Depression classification of the patients in meta-analyses studies affects the efficacy of St. John's wort

Eight studies from a meta-analysis on St. John's wort by Klaus et. al. (1996) were analyzed according to the severity of depression manifest by their patients. The studies were chosen according to inclusion criteria: 1) the study was random, 2) the study compared St. John's wort to a placebo or an antidepressant, 3) the study was controlled, 4) the study clearly stated the level of severity of depression demonstrated by subjects, and 5) the subjects were homogeneous for level of severity. The studies were then analyzed to determine whether the depression classification had an affect on the efficacy of St. John's wort. The Mantel-Haenszel test indicated that when the depression classification is major depression, the odds of improving for the St. John's wort group is greater than that of the placebo group, and to a lesser extent, the antidepressant group. The results indicated that the depression classification of the patients in the studies does affect the efficacy of St. John's wort in the meta-analysis of Klaus et. al. 1996

Design and clinical application of injectable hydrogels for musculoskeletal therapy

Musculoskeletal defects are an enormous healthcare burden and source of pain and disability for individuals. With an ageing population, the proportion living with these medical indications will increase. Simultaneously, there is pressure on healthcare providers to source efficient solutions, which are cheaper and less invasive than conventional technology. This has led to an increased research focus on hydrogels as highly biocompatible biomaterials that can be delivered through minimally invasive procedures. This review will discuss how hydrogels can be designed for clinical translation, particularly in the context of the new European Medical Device Regulation (MDR). We will then do a deep dive into the clinically used hydrogel solutions that have been commercially approved or have undergone clinical trials in Europe or the US. We will discuss the therapeutic mechanism and limitations of these products. Due to the vast application areas of hydrogels, this work focuses only on treatments of cartilage, bone, and the nucleus pulposus. Lastly, the main steps towards clinical translation of hydrogels as medical devices are outlined. We suggest a framework for how academics can assist small and medium MedTech enterprises conducting the initial clinical investigation and Post-Market Clinical Follow-up (PMCF) required in the MDR. It is evident that the successful translation of hydrogels is governed by acquiring high-quality pre-clinical and clinical data confirming the device mechanism of action and safety

Translational control of E2f1 regulates the Drosophila cell cycle

E2F transcription factors are master regulators of the eukaryotic cell cycle. In Drosophila, the sole activating E2F, E2F1, is both required for and sufficient to promote G1 -> S progression. E2F1 activity is regulated both by binding to RB Family repressors and by posttranscriptional control of E2F1 protein levels by the EGFR and TOR signaling pathways. Here, we investigate cis-regulatory elements in the E2f1 messenger RNA (mRNA) that enable E2f1 translation to respond to these signals and promote mitotic proliferation of wing imaginal disc and intestinal stem cells. We show that small upstream open reading frames (uORFs) in the 5' untranslated region (UTR) of the E2f1 mRNA limit its translation, impacting rates of cell proliferation. E2f1 transgenes lacking these 5'UTR uORFs caused TOR-independent expression and excess cell proliferation, suggesting that TOR activity can bypass uORF-mediated translational repression. EGFR signaling also enhanced translation but through a mechanism less dependent on 50'TR uORFs. Further, we mapped a region in the E2f1 mRNA that contains a translational enhancer, which may also be targeted by TOR signaling. This study reveals translational control mechanisms through which growth signaling regulates cell cycle progression.Peer reviewe

Integrated study of water Sr isotopes and carbonate Sr-C-O isotopes reveals long-lived fluid compartments in the Langfjellet oil discovery, Norwegian North Sea

Routine measurements of reservoir pressure variation with depth can detect pressure discontinuities indicative of barriers to vertical fluid movement. This study investigates how pressure data can be augmented by detailed profiles of formation water 87Sr/86Sr ratio to determine the precise location and cause of such barriers, and by C–O–Sr isotope analysis of carbonate cements to determine the duration over which the barrier has persisted. The study focuses on the clastic Hugin Formation reservoir in the Langfjellet Oil Discovery (Norwegian North Sea). Here, pressure data indicated a barrier somewhere within a 25 m depth interval. Formation water 87Sr/86Sr was measured with high spatial resolution by extraction from core samples using the residual salt analysis (RSA) method. This revealed three homogeneous populations of water separated by a small step in 87Sr/86Sr over a 7 m interval containing coal and shale layers, and a very large step in 87Sr/86Sr over a 1.2 m interval corresponding to a thin coal and shale layer situated below a major flooding surface. The latter is the main candidate for the pressure barrier. Modelling confirmed that this inferred pressure barrier also greatly retards Sr diffusion. Carbonate cements occur disseminated throughout the reservoir and in several heavily-cemented zones. Oxygen isotope-derived temperatures indicate that these formed in two episodes: (1) Pre-compactional, precipitated shortly after deposition in the zone of bacterial methanogenesis (~30 °C, ~200 m depth, ~162 Ma); (2) Post-compactional incorporating thermal decarboxylation-derived carbon (~90 °C, ~2500 m depth, ~46 Ma). Carbonate 87Sr/86Sr data reveal the same compositional populations present in the current formation water to be present in both cement generations. The water compositional stratification must thus have been present when the early and late cements precipitated, down till today. The persistence of a compositional step for most of the geological history of the rocks confirms the presence of a major fluid communication barrier. The Sr RSA data show invariant water composition across the heavily carbonate cemented intervals, implying no barrier effect. The combination of pressure data (to identify pressure barriers), Sr RSA (to add spatial resolution) and Sr–C–O isotopes of carbonates of different ages (to add a time dimension) is useful for identifying major long-term fluid communication barriers and differentiating them from smaller, less effective or shorter-term features. The method has applications for identifying seals in exploitation of petroleum and water resources, and underground storage of CO2 and radioactive waste

Mapping Tumor Hypoxia In Vivo Using Pattern Recognition of Dynamic Contrast-enhanced MRI Data

In solid tumors, hypoxia contributes significantly to radiation and chemotherapy resistance and to poor outcomes. The "gold standard" pO(2) electrode measurements of hypoxia in vivo are unsatisfactory because they are invasive and have limited spatial coverage. Here, we present an approach to identify areas of tumor hypoxia using the signal versus time curves of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data as a surrogate marker of hypoxia. We apply an unsupervised pattern recognition (PR) technique to determine the differential signal versus time curves associated with different tumor microenvironmental characteristics in DCE-MRI data of a preclinical cancer model. Well-perfused tumor areas are identified by rapid contrast uptake followed by rapid washout; hypoxic areas, which are regions of reduced vascularization, are identified by delayed contrast signal buildup and washout; and necrotic areas exhibit slow or no contrast uptake and no discernible washout over the experimental observation. The strength of the PR concept is that it captures the pixel-enhancing behavior in its entirety-during both contrast agent uptake and washout-and thus, subtleties in the temporal behavior of contrast enhancement related to features of the tumor microenvironment (driven by vascular changes) may be detected. The assignment of the tumor compartments/microenvironment to well vascularized, hypoxic, and necrotic is validated by comparison to data previously obtained using complementary imaging modalities. The proposed novel analysis approach has the advantage that it can be readily translated to the clinic, as DCE-MRI is used routinely for the identification of tumors in patients, is widely available, and easily implemented on any clinical magnet.close5

Changes of biomarkers with oral exposure to benzo(a)pyrene, phenanthrene and pyrene in rats

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants present in air and food. Among PAHs, benzo(a)pyrene(BaP), phenanthrene (PH) and pyrene (PY) are considered to be important for their toxicity or abundance. To investigate the changes of biomarkers after PAH exposure, rats were treated with BaP (150 µg/kg) alone or with PH (4,300 µg/kg) and PY (2,700 µg/kg) (BPP group) by oral gavage once per day for 30 days. 7-ethoxyresorufin-O-deethylase activity in liver microsomal fraction was increased in only BaP groups. The highest concentration (34.5 ng/g) of BaP, was found in muscle of rats treated with BaP alone at 20 days of treatment; it was 23.6 ng/g in BPP treated rats at 30 days of treatment. The highest PH concentration was 47.1 ng/g in muscle and 118.8 ng/g in fat, and for PY it was 29.7 ng/g in muscle and 219.9 ng/g in fat, in BPP groups. In urine, 114-161 ng/ml 3-OH-PH was found, while PH was 41-69 ng/ml during treatment. 201-263 ng/ml 1-OH-PY was found, while PH was 9-17 ng/ml in urine. The level of PY, PH and their metabolites in urine was rapidly decreased after withdrawal of treatment. This study suggest that 1-OH-PY in urine is a sensitive biomarker for PAHs; it was the most highly detected marker among the three PAHs and their metabolites evaluated during the exposure period and for 14 days after withdrawal

DLA Class II Alleles Are Associated with Risk for Canine Symmetrical Lupoid Onychodystropy (SLO)

Symmetrical lupoid onychodystrophy (SLO) is an immune-mediated disease in dogs affecting the claws with a suggested autoimmune aethiology. Sequence-based genotyping of the polymorphic exon 2 from DLA-DRB1, -DQA1, and -DQB1 class II loci were performed in a total of 98 SLO Gordon setter cases and 98 healthy controls. A risk haplotype (DRB1*01801/DQA1*00101/DQB1*00802) was present in 53% of cases and 34% of controls and conferred an elevated risk of developing SLO with an odds ratio (OR) of 2.1. When dogs homozygous for the risk haplotype were compared to all dogs not carrying the haplotype the OR was 5.4. However, a stronger protective haplotype (DRB1*02001/DQA1*00401/DQB1*01303, OR = 0.03, 1/OR = 33) was present in 16.8% of controls, but only in a single case (0.5%). The effect of the protective haplotype was clearly stronger than the risk haplotype, since 11.2% of the controls were heterozygous for the risk and protective haplotypes, whereas this combination was absent from cases. When the dogs with the protective haplotype were excluded, an OR of 2.5 was obtained when dogs homozygous for the risk haplotype were compared to those heterozygous for the risk haplotype, suggesting a co-dominant effect of the risk haplotype. In smaller sample sizes of the bearded collie and giant schnauzer breeds we found the same or similar haplotypes, sharing the same DQA1 allele, over-represented among the cases suggesting that the risk is associated primarily with DLA-DQ. We obtained conclusive results that DLA class II is significantly associated with risk of developing SLO in Gordon setters, thus supporting that SLO is an immune-mediated disease. Further studies of SLO in dogs may provide important insight into immune privilege of the nail apparatus and also knowledge about a number of inflammatory disorders of the nail apparatus like lichen planus, psoriasis, alopecia areata and onycholysis