Strain screen and haplotype association mapping of wheel running in inbred mouse strains.
Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (approximately 8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity.


The Socioeconomic Implications of Isolated Tibial and Femoral Fractures from Road Traffic Injuries in Uganda.
The purpose of this study was to determine the socioeconomic implications of isolated tibial and femoral fractures caused by road traffic injuries in Uganda. This prospective longitudinal study included adult patients who were admitted to Uganda's national referral hospital with an isolated tibial or femoral fracture. The primary outcome was the time to recovery following injury. We assessed recovery using 4 domains: income, employment status, health-related quality of life (HRQoL) recovery, and school attendance of the patients' dependents. The majority of the study participants (83%) were employed, and they were the main income earner for their household (74.0%) at the time of injury, earning a mean annual income of 2,375 U.S. dollars (USD). All of the patients had been admitted with the intention of surgical treatment; however, because of resource constraints, only 56% received operative treatment. By 2 years postinjury, only 63% of the participants had returned to work, and 34% had returned to their previous income level. Overall, the mean monthly income was 62% less than preinjury earnings, and participants had accumulated 1,069 USD in debt since the injury; 41% of the participants had regained HRQoL scores near their baseline, and 62% of school-aged dependents, enrolled at the time of injury, were in school at 2 years postinjury. At 2 years postinjury, only 12% of our cohort of Ugandan patients who had sustained an isolated tibial or femoral fracture from a road traffic injury had recovered both economically and physically. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Tissue Phenomics for prognostic biomarker discovery in low- and intermediate-risk prostate cancer.
Tissue Phenomics is the discipline of mining tissue images to identify patterns that are related to clinical outcome providing potential prognostic and predictive value. This involves the discovery process from assay development, image analysis, and data mining to the final interpretation and validation of the findings. Importantly, this process is not linear but allows backward steps and optimization loops over multiple sub-processes. We provide a detailed description of the Tissue Phenomics methodology while exemplifying each step on the application of prostate cancer recurrence prediction. In particular, we automatically identified tissue-based biomarkers having significant prognostic value for low- and intermediate-risk prostate cancer patients (Gleason scores 6-7b) after radical prostatectomy. We found that promising phenes were related to CD8(+) and CD68(+) cells in the microenvironment of cancerous glands in combination with the local micro-vascularization. Recurrence prediction based on the selected phenes yielded accuracies up to 83% thereby clearly outperforming prediction based on the Gleason score. Moreover, we compared different machine learning algorithms to combine the most relevant phenes resulting in increased accuracies of 88% for tumor progression prediction. These findings will be of potential use for future prognostic tests for prostate cancer patients and provide a proof-of-principle of the Tissue Phenomics approach.


Pulmonary tumour emboli: a difficult ante-mortem diagnosis.
A woman with known metastatic breast cancer presented with subacute dyspnoea. Investigations were non-conclusive; provisional diagnoses of pulmonary thromboemboli and carcinomatous lymphangitis were made. Despite treatment the patient died 10 days after admission. Post-mortem examination showed extensive tumour emboli within the pulmonary arteries. The appropriate investigation and management of such patients is discussed.


The INO80 Complex Requires the Arp5-Ies6 Subcomplex for Chromatin Remodeling and Metabolic Regulation.
ATP-dependent chromatin remodeling complexes are essential for transcription regulation, and yet it is unclear how these multisubunit complexes coordinate their activities to facilitate diverse transcriptional responses. In this study, we found that the conserved Arp5 and Ies6 subunits of the Saccharomyces cerevisiae INO80 chromatin-remodeler form an abundant and distinct subcomplex in vivo and stimulate INO80-mediated activity in vitro. Moreover, our genomic studies reveal that the relative occupancy of Arp5-Ies6 correlates with nucleosome positioning at transcriptional start sites and expression levels of >1,000 INO80-regulated genes. Notably, these genes are significantly enriched in energy metabolism pathways. Specifically, arp5Δ, ies6Δ, and ino80Δ mutants demonstrate decreased expression of genes involved in glycolysis and increased expression of genes in the oxidative phosphorylation pathway. Deregulation of these metabolic pathways results in constitutively elevated mitochondrial potential and oxygen consumption. Our results illustrate the dynamic nature of the INO80 complex assembly and demonstrate for the first time that a chromatin remodeler regulates glycolytic and respiratory capacity, thereby maintaining metabolic stability.


Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling.
Fructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. Permanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo. Our results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo. Taken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia.


Participation in leisure activities: differences between children with and without physical disabilities.
The aim of the current study was to compare varied dimensions of participation in leisure activities among school-aged children ages 10-16 with and without disabilities. The Children Leisure Activity Scale (CLASS) was administrated to 294 children, 81 with and 213 without physical disability. Two-way MANCOVA revealed significant differences between the frequency of participation in leisure activities of the study groups: an effect of disability F(4,265=239.57; p<0.001, η(2)=0.78); an effect of gender F(4,265=3.35; p<0.01, η(2)=0.05); and an interaction effect between gender and disability F(4,265=5.23; p<0.001, η(2)=0.64). Children with disabilities, and mostly girls, were found at risk to participate in a narrower variety of activities that involved fewer social interactions. Using linear regressions for each group two different models were identified. Using the CLASS the study contributes evidence-based data regarding children at risk for leisure participation. In addition, the research further established the discriminate validity of the CLASS.


Two dimensional CrGa2Se4: a spin-gapless ferromagnetic semiconductor with inclined uniaxial anisotropy.
Magnetic semiconductors with high critical temperature have long been the focus in materials science and are also known as one of the fundamental questions in two-dimensional (2D) materials. Based on density functional theory calculations, we predict a 2D spin-gapless ferromagnetic semiconductor of CrGa2Se4 monolayer, in which the type of spin-polarized current can be tuned by tailoring the Fermi energy. Moreover, the magnetic anisotropy energy calculations indicate that the CrGa2Se4 monolayer possesses spin anisotropy both in the basal plane and the vertical plane. This originates from the distortion-induced rearrangement of the 3d electrons in the CrSe6 octahedron and results in an inclined easy axis out of the film. The Curie temperature (Tc) of ferromagnetic phase transition for 2D CrGa2Se4 is more than 200 K. This 2D material shows promising transport properties for spintronics applications and is also important for fundamental research in 2D magnetism.


Time to first tumor progression as outcome predictor of a second trasuzumab-based therapy beyond progression in HER-2 positive metastatic breast cancer.
In a previous analysis performed on a cohort of 37 HER-2 positive metastatic breast cancer (MBC) patients treated with trastuzumab beyond progression, we found that a second trastuzumab-based therapy is associated with a considerable response rate and preserved time to progression as compared with a first trastuzumab-based therapy. In the present study, we extended the analysis to a total of 69 patients treated in four different italian Institutions, also trying to identify clinical predictors of sensitivity to a second trastuzumab-based therapy beyond progression. Efficacy results on the overall population confirmed that a second trastuzumab-based therapy beyond progression is an active regimen (27.5% of responses and 6.5 months of time to progression, respectively). Median time to progression to the first trastuzumab therapy (TTP1) identified two groups of patients with different sensitivity to trastuzumab beyond progression (group A, TTP1 >or= 8 months and group B, TTP1 < 8 months) in terms of time to second progression and post-progression survival (group A versus group B showed respectively a time to second progression of 7.6 versus 4.7 months, p = 0.05, and a post-progression survival of 31.7 months versus 21.8 months, p = 0.04). In the multivariate analysis, only TTP1 was a predictor of time to second progression and post-progression survival. Despite the recent approval of lapatinib plus capecitabine for trastuzumab-progressing patients, it is still reasonable to offer trastuzumab beyond progression to HER-2 positive MBC patients, because these data confirm the potential utility of such a conduct. In the clinic, time to first tumor progression may represent a useful tool to identify patients who are more likely to benefit from trastuzumab beyond progression.


Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity.
It has been thought that incretin signaling prevents arteriosclerosis, and very recently anti-arteriosclerotic effects through GLP-1 receptor were finally demonstrated in clinical human study. The purpose of this study was to investigate how vascular GLP-1 receptor expression is influenced in human subjects. First, we evaluated GLP-1 receptor expression in human arteries in immunostaining. Next, we separated the artery into the intima and media, and evaluated gene expression levels of various factors. We divided the subjects into obesity and non-obesity group and compared their expression levels between them. Finally, we evaluated which factors determine vascular GLP-1 receptor expression. GLP-1 receptor expression in intima and media was lower in obesity group compared to non-obesity group which was correlated with the alteration of TCF7L2 expression. Multiple regression analyses showed that BMI was an independent determining factor for GLP-1 receptor expression in the intima and media. Furthermore, using small interfering RNA method and TCF7L2-EGFP adenovirus, we showed that TCF7L2 was involved in GLP-1 receptor expression in human vascular cells. Taken together, vascular GLP-1 receptor and TCF7L2 expression was significantly down-regulated in human subjects with obesity. In addition, it is likely that TCF7L2 functions as a modulator of vascular GLP-1 receptor expression.


Reversible and irreversible vapor-induced guest molecule exchange in spin-crossover compounds.
Spin-crossover (SCO) complex [Fe(tpa)(NCS)(2)] (tpa = tri(2-pyridylmethyl)amine) crystallized in two solvate forms, yellow [Fe(tpa)(NCS)(2)]·X [Fe:X = 1:1; X = n-PrOH (complex is named as n-PrOH), i-PrOH (i-PrOH), CH(2)Cl(2) (CH(2)Cl(2)), CHCl(3) (CHCl(3)), MeCN (MeCN)] and red [Fe(tpa)(NCS)(2)](2)·Y [Fe:Y = 2:1; Y = MeOH (MeOH), EtOH (EtOH)], respectively. Between the two forms, interesting solvent-vapor induced in situ reversible and irreversible guest molecule exchanges, [Fe(tpa)(NCS)(2)]·X ⇌ [Fe(tpa)(NCS)(2)](2)·Y, occurred in the solid state followed by dramatic color changes as well as distinct structural and SCO behavior transformations. Comprehensive studies on structures and SCO behaviors associating guest exchanges have been conducted by X-ray single-crystal diffraction, PXRD, IR, elemental analysis, and magnetic measurements, respectively. This discrete molecular system shows unique solvent-dependent SCO behavior related to the nature of solvent molecules; the distinct color changes during guest exchange originate from the alternations of electronic states of the guest-sensitive Fe(II) centers, providing an effective route to fine-tune and optimize materials' properties by systematic structural perturbation, or serving for detection of toxic gases, such as CH(2)Cl(2) and CHCl(3).


Admission hyperglycemia predicts inhospital mortality and major adverse cardiac events after primary percutaneous coronary intervention in patients without diabetes mellitus.
Admission hyperglycemia is associated with high inhospital and long-term adverse events in patients that undergo primary percutaneous coronary intervention (PCI). We aimed to evaluate whether hyperglycemia predicts inhospital mortality. We prospectively analyzed 503 consecutive patients. The patients were divided into tertiles according to the admission glucose levels. Tertile I: glucose <118 mg/dL (n = 166), tertile II: glucose 118 to 145 mg/dL (n = 168), and tertile III: glucose >145 mg/dL (n = 169). Inhospital mortality was 0 in tertile I, 2 in tertile II, and 9 in tertile III (P < .02). Cardiogenic shock occurred more frequently in tertile III compared to tertiles I and II (10% vs 4.1% and 0.6%, respectively, P = .01). Multivariate logistic regression analysis revealed that patients in tertile III had significantly higher risk of inhospital major adverse cardiac events compared to patients in tertile I (odds ratio: 9.55, P < .02). Admission hyperglycemia predicts inhospital adverse cardiac events in mortality and acute ST-segment elevation myocardial infarction in patients that underwent primary PCI.


A Sound Prediction: EEG-Based Neural Synchrony Predicts Online Music Streams.
Neuroforecasting predicts population-wide choices based on neural data of individuals and can be used, for example, in neuromarketing to estimate campaign successes. To deliver true value, the brain activity metrics should deliver predictive value above and beyond traditional stated preferences. Evidence from movie trailer research has proposed neural synchrony, which compares the similarity of brain responses across participants and has shown to be a promising tool in neuroforecasting for movie popularity. The music industry might also benefit from these increasingly accurate success predictors, but only one study has been forecasting music popularity, using functional magnetic resonance imaging measures. Current research validates the strength of neural synchrony as a predictive measure for popularity of music, making use of electroencephalogram to capture moment-to-moment neural similarity between respondents while they listen to music. Neural synchrony is demonstrated to be a significant predictor for public appreciation on Spotify 3 weeks and 10 months after the release of the albums, especially when combined with the release of a single. On an individual level, other brain measures were shown to relate to individual subjective likeability ratings, including Frontal Alpha Asymmetry and engagement when combined with the factors artist and single release. Our results show the predictive value of brain activity measures outperforms stated preferences. Especially, neural synchrony carries high predictive value for the popularity on Spotify, providing the music industry with an essential asset for efficient decision making and investments, in addition to other practical implications that include neuromarketing and advertising industries.


Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber's hereditary optic neuropathy.
Leber's hereditary optic neuropathy (LHON) is a maternally transmitted eye disease due to the degeneration of retinal ganglion cells (RGCs). Mitochondrial 11778G > A mutation is the most common LHON-associated mitochondrial DNA (mtDNA) mutation. Our recent studies demonstrated some LHON families manifested by synergic interaction between m.11778G > A mutation and YARS2 allele (c.572G > T, p.Gly191Val) encoding mitochondrial tyrosyl-tRNA synthetase. However, the RGC-specific effects of LHON-associated mtDNA mutations remain elusive and there is no highly effective therapy for LHON. Here, we generated patients-derived induced pluripotent stem cells (iPSCs) from fibroblasts derived from a Chinese LHON family (both m.11778G > A and c.572G > T mutations, only m.11778G > A mutation, and control subject). The c.572G > T mutation in iPSC lines from a syndromic individual was corrected by CRISPR/Cas9. Those iPSCs were differentiated into neural progenitor cells and subsequently induced RGC-like cells using a stepwise differentiation procedure. Those RGC-like cells derived from symptomatic individual harboring both m.11778G > A and c.572G > T mutations exhibited greater defects in neuronal differentiation, morphology including reduced area of soma, numbers of neurites and shortened length of axons, electrophysiological properties than those in cells bearing only m.11778G > A mutation. Furthermore, these RGC-like cells revealed more drastic reductions in oxygen consumption rates, levels of mitochondrial ATP and increasing productions of reactive oxygen species than those in other cell models. These mitochondrial dysfunctions promoted the apoptotic process for RGC degenerations. Correction of YARS2 c.572G > T mutation rescued deficiencies of patient-derived RGC-like cells. These findings provide new insights into pathophysiology of LHON arising from RGC-specific mitochondrial dysfunctions and step toward therapeutic intervention for this disease.


Role of voltage-dependent calcium channels on the striatal in vivo dopamine release induced by the organophosphorus pesticide glyphosate.
In the present study, we investigated the role of voltage-sensitive calcium channels (VSCCs) on the striatal dopamine release induced by the pesticide glyphosate (GLY) using selective VSCC inhibitors. The dopamine levels were measured by in vivo cerebral microdialysis coupled to HPLC-ED. Nicardipine (L-type VSCC antagonist) or ω-conotoxin MVIIC (non-selective P/Q-type antagonist) had no effect on dopamine release induced by 5 mM GLY. In contrast, flunarizine (T-type antagonist) or ω-conotoxin GVIA (neuronal N-type antagonist) significantly reduced GLY-stimulated dopamine release. These results suggest that GLY-induced dopamine release depends on extracellular calcium and its influx through the T- and N-type VSCCs. These findings were corroborated by molecular docking, which allowed us to establish a correlation between the effect of GLY on blocked VSCC with the observed dopamine release. We propose new molecular targets of GLY in the dorsal striatum, which could have important implications for the assessment of pesticide risks in non-target organisms.


Preparation, Performance and Challenges of Catalyst Layer for Proton Exchange Membrane Fuel Cell.
In this paper, the composition, function and structure of the catalyst layer (CL) of a proton exchange membrane fuel cell (PEMFC) are summarized. The hydrogen reduction reaction (HOR) and oxygen reduction reaction (ORR) processes and their mechanisms and the main interfaces of CL (PEM|CL and CL|MPL) are described briefly. The process of mass transfer (hydrogen, oxygen and water), proton and electron transfer in MEA are described in detail, including their influencing factors. The failure mechanism of CL (Pt particles, CL crack, CL flooding, etc.) and the degradation mechanism of the main components in CL are studied. On the basis of the existing problems, a structure optimization strategy for a high-performance CL is proposed. The commonly used preparation processes of CL are introduced. Based on the classical drying theory, the drying process of a wet CL is explained. Finally, the research direction and future challenges of CL are pointed out, hoping to provide a new perspective for the design and selection of CL materials and preparation equipment.


Psychometric evaluation of the gambling self-efficacy questionnaire with treatment-seeking pathological gamblers.
Gambling-related self-efficacy has been shown to correspond with treatment success and maintenance of treatment gains. Accordingly, there is a need for gambling assessment measures that have been validated with treatment-seeking individuals. In this study, we reported on the evaluation of a measure of perceived self-efficacy to control gambling behavior in high-risk relapse situations, the Gambling Self-Efficacy Questionnaire (GSEQ; May, Whelan, Steenbergh, & Meyers, 2003). Confirmatory and exploratory factor analyses provided some support for the original single-factor solutions, but also suggested the presence of individual patterns of self-efficacy across high-risk situations. The GSEQ demonstrated convergence with indices of problem-gambling severity and scores on the measure significantly increased across a brief cognitive-behavioral intervention. The sensitivity and specificity were evaluated and the findings supported that an average self-efficacy rating of 70% corresponded with indices of pathological gambling.


Sustained effect of human growth hormone therapy on children with intrauterine growth retardation.
Previous studies have not clarified whether human growth hormone (HGH) therapy can significantly increase the height of patients with intrauterine growth retardation (IUGR). To determine whether the initial increase in growth rate is sustained through subsequent treatment, 19 prepubertal patients who had IUGR were treated with HGH. Ten of them received a second treatment course. Growth rates (in centimeters per year) were 4.8 +/- 1.4 (mean +/- SD) for the pretreatment period, 7.6 +/- 2.3 for the first treatment period, 4.2 +/- 2.5 for the interval between treatments, 5.9 +/- 1.4 for the second treatment period, and 4.3 +/- 2.6 for the posttreatment period. Growth rates for the two treatment periods were significantly greater than for the periods before, interval between, and posttreatment. Height expressed as the number of standard deviations below the mean for age increased significantly between the onset of treatment and the most recent measurement. These data indicate that HGH has a sustained positive effect on increasing growth rates in children with IUGR, although the magnitude of the effect may decrease with further treatment. Furthermore, we suggest that it is worthwhile to treat patients who have IUGR with HGH for prolonged periods of time, if supplies exceed those necessary to treat children with growth hormone deficiency.


INFLUENCE OF TOBACCO, ALCOHOL AND DIABETES ON THE COLLAGEN OF CREMASTER MUSCLE IN PATIENTS WITH INGUINAL HERNIAS.
New findings point out that the mechanism of formation of the hernias can be related to the collagenous tissues, under activity of aggressive agents such as the tobacco, alcohol and diabetes. To analyze the collagen present in the cremaster muscle in patients with inguinal hernias, focusing the effect of tobacco, alcohol, and diabetes. Fifteen patients with inguinal hernia divided in three groups were studied: group I (n=5) was control; group II (n=5) were smokers and/or drinkers; and group III (n=5) had diabetes mellitus. All subjects were underwent to surgical repair of the inguinal hernias obeying the same pre, intra and postoperative conditions. During surgery, samples of the cremaster muscle were collected for analysis in polarized light microscopy, collagen morphometry and protein. The area occupied by the connective tissue was higher in groups II and III (p<0.05). The collagen tissue occupied the majority of the samples analyzed in comparison to the area occupied by muscle cells. The content of total protein was higher in groups II and III compared to the control group (p<0.05). The tobacco, alcohol and diabetes cause a remodel the cremaster muscle, leading to a loss of support or structural change in this region, which may enhance the occurrences and damage related to inguinal hernias.


The ets-related transcription factor GABP directs bidirectional transcription.
Approximately 10% of genes in the human genome are distributed such that their transcription start sites are located less than 1 kb apart on opposite strands. These divergent gene pairs have a single intergenic segment of DNA, which in some cases appears to share regulatory elements, but it is unclear whether these regions represent functional bidirectional promoters or two overlapping promoters. A recent study showed that divergent promoters are enriched for consensus binding sequences of a small group of transcription factors, including the ubiquitous ets-family transcription factor GA-binding protein (GABP). Here we show that GABP binds to more than 80% of divergent promoters in at least one cell type. Furthermore, we demonstrate that GABP binding is correlated and associated with bidirectional transcriptional activity in a luciferase transfection assay. In addition, we find that the addition of a strict consensus GABP site into a set of promoters that normally function in only one direction significantly increases activity in the opposite direction in 67% of cases. Our findings demonstrate that GABP regulates the majority of divergent promoters and suggest that bidirectional transcriptional activity is mediated through GABP binding and transactivation at both divergent and nondivergent promoters.


Mapping QTL for important seed traits in an interspecific F2 population of pigeonpea.
Seed traits present important breeding targets for enhancing grain yield and quality in various grain legume crops including pigeonpea. The present study reports significant genetic variation for six seed traits including seed length (SL), seed width (SW), seed thickness (ST), seed weight (SWT), electrical conductivity (EC) and water uptake (WU) among Cajanus cajan (L.) Millspaugh acc. ICPL 20340 and Cajanus scarabaeoides (L.) Thouars acc. ICP 15739 and an F2 population derived from this interspecific cross. Maximum phenotypic values recorded for the F2 population were higher than observed in the parent ICPL 20340 [F2 max vs ICPL 20340: SW (7.05 vs 5.38), ST (4.63 vs 4.51), EC (65.17 vs 9.72), WU (213.17 vs 109.5)], which suggested contribution of positive alleles from the wild parent, ICP 15739. Concurrently, to identify the QTL controlling these seed traits, we assayed two parents and 94 F2 individuals with 113 polymorphic simple sequence repeat (SSR) markers. In the F2 population, 98 of the 113 SSRs showed Mendelian segregation ratio 1:2:1, whereas significant deviations were observed for 15 SSRs with their χ 2 values ranging between 6.26 and 20.62. A partial genetic linkage map comprising 83 SSR loci was constructed. QTL analysis identified 15 marker-trait associations (MTAs) for seed traits on four linkage groups i.e. LG01, LG02, LG04 and LG05. Phenotypic variations (PVs) explained by these QTL ranged from 4.4 (WU) to 19.91% (EC). These genomic regions contributing significantly towards observed variability of seed traits would serve as potential candidates for future research that aims to improve seed traits in pigeonpea.


Proximal tibial varus osteotomy for osteoarthritis of the lateral compartment of the knee.
From 1960 through 1979, a closing-wedge varus osteotomy of the proximal part of the tibia was performed in thirty-one knees (twenty-eight patients) for painful osteoarthritis of the lateral compartment of the knee that was associated with a valgus deformity. The patients were followed for two to seventeen years (average, 9.4 years). Twenty-four knees (77 per cent) had either no pain or only occasional mild pain at the last evaluation. Six knees had moderate pain and one, severe pain. Six knees required a subsequent total knee arthroplasty at an average of 9.8 years after the osteotomy. No patient had an infection or non-union. Osteotomy of the proximal part of the tibia is a reasonable method of treating unicompartmental degenerative arthritis in a knee with a valgus deformity. Although some patients with as much as 20 degrees of anatomical valgus deformity obtained a good result in this series, osteotomy in the supracondylar region of the femur is probably preferable if the valgus angulation exceeds 12 degrees or if the tilt of the tibial articular surface that will result from the surgery will exceed 10 degrees. Correction beyond the normal 5 to 7 degrees of valgus angulation to zero degree of anatomical tibiofemoral alignment is recommended to prevent recurrence of the valgus deformity and to decrease the load on the lateral tibiofemoral compartment.


Constrained selected reaction monitoring: quantification of selected post-translational modifications and protein isoforms.
Selected reaction monitoring (SRM) is a mass spectrometry method that can target signature peptides to provide for the detection and quantitation of specific proteins in complex biological samples. When quantifying a protein, multiple peptides are generated using a specific protease such as trypsin, thereby allowing a choice of signature peptides with robust signals. In contrast, signature peptide selection can be constrained when the goal is to monitor a specific post-translational modification (PTM) or protein isoform, as the signature peptide must include the amino acid residue(s) of PTM attachment or sequence variation. This can force the selection of a signature peptide with a weak SRM response or one that is confounded by high background. In this article, we discuss steps that can be optimized to maximize peptide selection and assay performance of constrained SRM assays, including tuning instrument parameters, fragmenting product ions, using a different protease, and enriching the sample. Examples are provided for phosphorylated or citrullinated peptides and protein isoforms.


Primary hyperhidrosis: Implications on symptoms, daily life, health and alcohol consumption when treated with botulinum toxin.
Primary hyperhidrosis affects approximately 3% of the population and reduces quality of life in affected persons. Few studies have investigated the symptoms of anxiety, depression and hazardous alcohol consumption among those with hyperhidrosis and the effect of treatment with botulinum toxin. The first aim of this study was to investigate the effect of primary hyperhidrosis on mental and physical health, and alcohol consumption. Our second aim was to study whether and how treatment with botulinum toxin changed these effects. One hundred and fourteen patients answered questionnaires regarding hyperhidrosis and symptoms, including hyperhidrosis disease severity scale (HDSS), visual analog scale (VAS) 10-point scale for hyperhidrosis symptoms, hospital anxiety and depression scale (HADS), alcohol use disorder identification test (AUDIT) and short-form health survey (SF-36) before treatment with botulinum toxin and 2 weeks after. The age of onset of hyperhidrosis was on average 13.4 years and 48% described heredity for hyperhidrosis. Significant improvements were noted in patients with axillary and palmar hyperhidrosis regarding mean HDSS, VAS 10-point scale, HADS, SF-36 and sweat-related health problems 2 weeks after treatment with botulinum toxin. Changes in mean AUDIT for all participants were not significant. Primary hyperhidrosis mainly impairs mental rather than physical aspects of life and also interferes with specific daily activities of the affected individuals. Despite this, our patients did not show signs of anxiety, depression or hazardous alcohol consumption. Treatment with botulinum toxin reduced sweat-related problems and led to significant improvements in HDSS, VAS, HADS and SF-36 in our patients.


Revised Kubelka-Munk theory. I. Theory and application.
Using a statistical analysis of light propagation in media, we propose a revision to Kubelka-Munk (K-M) theory by taking into account the effect of scattering on the path length of light propagation (path variation). This leads to new relationships between the K-M scattering S and absorbing K coefficients and the intrinsic scattering s and absorbing a coefficients of a material that indicate that the S and K coefficients depend non-linearly on both a and s. The additivity law that bridges K-M S and K coefficients of a composite medium, such as dye-dispersed paper (dyed paper) and those of its material components (dye and paper), is also revised. It is further shown that experimental findings on dyed paper that the original K-M theory failed to explain can be clearly understood and accommodated by the new K-M theoretical framework (two-flux approach). Numerical simulations with the revised theory on model ink, paper, and dyed paper have been carried out.


Point prevalence of healthcare-associated infections and antibiotic use in three large Swiss acute-care hospitals.
The overall burden of healthcare-associated infections (HAIs) remains high, even in high-income countries. However, the current burden of HAI in Switzerland is unknown. Prevalence surveys have a long tradition in the field of infection prevention and control for measuring both HAI and antimicrobial use. The objective of this survey was to test the point prevalence survey (PPS) methodology of the European Centre for Disease Prevention and Control (ECDC) in acute-care hospitals in Switzerland. Two tertiary care hospitals and one secondary care hospital in central and western Switzerland participated in the survey. Patients from all wards except for emergency departments and psychiatric wards were included. Data were collected on a single day for every ward with a maximum time frame of 2 weeks for completing data collection. Methodology and definitions were based on the most recent ECDC PPS protocol. Data on a total of 2421 patients were analysed. One hundred thirty-six patients had 153 HAIs, corresponding to a prevalence of 5.6% (95% confidence interval [CI] 4.7-6.5%). Rapidly fatal McCabe score, hospitalisation in the intensive care unit (ICU), and having a medical device in place were independent risk factors for HAI. Lower respiratory tract infection was the most frequent HAI type (24.8%), followed by surgical site infection (22.2%), bloodstream infection (17.0%) and urinary tract infection (13.7%). The highest HAI prevalence (26.2%) was observed in the ICU. In total, 60.8% of all HAIs were microbiologically confirmed. The most common microorganism was Escherichia coli (21.1%). Six hundred sixty-nine patients (27.6%, 95% CI 25.9-29.4%) received 893 antimicrobials for 705 indications. Community-acquired infections (39.0%) were the most common indication for antimicrobial use and amoxicillin-clavulanate was the most commonly prescribed antimicrobial (18.4%). HAI prevalence and antimicrobial use in this survey were similar to findings of the past ECDC PPS. The ECDC methodology proved applicable to Swiss acute-care hospitals.


Operational issues in the control of the vectors of Brugia.
An estimated 13 million people in the Oriental Region have brugian filariasis. The filarial parasites that cause this disease exist in periodic and sub-periodic forms and are transmitted by four genera of mosquito: Anopheles, Mansonia and, less frequently, Coquillettidia and Ochlerotatus. In most endemic countries, control of the disease has been entirely based on chemotherapy, although house-spraying and use of insecticide-treated bednets can be quite effective against the vectors of nocturnally periodic Brugia malayi and B. timori. The vector-control methods that may be applied against the Mansonia mosquitoes that transmit the parasites causing sub-periodic brugian filariasis are reviewed here. Most of the conventional methods for controlling the immature, aquatic stages of mosquitoes have proved unsatisfactory against Mansonia. The reason is that, unlike the those of other genera, the larvae and pupae of Mansonia spp. are relatively immobile and obtain air not at the water surface but from the underwater roots, stems and leaves of floating plants to which the larvae and pupae attach. Removal of host plants can be very effective in reducing Mansonia productivity, whereas large-scale use of herbicides is restricted by the potential adverse effects on the ecosystem. Environmental management in water-development projects remains the best option.


[Medical and occupational radiation exposure: present situation and countermeasures].
This paper describes the present status and countermeasures for patient dose and occupational exposure in Japan. The patient radiation dose resulting from a large number of diagnostic radiological procedures presents no substantial risk(deterministic and stochastic effects). Nevertheless, some procedures (e.g., interventional radiology: IVR) carry a risk of deterministic effects, such as skin injury. The regulatory dose limit of the occupational dose for most medical workers was not exceeded. Nevertheless, radiation injuries, such as cataracts, to physicians performing IVR have been reported recently, although not many cases. When radiation protection/optimization issues are addressed adequately, medical exposure will decrease without decreasing the diagnostic benefit to the patient. Consequently, decreasing the patient dose will also decrease occupational exposure.


Significance of the endo-vinyl group of bilirubin in photochemical reactions.
In photochemical experiments on bilirubin III alpha (no endo-vinyl group), IX alpha (one endo-vinyl group) and XIII alpha (two endo-vinyl groups) and in the photochemical, thermal and catalytical reversion of their photoproducts under anaerobic conditions, much more instability and complexity of photoproducts of bilirubin XIII alpha were observed than for those of bilirubin IX alpha or III alpha. On the basis of present and previous results of photochemical experiments in vitro and the fact that large amounts of (EZ)-cyclobilirubin IX alpha appear in the bile during phototherapy of neonatal hyperbilirubinaemia [Onishi, Kawade, Itoh, Isobe & Sugiyama (1980) Biochem. J. 190, 527-532], it is concluded that the endo-vinyl group plays a crucial role in the photochemical reaction of bilirubin IX alpha. On reversed-phase high-pressure liquid chromatography of photoisomers, it was found that the retention times of geometric isomers and E-cyclized structural isomers were shortened compared with those of Z-isomer and E-isomer, respectively, as precursor substances.


[Therapy for non-muscle invasive bladder cancer: HP-NAP].
Patients with non-muscle invasive bladder cancer recurrence after 2 induction courses of BCG are eligible for radical cystectomy. So, in the last years research to discover new drugs for the management of non-muscle invasive bladder cancer recurrence after failure of first and second line therapy is ongoing. In accordance to the results obtained with BCG, whose mechanism depends on the induction of the T helper 1 (TH1) immune response, we investigated the activity of a Toll-like receptor (TLR) 2 ligand, named Helicobacter Pylori Neutrophil Activating Protein (HP-NAP), that we recently demonstrated being able of enhancing the differentiation of Th1 cells, both in vitro and in vivo, because of its ability to create an IL-12 enriched milieu. We show here, in a mouse model of bladder neoplasm implants, that local administration of HP-NAP decreases tumor growth by inducing tumor necrosis. The result is joined up with a massive cluster of both CD4+ and CD8+ IFN-γ+ cells, within neoplasm and regional lymph nodes. It is of note that HP-NAP-treated tumors show also a reduced vascularization due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. The present study suggests that the activity of HP-NAP against urothelial tumor burden warrants subsequent in vivo studies.


Effects of LY104119, a thermogenic weight-reducing compound, on norepinephrine concentrations and turnover in obese and lean mice.
Dopamine (DA) accumulation in interscapular brown adipose tissue (IBAT), heart, and liver was linear for more than 60 min after injection of 1-cyclohexyl-2-mercapto-imidazole (CHMI), a DA beta-hydroxylase inhibitor, into mice and served as an index of the rate of synthesis of norepinephrine (NE) in these tissues. There was a marked diurnal rhythm of DA accumulation in all three tissues of mice fed ad libitum, the rhythm being dampened in obese mice in IBAT and liver but not in heart. LY104119 acutely decreased NE concentration in IBAT, heart and liver, but not in brain, and it also decreased DA accumulation after CHMI in IBAT, heart and liver. Chronic administration of LY104119 at doses that stimulated thermogenesis and reduced body weight decreased NE turnover in heart and liver but increased NE turnover in IBAT. These data suggest that the increased thermogenesis in IBAT after chronic LY104119 treatment may be mediated by increased noradrenergic tone.


Diacyl, Alkylacyl, and Alkenylacyl Phospholipids of Meloidogyne javanica Females.
The phospholipid composition and acyl, alkyl, and alkenyl group compositions of diacyl, alkylacyl, and alkenylacyl phosphoglycerides of M. javanica were investigated. Phospholipid was comprised of 61.7% choline phosphoglyceride, 22.0% ethanolamine phosphoglyceride, and smaller quantities of six other lipids. Phospholipid fatty acid was more unsaturated than neutral lipid fatty acid and contained 61.3% octadecenoic (18:1) acid. Fatty acid at the 1-position of diacyl phospholipids was shorter and more saturated than that at the 2-position. Compared to choline phosphoglyceride, ethanolantine phosphoglyceride contained less 18:1 and 20:5 and more 18:0 and 20:0 acid. Alkenylacyl and alkylacyl compounds comprised 34.6% and 9.3%, respectively, of the ethanolamine phosphoglyceride but only 0.5% and 0.6% of the choline phosphoglyceride. Alkenylacyl and alkylacyl ethanolamine phosphoglycerides contained a smaller percentage of 20-carbon polyunsaturated acid at their 2-positions than did their diacyl analogue. At least 95% of the alkenyl and alkyl groups were 18:0 compounds. Tomato roots did not contain alkenylacyl or alkylacyl phosphoglycerides; their occurrence in M. javanica is a significant biochemical difference between the nematode and its host.


Structure of the paws in Didelphis virginiana.
The paws of Didelphis virginiana show several unusual features. They possess dermatoglyphs on the foot pads, have opposable first digits and the pads show a peculiar vascular arrangement. The hallux lacks a claw. The degree of innervation and the number and size of Pacinian corpuscles indicates that the paws of the opossum are finely sensitive to pressure and vibration.


Conservative interdisciplinary treatment of a case with multiple facial and condyle fractures.
The purpose of this case report is to describe an interdisciplinary approach for a 51-year-old male who underwent multiple facial fractures including bilateral condyle fractures. The patient underwent emergency surgery, which included open reduction of the maxilla and mandibular symphysis and closed reduction of the bilateral condyle fractures. Although the patient recovered a comfortable range of mouth opening and alleviation of the temporomandibular joint (TMJ) symptoms after surgery, he suffered from a large anterior-posterior discrepancy due to less stability on the condyle-fossa relationships and from open bite with contacts only on both second molars and right second premolars. In this case, first, to increase the occlusal contact, comprehensive orthodontic treatment was completed. Second, occlusal equilibration was selectively performed to relieve the interferences and establish a stable range of mandibular movement without any changes in the vertical dimension. Third, both the upper central incisors and left lateral incisor were minimally restored with splinted and single zirconia crowns, which had modified lingual contours to provide adequate anterior guidance permitting the anterior-posterior discrepancy of the posterior teeth during protrusion. This conservative interdisciplinary treatment, including open and closed reduction, orthodontic treatment, occlusal adjustment, and minimal prosthetic restorations, resulted in a stable mandibular position and recovery of mastication function.


Epidemiology of genital papillomaviruses and cervical cancer.
Cervical cancer is an extremely common disease. Its natural history has been well described, and individual risk factors have been defined. It is clear from the epidemiologic evidence that cervical cancer has a multifactorial etiology involving infection with sexually transmitted agents such as genital papillomaviruses and cofactors such as pregnancy, smoking, use of hormonal contraceptives, and diet. The evidence implicating papillomavirus as an etiologic agent of cervical cancer has come from a variety of observational laboratory studies. Genital papillomaviruses induce dysplastic lesions. Most invasive cervical cancers contain papillomavirus DNA, as do cell lines derived from cervical cancers. Viral DNA, appears to be integrated into cellular DNA, and integration involves highly conserved, transcriptionally active regions of the viral DNA.


n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes.
We carried out a secondary analysis in high-risk patients with a previous myocardial infarction (MI) and diabetes in the Alpha Omega Trial. We tested the hypothesis that in these patients an increased intake of the n-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid (ALA) will reduce the incidence of ventricular arrhythmias and fatal MI. A subgroup of 1,014 post-MI patients with diabetes aged 60-80 years was randomly allocated to receive one of four trial margarines, three with an additional amount of n-3 fatty acids and one placebo for 40 months. The end points were ventricular arrhythmia-related events and fatal MI. The data were analyzed according to the intention-to-treat principle, using multivariable Cox proportional hazards models. The patients consumed on average 18.6 g of margarine per day, which resulted in an additional intake of 223 mg EPA plus 149 mg DHA and/or 1.9 g ALA in the active treatment groups. During follow-up, 29 patients developed a ventricular arrhythmia-related events and 27 had a fatal MI. Compared with placebo patients, the EPA-DHA plus ALA group experienced less ventricular arrhythmia-related events (hazard ratio 0.16; 95% CI 0.04-0.69). These n-3 fatty acids also reduced the combined end-point ventricular arrhythmia-related events and fatal MI (0.28; 0.11-0.71). Our results suggest that low-dose supplementation of n-3 fatty acids exerts a protective effect against ventricular arrhythmia-related events in post-MI patients with diabetes.


The pancreolauryl test. A method of assessing the combined functional efficacy of pancreatic esterase and bile salts in vivo?
The pancreolauryl test is marketed as a tubeless test of pancreatic function based on the specific splitting by pancreatic esterase of orally administered fluorescein dilaurate. We have evaluated the test in 50 patients, all of whom had at least one other pancreatic function test (secretin-pancreozymin, Lundh, BT PABA/14C index). The sensitivity of the pancreolauryl test was 75% if equivocal results (T/K 20-30) were excluded and 77% if the equivocal results were included amongst the abnormal results - figures which were similar to those obtained for the other three function tests. However, the specificity of the pancreolauryl test was 60% if equivocal results were excluded, decreasing to only 39% if equivocal results were considered to be abnormal. The false-positive tests chiefly occurred in patients who had previously undergone gastric or biliary by-pass, or vagotomy and cholecystectomy (BT PABA/14C test normal). These data, and the known dependence of esterase activity on bile salts, suggest that the pancreolauryl test assesses the combined functional efficacy of secreted esterase and bile salts. Despite the test's high sensitivity, its low specificity makes it unreliable as a test of pancreatic function per se. The pancreolauryl test may be particularly useful in evaluating patients with bile-pancreatic juice admixture problems.


National Institute for Health and Care Excellence clinical guidelines development principles and processes.
Clinical guidelines are developed by professional societies and also, in England, by an independent non-departmental public body, the National Institute for Health and Care Excellence (NICE). Similarities and differences between these guidelines should be viewed in the context of different objectives, responsibilities and roles of guideline developers. This review describes the NICE clinical guidelines development principles and processes with the aim to provide the reader an informed perspective on the recommendations made. NICE clinical guidelines are developed by an appointed independent advisory committee comprising healthcare professionals as well as lay members, supported by a professional team comprising project managers, information specialists, systematic reviewers and health economists. Furthermore, registered stakeholders comprising organisations that have an interest in the guideline topic, or represent people whose practice or care may be directly affected by the guideline, are consulted on the draft scope and draft guidelines. NICE selects a limited number of high impact questions to be answered by the review of evidence, rather than cover a certain topic exhaustively as the clinical guidelines developed by professional societies may do. NICE clinical guidelines recommendations reflect both the clinical effectiveness and the cost-effectiveness of interventions.


[Phenotypic methods for detection of methicillin-resistant Staphylococcus aureus].
Cefoxitin is a potent inducer of the mecA gene. It is currently as a screening recommended method for presumptive identification of isolates of methicillin resistant Staphylococcus aureus (MRSA). The aim of the study was to compare the sensitivity and specificity of the cefoxitin disc diffusion (30 μg) to oxacillin agar screening from detection of the mecA gene by PCR. Three hundred thirty-one strains of S. aureus isolated from blood cultures of patients from hospitals in Lima were used in the study. The following tests were performed: oxacillin screening agar (plates were inoculated with 4% NaCl and 6 mg/L of oxacillin), cefoxitin disc diffusion test (30 ug) and PCR to amplify the mecA gene. The mecA gene was detected in 165 out of 331 S. aureus isolates. Thus, the frequency of detection of MRSA was 50%. The evaluation of the cefoxitin disc diffusion test showed a 96.3% and 90.9% of sensitivity and specificity, respectively. Cefoxitin disc diffusion test correlated well with detection of the mecA gene by PCR. Therefore, this test can be an alternative to PCR for detection of MRSA in limited resources settings.


WHIPPET: a novel tool for prioritizing invasive plant populations for regional eradication.
Large geographic areas can have numerous incipient invasive plant populations that necessitate eradication. However, resources are often deficient to address every infestation. Within the United States, weed lists (either state-level or smaller unit) generally guide the prioritization of eradication of each listed species uniformly across the focus region. This strategy has several limitations that can compromise overall effectiveness, which include spending limited resources on 1) low impact populations, 2) difficult to access populations, or 3) missing high impact populations of low priority species. Therefore, we developed a novel science-based, transparent, analytical ranking tool to prioritize weed populations, instead of species, for eradication and tested it on a group of noxious weeds in California. For outreach purposes, we named the tool WHIPPET (Weed Heuristics: Invasive Population Prioritization for Eradication Tool). Using the Analytic Hierarchy Process that included expert opinion, we developed three major criteria, four sub-criteria, and four sub-sub-criteria, taking into account both species and population characteristics. Subject matter experts weighted and scored these criteria to assess the relative impact, potential spread, and feasibility of eradication (major criteria) for 100 total populations of 19 species. Species-wide population scores indicated that conspecific populations do not necessarily group together in the final ranked output. Thus, priority lists based solely on species-level characteristics are less effective compared to a blended prioritization based on both species attributes and individual population and site parameters. WHIPPET should facilitate a more efficacious decision-making process allocating limited resources to target invasive plant infestations with the greatest predicted impacts to the region under consideration.


Bcl-2 protein expression correlates with cell survival and androgen independence in rat prostatic lobes.
Castration of young and old male Brown Norway rats induces apoptosis in the ventral, but not in the dorsal and lateral, lobes of the prostate gland, and apoptosis in old rats is diminished by 50% compared with that in young rats. In this study we examined the lobe-specific and age-dependent expression of Bcl-2 and Bax proteins. Bcl-2 levels in the ventral lobe were 5-fold lower compared with expression in the dorsal and lateral lobes. Bax expression in the ventral lobe was 2- and 20-fold higher than that in the lateral and dorsal lobes, respectively. In all three lobes, Bcl-2 was detected in epithelial cells, but not in stromal cells, whereas Bax protein was localized in both cell types. After castration, Bcl-2 expression in the ventral lobe decreased significantly from the control level after 2-3 d, but increased significantly by 7-10 d. By contrast, Bax expression increased significantly by d 1, gradually decreased by 2-4 d, and was nearly undetectable by 7-10 d postcastration. In the dorsal and lateral lobes, neither Bcl-2 nor Bax expression was significantly altered after castration. In the ventral lobe of old rats after castration, Bcl-2 followed a pattern of expression similar to that observed in young rats. However, Bax levels were 50% lower in old rats compared with those in young rats on d 1 after castration. Therefore, cell death follows the down-regulation of Bcl-2 expression in the ventral lobe of young and old rats. Moreover, the higher relative levels of Bcl-2 expression in the dorsal and lateral lobes of intact animals and in the ventral lobe by 7-10 d after castration serve to protect cells from apoptosis.


[Bone formation and inflammation].
Role of BMP signaling is crucial in the osteoblast differentiation and bone formation. BMP induces expression of Runx2, a master gene for osteogenesis, and cooperates with Runx2 in mature osteoblast to express target genes. These functions are suppressed by TGF-beta-induced Smad7 together with Smurf1 by various mechanisms, including degradation of type I receptor, Smadl/5, and Runx2. Bone remodeling is achieved by "coupling" of osteoblasts and osteoclasts. Although excess maturation and activation of osteoclasts is well described during inflammation, effect of inflammation to the osteoblast function is still unclear. Further exploration in this area thus might lead to discovery of novel therapeutic targets of inflammatory bone diseases.


Hippocampal connectivity and Alzheimer's dementia: effects of synapse loss and tangle frequency in a two-component model.
Our prior research on patients with Alzheimer's disease (AD) found a high correspondence between premortem dementia and accumulation of neurofibrillary tangles (NFTs) with concurrent loss of synapse density in several brain regions. In the present study, we examined these same clinicopathologic relationships in the context of seven subregions of the hippocampal formation using a sample of 16 AD patients who had been administered three well-known mental status tests antemortem. We found NFT counts to be most strongly correlated with degree of dementia when they were seen in CA1, the subiculum, and CA4; NFTs in these subregions appeared significantly clustered on factor analysis. Synapse loss was most strongly correlated with dementia when it occurred in the molecular layers of the dentate fasciculus and stratum lacunosum, CA2/3, and CA4; synapse loss in these subregions appeared significantly clustered on factor analysis. In general, these results were compatible with a two-component model of hippocampal connectivity and function in the context of AD. The first component consists of subregions preceding CA1 in a hypothesized input-processing sequence intrinsic to the hippocampus that summates neuronal excitation and that influences cognition primarily through synapse density. The second component consists of an "output module," mainly CA1 and the subiculum, that receives the processed signal, passes it on to extrahippocampal cortical and subcortical targets, and affects cognition primarily by NFT accumulation in output neurons. A "net pathology" score combining standardized z-scores for synapse density and NFTs was significantly correlated with all three mental status measures in all hippocampal subregions except the entorhinal cortex, and stepwise regressions on these data found net pathology in CA4 to be the most independent significant predictor of premortem dementia.


ON THE DISTRIBUTION OF VITAMINS A(1) AND A(2).
The distribution of vitamins A(1) and A(2) has been determined in the eye tissues and livers of a number of fishes. The vitamins were differentiated by means of the antimony chloride reaction, which yields with A(1) a band at 615-620 mmicro and with A(2) a band at about 696 mmicro. In the retina the presence of vitamin A(1) is diagnostic of the operation of a rhodopsin, and vitamin A(2) of a porphyropsin cycle. The eye tissues of all permanently marine fishes examined, except the tautog, contain vitamin A(1) alone. Those of all permanently freshwater fishes possess only vitamin A(2). Those of all euryhaline (potentially migratory) fishes, except possibly the alewife, contain mixtures of both vitamins A, and always predominantly that one which ordinarily is associated with the environment in which the fish is spawned. These correlations extend in part to the liver oils, but most livers contain mixtures of both vitamins A, and occasionally in proportions the reverse of those in the eye tissues. The vitamin A configuration does not depend upon environmental circumstances, but is determined genetically. The transfer from vitamin A(1) to A(2) metabolism appears associated phylogenetically with migration of marine teleosts into fresh water.


Tricyclic antidepressants in serum by a Clin-ElutTM column extraction and high pressure liquid chromatographic analysis.
We sought a method for routine therapeutic monitoring of serum tricyclic antidepressants (TCAs) which offered good reproducibility, detection limits, linearity, and specificity, and which was simple, rapid, and inexpensive to perform. The method described utilizes Clin-Elut columns (Analytichem International, Inc., Lawndale, CA 90206) to facilitate the extraction. The analysis is by high pressure liquid chromatography (HPLC) with a CN bonded phase column, a mobile phase of acetonitrile/pH 7.0 phosphate/methanol and detection at 210 nm. This chromatographic system gives short equilibration times, stable calibration curves, high sensitivity and resolution, short retention times, and long column life. The method is useful for determination of amitriptyline, doxepin, imipramine, nortriptyline, nordoxepin, desipramine, and protriptyline. Trimipramine is used as an internal standard for the tertiary amines and protriptyline for the secondary amines. Recovery is linear from 25 ato 1,000 ng/ml. Rubber stoppers of a new formulation in Vacutainer blood collection tubes (Becton-Dickinson, Rutherford, NJ 07070) do not affect serum TCA levels. Sera from 53 psychiatric patients suffering from endogenous depression were analyzed using the procedure presented. The mean serum level of four patients on amitriptyline therapy having complete remission was 201 ng/ml (range, 123-259). The mean serum level of four patients on imipramine therapy rated as having complete remission was 200 ng/ml (range, 145-258). These values compare well with recently published therapeutic ranges.


Biomimetic brain tumor niche regulates glioblastoma cells towards a cancer stem cell phenotype.
Glioblastoma (GBM) is the most malignant primary brain tumor and contains tumorigenic cancer stem cells (CSCs), which support the progression of tumor growth. The selection of CSCs and facilitation of the brain tumor niches may assist the development of novel therapeutics for GBM. Herein, hydrogel materials composed of agarose and hydroxypropyl methyl cellulose (HMC) in different concentrations were established and compared to emulate brain tumor niches and CSC microenvironments within a label-free system. Human GBM cell line, U-87 MG, was cultured on a series of HMC-agarose based culture system. Cell aggregation and spheroids formation were investigated after 4 days of culture, and 2.5% HMC-agarose based culture system demonstrated the largest spheroids number and size. Moreover, CD133 marker expression of GBM cells after 6 days of culture in 2.5% HMC-agarose based culture system was 60%, relatively higher than the control group at only 15%. Additionally, cells on 2.5% HMC-agarose based culture system show the highest chemoresistance, even at the high dose of 500 µM temozolomide for 72 h, the live cell ratio was still > 80%. Furthermore, the results also indicate that the expression of ABCG2 gene was up-regulated after culture in 2.5% HMC-agarose based culture system. Therefore, our results demonstrated that biomimetic brain tumor microenvironment may regulate GBM cells towards the CSC phenotype and expression of CSC characteristics. The microenvironment selection and spheroids formation in HMC-agarose based culture system may provide a label-free CSC selection strategy and drug testing model for future biomedical applications.


Systematic review and meta-analysis on the global distribution, host range, and prevalence of Trypanosoma evansi.
Surra is an animal trypanosomosis, caused by infection with Trypanosoma evansi and leading to severe economic loss due to mortality and morbidity. Compared to tsetse-transmitted animal trypanosomoses, little attention is given to the epidemiology and control of surra. Understanding its epidemiology is a first step in local and global efforts to control the disease. We conducted a systematic review and meta-analysis of published studies on distribution, host ranges and prevalence of T. evansi infection. Four electronic databases were searched for publications on T. evansi that met our inclusion criteria for the systematic review. Subsets of publications were subjected to meta-analysis for the pooled prevalence of T. evansi in various hosts as determined by multiple detection methods. A total of 272 references published between 1906-2017 were included. Trypanosoma evansi was reported from 48 countries; largely confined to Africa and Asia with publications on natural T. evansi infections from 77% (n = 48) of countries, contrasting with seven countries in South America, and four in Europe where T. evansi is not endemic but was imported with infected animals. Although surra is a notifiable disease, many countries do not report surra cases to OIE. Trypanosoma evansi was mainly reported from dromedary camels in Africa and the Middle East, water buffaloes, cattle, dogs and horses in East and Southeast Asia. In South America, the acute form of the disease was reported in horses and dogs. Surra was also reported in a wide range of wild animals. Some rare human cases occurred in India and Vietnam. Meta-analysis on a subset of 165 publications indicated pooled prevalence of T. evansi in domestic animals ranging from 14-31%, 6-28% and 2-9% using respectively antibody detection, molecular and parasitological tests, with camels as the most affected, followed by buffalo and cattle. This study illustrates that T. evansi affects a wide range of domestic and wild animals in Africa, Asia and South America with highest prevalence observed in dromedary camels. For successful control of T. evansi, both locally and globally, the role of wild animals in the epidemiology of surra needs further investigation.


[The results and aims of Russian Federation Armed Forces medical service activities].
In the past year the main efforts were concentrated on bringing the medical service staff and structure into line with the Armed Forces fighting staff and the problems being solved. The medical forces and means of permanent battle readiness have gotten the further development. The system providing the medical equipment and property was subjected to radical reorganization. The normative-and-law basis of military health service was improved and the licensing of military medical institutions' activities including those stationed outside the Russian Federation was conducted. The significant result of 2006 was the approval of a Conception of military medical service regular policy, the main principles of which are the openness, the scientific substantiation of quantitative and qualitative characteristics of medical staff and the rise of military medical service prestige. In 2007 the main aims of medical service are connected with the problems of battle and mobilization readiness, organizational construction, treatment-and-prophylactic support, troop sanitary-and-epidemiological safety, regular work and military medical education.


Intrinsic Disorder in Human Proteins Encoded by Core Duplicon Gene Families.
Segmental duplications (i.e., highly homologous DNA fragments greater than 1 kb in length that are present within a genome at more than one site) are typically found in genome regions that are prone to rearrangements. A noticeable fraction of the human genome (∼5%) includes segmental duplications (or duplicons) that are assumed to play a number of vital roles in human evolution, human-specific adaptation, and genomic instability. Despite their importance for crucial events such as synaptogenesis, neuronal migration, and neocortical expansion, these segmental duplications continue to be rather poorly characterized. Of particular interest are the core duplicon gene (CDG) families, which are replicates sharing common "core" DNA among the randomly attached pieces and which expand along single chromosomes and might harbor newly acquired protein domains. Another important feature of proteins encoded by CDG families is their multifunctionality. Although it seems that these proteins might possess many characteristic features of intrinsically disordered proteins, to the best of our knowledge, a systematic investigation of the intrinsic disorder predisposition of the proteins encoded by core duplicon gene families has not been conducted yet. To fill this gap and to determine the degree to which these proteins might be affected by intrinsic disorder, we analyzed a set of human proteins encoded by the members of 10 core duplicon gene families, such as NBPF, RGPD, GUSBP, PMS2P, SPATA31, TRIM51, GOLGA8, NPIP, TBC1D3, and LRRC37. Our analysis revealed that the vast majority of these proteins are highly disordered, with their disordered regions often being utilized as means for the protein-protein interactions and/or targeted for numerous posttranslational modifications of different nature.


[Idiopathic pulmonary fibrosis: modern guideline-concordant diagnostics and innovative treatment].
Interstitial lung diseases are a heterogenic group of diseases who share in common manifestation of the disease process in the distal airways and alevolo-capilary membrane. Idiopathic pulmonary fibrosis (IPF) is of special interest as it is the most prevalent entity within the idiopathic interstitial pneumonias and it is associated with the worst prognosis. Diagnosis of IPF necessitates confirmation of a "usual interstitial pneumonia" (UIP) pattern on high-resolution computed tomography or on histology from a surgical lung biopsy. The recently published evidence-based IPF-guidelines for the first time define radiologic criteria for a UIP pattern and thus allow to make an IPF diagnosis in the absence of a surgical lung biopsy. Moreover, an IPF diagnosis can be made only after exclusion of any other cause for an interstitial lung disease.In the new IPF-guideline no medical therapy has received a positive recommendation. Based on the available evidence only pirfenidone has been shown to attenuate disease progression in mild to moderate IPF populations, with low-moderate quality of evidence. Pirfenidone has been approved for mild-moderate IPF in the European Union in February 2011 and is approved in Japan since 2009. In IPF-patients who cannot receive pirfenidone high-dose N-acetylcysteine is an "off-label-use" option that also has been shown to slow disease progression, however, based on low quality of evidence only. Recent studies suggest that anti-inflammatory therapies (prednione, azathioprine) may be harmful in IPF patients and cannot be recommended. Besides medical therapies IPF patients should receive best supportive care, which includes long-term oxygen therapy in hypoxemic patients and pulmonary rehabilitation as well as lung transplantation for eligible patients.


Reputation and socio-ecology in humans.
Reputation is a fundamental feature of human sociality as it sustains cooperative relationships among unrelated individuals. Research from various disciplines provides insights on how individuals form impressions of others, condition their behaviours based on the reputation of their interacting partners and spread or learn such reputations. However, past research has often neglected the socio-ecological conditions that can shape reputation systems and their effect on cooperation. Here, we outline how social environments, cultural values and institutions come to play a crucial role in how people navigate reputation systems. Moreover, we illustrate how these socio-ecological dimensions affect the interdependence underlying social interactions (e.g. potential recipients of reputational benefits, degree of dependence) and the extent to which reputation systems promote cooperation. To do so, we review the interdisciplinary literature that illustrates how reputation systems are shaped by the variation of prominent ecological features. Finally, we discuss the implications of a socio-ecological approach to the study of reputation and outline potential avenues for future research. This article is part of the theme issue 'The language of cooperation: reputation and honest signalling'.


The effect of intra-tympanic dexamethasone on the vestibular function in patients with recurrent vertigo.
The low clinical efficacy of the treatment for patients included in this work correlates with no noticeable effect on the vestibular function. To assess follow-up in patients with idiopathic and secondary Ménière's disease after treatment with intra-tympanic dexamethasone and correlate clinical findings with changes in the vestibular-ocular reflex elicited after stimulation of each of the six semicircular canals. This is a single center retrospective review of patients presenting the clinical symptomatology of Meniérè's disease treated with intra-tympanic dexamethasone. An audiometric evaluation was performed in each patient before and after treatment. The study cohort was divided into two groups: those evaluated after a short period of time and after a long period of time. The study included 30 patients, mean age = 61 years. Differences in mean pure-tone average before and after treatment were non-significant for both treated (0.61 dB, p = 0.723) and untreated (0.59 dB, p = 0.609) ears. Vestibular-ocular reflex gain averages in the treated ear after treatment were 0.73 (superior semicircular canal), 0.86 (horizontal semicircular canal), and 0.69 (posterior semicircular canal). The gain did not vary significantly in the Superior (p = 0.194), the Horizontal (p = 0.646), or the Posterior Semicircular Canal (p = 0.820). Similar were obtained for the untreated ear.


Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells.
Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity.


Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis.
Glycosphingolipids are controlled by the spatial organization of their metabolism and by transport specificity. Using immunoelectron microscopy, we localize to the Golgi stack the glycosyltransferases that produce glucosylceramide (GlcCer), lactosylceramide (LacCer), and GM3. GlcCer is synthesized on the cytosolic side and must translocate across to the Golgi lumen for LacCer synthesis. However, only very little natural GlcCer translocates across the Golgi in vitro. As GlcCer reaches the cell surface when Golgi vesicular trafficking is inhibited, it must translocate across a post-Golgi membrane. Concanamycin, a vacuolar proton pump inhibitor, blocks translocation independently of multidrug transporters that are known to translocate short-chain GlcCer. Concanamycin did not reduce LacCer and GM3 synthesis. Thus, GlcCer destined for glycolipid synthesis follows a different pathway and transports back into the endoplasmic reticulum (ER) via the late Golgi protein FAPP2. FAPP2 knockdown strongly reduces GM3 synthesis. Overall, we show that newly synthesized GlcCer enters two pathways: one toward the noncytosolic surface of a post-Golgi membrane and one via the ER toward the Golgi lumen LacCer synthase.


Mapping of cutaneous melanoma by femtosecond laser-induced breakdown spectroscopy.
Surgical excision (Mohs micrographic surgery) is the standard procedure to treat a melanoma, in which an in situ histologic examination of sectioned skin is carried out repeatedly until no cancer cells are detected. The possibility to identify melanoma from the surrounding skin by femtosecond laser-induced breakdown spectroscopy (fs-LIBS) is investigated. For experiments, melanoma induced on a hairless mouse by injection of B16/F10 murine melanoma cell was sampled in the form of frozen tissue sections as in Mohs surgery and analyzed by fs-LIBS (λ = 1030 nm, τ = 550 fs). For analysis, the magnesium signal normalized by carbon intensity was utilized to construct an intensity map around the cancer, including both melanoma and surrounding dermis. The intensity map showed a close match to the optically observed morphological and histological features near the cancer region. The results showed that when incorporated into the existing micrographic surgery procedure, fs-LIBS could be a useful tool for histopathologic interpretation of skin cancer possibly with significant reduction of histologic examination time.


Healing after torture: the role of moving on.
The experience and sociocultural context of torture and its treatment have received little attention in the biopsychosocial model of Western mental health for survivors of torture. The main focus has been on the reduction of symptoms of posttraumatic stress disorder and related conditions. Using grounded theory methodology, we investigated survivors' perceptions of the nature and process of healing after torture. The participants included 11 adult refugee torture survivors (9 men and 2 women) from African and Asian countries. Their stories of healing centered on the role of "moving on" with their lives, which included aspects of cognitive reframing and empowerment. Reliance on belief and value systems, safety measures, and social support, despite continuing psychological and physical symptomatology, enabled the moving-on process. Implications for theory, research, and practice are discussed.


Thrombosis of the inferior vena cava in a patient with spinal cord injury.
Thrombosis of the inferior vena cava developed in a 25-year-old man with quadriplegia. The condition occurred six years after his cervical spinal cord injury. The patient had no previous history of thromboembolic disease. Clinical features of inferior vena cava thrombosis were massive bilateral lower extremity edema and dilated superficial abdominal veins. Based on the literature and outcome in this patient, anticoagulants provide the most effective long-term treatment.


Epidural analgesia and perioperative kidney function after major liver resection.
Epidural analgesia (EDA) is a common analgesia regimen in liver resection, and is accompanied by sympathicolysis, peripheral vasodilatation and hypotension in the context of deliberate intraoperative low central venous pressure. This associated fall in mean arterial pressure may compromise renal blood pressure autoregulation and lead to acute kidney injury (AKI). This study investigated whether EDA is a risk factor for postoperative AKI after liver surgery. The incidence of AKI was investigated retrospectively in patients who underwent liver resection with or without EDA between 2002 and 2012. Univariable and multivariable analyses were performed including recognized preoperative and intraoperative predictors of posthepatectomy renal failure. A series of 1153 patients was investigated. AKI occurred in 8·2 per cent of patients and was associated with increased morbidity (71 versus 47·3 per cent; P = 0·003) and mortality (21 versus 0·3 per cent; P < 0·001) rates. The incidence of AKI was significantly higher in the EDA group (10·1 versus 3·7 per cent; P = 0·003). Although there was no significant difference in the incidence of AKI between patients undergoing minor hepatectomy with or without EDA (5·2 versus 2·7 per cent; P = 0·421), a substantial difference in AKI rates occurred in patients undergoing major hepatectomy (13·8 versus 5·0 per cent; P = 0·025). In multivariable analysis, EDA remained an independent risk factor for AKI after hepatectomy (P = 0·040). EDA may be a risk factor for postoperative AKI after major hepatectomy.


[Metastases in patients with breast cancer despite of negative sentinel lymph node. Has the concept to be changed?].
The sentinel lymph node (SLN) is of considerable prognostic relevance, because extended lymph node dissection may not be performed in patients presenting with histologically negative SLN. The aim of this study was to prove the prognostic value of the SLN-concept in these patients in long term follow-up. The clinical follow-up of 202 women with histologically proven breast cancer and metastatically uninvolved (negative) SLN, as determined using Tc-99m-nanocolloid, was observed for a mean period of 43.4 months. Histological examination included standard methods (HE-Test) and special histochemical techniques (antibodies against cytokeratin). All patients underwent clinical examinations and mamography according a standardised schema; other procedures like ultrasound examination, routine blood tests, and chest X-ray scans were performed in patients considered doubtful after clinical examination or mamography. Despite of negative SLN-findings in 14/202 patients (6.9%) metastases were found after a mean time period of 35.9 months. 4 patients showed local re-lapses, 3 patients presented with regional lymph node recurrences in the previously mapped (negative) SLN-basin, and 7 Patients developed distant metastases outside the primary lymphatic basin. In patients negative on SLN-biopsy the axillary lymph-node-recurrence-rate was low; in 3/202 patients (1.5%) a progression in the SLN-basin could be assessed, being real concept failures. Our results underline that there is no evidence to question this concept in patients presented with clinically metastatically uninvolved early stage of breast cancer.


Impact of Helicobacter pylori-Related Metabolic Syndrome Parameters on Arterial Hypertension.
Arterial hypertension is a risk factor for several pathologies, mainly including cardio-cerebrovascular diseases, which rank as leading causes of morbidity and mortality worldwide. Arterial hypertension also constitutes a fundamental component of the metabolic syndrome. Helicobacter pylori infection is one of the most common types of chronic infection globally and displays a plethora of both gastric and extragastric effects. Among other entities, Helicobacter pylori has been implicated in the pathogenesis of the metabolic syndrome. Within this review, we illustrate the current state-of-the-art evidence, which may link several components of the Helicobacter pylori-related metabolic syndrome, including non-alcoholic fatty liver disease and arterial hypertension. In particular, current knowledge of how Helicobacter pylori exerts its virulence through dietary, inflammatory and metabolic pathways will be discussed. Although there is still no causative link between these entities, the emerging evidence from both basic and clinical research supports the proposal that several components of the Helicobacter pylori infection-related metabolic syndrome present an important risk factor in the development of arterial hypertension. The triad of Helicobacter pylori infection, the metabolic syndrome, and hypertension represents a crucial worldwide health problem on a pandemic scale with high morbidity and mortality, like COVID-19, thereby requiring awareness and appropriate management on a global scale.


Somatostatin receptor scintigraphy in malignant lymphoma: first results and comparison with glucose metabolism measured by positron-emission tomography.
Somatostatin receptor scintigraphy with 111In-labeled octreotide was performed in 22 patients with suspected or known malignant lymphoma. The majority of extra-abdominal lesions (21/24 = 87.5%) were correctly localized, however, only one of nine intraabdominal lymphomas could be detected. No significant correlation was found between scintigraphic results and histological type of lymphoma. Metabolic imaging by positron-emission tomography with 18F-labeled deoxyglucose yielded a higher rate of detection of lymphoma manifestations (92% vs 64%) and better tumor contrast. Further prospective studies are needed to establish the clinical relevance of somatostatin receptor scintigraphy in malignant lymphoma.


Nonlinear Associations Between Cumulative Dietary Risk Factors and Cardiovascular Diseases, Cancer, and All-Cause Mortality: A Prospective Cohort Study From UK Biobank.
To develop a score from cumulative dietary risk factors and examine its nonlinear associations with cardiovascular disease (CVD) and cancer incidence and mortality, as well as all-cause mortality. There were 422,702 participants from UK Biobank included in this prospective study. Cumulative dietary risk factors were represented using a score ranging from 0 (healthiest) to 9 (least healthy). This was derived from 9 food items based on current UK guidelines using baseline data. Associations between the cumulative score and health outcomes were investigated using nonlinear penalized cubic splines fitted in Cox proportional hazard models. Follow-up was conducted until June 2020 for mortality, and for incidence, up to June 2020 in England and March 2017 in Wales and Scotland. The median follow-up period was 9.0 years for incidence outcomes and 9.3 years for mortality outcomes. Each 1-point increment in the cumulative dietary risk factors score was associated with higher risk for incidence and mortality of the outcomes studied. The highest risks were identified for mortality due to heart failure (8.0% higher), CVD, and ischemic heart disease (both 7.0% higher). In addition, a higher diet score accounted for 18.8% of all deaths, 4.47% of incident cases of CVD, 25.5% of CVD deaths, 7.7% of incident cancers, and 18.2% of all cancer deaths. Our findings show that dietary risk factors contributed to a large proportion of CVD and cancer events, as well as deaths, among those who did not meet most dietary recommendations.


Mucosal healing progression after acute colitis in mice.
Mucosal healing has become a therapeutic goal to achieve stable remission in patients with inflammatory bowel diseases. To achieve this objective, overlapping actions of complex cellular processes, such as migration, proliferation, and differentiation, are required. These events are longitudinally and tightly controlled by numerous factors including a wide range of distinct regulatory proteins. However, the sequence of events associated with colon mucosal repair after colitis and the evolution of the luminal content characteristics during this process have been little studied. To document the evolution of colon mucosal characteristics during mucosal healing using a mouse model with chemically-induced colitis. C57BL/6 male mice were given 3.5% dextran sodium sulfate (DSS) in drinking water for 5 d. They were euthanized 2 (day 7), 5 (day 10), 8 (day 13), and 23 (day 28) d after DSS removal. The colonic luminal environment and epithelial repair processes during the inflammatory flare and colitis resolution were analyzed with reference to a non-DSS treated control group, euthanized at day 0. Epithelial repair events were assessed histo-morphologically in combination with functional permeability tests, expression of key inflammatory and repairing factors, and evaluation of colon mucosa-adherent microbiota composition by 16S rRNA sequencing. The maximal intensity of colitis was concomitant with maximal alterations of intestinal barrier function and histological damage associated with goblet cell depletion in colon mucosa. It was recorded 2 d after termination of the DSS-treatment, followed by a progressive return to values similar to those of control mice. Although signs of colitis were severe (inflammatory cell infiltrate, crypt disarray, increased permeability) and associated with colonic luminal alterations (hyperosmolarity, dysbiosis, decrease in short-chain fatty acid content), epithelial healing processes were launched early during the inflammatory flare with increased gene expression of certain key epithelial repair modulators, including transforming growth factor-β, interleukin (Il)-15, Il-22, Il-33, and serum amyloid A. Whereas signs of inflammation progressively diminished, luminal colonic environment alterations and microscopic abnormalities of colon mucosa persisted long after colitis induction. This study shows that colon repair can be initiated in the context of inflamed mucosa associated with alterations of the luminal environment and highlights the longitudinal involvement of key modulators.


Investigating the influence of relevant pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of orally administered docetaxel combined with ritonavir.
The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic-pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes.


Clinical presentation of subacute sclerosing panencephalitis in Papua New Guinea.
Eighty-three children presented at Goroka Base Hospital in the Eastern Highlands Province (EHP) of Papua New Guinea over a period of 3 years and 9 months between February 1997 and November 2000 were confirmed to have subacute sclerosing panencephalitis (SSPE). Confirmation of the diagnosis was based on the demonstration of high titres of measles antibodies in the cerebrospinal fluid and/or serum in association with clinical features supportive of SSPE, including characteristic electroencephalographic changes and amplification of measles virus genome by reverse transcriptase polymerase chain reaction in some cases. The mean cerebrospinal fluid and serum enzyme immunoassay antibody levels among the SSPE patients were 38 250 and 860 580, respectively. The mean age of onset of SSPE was 7.9 +/- 2.6 years and ranged between 2 and 14 years. The overall male to female ratio was 1.2:1 and 1.4:1 for EHP.


Investigating the relationship between DMFT and mothers' knowledge and attitude about oral health and dmft of 6-12-year-old children with attention-deficit/hyperactivity disorder.
Children with attention-deficit/hyperactivity disorder (ADHD) are more prone to tooth decay. In this regard, parents, especially their mothers, play a major role in the oral health of their children. The present study was a cross-sectional descriptive study. The population of this study was 64 children with ADHD referred to pediatric psychiatric clinics in Isfahan. Inclusion criteria include willingness to participate in research. At least 6 months has passed since their child was diagnosed with the disorder and their child is receiving treatment.Lack of obvious physical disorders, psychotic disorders, mental retardation and chronic diseases in children with attention deficit/hyperactivity disorder with the approval of a psychiatrist. Collaboration for dental examination by a dentist. Exclusion criteria include obvious physical and mental disorders in mothers of children with attention-deficit/hyperactivity disorder. Simultaneous participation in a study similar to the present study due to the possibility of errors in the results. Dissatisfaction with participating in the study and leaving the study during the study. The data collection tool was interview-questionnaire-examination. Clinical interviews were conducted using the Kiddie Schedule for Affective Disorders and Schizophrenia to confirm ADHD and rule out other psychiatric illnesses. Information on decayed, missing, and filled teeth (DMFT) of permanent teeth and dmft of deciduous teeth is recorded separately. The score of each index (D, M, F), (f, m, d) as well as the total index (DMFT), (dmft) is calculated for each person. Data were entered into SPSS software version 26 by descriptive statistical methods, one-way analysis of variance, t-test, and calculation of Spearman correlation coefficient. P < 0.05 was considered statistically significant. The oral health status of children with ADHD did not show a significant relationship with the total score of attitude and knowledge of oral health behaviors of mothers (P > 0.05). The results showed a significant positive relationship between the level of knowledge of the participants and their education level (P < 0.05). The results revealed that mothers' knowledge and attitude about oral health and dental health of children with ADHD were generally at an undesirable level.


May-Thurner Syndrome: A Case Report and a Concise Review.
We report a case of a 31-year-oldman who presented to the hospital with extensive deep vein thrombosis (DVT) complicated by pulmonary embolism (PE) after a recent trauma and prolonged immobilization. He underwent contrast venography that revealed features of May-Thurner syndrome (MTS). He was managed with therapeutic anticoagulation, inferior vena cava filter placement, mechanical clot aspiration, catheter-directed thrombolytic therapy, and left common iliac vein stenting. MTS is a vascular condition caused by the compression of the left common iliac vein by an overlying right common iliac artery against a vertebral body. This results in indolent endothelial changes secondary to the pulsating nearby artery as well as the compression increasing the susceptibility to venous thrombosis. Females are thought to be more prone to the condition due to the nature of their pelvic anatomy. Most patients are asymptomatic or present with unspecific symptoms, rendering the condition underdiagnosed. The gold standard diagnostic modality is contrast venography that reveals collaterals and a pressure gradient greater than 2 mmHg at rest across the stenotic region. Treatment is revolved around the removal of the thrombus along with the correction of the anatomical defect through interventional or surgical treatment to prevent a recurrence. Untreated MTS complicated with DVT carries a risk of potentially life-threatening complications, such as PE, iliac vein rupture, retroperitoneal hematoma, or refractory DVT that is difficult to treat. Due to the chronicity of this syndrome, its management plan differs from that of other causes of DVT. Proper identification of MTS carries a positive outcome in treating DVT secondary to MTS. Here we are going to discuss a case diagnosed with MTS complicated by saddle PE outlying the possible pathophysiology, clinical manifestation, diagnostic tools, and management of complicated MTS.