Structural Factors Contributing to Compassion Fatigue, Burnout, and Secondary Traumatic Stress Among Hospital-Based Healthcare Professionals During the COVID-19 Pandemic.

High levels of burnout among healthcare providers (HCPs) have been a widely documented phenomenon, which have been exacerbated during the COVID-19 pandemic. In the United States, qualitative studies that are inclusive of HCPs in diverse professional roles have been limited. Therefore, we utilized a qualitative-quantitative design to examine professional quality of life in terms of compassion fatigue, burnout, and secondary traumatic stress among hospital-based HCPs, including social workers, hospitalists, residents, and palliative care team members during COVID-19. HCPs (n = 26) participated in virtual semi-structured focus groups or individual interviews and online surveys (n = 30) including the Professional Quality of Life (ProQOL) Scale. While ProQOL scores indicated low levels of compassion fatigue, burnout, and secondary traumatic stress, thematic analysis of our qualitative data included rich descriptions of compassion fatigue, burnout, and secondary traumatic stress. Safety concerns and value misalignment characterized structural stressors perceived to contribute to HCP compassion fatigue, burnout, and secondary traumatic stress. The discrepancy between our qualitative and quantitative findings may be indication that modifications to current screenings are warranted. These findings also suggest a need to identify and implement structural and policy changes that increase HCPs' physical and emotional safety and promote better alignment of institutional interests with HCP values.

Community engagement as a foundation for improving neighborhood health.

OBJECTIVE: Health inequities and disparities are associated with non-White race/ethnicity, immigrant status, income, and geographic location. Community engagement is essential to identify health and social needs and to plan health care and social services programs. To begin a larger community-based participatory study, the purpose of this study was to explore community residents' perceptions of barriers and facilitators to achieving and maintaining health. DESIGN, SAMPLE, AND MEASUREMENTS: This qualitative descriptive study used focus group interviews. We recruited a convenience sample (n = 50) from community meetings and gathering for five audio-recorded focus groups that used a semi-structured interview guide. Transcripts were coded to identify common topics in each group and major themes across groups. RESULTS: Participants were predominantly women (58%), Hispanic/Latinx, and Spanish-speaking (57%), who rented their homes (69%). Two main themes emerged: (a) social determinants as barriers to health and (b) need for trust to participate in health programs. CONCLUSIONS: Although health care providers are frequently concerned about providing access to care, community members identified a variety of social determinants that affected their health. Listening and responding to community members' priorities are the foundation to improving health in neighborhoods directly affected by inequities.

Schizophrenia-spectrum patients treated with long-acting injectable risperidone in real-life clinical settings: functional recovery in remitted versus stable, non-remitted patients (the EVeREST prospective observational cohort study).

BACKGROUND: Previous studies showed functional improvement in stable patients with schizophrenia treated with risperidone long-acting injection (LAI). We therefore re-investigated functional improvement with risperidone LAI in remitted patients, in comparison with stable patients. The study was conducted in real-life conditions because of the high heterogeneity of the patients' situations. METHOD: This was a multi-centre, prospective observational cohort study involving adult schizophrenia-spectrum chronic patients who were previously treated with risperidone LAI for 6 months. Remission was evaluated using the consensus criteria proposed by the Remission in Schizophrenia Working Group (RSWG). The primary endpoint was global functioning (assessed with the Global Assessment of Functioning scale, GAF) after one year of treatment. Social functioning was a secondary outcome. RESULTS: The analysis included 1490 patients. Attrition rate was 9.1 % at the end of the study. 27.7 % of patients were in remission after one year of risperidone LAI treatment. The mean GAF rating score (62.5 ± 1.5) was higher than the cut-off previously used to identify patients with satisfactory functioning (60) and significantly higher than the mean GAF score in stable, non-remitted patients (48.3, p < 0.001). Social functioning was also high in remitted patients (21.0 ± 3.6 vs. 17.2 ± 3.7 in non-remitted patients, p < 0.001). CONCLUSION: The results clearly show that after one year of treatment with risperidone LAI, RSWG-remitted patients have a high level of global functioning, which is significantly higher than in stable, non-remitted patients. Social functioning was also higher in remitted patients as compared with stable, non-remitted patients.

A Comprehensive Review of Silver and Gold Nanoparticles as Effective Antibacterial Agents.

The increasing threat from antibiotic-resistant bacteria has necessitated the development of novel methods to counter bacterial infections. In this context, the application of metallic nanoparticles (NPs), especially gold (Au) and silver (Ag), has emerged as a promising strategy due to their remarkable antibacterial properties. This review examines research published between 2006 and 2023, focusing on leading journals in nanotechnology, materials science, and biomedical research. The primary applications explored are the efficacy of Ag and Au NPs as antibacterial agents, their synthesis methods, morphological properties, and mechanisms of action. An extensive review of the literature on NPs synthesis, morphology, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and effectiveness against various Gram(+/-) bacteria confirms the antibacterial efficacy of Au and Ag NPs. The synthesis methods and characteristics of NPs, such as size, shape, and surface charge, are crucial in determining their antibacterial activity, as these factors influence their interactions with bacterial cells. Furthermore, this review underscores the urgent necessity of standardizing synthesis techniques, MICs, and reporting protocols to enhance the comparability and reproducibility of future studies. Standardization is essential for ensuring the reliability of research findings and accelerating the clinical application of NP-based antimicrobial approaches. This review aims to propel NP-based antimicrobial strategies by elucidating the properties that enhance the antibacterial activity of Ag and Au NPs. By highlighting their inhibitory effects against various bacterial strains and relatively low cytotoxicity, this work positions Ag and Au NPs as promising materials for developing antibacterial agents, making a significant contribution to global efforts to combat antibiotic-resistant pathogens.

Recent clinical trials with stem cells to slow or reverse normal aging processes.

Aging is associated with a decline in the regenerative potential of stem cells. In recent years, several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions). Information concerning those clinical trials was extracted from national and international databases (United States, EU, China, Japan, and World Health Organization). Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging. With regard to physical frailty, positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation), and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed. With regard to facial skin aging, positive results have been obtained with an autologous preparation of adipose-derived stem cells. A further sixteen clinical trials for physical frailty and facial skin aging are currently underway. Reducing physical frailty with intravenous mesenchymal stem cell administration can increase healthy life expectancy and decrease costs to the public health system. However, intravenous administration runs the risk of entrapment of the stem cells in the lungs (and could raise safety concerns). In addition to aesthetic purposes, clinical research on facial skin aging allows direct evaluation of tissue regeneration using sophisticated and precise methods. Therefore, research on both conditions is complementary, which facilitates a global vision.

Expansion of the Community Engagement Studio Method: Deepening Community Participation in Health Care Innovation.

BACKGROUND: The Community Engagement Studio (CE Studio) method has emerged as a valuable model for community participation in health innovation research, and we advance the model by expanding the timing and number of CE Studio sessions, as well as facilitation. OBJECTIVES: The authors expanded the CE Studio method first to include five sessions corresponding to five phases of innovation: a) health experiences, b) community readiness,c) design features, d) adoption, and e) sustainability. Community experts were engaged throughout the duration of the research. Second, the authors positioned the CE Studio Team to be deeply embedded within the research team and the community of interest through community health workers. METHODS: The expanded CE Studio method was incorporated into a federally funded research project focused on a health technology platform. The CE Studio Team held five sessions with each of four community expert panels (total of 20 sessions) based on race/ethnicity and language: African American, Asian American, English-speaking Latinx, and Spanishspeaking Latinx. CONCLUSIONS: CE Studio sessions revealed community experts' shared and unique evolving and deepening perspectives that show promise for expanding the model.

Fifty years of experience with loxapine for the rapid non-coercive tranquilization of acute behavioral disturbances in schizophrenia patients, and beyond.

INTRODUCTION: Acute behavioral disturbances in psychosis, including agitation, comprise a heterogeneous group of manifestations varying in intensity and duration they last for. They require rapid, non-coercive treatments ranging from verbal de-escalation to the calming effect of pharmacological agents. The treatment goals are reduction of patient suffering and prevention of disease deterioration. Stabilizing rather than sedating is preferred to ensure improved compliance and a stronger therapeutic alliance. Furthermore, animal pharmacology and clinical studies on agitation reveal the robust calming and anxiolytic properties of loxapine. AREAS COVERED: This review covers the pharmacological and clinical history of loxapine along with research developments. It emphasizes the advantages of its multiple formulations ranging from injectable forms and tablets to orally inhaled forms to attain rapid and fine-tuned tranquilization. EXPERT OPINION: Rapid tranquillization is achieved within 2-6 hours using liquid orally-consumed loxapine, and within an hour or less with its IM or orally inhaled forms. Loxapine has been adopted in the management of a wide range of acute disturbances, such as agitation in psychosis. In the context of personalized medicine, key cellular and molecular elements of the schizophrenia phenotype were recently shown to be improved with loxapine.

Interprofessional collaboration between social workers and community health workers to address health and mental health in the United States: A systematised review.

Collaboration between social workers (SW) and community health workers (CHW) plays an essential role in addressing health inequities in the United States (US). However, little is known about the current state of CHW/SW collaboration. The objectives of this review were to identify (a) the nature, goals and setting of CHWs and SW collaboration; (b) the patient outcomes utilised to measure intervention efficacy. The literature search was conducted in December 2020 using six databases. The inclusion criteria were (1) interventions that included CHWs and SWs; (2) US-based; (3) published between 2000-2020; (4) peer-reviewed journal articles; (5) examining health or mental health outcomes. Search results identified 281 articles, and 15 were included in the final analysis. Settings that utilised SW/CHW collaboration included outpatient clinics (n = 10); community organisations (n = 4) or hospital (n = 1). CHW and SW interventions focused on disease prevention (n = 8), chronic care (n = 4) and mental health (n = 3). Health outcomes were the most evaluated (n = 13), and significant improvement of at least one health outcome was reported in those studies. Mental health outcomes (n = 3) were also significantly improved, while social determinants of health (n = 2) were least common and descriptive only. This is the first review of SW and CHW collaboration. Clarity regarding SW and CHW roles and scopes of practice are needed to understand better SW/CHW collaboration and its impacts on community health outcomes and improve the process of collaboration. SW and CHW collaboration may increase clients' access to preventive care, mental health and address health inequities.

Impact of an educational program on the management of bipolar disorder in primary care.

OBJECTIVE: Government agencies and industry have recently undertaken educational programs for the management of bipolar disorder in primary care, but their medical impact is not well known. Therefore, we conducted a survey among general practitioners to evaluate the impact of the Bipolact Educational Program on the diagnosis and treatment of bipolar disorder. METHODS: A total of 45 general practitioners attending the Bipolact Educational Program (trained group) were compared with a control group of 50 untrained general practitioners on their ability to: (i) diagnose bipolar I and II disorders and (ii) treat bipolar disorder patients appropriately. RESULTS: Trained physicians, but not untrained physicians, showed a significant improvement (p < 0.0001, chi-square test) in the ability to identify patients as having bipolar I (from 10.4% to 28.8%) and bipolar II disorder (from 20.1% to 45.8%). This trend resulted in a strong decrease in nonidentified bipolar disorder patients (from 64.6% to 19.5%). Trained physicians, but not the untrained group, greatly increased the number of prescriptions for mood stabilizers for bipolar disorder patients, from 25.6% to 43.2% (p = 0.0013, chi-square test). Finally, trained physicians reduced the number of antidepressant prescriptions for bipolar disorder patients (the control group also reduced the number of antidepressant prescriptions, suggesting some bias in the survey). CONCLUSION: A well-designed education package on diagnosis and management of bipolar disorder greatly increased the likelihood of physicians correctly assigning a subtype, namely bipolar I or bipolar II disorder, to patients already perceived as having some form of bipolar illness, and to prescribing mood stabilizers instead of antidepressants to these patients.

Investigational drugs and nutrients for human longevity. Recent clinical trials registered in ClinicalTrials.gov and clinicaltrialsregister.eu.

Introduction:Several pharmacological drugs have shown proof of concept for longevity in animal models. I aimed to identify and review those longevity drug candidates that are undergoing clinical trials.Areas covered:Recent (post-2017) longevity clinical trials were found in US and EU clinical trial registries. Longevity drug candidates are the antidiabetic drugs metformin and acarbose, and the immunosuppressant rapamycin. These medicinal drugs are tested on biochemical and clinical markers of aging. In addition, vitamin D supplementation is being investigated in two mega-trials (sample size> 5000) for its efficacy in reducing all-cause mortality.Expert opinion:Anti-aging effects of longevity drug candidates suggest, but do not demonstrate that they prolong life. The two megatrials with vitamin D supplementation make it possible to detect differences in life expectancy between vitamin D and placebo. Therefore, a protocol similar to that for vitamin D could be used to demonstrate pro-longevity effects of metformin, acarbose, and rapamycin.

Dosing antipsychotics in special populations of patients with schizophrenia: severe psychotic agitation, first psychotic episode and elderly patients.

Antipsychotic (AP) dosing is well established in nonelderly patients with acute exacerbations of schizophrenia, but not in special populations.This review describes the AP dosing procedures that have been used in clinical studies for acute psychotic agitation, a first episode of psychosis (FEP), and elderly patients. AP dosing data was extracted from the databases of drug regulatory authorities, and from clinical studies available in the medical literature. In acute psychotic agitation, intramuscular and oral APs are frequently prescribed in higher doses than those that saturate D2 receptors. Supersaturating doses of APs should be avoided due to an increased risk of adverse effects. In FEP, many studies showed efficacy of low doses of APs. Studies with risperidone and haloperidol suggested a dose reduction of approximately one third. Titration with a lower starting dose is recommended in elderly patients, due to possible decreases in pharmacokinetic clearance, and due to the risk of concomitant diseases and drug interactions. Exposure to some APs has been associated with QTc prolongation and arrhythmias, and a small but significant increase in the risk of stroke and mortality with APs has been seen, particularly in older people with dementia-related psychosis.

Leptin and insulin in young adulthood are associated with weight in infancy.

Low weight in early infancy is a known risk factor for cardio-metabolic syndrome in adult life. However, little is known either about developmental programming in subjects of normal birthweight or about events between the ages which separate early programming and the occurrence of disease at late adulthood. We tested the hypothesis that circulating concentrations of leptin, adiponectin and insulin in young, healthy adults, born with a birth size within the normal range, are influenced by early life growth patterns. In an observational study of 188 healthy volunteers aged 18-25 years (97 males, 91 females) we investigated the association of metabolic function with their birth size, their growth during childhood and their body composition. High plasma leptin in early adulthood, a risk factor for cardio-metabolic syndrome, was associated with low weight at age 2 years (correlation coefficient controlled for adult weight = -0.21, P < 0.01). It was also positively associated with pre-prandial insulin and with HOMA (Homeostasis Model Assessment) insulin resistance. Leptin, leptin-adiponectin ratio and insulin correlated with lean mass, fat mass and percent fat (P < 0.0001). In conclusion, high leptin in early adulthood was associated with both low weight at age 2 years and insulin resistance. We speculate that high leptin is developmentally programmed and can contribute to the association between low weight in early infancy and increased cardio-metabolic risk in adulthood in healthy subjects.

Endothelium-independent vasorelaxation by the selective alpha estrogen receptor agonist propyl pyrazole triol in rat aortic smooth muscle.

OBJECTIVES: This study investigated the signalling mechanism of the relaxant responses to the estrogen receptor (ERalpha) agonist PPT (propyl pyrazole triol) in endothelium-denuded rat aortic rings. METHODS: Several compounds, including protein kinase G (PKG) inhibitors and potassium channel inhibitors, were tested against PPT-dependent rat aortic relaxation. Cyclic GMP and cytosolic calcium responses to PPT in isolated aortic smooth muscle were investigated in parallel. KEY FINDINGS: PPT vasorelaxation was largely reduced by the selective ERalpha antagonist methyl-piperidinopyrazole (MPP; -91.6+/-2.5%), by the selective PKG inhibitor Rp-8-Br-cGMP (-78.6+/-4.9%), by the specific soluble guanylyl cyclase inhibitor ODQ (1H-(1,2,4)-oxadiazolo[4,3-a]quinoxalin-1-one; -85.3+/-5.2%) and to a lesser extent by the selective BKCa (large-conductance calcium- and voltage-activated potassium channel) inhibitor iberiotoxin (-59.3%), the selective IKCa (intermediate-conductance calcium-activated potassium channel) inhibitor TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole; -50.7%) and the voltage-gated potassium channel inhibitor 4-aminopyridine (-40.8%). In isolated aortic smooth muscle, PPT strongly enhanced the cyclic GMP content (+144%) and Rp-8-Br-cGMP largely reduced the PPT-dependent calcium signal (-80.8%). CONCLUSIONS: ERalpha receptor stimulation in rat aortic smooth muscle evokes a PKG-signalling pathway, likely triggering relaxation by BKCa and IKCa channel opening.

Pharmacotherapeutic approaches to treating depression during the perimenopause.

Introduction: Although postnatal depression is now well recognized, there is also a risk of depressive symptoms during perimenopause. The mechanisms underlying perimenopausal depression are still poorly understood; however, there are available treatment options. Areas covered: This review describes: the current pharmacotherapeutic approaches for perimenopausal depression, their strengths and weakness, and provides recommendations on how current treatment can be improved in the future. An electronic search identified specific guidelines for the treatment of perimenopausal depression released in 2018, as well as recent clinical studies on the subject. Expert opinion: The 2018 guidelines recommend selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) as front-line medications for perimenopausal depression, but SSRIs and SNRIs are not always effective. The efficacy of estrogen in perimenopausal depression is well documented, but estrogen is not FDA-approved to treat mood disturbances in perimenopausal women. Clinical practice guidelines currently recommend to restrict hormone therapy to the symptomatic treatment of menopause (not for the prevention of chronic diseases). Research with new estrogenic compounds is under way to improve their benefit/risk ratio in perimenopausal depression.

Affinity of cyamemazine metabolites for serotonin, histamine and dopamine receptor subtypes.

Animal and human pharmacological studies indicate that the antipsychotic action of cyamemazine results from blockade of dopamine D(2) receptors, its anxiolytic properties from serotonin 5-HT(2C) receptor antagonism and the low incidence of extrapyramidal side effects from a potent 5-HT(2A) receptor antagonistic action. Cyamemazine is metabolized in monodesmethyl cyamemazine and cyamemazine sulfoxide, which are not known for their affinities for serotonin, dopamine and other brain receptor types considered to mediate central nervous systems effects of drugs. Hence, metabolite affinities were determined in human recombinant receptors expressed in CHO cells (hD(2) and hD4.4 receptors, h5-HT(1A), h5-HT(2A), h5-HT(2C) and h5-HT(7) receptors and hM(1), hM(2) and hM(3) receptors) and HEK-293 cells (h5-HT(3) receptors) or natively present in rat cerebral cortex (non-specific alpha(1)- and alpha(2)-adrenoceptors, GABA(A) and GABA(B) receptors) and guinea pig cerebellum (H(1) central histamine receptors) membranes. Monodesmethyl cyamemazine showed a neurotransmitter receptor profile similar to that of its parent compound cyamemazine, i.e.: high affinity for h5-HT(2A) receptors (K(i)=1.5 nM), h5-HT(2C) receptors (K(i)=12 nM) and hD(2) receptors (K(i)=12 nM). Cyamemazine sulfoxide showed high affinity for h5-HT(2A) receptors (K(i)=39 nM) and histamine H(1) receptors (K(i)=15 nM) and a reduced affinity for D(2) and 5-HT(2C) receptors. Therefore, monodesmethyl cyamemazine can contribute to enhance and prolong the therapeutic actions of cyamemazine. Further investigation is required to see if the high affinities of cyamemazine sulfoxide for H(1) and 5-HT(2A) receptors are of therapeutic benefit against sleep onset insomnia and/or sleep maintenance insomnia respectively.

Cyamemazine metabolites: effects on human cardiac ion channels in-vitro and on the QTc interval in guinea pigs.

Monodesmethyl cyamemazine and cyamemazine sulfoxide, the two main metabolites of the antipsychotic and anxiolytic phenothiazine cyamemazine, were investigated for their effects on the human ether-à-go-go related gene (hERG) channel expressed in HEK 293 cells and on native I(Na), I(Ca), I(to), I(sus) or I(K1) of human atrial myocytes. Additionally, cyamemazine metabolites were compared with terfenadine for their effects on the QT interval in anaesthetized guinea pigs. Monodesmethyl cyamemazine and cyamemazine sulfoxide reduced hERG current amplitude, with IC50 values of 0.70 and 1.53 microM, respectively. By contrast, at a concentration of 1 microM, cyamemazine metabolites failed to significantly affect I(Na), I(to), I(sus) or I(K1) current amplitudes. Cyamemazine sulfoxide had no effect on I(Ca) at 1 microM, while at this concentration, monodesmethyl cyamemazine only slightly (17%), albeit significantly, inhibited I(Ca) current. Finally, cyamemazine metabolites (5 mg kg(-1) i v.) were unable to significantly prolong QTc values in the guinea pig. Conversely, terfenadine (5 mg kg(-1) i.v.) significantly increased QTc values. In conclusion, cyamemazine metabolite concentrations required to inhibit hERG current substantially exceed those necessary to achieve therapeutic activity of the parent compound in humans. Moreover, cyamemazine metabolites, in contrast to terfenadine, do not delay cardiac repolarization in the anaesthetized guinea pig. These non-clinical findings explain the excellent cardiac safety records of cyamemazine during its 30 years of extensive therapeutic use.

Two-year study of relapse prevention by a new education program in schizophrenic patients treated with the same antipsychotic drug.

It is not clear whether patient's psycho-education enhances compliance to antipsychotic treatments and reduces the number of relapses. Here we investigated the impact of a new psycho-educational program (SOLEDUC) on the one- and two-years rate of relapse (primary outcome measure) and a number of clinical assessments (secondary outcome measures). This was a multicentric French clinical trial (51 centers) of Phase IV, open, controlled, randomized, consisting in two parallel groups: the Soleduc group (N=111) and the control group (N=109). All subjects received a variable dose over the 2-year period of the same antipsychotic drug (amisulpride). Soleduc consisted of a 7-session program (1h per session), presented three times (at baseline, 6-months and 12-months). Patients in the control group received a non-specific psychosocial training for an equivalent period of time. The models of Andersen-Gill (AG) and Prentice, Williams and Peterson (PWP) were used to analyze relapses. Patients in the Soleduc group attended 14.8+/-6.1 sessions (mean+/-SD), including 17 patients who never attended a session. Intent to treat analysis showed less patients relapsing in the Soleduc group as compared to the control group (21.6% versus 28.4% after 1 year and 84.4% versus 90.8% after 2years), but the differences were not statistically significant. Relapse risk was significantly reduced for patients who followed at least 7 modules (p=0.015 AG-test; p<0.001 PWP-test). In conclusion, no significant differences in relapse rates were found between patients attending the Soleduc program and the control group. Attendance of at least 7 out of 21 program sessions was required to see a modest, but significant two-year relapse prevention in schizophrenia. Other well designed studies are required to evaluate the medical impact of patient's education programs.

Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help.

Liver or lung metastases usually relapse under chemotherapy. Such life-threatening condition urgently needs new, systemic anticancer compounds, with original and efficient mechanisms of action. In B16 melanoma mice treated with cyclophosphamide, D'Agostini et al. [D'Agostini, C., Pica, F., Febbraro, G., Grelli, S., Chiavaroli, C., Garaci, E., 2005. Antitumour effect of OM-174 and Cyclophosphamide on murine B16 melanoma in different experimental conditions. Int. Immunopharmacol. 5, 1205-1212.] recently found that OM-174, a chemically defined Toll-like receptor(TLR)2/4 agonist, reduces tumor progression and prolongs survival. Here we review 149 articles concerning molecular mechanisms of TLR2/4 agonists, alone or in combination with chemotherapy. It appears that TLR2/4 agonists induce a well controlled tumor necrosis factor-alpha (TNF-alpha) secretion, at plasma levels known to permeabilize neoangiogenic tumor vessels to the passage of cytotoxic drugs. Moreover, TLR2/4 agonists induce inducible nitric oxide synthase (iNOS) expression, and nitric oxide is able to induce apoptosis of chemotherapy-resistant tumor cell clones. Finally, TLR2/4-stimulation activates dendritic cell traffic and its associated tumor-specific, cytotoxic T-cell responses. Therefore, parenteral TLR2/4 agonists seem promising molecules to prolong survival in cancer patients who relapse under chemotherapy.

Characterization of human cytochrome P450 enzymes involved in the metabolism of cyamemazine.

Recombinant human liver microsomal enzymes of the cytochrome P450 family (CYP1A2, CYP2A6, CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1) were used to determine the metabolic fate of the antipsychotic anxiolytic agent cyamemazine. An LC/MS-MS tandem methodology was developed specifically for identifying the presence of cyamemazine and its metabolites in reaction media. All P450 enzymes investigated, with the exception of CYP2A6 and CYP2E1, degraded cyamemazine, albeit to a different extent, with CYP1A2, CYP2C8 and CYP2C19 being the most efficient (>80%). However, in microsomes prepared from native human hepatocytes, only relatively specific competitors (inhibitors and/or substrates) of CYP1A2, CYP2C8, CYP2C9 and CYP3A4 reduced notably the degradation cyamemazine. The main routes of cyamemazine biotransformation are N-mono-demethylation (CYP1A2, CYP3A4 and CYP2C8) and mono-oxidation (either S-oxidized or hydroxylated derivatives which could not be discriminated because characterized by the same mass value) by CYP1A2 and CYP2C9. Secondary metabolic routes yields N,N-di-demethylated and N-demethylated mono-oxidized products. Thus, under in vitro conditions, cyamemazine is extensively degraded by at least four distinct P450 enzymes, into two primary hydrophilic metabolites. These results suggest that cyamemazine detoxification process is unlikely to be significantly impaired by co-administration of therapeutic agents that are substrates of the CYP metabolic system.

What can we learn from erythrocyte Na-K-Cl cotransporter NKCC1 in human hypertension?

Fluxes catalyzed by the human Na-K-Cl cotransporter NKCC1 (hNKCC1) were extensively investigated in erythrocytes from essential hypertensive patients. Using different techniques, four hNKCC1 abnormalities were described in a significant proportion of hypertensives: (i) low net sodium extrusion, (ii) high unidirectional inward cotransport, (iii) low apparent affinity for internal sodium and (iv) high maximal cotransport rate. All these four hNKCC1 abnormalities are compatible with an increased net inward cotransport. In hypertensive rat models, an increased net inward cotransport drives more chloride inside the cells, favoring membrane depolarization and hypertension. NKCC1 knock out mice are hypotensive and exhibit a compensatory elevation in renin secretion, apparently due to the lack of a functional NKCC1 in juxtaglomerular granular cells, which normally reduces basal renin release. This latter hypothesis is supported by the observation that human hypertensives with high cotransport have low renin hypertension and increased salidiuretic response to furosemide. Therefore, the human erythrocyte data validates animal studies showing increased net inward fluxes by NKCC1 in primary hypertension.