Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic Encephalopathy.

Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH.

Immunity and Breast Cancer: Focus on Eosinophils.

The role of eosinophils, a cell type involved in the immune response to parasitic infections and allergies, has been investigated in different cancer types, in both tumor tissue and at the circulating level. Most studies showed a role mainly in conjunction with immunotherapy in melanomas and lung tumors, while few data are available in breast cancer. In this review, we summarize literature data on breast cancer, showing a prognostic role of circulating eosinophil counts as well as of the presence of tumor tissue infiltration by eosinophils.

Differences in plasma microRNA content impair microRNA-based signature for breast cancer diagnosis in cohorts recruited from heterogeneous environmental sites.

Circulating microRNAs are non-invasive biomarkers that can be used for breast cancer diagnosis. However, differences in cancer tissue microRNA expression are observed in populations with different genetic/environmental backgrounds. This work aims at checking if a previously identified diagnostic circulating microRNA signature is efficient in other genetic and environmental contexts, and if a universal circulating signature might be possible.

Blood eosinophilic relative count is prognostic for breast cancer and associated with the presence of tumor at diagnosis and at time of relapse.

Background: Cancer outcome is associated with circulating immune cells, including eosinophils. Here we analyze the relative eosinophil count (REC) in different breast cancer subtypes.

Methods: Stage I-III breast cancer patients were included in the study and classified as REC-high vs low (cutoff 1.

GREB1L variants in familial and sporadic hereditary urogenital adysplasia and Mayer-Rokitansky-Kuster-Hauser syndrome.

Congenital uterine anomalies (CUA) may have major impacts on the health and social well-being of affected individuals. Their expressivity is variable, with the most severe end of the spectrum being the absence of any fully or unilaterally developed uterus (aplastic uterus), which is a major feature in Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). So far, etiologies of CUA remain largely unknown.

Pain management after laparoscopic hysterectomy: systematic review of literature and PROSPECT recommendations.

Background And Objectives: Laparoscopic hysterectomy is increasingly performed because it is associated with less postoperative pain and earlier recovery as compared with open abdominal hysterectomy. The aim of this systematic review was to evaluate the available literature regarding the management of pain after laparoscopic hysterectomy.

Strategy And Selection Criteria: Randomized controlled trials evaluating postoperative pain after laparoscopic hysterectomy published between January 1996 and May 2018 were retrieved, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, from the EMBASE and MEDLINE databases and the Cochrane Register of Controlled Trials.

Molecular characterization and virulence of an alphaherpesvirus isolated from a BoHV1 gB-seropositive and gE-seronegative Italian buffalo.

During a serological survey, 157 out of 681 unvaccinated buffaloes resulted seropositive for bovine alphaherpesvirus 1 (BoHV1) glycoprotein B (gB) and seronegative for BoHV1 glycoprotein E (gE). These serological results were generally expected in animals vaccinated with a BoHV1 gE-deleted vaccine but not in unvaccinated animals. Seroneutralization tests on 36 selected sera detected neutralizing antibody titers more than three times higher for BuHV1 than for BoHV1.

Variations of circulating cardiac biomarkers during and after anthracycline-containing chemotherapy in breast cancer patients.

Background: Over time, the chance of cure after the diagnosis of breast cancer has been increasing, as a consequence of earlier diagnosis, improved diagnostic procedures and more effective treatment options. However, oncologists are concerned by the risk of long term treatment side effects, including congestive heart failure (CHF).

Methods: In this study, we evaluated innovative circulating cardiac biomarkers during and after anthracycline-based neoadjuvant chemotherapy (NAC) in breast cancer patients.

Development of an analytical method for crystalline content determination in amorphous solid dispersions produced by hot-melt extrusion using transmission Raman spectroscopy: A feasibility study.

The development of a quantitative method determining the crystalline percentage in an amorphous solid dispersion is of great interest in the pharmaceutical field. Indeed, the crystalline Active Pharmaceutical Ingredient transformation into its amorphous state is increasingly used as it enhances the solubility and bioavailability of Biopharmaceutical Classification System class II drugs. One way to produce amorphous solid dispersions is the Hot-Melt Extrusion (HME) process.

Evaluation of flunixin meglumine pour-on administration on prostaglandin E concentration in inflammatory exudate after induction of inflammation in cattle.

The effect of flunixin transdermal pour-on solution (Finadyne® Transdermal; MSD Animal Health) on prostaglandin E (PGE) synthesis in bovine inflammatory exudate was evaluated in a tissue cage model of acute inflammation. Twelve calves were randomly allocated to two-treatment groups over two sequences. Three weeks prior to the first period, sterile hollow perforated polyethylene balls were surgically embedded in the subcutis at four distinct sites in each animal.

Global approach for the validation of an in-line Raman spectroscopic method to determine the API content in real-time during a hot-melt extrusion process.

Since the Food and Drug Administration (FDA) published a guidance based on the Process Analytical Technology (PAT) approach, real-time analyses during manufacturing processes are in real expansion. In this study, in-line Raman spectroscopic analyses were performed during a Hot-Melt Extrusion (HME) process to determine the Active Pharmaceutical Ingredient (API) content in real-time. The method was validated based on a univariate and a multivariate approach and the analytical performances of the obtained models were compared.

[Infiltration with ropivacaine improves postoperative analgesia following caesarean section].

The analgesia produced by parietal infiltrations with local anesthetics (ALs) results from a block of conduction and the anti-inflammatory effect of the ALs. The duration of the reported analgesia is variable : limited to the duration of action of the ALs, or sometimes very prolonged. The purpose of this randomized, double-blind, study is to investigate the duration of the analgesia of a parietal infiltration after caesarian.

Antimicrobial Susceptibility Monitoring of Bacterial Pathogens Isolated from Urinary Tract Infections in Dogs and Cats Across Europe: ComPath Results.

ComPath is a pan-European antimicrobial surveillance program collecting bacterial pathogens from dogs and cats not recently exposed to antimicrobials. We present minimum inhibitory concentration data obtained using Clinical and Laboratory Standards Institute methodology for 616 urinary tract infection (UTI) isolates collected between 2008 and 2010. In both dogs and cats, the most common pathogen was Escherichia coli (59.

Sampling only ten microliters of whole blood for the quantification of poorly soluble drugs: Itraconazole as case study.

Nowadays in animal studies, it is important to comply with the so-called Three Rs rule by replacing or reducing the number of tested animals. Volumetric absorptive microsampling (VAMS) can be used to collect small quantities (10 or 20μL) of whole blood, thereby limiting the amount of animals needed. In this study, a quantitative method was developed and subsequently validated for the poorly soluble drug itraconazole (ITZ) using VAMS and ultra-high performance liquid chromatography (UHPLC) coupled to tandem mass spectrometry (MS).

Bioavailability enhancement of itraconazole-based solid dispersions produced by hot melt extrusion in the framework of the Three Rs rule.

Solid dispersion formulations made of itraconazole (ITZ) and Soluplus® (polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer abbreviated SOL) were produced using hot melt extrusion. Since ITZ possesses a water solubility of less than 1ng/mL, the aim of this work was to enhance the aqueous solubility of ITZ, and thereby improve its bioavailability. The three formulations consisted of a simple SOL/ITZ amorphous solid dispersion (ASD), an optimized SOL/ITZ/AcDiSol® (super-disintegrant) ASD and an equimolar inclusion complex of ITZ in hydroxypropyl-β-cyclodextrin (substitution degree=0.

Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination.

The purpose of this work was to increase the solubility and the dissolution rate of itraconazole, which was chosen as the model drug, by obtaining an amorphous solid dispersion by hot melt extrusion. Therefore, an initial preformulation study was conducted using differential scanning calorimetry, thermogravimetric analysis and Hansen's solubility parameters in order to find polymers which would have the ability to form amorphous solid dispersions with itraconazole. Afterwards, the four polymers namely Kollidon VA64, Kollidon 12PF, Affinisol HPMC and Soluplus, that met the set criteria were used in hot melt extrusion along with 25wt.

Antimicrobial susceptibility monitoring of dermatological bacterial pathogens isolated from diseased dogs and cats across Europe (ComPath results).

Aims: The ComPath project is a pan-European programme dedicated to the monitoring of antimicrobial susceptibility of pathogens from diseased dogs and cats using standardized methods and centralized minimum inhibitory concentration (MIC) determination. Here, the susceptibility of major pathogens is reported from antimicrobial nontreated animals with acute clinical signs of skin, wound or ear infections in 2008-2010.

Methods And Results: MICs were determined by agar dilution for commonly used antibiotics and interpreted using CLSI breakpoints, if available.

Hot-melt extrusion as a continuous manufacturing process to form ternary cyclodextrin inclusion complexes.

The aim of this study was to evaluate hot-melt extrusion (HME) as a continuous process to form cyclodextrin (CD) inclusion complexes in order to increase the solubility and dissolution rate of itraconazole (ITZ), a class II model drug molecule of the Biopharmaceutics Classification System. Different CD derivatives were tested in a 1:1 (CD:ITZ) molar ratio to obtain CD ternary inclusion complexes in the presence of a polymer, namely Soluplus (SOL). The CD used in this series of experiments were β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD) with degrees of substitution of 0.

Antimicrobial susceptibility monitoring of bacterial pathogens isolated from respiratory tract infections in dogs and cats across Europe: ComPath results.

ComPath is a pan-European resistance monitoring programme collecting bacterial pathogens from dogs and cats. We present data for respiratory tract infection (RTI) isolates collected between 2008 and 2010. Antimicrobial minimal inhibitory concentrations (MICs) were determined and susceptibility calculated following Clinical Laboratory Standards Institute (CLSI) standards for veterinary medicine.

A simple calibration approach based on film-casting for confocal Raman microscopy to support the development of a hot-melt extrusion process.

When developing a new formulation, the development, calibration and validation steps of analytical methods based on vibrational spectroscopy are time-consuming. For each new formulation, real samples must be produced and a "reference method" must be used in order to determine the Active Pharmaceutical Ingredient (API) content of each sample. To circumvent this issue, the paper presents a simple approach based on the film-casting technique used as a calibration tool in the framework of hot-melt extrusion process.

Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions.

The difficulty to find a relevant in vitro dissolution test to evaluate poorly soluble drugs is a well-known issue. One way to enhance their aqueous solubility is to formulate them as amorphous solid dispersions. In this study, three formulations containing itraconazole (ITZ), a model drug, were tested in seven different conditions (different USP apparatuses and different media).

Circulating microRNA-based screening tool for breast cancer.

Circulating microRNAs (miRNAs) are increasingly recognized as powerful biomarkers in several pathologies, including breast cancer. Here, their plasmatic levels were measured to be used as an alternative screening procedure to mammography for breast cancer diagnosis.A plasma miRNA profile was determined by RT-qPCR in a cohort of 378 women.

Vibrational spectroscopy and microspectroscopy analyzing qualitatively and quantitatively pharmaceutical hot melt extrudates.

Since the last decade, more and more Active Pharmaceutical Ingredient (API) candidates have poor water solubility inducing low bioavailability. These molecules belong to the Biopharmaceutical Classification System (BCS) classes II and IV. Thanks to Hot-Melt Extrusion (HME), it is possible to incorporate these candidates in pharmaceutical solid forms.

A review of pharmaceutical extrusion: critical process parameters and scaling-up.

Hot melt extrusion has been a widely used process in the pharmaceutical area for three decades. In this field, it is important to optimize the formulation in order to meet specific requirements. However, the process parameters of the extruder should be as much investigated as the formulation since they have a major impact on the final product characteristics.

Treatment of naturally occurring bovine respiratory disease in juvenile calves with a single administration of a florfenicol plus flunixin meglumine formulation.

The efficacy and safety of a florfenicol plus flunixin meglumine formulation in the treatment of respiratory disease was evaluated in calves less than six weeks of age, compared with a positive control group treated with a well-established florfenicol formulation. A total of 210 calves, selected from nine sites in Belgium, France and Spain, showing severe signs of respiratory disease, were randomly assigned to treatment with either florfenicol plus flunixin meglumine (Resflor; MSD Animal Health) or florfenicol (Nuflor; MSD Animal Health), both administered subcutaneously once. Animals were clinically observed daily for 10 days following treatment initiation.