Stability of tedizolid phosphate-sodium rifampicin and tedizolid phosphate-meropenem admixtures in intravenous infusion bags stored at different temperatures.

This is a report on the chemical stability and physical compatibility of intravenous tedizolid phosphate 0.8 mg/mL-sodium rifampicin 2.4 mg/mL and tedizolid phosphate 0.8 mg/mL-meropenem 4 mg/mL combinations in polypropylene 0.9% sodium chloride infusion bags stored at different storage conditions. Triplicate solutions of both admixtures were prepared in 0.9% sodium chloride polypropylene infusion bags and stored under light protection at room temperature (25±2 °C), refrigeration (2-8 °C) or freezing (-15 - -25 °C) conditions. The study was performed using a validated and stability-indicating liquid chromatography (LC) method. For both admixtures and for all storage conditions, at least 90% of the initial drug concentration of tedizolid phosphate remained unchanged throughout the entire study period. Stability of sodium rifampicin at 25±2 °C was determined to be seven hours and six days when it was stored at 2-8 °C. Under the same storage conditions, meropenem was stable for 12 h or 6 days, respectively. Under freezing conditions, sodium rifampicin was stable throughout all 28 days, while stability of meropenem was only 8 days. Solutions of 0.8 mg/mL tedizolid phosphate admixtured with 2.4 mg/mL rifampicin or 4 mg/mL meropenem, in polypropylene 0.9% sodium chloride infusion bags, are stable for at least 7 or 12 hours, respectively, when stored at 25±2 °C. When stored at 2-8 °C, stability was increased to 6 days for both admixtures.

High-intensity ultrasound applied on cured pork: Sensory and physicochemical characteristics.

This research aimed to evaluate the physicochemical characteristics and their relationship with sensory properties of cured porcine m. longissimus lumborum assisted by high-intensity ultrasound (HIU, 37 kHz, 22 Wcm-2). An experiment was designed with three factors at two levels each: type of curing (immersion or ultrasound-assisted -UA-), immersion time (30 or 90 min), and steak thickness (1.27 or 2.54 cm). After treatment and 7 days of storage at 4°C, the percentage of salt, pH, CIE L* a* b* color, water holding capacity (WHC), and shear force were determined in the samples. A quantitative descriptive analysis was performed using eight trained panelists. The HIU significantly increased the percentage of NaCl (p < .0005) and decreased the color saturation of the meat (p < .05), but did not affect the luminosity, redness (a*), yellowness (b*), pH, WHC, or shear force (all p > .05). The thickness of the steak had significant effects on almost all of the evaluated variables. Samples with 1.27 cm thickness had lower shear force, higher WHC and salt percentage (p < .0001). In agreement with this, the sensory profiles showed that the 1.27 cm samples treated with HIU for 30 min were perceived as less tough (more tender) and juicier.

Microbiological properties of poultry breast meat treated with high-intensity ultrasound.

Lactic acid, psychrophilic, and mesophilic bacteria, Escherichia coli, Salmonella spp. and Staphylococcus aureus were enumerated on chicken breasts after treatment with different high intensity ultrasound (frequency 40 kHz, intensity 9.6 W/cm-2) application times (0, 30, and 50 min) and packaging atmospheres (aerobic and vacuum) after a 7-day storage. The experiment was performed in commercial 7-week-old chicken breasts. Counts were performed prior to and immediately after ultrasonication, and on the 7th day of chill-storage. After sonication and storage, mesophiles, psychrophiles, LAB and S. aureus increased statistically. Psychrophiles decreased significantly under anaerobic packaging. There were no differences among ultrasonication times in terms of mesophiles, psychrophiles, LAB, E. coli and Salmonella spp. S. aureus numbers had a significant reduction after 50 min sonication. Under these experimental conditions, high-intensity ultrasound for 50 min is a control method of S. aureus and the anaerobic packaging reduces numbers of psychrophiles in chicken breast. The effect of ultrasound is only significant after the storage time.

Treatment response and long term follow up in nineteen dogs diagnosed with chronic enteropathy in Australia.

Chronic enteropathy (CE) in dogs is common worldwide, but little data is available from Australia. The aim of this study was to describe treatment response and long-term outcome in a cohort of dogs with CE. Dogs were prospectively enrolled at Murdoch University and the University of Melbourne. After diagnostic investigation to rule out diseases other than CE, dogs underwent sequential therapeutic trials until achieving a clinical response (diet then antibiotics, and finally immunosuppressants). Success was defined as 75% reduction of clinical severity for a minimum of five weeks. A total of 21 dogs were enrolled, and 19 completed the study. One dog was euthanised for lack of response to treatment and one excluded for lack of owner compliance. Most dogs responded to diet (n = 10), followed by antibiotics (n = 7) and immunosuppressants (n = 2). Long-term remission (median 21.1 months, [3.0-44.7]) was achieved in eight out of ten dietary responders without additional treatment. In contrast, only two dogs with antibiotic response remained in long-term remission, of which one needed on-going antibiotic treatment. Longer term remission was achieved in the two dogs treated with immunosuppressants with on-going low dose therapy. This study concludes that most dogs referred for CE in Australia respond to dietary treatment (even after previous dietary interventions), and remission is long-term compared to dogs treated with an antibiotic. Furthermore, the need for long-term antibiotics in some dogs to maintain response may lead to antibiotic resistance. This study supports adequate dietary trials for CE in dogs, and a need for alternative second-line treatments.

Atypical E2Fs inhibit tumor angiogenesis.

Atypical E2F transcription factors (E2F7 and E2F8) function as key regulators of cell cycle progression and their inactivation leads to spontaneous cancer formation in mice. However, the mechanism of the tumor suppressor functions of E2F7/8 remain obscure. In this study we discovered that atypical E2Fs control tumor angiogenesis, one of the hallmarks of cancer. We genetically inactivated atypical E2Fs in epithelial and mesenchymal neoplasm and analyzed blood vessel formation in three different animal models of cancer. Tumor formation was either induced by application of 7,12-Dimethylbenz(a)anthracene/12-O-Tetradecanoylphorbol-13-acetate or by Myc/Ras overexpression. To our surprise, atypical E2Fs suppressed tumor angiogenesis in all three cancer models, which is in a sharp contrast to previous findings showing that atypical E2Fs promote angiogenesis during fetal development in mice and zebrafish. Real-time imaging in zebrafish displayed that fluorescent-labeled blood vessels showed enhanced intratumoral branching in xenografted E2f7/8-deficient neoplasms compared with E2f7/8-proficient neoplasms. DLL4 expression, a key negative inhibitor of vascular branching, was decreased in E2f7/8-deficient neoplastic cells, indicating that E2F7/8 might inhibit intratumoral vessel branching via induction of DLL4.

Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer.

E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much higher than for wild-type keratinocytes. Moreover, E2f7/8-deficient primary keratinocytes proliferate more efficiently under stress conditions, such as low/high confluence or DNA damage. Application of in vivo stress using the DMBA/TPA skin carcinogenesis protocol revealed that combined inactivation of E2f7/8 enhanced tumorigenesis and accelerated malignant progression. Loss of atypical E2Fs resulted in increased expression of E2F target genes, including E2f1. Additional loss of E2f1 did not rescue, but worsened skin tumorigenesis. We show that loss of E2F7/8 triggers apoptosis via induction of E2F1 in response to stress, indicating that the tumor-promoting effect of E2F7/8 inactivation can be partially compensated via E2F1-dependent apoptosis. Importantly, E2F7/8 repressed a large set of E2F target genes that are highly expressed in human patients with skin cancer. Together, our studies demonstrate that atypical E2Fs act as tumor suppressors, most likely via transcriptional repression of cell cycle genes in response to stress.

Proteomic analysis of the postsynaptic density implicates synaptic function and energy pathways in bipolar disorder.

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders such as schizophrenia and bipolar disorder. We enriched for this anatomical structure in the anterior cingulate cortex of 16 bipolar disorder samples and 20 controls from the Stanley Medical Research Institute. Unbiased shotgun proteomics incorporating label-free quantitation was used to identify differentially expressed proteins. Quantitative investigation of the PSD identified 2033 proteins, among which 288 were found to be differentially expressed. Validation of expression changes of DNM1, DTNA, NDUFV2, SEPT11 and SSBP was performed by western blotting. Bioinformatics analysis of the differentially expressed proteins implicated metabolic pathways including mitochondrial function, the tricarboxylic acid cycle, oxidative phosphorylation, protein translation and calcium signaling. The data implicate PSD-associated proteins, and specifically mitochondrial function in bipolar disorder. They relate synaptic function in bipolar disorder and the energy pathways that underpin it. Overall, our findings add to a growing literature linking the PSD and mitochondrial function in psychiatric disorders generally, and suggest that mitochondrial function associated with the PSD is particularly important in bipolar disorder.

Update Review and Clinical Presentation in Congenital Insensitivity to Pain and Anhidrosis.

Introduction. Congenital insensitivity to pain and anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV is an extremely rare syndrome. Three clinical findings define the syndrome: insensitivity to pain, impossibility to sweat, and mental retardation. This pathology is caused by a genetic mutation in the NTRK1 gene, which encodes a tyrosine receptor (TrkA) for nerve growth factor (NGF). Methods. The consultation of a child female in our center with CIPA and a tibia fracture in pseudoarthrosis encouraged us to carefully review literature and examine the therapeutic possibilities. A thorough review of literature published in Pubmed was done about CIPA and other connected medical issues mentioned in the paper. Conclusions. The therapeutic approach of CIPA remains unclear. The preventive approach remains the only possible treatment of CIPA. We propose two new important concepts in the therapeutic approach for these patients: (1) early surgical treatment for long bone fractures to prevent pseudoarthrosis and to allow early weight bearing, decreasing the risk of further osteopenia, and (2) bisphosphonates to avoid the progression of osteopenia and to reduce the number of consecutive fractures.

First indications that northern bottlenose whales are sensitive to behavioural disturbance from anthropogenic noise.

Although northern bottlenose whales were the most heavily hunted beaked whale, we have little information about this species in its remote habitat of the North Atlantic Ocean. Underwater anthropogenic noise and disruption of their natural habitat may be major threats, given the sensitivity of other beaked whales to such noise disturbance. We attached dataloggers to 13 northern bottlenose whales and compared their natural sounds and movements to those of one individual exposed to escalating levels of 1-2 kHz upsweep naval sonar signals. At a received sound pressure level (SPL) of 98 dB re 1 µPa, the whale turned to approach the sound source, but at a received SPL of 107 dB re 1 µPa, the whale began moving in an unusually straight course and then made a near 180° turn away from the source, and performed the longest and deepest dive (94 min, 2339 m) recorded for this species. Animal movement parameters differed significantly from baseline for more than 7 h until the tag fell off 33-36 km away. No clicks were emitted during the response period, indicating cessation of normal echolocation-based foraging. A sharp decline in both acoustic and visual detections of conspecifics after exposure suggests other whales in the area responded similarly. Though more data are needed, our results indicate high sensitivity of this species to acoustic disturbance, with consequent risk from marine industrialization and naval activity.

The effectiveness of a program of physical activity and diet to modify cardiovascular risk factors in patients with severe mental illness after 3-month follow-up: CAPiCOR randomized clinical trial.

BACKGROUND: The aim of this randomized clinical trial follow-up at three months was to evaluate the effectiveness of an educational intervention with a focus on diet and physical activity (PA) to change the amount of PA, body mass index (BMI) and the waist circumference (WC) in patients with severe mental illness. METHODS: We recruited 332 outpatients with severe mental disorders undergoing treatment with antipsychotic medication from Mental Healthcare Centers of Barcelona. They were randomly assigned to an intervention or a control group. The patients in the intervention group participated in a group PA and diet educational program. The blinded measurements at 0 and 3 months were: the level of PA (IPAQ questionnaire), BMI, WC, blood pressure, dietary habits (PREDIMED questionnaire), quality of life (SF-36 questionnaire) and laboratory parameters (cholesterol, triglycerides, glucose). RESULTS: The average age was 46.7 years and 55% were males. Schizophrenia had been diagnosed in 67.1% of them. At 3 months, the average weekly walking METs rose significantly in the IG 266.05 METs (95%CI: 16.86 to 515.25; P=0.036). The total MET average also rose although not significantly: 191.38 METs (95%CI: 1.38 to 381.38; P=0.086). However, the BMI decreased significantly more in the CG, by 0.26kg/m(2) (95%CI: 0.02 to 0.51; P=0.038), than in the IG. There were no significant differences in the WC. CONCLUSIONS: The short-term results suggest that the intervention increases the level of PA, but does not improve physical or laboratory parameters. TRIAL REGISTRATION: Clinicaltrials.gov NCT01729650 (effectiveness of a physical activity and diet program in patients with psychotic disorder [CAPiCOR]).

Reduced protein synthesis in schizophrenia patient-derived olfactory cells.

Human olfactory neurosphere-derived (ONS) cells have the potential to provide novel insights into the cellular pathology of schizophrenia. We used discovery-based proteomics and targeted functional analyses to reveal reductions in 17 ribosomal proteins, with an 18% decrease in the total ribosomal signal intensity in schizophrenia-patient-derived ONS cells. We quantified the rates of global protein synthesis in vitro and found a significant reduction in the rate of protein synthesis in schizophrenia patient-derived ONS cells compared with control-derived cells. Protein synthesis rates in fibroblast cell lines from the same patients did not differ, suggesting cell type-specific effects. Pathway analysis of dysregulated proteomic and transcriptomic data sets from these ONS cells converged to highlight perturbation of the eIF2α, eIF4 and mammalian target of rapamycin (mTOR) translational control pathways, and these pathways were also implicated in an independent induced pluripotent stem cell-derived neural stem model, and cohort, of schizophrenia patients. Analysis in schizophrenia genome-wide association data from the Psychiatric Genetics Consortium specifically implicated eIF2α regulatory kinase EIF2AK2, and confirmed the importance of the eIF2α, eIF4 and mTOR translational control pathways at the level of the genome. Thus, we integrated data from proteomic, transcriptomic, and functional assays from schizophrenia patient-derived ONS cells with genomics data to implicate dysregulated protein synthesis for the first time in schizophrenia.

Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia.

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders, and schizophrenia specifically. We enriched for this anatomical structure, in the anterior cingulate cortex, of 20 schizophrenia samples and 20 controls from the Stanley Medical Research Institute, and used unbiased shotgun proteomics incorporating label-free quantitation to identify differentially expressed proteins. Quantitative investigation of the PSD revealed more than 700 protein identifications and 143 differentially expressed proteins. Prominent among these were altered expression of proteins involved in clathrin-mediated endocytosis (CME) (Dynamin-1, adaptor protein 2) and N-methyl-D-aspartate (NMDA)-interacting proteins such as CYFIP2, SYNPO, SHANK3, ESYT and MAPK3 (all P<0.0015). Pathway analysis of the differentially expressed proteins implicated the cellular processes of endocytosis, long-term potentiation and calcium signaling. Both single-gene and gene-set enrichment analyses in genome-wide association data from the largest schizophrenia sample to date of 13,689 cases and 18,226 controls show significant association of HIST1H1E and MAPK3, and enrichment of our PSD proteome. Taken together, our data provide robust evidence implicating PSD-associated proteins and genes in schizophrenia, and suggest that within the PSD, NMDA-interacting and endocytosis-related proteins contribute to disease pathophysiology.

[Quality indicators in the storage and dispensing process in a Hospital Pharmacy]. / Indicadores de calidad en el proceso de almacenamiento y dispensación de medicamentos en un Servicio de Farmacia Hospitalaria.

OBJECTIVE: To establish indicators for the evaluation of the quality of the storage and dispensing processes related to semiautomatic vertical (SAVCS) and horizontal (SAHCS) carousel systems. MATERIAL AND METHODS: Descriptive observational study conducted between January-December 2012. Definition of quality indicators, a target value is established and an obtained value is calculated for 2012. RESULTS: Five quality indicators in the process of storage and dispensing of drugs were defined and calculated: indicator 1, error filling unidose trolleys: target (<1.67%), obtained (1.03%); indicator 2, filling accuracy unidose trolleys by using an SAVCS: target (<15%), obtained (11.5%); indicator 3, reliability of drug inventory in the process of drug entries using an SAHCS: target (<15%), obtained (6.53%); indicator 4, reliability of drug inventory in the picking process of orders replacement stock of clinical units using an SAHCS: target (<10%), obtained (1.97%); indicator 5, accuracy of the picking process of drug orders using an SAHCS: target (<10%), obtained (10.41%). CONCLUSIONS: Establishing indicators has allowed the quality in terms of safety, precision and reliability of semiautomatic systems for storage and dispensing drugs to be assessed.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Simultaneous determination of phenolic compounds in Cynthiana grape (Vitis aestivalis) by high performance liquid chromatography-electrospray ionisation-mass spectrometry.

Phenolic acids, flavanols, flavonols and stilbenes (PAFFS) were isolated from whole grapes, juice, or pomace and purified using enzymatic hydrolysis. Only anthocyanin mono-glucosides and a few of the oligomers from Cynthiana grape (Vitis aestivalis) were analysed. Flavonoid-anthocyanin mono-glucosides (FA) were isolated using methanol/0.1% hydrochloric acid extraction. In addition, crude extractions of phenolic compounds from Cynthiana grape using 50% methanol, 70% methanol, 50% acetone, 0.01% pectinase, or petroleum ether were also evaluated. Reverse phase high performance liquid chromatography (RP-HPLC) with photodiode array (PDA) detector was used to identify phenolic compounds. A method was developed for simultaneous separation, identification and quantification of both PAFFS and FA. Quantification was performed by the internal standard method using a five points regression graph of the UV-visible absorption data collected at the wavelength of maximum absorbance for each analyte. From whole grape samples nine phenolic compounds were tentatively identified and quantified. The individual phenolic compounds content varied from 3 to 875 mg kg⁻¹ dry weight. For juice, twelve phenolic compounds were identified and quantified. The content varied from 0.07 to 910 mg kg⁻¹ dry weight. For pomace, a total of fifteen phenolic compounds were tentatively identified and quantified. The content varied from 2 mg kg⁻¹ to 198 mg kg⁻¹ dry matter. Results from HPLC analysis of the samples showed that gallic acid and (+)-catechin hydrate were the major phenolic compounds in both whole grapes and pomace. Cyanidin and petunidin 3-O-glucoside were the major anthocyanin glucosides in the juice.