changed during the pandemic. A systematic search for systematic reviews and meta-analyses was conducted up to August 12, 2022, and 38 systematic reviews were identified. Main disruptions during COVID-19 were reduced access to outpatient mental health care and reduced admissions and earlier discharge from inpatient care. In response, synchronous telemental health tools such as videoconferencing were used to provide remote care similar to pre-COVID care, and to a lesser extent asynchronous virtual mental health tools such as apps. Implementation of synchronous tools were facilitated by time-efficiency and flexibility during the pandemic but there was a lack of accessibility for specific vulnerable populations. Main barriers among practitioners and patients to use digital mental health tools were poor technological literacy, particularly when preexisting inequalities existed, and beliefs about reduced therapeutic alliance particularly in case of severe mental disorders. Absence of organizational support for technological implementation of digital mental health interventions due to inadequate IT infrastructure, lack of funding, as well as lack of privacy and safety, challenged implementation during COVID-19. Reviews were of low to moderate quality, covered heterogeneously designed primary studies and lacked findings of implementation in low- and middle-income countries. These gaps in the evidence were particularly prevalent in studies conducted early in the pandemic. This umbrella review shows that during the COVID-19 pandemic, practitioners and mental health care institutions mainly used synchronous telemental health tools, and to a lesser degree asynchronous tools to enable continued access to mental health care for patients. Numerous barriers to these tools were identified, and call for further improvements. In addition, more high quality research into comparative effectiveness and working mechanisms may improve scalability of mental health care in general and in future infectious disease outbreaks.

Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE).

BACKGROUND: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. METHODS: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210. FINDINGS: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. INTERPRETATION: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe. FUNDING: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

Role of Pro-Brain Natriuretic Peptide Serum Concentration in the Detection of Pulmonary Hypertension in Patients With End-Stage Lung Diseases Referred for Lung Transplantation.

BACKGROUND: Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration is elevated in patients with pulmonary hypertension (PH); however, its role in the detection of PH associated with lung disease is not well established. AIM: The aim of this study was to assess the value of NT-proBNP in the detection of PH in patients with end-stage lung disease (esLD) referred for lung transplantation. MATERIALS AND METHODS: The study population consisted of 65 patients: 37 with idiopathic pulmonary fibrosis (IPF), 20 with chronic obstructive pulmonary disease, and 8 patients with other interstitial lung diseases (75% men, mean age 53.3 ± 9.5 years). Serum concentration of NT-proBNP was assessed with an immunoradiometric assay kit. The mean pulmonary artery pressure (mPAP) was measured using a Swan-Ganz catheter. PH was defined as mPAP ≥ 25 mm Hg. RESULTS: Median NT-proBNP concentrations were significantly higher in patients with PH than in patients without PH: 139 (49-1236) pg/mL vs 67 (38-116) pg/mL, respectively; P = .016. Receiver operating characteristic (ROC) analysis revealed that NT-proBNP concentration higher than 131.5 pg/mL was a predictor of PH with good specificity (81%) and positive predictive value (78.9%) but low sensitivity (55.6%) and negative predictive value (58.6%). The area under the ROC curve of serum NT-proBNP concentration for PH was 0.71 (95% confidence interval 0.57-0.85, P = .039). CONCLUSION: Serum concentration of NT-proBNP may be useful in the diagnosis of PH in patients with esLD referred for lung transplantation.

Prognostic Value of Mean, Diastolic, and Systolic Pulmonary Artery Pressure in Patients With End-stage Lung Disease Referred for Lung Transplantation.

BACKGROUND: Pulmonary hypertension (PH) is a common complication in end-stage lung disease (esLD). The aim of this study was to establish the best threshold values for mean, systolic, and diastolic artery pressure (mPAP, dPAP, and sPAP, respectively) to identify patients with esLD referred for lung transplantation and to predict 1-year prognosis. METHODS: Sixty-five patients were enrolled in the study (75% men) with a mean age of 53.3 ± 9.5 years; 31% had chronic obstructive pulmonary disease (COPD), 57% had idiopathic pulmonary fibrosis (IPF), and 12% had interstitial lung diseases (ILDs). The mean period of observation was 14.4 ± 5 months. We assessed invasively mPAP, dPAP, and sPAP, as well as pulmonary capillary wedge pressure (PCWP), using a Swan-Ganz catheter. Receiver-operating characteristic (ROC) curves were constructed to identify the best cutoff points for mPAP, dPAP, and sPAP to predict survival. The study endpoint was defined as 1-year mortality before transplantation. Survival analysis was completed according to the Kaplan-Meier method. RESULTS: During follow-up, 30 (46.1%) patients died and 19 (29%) underwent lung transplantation. Based on ROC curve analysis, we estimated mPAP ≥30 mm Hg, dPAP ≥20 mm Hg, and sPAP ≥44 mm Hg as the best threshold values with the highest sensitivity (70%, 70%, and 73%, respectively) and specificity (76%, 69%, and 72%, respectively) and the acceptable area under curve (0.67, 0.68, and 0.72, respectively). The negative predictive values for mPAP, dPAP, and sPAP were higher than the positive predictive values (79%, 77%, and 81% vs 67%, 61%, and 64%, respectively). We also constructed Kaplan-Meier curves for mPAP, dPAP, and sPAP threshold values. There were significant differences in 1-year survival between patients with and without PH for mPAP, dPAP, and sPAP threshold values (P = .005, P = .035, and P < .001; respectively). CONCLUSION: Elevated mPAP, dPAP, and sPAP are related to worse prognosis in patients with esLD referred for lung transplantation.

Red Blood Cell Distribution Width in End-Stage Heart Failure Patients Is Independently Associated With All-Cause Mortality After Orthotopic Heart Transplantation.

BACKGROUND: Red blood cell markers (RBCM) have been found to be predictors of mortality in various populations. However, there is no information regarding the association between the values of RBCM and long-term outcomes after orthotopic heart transplantation (OHT). The aim of this study was to assess whether the values of inflammatory markers and RBCM obtained directly before OHT are associated with mortality in patients diagnosed as having end-stage heart failure undergoing OHT. METHODS: We retrospectively analyzed data of 173 nonanemic adult patients diagnosed as having end-stage heart failure undergoing primary OHT between 2007 and 2014. Clinical and laboratory data were obtained at the time of admission for the OHT. RBCM were analyzed using an automated blood counter (Sysmex XS-1000i and XE-2100, Sysmex Corporation, Kobe, Japan). RESULTS: Mean age of the patients was 54 (41-59) and 72% of them were male. During the observation period, the mortality rate was 32%. Multivariable analysis of Cox proportional hazard confirmed that elevated pretransplantation red blood cell distribution width value (hazard ratio [HR], 1.38 [1.25-1.48], P < .001) was the sole independent predictor of death during long-term follow-up. Other red blood cell distribution width such as mean corpuscular volume, mean corpuscular hemoglobin concentration, and mean corpuscular hemoglobin (HR, 0.88 [0.84-0.91]; P < .001; HR, 0.75 [0.53-1.05]; P < .05; HR, 0.78 [0.64-0.96]; P < .05, respectively) had predictive value in univariable analysis. CONCLUSIONS: In summary, we have demonstrated that elevated red blood cell distribution width immediately before OHT is an independent predictor of all-cause mortality in heart transplant recipients. Other factors associated with posttransplantation mortality include lower values of mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration.

Predictive Value of the Model for End-Stage Liver Disease Score Excluding International Normalized Ratio One Year After Orthotopic Heart Transplantation.

BACKGROUND: The Model for End-Stage Liver Disease (MELD) scoring system incorporating a combination of hepatic and renal laboratory parameters does not adequately reflect the degree of multi-organ dysfunction in patients with heart failure, who need oral anticoagulation. In order to exclude the impact of oral anticoagulation on the international normalized ratio (INR), we used the MELD excluding INR (MELD-XI) score. The aims of the study were to calculate the individual preoperative MELD-XI score and its ability to predict 1-year mortality after heart transplantation and to identify other preoperative laboratory prognostic parameters. METHODS: We retrospectively analysed data of 87 consecutive adults undergoing heart transplantation between 2011 and 2014. Clinical data and laboratory parameters for the calculation of the MELD-XI score were obtained at the time of admission for the heart transplantation. RESULTS: The average age of the patients was 48.8 ± 13.3 years and 68.9% of them were male. During the observation period, the mortality rate was 18.4%. Multivariate analysis of Cox proportional hazard confirmed that the pretransplantation MELD-XI score (hazard ratio [HR] = 1.625 [1.286-2.053]; P < .001), sodium serum concentration (HR = 0.824 [0.677-1.001]; P < .05) and highly sensitive C-reactive protein (hs-CRP) serum concentration (HR = 1.045 [1.008-1.083]; P < .02) were independent predictors of death during the first year after heart transplantation. Area under the receiver operating characteristic (ROC) curve (AUC) indicated a good discriminatory power of MELD-XI (AUC 0.997; P < .04) and plasma sodium concentration (AUC 0.901; P < .01) in death prediction. CONCLUSIONS: Our study confirms that the pretransplantation MELD-XI score, as well as serum sodium and hsCRP concentrations, may be used to estimate postoperative risk in heart transplant recipients during a 1-year follow-up.

Perioperative Risk Factors of Cardiac Allograft Vasculopathy in the Long-Term Follow-up.

BACKGROUND: Cardiac allograft vasculopathy (CAV) still remains to be one of the most important limiting factors for heart transplant recipients' long-term survival. The aim of our study was to identify the perioperative risk factors impacting the occurrence of CAV during the long-term follow-up. METHODS: We retrospectively analysed the data from 198 consecutive adult patients, who underwent heart transplantation between 2007 and 2012, in whom at least one routine coronarography (CAG) was performed. CAV onset was defined as any lesion seen at least at one routine CAG. RESULTS: The average follow-up was 63.6 ± 14.7 months. The frequency of CAV in the analysed population was 36 (18.1%). Multivariate stepwise logistic regression analysis confirmed that NT-proBNP plasma concentration directly before heart transplant [logNT-proBNP OR = 16.455 (4.587-31.036), P < .0001], fibrinogen plasma concentration a month after heart transplant [OR = 1.022 (1.009-1.035), P < .001] and occurrence of diabetes [OR = 12.355 (1.417-35.750), P < .001], were independent predictors of CAV. Area under the ROC curves (AUC) indicated a well discriminatory power of plasma fibrinogen [AUC 0.9278, P < .001] and plasma NTproBNP concentration [AUC 0.9514, P < .001] in CAV prediction. The optimal cut-off value of fibrinogen was 509 mg/dL, and of NT-proBNP was 10080 pg/mL. CONCLUSIONS: Our data show that NT-proBNP and fibrinogen plasma concentrations as well as occurence of diabetes, both preexisting and new onset after heart transplant can be used to identify patients at risk of developing CAV.

Predictive Value of Hepatic and Renal Dysfunction Based on the Models for End-Stage Liver Disease in Patients With Heart Failure Evaluated for Heart Transplant.

BACKGROUND: The evaluation of prognosis and determination of a long-term treatment strategy is an important element of management in patients with heart failure (HF). METHODS: The aim of the study was to determine the prognostic value of the Model for End-Stage Liver Disease (MELD) and its modifications, MELD and serum sodium (MELD-Na) and MELD excluding the international normalized ratio (MELD-XI), as well as other independent risk factors for death during a 4-year follow-up. We analyzed retrospectively 143 patients with advanced HF, evaluated for heart transplant between 2009 and 2011. Patients using warfarin were excluded from the study. The long-term follow-up data were obtained during follow-up visits and/or phone contact with the patients or their families. RESULTS: The age of the patients was 54 (48-59) years and 88.1% of patients were male. Mortality rate during the follow-up period was 49%. The MELD scores (hazard ratio [HR], 1.12; P < .001), as well as serum high-sensitivity C-reactive protein (hs-CRP; HR, 1.01; P < .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; HR, 1.01; P < .05) levels, were independent risk factors for death. Receiver operator characteristic analysis indicated that a MELD cutoff of 10 (area under the curve [AUC], 0.756; P < .0001], MELD-XI cutoff of 13.0 (AUC, 0.720; P < .0001), MELD-Na cutoff of 13.0 (AUC, 0.813; P < .0001), hs-CRP cutoff of 4.02 (AUC, 0.686; P < .001), and NT-proBNP cutoff of 1055 (AUC, 0.722; P < .001) were the best predictive values as predictors of death. CONCLUSIONS: MELD, MELD-Na, and MELD-XI scores are prognostic factors for death during a 4-year follow-up. A high MELD score is an independent prognostic factor for death. NT-proBNP and hs-CRP serum concentrations are other independent factors influencing death.

Effect of trimetazidine on serum interleukin-6 and C-reactive protein concentrations in patients with stable coronary artery disease.

Trimetazidine is widely used in the treatment of stable coronary artery disease (CAD) and its cytoprotective effect has been confirmed in animal studies and in many clinical trials. Given the inflammatory milieu of CAD and trimetazidine effect on the inflow of neutrophilis to the ischemic area, it is interesting to consider whether trimetazidine actions could be also explained through the inhibition of inflammatory mediators, including cytokines. The aim of this study was to (i) examine the influence of treadmill exercise test (TET) on serum C-reactive protein (CRP) and interleukin-6 (IL-6), and (ii) the influence of three-month trimetazidine therapy on serum CRP and IL-6 concentrations. One hundred and fifty-six patients with stable CAD were included. TET was performed (according to the standard Bruce protocol) twice for all subjects – at baseline and after the three-month trimetazidine treatment. Serum IL-6 and CRP concentrations were determined prior to and after performing each TET. Exercise led to the increase of CRP (2.35 vs 2.81 mg/L, p < 0.05) and IL-6 concentrations (1.64 vs 1.92 pg/ml, p=0.0318) in patients without trimetazidine. Three-month treatment resulted in the increase in the TET duration (378.0s vs 410.9s, p < 0.05) and decrease in serum CRP concentration, both before (2.35 vs 1.51 mg/L, p < 0.05) and after TET (2.81 vs 1.69 mg/L, p < 0.05). There was no significant increase of CRP after the second TET (1.51 vs 1.69 mg/l, p=NS). Three-month trimetazidine treatment increased IL-6 concentrations (1.64 vs 2.23 pg/mL, p < 0.05). TET was not associated with further changes in IL-6 concentrations (2.23 vs 2.18 pg/mL, p=NS). Serum IL-6 and CRP concentrations increase during exercise in patients without trimetazidine. Three-month trimetazidine prolonged the duration of TET. Moreover, it resulted in the reduction of CRP concentration The increase of IL-6 concentration after three-month trimetazidine treatment and the lack of changes of its concentration after TET is associated with yet another mechanism of trimetazidine.

Serum concentration of insulin-like growth factor-I, but not tumor necrosis factor-alpha, measured twelve months after stenting of the infarct-related artery, is associated with in-stent restenosis.

Percutaneous coronary intervention (PCI) has revolutionized the management of and outcomes in patients with ST-segment elevation myocardial infarction (STEMI). The role of insulin-like growth factor-I (IGF-I) and tumor necrosis factor-alpha (TNF-alpha) in restenosis has been intensively studied. We aimed to investigate the power of serum IGF-I and TNF-alpha concentrations to predict restenosis in patients who had previously undergone PCI for STEMI. Thirty-seven patients were enrolled in the study. Twelve months prior to the study they underwent successful PCI with stent placement for STEMI. The patients were divided into two groups: group 1 - patients with in-stent restenosis in the infarct-related artery (N=9); group 2 - patients without in-stent restenosis in the infarct-related artery (N=28). Baseline profile was similar in both groups. The mean diameter and length of placed stents were similar in both groups. Smaller minimal lumen diameter (MLD) and greater lumen loss (LL) were observed in group 1. Median IGF-I concentrations were substantially higher in patients with ISR compared to those without ISR (170 ng/mL vs 115 ng/mL, p=0.004). Strikingly, median TNF-alpha levels were lower in group 1 (2.4 pg/mL vs 4.1 pg/mL, p=0.05). Correlation analysis showed that serum IGF-I levels were significantly associated with diameter stenosis (R=0.29 p=0.05), LL (R=0.37 p=0.02), MLD (R= -0.38 p=0.03), and stent length (R=0.30 p=0.05). The cut-off value to predict restenosis for IGF-I was less than 158 ng/mL (sensitivity 55 percent, specificity 93 percent, positive predictive value 71 percent, negative predictive value 87 percent). IGF-I detected twelve months after stent placement during the acute phase of AMI may be a late determinant of restenosis. High concentrations of IGF-I could play a permissive role in the progression of NIH and subsequently restenosis. It seems that as far as TNF-alpha is concerned, diagnostic value remains inconclusive.

The role of interleukin-6 and transforming growth factor-beta1 in predicting restenosis within stented infarct-related artery.

Despite high efficacy of percutaneous coronary intervention (PCI), in-stent restenosis proves to be a significant problem of therapy. Restenosis concerns around 30 percent of patients. Studies have suggested that restenosis is initiated by cells which participate in intense inflammatory reaction caused by stent implantation. Atherosclerotic plaque rupture during stent implantation and PCI-associated injury of the vessel wall lead to hemorrhage and release of various cytokines. They are probably responsible for quick recurrence of vascular lumen stenosis (restenosis). Interleukin-6 (IL-6) is known as a main pro-inflammatory cytokine, whereas Transformig Growth Factor-beta1 (TGF-beta1) has anti-inflammatory properties. The study population comprised 36 patients with myocardial infarction treated with PCI with stent implantation. They underwent control coronary angiography after 12 months. At this time plasma concentration of IL-6 and TGF-beta was measured in peripheral blood. Serum IL-6 concentration in the analyzed population correlates with lumen loss (p<0.01) and the severity of stenosis (p<0.001). No such correlation was found between serum TGF-beta1 concentration and lumen loss (p=NS) or the severity of stenosis (p=NS). The IL-6 plasma concentration may be a marker of in-stent restenosis in patients after PTCA, while the concentration of TGF-beta1 is not associated with the occurrence of restenosis at one year of follow-up.

The dopamine D3/D2 agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] protects against acute and cocaine-kindled seizures in mice: further evidence for the involvement of D3 receptors.

Previous findings have demonstrated a protective role for dopamine D(3)/D(2) receptor agonists in the convulsant and lethal effects of acutely administered cocaine. Data are provided here to establish that the protection occurs through a D(3)-linked mechanism and that protection is extended to seizure kindling. The D(3) antagonist SB-277011-A [4-quinolinecarboxamide,N-[trans-4-[2-(6-cyano-3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-cyclohexyl]-(9CI)] prevented the anticonvulsant effect of the D(3)/D(2) receptor agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] on cocaine-induced seizures. The protection afforded by the D(3)/D(2) agonist, (+)-PD-128,907, was eliminated in D(3) receptor-deficient mice. In D(2) receptor knockout mice, the anticonvulsant effects of (+)-PD-128,907 were preserved. (+)-PD-128,907 also prevented the acquisition and expression of cocaine-kindled seizures engendered by repeated daily dosing with 60 mg/kg cocaine. (+)-PD-128,907 also blocked the seizures induced in mice fully seizure kindled to cocaine. Although repeated dosing with cocaine increased the potency of cocaine to produce seizures and lethality (decreased ED(50) values), daily coadministration of (+)-PD-128,907 significantly prevented this potency shift. In mice treated daily with cocaine and (+)-PD-128,907, the density, but not the affinity, of D(3) receptors was increased. The specificity with which (+)-PD-128,907 acts upon this cocaine-driven process was demonstrated by the lack of a significant effect of (+)-PD-128,907 on seizure kindling to a GABA(A) receptor antagonist, pentylenetetrazol. Taken together and with literature findings, the data indicate that dopamine D(3) receptors function in the initiation of a dampening mechanism against the toxic effects of cocaine, a finding that might have relevance to psychiatric disorders of drug dependence, schizophrenia, and bipolar depression.

Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania.

The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with bipolar disorder (BPD), but its function in affective regulation is unknown. Compared with wild-type (WT) and GluR5 knockout (KO) mice, GluR6 KO mice were more active in multiple tests and super responsive to amphetamine. In a battery of specific tests, GluR6 KO mice also exhibited less anxious or more risk-taking type behavior and less despair-type manifestations, and they also had more aggressive displays. Chronic treatment with lithium, a classic antimanic mood stabilizer, reduced hyperactivity, aggressive displays and some risk-taking type behavior in GluR6 KO mice. Hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. The membrane levels of other glutamatergic receptors were not significantly altered by GluR6 ablation or chronic lithium treatment. Together, these biochemical and behavioral results suggest a unique role for GluR6 in controlling abnormalities related to the behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggressiveness, driven or increased goal-directed pursuits, risk taking and supersensitivity to psychostimulants. Whether GluR6 perturbation is involved in the mood elevation or thought disturbance of mania and the cyclicity of BPD are unknown. The molecular mechanism underlying the behavioral effects of lithium in GluR6 KO mice remains to be elucidated.

Protection against cocaine toxicity in mice by the dopamine D3/D2 agonist R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol [(+)-PD 128,907].

Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D(3/)D(2) receptor agonists dose dependently and completely prevented the convulsant and lethal effects of cocaine. The D(3)-preferring agonists R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol) [(+)-PD 128,907], (+)-7-hydroxy-dipropylaminotetralin, and the mixed D(3/)D(2) agonists quinpirole and quinelorane were all effective against cocaine toxicity in mice. The anticonvulsant effects of these compounds occurred at doses below those that produced motor impairment as assessed in the inverted screen test. Protection against the convulsant effects of the selective dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy] ethyl]-4-[3-phenyl-propyl]piperazine (GBR 12909) was also conferred by (+)-PD 128,907. The possible selectivity of the effects of (+)-PD 128,907 (3 mg/kg) for these dopaminergic compounds was demonstrated by its general lack of protective efficacy against a host of convulsants acting through other neural mechanisms [pentylenetetrazol, (+)-bicuculline, and picrotoxin, 4-aminopyridine, and t-butylbiclyclophosphoorothionate, N-methyl-d-aspartate, kainate, pilocarpine, nicotine, strychnine, aminophylline, threshold electric shock, and 6-Hz electrical stimulation]. Direct and correlational evidence suggests that these effects were mediated by D(3) receptors. Protection was stereospecific and reversible by an antagonist of D(3) receptors [3-[4[1-(4-[2[4-(3-diethyamino-propoxy)-phenyl]-benzoimidazol-l-yl]-butyl)-1H-benzoimidazol-2-yl]-phenoxy]-propyl)-diethyl-amine; PD 58491] but not D(2) receptors [3[[4-(4-chlorophenyl)-4 hydroxypipeidin-1-yl]methyl-1H-indole; L-741,626]. Anticonvulsant potencies were positively associated with potencies in a functional assay of D(3) but not D(2) receptor function. Together, these findings suggest that the prevention of cocaine convulsions and lethality by (+)-PD 128,907 may be due to D(3) receptor-mediated events.

Postinfarction ventricular septal defect closure with Amplatzer occluders.

OBJECTIVE: Postinfarction ventricular septal defect (PIVSD) is a rare and life-threatening complication with high risk of both surgical and medical treatment. Another option available now is transcatheter closure. The purpose of this paper is to report the results of such treatment with Amplatzer occluders. METHOD: Seven patients aged from 51 to 71 years were included. The procedure was performed between 2 and 10 weeks after myocardial infarction. One patient had double residual VSD (2 months after previous surgery) and another, coexisting critical stenosis of right coronary artery (RCA). All patients were in III/IV NYHA class, on intropes, one patient on aortic balloon counterpulsation. Venous jugular approach was used to close the VSD in six patients, venous transfemoral in one patient. Implantation of six Ampaltzer atrial septal occluders (ASO) and one muscular Amplatzer VSD occluder (VSO) were performed. RESULTS: All procedures but two were finished successfully. In one patient, the defect could not be entered neither from the venous nor the arterial side due to unusual oblique course (which was confirmed during subsequent operation). In the second patient (2 weeks after MI), the reason was unstable position of 24 mm ASO (probably due to necrotic borders of VSD). Immediate significant clinical improvement was achieved in all patients, in whom PIVSD was closed with Amplatzer occluders. In one postsurgical patient, two ASO were used; in another patient, prior to VSD closure, PTCA and stent implantation to RCA was performed. The stretched diameter of PIVSD ranged from 8 to 22 mm, the size of implanted Amplatzer occluders from 12 to 24 mm. Fluoroscopy time was 60 min (18-120). During the procedure, ventricular fibrillation requiring defibrillation was observed in three patients. One patient died 1 week after the procedure because of multiorgan failure and increasing mitral incompetence (MI). CONCLUSIONS: Despite some technical problems, implantation of Amplatzer occluders, is an attractive option of treatment of patients with subacute PIVSD.

Inflammatory components in endarterectomy lesions: an immunohistological study.

The aim of this study was to characterize the immunohistological components of chronic inflammation in endarterectomy lesions. Therefore, in 24 patients endarterectomy specimens were obtained from coronary arteries during CABG surgery (16 from RCA and 8 from LCA) and immunohistologically analyzed using avidin-biotin method (LSAB(R)/AP) with monoclonal antibodies. Macrophages and CD3 lymphocytes were counted under 200x magnification but MHC class II and ICAM-1 adhesion molecules were analyzed semi-quantitatively (scale from 0 to 3+). The mean macrophages density was 47.8+/-9.8 cells per mm2 and mean CD3 lymphocyte density was 1.3+/-0.6 cells per mm2. Lack or weak expression of HLA-DR (0-1+) on macrophages was found in 17 of 24 cases (70.8%). In the remaining seven cases (29.2%) there was a moderate and strong expression (2+ and 3+) of HLA-DR antigens. Similarly, no or weak ICAM-1 expression on macrophages was detected in 19 cases (79.2%). These cells were positively stained for ICAM-1 in only five cases (20.8%). Our data suggest that in advanced primary atherosclerotic lesions chronic inflammation is still present. On the other hand, the small number of activated inflammatory cells and the absence of positively stained endothelium suggests that inflammatory process tends to be burnt-out.

[ST-segment shift in V1-V3 in patients with inferior wall infarction depend on angiographic localization of right artery occlusion]. / Zmiana polozenia odcinka ST elektrokardiogramu w odprowadzeniach V1 do V3 u chorych z zawalem sciany dolnej w zaleznosci od angiograficznej lokalizacji zamkniecia prawej tetnicy wiencowej.

Two electrocardiographic types of inferior wall infarct were isolated based on angiographic localization of right coronary artery occlusion. In proximal occlusion of RCA before right ventricular branch there is no depression or more rarely elevation of ST segment in V1-V3 especially in V1 (the first morphological type). ST segment depression in V1-V3 (second morphological type) is characteristic for distal segment of RCA occlusion.

Changes in the ambulatory activity and discriminative stimulus effects of psychostimulant drugs in rats chronically exposed to caffeine: effect of caffeine dose.

Caffeine is a common psychoactive constituent of coffee, carbonated beverages, and over-the-counter medications. This study examined the effects of chronic caffeine exposure on the behavioral response to acute administrations of psychostimulant drugs on ambulatory activity and on the pharmacological characteristics of nicotine discrimination in rats. Rats were maintained continuously on caffeine added to the drinking water at a concentration of 0.25 or 1. 0 mg/ml that resulted in plasma caffeine concentrations ranging from 0.37 to 5.95 microg/ml. Rats maintained on tap water served as control groups. Exposure to the lower caffeine concentration (0.25 mg/ml) potentiated stimulatory effects of nicotine, amphetamine, and cocaine on ambulatory activity and failed to produce tolerance to the acute stimulatory effects of caffeine. In contrast, exposure to the higher caffeine concentration (1.0 mg/ml) did not alter the effects of the psychomotor stimulants on ambulatory behaviors but resulted in the development of complete, insurmountable tolerance to the acute stimulatory effects of caffeine. In the nicotine discrimination paradigm (0.4 mg/kg, training dose, a fixed-ratio 10 schedule of food delivery in a two-lever choice paradigm), rats exposed to the lower, but not to the higher, caffeine concentration acquired the nicotine discrimination significantly faster and were more sensitive to the effects of amphetamine and cocaine in substitution tests than water-drinking rats. Caffeine exposure did not change pharmacokinetic properties of nicotine (i.e., plasma levels, metabolism). In summary, exposure to two different caffeine solutions within a range of plasma levels observed in humans resulted in quantitatively distinct changes in psychostimulant-induced nonoperant and operant measures of behavior. These results suggest that dietary consumption of moderate doses of caffeine may be associated with enhanced reactions to some psychostimulants.

Chlormethiazole: effectiveness against toxic effects of cocaine in mice.

Chlormethiazole positively modulates the gamma-aminobutyric acid (GABA)(A) receptor complex and is primarily used to treat certain life-threatening neurological events (e.g., refractory seizures and ethanol withdrawal syndrome). On account of several experimental and clinical studies reporting effectiveness against the toxic effects of heroin and methamphetamine, chlormethiazole was systematically tested in the present study for its effectiveness against cocaine-induced seizures and lethality in mice. The protective effects of chlormethiazole were evaluated against single, submaximal convulsive (75 mg/kg) or lethal (110 mg/kg) doses of cocaine. Chlormethiazole also was tested against the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures, and against fully developed kindled seizures. Cocaine-kindled seizures were produced by a total of five daily treatments with 60 mg/kg cocaine. The inverted-screen test was used to assess behavioral side effects of chlormethiazole. Chlormethiazole protected against acute cocaine-induced convulsions (ED(50) = 7.0 mg/kg) and lethality (ED(50)= 21.8 mg/kg) with a robust separation [protective index (PI) = TD(50)/ED(50) = 22.3 and 7.2, respectively] from doses producing behavioral side effects (TD(50) = 156 mg/kg). Chlormethiazole suppressed the behavioral expression of cocaine-kindled seizures and prevented the development of sensitization to the convulsant effects of cocaine. It was also effective in suppressing fully developed kindled seizures. Relative to cocaine seizures in naive mice, chlormethiazole was equieffective, less potent (ED(50) = 22.3 mg/kg), and had a reduced protective index (PI = 3.7) against cocaine-induced seizures in kindled mice. The protective profile and protective index of chlormethiazole were superior to those of the benzodiazepines clonazepam and diazepam, which were of limited efficacy and had low protective indices (PI = approximately 1). The results of this study predict the potential utility of chlormethiazole for the treatment of life-threatening complications of cocaine abuse for which no specific treatment has yet been identified.

Low propensity of conventional antiepileptic drugs for interaction with felbamate against maximal electroshock-induced seizures in mice.

The objective of this study was to evaluate an interaction of the novel antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with conventional antiepileptic drugs against maximal electroshock-induced convulsions in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of antiepileptic drugs were measured by immunofluorescence. Felbamate (7.5-30 mg/kg) significantly increased the electroconvulsive threshold. Felbamate at the subprotective dose of 5 mg/kg did not affect the anticonvulsive action of antiepileptics studied. On the other hand, this drug used at the lowest protective dose of 7.5mg/kg remained without effect upon the activity of valproate, carbamazepine or phenobarbital, but significantly potentiated the protective potential of diphenylhydantoin. No adverse effects were observed with combinations of felbamate with these antiepileptics. Neither brain nor free plasma levels of antiepileptic drugs were changed by felbamate. The results indicate that the combination of felbamate with conventional antiepileptic drugs is not promising from the experimental point of view.