DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs.
The vertebrate-conserved RNA-binding protein DND1 is required for the survival of primordial germ cells (PGCs), as well as the suppression of germ cell tumours in mice. Here we show that in mice DND1 binds a UU(A/U) trinucleotide motif predominantly in the 3' untranslated regions of mRNA, and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase complex. Transcriptomic analysis reveals that the extent of suppression is dependent on the number of DND1-binding sites. This DND1-dependent mRNA destabilization is required for the survival of mouse PGCs and spermatogonial stem cells by suppressing apoptosis. The spectrum of target RNAs includes positive regulators of apoptosis and inflammation, and modulators of signalling pathways that regulate stem-cell pluripotency, including the TGFβ superfamily, all of which are aberrantly elevated in DND1-deficient PGCs. We propose that the induction of the post-transcriptional suppressor DND1 synergizes with concurrent transcriptional changes to ensure precise developmental transitions during cellular differentiation and maintenance of the germ line.


The Originality of Neuro Rehabilitation Protocols in a Definitive Case of Syringomyelia Related to Chiari I Malformation.
Syringomyelia is a center-medullary syndrome characterized by the presence of fluid-filled spaces known as syrinx within the spinal canal. Arnold Chiari Malformation (CM-I), a rhombencephalon anomaly formerly identified as hindbrain hernia, is usually associated with it. This disorder causes the brain (cerebellum) to bulge through the opening in the skull known as the foramen magnum. Some asymptomatic patients may develop symptoms quickly if they jolt their heads and cough for a lengthy period of time. Syringomyelia can be caused by trauma, illness, inflammation, or previous surgery that affects the circulation of cerebral spinal fluid resulting in CSF flow obstruction. The discomfort is acute and progressive, radiating to the neck and shoulder, and is accompanied by sensory loss, motor atrophy, decreased hearing, oscillopsia, and cerebellar abnormalities. This case report is of a 39-year-old woman diagnosed with syringomyelia associated with Arnold Chiari malformation and showed similar symptoms managed by foramen decompression and tonsillar elevation surgery. It involves removing a small piece of bone from the skull and a small section of the 1st vertebra from the back of the neck and head. In this way, there is an increase in skull space. Decompression of the spinal canal increases the size of the subarachnoid cisterns and constricts the syrinx cavity. After surgery, physiotherapy was advised because all superficial sensations over C8 and T1 were diminished, the range of motion along with strength was reduced, doing daily activities was difficult, and quality of life was affected. So, by decreasing symptoms and improving the patient's quality of life, physiotherapy improved the patient's condition significantly in this case report. The rationale of this study is to show the importance of physiotherapy in recovering after a neurological condition followed by corrective neurosurgery.


Congenital adrenal hyperplasia with a CYP21A2 deletion overlapping the tenascin-X gene: an atypical presentation.
Congenital Adrenal Hyperplasia (CAH) is a group of genetic diseases characterized by impaired cortisol biosynthesis. 95% of CAH cases result from mutation in the CYP21A2 gene encoding 21-hydroxilase. TNX-B gene partially overlaps CYP21A2 and encodes a matrix protein called Tenascin-X (TNX). Complete tenascin deficiency causes Enlers-Danlos syndrome (EDS). A mono allelic variant called CAH-X CH-1 was recently described, resulting from a CYP21A2 complete deletion that extends into the TNXB. This haploinsufficiency of TNX may be associated with a mild hypermobility form of EDS, as well as other connective tissue comorbidities such as hernia, cardiac defects and chronic arthralgia. We report four patients heterozygous for a CAH-X CH-1 allele that do not present clinical manifestations of the EDS. All CAH patients, carriers of these TNXA/TNXB chimeras, should be evaluated for clinical manifestations related to connective tissue hypermobility, cardiac abnormalities and other EDS features, allowing for better clinical surveillance management.


Mycobacterium xenopi infection in a patient with acquired immunodeficiency syndrome.
A case of Mycobacterium xenopi infection in a patient with acquired immunodeficiency syndrome (AIDS) is described and the clinical experience of others in the United States with this organism is reviewed. Disseminated infection by this organism appears to occur only in the immunocompromised host. Because M xenopi has been found in hot water systems by others and is an organism more susceptible to the traditional antituberculosis antibiotics, recognition and distinction of this organism from the more resistant and difficult to treat Mycobacterium avium-intracellulare in the patients with AIDS may be important.


Steady States of Infinite-Size Dissipative Quantum Chains via Imaginary Time Evolution.
Directly in the thermodynamic limit, we show how to combine local imaginary and real-time evolution of tensor networks to efficiently and accurately find the nonequilibrium steady states (NESSs) of one-dimensional dissipative quantum lattices governed by a local Lindblad master equation. The imaginary time evolution first bypasses any highly correlated portions of the real-time evolution trajectory by directly converging to the weakly correlated subspace of the NESS, after which, real-time evolution completes the convergence to the NESS with high accuracy. We demonstrate the power of the method with the dissipative transverse field quantum Ising chain. We show that a crossover of an order parameter shown to be smooth in previous finite-size studies remains smooth in the thermodynamic limit.


Complex Bilateral Interactions Determine the Fate of Polystyrene Micro- and Nanoplastics and Soil Protists: Implications from a Soil Amoeba.
Nano- and microplastics have become a serious global concern, threatening our living environments. Previous studies have shown that many organisms, including bacteria, animals, and plants, can be affected by microplastics. However, little is known about one ecologically important group of soil organisms, the protists. In this study, we investigated how polystyrene micro- and nanoplastics interacted with a soil amoeba Dictyostelium discoideum. The results showed that environmental concentrations of nano- and microplastics could negatively affect the soil amoeba's fitness and development. D. discoideum ingested both nano- and microplastics through phagocytosis but packed and excreted them during slug migration, which also promoted their biodegradation. Fourier transform infrared spectroscopy analyses revealed the formation of new oxygen-containing functional groups and the sign of possible oxidation of polystyrene. Also, nano- and microplastic exposure disrupted the nutrient and energy metabolisms of D. discoideum and affected the expression of key genes (e.g., cf45-1, dcsA, aprA, dymB, and gefB) related to morphogenesis and phagocytosis. In conclusion, our results show that nano- and microplastics have complex bilateral interactions with the soil amoeba, affecting each other's fate in the soil environment. This study provides new insights into how soil protists interact with nano- and microplastics in the soil ecosystem.


Workplace Violence Interventions Used by Home Healthcare Workers: An Integrative Review.
The threat of workplace violence (WPV) is a significant occupational hazard for home healthcare workers (HHCWs). The purpose of this integrative review is to examine WPV interventions used by HHCWs to stay safe while working in the patient's home and community. The methodology used was the integrative review by , which allows for inclusion of experimental and non-experimental research, reflecting the state of the science on interventions used by HHCWs to mitigate and prevent WPV. A total of 17 articles pertained to interventions used by HHCWs. Interventions were further categorized by WPV Type. There are a number of interventions used for Type I and II WPV. However, interventions for Type III WPV are minimal and interventions for Type IV WPV are obsolete. Safety and health training were shown to be significant in increasing HHCWs' confidence and knowledge about WPV prevention. Researchers demonstrated safety and health training are effective in promoting a safe work environment and reducing incidents of WPV. This review begins to fill the gap in the literature on interventions used by HHCWs to mitigate and prevent WPV.


Polymorphisms of Il-10 (-1082) and RANKL (-438) Genes and the Failure of Dental Implants.
Background. Genetic polymorphisms in certain cytokines and chemokines have been investigated to understand why some individuals display implant flaws despite having few risk factors at the time of implant. Purpose. To investigate the association of genetic polymorphisms in interleukin- (IL-) 10 [-1082 region (A/G)] and RANKL [-438 region (A/G)] with the failure of dental implants. Materials and Methods. This study included 90 partially edentulous male and female patients who were rehabilitated with a total of 245 Straumann dental implants. An implant was considered a failure if any of the following occurred: mobility, persistent subjective complaint, recurrent peri-implant infection with suppuration, continuous radiolucency around the implant, probing depth ≥ 5 mm, and bleeding on probing. Buccal mucosal cells were collected for analysis of RANKL438 and IL-10. Results. The implant success rate in this population was 34.4%. The mutant allele (G) in RANKL had an incidence of 52.3% and mutant allele (A) in IL-10 was observed in 37.8%. No statistically significant difference was detected between the failure of the implant and the genotypes and allelic frequencies. Conclusion. No association was detected between the genetic polymorphisms of RANKL (-438) and IL-10 (-1082) and the failure of dental implants in the population studied.


Expression profile of early lung adenocarcinoma: identification of MRP3 as a molecular marker for early progression.
Early lung adenocarcinoma is well-recognized as a small-sized non-invasive adenocarcinoma or localized non-mucinous bronchioloalveolar carcinoma (LNMBAC); however, the molecular events associated with these early lesions are not clear. To determine the genes involved in tumorigenesis at the early stage of lung adenocarcinoma, we compared the mRNA expression profiles of LNMBAC and normal lungs with an oligonucleotide array. Immunohistochemical analyses were performed to confirm the expression of detected genes. We identified 183 differentially expressed genes, of which 15 were up-regulated and 168 down-regulated. Among them, most up-regulated genes, such as AQP3 and Claudin-4, were expressed in both adenocarcinoma cells and type II alveolar pneumocytes, corresponding to the histological similarity between these cell types. However, multidrug resistant protein 3 (MRP3) was only expressed on tumour cell membranes and not in type II alveolar pneumocytes, as confirmed by immunohistochemistry. Moreover, the number of MRP3-positive cells significantly increased from AAH (the precursor lesion of lung adenocarcinoma) to LNMBAC. We conclude that MRP3 could be a novel molecular marker for LNMBAC, whose expression increases during the early progression of tumourigenesis.


Correlation of iodine uptake and perfusion parameters between dual-energy CT imaging and first-pass dual-input perfusion CT in lung cancer.
To investigate the potential relationship between perfusion parameters from first-pass dual-input perfusion computed tomography (DI-PCT) and iodine uptake levels estimated from dual-energy CT (DE-CT).The pre-experimental part of this study included a dynamic DE-CT protocol in 15 patients to evaluate peak arterial enhancement of lung cancer based on time-attenuation curves, and the scan time of DE-CT was determined. In the prospective part of the study, 28 lung cancer patients underwent whole-volume perfusion CT and single-source DE-CT using 320-row CT. Pulmonary flow (PF, mL/min/100 mL), aortic flow (AF, mL/min/100 mL), and a perfusion index (PI = PF/[PF + AF]) were automatically generated by in-house commercial software using the dual-input maximum slope method for DI-PCT. For the dual-energy CT data, iodine uptake was estimated by the difference (λ) and the slope (λHU). λ was defined as the difference of CT values between 40 and 70 KeV monochromatic images in lung lesions. λHU was calculated by the following equation: λHU = |λ/(70 - 40)|. The DI-PCT and DE-CT parameters were analyzed by Pearson/Spearman correlation analysis, respectively.All subjects were pathologically proved as lung cancer patients (including 16 squamous cell carcinoma, 8 adenocarcinoma, and 4 small cell lung cancer) by surgery or CT-guided biopsy. Interobserver reproducibility in DI-PCT (PF, AF, PI) and DE-CT (λ, λHU) were relatively good to excellent (intraclass correlation coefficient [ICC]Inter = 0.8726-0.9255, ICCInter = 0.8179-0.8842; ICCInter = 0.8881-0.9177, ICCInter = 0.9820-0.9970, ICCInter = 0.9780-0.9971, respectively). Correlation coefficient between λ and AF, and PF were as follows: 0.589 (P < .01) and 0.383 (P < .05). Correlation coefficient between λHU and AF, and PF were as follows: 0.564 (P < .01) and 0.388 (P < .05).Both the single-source DE-CT and dual-input CT perfusion analysis method can be applied to assess blood supply of lung cancer patients. Preliminary results demonstrated that the iodine uptake relevant parameters derived from DE-CT significantly correlated with perfusion parameters derived from DI-PCT.


Effect of Nutrient Availability on Progenitor Cells in Zebrafish (Danio Rerio).
In zebrafish brains, populations of continuously proliferating cells are present during an entire life span. Under normal conditions, stem cells give rise to rapidly proliferating progenitors that quickly exit the cell cycle and differentiate. Hence fish are favorable models to study what regulates postembryonic neurogenesis. The aim of this study was to determine if optic tectum (OT) cell proliferation is halted during nutritional deprivation (ND) and whether or not it can be restored with refeeding. We examined the effect of ND on the proliferation of Neuroepithelial/Ependymal Progenitor cell (NeEPC) and transitory-amplifying progenitors (TAPs). Following ND, no PCNA immunostaining was found in OT of starved fish, while positive cell populations of PCNA positive progenitors are found at its periphery in control fish. This indicated that active proliferation stopped. To label retaining progenitor cells, BrdU was applied and a chase-period was accompanied by ND. Positive NeEPCs were detected in the external tectum marginal zone of starved fish suggesting that these progenitors are relatively immune to ND. Moreover in the internal tectum marginal zone labeled retaining cells were observed leaving the possibility that some arrested TAPs were present to readily restart proliferation when nutrition was returned. Our results suggest that neurogenesis was maintained during ND and that a normal proliferative situation was recovered after refeeding. We point to the mTOR pathway as a necessary pathway in progenitors to regulate their mitosis activity. Thus, this study highlights mechanisms involved in neural stem and progenitor cell homeostatic maintenance in an adverse situation. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 26-38, 2017.


Cell-dependent interference of a series of new 6-aminoquinolone derivatives with viral (HIV/CMV) transactivation.
Quinolone derivatives have been shown to inhibit human immunodeficiency virus (HIV) replication at the transcriptional level. Recently, a series of new 6-aminoquinolones that are endowed with more pronounced anti-HIV activities compared with the formerly reported quinolone derivatives have been published. These potent 6-aminoquinolones were further evaluated for their broad-spectrum antiviral properties. Latently HIV-1-infected cell lines as well as cytomegalovirus (CMV)-infected fibroblasts were used to evaluate the antiviral potency of the 6-aminoquinolone derivatives. Additionally green fluorescent protein (GFP) transactivation experiments using different promoters were conducted. The compounds completely suppressed tumour necrosis factor alpha (TNF-alpha)- and phorbol 12-myristate 13-acetate (PMA)-induced HIV-1 expression in latently HIV-1-infected OM-10.1 and U1 cell lines at non-toxic concentrations. In addition, HIV-1 mRNA production was dramatically suppressed in both cell lines in a dose-dependent manner. In the same concentration range, the compounds inhibited TNF-alpha release from PMA-induced OM-10.1 cells but allowed TNF-alpha production from PMA-induced U1 cells at all concentrations tested. The 6-aminoquinolone derivatives were not only inhibitory to the Tat-mediated transactivation of the HIV-1 LTR promoter, but were also found to interfere in a cell-dependent way with the transactivation process mediated from the human CMV immediate early and the human EF-1alpha promoter. Additionally, the 6-aminoquinolone derivatives were also found to be inhibitory to CMV replication in fibroblast cells. It thus appears that the antiviral spectrum of this class of compounds is not confined to the specific inhibition of HIV but encompasses CMV as well. This broad-spectrum activity window might provide an interesting platform for future applications for the 6-aminoquinolone derivatives.


Outcome of Non-Malignant Papillary Lesions of the Breast on Core Biopsy: An Experience from a Tertiary Care Center in Pakistan.
Background Papillary lesions of the breast constitute a heterogeneous group ranging from non-malignant papillomas to papillary carcinoma. While surgical excision is recommended for atypical papilloma or papillary DCIS/ carcinoma on core biopsy, controversy persists in the management of benign papillomas which are diagnosed with core needle biopsy (CNB) since there are variable reported rates for tumor upgrade. The purpose of this study was to determine the outcome of papillary lesions of the breast diagnosed at image-guided CNB, after surgical excision or follow-up, and to identify potential predictors of high-risk lesions/malignancy on imaging. Materials and methods We retrospectively identified 52 non-malignant papillary lesions on core biopsy between January 2012 and June 2018. The outcome of surgical excision, as well as clinical and imaging features of these lesions, were assessed. The final histologic upgrade was recorded, and variables were compared between benign and atypical lesions on core biopsy as well as between upgraded and non-upgraded lesions after surgical excision. Results Thirty-six lesions out of 52 lesions were benign papillomas on core biopsy, while 16 were papillary lesions with ADH/DCIS. All of these lesions except four benign papillomas were excised. Of the 32 benign papillomas excised, 7 were upgraded to papilloma with ADH/DCIS and one to DCIS with the focus of invasion. Among the 16 atypical lesions excised, one was upgraded to papillary DCIS with a final upgrade rate of 17.3%. There was no statistically significant clinical or imaging feature among those that were upgraded on excision from those that were not upgraded. Conclusion Non-malignant papillary lesions have a significant upgrade rate. There are no reliable clinical or imaging features that can pre-surgically predict upgrade. Therefore, surgical excision of all papillary lesions is recommended for definitive diagnosis.


[Structural changes in jaw bone marrow after hemorrhagic infiltration].
Normal saline solution flushing of the inner mandible was done on twelve dogs, to confirm the effect of hemorrhagic infiltration that occurs in the fatty marrow. Histological examinations were performed at 1 hour, 5 days, 10 days, 2 weeks, 1 month and 3 months. 1. Marrow extrusion occurred at approximately 1 atm (injection pressure). 2. At 1 hour, marrow cavities located between the 2 injection holes with the exception of the extraction sites were filled with infiltrated blood cells. Fatty marrow was moderately replaced by the infiltrated blood cells in the extraction cavities and outer distal areas of the injection holes. 3. A sequence of histogenetic events occurred. The area of bone formation gradually expanded in the fibrous tissue area. 4. Expansion of the bone formation area was almost completed at 2 weeks. Most of the original marrow was transformed into thin trabeculae-forming areas, and hematopoiesis and sinusoidal capillaries formed in the new marrow. These conditions at 2 weeks were similarly maintained at 1 month. 5. At 3 months, the number of trabeculae, sinusoidal capillaries and hematopoietic area decreased, with the increase of adipose cells. 6. These results indicate that the area of fatty marrow where the hemorrhagic infiltration occurred was transformed into the bone formation area, and the marrow activates particularly high between the period of 2 weeks and 1 month.


[Clinical performance of antigen-specific interferon-gamma assay for the diagnosis of latent tuberculosis in risky hospital-based populations].
To evaluate the performance and the usefulness of an in vitro interferon gamma release assay in the diagnosis of latent tuberculosis infection in immunocompromised hospital-based population. A cohort of 445 high-risk adults from a hospital located in an intermediate tuberculosis burden area were prospectively evaluated for latent tuberculosis by means of the whole blood in vitro QuantiFERON-TB Gold assay (QTF), measuring tuberculosis-specific interferon gamma release by memory-effector T lymphocytes. Overall the test displayed a positive result in 15.43% patients. Among the different risk groups, hemodialysis patients revealed the highest positive rates (30.23%). Indeterminate results (10.19% on the whole) were more often seen in neoplastic (18.03%) patients and in patients with autoimmune disease (17%). In 291 patients in whom QTF and Mantoux were simultaneously performed, concordance was moderate (kappa = 0.4520) with a 76.8% agreement when Mantoux was negative (179/233) but reaching only 50% (29/58) when Mantoux positive patients were selected. QFT test is suitable for routine latent tuberculosis diagnosis in hospital-based immunocompromised patients. At least in some of them, i.e. hemodialysis and patients with autoimmune suppression, QFT adds valuable information for therapeutical decision-making. In Mantoux positive patients, it is very useful for ruling-out false positives due to BCG-vaccination and/or non-tuberculous mycobacterial infection.


Cellular and Molecular Mechanisms Mediated by recPrPC Involved in the Neuronal Differentiation Process of Mesenchymal Stem Cells.
Human Dental Pulp Stem Cells (hDPSCs) represent a type of adult mesenchymal stem cells that have the ability to differentiate in vitro in several lineages such as odontoblasts, osteoblasts, chondrocytes, adipocytes and neurons. In the current work, we used hDPSCs as the experimental model to study the role of recombinant prion protein 23⁻231 (recPrPC) in the neuronal differentiation process, and in the signal pathway activation of ERK 1/2 and Akt. We demonstrated that recPrPC was able to activate an intracellular signal pathway mediated by extracellular-signal-regulated kinase 1 and 2 (ERK 1/2) and protein kinase B (Akt). Moreover, in order to understand whether endogenous prion protein (PrPC) was necessary to mediate the signaling induced by recPrPC, we silenced PrPC, demonstrating that the presence of endogenous PrPC was essential for ERK 1/2 and Akt phosphorylation. Since endogenous PrPC is a well-known lipid rafts component, we evaluated the role of these structures in the signal pathway induced by recPrPC. Our results suggest that lipid rafts integrity play a key role in recPrPC activity. In fact, lipid rafts inhibitors, such as fumonisin B1 and MβCD, significantly prevented ERK 1/2 and Akt phosphorylation induced by recPrPC. In addition, we investigated the capacity of recPrPC to induce hDPSCs neuronal differentiation process after long-term stimulation through the evaluation of typical neuronal markers expression such as B3-Tubulin, neurofilament-H (NFH) and growth associated protein 43 (GAP43). Accordingly, when we silenced endogenous PrPC, we observed the inhibition of neuronal differentiation induced by recPrPC. The combined data suggest that recPrPC plays a key role in the neuronal differentiation process and in the activation of specific intracellular signal pathways in hDPSCs.


Deep-sea food bonanzas: early Cenozoic whale-fall communities resemble wood-fall rather than seep communities.
The evolutionary history of invertebrate communities utilizing whale carcasses and sunken wood in the deep-sea is explored using fossil evidence. Compared to modern whale-fall communities, the Eo-Oligocene examples lack those vent-type taxa that most heavily rely on sulphide produced by anaerobic breakdown of bone lipids, but are very similar in their trophic structure to contemporaneous wood-falls. This sheds doubt on the hypothesis that whale-falls were evolutionary stepping stones for taxa that now inhabit hydrothermal vents and seeps. We suggest that the whale-fall communities reported here represent a new ecologic stage among whale-falls, which we have coined the 'chemosymbiotic opportunist stage' and that the 'sulphophilic stage' of modern whale-falls developed during the Early Miocene, resulting from a significant increase in both body size and/or oil content of bones among cetaceans during this time.


Sigmoid Volvulus Complicating Postpartum Period.
Background. Sigmoid volvulus is a rare complication of pregnancy and the puerperium. Case. A 19-year-old patient, gravida 1 para 0 at 41 0/7 weeks of gestation, admitted for late-term induction of labor underwent an uncomplicated primary low transverse cesarean delivery for arrest of descent. Her postoperative period was complicated by sudden onset of abdominal pain and the ultimate diagnosis of sigmoid volvulus. Conclusion. Prompt surgical evaluation of an acute abdomen in the postpartum period is essential; delayed diagnosis and treatment can lead to significant maternal morbidity and mortality.


[Amiodarone and hyperthyroidism].
22 cases of hyperthyroidism occurring during or following treatment with amiodarone are reported and compared with more than 15 cases in the literature. The specific clinical features of these cases of hyperthyroidism are presented and the problems in interpretation of the laboratory thyroid function tests are discussed. A study of the course of these cases reveals a number of prognostic factors. Finally, the authors describe the practical management of this form of hyperthyroidism.


Experimental Study and ANN Dual-Time Scale Perturbation Model of Electrokinetic Properties of Microbiota.
The electrokinetic properties of the rumen microbiota are involved in cell surface adhesion and microbial metabolism. An in vitro study was carried out in batch culture to determine the effects of three levels of special surface area (SSA) of biomaterials and four levels of surface tension (ST) of culture medium on electrokinetic properties (Zeta potential, ξ; electrokinetic mobility, μe), fermentation parameters (volatile fatty acids, VFAs), and ST over fermentation processes (ST-a, γ). The obtained results were combined with previously published data (digestibility, D; pH; concentration of ammonia nitrogen, c(NH3-N)) to establish a predictive artificial neural network (ANN) model. Concepts of dual-time series analysis, perturbation theory (PT), and Box-Jenkins Operators were applied for the first time to develop an ANN model to predict the variations of the electrokinetic properties of microbiota. The best dual-time series Radial Basis Functions (RBR) model for ξ of rumen microbiota predicted ξ for >30,000 cases with a correlation coefficient >0.8. This model provided insight into the correlations between electrokinetic property (zeta potential) of rumen microbiota and the perturbations of physical factors (specific surface area and surface tension) of media, digestibility of substrate, and their metabolites (NH3-N, VFAs) in relation to environmental factors.


PAR-TERRA directs homologous sex chromosome pairing.
In mammals, homologous chromosomes rarely pair outside meiosis. One exception is the X chromosome, which transiently pairs during X-chromosome inactivation (XCI). How two chromosomes find each other in 3D space is not known. Here, we reveal a required interaction between the X-inactivation center (Xic) and the telomere in mouse embryonic stem (ES) cells. The subtelomeric, pseudoautosomal regions (PARs) of the two sex chromosomes (X and Y) also undergo pairing in both female and male cells. PARs transcribe a class of telomeric RNA, dubbed PAR-TERRA, which accounts for a vast majority of all TERRA transcripts. PAR-TERRA binds throughout the genome, including to the PAR and Xic. During X-chromosome pairing, PAR-TERRA anchors the Xic to the PAR, creating a 'tetrad' of pairwise homologous interactions (Xic-Xic, PAR-PAR, and Xic-PAR). Xic pairing occurs within the tetrad. Depleting PAR-TERRA abrogates pairing and blocks initiation of XCI, whereas autosomal PAR-TERRA induces ectopic pairing. We propose a 'constrained diffusion model' in which PAR-TERRA creates an interaction hub to guide Xic homology searching during XCI.


Experimental photodynamic effects of hypocrellin A on the choriocapillaris.
To investigate the use of the photosensitizer hypocrellin A as a photodynamic agent to occlude the choriocapillaris in the eyes of pigmented rabbits. Hypocrellin A (500 microg/kg) incorporated into liposomes was injected intravenously in pigmented rabbits. Ten to 15 minutes later, the retinas were irradiated with a dye laser (spot size, 2 mm; 10-60 mW; 10-60 seconds; fluences 3.2 to 95.5 J/cm2) at two wavelengths: yellow (568 nm) and red (647 nm). Fluorescein angiography was performed 2 and 24 hours later. Parallel controls were irradiated without a photosensitizer. Histology was performed immediately after the 24-hour angiogram. observed 24 hours after PDT in eyes subjected to yellow laser irradiation at 20 mW for 60 seconds (fluence, 38.2 J/cm2) and at higher powers for lesser durations: 30 mW for 40 seconds (fluence, 38.2 J/cm2), 40 mW for 20 seconds (fluence, 25.4 J/cm2), and 50 and 60 mW for 10 seconds (fluences, 15.9 and 19.1 J/cm2, respectively). Light microscopy showed occlusion of the choriocapillaris in all eyes with angiographic responses. Control eyes and eyes irradiated with the red laser revealed no angiographic or histologic changes. Photodynamic therapy using liposomal hypocrellin A and the yellow laser of 568 nm was effective in occluding the choriocapillaris of pigmented rabbits.


Phenotypic changes in large cell transformation of small cell lymphoid malignancies.
Large cell transformation of two cases of chronic lymphocytic leukemia and two cases of small lymphocytic lymphoma were studied. Changes in surface immunoglobulins were observed in two cases. In one case, there was a change from IgM to IgG. In another case, the large cells bore kappa light chains whereas the small cells had lambda light chains. Surface antigens other than immunoglobulin might also differ. All three small cell malignancies tested, but none of the large cell tumors, expressed the antigen T1 (Leu 1). The antigens HLA-DR, Leu 14, B1, and BA1 were expressed by both the small and large cell malignancies with one exception. The staining intensity might, however, change on transformation. The common acute lymphocytic leukemia antigen was not detected on any of the tumors studied and the expression of BA2 was variable. Surface marker studies cannot confidently distinguish between large cell lymphomas resulting from clonal evolution and those arising de novo. More definitive studies such as analyzing the idiotypic determinants on and amino acid sequences of the heavy and light chains or analyses of immunoglobulin gene rearrangements are necessary to confirm or exclude the same clonal origin in such cases.


Chemically Defined Culture and Cardiomyocyte Differentiation of Human Pluripotent Stem Cells.
Since the first discovery that human pluripotent stem cells (hPS cells) can differentiate to cardiomyocytes, efforts have been made to optimize the conditions under which this process occurs. One of the most effective methodologies to optimize this process is reductionist simplification of the medium formula, which eliminates complex animal-derived components to help reveal the precise underlying mechanisms. Here we describe our latest, cost-effective and efficient methodology for the culture of hPS cells in the pluripotent state using a modified variant of chemically defined E8 medium. We provide exact guidelines for cell handling under these conditions, including non-enzymatic EDTA passaging, which have been optimized for subsequent cardiomyocyte differentiation. We describe in depth the latest version of our monolayer chemically defined small molecule differentiation protocol, including metabolic selection-based cardiomyocyte purification and the addition of triiodothyronine to enhance cardiomyocyte maturation. Finally, we describe a method for the dissociation of hPS cell-derived cardiomyocytes, cryopreservation, and thawing.


[Indications for urodynamic studies before and after adenomectomy].
Preoperative urodynamic examinations are an important supplement to our diagnostic repertoire in cases of adenoma of the vesical cervix. Flow measurement should always be carried out. In routine practice further urodynamic examinations are only indicated in uncertain cases. Exact preoperative diagnosis will greatly improve the results of adenectomy. Persistent dysuria or incontinence are always an indication for post operative urodynamic examinations. Here efficient therapy is made possible by exact diagnosis.


STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.
Tumor cells need to attain anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The mechanism by which pancreatic cancer cells resist anoikis and metastasize is not well established. Significant proportion of pancreatic cancer cells resisted anoikis when grown under anchorage-independent conditions. The cells that resisted anoikis showed higher migratory and invasive characteristics than the cells that were cultured under anchorage-dependent condition. Interestingly, anoikis-resistant cells exhibited significantly increased expression and phosphorylation of signal transducer and activation of transcription 3 (STAT3) at Tyr 705, as compared to adherent cells. AG 490 and piplartine (PL) induced significant anoikis in anoikis-resistant pancreatic cancer cells. Silencing STAT3 not only reduced the capacity of pancreatic cancer cells to resist anoikis but also reversed its invasive characteristics. Interleukin-6 treatment and overexpression of STAT3 enhanced anoikis resistance and protected the cells from PL-induced anoikis. PL-treated cells completely failed to develop tumors when injected subcutaneously in immune-compromised mice. Moreover, these cells also failed to metastasize when injected intravenously. On the other hand, untreated anoikis-resistant cells not only formed aggressive tumors but also metastasized substantially to lungs and liver when injected intravenously. Metastatic nodules formed by untreated anoikis-resistant cells in lungs exhibited significant phosphorylation of STAT3 at Tyr705. Taken together, our results established the critical involvement of STAT3 in conferring anoikis resistance to pancreatic cancer cells and increased metastasis.


Isoniazid exposure and pyridoxine levels in human immunodeficiency virus associated distal sensory neuropathy.
Distal sensory polyneuropathy (DSP) may manifest in human immunodeficiency virus (HIV) infected individuals before or after antiretroviral therapy (ART). DSP can also occur in response to isoniazid (INH); this can be prevented by pyridoxine supplementation. N-acetyltransferase 2 (NAT2) polymorphisms influence drug acetylation and possibly the risk for INH-associated DSP. To investigate the relationship between previous/current TB, pyridoxine deficiency and DSP in HIV-infected individuals enrolled in a government-sponsored HIV programme. Neuropathy assessments were performed among 159 adults pre-ART and 12 and 24 weeks thereafter. DSP was defined as ⩾1 neuropathic symptom and sign. NAT2 genotypes predicted acetylation phenotype. Serum pyridoxine levels (PLP) were quantified at baseline and week 12. DSP was present in 16% of individuals pre-ART and was associated with previous/current TB (P = 0.020). Over 50% were pyridoxine deficient (PLP < 25 nmol/l), despite supplementation with vitamin B complex supplements (2-4 mg/day pyridoxine). Those with a history of TB and pre-ART DSP were more likely to be pyridoxine deficient (P = 0.029), and slow/intermediate NAT2 phenotypes impacted on their PLP levels. Incident/worsening DSP after ART developed in 21% of the participants. PLP levels remained low after ART, particularly among those with prior TB, but without an association between DSP or NAT2 phenotypes. Adequate pyridoxine supplementation before ART initiation should be prioritised, particularly in those with a history of TB or current TB.


Morpho-agronomic variability of okra [Abelmoschus esculentus (L.) Moench] genotypes in Dire Dawa, eastern Ethiopia.
A total of 21 okra genotypes were evaluated for 25 morpho-agronomic traits in 2020 at Dire Dawa, Ethiopia in a randomized complete block design with three replications. Analysis of variance showed significant differences at p<0.05 level of significance for all traits. Estimates of genotypic (GCV) and phenotypic (PCV) coefficients of variation range from 9.16 to 42.3% and 9.33 to 44.16%, respectively. Heritability in a broad sense (H2) and genetic advance as a percent of the mean (GAM) ranged from 29.57 to 91.89% and 10.39 to 83.53%, respectively. Estimated variability components (GCV, PCV, H2, and GAM) were high and moderate for all traits except days to 50% emergence 9.33% of GCV and PCV, internode length 9.16% of GCV and green fruit width 29.57% of H2 that were categorized under low. The first four principal component axes (PCA1 to PCA4) accounted for 7.83 to 35.02%, which accounted 74.56% of the total variability with eigenvalues that ranged from 1.95 to 8.75. Genetic distances estimated by Euclidean distance from the 25 traits ranged from 2.33 to 12.56 with a mean of 6.83, standard deviation of 1.8, and a coefficient of variation of 26.46%. The genotypes were grouped into four distinct clusters using the Euclidean distance matrix using UPGMA. Indigenous okra genotypes collected from Ethiopia were more divergent with high genetic distances and had a higher performance for most of the traits including growth, green fruit yield, and seed yield than introduced genotypes. In conclusion, this study showed the presence of variation among genotypes for most of the traits, indicating that selection of genotypes could be effective to develop okra varieties with high green fruit and seed yield through direct selection or crossing.


The National Resuscitation Council, Singapore, and 34 years of resuscitation training: 1983 to 2017.
Training in the modern form of cardiopulmonary resuscitation (CPR) started in Singapore in 1983. For the first 15 years, the expansion of training programmes was mainly owing to the interest of a few individuals. Public training in the skill was minimal. In an area of medical care where the greatest opportunity for benefit lies in employing core resuscitation skills in the prehospital environment, very little was being done to address such a need. In 1998, a group of physicians, working together with the Ministry of Health, set up the National Resuscitation Council (NRC). Over the years, the NRC has created national guidelines on resuscitation and reviewed them at five-yearly intervals. Provider training manuals are now available for most programmes. The NRC has set up an active accreditation system for monitoring and maintaining standards of life support training. This has led to a large increase in the number of training centres, as well as recognition and adoption of the council's guidelines in the country. The NRC has also actively promoted the use of bystander CPR through community-based programmes, resulting in a rise in the number of certified providers. Improving the chain of survival, through active community-based training programmes, will likely lead to more lives being saved from sudden cardiac arrest.


Stereotactic body radiotherapy of bone metastases in oligometastatic disease: prognostic factors of oncologic outcomes.
To evaluate the safety of stereotactic body radiotherapy (SBRT) of bone metastases in oligometastatic disease and to investigate prognostic factors of local control (LC), progression/disease-free survival (PDFS), and overall survival (OS). Eligibility criteria were number of metastates ≤5, controlled primary tumor without evidence of progression under systemic therapy, exclusion of surgery, and no previous radiotherapy of the lesion of interest. Oligometastatic status was classified into only bone (BOD) and outside bone disease (OBOD), whereas SBRT was delivered to bone lesions using 2 different schedules: 24 Gy/1 fraction or 27 Gy/3 fractions. A positron emission tomography study of the lesion of interest was performed at baseline and at 3 months after SBRT to evaluate metabolic response according to European Organization for Research and Treatment of Cancer (EORTC) criteria. A Cox regression model was used for univariate and multivariate analysis. Between January 2010 and December 2013, 40 patients were enrolled. Only 1 patient experienced severe late toxicity (radiation-related fracture). Local control was longer among responders' than nonresponders' lesions (94.2% and 91.2% versus 63% and 35% at 1 and 2 years, respectively) (p = 0.004; hazard ratio = 9.958). The multivariate analysis of PDFS showed a significant correlation with planning target volume (PTV) size (p = 0.003) and oligometastatic status (p = 0.002). The multivariate analysis of OS confirmed a statistically significant value of the oligometastatic status (p = 0.002) and a significant trend for PTV size (p = 0.065). Stereotactic body radiotherapy is safe with a low incidence of severe toxicity. Positron emission tomography response was a strong prognostic factor of LC whereas BOD status and small PTV size could identify a subset of oligometastatic patients at better prognosis.


Lessons for clinicians from physician-patient communication literature.
Research about the communication between physicians and patients contains information that can help clinicians be better diagnosticians and achieve greater compliance and can lead to improved patient health and satisfaction. We present research results that can be useful for the physician in daily clinical practice.


[Sociomedical examination and rehabilitation of patients with tuberculosis].
The paper provides primary and secondary disability rates during 5 years (1993-1997), derived by the tuberculosis agency of a Moscow sociomedical examination commission. Examination was made mainly in patients with pulmonary and extrapulmonary tuberculosis, chronic nonspecific lung diseases, silicosis, cancer, and concomitant diseases of the heart, liver, kidney, etc. There was a rise in primary and secondary disability rates due to the increases of Groups 2 and 3. More than 50% of the patients do not work as unemployment is on the rise in Russia. Group 3 patients were the smallest proportion and temporarily disabled patients were also few.


Reduced expression of selective immune-related genes in silver catfish (Rhamdia quelen) monocytes exposed to atrazine.
The effect of atrazine (ATZ) and its metabolites on aquatic vertebrate species has been a matter of concern to researchers and environmentalist. In this study we exposed head kidney monocytes to sublethal concentrations of atrazine (1 and 10 μg/ml-1), corresponding to 1% and 10% of the LC50-96h, to evaluate the expression of immune-related genes central to immune stimulation. The mRNA levels of TNF-α, Mieloperoxidase and Mx genes were significantly reduced following 24 h exposure to both concentrations of ATZ. The mRNA levels of iRAK4 were reduced only at the higher ATZ concentration and the mRNA levels of IL-1β were not affected. The results reported here support our previous findings on the immunosuppressive effect of ATZ indicating its potential to interfere with the expression of immune-related genes, and strengthen the need to regulate ATZ usage aiming to preserve animal and human health.


Allergic colitis in infants related to cow's milk: clinical characteristics, pathologic changes, and immunologic findings.
Allergic colitis (AC) is an inflammatory condition characterized by eosinophils infiltrating the colonic wall. It can be a benign and/or severe illness among gastrointestinal diseases in infants. We report five infants who, since January 2009, in whom AC under fibrotic endoscopic examinations has been diagnosed. The criterion for histopathologic diagnosis of AC in this study was five or more eosinophils per high-power field. Patients' clinical symptoms, pathologic findings, and immunologic studies, such as specific antibodies against component of cow's milk protein, were compared with those of allergic children without AC and those of nonatopic control children. Histopathologic examinations of biopsy specimens revealed acute inflammation with characteristic eosinophilic infiltration of lamina propria (5-15 eosinophils per high-power field) in all five patients. They all had strongly positive skin prick tests against milk protein, which were not correlated with in vitro allergen-specific immunoglobulin (Ig) E levels. In contrast, there were significantly higher levels of IgE antibodies, and lower specific IgG4 and IgA levels to components and whole milk proteins in AC, as compared to control children without AC. Endoscopic biopsy specimens of intestine confirm the diagnosis of AC. However, allergen skin prick test and IgE antibody to milk protein components also provide helpful diagnostic tools for this rare disease in children.


The curative effect of adefovir dipivoxil treating HBeAg negative chronic hepatitis B and treating HBeAg positive chronic hepatitis B combining interferon α-2b.
This study aimed to research the efficiency of adefovir dipivoxil in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treatment and in combination with α-2b interferon in the treatment of HBeAg-positive chronic hepatitis B. A total of 102 cases of adult patients with HBeAg chronic hepatitis B were selected for testing. HBeAg negative chronic hepatitis B patients took 10mg adefovir dipivoxil capsules once daily, while positive chronic hepatitis B patients were randomly divided into either a treatment group or a control group. The treatment group was administrated with 10mg adefovir dipivoxil capsules, 1 time daily, and injected with 5 million U Recombinant Human Interferon α-2b through muscle every other day. The control group was treated with 10mg adefovir dipivoxil capsules, 1 time per day. We examined alanine aminotransferase (ALT) normalization and the Hepatitis B Virus (HBV)-DNA negative rate (undetectable rate), as well as, HBeAg / hepatitis B e antibody (HBeAb) sero-conversion rate to detect treatment effects. The results proved that after 6 months of medication therapy, the ALT normalization rate was 49.9% and the HBV-DNA negative conversion rate was 54.3%. 18 months into the treatment, showed an ALT normalization rate of 73.2%, while the HBV-DNA negative conversion rate grew to 76.8%. The use of adefovir dipivoxil treatment of the negative chronic HBV has a certain extent combined with α-2b Interferon therapy in treatment of HbeAg positive chronic hepatitis B. After a 48-week observation period, ALT normalization and HBV-DNA rate could not be measured, HBeAg/HBeAb sero-conversion rose higher, indicating that the treatment of the combined drugs is more efficient than taking adefovir dipivoxil by itself, and the data were comparable with the control group (P<0.05). Thus adefovir dipivoxil can greatly improve the restrain function to HBV-DNA and improve the immunity and control ability of the body, with obvious short-term effects, in combination with Interferon.


Neuroinflammation in Gulf War Illness is linked with HMGB1 and complement activation, which can be discerned from brain-derived extracellular vesicles in the blood.
Cognitive dysfunction and neuroinflammation are conspicuously observed in Gulf War Illness (GWI). We investigated whether brain inflammation in GWI is associated with activation of high mobility group box-1 (HMGB1) and complement-related proteins in neurons and astrocytes, and brain inflammation can be tracked through neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived EVs (ADEVs) found in the circulating blood. We exposed animals to GWI-related chemicals pyridostigmine bromide, DEET and permethrin, and moderate stress for 28 days. We performed behavioral tests 10 months post-exposure and quantified activated microglia and reactive astrocytes in the cerebral cortex. Then, we measured the concentration of HMGB1, proinflammatory cytokines, and complement activation-related proteins in the cerebral cortex, and NDEVs and ADEVs in the circulating blood. Cognitive impairments persisted in GWI rats at 10 months post-exposure, which were associated with increased density of activated microglia and reactive astrocytes in the cerebral cortex. Moreover, the level of HMGB1 was elevated in the cerebral cortex with altered expression in the cytoplasm of neuronal soma and dendrites as well as the extracellular space. Also, higher levels of proinflammatory cytokines (TNFa, IL-1b, and IL-6), and complement activation-related proteins (C3 and TccC5b-9) were seen in the cerebral cortex. Remarkably, increased levels of HMGB1 and proinflammatory cytokines observed in the cerebral cortex of GWI rats could also be found in NDEVs isolated from the blood. Similarly, elevated levels of complement proteins seen in the cerebral cortex could be found in ADEVs. The results provide new evidence that persistent cognitive dysfunction and chronic neuroinflammation in a model of GWI are linked with elevated HMGB1 concentration and complement activation. Furthermore, the results demonstrated that multiple biomarkers of neuroinflammation could be tracked reliably via analyses of NDEVs and ADEVs in the circulating blood. Execution of such a liquid biopsy approach is especially useful in clinical trials for monitoring the remission, persistence or progression of brain inflammation in GWI patients with drug treatment.


Apert's syndrome correlates with low fibroblast growth factor receptor activity in stenosed cranial sutures.
Recent genetic studies have shown that Apert's syndrome results from mutations of the fibroblast growth factor (FGF) receptor 2 gene. We were interested in investigating the expression of FGF receptor 2 at the tissue level in children with Apert's syndrome. We studied FGF receptor activity in cranial sutures of children with Apert's syndrome and nonsyndromic, isolated craniosynostosis. Fourteen children between the ages of 6 months and 12 months were studied. Five of these children had Apert's syndrome with coronal suture stenosis. Nine children had an isolated, nonsyndromic coronal stenosis. Stenosed and nonstenosed cranial sutures were removed at the time of cranioplasty, fixed, decalcified, and paraffinized. Immunohistochemistry was performed with labeled, specific anti-FGR receptor 2 antibodies. We found lower levels of FGF receptor 2 staining in both stenosed and unstenosed sutures of children with Apert's syndrome compared with those from children with a nonsyndromic suture stenosis. Furthermore, fused sutures from children with Apert's syndrome demonstrated lower levels of FGF receptor 2 staining than unfused sutures from the same sample. The findings suggest that Apert's syndrome correlates with low FGF receptor 2 activity in cranial sutures. These results are consistent with and similar to our findings in Crouzon's syndrome, and support genetic studies showing localized mutational changes occurring at the FGF receptor 2 gene for both Apert's and Crouzon's syndromes. Furthermore, the findings suggest the possibility that variable expression of FGF receptor 2 occurs at the tissue level in patients with Apert's syndrome.


Microsatellite instability in nasopharyngeal and lymphoepithelial carcinomas of the head and neck.
Lymphoepithelial carcinoma (LEC) is a descriptive diagnosis for an undifferentiated carcinoma that has a typical morphologic appearance of large vesicular cells with prominent nucleoli and infiltrating lymphocytes. Tumors with this histopathologic appearance in the head and neck can be categorized as either those that occur in endemic areas, such as Southeast Asia and are associated with Epstein-Barr virus (EBV) infection, or those that occur in other countries and are less commonly associated with EBV. The molecular changes in endemic EBV-related LEC have been fairly well studied and include both alterations in tumor suppressor genes and 1 report of high levels of microsatellite instability. In nonendemic LECs arising in western countries, there is very little data related to molecular mutational profiles. In this study, we examined 19 cases of LEC from the United States for evidence of microsatellite instability at the DNA level and for alterations in the DNA mismatch repair (MMR) system at the immunohistochemical staining level. Only 3/19 cases showed high-level microsatellite instability and only 1 of these showed an alteration in the DNA MMR protein expression hMLH1. These data suggest that alterations in DNA MMR system are not a common mechanism of tumorigenesis in LEC of the head and neck in a nonendemic country.


Polypoid lipoma of the palatine tonsil.
A polypoid, pedunculated tumour of the left palatine tonsil was incidentally detected in a 42-year-old female. It was composed of mature fat and was covered by a nonkeratinizing squamous epithelium with an underlying rim of fibrous tissue. The literature on tonsillar lipoma is reviewed and the differential diagnosis of polypoid lesions of the tonsil is discussed.


The potency of erythropoietin-mimic antibodies correlates inversely with affinity.
Preclinical animal studies have shown that Ab12.6, an agonistic human Ab targeting the erythropoietin receptor (EPOR), exhibits several potential dosing and safety features that make it an attractive clinical candidate for the treatment of anemia. Ab12.6 was derived by yeast display affinity maturation of parental Ab12, a strategy initially intended to improve off-rate and affinity for EPOR, thereby enhancing erythropoietic activity. Analysis of full-length IgGs derived from yeast clones identified sequences within Ab12 CDRH2 that independently influenced both affinity and potency. The Ab12.6 derivative displayed improved in vitro potency and in vivo efficacy, although its binding affinity to the EPOR was lower than that of the parent Ab12. Additional Ab12 derivatives also exhibited an inverse correlation between affinity and potency. These results suggest that for this class of agonistic Abs, faster off-rates may permit continuous receptor stimulation and more efficient erythropoiesis.


Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer.
Intracranial metastases are a common cause of morbidity and mortality in patients with advanced NSCLC, and are frequently managed with radiation therapy (RT). The safety of cranial RT in the setting of treatment with immune checkpoint inhibitors (ICIs) has not been established. We identified patients with advanced NSCLC with brain metastases who received cranial RT and were treated with or without programmed cell death 1/programmed death ligand 1 inhibitors between August 2013 and September 2016. RT-related adverse events (AEs) were retrospectively evaluated and analyzed according to ICI treatment status, cranial RT type, and timing of RT with respect to ICI. Of 163 patients, 50 (31%) received ICIs, whereas 113 (69%) were ICI naive. Overall, 94 (58%), 28 (17%), and 101 (62%) patients received stereotactic radiosurgery, partial brain irradiation, and/or whole brain RT, respectively. Fifty percent of patients received more than one radiation course. We observed no significant difference in rates of all-grade AEs and grade 3 or higher AEs between the ICI-naive and ICI-treated patients across different cranial RT types (grade ≥3 AEs in 8% of ICI-naive patients versus in 9% of ICI-treated patients for stereotactic radiosurgery [p = 1.00] and in 8% of ICI-naive patients versus in 10% of ICI-treated patients for whole brain RT [p = 0.71]). Additionally, there was no difference in AE rates on the basis of timing of ICI administration with respect to RT. Treatment with an ICI and cranial RT was not associated with a significant increase in RT-related AEs, suggesting that use of programmed cell death 1/programmed death ligand 1 inhibitors in patients receiving cranial RT may have an acceptable safety profile. Nonetheless, additional studies are needed to validate this approach.


Low back pain patients demonstrate increased hip extensor muscle activity during standardized submaximal rotation efforts.
A comparative study of trunk and hip extensor muscle recruitment patterns in 2 subject groups. To examine for changes in recruitment of the hip and back extensor muscles during low level isometric trunk rotation efforts in chronic low back pain (CLBP) subjects by comparison with matched asymptomatic control subjects. Anatomic and biomechanical models have provided evidence that muscles attaching to the thoracolumbar fascia (TLF) are important for providing stabilization to the lumbopelvic region during trunk rotation. This has guided rehabilitation programs. The muscles that link diagonally to the posterior layer of the TLF have not previously been examined individually and compared during low-level trunk rotation efforts in CLBP patients and matched controls. Thirty CLBP patients and 30 matched controls were assessed using surface electromyography (EMG) as they performed low-level isometric rotation efforts while standing upright. Muscles studied included latissimus dorsi, erector spinae, upper and lower gluteus maximus, and biceps femoris. Subjects performed the rotation exertion with various levels of external trunk support, related to different functional tasks. EMG results demonstrated that subjects with CLBP had significantly higher levels of recruitment for the lower and upper gluteus maximus (P < 0.05), hamstrings (P < 0.05), and erector spinae muscles (P < 0.05) during rotation to the left compared with the control subjects. This study provided evidence of increased muscle recruitment in CLBP patients when performing a standardized trunk rotation task. These results may have implications for the design of therapeutic exercise programs for CLBP patients.


Optimization of the performance of a voltage measuring station using genetic algorithm.
This article describes the use of the genetic algorithm (GA) for the optimization of the performance of a voltage measuring station. This procedure can be used for the instruments for which regular and systematic calibration is required for better performance. Here, a GA-based correction module has been used to internally store a few previous measured-value and measured-time pairs and to use these values to correct the current readings. Sanity-checking runs against zero and standard voltages from time to time and auto-calibrates itself. The genetic algorithm libraries have been developed along with the correction module. This system can also be considered as a test bed for the study of self-calibration algorithms.


Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy.
Macroautophagy (hereafter autophagy) is a ubiquitous process in eukaryotic cells that is integrally involved in various aspects of cellular and organismal physiology. The morphological hallmark of autophagy is the formation of double-membrane cytosolic vesicles, autophagosomes, which sequester cytoplasmic cargo and deliver it to the lysosome or vacuole. Thus, autophagy involves dynamic membrane mobilization, yet the source of the lipid that forms the autophagosomes and the mechanism of membrane delivery are poorly characterized. The TRAPP complexes are multimeric guanine nucleotide exchange factors (GEFs) that activate the Rab GTPase Ypt1, which is required for secretion. Here we describe another form of this complex (TRAPPIII) that acts as an autophagy-specific GEF for Ypt1. The Trs85 subunit of the TRAPPIII complex directs this Ypt1 GEF to the phagophore assembly site (PAS) that is involved in autophagosome formation. Consistent with the observation that a Ypt1 GEF is directed to the PAS, we find that Ypt1 is essential for autophagy. This is an example of a Rab GEF that is specifically targeted for canonical autophagosome formation.


How to effectively obtain informed consent in trauma patients: a systematic review.
Obtaining adequate informed consent from trauma patients is challenging and time-consuming. Healthcare providers must communicate complicated medical information to enable patients to make informed decisions. This study aimed to explore the challenges of obtaining valid consent and methods of improving the quality of the informed consent process for surgical procedures in trauma patients. We conducted a systematic review of relevant English-language full-text original articles retrieved from PubMed (1961-August 2018) that had experimental or observational study design and involved adult trauma patients. Studies involving informed consent in clinical or research trials were excluded. Titles and abstracts of searched articles were reviewed and relevant data were extracted with a structured form. Results were synthesized with a narrative approach. A total of 2044 articles were identified in the initial search. Only eight studies were included in the review for narrative synthesis. Six studies involved orthopedic surgeries, one involved nasal bone surgeries, and one involved trauma-related limb debridement. Only one study was conducted in an emergency department. Information recall was poor for trauma patients. Risk recall and comprehension were greater when written or video information was provided than when information was provided only verbally. Patient satisfaction was also greater when both written and verbal information were provided than when verbal information alone was provided; patients who received video information were more satisfied than patients who received written or verbal information. Many articles have been published on the subject of informed consent, but very few of these have focused on trauma patients. More empirical evidence is needed to support the success of informed consent for trauma patients in the emergency department, especially within the necessarily very limited time frame. To improve the informed consent process for trauma patients, developing a structured and standardized informed consent process may be necessary and achievable; its effectiveness would require evaluation. Adequately educating and training healthcare providers to deliver structured, comprehensive information to trauma patients is crucial. Institutions should give top priority to ensuring patient-centered health care and improved quality of care for trauma patients.


Rat carbamyl-phosphate synthetase I gene. Promoter sequence and tissue-specific transcriptional regulation in vitro.
The region flanking the 5'-end of the rat gene encoding the cytoplasmic precursor of carbamyl-phosphate synthetase I, a mitochondrial matrix enzyme, has been cloned and partially characterized. S1 nuclease and primer extension analyses position the starts of transcription 138-140 nucleotides upstream of the translation initiation codon. Exon 1 contains this untranslated sequence and extends downstream to include the coding region for the pre-enzyme signal peptide (38 amino acids) plus 4 amino acids from the amino terminus of the mature protein. The 5'-flanking sequence contains typical promoter elements, including putative TATA and CAAT motifs at -21 and -82 nucleotides, respectively. In addition, several copies of consensus sequences corresponding to the H4TF-1 recognition element, GATTTC, together with the enhancer-like octamer, ATTTGCAT, are also present. Carbamyl-phosphate synthetase I is a cell-type specific enzyme, being expressed only in hepatocytes and epithelial cells of the intestinal mucosa. It is also synthesized at relatively high levels in the hepatoma cell line, Hep G2. Employing pCPS2.1, a minigene containing the promoter and part of exon 1, we show that nuclear extracts from Hep G2 support accurate carbamyl-phosphate synthetase I gene transcription in vitro. No such activity was observed, however, in extracts from HeLa, a cell line which does not express carbamyl-phosphate synthetase I.


Comparative study of extralevator vs. conventional abdominoperineal excision in a single centre in the developing world.
Abdominoperineal excision (APE) is used to resect cancers in the distal rectum and anus where sphincterpreserving surgery is not possible. It is associated with increased local recurrence rates compared to anterior resection. The extralevator abdominoperineal excision (ELAPE) was developed to reduce local recurrence and was widely adopted without sound evidence. To compare the short-term (2 years) outcomes of patients managed with ELAPE to those with conventional APE in a single institution in a developing country. A prospective database on all patients treated with prone ELAPE from 2010 to 2014 was compared to patients treated with conventional APE. Patient demographics, tumour characteristics, intra-operative tumour perforation, involvement of the circumferential resection margin (CRM), surgical complications and mortality are reported. Fifty-six patients were treated with APE of which 29 were male. Median age was 56. Thirty underwent conventional APE (16 male; 14 female) and 26 underwent ELAPE (15 male; 11 female). The groups were similar in age, tumour histology, height above anal verge clinical staging and response to neoadjuvant treatment. Perineal closure techniques in both cohorts were similar. There was no difference in intra-operative tumour perforation, involvement of the CRM, perineal wound complications or 30-day mortality in the 2 groups. There is no difference in the important short-term outcomes of conventional APE when compared to ELAPE.


Principal component analysis based feature extraction approach to identify circulating microRNA biomarkers.
The discovery and characterization of blood-based disease biomarkers are clinically important because blood collection is easy and involves relatively little stress for the patient. However, blood generally reflects not only targeted diseases, but also the whole body status of patients. Thus, the selection of biomarkers may be difficult. In this study, we considered miRNAs as biomarker candidates for several reasons. First, since miRNAs were discovered relatively recently, they have not yet been tested extensively. Second, since the number of miRNAs is relatively limited, selection is expected to be easy. Third, since they are known to play critical roles in a wide range of biological processes, their expression may be disease specific. We applied a newly proposed method to select combinations of miRNAs that discriminate between healthy controls and each of 14 diseases that include 5 cancers. A new feature selection method is based on principal component analysis. Namely this method does not require knowledge of whether each sample was derived from a disease patient or a healthy control. Using this method, we found that hsa-miR-425, hsa-miR-15b, hsa-miR-185, hsa-miR-92a, hsa-miR-140-3p, hsa-miR-320a, hsa-miR-486-5p, hsa-miR-16, hsa-miR-191, hsa-miR-106b, hsa-miR-19b, and hsa-miR-30d were potential biomarkers; combinations of 10 of these miRNAs allowed us to discriminate each disease included in this study from healthy controls. These 12 miRNAs are significantly up- or downregulated in most cancers and other diseases, albeit in a cancer- or disease-specific combinatory manner. Therefore, these 12 miRNAs were also previously reported to be cancer- and disease-related miRNAs. Many disease-specific KEGG pathways were also significantly enriched by target genes of up-/downregulated miRNAs within several combinations of 10 miRNAs among these 12 miRNAs. We also selected miRNAs that could discriminate one disease from another or from healthy controls. These miRNAs were found to be largely overlapped with miRNAs that discriminate each disease from healthy controls.


War-related illness symptoms among Operation Iraqi Freedom/ Operation Enduring Freedom returnees.
Our objective was to determine the pattern of war-related illness (WRI) symptoms among returnees of Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) living on Long Island, NY. We conducted an anonymous mail survey of WRI symptoms of a random cohort of 786 returnees (718 male, 68 female) living on Long Island from among 5,500 who registered with the OIF/OEF Registry. From among the 786 returnees whom we surveyed, we subsequently excluded 111 whose surveys were either returned unopened or who changed address. Two hundred seventy-four of the remaining 675 returnees responded to the survey (a 41% response rate). Disabling WRI symptoms were documented in approximately 2/3 of the responders and 75% of these responders had two or more symptoms. War-related illness symptoms are very common among OIF/OEF returnees suggesting the need for management strategies targeting their symptoms. Military conflicts have produced war-related illness (WRI) among our troops and veterans since the Civil War. Common to all these WRIs are a group of symptoms including body pain, fatigue, headache, sleep disturbance, diarrhea, forgetfulness, and impaired concentration. Also common to them is the absence of a discernable pathophysiology. Because WRI is poorly understood, we cannot prevent new occurrences with each new engagement of our armed forces.


Age-related changes in the structure and function of skeletal muscles.
1. For animals of all ages, during activation of skeletal muscles and the subsequent contraction, the balance between the force developed by the muscle and the external load determines whether the muscle shortens, remains at fixed length (isometric) or is lengthened. With maximum activation, the force developed is least during shortening, intermediate when muscle length is fixed and greatest during lengthening contractions. During lengthening contractions, when force is high, muscles may be injured by the contractions. 2. 'Frailty' and 'failure to thrive' are most frequently observed in elderly, physically inactive people. A 'frail' person is defined as one of small stature, with muscles that are atrophied, weak and easily fatigued. The condition of 'failure to thrive' is typified by a lack of response to well-designed programmes of nutrition and physical activity. 3. With ageing, skeletal muscle atrophy in humans appears to be inevitable. A gradual loss of muscle fibres begins at approximately 50 years of age and continues such that by 80 years of age, approximately 50% of the fibres are lost from the limb muscles that have been studied. For both humans and rats, the observation that the timing and magnitude of the loss of motor units is similar to that for muscle fibres suggests that the mechanism responsible for the loss of fibres and the loss of whole motor units is the same. The degree of atrophy of the fibres that remain is largely dependent on the habitual level of physical activity of the individual. 4. 'Master athletes' maintain a high level of fitness throughout their lifespan. Even among master athletes, performance of marathon runners and weight lifters declines after approximately 40 years of age, with peak levels of performance decreased by approximately 50% by 80 years of age. The success of the master athletes and of previously sedentary elderly who undertake well-designed, carefully administered training programmes provide dramatic evidence that age-associated atrophy, weakness and fatigability can be slowed, but not halted.


Estrogen, progesterone and testosterone receptors in human fetal cartilaginous tissue: immunohistochemical studies.
Computerized image analysis was used to study the distribution in cartilage of receptors to estrogen, progesterone, and testosterone during human fetal development. We have examined three histologically distinct cell groups (hypertrophic, proliferating, and reserve zones) in long bones, vertebrae, and trachea from 19 fetuses. Comparisons were made across gender and gestational age. Contrasting with controls, we examined the density of receptors, the size of the nuclear area in which the receptors were detected, the number of hormone receptor-bearing cells, and the total receptor quantity per sample. We found that estrogen, progesterone, and testosterone receptors were detected in the nuclei of all cell types, in both female and male embryonic cartilaginous tissue. Gender differences were small and inconsistent. Changes associated with gestational age depicted a pattern of hormone receptor manifestation, shifting from the immature cell types to more differentiated cells. This was evident from the receptor densities and from the cellular area in which receptors were sighted. These dynamics are accompanied by a general increase in receptor content per sample, brought about by the concomitant increase in receptor containing area size and cell number. The increase in receptor levels seems to reflect the maturation and growth of the fetal skeleton.


Application of solar AOPs and ozonation for elimination of micropollutants in municipal wastewater treatment plant effluents.
Conventional municipal wastewater treatment plants are not able to entirely degrade some organic pollutants that end up in the environment. Within this group of contaminants, Emerging Contaminants are mostly unregulated compounds that may be candidates for future regulation. In this work, different advanced technologies: solar heterogeneous photocatalysis with TiO(2), solar photo-Fenton and ozonation, are studied as tertiary treatments for the remediation of micropollutants present in real municipal wastewater treatment plants effluents at pilot plant scale. Contaminants elimination was followed by Liquid Chromatography/Quadrupole ion trap Mass Spectrometry analysis after a pre-concentration 100:1 by automatic solid phase extraction. 66 target micropollutants were identified and quantified. 16 of those contaminants at initial concentrations over 1000 ng L(-1), made up over 88% of the initial total effluent pollutant load. The order of micropollutants elimination efficiency under the experimental conditions evaluated was solar photo-Fenton > ozonation > solar heterogeneous photocatalysis with TiO(2). Toxicity analyses by Vibrio fischeri and respirometric tests showed no significant changes in the effluent toxicity after the three tertiary treatments application. Solar photo-Fenton and ozonation treatments were also compared from an economical point of view.


Prediction of complicated urinary tract infections in patients with type 2 diabetes: a questionnaire study in primary care.
Relatively few data are available to predict a complicated course of community-acquired complicated urinary tract infections (UTIs) in patients with diabetes type 2 (DM2). The aim of this study was to assess predictors for a complicated course of UTIs in DM2 patients in primary care. We conducted a cross-sectional questionnaire study among DM2 patients aged over 45 years as part of an educational trial. The combined outcome measure was a complicated course of UTI, defined as a self-reported episode of acute pyelonephritis, prostatitis or recurrent cystitis in the 12 months before the trial. Patients with an outcome were all verified by review of medical records. A prediction model was derived with multivariable logistic regression analysis. Of the 1151 trial participants, 94 (8%) had a self-reported community-acquired complicated course of UTIs and 62 (66%) of these were medically-attended. Independent predictors for a complicated course were age above 60 years (adjusted odds ratio (OR): 1.74; 95% confidence interval (CI): 0.99-3.03), chronic use of antibiotics (adjusted OR: 5.50; 95% CI: 2.31-13.08), more than 6 physician contacts in previous year (adjusted OR: 3.60; 95% CI: 2.00-6.49), hospitalization in previous year (adjusted OR: 1.36; 95% CI: 1.00-1.85), renal disease (adjusted OR: 4.92; 95% CI: 1.59-15.18) and incontinence of urine (adjusted OR: 3.78; 95% CI: 1.93-7.38). Area under the receiver-operating curve was 0.72 (95% CI: 0.66-0.78). Analysis according to medically attended complicated UTIs did not change our findings. Easily obtainable predictors from medical history can be used to accurately predict a complicated course of UTIs in DM2 patients.


Studies on the E. coli groNB (nusB) gene which affects bacteriophage lambda N gene function.
Escherichia coli mutants, called groNB, which block the growth of bacteriophage lambda at the level of action of the gene N product, have been isolated as survivors at 42 degrees C of bacteria carrying a) the defective prophage lambda bio11 i lambda cI857 delta H1 or b) the pcR1 plasmid containing the EcoRI immunity fragment of phage lambda cI857. In addition, groNB bacterial mutants have been isolated at 37 degrees C, as large colony formers in the presence of lambda i lambda cI h434, lambda i lambda cI h lambda, and lambda i lambda cI h80 phage. The groNB locus is located at 9 minute of the E. coli genetic map with the order of the neighboring loci being proC tsx groNB purE. Most groNB mutations isolated at 42 degrees C were found to interfere in addition with bacterial growth at low temperatures, since (a) the GroNB phenotypes of lambda growth inhibition and bacterial cold sensitivity cannot be separated by P1 transduction, and (b) some cold resistant revertants simultaneously become Gro+ for lambda growth. Lambda transducing phages carrying the groNB+ bacterial gene have been isolated. GroNB mutant bacteria lysogenized by the transducing phage acquire the Gro+ phenotype and simultaneously the cold resistant phenotype, suggesting that the groNB mutations are recessive to the wild-type gene.


Determination of ethylene glycol tissue content after fatal oral poisoning and pathologic findings.
A 23-year-old comatose man who had drunk an unknown amount of ethylene glycol was admitted to the hospital 5 hours after ingestion. The initial plasma ethylene glycol concentration was 116.2 mg/100 ml. A severe metabolic acidosis was present. Despite aggressive therapy with ethanol, hemodialysis, and intensive care support, the patient died 27 hours after poisoning. The plasma ethylene glycol concentration immediately before death was 35.9 mg/100 ml. Brain edema and acute renal tubular necrosis were evident at postmortem examination. Oxalate crystals were identified in both organs. Ethylene glycol content or concentration was determined in tissues and biologic fluids.


Congenital granular cell epulis. Immunohistochemical and ultrastructural observations.
Tumor cells of the congenital granular cell epulis (GCE), unlike those of the granular cell tumor (GCT), did not stain with antiserum to S-100 protein. Based on immunohistochemical findings it is concluded that the GCE and GCT differ in histogenesis; furthermore, ultrastructural studies of the authors are in agreement with others in supporting a mesenchymal origin of the GCE.


California psychological inventory profiles of peer-nominated assertives, unassertives, and aggressives.
Examined the California Psychological Inventory (CPI) profiles of peer-nominated assertives , unassertives , and aggressives . Eighty males from two social fraternities peer-nominated assertives , unassertives and aggressives . The nomination procedure yielded 12 nominees per group. A profile analysis of the CPI indicated that assertives and aggressives were significantly more similar than were assertives and unassertives , and unassertives and aggressives . Results of a subscale analysis indicated that assertives and aggressives were significantly higher on Dominance, Capacity for Status, Sociability, and Social Presence than Unassertives , but were not significantly different from each other on these subscales. Also, assertives were significantly higher on Socialization, Self-Control, and Achievement via Conformance than were aggressives . Finally, assertives were significantly higher on Achievement via Conformance than were unassertives and aggressives . Implications are discussed.


Battered Child Syndrome; a Case Study.
One of the important and usual missed causes of pediatric traumas is child abuse. This ominous phenomenon, which can be presented physically, psychologically, sexually, and emotionally has grown significantly in recent years. Many children are not diagnosed in the early stages of evaluation. Battered Child Syndrome is used to describe the clinical condition of the child serious physical abuse by parents or caregivers. Medical staff should always keep the syndrome in their mind for those brought to the emergency department with trauma. In this report, we described a patient complained of dysphagia following a falling from a height and multiple epidural hematomas and final diagnosis of battered child syndrome.


Association of the miR-149 Rs2292832 polymorphism with papillary thyroid cancer risk and clinicopathologic characteristics in a Chinese population.
(1) BACKGROUND: The genetic predisposition to papillary thyroid cancer (PTC) is far from clearly elucidated. Rs2292832 is a genetic polymorphism that located in the precursor of mir-149 and has been studied in diverse cancers. Thus far, the role of rs2292832 in PTC tumorigenesis and progression was unclear; (2) METHOD: Rs2292832 was genotyped in 838 PTCs, 495 patients with thyroid benign tumors (BNs) and 1006 controls in a Chinese Han population. Clinicopathological data was collected and compared. The expression level of mature mir-149 was examined in 55 normal thyroid tissue samples; (3) RESULTS: The CC genotype of rs2292832 was significantly associated with an increased risk of PTC compared with TT homozygote (OR = 1.60, 95% CI: 1.72-2.20, p = 0.003) and TT/TC combined genotype (OR = 1.54, 95% CI: 1.14-2.09, p = 0.005). Rs2292832 is an independent risk factor correlated with tumor invasion (p = 0.006) and higher T stage in PTC patients (p = 0.007), but uncorrelated with short-term disease persistence of PTC. PTC subjects carrying CC genotype have lower mir-149-5p expression than those with TC genotype (p = 0.002). Twelve predicted target genes have been identified by collaboratively using computational tools; (4) CONCLUSION: Rs2292832 was possibly involved in the susceptibility and local progression of PTC in Chinese patients, by altering the expression level of mir-149-5p and its target genes.


Variation in morphological and biochemical O3 injury attributes of mature Jeffrey pine within canopies and between microsites.
Crown morphology and leaf tissue chemical and biochemical attributes associated with ozone (O3) injury were assessed in the lower, mid- and upper canopy of Jeffrey pine (Pinus jeffreyi Grev. & Balf.) growing in mesic and xeric microsites in Sequoia National Park, California. Microsites were designated mesic or xeric based on topography and bole growth in response to years of above-average precipitation. In mesic microsites, canopy response to O3 was characterized by thinner branches, earlier needle fall, less chlorotic leaf mottling, and lower foliar antioxidant capacity, especially of the aqueous fraction. In xeric microsites, canopy response to O3 was characterized by higher chlorotic leaf mottling, shorter needles, lower needle chlorophyll concentration, and greater foliar antioxidant capacity. Increased leaf chlorotic mottle in xeric microsites was related to drought stress and increased concurrent internal production of highly reactive oxygen species, and not necessarily to stomatal O3 uptake. Within-canopy position also influenced the expression of O3 injury in Jeffrey pine.


Self-assembly of double-stranded DNA molecules at nanomolar concentrations.
Some proteins have the property of self-assembly, known to be an important mechanism in constructing supramolecular architectures for cellular functions. However, as yet, the ability of double-stranded (ds) DNA molecules to self-assemble has not been established. Here we report that dsDNA molecules also have a property of self-assembly in aqueous solutions containing physiological concentrations of Mg2+. We show that DNA molecules preferentially interact with molecules with an identical sequence and length even in a solution composed of heterogeneous DNA species. Curved DNA and DNA with an unusual conformation and property also exhibit this phenomenon, indicating that it is not specific to usual B-form DNA. Atomic force microscopy (AFM) directly reveals the assembled DNA molecules formed at concentrations of 10 nM but rarely at 1 nM. The self-assembly is concentration-dependent. We suggest that the attractive force causing DNA self-assembly may function in biological processes such as folding of repetitive DNA, recombination between homologous sequences, and synapsis in meiosis.


Entropic origin of disassortativity in complex networks.
Why are most empirical networks, with the prominent exception of social ones, generically degree-degree anticorrelated? To answer this long-standing question, we define the ensemble of correlated networks and obtain the associated Shannon entropy. Maximum entropy can correspond to either assortative (correlated) or disassortative (anticorrelated) configurations, but in the case of highly heterogeneous, scale-free networks a certain disassortativity is predicted--offering a parsimonious explanation for the question above. Our approach provides a neutral model from which, in the absence of further knowledge regarding network evolution, one can obtain the expected value of correlations. When empirical observations deviate from the neutral predictions--as happens for social networks--one can then infer that there are specific correlating mechanisms at work.


The thoracic anterior spinal cord adhesion syndrome.
This study included a series of middle-aged male and female patients who presented with chronic anterior hemicord dysfunction progressing to paraplegia. Imaging of anterior thoracic cord displacement by either a dural adhesion or a dural defect with associated cord herniation is presented. This is a retrospective review of cases referred to a tertiary neuroscience centre over a 19-year period. Imaging series were classified by two experienced neuroradiologists against several criteria and correlated with clinical examination and/or findings at surgery. 16 cases were available for full review. Nine were considered to represent adhesions (four confirmed surgically) and four to represent true herniation (three confirmed surgically). In the three remaining cases the diagnosis was radiologically uncertain. The authors propose "thoracic anterior spinal cord adhesion syndrome" as a novel term to describe this patient cohort and suggest appropriate clinicoradiological features for diagnosis. Several possible aetiologies are also suggested, with disc rupture and inflammation followed by disc resorption and dural pocket formation being a possible mechanism predisposing to herniation at the extreme end of a clinicopathological spectrum.


Retinal vascular biomarkers for early detection and monitoring of Alzheimer's disease.
The earliest detectable change in Alzheimer's disease (AD) is the buildup of amyloid plaque in the brain. Early detection of AD, prior to irreversible neurological damage, is important for the efficacy of current interventions as well as for the development of new treatments. Although PiB-PET imaging and CSF amyloid are the gold standards for early AD diagnosis, there are practical limitations for population screening. AD-related pathology occurs primarily in the brain, but some of the hallmarks of the disease have also been shown to occur in other tissues, including the retina, which is more accessible for imaging. Retinal vascular changes and degeneration have previously been reported in AD using optical coherence tomography and laser Doppler techniques. This report presents results from analysis of retinal photographs from AD and healthy control participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing. This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain. We demonstrate relationships between retinal vascular parameters, neocortical brain amyloid plaque burden and AD. A number of RVPs were found to be different in AD. Two of these RVPs, venular branching asymmetry factor and arteriolar length-to-diameter ratio, were also higher in healthy individuals with high plaque burden (P = 0.01 and P = 0.02 respectively, after false discovery rate adjustment). Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments.


Preface.
The Asian Society of Ichthyologists (ASI) was established in February 2014 in Penang, Malaysia following organizational meetings in 2012 in Chiang Mai, Thailand and in 2013 in Bandar Seri Begawan, Brunei.


[Problems and new developments in the management of Graves' disease: medical therapy].
Since no causative treatment of Graves' disease is available, symptomatic therapy has been derived from clinical studies (evidence class I and II). To date, conservative treatment still has a relapse rate of 30-50% that is most likely due to the heterogeneity of patients. There is no clear data about the duration of therapy necessary for the individual patient. Previous prospective randomised studies have evaluated prognostic parameters including the use of levothyroxine for relapse prevention. For an improved characterisation of the natural course of Graves' disease, the period after drug withdrawal was studied. As patients treated with high doses of antithyroid drugs (< 10 mg thiamazole) and patients with large goitres (< 50 ml) often develop hyperthyroidism, they make likely candidates for radioiodine therapy or surgery. Smoking is a very strong independent risk factor for relapse. A prospective multi-centre trial of the Thyroid Chapter of the German Endocrine Society (DGE-SSD) demonstrated that the basal TSH is the strongest prognostic parameter to predict relapse of hyperthyroidism with an accuracy of 75%. In the present study, levothyroxine supplementation did not prevent recurrent hyperthyroidism. In order to avoid hypothyroidism levothyroxine should only be used in combination with antithyroid drugs. In the face of the amelioration of nutritional iodine uptake in Germany, the application of low doses of antithyroid drugs will very likely no longer be sufficient. Future therapeutic recommendations will be based on selection criteria such as iodine supplementation, volume of goitre, smoking habits and basal TSH. used in combination with antithyroid drugs. In the face of the amelioration of nutritional iodine uptake in Germany, the application of low doses of antithyroid drugs will very likely no longer be sufficient. Future therapeutic recommendations will be based on selection criteria such as iodine supplementation, volume of goitre, smoking habits and basal TSH.


Fatal proteinuric kidney disease in a 30-month-old German Fleckvieh heifer caused by unilateral focal segmental glomerulosclerosis subsequent to a non-functional counterpart kidney.
A case of secondary focal segmental glomerulosclerosis (FSGS) in a heifer is presented. A 30-month-old female German Fleckvieh heifer showed deterioration of the general condition, a poor nutritional status, proteinuria, hypoalbuminemia, and renal azotemia. Pathologically, it was diagnosed with unilateral hydronephrosis, and contralateral renal fibrosis with numerous cysts. Histologically, the fibrotic kidney showed FSGS, hyaline reabsorption droplets in proximal tubular epithelial cells, interstitial fibrosis, and tubulointerstitial inflammation. Apart from that, thrombotic microangiopathy (TMA) was seen in few renal arteries and meningeal arterioles. Pathogenesis of FSGS secondary to unilateral renal parenchymal loss (hydronephrosis) and TMA is discussed.


Innovations in student-centered interdisciplinary teaching for general education in aging.
The University of California-Los Angeles (UCLA) General Education "Clusters" are innovations in student-centered undergraduate education focused on complex phenomena that require an interdisciplinary perspective. UCLA gerontology and geriatric faculty recognized the opportunity to introduce freshmen to the field of aging through this new initiative. In 2000, with support of the College of Letters and Science, the School of Medicine Multicampus Program in Geriatric Medicine and Gerontology created "Frontiers in Human Aging: Biomedical, Social and Policy Perspectives". The active and cooperative student-centered teaching of aging that is integral to this course has successfully contributed to the development of intellectual skills needed for academic and life success in over 1,200 freshman honors students.


Inflammatory pathways as promising targets to increase chemotherapy response in bladder cancer.
While more and more physicians are choosing chemotherapy for patients with bladder cancer, the current treatment is still far from satisfactory due to low response rate and severe side effects. Emerging evidence indicates that inflammatory microenvironment is involved in the pathogenesis of bladder cancer. Recent studies have also provided ample evidence that chemotherapy response is influenced by activation of major inflammatory mediators, including transcription factors, cytokines, chemokines, and COX-2. We reviewed all published literature addressing the roles of inflammatory microenvironment in bladder cancer and evaluating emerging evidence that inflammatory pathways represent potential therapeutic targets to enhance chemotherapy of bladder cancer.


Copper reduces Aβ oligomeric species and ameliorates neuromuscular synaptic defects in a C. elegans model of inclusion body myositis.
Alzheimer's disease and inclusion body myositis (IBM) are disorders frequently found in the elderly and characterized by the presence of amyloid-β peptide (Aβ) aggregates. We used Caenorhabditis elegans that express Aβ in muscle cells as a model of IBM, with the aim of analyzing Aβ-induced muscle pathology and evaluating the consequences of modulating Aβ aggregation. First, we tested whether the altered motility we observed in the Aβ transgenic strain could be the result of a compromised neuromuscular synapse. Our pharmacological analyses show that synaptic transmission is defective in our model and suggest a specific defect on nicotine-sensitive acetylcholine receptors (AChRs). Through GFP-coupled protein visualization, we found that synaptic dysfunction correlates with mislocalization of ACR-16, the AChR subunit essential for nicotine-triggered currents. Histological and biochemical analysis allowed us to determine that copper treatment increases the amyloid deposits and decreases Aβ oligomers in this model. Furthermore, copper treatment improves motility, ACR-16 localization, and synaptic function and delays Aβ-induced paralysis. Our results indicate that copper modulates Aβ-induced pathology and suggest that Aβ oligomers are triggering neuromuscular dysfunction. Our findings emphasize the importance of neuromuscular synaptic dysfunction and the relevance of modulating the amyloidogenic component as an alternative therapeutic approach for this debilitating disease.


Consequences of tooth luxation associated with complicated crown fracture: a case report.
The objective of this clinical case report is to describe the late treatment performed in a 10-year-old patient who suffered a complicated crown fracture associated with luxation of the maxillary left central incisor. The patient-s parents reported that the patient fell and was immediately taken to a hospital, where radiographs, splinting, and suturing were performed and an anti-inflammatory prescription was provided, but no treatment was given for the exposed pulp. The parents and patient sought treatment at a pediatric dentistry clinic 16 days post-trauma. The clinical examination revealed the presence of a left central incisor with a fracture of enamel and dentin involving the pulp, which was necrotic, and a splint extending from the right lateral incisor to the left lateral incisor. However, it was not possible to diagnose the type of luxation that had occurred. The fractured incisor was treated with periodic changes of calcium hydroxide dressing for apexification for 10 months, and the root was subsequently obturated with gutta percha and root canal sealer. The tooth fragment was stored in physiologic solution during this time. After obturation, tooth darkening was observed, and LED-assisted tooth bleaching was accomplished prior to reattachment of the fractured fragment. The tooth was reexamined every 6 months. Two years after the traumatic event, the left central incisor was infraoccluded in relation to the right central incisor. A radiograph confirmed ankylosis of the traumatized tooth. When trauma affects the enamel, dentin, pulp, and supporting tissues, the prognosis can be unfavorable even when late treatment is adequate, especially when a tooth in a growing patient has points of ankylosis.