Evaluation of vilazodone for the treatment of depressive and anxiety disorders

Introduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD.

Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library.

Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug’s dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD.     

Interleukin-3 dependent c-myc protein expression during the cell cycle of murine mast cells.

Aim of the study was to evaluate the relationship between the mitogenic stimulus interleukin-3 to normal murine mast cells and the cell cycle dependent expression of the nuclear c-myc protein. In order to do that on a cell by cell basis, we measured the nuclear c-myc protein simultaneously by flow cytometry, via specific monoclonal antibodies, and the DNA content via the intercalating dye propidium iodide. When cells were deprived from interleukin-3 (IL-3), proliferation was inhibited and the majority of cells arrested in early G1 (G1A, characterized by low c-myc content). Readdition of IL-3 resulted in a slow transition of cells from G1A to late G1 (G1B, at higher c-myc content) before DNA synthesis started. G1A cells with low c-myc content do not undertake DNA synthesis. Using a stathmokinetic methodology we confirmed that the G1A cells are early postmitotic G1 phase cells. The low content of c-myc within these cells appears a direct consequence of reduced c-myc levels during mitosis. Cumulatively, the data suggest that c-myc protein levels of murine mast cells fall at mitosis and that these levels must rise before cells can traverse the G1 phase. Our data are compatible with a model in which c-myc protein content of G1 phase cells has to reach a critical threshold before the cells can move further into the cell cycle.     

Prognostic relevance of histological grade and its components in node-negative breast cancer patients.

Available results highlight the lack of good level of evidence studies on the pure prognostic value of histological grade. In the present study, the prognostic relevance of histological grade and of its three components, tubule formation, nuclear pleomorphism and mitotic count, was analyzed in a series of 372 patients with node-negative breast cancer treated with locoregional therapy alone until early relapse. Histological grade was determined blindly by two observers and discordance between evaluations was resolved after joint review using a multihead microscope. No relation was observed between histological grade and any of its three components and disease-free survival. Conversely, a significant relation was observed between histological grade and distant metastasis-free survival (at 6 years, 94, 86 and 76% for grades 1, 2 and 3, respectively, P=0.013) as well as overall survival (98, 90 and 86%, P=0.001). A breakdown analysis as a function of the three components showed that neither tubule formation nor nuclear pleomorphism was associated with prognosis, and only mitotic count strongly influenced both distant metastasis-free survival (91, 82 and 74%, P=0.014) and overall survival (97, 87 and 85%, P=0.011). Histological grade suffers from a much higher subjectivity than any other microscopic evaluation of biomarkers as it is the sum of three different morphological features. Within the Italian Network for Quality Assessment of Tumor Biomarkers program we observed that histological grade is an independent prognostic variable, but also that this role is ascribable only to the number of mitotic figures. In conclusion, due to the ever smaller size of diagnosed breast cancers, resulting in less cancer tissue for biofunctional and molecular analysis, mitotic count evaluated under strict quality control conditions seems to be an accurate and feasible prognostic variable.     

Perceived adherence to prescribed treatment in juvenile idiopathic arthritis over a one‐year period

Objective

To document perceived adherence to treatment (taking medications and performing exercises) in patients with juvenile idiopathic arthritis (JIA) over a 1‐year period and to identify related factors.

Methods

We surveyed parents of patients with JIA at the Montreal Children's Hospital and British Columbia's Children's Hospital in Vancouver. Parents were asked to respond to a series of questionnaires every 3 months over a 12‐month period. Perceived adherence was evaluated on a 100‐mm visual analog scale (VAS) in the Parent Adherence Report Questionnaire (PARQ). Parental coping, distress, child function, disease severity and duration, perceived helpfulness of treatment, problems encountered, and sociodemographic data were also assessed.

Results

The mean age of our sample of 175 children was 10.2 years; mean age at diagnosis was 6.1 years and mean disease duration was 4.1 years. Perceived adherence to medications was consistently high, with average adherence at baseline, 3, 6, 9, and 12 months being 86.1, 91.7, 90.4, 92.0, and 88.8, respectively, on the PARQ VAS. Perceived adherence to exercise was lower but remained steady, with corresponding means of 54.5, 64.1, 61.2, 63.0, and 54.3, respectively. Using generalized estimating equation analysis, factors associated with higher perceived adherence to medications included perceived helpfulness of medications and lower disease severity; those associated with higher perceived adherence to exercise were younger age of the child, child involvement in responsibility for treatment, and higher perceived helpfulness of the treatment.

Conclusion

Belief in helpfulness of treatment is associated with higher parental perceived adherence to treatment.     

Microorganisms isolated from clinical specimens of patients from the Department of Thoracic Surgery

The clinical specimens received from patients hospitalized in Department of Thoracic Surgery between 1997 and 2001 were microbiologically examined. The main specimen for microbiological examination was pleural fluid (median 34%). The frequency of specimens from bronchial tree increased significantly (from 4% to 26%) with concurrent decrease of sputum (from 29% to 6%). Among isolated pathogens, Gram negative rods were the most frequent (median 48%) and Pseudomonas sp. was the main pathogen among them. Occurrence of staphylococci was median 22% and Staphylococcus aureus, with a little decrease in analyzed period, was still the main Gram positive pathogen. Simultaneously the occurrence of MRSA in the last three years dropped three times. The number of isolations of yeasts have risen from 5.8% to 10.3%.     

Expression studies of two novel in CIS-mutations identified in an intermediate case of Hunter syndrome

Hunter syndrome (Mucopolysaccharidosis type II) is a rare X-linked recessive lysosomal storage disorder caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS). To date, more than 200 different mutations have been reported in the IDS gene, located on Xq27.3-q28. Here, we report two new mutations (M488I and G489A) identified in hemizygosity in an Italian Hunter patient. Their "in vitro" expression by COS 7 cells was carried out in order to evaluate their functional consequence on enzyme activity as well as their possible cumulative effect on the malfunctioning of the protein. The results obtained enabled us to confirm the G489A mutation as causative. The M488I mutation, however, could not be unequivocally considered as causing disease because of its residual activity. Although a cumulative effect of the two mutations can be excluded "in vitro," we are cautious about drawing a conclusion with regard to the possible role that the two mutations could have played "in vivo" in modulating the phenotype of the patient. Finally, the knowledge of the molecular defect of the patient has enabled us to identify the carriers, providing reliable genetic counselling to the females of the family.     

Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research

Within the GEN-COVID Multicenter Study, biospecimens from more than 1000 SARS-CoV-2 positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O₂ supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical clustering analysis identified five main clinical categories: (1) severe multisystemic failure with either thromboembolic or pancreatic variant; (2) cytokine storm type, either severe with liver involvement or moderate; (3) moderate heart type, either with or without liver damage; (4) moderate multisystemic involvement, either with or without liver damage; (5) mild, either with or without hyposmia. GCB and GCPR are further linked to the GCGDR, which includes data from whole-exome sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population, and mapping genetically COVID-19 severity and clinical complexity among patients.Subject terms: Genetics research, Viral infection     

NK-active cytokines IL-2, IL-12, and IL-15 selectively modulate specific protein kinase C (PKC) isoforms in primary human NK cells.

Natural killer (NK) cell function is largely modulated by growth factors and cytokines. In particular, interleukin (IL)-2, IL-12, and IL-15 have major effects on the proliferative and cytotoxic activities of NK cells against tumor and virus-infected cells. It is thought that the members of the protein kinase C (PKC) family of serine/threonine kinases play an important role in mediating the pleiotropic effects of cytokines on their target cells. We have investigated the downstream effects generated in purified human NK cells by IL-2, IL-12, and IL-15 on PKCalpha and PKCepsilon--a canonical and a novel isoform of PKC, respectively. By means of Western blotting, PKC activity assays, and immunofluorescence performed on highly purified preparations of primary human NK cells, we demonstrate that: 1) the three cytokines have similar effects on PKCalpha and PKCepsilon activities; 2) whereas PKCepsilon activity is induced by cytokine stimulation, PKCalpha activity is inhibited; and 3) both the induction of PKCepsilon and the inhibition of PKCalpha functional activity are relatively early events in NK cells, while longer cytokine stimulations do not generate significant variations in enzyme activity, suggesting that the activation of both the canonical and novel isoforms of PKC are events required in the early phases of cytokine-induced NK cell stimulation.