The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation.
Inter-alpha-trypsin inhibitors (ITIs) are protease inhibitors stabilizing the extracellular matrix. ITIs consist of one light (bikunin) and two heavy chains (ITIHs). We have recently characterized ITIH5, a novel member of the ITIH gene family, and showed that its messenger RNA is lost in a high proportion of breast tumours. In the present study, an ITIH5-specific polyclonal antibody was generated, validated with western blot and used for immunohistochemical analysis on a tissue microarray; ITIH5 was strongly expressed in epithelial cells of normal breast (n=11/15), while it was lost or strongly reduced in 42% (92/217) of invasive breast cancers. ITIH5 expression in invasive carcinomas was associated with positive expression of oestrogen receptor (P=0.008) and histological grade (P=0.024). Correlation of ITIH5 expression with clinical outcome revealed that patients with primary tumours retaining abundant ITIH5 expression had longer recurrence-free survival (RFS; P=0.037) and overall survival (OS; P=0.044), compared to those with reduced expression (mean RFS: 102 vs 78 months; mean OS: 120 vs 105 months). Methylation-specific PCR analysis frequently showed strong methylation of the ITIH5 promoter in primary breast tumours (41%, n=109) and breast cancer cell lines (n=6). Methylation was significantly associated with mRNA loss (P<0.001; n=39), and ITIH5 expression was induced after treatment of tumour cell lines with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, ITIH5 promoter methylation was significantly associated with reduced OS (P=0.008). The cellular function of ITIH5 was evaluated by forced expression of a full-length ITIH5 complementary DNA in the breast cancer cell line MDA-MB-231, which does not endogenously express ITIH5. ITIH5-expressing clones showed a 40% reduced proliferation rate compared to mock-transfected cells. Overall, these data show that promoter methylation-mediated loss of ITIH5 expression is associated with unfavourable outcome in breast cancer patients, and thus ITIH5 could be used as a prognostic marker, although this marker is not multivariate independent due to its close association with ER expression. Our data indicate that ITIH5 is a candidate class II tumour suppressor gene and could be involved in tumour progression, invasion and metastasis, as its absence is associated with increased proliferation rates and a prognostic value indicating poor clinical outcome.


Local release of pioglitazone (a peroxisome proliferator-activated receptor γ agonist) accelerates proliferation and remodeling phases of wound healing.
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily known for its anti-inflammatory and macrophage differentiation effects, as well as its ability to promote fat cell differentiation and reduce insulin resistance. Pioglitazone (Pio) is a PPARγ agonist used clinically as an anti-diabetic agent for improving insulin sensitivity in patients with diabetes. The objective of this study was to develop a drug delivery system (DDS) for the local release of Pio to promote wound healing. Pio of low aqueous solubility was water-solubilized by micelles formed from gelatin grafted with L-lactic acid oligomers, and incorporated into a biodegradable gelatin hydrogel. An 8-mm punch biopsy tool was used to prepare two skin wounds on either side of the midline of 8-week-old mice. Wounds were treated by the hydrogels with (Pio-hydrogel group) or without (control group) Pio, and the wound area were observed 1, 4, 7, and 14 days after treatment. In addition, a protein assay and immunohistological stain were performed to determine the effects of the Pio-hydrogel on inflammation and macrophage differentiation. The Pio-hydrogels promote wound healing. Moreover, Western blotting analysis demonstrated that treatment with Pio-hydrogels resulted in decreased levels of the cytokines MIP-2 and TGF-β, and increased levels of glucose-regulating adiponectin. It is concluded that Pio-incorporated hydrogels promote the proliferation and remodeling phases of wound healing, and may prove to be effective as wound dressings.


Effectiveness and Outcome of Pulmonary Arterial Hypertension-Specific Therapy in Japanese Patients With Pulmonary Arterial Hypertension.
The trend of the initial treatment strategy for pulmonary arterial hypertension (PAH) has changed from monotherapies to upfront combination therapies. This study analyzed treatments and outcomes in Japanese patients with PAH, using data from the Japan PH Registry (JAPHR), which is the first organized multicenter registry for PAH in Japan.Methods and Results:We studied 189 consecutive patients (108 treatment-naïve and 81 background therapy patients) with PAH in 8 pulmonary hypertension (PH) centers enrolled from April 2008 to March 2013. We performed retrospective survival analyses and analyzed the association between upfront combination and hemodynamic improvement, adjusting for baseline NYHA classification status. Among the 189 patients, 1-, 2-, and 3-year survival rates were 97.0% (95% CI: 92.1-98.4), 92.6% (95% CI: 87.0-95.9), and 88.2% (95% CI: 81.3-92.7), respectively. In the treatment-naïve cohort, 33% of the patients received upfront combination therapy. In this cohort, 1-, 2-, and 3-year survival rates were 97.6% (95% CI: 90.6-99.4), 97.6% (95% CI: 90.6-99.4), and 95.7% (95% CI: 86.9-98.6), respectively. Patients on upfront combination therapy were 5.27-fold more likely to show hemodynamic improvement at the first follow-up compared with monotherapy (95% CI: 2.68-10.36). According to JAPHR data, initial upfront combination therapy is associated with improvement in hemodynamic status.


Changes in the expression and functional activities of Myosin II isoforms in human hyperplastic prostate.
Benign prostatic hyperplasia (BPH) is a common disease among aging males with the etiology remaining unclear. We recently found myosin II was abundantly expressed in rat and cultured human prostate cells with permissive roles in the dynamic and static components. The present study aimed to explore the expression and functional activities of myosin II isoforms including smooth muscle (SM) myosin II (SMM II) and non-muscle myosin II (NMM II) in the hyperplastic prostate. Human prostate cell lines and tissues from normal human and BPH patients were used. Hematoxylin and Eosin (H&E), Masson's trichrome, immunohistochemical staining, in vitro organ bath, RT-polymerase chain reaction (PCR) and Western-blotting were performed. We further created cell models with NMM II isoforms silenced and proliferation, cycle, and apoptosis of prostate cells were determined by cell counting kit-8 (CCK-8) assay and flow cytometry. Hyperplastic prostate SM expressed more SM1 and LC17b isoforms compared with their alternatively spliced counterparts, favoring a slower more tonic-type contraction and greater force generation. For BPH group, blebbistatin (BLEB, a selective myosin II inhibitor), exhibited a stronger effect on relaxing phenylephrine (PE) pre-contracted prostate strips and inhibiting PE-induced contraction. Additionally, NMMHC-A and NMMHC-B were up-regulated in hyperplastic prostate with no change in NMMHC-C. Knockdown of NMMHC-A or NMMHC-B inhibited prostate cell proliferation and induced apoptosis, with no changes in cell cycle. Our novel data demonstrate that expression and functional activities of myosin II isoforms are altered in human hyperplastic prostate, suggesting a new pathological mechanism for BPH. Thus, the myosin II system may provide potential new therapeutic targets for BPH/lower urinary tract symptoms (LUTS).


Calcium channel blockers as drug repurposing candidates for gestational diabetes: Mining large scale genomic and electronic health records data to repurpose medications.
New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM). In parallel, we tested the association between drugs and glucose tolerance during pregnancy as measured by the glucose recorded during a routine 50-g glucose tolerance test (GTT). We found an association between GDM/DM2 and the genes targeted by 11 drug classes. In the EMR analysis, 6 drug classes were associated with changes in GTT. Two classes were identified in both analyses. L-type calcium channel blocking antihypertensives (CCBs), were associated with a 3.18 mg/dL (95% CI -6.18 to -0.18) decrease in glucose during GTT, and serotonin receptor type 3 (5HT-3) antagonist antinausea medications were associated with a 3.54 mg/dL (95% CI 1.86-5.23) increase in glucose during GTT. CCBs were identified as a class of drugs considered safe in pregnancy could have efficacy in treating or preventing GDM. 5HT-3 antagonists may be associated with worse glucose tolerance.


Medium-term outcomes of conventional versus short uncemented femoral stems for primary total hip arthroplasty in patients younger than 55 years.
Short stems are designed with a bone preservation philosophy in mind. This study aims to compare the outcomes/complications and survival of a collarless fully hydroxyapatite (HA)-coated conventional tapered stem and a HA-coated partial neck-retaining uncemented short stem in patients ⩽55 years old at medium-term follow-up. We retrospectively studied 247 uncemented THAs operated between 2010 and 2014, comparing 146 patients treated with the fully HA-coated collarless stem (Group A) with 101 patients treated with a partial neck preserving, HA-coated short stem (Group B). 87 and 62 males were in groups A and B, respectively (p = 0.11). The mean age of the series was 46 years (17-55) (p =0.16). The mean follow-up of groups A and B were 9.9 (7-12) years and 9.7 (7-12) years, respectively (p =0.21). Mean Harris Hip Score improved from 55 to 92 in group A (p <0.001) and from 54 to 95 in group B (p <0.001), without differences between groups. Mean femoral neck length preservation in groups A and B was 13.6 (0-28) mm and 26 (11-38) mm, respectively (p =0.001). 13 (8.9%) and 1 (1%) patients in groups A and B presented postoperative complications, respectively (p =0.008). The conventional stem group had more aseptic loosening (Group A 3.4% vs. Group B 0%, p =0.06) along with more Symptomatic radiolucent lines (Group A 3.4% vs. Group B 0%, p =0.06). Both conventional and short stems showed excellent implant survival rates and functional outcomes at a mean follow-up of 9.8 years. However, complications and radiolucent lines were more frequent with a collarless conventional-length stem. Bone preservation of the femoral neck and diaphysis may be preferred in active young patients.


Characterization of Mycobacterium chelonae-Like Strains by Comparative Genomics.
Isolates of the Mycobacterium chelonae-M. abscessus complex are subdivided into four clusters (CHI to CHIV) in the INNO-LiPA® Mycobacterium spp DNA strip assay. A considerable phenotypic variability was observed among isolates of the CHII cluster. In this study, we examined the diversity of 26 CHII cluster isolates by phenotypic analysis, drug susceptibility testing, whole genome sequencing and single-gene analysis. Pairwise genome comparisons were performed using several approaches, including average nucleotide identity (ANI) and genome-to-genome distance (GGD) among others. Based on ANI and GGD the isolates were identified as M. chelonae (14 isolates), M. franklinii (2 isolates) and M. salmoniphium (1 isolate). The remaining 9 isolates were subdivided into three novel putative genomospecies. Phenotypic analyses including drug susceptibility testing, as well as whole genome comparison by TETRA and delta differences, were not helpful in separating the groups revealed by ANI and GGD. The analysis of standard four conserved genomic regions showed that rpoB alone and the concatenated sequences clearly distinguished the taxonomic groups delimited by whole genome analyses. In conclusion, the CHII INNO-LiPa is not a homogeneous cluster; on the contrary, it is composed of closely related different species belonging to the M. chelonae-M. abscessus complex and also several unidentified isolates. The detection of these isolates, putatively novel species, indicates a wider inner variability than the presently known in this complex.


Combinatorial suicide gene strategies for the safety of cell therapies.
Gene-modified cellular therapies carry inherent risks of severe and potentially fatal adverse events, including the expansion of alloreactive cells or malignant transformation due to insertional mutagenesis. Strategies to mitigate uncontrolled proliferation of gene-modified cells include co-transfection of a suicide gene, such as the inducible caspase 9 safety switch (ΔiC9). However, the activation of the ΔiC9 fails to completely eliminate all gene-modified cells. Therefore, we tested a two suicide gene system used independently or together, with the goal of complete cell elimination. The first approach combined the ΔiC9 with an inducible caspase 8, ΔiC8, which lacks the endogenous prodomain. The rationale was to use a second caspase with an alternative and complementary mechanism of action. Jurkat cells co-transduced to co-express the ΔiC8, activatable by a BB homodimerizer, and the ΔiC9 activatable by the rapamycin analog sirolimus were used in a model to estimate the degree of inducible cell elimination. We found that both agents could activate each caspase independently, with enhanced elimination with superior reduction in cell regrowth of gene-modified cells when both systems were activated simultaneously. A second approach was employed in parallel, combining the ΔiC9 with the RQR8 compact suicide gene. RQR8 incorporates a CD20 mimotope, targeted by the anti-CD20 monoclonal antibody rituxan, and the QBend10, a ΔCD34 selectable marker. Likewise, enhanced cell elimination with superior reduction in cell regrowth was observed when both systems were activated together. A dose-titration effect was also noted utilizing the BB homodimerizer, whereas sirolimus remained very potent at minimal concentrations. Further in vivo studies are needed to validate these novel combination systems, which may play a role in future cancer therapies or regenerative medicine.


Metaphors are physical and abstract: ERPs to metaphorically modified nouns resemble ERPs to abstract language.
Metaphorical expressions very often involve words referring to physical entities and experiences. Yet, figures of speech such as metaphors are not intended to be understood literally, word-by-word. We used event-related brain potentials (ERPs) to determine whether metaphorical expressions are processed more like physical or more like abstract expressions. To this end, novel adjective-noun word pairs were presented visually in three conditions: (1) Physical, easy to experience with the senses (e.g., "printed schedule"); (2) Abstract, difficult to experience with the senses (e.g., "conditional schedule"); and (3) novel Metaphorical, expressions with a physical adjective, but a figurative meaning (e.g., "thin schedule"). We replicated the N400 lexical concreteness effect for concrete vs. abstract adjectives. In order to increase the sensitivity of the concreteness manipulation on the expressions, we divided each condition into high and low groups according to rated concreteness. Mirroring the adjective result, we observed a N400 concreteness effect at the noun for physical expressions with high concreteness ratings vs. abstract expressions with low concreteness ratings, even though the nouns per se did not differ in lexical concreteness. Paradoxically, the N400 to nouns in the metaphorical expressions was indistinguishable from that to nouns in the literal abstract expressions, but only for the more concrete subgroup of metaphors; the N400 to the less concrete subgroup of metaphors patterned with that to nouns in the literal concrete expressions. In sum, we not only find evidence for conceptual concreteness separable from lexical concreteness but also that the processing of metaphorical expressions is not driven strictly by either lexical or conceptual concreteness.


Cytotoxic activity of ursolic acid derivatives obtained by isolation and oxidative derivatization.
Structure-activity relationships of ursane-type pentacyclic triterpenes obtained from natural sources and by chemical derivatization are reviewed. Ursolic acid, corosolic acid, and a new ursane-type pentacyclic triterpene, 7,24-dihydroxyursolic acid, were isolated from the methanolic extract of the leaves of the Bangladeshi medicinal plant, Saurauja roxburghii. Derivatization of ursolic acid by oxidation with dioxoruthenium (VI) tetraphenylporphyrins was investigated. Oxidation selectivity on the terpene structure was modulated by the auxiliaries introduced on the tetraphenylporphyrin. The natural triterpenes and oxidized derivatives were tested for cytotoxicity against the C6 rat glioma and A431 human skin carcinoma cell lines. Although they have the same ursane-type pentacyclic triterpene cores, the position and numbers of hydroxyls on the terpene structures significantly affected the activity and the selectivity towards the tested cell lines.


Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy.
Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct antitumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.


Individual heterogeneity in fitness in a long-lived herbivore.
Heterogeneity in the intrinsic quality and nutritional condition of individuals affects reproductive success and consequently fitness. Black brant (Branta bernicla nigricans) are long-lived, migratory, specialist herbivores. Long migratory pathways and short summer breeding seasons constrain the time and energy available for reproduction, thus magnifying life-history trade-offs. These constraints, combined with long lifespans and trade-offs between current and future reproductive value, provide a model system to examine the role of individual heterogeneity in driving life-history strategies and individual heterogeneity in fitness. We used hierarchical Bayesian models to examine reproductive trade-offs, modeling the relationships between within-year measures of reproductive energy allocation and among-year demographic rates of individual females breeding on the Yukon-Kuskokwim Delta, Alaska, using capture-recapture and reproductive data from 1988 to 2014. We generally found that annual survival tended to be buffered against variation in reproductive investment, while breeding probability varied considerably over the range of clutch size-laying date combinations. We provide evidence for relationships between breeding probability and clutch size, breeding probability and nest initiation date, and an interaction between clutch size and initiation date. Average lifetime clutch size also had a weak positive relationship with apparent survival probability. Our results support the use of demographic buffering strategies for black brant. These results also indirectly suggest associations among environmental conditions during growth, fitness, and energy allocation, highlighting the effects of early growth conditions on individual heterogeneity, and subsequently, lifetime reproductive investment.


[Clinico-psychopathologic varieties of the acute Kandinsky-Clerambault syndrome in schizophrenia].
Acute cases of the Kandinsky-Clerambault syndrome first manifested in adulthood were studied in schizophrenic patients. On the basis of the clinical mechanisms of the development of psychosis and the specific features of acute delirious disturbances in the structure of psychosis 3 clinical variants of the acute syndrome of psychic automatism were identified: developing according to the type of reaction in the structure of acute paranoid (the first variant), according to the regularities of endogenic paroxysm in the picture of acute sensory delirium (the second variant) and according to the mechanism of exacerbation of chronic delirium entering the structure of acute interpretative delirium (the third variant).


Atorvastatin Reduces In Vivo Fibrin Deposition and Macrophage Accumulation, and Improves Primary Patency Duration and Maturation of Murine Arteriovenous Fistula.
Arteriovenous fistulas placed surgically for dialysis vascular access have a high primary failure rate resulting from excessive inward remodeling, medial fibrosis, and thrombosis. No clinically established pharmacologic or perisurgical therapies currently address this unmet need. Statins' induction of multiple anti-inflammatory and antithrombotic effects suggests that these drugs might reduce arteriovenous fistula failure. Yet, the in vivo physiologic and molecular effects of statins on fistula patency and maturation remain poorly understood. We randomized 108 C57Bl/6J mice to receive daily atorvastatin 1.14 mg/kg or PBS (control) starting 7 days before end-to-side carotid artery-jugular vein fistula creation and for up to 42 days after fistula creation. We then assessed longitudinally the effects of statin therapy on primary murine fistula patency and maturation. We concomitantly analyzed the in vivo arteriovenous fistula thrombogenic and inflammatory macrophage response to statin therapy, using the fibrin-targeted, near-infrared fluorescence molecular imaging agent FTP11-CyAm7 and dextranated, macrophage-avid nanoparticles CLIO-VT680. In vivo molecular-structural imaging demonstrated that atorvastatin significantly reduced fibrin deposition at day 7 and macrophage accumulation at days 7 and 14, findings supported by histopathologic and gene-expression analyses. Structurally, atorvastatin promoted favorable venous limb outward remodeling, preserved arteriovenous fistula blood flow, and prolonged primary arteriovenous fistula patency through day 42 (P<0.05 versus control for all measures). These findings provide new in vivo evidence that statins improve experimental arteriovenous fistula patency and maturation, indicating that additional clinical evaluation of statin therapy in patients on dialysis undergoing arteriovenous fistula placement is warranted.


Engineering for an HPV 9-valent vaccine candidate using genomic constitutive over-expression and low lipopolysaccharide levels in Escherichia coli cells.
The various advantages associated with the growth properties of Escherichia coli have justified their use in the production of genetically engineered vaccines. However, endotoxin contamination, plasmid vector instability, and the requirement for antibiotic supplementation are frequent bottlenecks in the successful production of recombinant proteins that are safe for industrial-scaled applications. To overcome these drawbacks, we focused on interrupting the expression of several key genes involved in the synthesis of lipopolysaccharide (LPS), an endotoxin frequently responsible for toxicity in recombinant proteins, to eliminate endotoxin contamination and produce better recombinant proteins with E. coli. Of 8 potential target genes associated with LPS synthesis, we successfully constructed 7 LPS biosynthesis-defective recombinant strains to reduce the production of LPS. The endotoxin residue in the protein products from these modified E. coli strains were about two orders of magnitude lower than that produced by the wild-type strain. Further, we found that 6 loci-lpxM, lpxP, lpxL, eptA, gutQ and kdsD-were suitable for chromosomal integrated expression of HPV L1 protein. We found that a single copy of the expression cassette conferred stable expression during long-term antibiotic-free cultivation as compared with the more variable protein production from plasmid-based expression. In large-scale fermentation, we found that recombinant strains bearing 3 to 5 copies of the expression cassette had 1.5- to 2-fold higher overall expression along with lower endotoxin levels as compared with the parental ER2566 strain. Finally, we engineered and constructed 9 recombinant E. coli strains for the later production of an HPV 9-valent capsid protein with desirable purity, VLP morphology, and antigenicity. Reengineering the LPS synthesis loci in the E. coli ER2566 strain through chromosomal integration of expression cassettes has potential uses for the production of a 9-valent HPV vaccine candidate, with markedly reduced residual endotoxin levels. Our results offer a new strategy for recombinant E. coli strain construction, engineering, and the development of suitable recombinant protein drugs.


Fusion techniques for failed total ankle arthroplasty.
Salvage of failed total ankle arthroplasty is challenging because of the large bony deficit and disturbed soft tissue envelope, and often is a concomitant subtalar joint disorder. Failures may be revised by implant removal and arthrodesis with or without bone graft. The four common fusion methods are reviewed.


Linking protein fractionation with multidimensional monolithic reversed-phase peptide chromatography/mass spectrometry enhances protein identification from complex mixtures even in the presence of abundant proteins.
Recently, multidimensional shotgun proteomics has proven to be an alternative technology able to identify hundreds of proteins from single samples. Two major limitations of the technology are the presence of high abundance proteins (e.g. RUBISCO in plant leaf tissue) and the enormous number of co-eluting peptides that overstrain the loading and resolving capacity of conventional particle-packed columns as well as the capacity of electrospray ionisation due to ion suppression. Here, the coupling of fast performance liquid chromatography (FPLC) pre-fractionation of an Arabidopsis leaf protein extract and subsequent two-dimensional liquid chromatography/mass spectrometry with improved resolution using a monolithic silica C18 capillary column allowed the identification of 1032 unique proteins in a single 4 mg total protein plant leaf tissue sample. The reassignment of peptide IDs to distinct FPLC protein fractions enhances the identification procedure, especially in the case of present protein isoforms. The proposed strategy is useful to detect proteins otherwise not seen in conventional multidimensional chromatography/mass spectrometry approaches.


30 Years of postdisturbance recruitment in a Neotropical forest.
Long-term community response to disturbance can follow manifold successional pathways depending on the interplay between various recruitment processes. Analyzing the succession of recruited communities provides a long-term perspective on forest response to disturbance. Specifically, postdisturbance recruitment trajectories assess (a) the successive phases of postdisturbance response and the role of deterministic recruitment processes, and (b) the return to predisturbance state of recruits taxonomic/functional diversity/composition. Amazonian rainforest, Paracou station, French Guiana. We analyzed trajectories of recruited tree communities, from twelve forest plots of 6.25 ha each, during 30 years following a disturbance gradient that ranged from 10% to 60% of aboveground biomass removed. We measured recruited community taxonomic composition turnover, compared to whole predisturbance community, and assessed their functional composition by measuring the community weighted means for seven leaf, stem, and life-history functional traits. We also measured recruited community taxonomic richness, taxonomic evenness, and functional diversity and compared them to the diversity values from a random recruitment process. While control plots trajectories resembled random recruitment trajectories, postdisturbance trajectories diverged significantly. This divergence corresponded to an enhanced recruitment of light-demanding species that became dominant above a disturbance intensity threshold. After breakpoints in time, though, recruitment trajectories returned to diversity values and composition similar to those of predisturbance and control plots community. Following disturbance, recruitment processes specific to undisturbed community were first replaced by the emergence of more restricted, deterministic recruitment processes favoring species with efficient light use and acquisition. Then, a second phase corresponded to a decades-long recovery of recruits predisturbance taxonomic and functional diversity and composition that remained unachieved after 30 years.


BuDDI: Bulk Deconvolution with Domain Invariance to predict cell-type-specific perturbations from bulk.
While single-cell experiments provide deep cellular resolution within a single sample, some single-cell experiments are inherently more challenging than bulk experiments due to dissociation difficulties, cost, or limited tissue availability. This creates a situation where we have deep cellular profiles of one sample or condition, and bulk profiles across multiple samples and conditions. To bridge this gap, we propose BuDDI (BUlk Deconvolution with Domain Invariance). BuDDI utilizes domain adaptation techniques to effectively integrate available corpora of case-control bulk and reference scRNA-seq observations to infer cell-type-specific perturbation effects. BuDDI achieves this by learning independent latent spaces within a single variational autoencoder (VAE) encompassing at least four sources of variability: 1) cell-type proportion, 2) perturbation effect, 3) structured experimental variability, and 4) remaining variability. Since each latent space is encouraged to be independent, we simulate perturbation responses by independently composing each latent space to simulate cell-type-specific perturbation responses. We evaluated BuDDI's performance on simulated and real data with experimental designs of increasing complexity. We first validated that BuDDI could learn domain invariant latent spaces on data with matched samples across each source of variability. Then we validated that BuDDI could accurately predict cell-type-specific perturbation response when no single-cell perturbed profiles were used during training; instead, only bulk samples had both perturbed and non-perturbed observations. Finally, we validated BuDDI on predicting sex-specific differences, an experimental design where it is not possible to have matched samples. In each experiment, BuDDI outperformed all other comparative methods and baselines. As more reference atlases are completed, BuDDI provides a path to combine these resources with bulk-profiled treatment or disease signatures to study perturbations, sex differences, or other factors at single-cell resolution.


Learning curve and factors influencing the feasibility of performing fetal echocardiography at the time of the first-trimester scan.
The purpose of this study was to assess the learning curve and factors influencing the feasibility of performing a complete fetal cardiac examination at the time of the first-trimester scan. The study included 103 fetuses undergoing first-trimester scans. The maternal body mass index, fetal crown-rump length, and 8 cardiac parameters were evaluated: 4-chamber view, tricuspid regurgitation, outflow tract crossover, bifurcating pulmonary artery, 3-vessel view, aortic arch, superior and inferior venae cavae on sagittal views, and Doppler images of the ductus venosus. All examinations were performed transabdominally by a single sonologist. The average times from the first to last cardiac images obtained were calculated. A complete examination was feasible in 55% of the cases: 15% of the first 52 and 94% of the last 51. Of the 8 cardiac parameters, 59.5% were seen in cases 1 to 21, 75.0% in cases 22 to 52, and 98.6% in the last 51 cases (P = .0001). The average times spent on the examinations increased from 4.37 to 9.3 minutes among the 3 groups (P = .032). There was no statistically significant influence for the crown-rump length (P = .899) or body mass index (P = .752). This study indicates that a fetal cardiac examination is feasible in the first trimester. Sonographer experience and the examination duration seem to be the most influential factors affecting the completeness of the examination.


Sterile inflammation in liver transplantation.
Sterile inflammation is the immune response to damage-associated molecular patterns (DAMPs) released during cell death in the absence of foreign pathogens. In the setting of solid organ transplantation, ischemia-reperfusion injury results in mitochondria-mediated production of reactive oxygen and nitrogen species that are a major cause of uncontrolled cell death and release of various DAMPs from the graft tissue. When properly regulated, the immune response initiated by DAMP-sensing serves as means of damage control and is necessary for initiation of recovery pathways and re-establishment of homeostasis. In contrast, a dysregulated or overt sterile inflammatory response can inadvertently lead to further injury through recruitment of immune cells, innate immune cell activation, and sensitization of the adaptive immune system. In liver transplantation, sterile inflammation may manifest as early graft dysfunction, acute graft failure, or increased risk of immunosuppression-resistant rejection. Understanding the mechanisms of the development of sterile inflammation in the setting of liver transplantation is crucial for finding reliable biomarkers that predict graft function, and for development of therapeutic approaches to improve long-term transplant outcomes. Here, we discuss the recent advances that have been made to elucidate the early signs of sterile inflammation and extent of damage from it. We also discuss new therapeutics that may be effective in quelling the detrimental effects of sterile inflammation.


Probing cellular response to topography in three dimensions.
Biophysical aspects of in vivo tissue microenvironments include microscale mechanical properties, fibrillar alignment, and architecture or topography of the extracellular matrix (ECM). These aspects act in concert with chemical signals from a myriad of diverse ECM proteins to provide cues that drive cellular responses. Here, we used a bottom-up approach to build fibrillar architecture into 3D amorphous hydrogels using magnetic-field driven assembly of paramagnetic colloidal particles functionalized with three types of human ECM proteins found in vivo. We investigated if cells cultured in matrices comprised of fibrils of the same size and arranged in similar geometries will show similar behavior for each of the ECM proteins tested. We were able to resolve spatial heterogeneities in microscale mechanical properties near aligned fibers that were not observed in bulk tissue mechanics. We then used this platform to examine factors contributing to cell alignment in response to topographical cues in 3D laminin-rich matrices. Multiple human cell lines extended protrusions preferentially in directions parallel or perpendicular to aligned fibers independently of the ECM coating. Focal adhesion proteins, as measured by paxillin localization, were mainly diffuse in the cytoplasm, with few puncta localized at the protrusions. Integrin β1 and fascin regulated protrusion extension but not protrusion alignment. Myosin II inhibition did not reduce observed protrusion length. Instead, cells with reduced myosin II activity generated protrusions in random orientations when cultured in hydrogels with aligned fibers. Similarly, myosin II dependence was observed in vivo, where cells no longer aligned along the abluminal surfaces of blood vessels upon treatment with blebbistatin. These data suggest that myosin II can regulate sensing of topography in 3D engineered matrices for both normal and transformed cells.


Small airways obstruction syndrome in clinical practice.
Small airways obstruction syndrome (SAOS) is a particular pulmonary function test (PFT) pattern showing decreased VC and FEV(1) but a normal FEV(1)/VC ratio and TLC. The significance of this syndrome in clinical practice has not been comprehensively investigated. This study retrospectively identified all patients who had performed PFT that showed a SAOS pattern at a university teaching hospital over 1 year. A simple algorithm for differential diagnosis was developed and validated. Of the 3207 PFT performed, 153 (4.8%) showed a pattern indicating SAOS. Among these, a final diagnosis was confirmed for 85 (63.4%) of the patients. The causes of SAOS included both restrictive and obstructive lung diseases with the leading causes being early interstitial lung disease (n = 20; 23.3%), chest wall deformity (n = 12; 14.1%) and asthma (n = 10; 11.6%). Using a cut-off point of TLC of <95% predicted value to identify restrictive ventilatory defects (P = 0.002) and of > or =95% predicted combined with RV/TLC > or =55% to identify obstructive ventilatory defects (P < 0.001), a simplified algorithm with good accuracy (86.6%) was identified. Validation in an independent group showed accuracy of 91%. The PFT pattern called SAOS is not uncommon. The most common causes of SAOS were early interstitial lung disease, chest wall deformity and asthma. A diagnostic algorithm was proposed, which may help physicians' decision-making in their daily practice.


Evidence-based treatment recommendations for uremic bleeding.
Uremic bleeding syndrome is a recognized consequence of renal failure and can result in clinically significant sequelae. Although the pathophysiology of the condition has yet to be fully elucidated, it is believed to be multifactorial. This article is a review of both the normal hemostatic and homeostatic mechanisms that operate within the body to prevent unnecessary bleeding, as well as an in-depth discussion of the dysfunctional components that contribute to the complications associated with uremic bleeding syndrome. As a result of the multifactorial nature of this syndrome, prevention and treatment options can include one or a combination of the following: dialysis, erythropoietin, cryoprecipitate, desmopressin, and conjugated estrogens. Here, these treatment options are compared with regard to their mechanism of action, and onset and duration of efficacy. An extensive review of the clinical trials that have evaluated each treatment is also presented. Lastly, we have created an evidence-based treatment algorithm to help guide clinicians through most clinical scenarios, and answered common questions related to the management of uremic bleeding.


Differentiation of V2a interneurons from human pluripotent stem cells.
The spinal cord consists of multiple neuronal cell types that are critical to motor control and arise from distinct progenitor domains in the developing neural tube. Excitatory V2a interneurons in particular are an integral component of central pattern generators that control respiration and locomotion; however, the lack of a robust source of human V2a interneurons limits the ability to molecularly profile these cells and examine their therapeutic potential to treat spinal cord injury (SCI). Here, we report the directed differentiation of CHX10+ V2a interneurons from human pluripotent stem cells (hPSCs). Signaling pathways (retinoic acid, sonic hedgehog, and Notch) that pattern the neural tube were sequentially perturbed to identify an optimized combination of small molecules that yielded ∼25% CHX10+ cells in four hPSC lines. Differentiated cultures expressed much higher levels of V2a phenotypic markers (CHX10 and SOX14) than other neural lineage markers. Over time, CHX10+ cells expressed neuronal markers [neurofilament, NeuN, and vesicular glutamate transporter 2 (VGlut2)], and cultures exhibited increased action potential frequency. Single-cell RNAseq analysis confirmed CHX10+ cells within the differentiated population, which consisted primarily of neurons with some glial and neural progenitor cells. At 2 wk after transplantation into the spinal cord of mice, hPSC-derived V2a cultures survived at the site of injection, coexpressed NeuN and VGlut2, extended neurites >5 mm, and formed putative synapses with host neurons. These results provide a description of V2a interneurons differentiated from hPSCs that may be used to model central nervous system development and serve as a potential cell therapy for SCI.


Separation of early and late responses to herbivory in Arabidopsis by changing plasmodesmal function.
Herbivory results in an array of physiological changes in the host that are separable from the associated physical damage. We have made the surprising observation that an Arabidopsis line (pdko3) mutated in genes encoding plasmodesmal proteins is defective in some, but not all, of the typical plant responses to herbivory. We tested the responses of plasma transmembrane potential (Vm) depolarization, voltage gated K(+) channel activity, cytosolic calcium [Ca2+]cyt and reactive oxygen species (ROS) (H2 O2 and NO) release, shoot-to-root signaling, biosynthesis of the phytohormone jasmonic acid (JA) and the elicitation of volatile organic compounds (VOCs). Following herbivory and the release of factors present in insect oral secretions (including a putative β-galactofuranose polysaccharide), both the pdko3 and wild type (WT) plants showed a increased accumulation of [Ca2+]cyt , NO and H2 O2 . In contrast, unlike WT plants, the mutant line showed an almost complete loss of voltage gated K(+) channel activity and Vm depolarization, a loss of shoot-induced root-Vm depolarization, a loss of activation and regulation of gene expression of the JA defense pathway, and a much diminished release and altered profile of VOCs. The mutations in genes for plasmodesmal proteins have provided valuable genetic tools for the dissection of the complex spectrum of responses to herbivory and shown us that the responses to herbivory can be separated into a calcium-activated oxidative response and a K(+) -dependent Vm-activated jasmonate response associated with the release of VOCs.


Autologous stem cell transplantation for primary refractory Hodgkin's disease: results and clinical variables affecting outcome.
Patients with primary refractory Hodgkin's disease (PR-HD) have a dismal prognosis when treated with conventional salvage chemotherapy. We analyzed time to treatment failure (TTF), overall survival (OS) and clinical variables influencing the outcome in patients undergoing autologous stem cell transplantation (ASCT) for PR-HD and reported to the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO). Sixty-two patients, 41 males and 21 females with a median age of 27 years (range 13-55) were analyzed. Forty-two patients (68%) had advanced stage at diagnosis, 47 (76%) presented with B symptoms and 29 (47%) with a bulky mediastinal mass. Seventy-five percent of the patients had received more than one line of therapy before ASCT. Thirty-three patients received bone marrow as a source of hematopoietic progenitors, and 29 peripheral blood. Six patients were conditioned with high-dose chemotherapy plus total-body irradiation and 56 received chemotherapy-based protocols. One-year transplantation-related mortality was 14% [95% confidence interval (CI) 6% to 23%]. Response rate at 3 months after ASCT was 52% [complete remission in 21 patients (34%), partial remission in 11 patients (18%)]. Actuarial 5-year TTF and OS were 15% (95% CI 5% to 24%) and 26% (95% CI 13% to 39%), respectively. The presence of B symptoms at ASCT was the only adverse prognostic factor significantly influencing TTF [relative risk (RR) 1.75, 95% CI 0.92-3.35, P = 0.08]. The presence of B symptoms at diagnosis (RR 2.08, 95% CI 0.90-4.79, P = 0.08), MOPP-like regimens as first-line therapy (RR 3.84, 95% CI 1.69-9.09, P = 0.001), bulky disease at ASCT (RR 2.79, 95% CI 0.29-6.03, P = 0.009) and two or more lines of therapy before ASCT (RR 2.24, 95% CI 0.95-5.27, P = 0.06) adversely influenced OS. In our experience, although overall results of ASCT in PR-HD patients are poor, one-quarter of the patients remain alive at 5 years. Despite this, other therapeutic strategies should be investigated in this group of patients to improve the outcome.


Quality of life and life satisfaction in families after a child has undergone corpus callostomy.
Epilepsy is a chronic neurological condition which can have a detrimen tal effect on patients' quality of life (QOL). We evaluated the overall satisfaction with QOL and changes in QOL in 25 families with children who had undergone corpus callostomy for severe epilepsy. The mean age of seizure onset was 3.4 years, and the mean period from seizure onset to operation was 5.2 years. Mean follow-up was 19.3 months. Twenty of 22 patients had various degrees of mental retardation. Mean reduction in severity of seizure activity was 64%. Nineteen of 25 (76%) parents were satisfied with the surgical result. Eighteen of 25 parents (72%) described a good level of satisfaction with their families QOL after callostomy. Reduction in severity of seizure activity was significantly correlated with how successful families considered the surgery to be and how satisfied they were with their QOL (r = 0.72 and 0.77, respectively). Life domains showing one greatest improvement after callostomy included level of self-care, family life, and school performance. Improvements in level of self-care, family life, and school performance were associated with higher levels of life satisfaction (r = 0.69, 0.60, and 0.59, respectively). Hyperactivity, attention span, and social skills improved significantly in 11 patients after surgery. Callostomy did not improve mental performance. We conclude that improved seizure control after callostomy is also associated with improved QOL.


Functional analysis of the activation domain of RF2a, a rice transcription factor.
Rice transcription factor RF2a binds to the BoxII cis element of the promoter of rice tungro bacilliform virus and activates promoter expression. The acidic acid-rich domain of RF2a is a transcription activator and has been partially characterized (Dai et al., 2003). The RF2a acidic domain (A; amino acids 49-116) was fused with the synthetic zinc finger ZF-TF 2C7 and was co-introduced with a reporter gene into transgenic Arabidopsis plants. Expression of the reporter gene was increased up to seven times by the effector. In transient assays in tobacco BY-2 protoplasts, we identified a subdomain comprising amino acids 56-84 (A5) that was equally as effective as an activator as the entire acidic domain. A chemically inducible system was used to show determined that A and A5 domains are equally as effective in transcription activation as the well-characterized VP16 activation domain. Bioinformatics analyses revealed that the A5 domain is present only in b-ZIP transcription factors. In dicots, the A domain contains an insertion of four amino acids that is not present in monocot proteins. The A5 domain, and similar domains in other b-ZIP transcription factors, is predicted to form an anti-parallel beta sheet structure.


Health inequities in the United States: prospects and solutions.
An overview of the role that social determinants of health play in influencing health is provided. Emphasis is on the impact of economic inequality in creating health inequities among Americans. Economic inequality is seen as impacting health in three ways: increasing economic inequality weakens population health by creating poverty; weakening communal social structures that support health such as social and health services; and decreasing social cohesion and civil commitment. Documentation is provided of the growing degree of economic inequality in the USA and complicating issues of racial segregation are considered. Specific recommendations for addressing economic inequality, from USA, British, and Canadian sources, are presented. These recommendations indicate the need to move from epidemiologic research to public health action, from demonstrating the major impact of economic inequality on community health to the development and implementation of specific policies and programs to reverse the continuing increase in economic inequality.


A large-scale horizontal-vertical illusion produced with small objects separated in depth.
We conducted two experiments (total N = 81) to investigate the basis for the large-scale horizontal-vertical illusion (HVI), which is typically measured as 15%-20% and has previously been linked to the presence of a ground plane. In a preliminary experiment, vertical rods of similar angular extents that were either large (4.5-7.5 m) and far, or small (0.9-1.5 m) and near, were matched to horizontal extents in a virtual environment by adjustment of horizontal gaps or rods. Large/far objects showed a larger HVI (∼13%) than did small objects (∼7%), as has been shown before, but the horizontal gap normally used to measure the large-scale HVI was not the source of the larger bias. In the second experiment, we found that simply separating the comparison rod in depth from the vertical rod (thus forcing an evaluation of size at a distance) was sufficient to produce a large HVI (17%), even with small rods. The results are interpreted in light of evidence that the large-scale HVI is dependent on ground plane orientation and may be related to differential angular expansion in the visual coding of elevation and azimuth. (PsycINFO Database Record


[Cellular apoptosis in the radiation pathomorphosis of tumors].
Results of histologic and electron microscopic study of rectum cancer before and after radiation therapy are presented. A peculiar form of cancer cell death--apoptosis--was observed in all the tumours. The differences between necrosis and apoptosis are indicated, feasible mechanisms of cell death are considered. The justification of a further investigation of apoptosis is given.


Aggregation and beyond: alpha-synuclein-based biomarkers in synucleinopathies.
Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic inclusions rich in alpha-synuclein called 'Lewy bodies' and 'Lewy neurites'. Together with dementia with Lewy bodies and multiple system atrophy, Parkinson's disease is part of a group of disorders called synucleinopathies. Currently, diagnosis of synucleinopathies is based on the clinical assessment which often takes place in advanced disease stages. While the causal role of alpha-synuclein aggregates in these disorders is still debatable, measuring the levels, types, or seeding properties of different alpha-synuclein species hold great promise as biomarkers. Recent studies indicate significant differences in peptide, protein, and RNA levels in blood samples from PD patients. Seed amplification assays using CSF, blood, skin biopsy, olfactory swab samples show great promise for detecting synucleinopathies and even for discriminating between different synucleinopathies. Interestingly, small extracellular vesicles, such as exosomes, display differences in their cargoes in Parkinson's disease patients versus controls. In this update, we focus on alpha-synuclein aggregation and possible sources of disease-related species released in extracellular vesicles, which promise to revolutionize the diagnosis and the monitoring of disease progression.


PSYCHOLOGICAL ASPECTS OF HEADACHE.
Headache is considered as a non-specific syndrome illustrating the concept of pain as an emotion. Viewed in this way, its meaning looms larger than its site.Pain indicates dis-ease of the patient, sometimes with his body, but more often with his life. No pain is "imaginary", nor can some pain be assigned to physiological and some to psychological pathways. Such a decision is often merely a judgmental one.Just as the "brain" cannot easily be separated from the "mind", so to believe that some pain is "physical" and some "emotional" is a distortion. All painful syndromes are mixed and the problem is to decipher the meaning of the pain. Only rarely will headache respond to physical measures alone.


Bird T. Baldwin: a holistic scientist in occupational therapy's history.
Holistic patient care and the scientific research method are two important aspects of occupational therapy. Bird T. Baldwin contributed to the formulation of these tenets at the beginning of this century. Baldwin, a psychologist by training, became the director of the occupational therapy department at Walter Reed General Hospital in Washington, DC, during World War I. In his department, functional rehabilitation was achieved via scientifically analyzed purposeful activities. He believed that purposeful activity was superior to exercise. Activity choice was based on physical, vocational, social, and emotional considerations. True to his scientific approach, Baldwin designed and adapted devices to provide standardized treatment protocols. Because Bird T. Baldwin's approach to rehabilitation remains of value today, a review of his work is relevant to the occupational therapy community.


Relationship between the downregulation of HLA class I antigen and clinicopathological significance in gastric cancer.
To discuss the expression of human leukocyte antigen (HLA) class I antigens in gastric cancer and correlate these with pathologic type and TNM stage. The expression of HLA class I antigen was detected by immunohistochemistry in 185 specimens of gastric cancer, 20 gastric cancer specimens with lymphatic metastasis and 22 controls of normal gastric mucosa using four monoclonal antibodies. The expression of HLA class I antigen (B/C locus) was significantly downregulated in gastric cancer and in lymphatic metastasis than that in normal gastric mucosa (chi2=7.712, P<0.05). The expression of other HLA class I antigens was also downregulated, but the change was slight. There was no relationship between the downregulation of HLA class I antigen and that of beta2m and LMP2. The expression of HLA class I (B/C locus) was statistically correlated with pathologic stage in gastric adenocarcinoma (chi2=4.164, P<0.05). The expression of HLA class I antigen (B/C locus) was obviously downregulated in gastric cancer and in lymphatic metastasis. This abnormal expression would provide the tumor cells with a way to avoid immunological recognition.


Constitutive expression of IL-18 binding protein in murine testicular tissues and cells.
In the present study, we examined the cellular origin and the expression levels of interleukin-18 binding protein (IL-18 BP), during normal maturation of murine testis. Immunohistochemical staining of testicular tissues from sexually mature mice, shows that testicular germ cells, at different stages of differentiation, express IL-18 BP. Leydig cells/interstitial cells and peritubular cells express higher levels of IL-18 BP, as compared to other testicular cells. The levels of IL-18 BP were similar in testicular tissues and homogenates from sexually immature and mature mice, as examined by western blot, ELISA and real time PCR analysis. Our results demonstrate, for the first time, the expression of IL-18 BP in murine testicular tissues and cells. Together with our previous studies, which showed over-expression of IL-18 in testicular tissues of immature mice as compared with mature mice, these results may indicate a role for IL-18 in testicular development, and also in the regulation of testicular functions under physiological conditions.


Competing influence of visual speech on auditory neural adaptation.
Visual information from a speaker's face enhances auditory neural processing and speech recognition. To determine whether auditory memory can be influenced by visual speech, the degree of auditory neural adaptation of an auditory syllable preceded by an auditory, visual, or audiovisual syllable was examined using EEG. Consistent with previous findings and additional adaptation of auditory neurons tuned to acoustic features, stronger adaptation of N1, P2 and N2 auditory evoked responses was observed when the auditory syllable was preceded by an auditory compared to a visual syllable. However, although stronger than when preceded by a visual syllable, lower adaptation was observed when the auditory syllable was preceded by an audiovisual compared to an auditory syllable. In addition, longer N1 and P2 latencies were then observed. These results further demonstrate that visual speech acts on auditory memory but suggest competing visual influences in the case of audiovisual stimulation.


Challenges threaten, opportunity awaits hyperbaric medicine and the head and neck cancer patient.
Over the past four decades, hyperbaric oxygen (HBO2) therapy has played a prominent role in both the prevention and treatment of mandibular osteoradionecrosis (ORN). It has done so on the strength of laboratory observations and clinical reports, yet only limited efficacy data. This dual role has come under increasing scrutiny in the modern radiotherapy (RT) and surgical eras. The ability to spare healthy "non-target" tissue has markedly improved since the two-dimensional planning and delivery techniques in use when HBO2's prophylactic value was first demonstrated. A recent study failed to identify this same benefit in patients who received high-precision imaging and conformal RT. HBO2 therapy is under challenge as preferred treatment for early stage ORN. A recently introduced "fibroatrophic" mechanism contrasts with the hypovascular-hypocellular-hypoxic injury pattern that formed the basis for HBO2's therapeutic use. This alternative pathophysiologic state appears to benefit from an oral antioxidant medication regimen. The continuing necessity of HBO2 in support of mandibular reconstruction for advanced ORN is in question. Microsurgery-based vascularized bone flaps increasingly represent standard care, invariably in the absence of perioperative HBO2. Renewed interest in hyperbaric oxygen as a radiation sensitizer offers some promise. Hypoxia remains a critical radio-resistant factor in many solid tumors. Malignant gliomas have been a primary focus of several small studies, with resulting improvements in local control and median survival. Hyperbaric radiation sensitization has recently addressed oropharyngeal cancer. Preliminary data indicates that addition of HBO2 to chemo-radiation standard of care is technically feasible, well tolerated and safe. A Phase II efficacy trial will investigate the potential for of HBO2 to improve progression-free and relapse-free survival in newly diagnosed locally advanced head and neck cancers. What follows is a review and summary of relevant peer-reviewed literature.


Sexual distancing during five periods around and during the COVID-19 pandemic, Amsterdam, the Netherlands.
Social- and sexual distancing (i.e., abstaining from sex with persons outside one's household) was important in the control of the COVID-19 pandemic. Compliance to distancing measures can change over time. We assessed changes in compliance to the sexual distancing measures during five periods of the COVID-19 pandemic in the Netherlands. Between November 2021 and March 2022, we used a structured questionnaire containing questions about sexual behavior and factors that could have influenced compliance with sexual distancing. Variables related to sexual behavior were measured for five time periods, before and during the pandemic, delineated by imposement and relaxation of lockdown measures. 870 participants (predominantly MSM) completed the questionnaire. We found that compliance to the sexual distancing measures decreased over time. The number of casual partners was highest after the lockdown measures were relaxed for the second time (April 2021 - March 2022), and even higher than before the first lockdown. Factors positively associated with sexual distancing compliance were: having confidence in the information provided by the government and experiencing less or similar need for physical contact compared to before the pandemic. Previously having had COVID-19, perceiving the lockdown measures as overstated, having sex with casual partners and similar drug use during the pandemic as before lowered compliance over time. Our findings suggest that sexual distancing measures are difficult to maintain for a long period of time. Other measures, such as confinement to a small network of known partners, might be more effective for longer pandemics in minimizing the spread of infectious diseases.


Tocotrienols from palm oil as potent inhibitors of lipid peroxidation and protein oxidation in rat brain mitochondria.
The tocotrienol-rich-fraction (TRF) from palm oil, being tried as a more economical and efficient substitute for alpha-tocopherol, significantly inhibited oxidative damage in vitro to both lipids and proteins in rat brain mitochondria induced by ascorbate-Fe2+, the free radical initiator azobis(2-amidopropane)dihydrochloride (AAPH) and photosensitisation. The observed inhibitory effect was both time- and concentration-dependent. At a low concentration of 5 microM, TRF can significantly inhibit oxidative damage to both lipids and proteins. The inhibitory effect of TRF seems to be mainly due to gamma-tocotrienol and to a lesser extent alpha- and delta-tocotrienols. TRF was significantly more effective than alpha-tocopherol. This fraction from palm oil can be considered a natural antioxidant supplement capable of protecting the brain against oxidative damage and thereby from the ensuing adverse alterations.


Laryngeal amyloidosis with laryngocele.
Both laryngocele and laryngeal amyloidosis are uncommon, and simultaneous occurrences of these entities are extremely rare. A case of laryngeal amyloidosis with laryngocele in which the computed tomography (CT) and magnetic resonance (MR) imaging of the larynx, clearly demonstrating both disease processes, is discussed. Diagnosis is confirmed by histopathologic specimens. Only two cases have been reported in the world literature, and this is the third case of laryngeal amyloidosis associated with laryngocele.


ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression.
Direct reprogramming of fibroblasts to cardiomyocytes represents a potential means of restoring cardiac function following myocardial injury. AKT1 in the presence of four cardiogenic transcription factors, GATA4, HAND2, MEF2C, and TBX5 (AGHMT), efficiently induces the cardiac gene program in mouse embryonic fibroblasts but not adult fibroblasts. To identify additional regulators of adult cardiac reprogramming, we performed an unbiased screen of transcription factors and cytokines for those that might enhance or suppress the cardiogenic activity of AGHMT in adult mouse fibroblasts. Among a collection of inducers and repressors of cardiac reprogramming, we discovered that the zinc finger transcription factor 281 (ZNF281) potently stimulates cardiac reprogramming by genome-wide association with GATA4 on cardiac enhancers. Concomitantly, ZNF281 suppresses expression of genes associated with inflammatory signaling, suggesting the antagonistic convergence of cardiac and inflammatory transcriptional programs. Consistent with an inhibitory influence of inflammatory pathways on cardiac reprogramming, blockade of these pathways with anti-inflammatory drugs or components of the nucleosome remodeling deacetylase (NuRD) complex, which associate with ZNF281, stimulates cardiac gene expression. We conclude that ZNF281 acts at a nexus of cardiac and inflammatory gene programs, which exert opposing influences on fibroblast to cardiac reprogramming.


Effectiveness of aerobic exercise for adults living with HIV: systematic review and meta-analysis using the Cochrane Collaboration protocol.
People with HIV are living longer with the health-related consequences of HIV, multi-morbidity, and aging. Exercise is a key strategy that may improve or sustain health for people living with HIV. Our aim was to examine the safety and effectiveness of aerobic exercise interventions on immunological, virological, cardiorespiratory, strength, weight, body composition, and psychological outcomes in adults living with HIV. We conducted a systematic review using the Cochrane Collaboration protocol. We searched databases up to April 2013. We included randomized controlled trials comparing aerobic exercise with no exercise or another intervention performed at least three times per week for at least four weeks among adults living with HIV. Two reviewers independently determined study eligibility. Data were extracted from studies that met inclusion criteria using standardized forms. We assessed risk of bias using the Cochrane Collaboration's tool for assessing risk of bias. Outcomes were analyzed as continuous and meta-analyses conducted using random effects models with Review Manager (RevMan) computer software. Twenty-four studies met inclusion criteria (n = 936 participants at study completion); the majority of participants were men (73 %) and the majority were taking antiretroviral therapy (19/24 included studies). The exercise intervention included aerobic exercise alone (11 studies) or a combination of aerobic and resistive exercise (13 studies) ranging from 5 to 52 weeks. Fifty-eight meta-analyses were performed. Main results indicated statistically significant improvements in selected outcomes of cardiorespiratory status (maximum oxygen consumption, exercise time), strength (chest press, knee flexion), body composition (lean body mass, percent body fat, leg muscle area), depression symptoms, and quality of life (SF-36 questionnaire) among exercisers compared with non-exercisers. No significant differences in change in CD4 count and viral load were found. Performing aerobic exercise or a combination of aerobic and resistive exercise at least three times per week for at least five weeks is safe and can lead to improvements in cardiorespiratory fitness, strength, body composition and quality of life for adults with HIV. Aerobic exercise is safe and beneficial for adults living with HIV who are medically stable.


Chicken manure application alters microbial community structure and the distribution of antibiotic-resistance genes in rhizosphere soil of Cinnamomum camphora forests.
The distribution of antibiotic-resistance genes (ARGs) in environmental soil is greatly affected by livestock and poultry manure fertilization, the application of manure will lead to antibiotic residues and ARGs pollution, and increase the risk of environmental pollution and human health. Cinnamomum camphora is an economically significant tree species in Fujian Province, China. Here, through high-throughput sequencing analysis, significant differences in the composition of the bacterial community and ARGs were observed between fertilized and unfertilized rhizosphere soil. The application of chicken manure organic fertilizer significantly increased the relative abundance and alpha diversity of the bacterial community and ARGs. The content of organic matter, soluble organic nitrogen, available phosphorus, nitrate reductase, hydroxylamine reductase, urease, acid protease, β-glucosidase, oxytetracycline, and tetracycline in the soil of C. camphora forests have significant effects on bacterial community and ARGs. Significant correlations between environmental factors, bacterial communities, and ARGs were observed in the rhizosphere soil of C. camphora forests according to Mantel tests. Overall, the findings of this study revealed that chicken manure organic fertilizer application has a significant effect on the bacterial community and ARGs in the rhizosphere soil of C. camphora forests, and several environmental factors that affect the bacterial community and ARGs were identified.


Drug-Associated Risk Tool: development and validation of a self-assessment questionnaire to screen for hospitalised patients at risk for drug-related problems.
Identifying patients with a high risk for drug-related problems (DRPs) might optimise the allocation of targeted pharmaceutical care during the hospital stay and on discharge. To develop a self-assessment screening tool to identify patients at risk for DRPs and validate the tool regarding feasibility, acceptability and the reliability of the patients' answers. Prospective validation study. Two mid-sized hospitals (300-400 beds). 195 patients, exclusion criteria: under 18 years old, patients with a health status not allowing a meaningful communication (eg, delirium, acute psychosis, advanced dementia, aphasia, clouded consciousness state), palliative or terminally ill patients. Twenty-seven risk factors for the development of DRPs, identified in a previous study, provided the basis of the self-assessment questionnaire, the Drug-Associated Risk Tool (DART). Consenting patients filled in DART, and we compared their answers with objective patient data from medical records and laboratory data. One hundred and sixty-four patients filled in DART V.1.0 in an average time of 7 min. After a first validation, we identified statements with a low sensitivity and revised the wording of the questions related to heart insufficiency, renal impairment or liver impairment. The revised DART (V.2.0) was validated in 31 patients presenting heart insufficiency, renal impairment or liver impairment as comorbidity and reached an average specificity of 88% (range 27-100) and an average sensitivity of 67% (range 21-100). DART showed a satisfying feasibility and reliability. The specificity of the statements was mostly high. The sensitivity varied and was higher in statements concerning diseases that require regular disease control and attention to self-care and drug management. Asking patients about their conditions, medications and related problems can facilitate getting a first, broad picture of the risk for DRPs and possible pharmaceutical needs.


[Calcium homeostasis and nitric oxide processes in children with migraine].
Eighty-one children aged 6 to 17 years who had migraine were examined by clinical and biochemical studies. The activity of Ca2(+)-ATPase and the levels of total intracellular calcium of platelets and plasma nitrites were studied in the attack-free period. Children with migraine were fond to have elevated levels of stable nitric oxide metabolites (nitrites). The level of intracellular calcium was 2 times greater than that in healthy children of the same age, which was followed by compensatory Ca2(+)-ATPase activation. There was a relationship of the parameters of calcium homeostasis and the plasma level of nitrites to the clinical and pathogenetic manifestations of migraine.


Streptozotocin-induced diabetes mellitus in cynomolgus monkeys: changes in carbohydrate metabolism, skin glycation, and pancreatic islets.
Chronic hyperglycemia has been implicated in a number of diabetes mellitus-related conditions in the human population, including retinopathy, neuropathy, nephropathy, and vasculopathy. However, it has been difficult to evaluate the effect of long-term hyperglycemia in a research setting because of the disease's slow progression. In this study, we used streptozotocin (30 mg/kg of body weight, intravenously) to induce a state of chronic hyperglycemia in eight cynomolgus monkeys, and compared these monkeys with a matched control group (n = 8). Seven of eight monkeys with streptozotocin-induced diabetes required insulin therapy to avoid ketosis. After disease induction, all diabetic monkeys had significantly higher preprandial plasma glucose and glycated hemoglobin values, compared with their baseline values or values for control monkeys. Diabetic monkeys also had abnormal responses to an intravenous glucose tolerance test. Consistent with the chronic hyperglycemic state and formation of advanced glycation end products, diabetic monkeys had a significant increase in skin fluorescence over the course of the 6-month study. Plasma triglyceride and cholesterol concentrations increased, but not significantly so, in the diabetic monkeys after disease induction and were not significantly different from concentrations in control monkeys. Six months after disease induction, monkeys were necropsied, and immunohistochemical staining for insulin in the pancreatic islets indicated that diabetic monkeys had a significantly decreased amount of staining for the hormone. The percentage of islet insulin staining was significantly correlated with physiologic responses to the postinduction intravenous glucose tolerance test in all monkeys. Because cynomolgus monkeys are well-characterized models of atherosclerosis, this model may be useful for determining mechanisms whereby diabetes mellitus increases cardiovascular disease.


Aseptic Glenoid Baseplate Loosening After Reverse Total Shoulder Arthroplasty: A Systematic Review and Meta-Analysis.
Aseptic glenoid baseplate loosening can lead to the failure of reverse total shoulder arthroplasty (RTSA). Estimates of the prevalence of aseptic glenoid baseplate loosening after RTSA are required to guide clinical decisions, but published results are variable and lack precision. The goal of this meta-analysis was to determine a precise estimate of the prevalence of aseptic glenoid baseplate loosening after RTSA and to explore variation in the prevalence according to different variables, such as the type of procedure (primary or revision), preoperative diagnosis, the center of rotation of the glenoid component (medialized or lateralized), study size, the definition of aseptic glenoid baseplate loosening, and the duration of follow-up. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. We searched the MEDLINE and Embase databases for English-language articles describing the outcomes after RTSA with a minimum 12-month follow-up in which radiographic findings of aseptic glenoid baseplate loosening were reported. Random-effects meta-analysis was performed, and meta-regression was used to explore the influence of variables on heterogeneity. Subgroup analyses and sensitivity analyses were performed. One hundred and three studies (covering 6,583 RTSAs) performed from 1991 to 2015 met our inclusion criteria. The pooled prevalence of radiographic aseptic glenoid baseplate loosening for all RTSAs was 1.16% (95% confidence interval [CI], 0.80% to 1.69%). The prevalence of aseptic glenoid baseplate loosening was lower among primary RTSAs (0.90%; 95% CI, 0.54% to 1.49%) than among revision RTSAs (3.64%; 95% CI, 1.91% to 6.84%). The pooled prevalence of aseptic glenoid baseplate loosening by diagnosis was 2.69% for osteoarthritis with bone loss, 1.71% for cuff tear arthropathy, 1.20% for rheumatoid arthritis, 1.08% for sequelae of fracture, 0.94% for irreparable massive cuff tear, and 0.25% for acute proximal humeral fracture. The prevalence of aseptic glenoid baseplate loosening was not significantly different for prostheses with a medialized center of rotation (1.15%) versus a lateralized center of rotation (1.84%). To our knowledge, the present study represents the first meta-analysis investigating only aseptic glenoid baseplate loosening after RTSA. Multiple variables were found to be associated with the prevalence of aseptic glenoid baseplate loosening. The rates reported here are lower than those reported previously because of the inclusion of more recent evidence and more studies that evaluated aseptic glenoid baseplate loosening. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Intracellular trafficking and membrane targeting mechanisms of the human reduced folate carrier in Mammalian epithelial cells.
The major pathway for cellular uptake of the water-soluble vitamin folic acid in mammalian cells is via a plasma membrane protein known as the reduced folate carrier (RFC). The molecular determinants that dictate plasma membrane expression of RFC as well as the cellular mechanisms that deliver RFC to the cell surface remain poorly defined. Therefore, we designed a series of fusion proteins of the human RFC (hRFC) with green fluorescent protein to image the targeting and trafficking dynamics of hRFC in living epithelial cells. We show that, in contrast to many other nutrient transporters, the molecular determinants that dictate hRFC plasma membrane expression reside within the hydrophobic backbone of the polypeptide and not within the cytoplasmic NH(2)- or COOH-terminal domains of the protein. Further, the integrity of the hRFC backbone is critical for export of the polypeptide from the endoplasmic reticulum to the cell surface. This trafficking is critically dependent on intact microtubules because microtubule disruption inhibits motility of hRFC-containing vesicles as well as final expression of hRFC in the plasma membrane. For the first time, these data define the mechanisms that control the intracellular trafficking and cell surface localization of hRFC within mammalian epithelia.


Transformation of rodent cells by a cloned DNA fragment of herpes simplex virus type 2.
Transformation of rodent cells with isolated restriction endonuclease fragments of herpes simplex virus type 2 DNA identified a region of the genome located between map positions 0.58 and 0.62. These sequences were cloned into pBR322, and the recombinant plasmid was used to transform primary rat embryo cells and NIH 3T3 cells. The transformants were selected for their ability to form dense foci on a monolayer or to form colonies in semisolid medium. In contrast to the parental rat or mouse cells, cell lines transformed with the cloned herpes simplex virus type 2 fragment grow to high saturation densities, replicate in medium containing 1% serum, form colonies in dilute methylcellulose, show reduced levels of fibronectin, and are tumorigenic in nude mice and in their syngeneic hosts. Southern blot hybridizations have detected sequences homologous to the viral fragment in high-molecular-weight DNA from the transformed cell lines that are not present in DNA from normal rodents. In all cases, the plasmid DNA was present in less than one copy per cell, and the patterns of viral sequences changed with passage of the cell line in vivo.


A role for anti-transglutaminase 2 autoantibodies in the pathogenesis of coeliac disease?
Coeliac disease is an autoimmune-mediated disorder with both innate and adaptive immune components. The disease is triggered by dietary gluten, which provokes the development of a massive immune reaction leading to the destruction of the small-intestinal mucosal morphology and intestinal dysfunction. Besides the typical small-bowel symptoms extraintestinal manifestations may also arise in a subset of coeliac disease patients. In addition, gluten evokes the production of antibodies mainly targeting deamidated gluten peptides or transglutaminase 2. Although coeliac disease has traditionally been regarded as a T cell-mediated disorder, this review discusses the role of the gluten-induced disease-specific anti-transglutaminase 2-autoantibodies in the pathogenesis of the disease.


Adolescent type D personality and social networking sites addiction: A moderated mediation model of restorative outcomes and affective relationships.
Type D personality denotes the joint tendency towards negative affectivity and social inhibition. The recent research has regarded Type D personality as a risk factor of social networking sites addiction. The current study aimed to test whether restorative outcomes would mediate the relation between Type D personality and social networking sites addiction, and whether affective relationships would moderate simultaneously the mediating process. A valid sample of 679 adolescents (mean age = 13.29 ± 0.77 years) participated in our paper-and-pencil survey. Results showed that, after controlling for age and gender, Type D personality positively correlated with social networking sites addiction, and it increased social networking sites addiction via escalating participants' restorative outcomes. Moreover, only affective relationships with friends moderated the mediating effect: for adolescents with low levels of affective relationships with friends, the indirect effect of Type D personality on social networking sites addiction was significant; contrarily, the indirect effect for high levels of affective relationships with friends was non-significant. The current study indicated that Type D personality as a risk factor interacted with other factors (e.g., affective relationships with friends) to contribute to adolescent social networking sites addiction. The limitations and practical implications were discussed.


15N NMR study of the ionization properties of the influenza virus fusion peptide in zwitterionic phospholipid dispersions.
Influenza virus hemagglutinin (HA)-mediated membrane fusion involves insertion into target membranes of a stretch of amino acids located at the N-terminus of the HA(2) subunit of HA at low pH. The pK(a) of the alpha-amino group of (1)Gly of the fusion peptide was measured using (15)N NMR. The pK(a) of this group was found to be 8.69 in the presence of DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine). The high value of this pK(a) is indicative of stabilization of the protonated form of the amine group through noncovalent interactions. The shift reagent Pr(3+) had large effects on the (15)N resonance from the alpha-amino group of Gly(1) of the fusion peptide in DOPC vesicles, indicating that the terminal amino group was exposed to the bulk solvent, even at low pH. Furthermore, electron paramagnetic resonance studies on the fusion peptide region of spin-labeled derivatives of a larger HA construct are consistent with the N-terminus of this peptide being at the depth of the phosphate headgroups. We conclude that at both neutral and acidic pH, the N-terminal of the fusion peptide is close to the aqueous phase and is protonated. Thus neither a change in the state of ionization nor a significant increase in membrane insertion of this group is associated with increased fusogenicity at low pH.


Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1β via caspase-8 in dendritic cells.
The identification of noncanonical (caspase-1-independent) pathways for IL-1β production has unveiled an intricate interplay between inflammatory and death-inducing signaling platforms. We found a heretofore unappreciated role for caspase-8 as a major pathway for IL-1β processing and release in murine bone marrow-derived dendritic cells (BMDC) costimulated with TLR4 agonists and proapoptotic chemotherapeutic agents such as doxorubicin (Dox) or staurosporine (STS). The ability of Dox to stimulate release of mature (17-kDa) IL-1β was nearly equivalent in wild-type (WT) BMDC, Casp1(-/-)Casp11(-/-) BMDC, WT BMDC treated with the caspase-1 inhibitor YVAD, and BMDC lacking the inflammasome regulators ASC, NLRP3, or NLRC4. Notably, Dox-induced production of mature IL-1β was temporally correlated with caspase-8 activation in WT cells and greatly suppressed in Casp8(-/-)Rip3(-/-) or Trif(-/-) BMDC, as well as in WT BMDC treated with the caspase-8 inhibitor, IETD. Similarly, STS stimulated robust IL-1β processing and release in Casp1(-/-)Casp11(-/-) BMDC that was IETD sensitive. These data suggest that TLR4 induces assembly of caspase-8-based signaling complexes that become licensed as IL-1β-converting enzymes in response to Dox and STS. The responses were temporally correlated with downregulation of cellular inhibitor of apoptosis protein 1, suggesting suppressive roles for this and likely other inhibitor of apoptosis proteins on the stability and/or proteolytic activity of the caspase-8 platforms. Thus, proapoptotic chemotherapeutic agents stimulate the caspase-8-mediated processing and release of IL-1β, implicating direct effects of such drugs on a noncanonical inflammatory cascade that may modulate immune responses in tumor microenvironments.


Serrated and microtubular colorectal adenomas in Italian patients. A 5-year survey.
Colorectal adenomas from 1552 Italian patients were histologically classified into tubular (TAs), tubulo-villous (TVAs), villous (VAs), serrated (SAs) and microtubular (MTAs). The purpose was to compare the results to those in 3135 colorectal adenomas from Swedish patients. Of the 1552 adenomas, 827 (53%) were TAs, 352 (23%) TVAs, 196 (12%) VAs, 102 (7%), SAs and 14 (0.9%) MTAs. The remaining 61 (4%) were of combined phenotypes (COMBAs). The percentage of VA (considered as the most important dysplastic precursor of colorectal cancer) was higher in Florence than in Stockholm. Notably, the incidence of colorectal cancer in males was also higher in Florence (78.6/10(5)) than in Stockholm (57.2/10(5)). Notwithstanding, the highest rate of submucosal invasion (7%) was found among SAs. The diameter of the largest section was used to define the size of the largest adenoma in individual patients. Of the 1380 neoplasias measuring < or =12 mm, only 0.9% (n=13) had invasive carcinomas, but as many as 8.1% (n=14) of the 172 neoplasias measuring > or =13 mm. SAs and MTAs are special adenoma phenotypes with particular morphological and cell proliferative attributes at variance from those of TAs, VAs or TVAs. In the light of the present results, it is proposed that SAs and MTAs are included in future reports of colorectal adenomas in order to compare their frequency worldwide.


[Microbiological public health aspects in the use of rain water as water reservoirs for toilet flushing, garden irrigation and laundry].
From a total of 102 rain water cisterns in use for toilet flushing, garden irrigation and laundering washing about 1,600 water samples were collected and subjected to microbiological analysis. The assays included aerobic heterotrophic microorganisms growing at 20 and 37 degrees C, respectively, as well as the identification of Escherichia coli, coliform organisms, faecal streptococci, Pseudomonas aeruginosa, staphylococci, yersiniae, salmonellae, shigellae, legionellae and yeasts. The median of the total number of cells per ml was 1,200 at 20 degrees C and 230 at 37 degrees C, respectively. Approximately 26 E. coli cells and 198 coliform organisms (median values) were found per 100 ml. In the case of cisterns manufactured of plastic the total number of cells was generally found to be lower than in samples collected from concrete or brick-made storage tanks. With the exception of the ubiquitously distributed organism Pseudomonas aeruginosa (found in 11.8% of the samples) and salmonella in only one sample, no other pathogens were detected. More than 95% of all analysed samples met the quality standards for bathing waters as set by the European Community. Provided certain precautions are taken, such as strict separation of mains for drinking water and rain water, as well as correct labelling of pipelines and collection sites, the use of rain water for toilet flushing, garden irrigation and laundry washing presents no unacceptable risk to public health.


Brain beta-hydroxybutyrate utilization in neonatal hypothyroidism in rats.
The in vitro and in vivo utilization of 14C-beta-hydroxybutyrate (BOHB) by the brain in neonatal hypothyroidism was studied in rat pups made hypothyroid by feeding dams a diet containing 0.02% propylthiouracil during pregnancy and lactation. In the in vitro studies, the oxidation of BOHB to CO2 was lower at 14 and 21 days of age in hypothyroid pups than in pair-fed controls but higher at 35 days. The incorporation of BOHB into brain lipid was significantly higher in hypothyroid pups at 14, 21 and 35 days. In contrast, in the in vivo studies, incorporation of BOHB into lipid was significantly lower in hypothyroid pups at 14 and 21 days. These results suggest that hypothyroid pups may have a normal or increased capability to use BOHB for lipid synthesis, but were unable to achieve normal rates of utilization in vivo, possibly due to a decreased substrate availability. These findings may have implications for the decreased brain lipid content characteristic of neonatal hypothyroidism.


Using the Blackburne-Peel index to measure the patellar height on magnetic resonance images.
To reveal the normal values of patellar height measurements using the Blackburne-Peel index on magnetic resonance (MR) images and to show the gender and age differences regarding this measurement technique. This retrospective cross-sectional study investigated 148 knee MR images, and those images were re-evaluated to find out the normal values of patellar height using the Blackburne-Peel index (BPI). An adapted measurement technique of this index was applied to MR images. The study group was analyzed regarding the sex and age differences, correlation with age was investigated, and all descriptive data were presented. Independent Samples T-test, Kruskal-Wallis variance analysis, and Spearman's Rho correlation test was applied to calculate the results. The mean value was 0.80 ± 0.09 for the total of patients. The measurements regarding the height of the inferior edge of the patella articular surface and the length of the patella articular surface indicated a significant difference between females and males (p < 0.001 for both measurements). The descriptive data obtained from this study revealed the mean values of the whole study group, different sexes, and age groups separately. Additional studies are needed for adapting BPI on MR images and verifying the normal values of the population.


Hearing-aid assembly management among adults from culturally and linguistically diverse backgrounds: toward the feasibility of self-fitting hearing aids.
The purpose of the study was twofold: (1) to assess the ability of hearing-impaired adults in the developing world to independently and accurately assemble a pair of hearing aids by following instructions that were written and illustrated according to best-practice health literacy principles; and (2) to determine which factors influence independent and accurate task completion. Correlational study. Forty South African and 40 Chinese adults with a hearing loss and their partners. The participant group included 42 females and 38 males ranging in age from 32 to 92 years. Ninety-five percent of South African and 60% of Chinese participants completed the assembly task, either on their own or with assistance from their partners. Better health literacy, younger age, and a more prestigious occupation were significantly associated with independent task completion for the South African and Chinese participants. Task accuracy was significantly linked to higher levels of cognitive function among South African participants, while a paucity of valid data prevented an analysis of accuracy from being conducted with the Chinese data. Individuals of diverse backgrounds can manage the self-fitting hearing-aid assembly task as long as health literacy levels and cultural differences are considered.


Oral iron chelation therapy with deferiprone in patients with Thalassemia Major.
To determine the efficacy and adverse effects of deferiprone in patients with Thalassemia Major. A prospective case series study was conducted at the Fatimid Foundation Blood Bank and Haematological Diseases center Lahore. A total of 87 patients entered into the study between September 2005 and November 2006. Deferiprone was given at subsidized rates at a dose of 75/mg/day for seven days. Physical examination and initial Laboratory investigations were done in all patients at the start of the study. Physical and laboratory data were filled on a questionnaire and analyzed using SPSS version 10.0. Eighty seven patients with mean age of 10.0 +/- 4.33 years (range 4-27 years) were included in the study. Mean follow up was 8 +/- 3.94 months (range 2-12 months). The mean Ferritin at the start of study was 4656 +/- 2052.5 ug/L (range 1200-14630 ug/L) and at the end of study period was 4139 +/- 1710.4 ug/L (range 749-8961) (p < 0.001). Adverse events were joint pains in 10% patients, gastrointestinal symptoms in 11% and no adverse events in 79% patients. There was no evidence of agranulocytosis in any patient. Deferiprone was well tolerated, had few adverse effects and was effective in lowering the patient's serum ferritin level.


Effects of Music Listening During Loop Electrosurgical Excision Procedure on Pain and Anxiety: A Randomized Trial.
The aim of the study was to compare pain, anxiety, and satisfaction between women, who listened to music, and those who did not during loop electrosurgical excision procedure (LEEP). Participants were randomly assigned into two groups. In group 1 (music), the participants listened to relaxing instrumental music through the stereo headset from the time of arrival at the preoperative waiting room until the procedure completed. For group 2 (control), the participants underwent LEEP without music listening. The women rated pain, anxiety, and satisfaction according to 10-cm visual analog scales. Pain was assessed at the time of speculum insertion (baseline pain) and immediately after the LEEP completed (procedural pain). Anxiety and satisfaction were examined just before starting the LEEP and 10 minutes after the procedure completed. One hundred fifty patients (74 in music group and 76 in control group) participated. Mean baseline pain scores after speculum insertion were comparable between the groups (3.7 in the music group vs. 3.5 in the control group, p = .55). Mean procedural pain scores were not different between the groups (4.7 in the music group vs. 5.2 in the control group, p = .32). The differences of the procedural pain scores from baseline were statistically comparable between the study groups (0.9 in the music group vs. 1.7 in the control group, p = .15). There were no significant differences in anxiety and satisfaction scores at any time points assessed between the groups. The effects of music listening on reducing pain and anxiety during LEEP could not be demonstrated in this study.


Effects of dietary camelina, flaxseed, and canola oil supplementation on transepidermal water loss, skin and coat health parameters, and plasma prostaglandin E2, glycosaminoglycan, and nitric oxide concentrations in healthy adult horses.
Camelina oil is derived from a low-input, high-yield crop and, in comparison to many other dietary fat sources currently used in equine diets, provides a greater amount of α-linolenic acid [ALA; (n-3)], than linoleic acid [LA; (n-6)]. However, no research exists assessing the effects of feeding camelina oil to horses in contrast to other commonly used oils. The objective of this study was to compare the effect of supplementing camelina oil to that of flaxseed and canola oil supplementation, on outcomes related to skin and coat health in horses. Thirty adult horses [23 mares, 7 geldings; 14.9 years ± 5.3 years; 544 ± 66 kg body weight (BW) (mean ± SD)] underwent a 4-week wash-in period consuming hay and sunflower oil. Following the wash-in period, horses were blocked by location, age, and BW, and assigned to one of three treatment oils for 16 weeks (370 mg oil/kg BW): camelina (CAM), canola (OLA), or flaxseed (FLX) oil. Blood samples were collected and plasma prostaglandin E2 (PGE2; ELISA), nitric oxide (NO; Griess Reaction), and glycosaminoglycan (GAG; DMMB) concentrations were measured on weeks 0 (n = 30), 14 (n = 24), and 16 (n = 30). On weeks 0, 2, 4, 8, and 16, transepidermal water loss (TEWL) was measured pre- and post-acetone application using a VapoMeter (n = 26), and a 5-point-Likert scale was used to assess skin and coat characteristics on the side and rump of the horses (n = 30). All data were analyzed with repeated measures ANOVA using PROC GLIMMIX in SAS. Independent of treatment, coat color, and quality increased from baseline. There were no differences in the outcomes assessed between the horses supplemented camelina oil and those supplemented canola or flaxseed oil. These results suggest that independent of treatment, all oil supplements improved coat color and quality in horses. This provides indication that camelina oil is comparable to existing plant-based oil supplements in supporting skin and coat health and inflammation in horses.