Inflammatory Biomarker and Response to Antidepressant in Major Depressive Disorder: a Systematic Review and Meta-Analysis.

Inadequate response to antidepressant treatment, in a significant proportion of patients diagnosed with Major Depressive Disorder, contributes to the large burden of disability associated with the disease; thus, predicting treatment response is one of the most important challenge for clinicians who deal with depressed patients. The cytokine hypothesis of depression suggests that altered pheripheral cytokine levels are involved in the pathophysiology of depressive disorder and in modulating response to treatment. Present meta-analysis aimed to investigate the association between cytokine levels at baseline and response to antidepressant therapies. Authors performed a systematic search of PubMed and Embase databases for studies published between 2010 and January 2021: of 3345 identified records, 31 studies met the inclusion criteria for the qualitative synthesis, whereas 19 studies were eligible for quantitative analysis. Patients who failed to respond to antidepressant had aberrant inflammatory process, namely higher baseline levels of C-Reactive Protein and Interleukine-8, which is associated with treatment outcome in Major Depressive Disorder. Despite these promising results, further investigations are needed in order to replicate the data and to examine the potential role of inflammatory marker as a novel predictive tool for pharmacological treatment of depressive disorder.

Non-pharmacological interventions for reducing aggression and violence in serious mental illness: A systematic review and narrative synthesis.

BACKGROUND: For people with mental illness that are violent, a range of interventions have been adopted with the aim of reducing violence outcomes. Many of these interventions have been borrowed from other (offender) populations and their evidence base in a Serious Mental Illness (SMI) population is uncertain. AIMS: To aggregate the evidence base for non-pharmacological interventions in reducing violence amongst adults with SMI and PD (Personality Disorder), and to assess the efficacy of these interventions. We chose to focus on distinct interventions rather than on holistic service models where any element responsible for therapeutic change would be difficult to isolate. METHODS: We performed a systematic review and narrative synthesis of non-pharmacological interventions intended to reduce violence in a SMI population and in patients with a primary diagnosis of PD. Five online databases were searched alongside a manual search of seven relevant journals, and expert opinion was sourced. Eligibility of all returned articles was independently assessed by two authors, and quality of studies was appraised via the Cochrane Collaboration Tool for Assessing Risk of Bias. RESULTS: We included 23 studies of diverse psychological and practical interventions, with a range of experimental and quasi-experimental study designs that included 7 Randomised Controlled Trials (RCTs). The majority were studies of Mentally Disordered Offenders. The stronger evidence existed for patients with a SMI diagnosis receiving Cognitive Behavioural Therapy or modified Reasoning & Rehabilitation (R&R). For patients with a primary diagnosis of PD, a modified version of R&R appeared tolerable and Enhanced Thinking Skills showed some promise in improving attitudes over the short-term, but studies of Dialectical Behaviour Therapy in this population were compromised by high risk of experimental bias. Little evidence could be found for non-pharmacological, non-psychological interventions. CONCLUSIONS: The evidence for non-pharmacological interventions for reducing violence in this population is not conclusive. Long-term outcomes are lacking and good quality RCTs are required to develop a stronger evidence base.

Maturation of mononuclear phagocytes in the lungs of young calves--in vitro study.

The influences of age in calves' immune system are described in their first phase of life. We hypothesized that variations that occur in the main mechanisms of lung innate response can help to identify periods of greater susceptibility to the respiratory diseases that affect calves in the first stage of their life. This study aimed to evaluate the innate immune system. Nine healthy calves were monitored for 3 mo and 8 immunologic evaluations were performed. Bronchoalveolar lavage samples were recovered by bronchoscopy. The alveolar macrophages in samples were identified by protein expression of cluster of differentiation 14 (CD14) and underwent functional evaluation of phagocytosis (Staphylococcus aureus stained with propidium iodide and Escherichia coli). Data was assessed by one-way ANOVA (unstacked and parametric) and the Mann-Whitney test (nonparametric). Functional alterations in CD14-positive phagocytes were observed, with punctual higher intensity of phagocytosis in the third week and its decrease starting at 45 d of life. A gradual increase in phagocytosis rate was observed starting at this date. It is concluded that from 45 d of life on, alveolar macrophages have less phagocytic capacity but more cells perform this function. We suggest that this occurs because lung macrophages of calves start to maintain their immune response without passive immunity influence. Until 90 d of life, calves did not achieve the stability to conclude the maturation of local innate immune response.

Antibody dynamics in Holstein Friesian heifers vaccinated with Brucella abortus strain 19, using seven serological tests.

The serological response induced by Brucella abortus strain 19 was evaluated in 52 Holstein females from a brucellosis-free herd using seven serological tests. Each calf was vaccinated at an age of 4 and 8 months old with 3 x 10(10) CFU B. abortus S19 and the antibody response was determined as the proportion of positive results to each test. The antibody dynamics, measured with the buffered plate antigen (BPA) test and the rapid automated presumptive (RAP) test, were similar. The proportion of positive reactions in these tests reached 100% one week after vaccination and remained at this level for seven weeks, after which the proportion of positive samples slowly declined to 8% (BPA) and 2% (RAP) at week 50. The response in the indirect enzyme immunoassay (i-ELISA) was similar, but shorter than that observed with the BPA/RAP. The antibody dynamic, measured using the seroagglutination test (SAT) in parallel with the 2-mercaptoethanol (2-Me) test and the complement fixation test (CFT) were similar to the RAP/BPA, but of slightly shorter duration. The competitive ELISA (c-ELISA) was positive in all animals for 3 weeks, followed by a rapid decline. The fluorescence polarization assay (FPA) reached a maximum of 68.5% positive animals at week 4 and then declined. Based on these data, the c-ELISA and FPA discriminated residual antibody activity due to vaccination more efficiently than the other tests.

Does a diol cyclic urea inhibitor of HIV-1 protease bind tighter than its corresponding alcohol form? A study by free energy perturbation and continuum electrostatics calculations.

The cyclic urea inhibitors of HIV-1 protease generally have two hydroxyl groups on the seven-membered ring. In this study, free energy perturbation and continuum electrostatic calculations were used to study the contributions of the two hydroxyl groups to the binding affinity and solubility of a cyclic urea inhibitor DMP323. The results indicated that the inhibitor with one hydroxyl group has better binding affinity and solubility than the inhibitor with two hydroxyl groups. Therefore, removal of one hydroxyl group from DMP323 may help to improve the properties of DMP323. This is also likely to be true for other cyclic urea inhibitors. The study also illustrated the difficulty in accurate modeling of the binding affinities of HIV-1 protease inhibitors, which involves many possible protonation states of the two catalytic aspartic acids in the active site of the enzyme.

Stereospecific synthesis, structure-activity relationship, and oral bioavailability of tetrahydropyrimidin-2-one HIV protease inhibitors.

The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of Ki to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.

Nonsymmetric P2/P2' cyclic urea HIV protease inhibitors. Structure-activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues.

Using the structural information gathered from the X-ray structures of various cyclic urea/HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (Ki) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).

SCH 43478 and analogs: in vitro activity and in vivo efficacy of novel agents for herpesvirus type 2.

SCH 43478 and analogs are a class of non-nucleoside antiviral agents that have potent and selective activity against herpes simplex virus type 2 (HSV-2). The IC50 for these compounds in plaque reduction analysis using Vero cells ranges from 0.8 to 2.0 microg/ml. All compounds have a LC50 > 100 microg/ml in cytotoxicity analysis. Mechanism of action studies suggest that these molecules have an effect on the transactivation of viral immediate early (alpha) gene expression. Time of addition studies indicate that antiviral activity of these analogs is limited to the initial 2-3 h after infection and is not due to inhibition of viral adsorption or penetration. Analysis of HSV protein expression demonstrates that SCH 49286 inhibits the accumulation of viral immediate early (alpha) gene products. SCH 43478 demonstrates statistically significant efficacy (P < 0.05) in the guinea pig genital model of HSV infection. Following subcutaneous administration in a therapeutic treatment regimen, SCH 43478 (90 mg/kg/day) is efficacious in reducing the number and severity of lesions and the neurological complications of acute HSV infection. Thus, SCH 43478 and analogs are anti-herpesvirus agents with a unique mechanism of action.

Design, synthesis, and evaluation of tetrahydropyrimidinones as an example of a general approach to nonpeptide HIV protease inhibitors.

Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this process is applied to the diamino alcohol class of HIVPR inhibitors to give tetrahydropyrimidinones. Conformational analysis of the tetrahydropyrimidinones and modeling of its interaction with the active site of HIVPR suggested modifications which led to very potent inhibitors of HIVPR (24 with a Ki = 0.018 nM). The X-ray crystallographic structure of the complex of 24 with HIVPR confirms the analysis and modeling predictions. The example reported in this study and other examples that are cited indicate that this process may be generally applicable to other linear inhibitors.

Prognostic factors for survival in metastatic renal cell carcinoma: retrospective analysis from 109 consecutive patients.

OBJECTIVE: Metastatic renal cell cancer (RCC) portends a bad prognosis, but survival is quite different among different patients. The objective of this study was to determine prognostic factors for survival with the aim to offer patients proper therapeutic options. METHODS: A consecutive series of 109 metastatic RCC patients admitted to our department since 1988 was reviewed, and survival from the time of diagnosis with metastases recognition was considered. The role of age, sex, disease-free interval (DFI), ECOG performance status (PS), stage at diagnosis, grading, number and type of metastatic sites, nephrectomy, blood levels of hemoglobin, creatinine, albumin, calcium, lactate dehydrogenase (LDH), ferritin, alkaline phosphatase, triglycerides was assessed in univariate and multivariate analysis. RESULTS: In our study, the following variables were found to be statistically significant at the univariate analysis (p < 0.01): DFI, ECOG PS, stage at diagnosis, grading, nephrectomy, sites of metastases, blood hemoglobin, serum albumin, calcium, LDH, alkaline phosphatase. Indeed, only an ECOG PS of 2-3 (relative risk 1.82; p = 0.003) and blood hemoglobin levels < or = 10 g/100 ml (relative risk 1.20; p = 0.017) retained their value as independent risk factors for poor survival at multivariate analysis. According to the number of independent risk factors, three groups of patients were identified, with significantly different median survival (21.7 vs. 8.6 vs. 3.5 months; log-rank test: p = 0.00004, p = 0.04126 and p = 0.00047, respectively). CONCLUSIONS: Poor performance status and anemia at diagnosis of metastatic RCC predict the worst outcome in our series. These factors could be taken into account to stratify patients in clinical trails and to select the proper treatment option in oncological practice.

Estudio clínico de eficacia y tolerancia con sultamicilina fipexiam en procesos infecciosos de tratamiento ambulatorio / Clinic study of efficacy and toleration with sultamicilina fipeham in infectious process of ambulatory treatment

Se realizó un estudio abierto, multicéntrico, no comparativo donde se avaluó la eficacia y tolerancia de la combinación Ampicilina/Sulbatam por vía oral-Sultamicilina-(Fipexiam), en adultos y niños con infecciones del tracto respiratorio superior e inferior y con infeciones de piel y partes blandas, y adultos con Enfermedad Inflamatoria Pélvica (EIP). El estudio reunió los investigadores de 73 Centros. Se trataron un total de 195 pacientes obteniéndose una efectividad global de 93.3 por ciento. De estos pacientes 84 presentaron Otitis media aguda, resultando curas clínicas en el 89.2 por ciento, 67 presentaron procesos orofaríngeos con curación en el 94 por ciento; en los casos con infecciones de piel y partes blandas, así como en las mujeres tratadas con (EIP) la curación clínica fue de 100 por ciento. Se reportaron efectos adversos en 10.9 por ciento, siendo las molestias gastrointestinales más resaltantes con 8.7 por ciento de los casos reportados, siendo menores a lo reportado por la literatura médica

Plasma nitrate plus nitrite changes during continuous intravenous infusion interleukin 2.

Nitric oxide (NO), a biologically active mediator generated in many cell types by the enzyme NO synthase, may play an important role in cardiovascular toxicity that is frequently observed in cancer patients during intravenous (i.v.) interleukin 2 (IL-2) therapy. The induction of NO synthase and the production of NO seem to be involved in the pathogenesis of the vascular leakage syndrome, as well as in the regulation of myocardial contractility. In the present study, we evaluated the pattern of plasmatic NO changes during multiple cycles of continuous i.v. infusion (CIVI) of IL-2 in ten advanced cancer patients (five males, five females, median age 59 years, range 33-67 years; eight affected by renal cell cancer and two affected by malignant melanoma). The patients received IL-2 at 18 MIU m-2 day-1 (14 cycles) or 9 MIU m-2 day-1 (seven cycles) for 96 h, repeated every 3 weeks. Interferon alpha (IFN alpha) was also administered subcutaneously (s.c) during the 3 week interval between IL-2 cycles. For each cycle, plasma samples were collected before treatment (t0), 24 h (t1), 48 h (t2), 72 h (t3) and 96 h (t4) after the start of IL-2 infusion, and 24 h after the end of the cycle. NO concentration was determined spectrophotometrically by measuring the accumulation of both nitrite and nitrate (after reduction to nitrite). The following observations may be drawn from data analysis: (1) plasma nitrate + nitrite significantly raised during treatment (P = 0.0226 for t0 vs t3), but statistical significance was retained only when cycles administered with IL-2 18 MIU m-2 day-1 are considered (P = 0.0329 for t0 vs t3; P = 0.0354 for t0 vs t2 vs t4) (dose-dependent pattern); (2) during subsequent cycles a significant trend toward a progressive increase of plasma nitrate + nitrite levels, with increasing cumulative dose of IL-2, was observed (linear regression coefficient r = 0.62, P = 0.0141 for t0; r = 0.80, P = 0.0003 for t1; r = 0.62, P = 0.013 for t2; r = 0.69, P = 0.045 for t3); (3) plasma nitrate + nitrite levels peaked earlier in subsequent cycles than in the first cycle; (4) all patients experienced hypotension. The mean of the systolic blood pressure values was significantly lower at the time of plasma nitrate + nitrite peak than at t0 (P = 0.0004); (5) the two cases of grade III hypotension occurred in patients with the higher mean and peak plasma nitrate + nitrite values. We conclude that determination of plasma nitrate + nitrite levels during CIVI IL-2 can usefully estimate, in a dose-dependent pattern, the degree of peripheral vascular relaxation and capillary leakage associated with cytokine action, clinically manifested as hypotension. However, isolated cardiac toxicity that continues to represent a relevant problem during IL-2 therapy, does not appear to correlate with plasma nitrate + nitrite levels; therefore, further studies are required to understand adequately the mechanisms underlying IL-2-induced cardiac toxicity.

Preparation and structure-activity relationship of novel P1/P1'-substituted cyclic urea-based human immunodeficiency virus type-1 protease inhibitors.

A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

Isolated left ventricular filling abnormalities may predict interleukin-2-induced cardiovascular toxicity.

Interleukin-2 (IL-2) is a cytokine with proven activity against metastatic renal cell carcinoma (RCC) and malignant melanoma (MM). The intravenous administration of high-dose IL-2 is limited by important cardiovascular side effects such as hypotension, fluid retention, arrhythmias, and myocardial ischemia, which often cause dose reduction and/or treatment withdrawal. The occurrence of these toxic events is not predicted by routine pretreatment examinations. The aim of the present study was to test the reliability of serial echocardiography in predicting subsequent cardiac adverse effects in patients undergoing IL-2 administration. In 19 patients (15 men, 4 women; median age: 51 years, range 27-71 years; 10 affected by metastatic RCC and 9 affected by MM) we performed two-dimensional and Doppler echocardiography before and immediately after 28 continuous intravenous infusions (CIVI) of IL-2 at the dose of 18 MIU/m2/day for 4 days. Left ventricular systolic function and the diastolic transmitral flow pattern were assessed before and after IL-2 administration. Significant changes of two indexes of left ventricular filling were noted: a decrease of the ratio of maximal flow velocity in early diastole to that in late diastole (E/A) (basal: 1.12 +/- 0.46, mean +/- SD; posttreatment: 0.83 +/- 0.27; p < 0.01) and an increase of the percentage of the atrial contribution to left ventricular filling (basal: 37.75 +/- 11.58%; posttreatment: 49.43 +/- 16.48%; p < 0.01). Eight major cardiovascular events causing IL-2 infusion withdrawal were observed (two ischemic electrocardiographic modifications, three grade III-IV hypotension, one atrial fibrillation, one pericardial effusion, one acute heart failure). These major cardiovascular events were observed more often when an abnormal basal E/A ratio < 1.0 (p < 0.05) was found. We conclude that Doppler transmitral flow pattern analysis before and subsequent to IL-2 infusion is a useful and easily available procedure for the monitoring of cardiac modifications during CIVI IL-2 administration. It might also predict a major cardiovascular event during IL-2 administration. Patients with basal E/A ratio < 1.0 should be more carefully monitored during treatment and/or should be treated with lower IL-2 doses to avoid cardiovascular toxicity.

Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous alpha-interferon.

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell cancer (RCC) of recombinant interleukin-2 (rIL-2) and alpha-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 x 10(6) U/m2/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m2/day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.014), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and prothrombin time elongation (P = 0.038).(ABSTRACT TRUNCATED AT 400 WORDS)

Autoimmune thyroiditis following interleukin-2 and LAK cell therapy for metastatic renal cell carcinoma: correlation with tumor regression.

A 63-year-old woman receiving recombinant interleukin-2 (rIL-2) + lymphokine activated killer cells for metastatic renal cell carcinoma developed autoimmune thyroiditis with clinical hypothyroidism and high titer anti-thyroglobulin and anti-microsomal antibodies. The onset of thyroid dysfunction was associated with tumor regression and resulted in complete response at the end of the treatment. Cytologic and cytofluorimetric studies on thyroid tissue showed two distinct populations, mainly consisting of small lymphocytes and large thyrocytes, and the latter expressed MHC class II antigens. After completion of rIL-2 treatment, hypothyroidism gradually decreased until resolution; complete tumor remission lasted 18 months. Mechanisms underlying the association between autoimmune thyroiditis and cancer regression are discussed.