Increasing Use of Shorter-Course Radiotherapy for Prostate Cancer.
Randomized clinical trials have demonstrated the noninferiority of shorter radiotherapy (RT) courses (termed hypofractionation) compared with longer RT courses in patients with localized prostate cancer. Although shorter courses are associated with cost-effectiveness, convenience, and expanded RT access, their adoption remains variable. To identify the current practice patterns of external beam RT for prostate cancer in the US. This cohort study obtained data from the National Cancer Database, which collects hospital registry data from more than 1500 accredited US facilities on approximately 72% of US patients with cancer. Patients were included in the sample if they had localized prostate adenocarcinoma that was diagnosed between 2004 and 2020 and underwent external beam RT with curative intent. Analyses were conducted between February and March 2023. Radiotherapy schedules, which were categorized as ultrahypofractionation (≤7 fractions), moderate hypofractionation (20-30 fractions), and conventional fractionation (31-50 fractions). Longitudinal pattern in RT fractionation schedule was the primary outcome. Multivariable logistic regression was performed to evaluate the variables associated with shorter RT courses. Covariables included age, National Comprehensive Cancer Network risk group, rurality, race, facility location, facility type, median income, insurance type or status, and Charlson-Deyo Comorbidity Index. A total of 313 062 patients with localized prostate cancer (mean [SD] age, 68.8 [7.7] years) were included in the analysis. There was a temporal pattern of decline in the proportion of patients who received conventional fractionation, from 76.0% in 2004 to 36.6% in 2020 (P for trend <.001). From 2004 to 2020, use of moderate hypofractionation increased from 22.0% to 45.0% (P for trend <.001), and use of ultrahypofractionation increased from 2.0% to 18.3% (P for trend <.001). By 2020, the most common RT schedule was ultrahypofractionation for patients in the low-risk group and moderate hypofractionation for patients in the intermediate-risk group. On multivariable analysis, treatment at a community cancer program (compared with academic or research program; odds ratio [OR], 0.54 [95% CI, 0.52-0.56]; P < .001), Medicaid insurance (compared with Medicare; OR, 1.49 [95% CI, 1.41-1.57]; P < .001), Black race (compared with White race; OR, 0.90 [95% CI, 0.87-0.92]; P < .001), and higher median income (compared with lower median income; OR, 1.28 [95% CI, 1.25-1.31]; P < .001) were associated with receipt of shorter courses of RT. Results of this cohort study showed an increase in the use of shorter courses of RT for prostate cancer from 2004 to 2020; a number of social determinants of health appeared to be associated with reduced adoption of shorter treatment courses. Realignment of reimbursement models may be necessary to enable broader adoption of ultrahypofractionation to support technology acquisition costs.


Effectiveness of Dupilumab in the Treatment of Patients with Severe Uncontrolled CRSwNP: A "Real-Life" Observational Study in the First Year of Treatment.
The aim of this study was to evaluate the efficacy of dupilumab in the treatment of severe uncontrolled Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), with or without asthma as add-on therapy with intra-nasal corticosteroids in a real-life setting over the first year of treatment. Our data demonstrated that subcutaneous 300 mg dupilumab administered at home via a pre-filled auto-injector every two weeks, based on indications set by the Italian Medicines Agency, was rapidly effective in reducing the size of polyps, decreasing symptoms of disease, improving quality of life, and recovering olfaction. Significant improvement was observed after only 15 days of treatment, and it progressively increased at 6 and 12 months. Dupilumab was also effective in reducing the local nasal eosinophilic infiltrate, in decreasing the need for surgery and/or oral corticosteroids, and in improving control of associated comorbidities such as chronic eosinophilic otitis media and bronchial asthma. After 12 months of treatment, 96.5% of patients had a moderate/excellent response. From our data, it was evident that there was a group of patients that showed a very early response within one month of therapy, another group with early response within six months from baseline, and a last group that improved later within 12 months. The results of this study support the use of dupilumab as an effective option in the current standard of care for patients affected by severe uncontrolled CRSwNP.


James Homer Wright: a biography of the enigmatic creator of the Wright stain on the occasion of its centennial.
James Homer Wright (1869-1928), the eldest son of a Pittsburgh glass merchant, was educated in Baltimore and practiced pathology in Boston from 1893 until his death in 1928. In 1896, when not quite 27 years old, he assumed directorship of the newly founded Pathology Laboratory at the Massachusetts General Hospital, a post he held for the next 30 years. He is remembered eponymously by the blood cell stain that bears his name and the Homer Wright pseudorosettes of neuroblastoma, but he made many additional contributions to pathology. These include the following: determination of the cellular lineage of multiple myeloma, identification of the megakaryocyte as the cell of origin of blood platelets, recognition of the cell of origin of the neuroblastoma, demonstration of spirochetes in syphilitic aneurysms of the aorta, and clarification of misconceptions about actinomycosis. Additionally, Wright coauthored, with Dr. Frank B. Mallory, the book Pathological Technique, which was a staple of laboratories for >40 years and exemplifies Wright's wide-ranging interests in, and contributions to, practical aspects of pathology including staining, culture and frozen section techniques, photography, and development of the rotary microtome. He received Honorary Doctor of Science Degrees from Harvard University, the University of Maryland (his alma mater), and the University of Missouri. He was the recipient of the Gross prize in 1905 for his publication on actinomycosis and the Boylston Medical Prize in 1908 for his discovery of the origin of platelets, and he was inducted into the American Academy of Arts and Sciences in 1915. Although shy and somewhat austere in the workplace, a different side was shown by his anonymously sending flowers to a young Norwegian opera singer whom he subsequently married. The pathology laboratories of the Massachusetts General Hospital were named the "James Homer Wright Pathology Laboratories" in 1956. Today James Homer Wright is remembered and honored 100 years after his description of the stain that, along with the pseudorosettes of neuroblastoma, carry his name into eternity and ensure his great contributions will never be forgotten.


[Psychoses of physical origin--traditional interpretation and DSM III nomenclature].
Classification of organic psychoses according to the revised version of DSM III and in accordance with the terminology used in traditional German psychopathology, are compared. In DSM III, organic Psychoses are presented as a heterogeneous group divided into psychoses of known or suspected origin and in psychoses of unknown aetiology. Relevant differences in the use of diagnostic terms such as delir are noticeable, whereas known syndromes such as Korsakoff's syndrome (Korsakoff's psychosis or alcoholic psychosis) are not considered and incorporated into larger categories in DSM nomenclature.


In vivo zebrafish morphogenesis shows Cyp26b1 promotes tendon condensation and musculoskeletal patterning in the embryonic jaw.
Integrated development of diverse tissues gives rise to a functional, mobile vertebrate musculoskeletal system. However, the genetics and cellular interactions that drive the integration of muscle, tendon, and skeleton are poorly understood. In the vertebrate head, neural crest cells, from which cranial tendons derive, pattern developing muscles just as tendons have been shown to in limb and trunk tissue, yet the mechanisms of this patterning are unknown. From a forward genetic screen, we determined that cyp26b1 is critical for musculoskeletal integration in the ventral pharyngeal arches, particularly in the mandibulohyoid junction where first and second arch muscles interconnect. Using time-lapse confocal analyses, we detail musculoskeletal integration in wild-type and cyp26b1 mutant zebrafish. In wild-type fish, tenoblasts are present in apposition to elongating muscles and condense in discrete muscle attachment sites. In the absence of cyp26b1, tenoblasts are generated in normal numbers but fail to condense into nascent tendons within the ventral arches and, subsequently, muscles project into ectopic locales. These ectopic muscle fibers eventually associate with ectopic tendon marker expression. Genetic mosaic analysis demonstrates that neural crest cells require Cyp26b1 function for proper musculoskeletal development. Using an inhibitor, we find that Cyp26 function is required in a short time window that overlaps the dynamic window of tenoblast condensation. However, cyp26b1 expression is largely restricted to regions between tenoblast condensations during this time. Our results suggest that degradation of RA by this previously undescribed population of neural crest cells is critical to promote condensation of adjacent scxa-expressing tenoblasts and that these condensations are subsequently required for proper musculoskeletal integration.


Growth arrest specific protein 6 alleviated white matter injury after experimental ischemic stroke.
Ischemic white matter injury leads to long-term neurological deficits and lacks effective medication. Growth arrest specific protein 6 (Gas6) clears myelin debris, which is hypothesized to promote white matter integrity in experimental stroke models. By the middle cerebral artery occlusion (MCAO) stroke model, we observed that Gas6 reduced infarcted volume and behavior deficits 4 weeks after MCAO. Compared with control mice, Gas6-treatment mice represented higher FA values in the ipsilateral external capsules by MRI DTI scan. The SMI32/MBP ratio of the ipsilateral cortex and striatum was profoundly alleviated by Gas6 administration. Gas6-treatment group manifested thicker myelin sheaths than the control group by electron microscopy. We observed that Gas6 mainly promoted OPC maturation, which was closely related to microglia. Mechanically, Gas6 accelerated microglia-mediated myelin debris clearance and cholesterol transport protein expression (abca1, abcg1, apoc1, apoe) in vivo and in vitro, accordingly less myelin debris and lipid deposited in Gas6 treated stroke mice. HX531 (RXR inhibitor) administration mitigated the functions of Gas6 in speeding up debris clearance and cholesterol transport protein expression. Generally, we concluded that Gas6 cleared myelin debris and promoted cholesterol transportation protein expression through activating RXR, which could be one critical mechanism contributing to white matter repair after stroke.


Exciton Dynamics in Monolayer Transition Metal Dichalcogenides.
Since the discovery of semiconducting monolayer transition metal dichalcogenides, a variety of experimental and theoretical studies have been carried out seeking to understand the intrinsic exciton population recombination and valley relaxation dynamics. Reports of the exciton decay time range from hundreds of femtoseconds to ten nanoseconds, while the valley depolarization time can exceed one nanosecond. At present, however, a consensus on the microscopic mechanisms governing exciton radiative and non-radiative recombination is lacking. The strong exciton oscillator strength resulting in up to ~ 20% absorption for a single monolayer points to ultrafast radiative recombination. However, the low quantum yield and large variance in the reported lifetimes suggest that non-radiative Auger-type processes obscure the intrinsic exciton radiative lifetime. In either case, the electron-hole exchange interaction plays an important role in the exciton spin and valley dynamics. In this article, we review the experiments and theory that have led to these conclusions and comment on future experiments that could complement our current understanding.


Clinical Outcomes Following Use of Tranexamic Acid in High Tibial Osteotomy: A Systematic Review.
This study aimed to evaluate the clinical outcomes following administration of tranexamic acid (TXA) in patients undergoing high tibial osteotomy (HTO) through a systematic review of current available evidence. A systematic database search of PubMed, Embase and Cumulative Index of Nursing and Allied Health Literature (CINAHL) was performed from inception up to December 2022, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Inclusion criteria were (i) randomised control trials, cohort studies or case-control studies that had more than 10 patients; (ii) studies reporting outcomes after TXA administration, of any route, before or after HTO, compared to placebo, control and different doses or routes; and (iii) studies reporting blood loss, including haemoglobin (Hb) drop, estimated blood loss, transfusion requirement and complications. Case reports, reviews, abstracts, non-HTO studies, non-human studies and duplicates were excluded. A synthesized comparison of drain output, wound complications, transfusion requirement and pooled analyses of blood loss and Hb drop was performed. Eleven studies involving 974 patients were included. Nine studies had placebo comparison, and two used single-dose TXA versus multiple doses. All studies reported on postoperative hemoglobin and nine on blood loss. In the six TXA versus placebo studies reporting on total blood loss, the TXA group had a pooled, estimated standardised mean difference (SMD) in blood loss of -2.37 (95% confidence interval (CI) -3.67, -1.07; P = 0.0004). For the Hb drop, on postoperative days (PODs) one, two, and five, the SMDs were -0.97 (95% CI -1.19, -0.75; P < 0.00001) for POD1, -0.74 (95% CI -1.03, -0.46; P < 0.00001) for POD2 and -0.87 (95% CI -1.10, -0.64; P < 0.00001) for POD5. TXA administration in HTO significantly reduces perioperative blood loss. This can greatly improve recovery, reduce complications and shorten length of stay. This is especially pertinent given supply shortages of NHS blood resources.


The development of impulsivity and suicidality in borderline personality disorder.
Borderline personality disorder (BPD) is characterized by a broad pattern of impulsivity and suicidality. BPD usually begins in adolescence; the full clinical picture of the disorder is associated with developmental increases in impulsivity. However, BPD also has childhood precursors. The developmental pathways are similar to those found in other impulsive spectrum disorders, but children who later develop BPD probably have both externalizing and internalizing symptoms. Research in this area has made use of retrospective data from adults, prospective data from community studies, follow-up studies from children at risk, as well as research on "borderline pathology of childhood" (a condition with symptoms similar to adult BPD). Existing evidence suggests that both temperamental and environmental risk factors play a role in the development of the behavioral patterns associated with the disorder. These pathways also help account for the life course and outcome of BPD in adulthood.


iPSC-Derived Retinal Pigment Epithelium Allografts Do Not Elicit Detrimental Effects in Rats: A Follow-Up Study.
Phototransduction is accomplished in the retina by photoreceptor neurons and retinal pigment epithelium (RPE) cells. Photoreceptors rely heavily on the RPE, and death or dysfunction of RPE is characteristic of age-related macular degeneration (AMD), a very common neurodegenerative disease for which no cure exists. RPE replacement is a promising therapeutic intervention for AMD, and large numbers of RPE cells can be generated from pluripotent stem cells. However, questions persist regarding iPSC-derived RPE (iPS-RPE) viability, immunogenicity, and tumorigenesis potential. We showed previously that iPS-RPE prevent photoreceptor atrophy in dystrophic rats up until 24 weeks after implantation. In this follow-up study, we longitudinally monitored the same implanted iPS-RPE, in the same animals. We observed no gross abnormalities in the eyes, livers, spleens, brains, and blood in aging rats with iPSC-RPE grafts. iPS-RPE cells that integrated into the subretinal space outlived the photoreceptors and survived for as long as 2 1/2 years while nonintegrating RPE cells were ingested by host macrophages. Both populations could be distinguished using immunohistochemistry and electron microscopy. iPSC-RPE could be isolated from the grafts and maintained in culture; these cells also phagocytosed isolated photoreceptor outer segments. We conclude that iPS-RPE grafts remain viable and do not induce any obvious associated pathological changes.


[Calculi in artificial urethra].
The article presents a successful experience of the treatment of long-term complication of ure-throplasty performed by the modified Cecil-Culp procedure using flap of skin of the scrotum with preserved hair follicles. The removal of calculi in artificial urethra occurring decades after the surgery was required. The use of combined method oftreatment led to a good clinical outcome.


Carcinoembryonic antigen-positive pleural effusion in early stage non-small cell lung cancer without pleural infiltration.
Carcinoembryonic antigen (CEA) is a tumor marker for detecting recurrences of adenocarcinomas such as colon cancer. In lung adenocarcinoma, CEA elevation can be found in both serum and malignant pleural effusion. However, CEA elevation in cytologically negative pleural effusion in the presence of adenocarcinoma without pleural infiltration has not been described. We here present the case of an 82-year-old man with incidental early stage adenocarcinoma of the right upper lobe showing CEA elevation in pleural fluid and serum despite negative cytological findings. Due to limited lung reserve the tumor was removed by wide wedge resection, but the visceral pleura was not affected and infiltration of the parietal pleura was ruled out by pleural biopsies. Serum and pleural CEA levels declined postoperatively as measured at 1 and 2 months follow-up. This case shows CEA elevation in serum and pleural fluid in early stage lung adenocarcinoma with negative cytology and no sign of pleural infiltration. Previous research revealed that CEA level in pleural effusion correlates to serum CEA and is significantly higher in adenocarcinoma of the lung than in other lung cancer entities. Firstly, this case suggests that determination of CEA levels can increase the diagnostic sensitivity in cases with cytologically negative pleural effusion suspicious of malignant origin and secondly, it contributes valuable information to the decision whether follow-up of pulmonary nodules or continuative diagnostics such as video-assisted thoracoscopic surgery (VATS) wedge resection is indicated.


Dissecting Tn5 transposition using HIV-1 integrase diketoacid inhibitors.
Diketoacid (DKA) compounds have been shown to inhibit HIV-1 integrase by a mechanism that involves sequestration of the active site metals. Because HIV-1 integrase and Tn5 transposase have similar active site architectures and catalytic mechanisms, we investigated whether DKA analogues would inhibit Tn5 transposase activity and provide a model system to explore the mechanisms of action of these inhibitors. A screen of several hundred DKA analogues identified several with activity against Tn5 Tnp. Six DKA inhibitors used in this study manifested a variety of effects on different transposition steps suggesting that different analogues may have different binding contacts with transposase. All DKA compounds inhibited paired end complex (PEC) formation in which the nucleoprotein complex required for catalysis is assembled. Dissociation of PECs by some DKA compounds indicates that these inhibitors can decrease PEC stability. Four DKA compounds inhibited the two cleavage steps releasing transposon DNA from flanking DNA, and one of these four compounds preferentially inhibited the second cleavage step. The differential effect of this inhibitor on the second cleavage event indicates that cleavage of the two transposon-donor DNA boundaries is a sequential process requiring a conformational change. The requirement for a conformational change between cleavage events was also demonstrated by the inability of transposase to perform second cleavage at 25 degrees C. Finally, all six compounds inhibit strand transfer, the final step of Tn5 transposition. Two of the compounds that inhibited strand transfer have no effect on DNA cleavage. The strand transfer inhibition properties of various DKA compounds was sensitive to the structure of the 5'-non-transferred strand, suggesting that these compounds bind in or near the transposase active site. Other results that probe compound binding sites include the effects of active site mutations and donor DNA on DKA compound inhibition activities. Thus, DKA inhibitors will provide an important set of tools to investigate the mechanism of action of transposases and integrases.


Cellular effects of N(4-ethoxyphenyl)p-benzoquinone imine, a p-phenetidine metabolite formed during peroxidase reactions.
The interaction of N-(4-ethoxyphenyl)p-benzoquinone imine (NEPBQI), a metabolite formed during peroxidase catalyzed metabolism of p-phenetidine, with GSH and its effects in isolated rat hepatocytes were investigated. When reacted with GSH NEPBQI formed both a mono- and a diglutathione conjugate as well as GSSG. Formation of glutathione conjugates and GSSG also occurred when NEPBQI was added to isolated hepatocytes. The formation of GSSG was, however, only detectable if the hepatocytes had been pretreated with the GSSG reductase inhibitor BCNU (1,3-bis-(2-chloroethyl-1-nitrosourea). Similarly, NEPBQI caused a rapid decrease in cellular free protein thiols when added to hepatocytes, however this was expressed at higher concentrations than for effects on GSH. The protein thiol decrease was correlated with protein binding of NEPBQI. NEPBQI was also shown to be toxic to isolated hepatocytes. At a concentration of 400 microM extensive bleb formation was followed by loss of cell membrane integrity and cell death. To assess further the subcellular metabolism of NEPBQI microsomes and cytosol was used. NEPBQI was found to be preferentially reduced by cytochrome P-450 reductase in the microsomes whereas DT-diaphorase catalyzed its reduction in cytosol. NEPBQI did not undergo significant redox cycling since no formation of O2 was observed. Thus, the cytotoxic effect of NEPBQI appears to be due to protein arylation rather than redox cycling.


The English Government Hits Limits: Knowledge Politics and Covid-19.
Tragic its consequences, the Covid-19 pandemic has ripped through societies with, at the time of writing, global death rates exceeding two and a half million people. In the process, there has been variability in terms of how effectively governments have dealt with the pandemic. Differences between political responses, forms of governance and the relationships between science and politics are apparent. This article investigates these relations in the United Kingdom with a particular focus upon the interpretations that informed the response of the English Government and their interactions with the scientific community. For this purpose, it provides an exploration of the political and socio-economic conditions prevailing in the United Kingdom prior to the pandemic. It then examines the interactions between science and politics as the pandemic unfolded during 2020. Then, building on these discussions it views the tensions that arose through a clash between two characteristics within democratic societies: the redemptive and pragmatic. What becomes apparent is the tendency for a form of the redemptive to be favoured over the pragmatic which results in an exposure of limits to usual and narrow political ways of governing.


Shoulder Arthrodesis for Traumatic Brachial Plexus Injuries: Functional Outcomes and Complications.
The external rotation and abduction of shoulder are considered one of the priorities of reconstruction in brachial plexus injury. The aim of this study was to evaluate the functional results and complications of shoulder arthrodesis in patients with brachial plexus injury to better comprehend the benefits of this procedure. Between 2015 and 2019, 15 shoulder arthrodesis were performed in patients with long-standing brachial plexus injury. The main indication for arthrodesis was absent or poor recovery of shoulder abduction and external rotation. Patients presented different levels of injury. Shoulder measurements of active abduction and external rotation were made based on image records of the patients. A long 4.5-mm reconstruction plate was fit along the scapular spine, acromion, and lateral proximal third of the humerus. Structured bone graft was fit into the subacromial space. The mean preoperative abduction was 16°, and the mean postoperative abduction was 42°. The mean preoperative external rotation was -59°, and the mean postoperative external rotation was -13°. The mean increase in abduction and external rotation was 25° and 45°, respectively. Bone union was achieved in all cases at an average time of 5.23 months. We experienced humeral fractures in 26.66% of the cases, which were all successfully treated nonoperatively. Shoulder arthrodesis is a rewarding procedure for patients with brachial plexus injuries. A marked improvement in the upper limb positioning was observed in all patients. It should be considered as the main therapeutic option in cases where nerve reconstruction is no longer possible.


Methylotrophic methanogenic Thermoplasmata implicated in reduced methane emissions from bovine rumen.
Rumen methanogens are major sources of anthropogenic methane emissions, and these archaea are targets in strategies aimed at reducing methane emissions. Here we show that the poorly characterised Thermoplasmata archaea in bovine rumen are methylotrophic methanogens and that they are reduced upon dietary supplementation with rapeseed oil in lactating cows. In a metatranscriptomic survey, Thermoplasmata 16S rRNA and methyl-coenzyme M reductase (mcr) transcripts decreased concomitantly with mRNAs of enzymes involved in methanogenesis from methylamines that were among the most abundant archaeal transcripts, indicating that these Thermoplasmata degrade methylamines. Their methylotrophic methanogenic lifestyle was corroborated by in vitro incubations, showing enhanced growth of these organisms upon methylamine supplementation paralleled by elevated methane production. The Thermoplasmata have a high potential as target in future strategies to mitigate methane emissions from ruminant livestock. Our findings and the findings of others also indicate a wider distribution of methanogens than previously anticipated.


Predicting the adsorption of second generation biofuels by polymeric resins with applications for in situ product recovery (ISPR).
The application of hydrophobic polymeric resins as solid-phase adsorbent materials for the recovery and purification of prospective second generation biofuel compounds, including ethanol, iso-propanol, n-propanol, iso-butanol, n-butanol, 2-methyl-1-butanol, 3-methyl-1-butanol, and n-pentanol, has been investigated. A simple, yet robust correlation has been proposed to model the relative equilibrium partitioning behavior of a series of branched and n-alcohols as a function of their relative hydrophobicity, and has been applied to ultimately predict their adsorption potential. The proposed model adequately predicts the adsorption behavior of the entire series of alcohols studied, as well as with six different adsorbent phases composed of three different polymer matrices. Those resins with a non-polar monomeric structure and high specific surface area provided the highest overall adsorption of each of the studied compounds. Meanwhile, longer chain alcohols were subject to greater adsorption due to their increasingly hydrophobic nature. Among the tested series of alcohols, five-carbon isomers displayed the greatest potential for economical recovery in future, multiphase bioprocess designs. The present study provides the first demonstration of the ability of hydrophobic polymer resins to serve as effective in situ product recovery (ISPR) devices for the production of second generation biofuels.


Dopamine Detection using Mercaptopropionic Acid and Cysteamine for Electrodes Surface Modification.
Gold electrodes are often not suitable for dopamine measurements as dopamine creates a non-conducting polymer layer on the surface of the electrodes, which leads to increased amount of electrode passivity with the gradual increase in voltammograms measurement. This work presents the impedance spectroscopy and cyclic-voltammetry comparative study for dopamine detection with two modifications for the surface of Au electrodes; cysteamine and mercaptopropionic acid for thermally bonded and ultrasonically welded microfluidic chips, respectively. The effects of optimized tubing selection, bonding techniques, and cleaning methods of the devices with KOH solution played crucial role for improvements in dopamine detection, which are observed in the results. Furthermore, comparison for the modification with unmodified chips, and finding the unknown concentration of dopamine solution using flow injection techniques, is also illustrated.


Effects of echothiophate on enzymatic hydrolysis of dipivefrin.
Dipivefrin is an antiglaucoma prodrug that is hydrolyzed to the active drug, epinephrine, by esterases in the cornea. Since cholinergic antiglaucoma agents are frequently used in combination with adrenergic agents, it was of interest to determine the effects of a commonly used irreversible cholinesterase inhibitor, echothiophate (Phospholine) iodide, on the dipivefrin esterases. In vitro studies showed that echothiophate is a competitive, reversible inhibitor of the soluble corneal dipivefrin esterases. In vivo studies substantiated the reversible nature of echothiopate inhibition, since no inhibition of dipivefrin hydrolysis could be detected 1 3/4 hours after echothiophate treatment and as early as 15 minutes after dipivefrin application.


[The extracorporeal connection of a donor spleen in the treatment of anaerobic sepsis].
In 12 patients with anaerobic sepsis, extracorporeal connection of donor spleen, its sections and transfusion of perfusates of xenospleen were used in the complex treatment. A positive result--reduction of intoxication, improvement of general state, normalization of immunologic indices--has been obtained.


Rare CIDEC coding variants enriched in age-related macular degeneration patients with small low-luminance deficit cause lipid droplet and fat storage defects.
The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro. We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better anti-VEGF treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes. As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.


Brachytherapy in lip cancer.
Lip cancer is one of the most prevalent skin tumours of the head and neck. The characteristics of the tumour relate to their exophyitic growth in an area of easy visual acces which allows their diagnosis in early stages. As a result, there is a better prognosis with the present treatments. In early stages the treatment can be performed by surgery or by brachytherapy, and the results are similar on local control; nevertheless brachytherapy offers the best functional and esthetic results. We are reporting on a review of the literature in relation to indications, techniques and results of brachytherapy for lip cancer.


Bacteriophage SPO1 protein Gp46 suppresses functions of HU protein in Francisella tularensis.
The nucleoid-associated protein HU is a common bacterial transcription factor, whose role in pathogenesis and virulence has been described in many bacteria. Our recent studies showed that the HU protein is an indispensable virulence factor in the human pathogenic bacterium Francisella tularensis, a causative agent of tularemia disease, and that this protein can be a key target in tularemia treatment or vaccine development. Here, we show that Francisella HU protein is inhibited by Gp46, a protein of Bacillus subtilis bacteriophage SPO1. We predicted that Gp46 could occupy the F. tularensis HU protein DNA binding site, and subsequently confirmed the ability of Gp46 to abolish the DNA-binding capacity of HU protein. Next, we showed that the growth of Francisella wild-type strain expressing Gp46 in trans corresponded to that of a deletion mutant strain lacking the HU protein. Similarly, the efficiency of intracellular proliferation in mouse macrophages resembled that of the deletion mutant strain, but not that of the wild-type strain. These results, in combination with findings from a recent study on Gp46, enabled us to confirm that Gp46 could be a universal inhibitor of HU proteins among bacterial species.


Endogenous testosterone levels are associated with amygdala and ventromedial prefrontal cortex responses to anger faces in men but not women.
Testosterone moderates behavioral and physiological responses to the emotion anger. However, little is known about the effects of testosterone in the human brain in the context of the perception of anger. We used fMRI to measure BOLD responses to anger faces in the amygdala and ventromedial prefrontal cortex (vmPFC) as a function of endogenous testosterone levels in 24 participants (10 men). In one task, participants passively viewed anger faces and neutral faces and in another task, participants engaged in an oddball task while viewing anger and neutral faces. Men's, but not women's, amygdala BOLD response to anger faces was negatively correlated with their endogenous testosterone levels in both tasks. Men's, but not women's, vmPFC BOLD response to anger faces was positively correlated with their endogenous testosterone levels in the passive-viewing task. In men, amygdala and vmPFC BOLD responses to anger faces were negatively associated. Our results extend past research by documenting associations between endogenous testosterone levels and BOLD responses to anger faces in the amygdala and vmPFC in men, and our results also support research that documents negative associations between amygdala and vmPFC activity.


Dairy goat production systems: status quo, perspectives and challenges.
Goat production concentrated in developing countries (tropics, dry areas), contributes largely to the livelihoods of low and medium income farmers. Farming systems in these areas have evolved to cope with the formidable constraints imposed by harsh natural and economic conditions by adapting integrated crop/livestock production strategies. In Asia, Africa and Latin America, due to its almost exclusive extensive nature, goat production relies mainly on grazing on communal lands that hardly provide the minimum nutrient requirements due to overstocking and degradation. While some of these production systems are becoming semi-intensive, appropriate breeding strategies should be designed to promote conservation and improvement of their unique attributes, such as adaptability, water use efficiency and suitability under harsh climatic conditions. In Europe, dairy goat production is more common around the Mediterranean basin, where it is important from an economic, environmental and sociological perspective to the Mediterranean countries: Spain, France, Italy and Greece. Europe owns only 5.1 % of the world's dairy goat herds, but produces 15.6 % of the world's goat milk; this is the only continent where goat milk has such an economic importance and organization. In developing countries the dairy goat sector requires a systemic approach, whereby nutrition, animal health, breeding, know-how, inputs and technologies must be assembled. This would allow the optimization of natural and local resources and would promote the transition from a risk reduction strategy towards an increased productivity strategy. Such an increase would privilege production efficiency based on clean, green and ethical practices for responsible innovation.


Polypharmacy among the elderly in the city of São Paulo, Brazil - SABE Study.
Polypharmacy for the elderly and associated factors were assessed. A cross-sectional study was conducted using data from the SABE Study (Health, Well-being and Aging), 2006. 1,115 individuals representing 422,377 elderly aged 65 or more, living in São Paulo City, were interviewed. Polypharmacy was defined as the use of five or more medications. A multivariate regression logistics was used. Polypharmacy prevalence was 36%. Female (OR = 1.7; IC 95%: 1.0; 2.9), age over 75 years (OR = 1.9; CI 95%: 1.3; 2.7), higher income (OR = 1.8; CI 95%: 1.2; 2.8), working (OR = 1.8; CI 95%: 1.1; 2.9), regular self assessed health (OR = 1.6; CI 95%: 1.1; 2.3) or poor (OR = 2.6; CI 95%: 1.4; 4.9), hypertension (OR = 2.0; CI 95%: 1.4; 2.9), diabetes (OR = 4.1; CI 95%: 2.2; 7.5), rheumatic diseases (OR = 2.3; CI 95%: 1.5; 3.6) and cardiac problems (OR = 2.9; CI 95%: 1.9; 4.5) were associated positively with polypharmacy. Using only the public health system (OR = 0.5, 95% CI: 0.3; 0.7) was inversely associated with polypharmacy. Medicines for the cardiovascular system and for the alimentary tract and metabolism were the most used. The knowledge of factors associated with polypharmacy, such as those identified in this study, may be useful to alert health professionals about the importance of identifying and monitoring the elderly groups most vulnerable to polypharmacy.


4-Iodopyrimidine Labeling Reveals Nuclear Translocation and Nuclease Activity for Both MIF and MIF2.
Macrophage migration inhibitory factor (MIF) and its homolog MIF2 (also known as D-dopachrome tautomerase or DDT) play key roles in cell growth and immune responses. MIF and MIF2 expression is dysregulated in cancers and neurodegenerative diseases. Accurate and convenient detection of MIF and MIF2 will facilitate research on their roles in cancer and other diseases. Herein, we report the development and application of a 4-iodopyrimidine based probe 8 for the selective labeling of MIF and MIF2. Probe 8 incorporates a fluorophore that allows in situ imaging of these two proteins. This enabled visualization of the translocation of MIF2 from the cytoplasm to the nucleus upon methylnitronitrosoguanidine stimulation of HeLa cells. This observation, combined with literature on nuclease activity for MIF, enabled the identification of nuclease activity for MIF2 on human genomic DNA.


The Renoprotective Effect of Linagliptin in Type 2 Diabetic Patients with Severely Increased Albuminuria.
Previous studies have suggested that linagliptin may represent renoprotective effects besides its anti-hyperglycemic properties in patients with type 2 diabetes. However, there is a lack of decisive evidence to support this assumption. This study aimed to address the effect of linagliptin in type 2 diabetic patients with severely increased albuminuria. In this randomized double-blind, placebo-controlled clinical trial, type 2 diabetic patients with severely increased albuminuria (albuminuria ≥ 300 mg/24 h) were enrolled. Patients were randomized to linagliptin (5 mg/d) and placebo based on a computer-generated list of random numbers. Biochemical (fasting blood sugar (FBS) (mg/dL), hemoglobin A1c (HbA1c) (%), proteinuria (mg/24h), blood urea nitrogen (BUN) (mg/dL), serum creatinine (mg/dL)) and clinical variables (weight (kg), systolic, and diastolic blood pressure (mmHg)) were measured at baseline and 3 and 6 months post intervention. At baseline, no statistically significant difference was detected in demographic characteristics between the two groups (P > .05). A significant decrease was observed in proteinuria, FBS, weight, SBP, and DBP in the intervention group after 6 months (Ptime < .05), however; none of the clinical and biochemical variables showed a significant difference between groups after 6 months (Pgroup > .05). Linagliptin may serve as a renoprotective therapeutic option in diabetic patients with severely increased albuminuria due to its role in proteinuria reduction. Results of this study can be used for future large-scale, long-term studies investigating the renoprotective effects of linagliptin in patients with diabetic nephropathy. DOI: 10.52547/ijkd.6110.


Voice Therapy for Benign Voice Disorders in the Elderly: A Randomized Controlled Trial Comparing Telepractice and Conventional Face-to-Face Therapy.
Purpose Previous studies have reported that voice therapy via telepractice is useful for patients with nodules and muscle tension dysphonia. Nevertheless, telepractice for elderly patients with voice disorders has not yet been investigated. We conducted this study to examine the hypothesis that voice therapy via telepractice is not inferior to conventional voice therapy. Method Eighty patients with dysphonia aged more than 55 years participated in this study from September 2016 to June 2018. After screening the inclusion and the exclusion criteria, 69 patients were randomized into telepractice (33 patients) and conventional (36 patients) groups. The outcome measurements included Voice Handicap Index-10, videolaryngostroboscopy, maximum phonation time, auditory-perceptual evaluation, and acoustic analysis. Paired t test, Wilcoxon signed-ranks test, and repeated measures analysis of variance were used to examine treatment outcomes. Results The diagnoses of voice disorders included atrophy (n = 33), unilateral vocal paralysis (n = 13), muscle tension dysphonia (n = 7), nodules (n = 6), and polyps (n = 10). No significant differences were observed in age, sex, and baseline measurements between the two groups. Twenty-five patients in the telepractice group and 24 patients in the control group completed at least four weekly sessions. Significant improvements were observed for all the outcome measures (p < .05) in both groups. Improvements in Voice Handicap Index-10 in the telepractice group (24.84 ± 5.49 to 16.80 ± 8.94) were comparable to those in the conventional group (22.17 ± 7.29 to 13.46 ± 9.95, p = .764). Other parameters also showed comparable improvements between the two groups without statistically significant differences. Conclusions This is the first randomized controlled trial comparing telepractice and conventional voice therapy in elderly patients with voice disorders. The results showed that the effectiveness of voice therapy via telepractice was not inferior to that of conventional voice therapy, indicating that telepractice can be used as an alternative to provide voice care for elderly patients with vocal disorders.


Graphics and statistics for cardiology: survival analysis.
Reports of data in the medical literature frequently lack information needed to assess the validity and generalisability of study results. Some recommendations and standards for reporting have been developed over the last two decades, but few are available specifically for survival data. We provide recommendations for tabular and graphical representations of survival data. We argue that data and analytic software should be made available to promote reproducible research.


Induction of miR-31 causes increased sensitivity to 5-FU and decreased migration and cell invasion in gastric adenocarcinoma.
Drug resistance is the main obstacle in the treatment of gastric cancer, the third most common cause of cancer-related death in the world. Due to their small size, easy entrance to cells and multiple targets, microRNAs (miRs) are considered novel and attractive targets. In the current study, parental MKN-45, MKN-45-control vector, and MKN-45-miR-31 populations were compared in terms of cell cycle transitions, migration, cell invasion, and proliferation. In addition, downstream targets of miR-31, including E2F6, and SMUG1 were examined using Real-time RT-PCR and western blotting. MKN-45-miR-31 showed an increased sensitivity to 5-FU, decreased migration and cell invasion compared to the control groups (p = 0.0001, p = 0.01 and p = 0.01, respectively). There was a significant increase in the percentage of cells in G1/pre-G1 phase in MKN-45-miR-31 relative to the control groups (p = 0.001). Induction of miR-31 expression in MKN-45 caused a significant reduction of E2F6 and SMUG1 genes. Our findings indicated that induction of miR-31 expression could increase drug sensitivity, and diminish tumor cell migration and invasion of gastric cancer cells. Therefore, miR-31 can be considered as a potential target molecule in the targeted therapy of gastric cancer (Fig. 2, Ref. 43). Keywords: gastric cancer, miR-31, drug resistance, E2F6, SMUG1.


Chemotherapy for second-stage human African trypanosomiasis: drugs in use.
Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions. OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT). On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations. Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use. Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI). MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up. We judged the study to be at low risk of bias in all domains except blinding; as the route of administration and dosing regimens differed between treatment groups, participants and personnel were not blinded, resulting in a high risk of performance bias. Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence). We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence.


Cysteine scanning mutagenesis and topological mapping of the Escherichia coli twin-arginine translocase TatC Component.
The TatC protein is an essential component of the Escherichia coli twin-arginine (Tat) protein translocation pathway. It is a polytopic membrane protein that forms a complex with TatB, together acting as the receptor for Tat substrates. In this study we have constructed 57 individual cysteine substitutions throughout the protein. Each of the substitutions resulted in a TatC protein that was competent to support Tat-dependent protein translocation. Accessibility studies with membrane-permeant and -impermeant thiol-reactive reagents demonstrated that TatC has six transmembrane helices, rather than the four suggested by a previous study (K. Gouffi, C.-L. Santini, and L.-F. Wu, FEBS Lett. 525:65-70, 2002). Disulfide cross-linking experiments with TatC proteins containing single cysteine residues showed that each transmembrane domain of TatC was able to interact with the same domain from a neighboring TatC protein. Surprisingly, only three of these cysteine variants retained the ability to cross-link at low temperatures. These results are consistent with the likelihood that most of the disulfide cross-links are between TatC proteins in separate TatBC complexes, suggesting that TatC is located on the periphery of the complex.


Cyclic nucleotide phosphodiesterase (PDE) inhibitors: novel therapeutic agents for progressive renal disease.
Cyclic nucleotides are recognized as critical mediators of many renal functions, including solute transport, regulation of vascular tone, proliferation of parenchymal cells, and inflammation. Although most studies have linked elevated cAMP levels to activation of protein kinase A, cAMP can also directly activate cyclic nucleotide gated ion channels and can signal through activation of GTP exchange factors. Cyclic AMP signaling is highly compartmentalized through plasma membrane localization of adenylyl cyclase and expression of scaffolding proteins that anchor protein kinase A to specific intracellular locations. Cyclic nucleotide levels are largely regulated through catabolic processes directed by phosphodiesterases (PDEs). The PDE superfamily is large and complex, with over 60 distinct isoforms that preferentially hydrolyze cAMP, cGMP, or both. PDEs contribute to compartmentalized cyclic nucleotide signaling. The unique cell- and tissue-specific distribution of PDEs has prompted the development of highly specific PDE inhibitors to treat a variety of inflammatory conditions. In experimental systems, PDE inhibitors have been employed to demonstrate functional compartmentalization of cyclic nucleotide signaling in the kidney. For example, mitogenesis in glomerular mesangial cells and normal tubular epithelial cells is negatively regulated by an intracellular pool of cAMP that is metabolized by PDE3, but not by other PDEs. In Madin-Darby canine kidney cells, an in vitro model of polycystic kidney disease, an intracellular pool of cAMP directed by PDE3 stimulates mitogenesis. In mesangial cells, an intracellular pool of cAMP directed by PDE4 inhibits reactive oxygen species and expression of the potent proin-flammatory cytokine monocyte chemoattractant protein 1. An intracellular pool of cGMP directed by PDE5 regulates solute transport. PDE5 inhibitors ameliorate renal injury in a chronic renal disease model. In this overview, we highlight recent studies to define relationships between PDE expression and renal function and to provide evidence that PDE inhibitors may be effective agents in treating chronic renal disease.


A fusion protein of the gp130 and interleukin-6Ralpha ligand-binding domains acts as a potent interleukin-6 inhibitor.
Interleukin (IL)-6 is involved in the maintenance and progression of several diseases such as multiple myeloma, rheumatoid arthritis, or osteoporosis. The present work aims at the development of an IL-6 inhibitor for the use in anti-cytokine therapies. The IL-6 receptor is composed of two different subunits, an alpha-subunit (IL-6Ralpha) that binds IL-6 with low affinity and a beta-subunit (gp130) that binds the IL-6.IL-6Ralpha complex with high affinity and as a result triggers intracellular signaling. In its soluble form, gp130 is a natural antagonist that neutralizes IL-6.soluble IL-6Ralpha complexes. It was our strategy to appropriately fuse the two receptor subunit fragments involved in IL-6 receptor complex formation to bind IL-6 with high affinity and to antagonize its effects. The ligand-binding domains of gp130 (D1-D2-D3) and IL-6Ralpha (D2-D3) were connected using three different linkers. The resulting constructs were expressed in stably transfected insect cells and tested for their ability to inhibit IL-6 activity in several in vitro systems. All fusion proteins were strong inhibitors of IL-6 signaling and abrogated IL-6-induced phosphorylation of STAT3, proliferation of transfected Ba/F3 cells, and induction of acute-phase protein synthesis. As intended, the fused receptors were much more effective than the separately expressed soluble receptor proteins. The fusion protein strategy presented here can also be applied to other cytokines that signal via receptors composed of two different subunits to design new potent inhibitors for anti-cytokine therapies.


The affordability of a healthy and sustainable diet: an Australian case study.
EAT-Lancet Commission's Planetary Health Diet proposed a diet that integrates nutrition and sustainability considerations, however its affordability is unknown in many country-specific contexts, including Australia. The aim of this study is to develop a healthy and sustainable food basket modelled on the Planetary Health Diet to determine the affordability of the Planetary Health Diet basket across various socio-economic groups, and compare this affordability with a food basket modelled on the typical current diet, in an Australian setting. An Australian-specific Planetary Health Diet basket was developed for a reference household (2 adults and 2 children) modelled on the Planetary Health Diet reference diet, and compared to a previously-developed Typical Australian Diet basket. The cost of each food basket was determined by online supermarket shopping surveys in low, medium and high socio-economic areas in each Australian state. Basket affordability was determined for the reference household by comparing the basket cost to disposable income in each socio-economic group in each state. Mann-Whitney U tests then determined if there were significant differences between the median costs and the median affordability of both baskets. The Planetary Health Diet basket was shown to be less expensive and more affordable than the Typical Australian Diet basket nationally, in all metropolitan areas, in all socio-economic groups across Australia (median cost: Planetary Health Diet = AUD$188.21, Typical Australian Diet = AUD$224.36; median affordability: Planetary Health Diet = 13%, Typical Australian Diet = 16%; p = < 0.05). This study showed the Planetary Health Diet to be more affordable than the Typical Australian Diet for metropolitan-dwelling Australians. These results can help to inform public health and food policy aimed at achieving a healthy and sustainable future for all Australians, including reductions in overweight/obesity rates and increased food security.


Broadband control of the optical properties of semiconductors through site-controlled self-assembly of microcrystals.
We investigate light-matter interactions in periodic silicon microcrystals fabricated combining top-down and bottom-up strategies. The morphology of the microcrystals, their periodic arrangement, and their high refractive index allow the exploration of photonic effects in microstructured architectures. We observe a notable decrease in reflectivity above the silicon bandgap from the ultraviolet to the near-infrared. Finite-difference time-domain simulations show that this phenomenon is accompanied by a ∼2-fold absorption enhancement with respect to a flat sample. Finally, we demonstrate that ordered silicon microstructures enable a fine tuning of the light absorption by changing experimentally accessible knobs as pattern and growth parameters. This work will facilitate the implementation of optoelectronic devices based on high-density microcrystals arrays with optimized light-matter interactions.


A Sleep Analysis of Elite Female Soccer Players During a Competition Week.
(1) To compare the sleep of female players from a professional soccer team to nonathlete controls across an in-season week and (2) to compare the sleep of core and fringe players from the same team on the night after a match to training nights. Using an observational design, 18 professional female soccer players and 18 female nonathlete controls were monitored for their sleep via wristwatch actigraphy across 1 week. Independent-sample t tests and Mann-Whitney U tests were performed to compare sleep between groups, while an analysis of variance compared sleep on training nights to the night after a match. Soccer players had significantly greater sleep duration than nonathlete controls (+38 min; P = .009; d: 0.92), which may have resulted from an earlier bedtime (-00:31 h:min; P = .047; d: 0.70). The soccer players also had less intraindividual variation in bedtime than nonathletes (-00:08 h:min; P = .023; r: .38). Despite this, sleep-onset latency was significantly longer among soccer players (+8 min; P = .032; d: 0.78). On the night after a match, sleep duration of core players was significantly lower than on training nights (-49 min; P = .010; d: 0.77). In fringe players, there was no significant difference between nights for any sleep characteristic. During the in-season period, sleep duration of professional female soccer players is greater than nonathlete controls. However, the night after a match challenges the sleep of players with more match involvement and warrants priority of sleep hygiene strategies.


Cardioprotective effects of the novel adenosine A1/A2 receptor agonist AMP 579 in a porcine model of myocardial infarction.
This study examined the cardioprotective effects and pharmacology of the novel adenosine A1/A2 receptor agonist ([1S-[1a,2b,3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-3H-imida zo[4,5-b] pyridyl-3-yl] cyclopentane carboxamide) (AMP 579), in a model of myocardial infarction. Experiments were performed in pentobarbital-anesthetized pigs in which myocardial infarction was induced by a 40-min occlusion of the left anterior descending coronary artery, followed by 3 hr of reperfusion. This procedure resulted in approximately 20% of the left ventricle being made ischemic in all test groups. In untreated animals, an infarct size equal to 56 +/- 5% of the ischemic area was observed. Preconditioning, with two cycles of 5 min of ischemia followed by 10-min reperfusion, resulted in a 70% reduction in infarct size (17 +/- 5%) relative to risk area. Administration of AMP 579 30 min before ischemia (3 microg/kg i.v. followed by 0.3 microg/kg/min i.v. through 1 hr of reperfusion) did not change blood pressure, HR or coronary blood flow but resulted in marked cardioprotection: a 98% reduction in infarct size (1 +/- 1%) relative to risk area. Moreover, whereas approximately 90% of control pigs suffered ventricular fibrillation during ischemia, no fibrillation was observed in animals treated with AMP 579. Further experiments determined the effects of AMP 579 when administered 30 min after the onset of myocardial ischemia, 10 min before reperfusion. Two doses were studied: a low hemodynamically silent dose (3 microg/kg + 0.3 microg/kg/min through 1 hr of reperfusion) and a 10-fold higher dose that did cause reductions in blood pressure and HR. Both doses of AMP 579 produced a comparable cardioprotective effect, reducing infarct size to approximately 50% of that observed in control animals. The cardioprotective effect of AMP 579 was a consequence of adenosine receptor stimulation, because it was completely inhibited by pretreatment with the specific adenosine receptor antagonist CGS 15943 (1 mg/kg i.v.). However, the selective A1 receptor agonist GR 79236 (3 microg/kg + 0.3 microg/kg/min i.v.) did not reduce infarct size, which suggests that under these experimental conditions, stimulation of adenosine A2 receptors is important for the cardioprotective effect of AMP 579. The adenosine-regulating agent acadesine (5 mg/kg + 0.5 mg/kg/min i.v.) also failed to reduce infarct size. In conclusion, the novel adenosine A1/A2 receptor agonist AMP 579 produces marked cardioprotection whether administered before myocardial ischemia or reperfusion. Cardioprotection is not dependent on changes in afterload or myocardial oxygen demand and is a consequence of adenosine receptor stimulation. The pharmacological profile of AMP 579 in this model is consistent with its potential utility in the treatment of acute myocardial infarction.


The Face – A Vascular Perspective. A literature review
Vascular supply is key for maintenance of healthy tissue conditions but also with regard to healing following trauma or therapeutic interventions. The face is probably the most exposed part of the body and any changes of vascularity are readily visible (skin blanching, ecchymosis, hematoma, edema). With regard to the arterial supply, all vessels reaching the facial skin originate from the bilateral common carotid arteries. The ophthalmic artery is considered the major arterial shunt between the internal and external carotid artery systems. Main arterial contributors to the face include the facial, transverse facial, and infraorbital arteries. In general, homonymous veins accompany the arteries, but there are some exceptions (inferior ophthalmic vein, retromandibular vein). Furthermore, the facial vein demonstrates a consistently more posterior course compared to the facial artery. Lymphatic vessels including lymph nodes play an important role for facial drainage.


The Framework of Historical Oppression, Resilience and Transcendence to Understand Disparities in Depression Amongst Indigenous Peoples.
Given chronic experiences of historical oppression, Indigenous peoples tend to experience much higher rates of depression than the general US population, which then, drives disproportionately high rates of suicide and other health disparities. The purpose of this research was to examine the core components of the culturally grounded Framework of Historical Oppression, Resilience, and Transcendence as they relate to depressive symptoms experienced by Indigenous peoples. As part of a larger convergent mixed-methods study, in this quantitative survey component, we utilised data from a sample of 127 Indigenous adults across two Southeastern US tribes. Regression analysis results signified support for the framework, indicating that historical oppression and proximal stress (daily stressors and lower incomes) were risk factors, whereas family resilience and life satisfaction (a measure of transcendence) were protective factors related to depressive symptoms. The results provide a foundation for future research to build upon in identifying culturally relevant risk and protective factors to ameliorate depression and other health disparities.


Effect of subsequent bladder cancer on survival in upper tract urothelial carcinoma patients post-radical nephroureterectomy: a systematic review and meta-analysis.
Radical nephroureterectomy (RNU) is the primary treatment strategy for upper tract urothelial carcinoma (UTUC). However, the intravesical recurrence occurs in 20-50% of all patients. The specific effect of subsequent bladder cancer (SBCa) on survival remains unclear. Therefore, we investigated the effect of SBCa following RNU in patients with UTUC. PubMed, EMBASE, and Cochrane Library were exhaustively searched for studies comparing oncological outcomes between SBCa and without SBCa. Standard cumulative analyses using hazard ratios (HR) with 95% confidence intervals (CI) were performed using Review Manager (version 5.3). Five studies involving 2057 patients were selected according to the predefined eligibility criteria. Meta-analysis of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences between the SBCa and non-SBCa groups. However, subgroup analysis of pT0-3N0M0 patients suggested that people with SBCa had worse CSS (HR = 5.13, 95%CI 2.39-10.98, p < 0.0001) and OS (HR = 4.00, 95%CI 2.19-7.31, p < 0.00001). SBCa appears to be associated with worse OS in patients with early stage UTUC. However, caution must be taken before recommendations are made because this interpretation is based on very few clinical studies and a small sample size. Research sharing more detailed surgical site descriptions, as well as enhanced outcome data collection and improved reporting, is required to further investigate these nuances.


Highly specific mRNA biomarkers for the identification of vaginal secretions in sexual assault investigations.
The inability to definitively determine the tissue source of origin of forensically relevant biological fluids could result in a failure to provide crucial information necessary to the investigation and prosecution of the case. For example, in instances of sexual assault with a foreign object or digital penetration, the identification of vaginal secretions (VS) transferred to such objects or the perpetrators might be critical in establishing the circumstances of the assault. Conventional serological and immunological methods for body fluid identification can confirm the presence of human blood and semen. However, currently none of the routinely used biochemical tests can definitively identify the presence of human saliva or VS. It has been demonstrated that mRNA (or miRNA) profiling of body fluid stains can provide a degree of identification specificity of tissue and body fluids heretofore unattainable by conventional means. Early promising VS candidate RNA biomarkers, however, failed to exhibit the required degree of specificity or sensitivity and thus, at present, it is not possible for the forensic scientist to definitively identify VS using molecular genetics techniques. The aim of this work was to find novel highly specific RNA biomarkers for the identification of VS. Whole transcriptome profiling (RNA-Seq) of vaginal swab samples from different donors resulted in the identification of a number of putative VS-specific mRNA candidates. After detailed evaluation of >200 candidates from the tens of thousands of mRNA species found in VS, six promising candidates were identified. From these, two gene transcripts, namely CYP2B7P1 and MYOZ1, consistently demonstrated high specificity and sensitivity for VS when used in a qualitative capillary electrophoresis-based assay. Importantly these two biomarkers are able to differentiate between VS and other body fluids containing significant numbers of epithelia, particularly saliva and skin. Significantly, CYP2B7P1 is exceedingly specific with no detectable cross reactivity with other forensically relevant body fluids/tissues noted to date. The other four putatively specific biomarkers are expressed at higher levels in VS compared with saliva and will be more suitable for use with a quantitative (i.e. qRT-PCR) assay format.


Salubrinal Exposes Anticancer Properties in Inflammatory Breast Cancer Cells by Manipulating the Endoplasmic Reticulum Stress Pathway.
The endoplasmic reticulum (ER) regulates protein folding, post-translational modifications, lipid synthesis, and calcium signaling to attenuate the accumulation of misfolded proteins causing ER stress and maintains cellular homeostasis. The tumor microenvironment is rich in soluble cytokines, chemokines, growth, and angiogenic factors and can drive the ER's abnormal functioning in healthy cells. Cancer cells adapt well to the tumor microenvironment induced ER stress. We identified that the inflammatory breast cancer (IBC) cells abundantly express osteoprotegerin (OPG) and their tumor microenvironment is rich in OPG protein. OPG also called osteoclast differentiation factor/osteoclastogenesis inhibitory factor (OCIF) is a soluble decoy receptor for receptor activator of nuclear factor-kappa B ligand (RANKL). Employing mass spectrometry analysis, we identified a set of ER chaperones associated with OPG in IBC cell lysates (SUM149PT, SUM1315MO2) compared to healthy human mammary epithelial cells (HMEC). Proximity ligation assay (PLA) and immunoprecipitation assay validated the interaction between OPG and ER chaperone and master regulator of unfolded protein response (UPR) GRP78/BiP (glucose-regulated protein/Binding immunoglobulin protein). We detected remarkably high gene expression of CCAAT enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE1α), protein disulfide-isomerase (PDI), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP-1) and growth arrest and DNA damage-inducible protein (GADD34) in SUM149PT and SUM190PT cells when compared to HMEC. Similarly, tissue sections of human IBC expressed high levels of ER stress proteins. We evaluated cell death and apoptosis upon Salubrinal and phenylbutyrate treatment in healthy and IBC cells by caspase-3 activity and cleaved poly (ADP-ribose) polymerase (PARP) protein assay. IBC (SUM149PT and SUM190PT) cells were chemosensitive to Salubrinal treatment, possibly via inhibition in OPG secretion, upregulating ATF4, and CHOP, thus ultimately driving caspase-3 mediated IBC cell death. Salubrinal treatment upregulated PDI, which connects ER stress to oxidative stress. We observed increased ROS production and reduced cell proliferation of Salubrinal treated IBC cells. Treatment with antioxidants could rescue IBC cells from ROS and aborted cell proliferation. Our findings implicate that manipulating ER stress with Salubrinal may provide a safer and tailored strategy to target the growth of inflammatory and aggressive forms of breast cancer.


The evolution of acute stroke recorded by multimodal magnetic resonance imaging.
Events associated with an evolving cerebral infarction were studied using multiple magnetic resonance imaging (MRI) techniques at 4.7 T in a rat model of middle cerebral artery occlusion. High resolution perfusion images revealed a core of absent perfusion surrounded by a zone of slow, but measurable perfusion. Only the core of severest perfusion deficit demonstrated restricted water diffusion as early as 1 hr, consistent with "cytotoxic" cellular edema in the most vulnerable region. Within 24 hours, the area of restricted diffusion encompassed the entire region destined to become infarcted. In spin-echo images, hypointensity, likely reflecting deoxygenated hemoglobin, was visible in the ischemic hemisphere. Edema accumulated over 72 hr primarily in the surrounding slowly perfused rim, consistent with the concept of "vasogenic" edema. These studies demonstrate that multimodal MRI can visualize events which define the ischemic penumbra--deoxygenation, maintenance of transmembrane ionic gradients, reduced flow, and delayed cell death. These experiments noninvasively visualized differential hemodynamic and biochemical processes within the core and perifocal penumbra and will allow quantitation over time of the relationship between blood flow, cytotoxicity and edema in stroke.


Epilepsy and perisylvian polymicrogyria in a patient with Kabuki syndrome.
Kabuki syndrome is a dysmorphogenic syndrome which has been reported in over 300 patients since it was first described in Japan in 1981. In addition to its cardinal features (typical facies, mild-to-moderate learning disability, short stature, skeletal anomalies, and dermatoglyphic abnormalities with persistent foetal fingerpads), neurological anomalies are frequently reported, including epilepsy in 8% of those with the syndrome. We present here a 22-year-old white female patient with refractory partial epilepsy, Kabuki syndrome, and bilateral perisylvian polymicrogyria on MRI: the first reported case of this association. The aetiology of the syndrome, including the diverse genetic changes recognized, is then discussed.


Osmotic buckling of spherical capsules.
We study the buckling of elastic spherical shells under osmotic pressure with the osmolyte concentration of the exterior solution as a control parameter. We compare our results for the bifurcation behavior with results for buckling under mechanical pressure control, that is, with an empty capsule interior. We find striking differences for the buckling states between osmotic and mechanical buckling. Mechanical pressure control always leads to fully collapsed states with opposite sides in contact, whereas uncollapsed states with a single finite dimple are generic for osmotic pressure control. For sufficiently large interior osmolyte concentrations, osmotic pressure control is qualitatively similar to buckling under volume control with the volume prescribed by the osmolyte concentrations inside and outside the shell. We present a quantitative theory which also captures the influence of shell elasticity on the relationship between osmotic pressure and volume. These findings are relevant for the control of buckled shapes in applications. We show how the osmolyte concentration can be used to control the volume of buckled shells. An accurate analytical formula is derived for the relationship between the osmotic pressure, the elastic moduli and the volume of buckled capsules. This also allows use of elastic capsules as osmotic pressure sensors or deduction of elastic properties and the internal osmolyte concentration from shape changes in response to osmotic pressure changes. We apply our findings to published experimental data on polyelectrolyte capsules.


AgNO3 Sterilizes Grains of Barley (Hordeum vulgare) without Inhibiting Germination-A Necessary Tool for Plant-Microbiome Research.
To understand and manipulate the interactions between plants and microorganisms, sterile seeds are a necessity. The seed microbiome (inside and surface microorganisms) is unknown for most plant species and seed-borne microorganisms can persist and transfer to the seedling and rhizosphere, thereby obscuring the effects that purposely introduced microorganisms have on plants. This necessitates that these unidentified, seed-borne microorganisms are removed before seeds are used for studies on plant-microbiome interactions. Unfortunately, there is no single, standardized protocol for seed sterilization, hampering progress in experimental plant growth promotion and our study shows that commonly applied sterilization protocols for barley grains using H2O2, NaClO, and AgNO3 yielded insufficient sterilization. We therefore developed a sterilization protocol with AgNO3 by testing several concentrations of AgNO3 and added two additional steps: Soaking the grains in water before the sterilization and rinsing with salt water (1% (w/w) NaCl) after the sterilization. The most efficient sterilization protocol was to soak the grains, sterilize with 10% (w/w) AgNO3, and to rinse with salt water. By following those three steps, 97% of the grains had no culturable, viable microorganism after 21 days based on microscopic inspection. The protocol left small quantities of AgNO3 residue on the grain, maintained germination percentage similar to unsterilized grains, and plant biomass was unaltered. Hence, our protocol using AgNO3 can be used successfully for experiments on plant-microbiome interactions.


Transcriptional control of the Saccharomyces cerevisiae PGK gene by RAP1.
The promoter of the yeast glycolytic gene encoding phosphoglycerate kinase (PGK) contains an upstream activation sequence between bases -538 and -402 upstream of the initiating ATG. The upstream activation sequence contains multiple functional elements, including an essential region called the activator core (AC) sequence and three copies of the pentamer 5'-CTTCC-3'. The AC sequence shows strong homology to the consensus binding sites for the yeast proteins RAP1 (GRF1) and TUF. We have demonstrated that the yeast protein which interacts with the AC sequence is the DNA-binding protein RAP1. Expression of the PGK gene is found to be regulated according to the carbon source in the growth medium. PGK mRNA levels are high in yeast cells grown in glucose medium but low in yeast cells grown in media containing carbon sources such as pyruvate and acetate. This carbon source regulation of transcription was found to be mediated, in part, via regulation of RAP1 binding to the AC sequence. The promoters of many other yeast glycolytic genes also contain consensus RAP1-binding sites and copies of the CTTCC pentamer. This suggests that RAP1 may be involved in transcriptional control of many other glycolytic genes in addition to the PGK gene.


Unbalanced expression of protease-activated receptors-1 and -2 in the colon of diarrhea-predominant irritable bowel syndrome patients.
The aim of this study is to determine whether a changed expression ratio of PAR-1 and PAR-2 in the colon is associated with diarrhea-predominant IBS patients. PAR-1, -2, thrombin, mast cell tryptase, tryptophan hydroxylase (TPH), and chromgranin A (ChrA) in colonic biopsy samples from 10 diarrhea-predominant IBS patients and 13 healthy control subjects were semiquantified with immunofluorescence and image analysis. Serotonin concentrations in biopsy samples were evaluated by capillary electrophoresis. Significantly lower expression of PAR-1 and higher expression of mast cell tryptase was detected in the colons of patients, with statistically unchanged expression of PAR-2. Thrombin-, TPH-, and ChrA-positive cells were markedly increased in IBS patients, but no significant difference in serotonin concentration existed in the colons between two groups. The ratio of PAR-1/PAR-2 expression was significantly decreased in patients (0.33+/-0.19 versus 0.66+/-0.22, P=0.001) and negatively correlated to ChrA-positive cells. Changed expression ratio of PAR-1 to PAR-2 in the colon is connected with diarrhea-predominant IBS patients. Methods to restore an appropriate balance of PAR-1 and PAR-2 activation in the colon may offer a promising future therapeutic strategy for IBS patients.


Patient perception of contemporary nurse attire: a pilot study.
Patients have expressed difficulty accurately distinguishing registered nurses (RNs) from other hospital personnel because standardized uniforms are no longer worn by RNs. According to American studies, such complaints are widespread; moreover, patients' perceptions of nurse caring and competence and of other traits associated with nurses' professional image have been negatively affected by casual, non-conventional attire. As there are no published Canadian studies, we conducted a pilot study to examine patient perception of the nurse uniform. Adult patients viewed photographs of the same RN dressed in eight different uniforms and rated each uniform according to 10 traits associated with nurses' professional image. The white pantsuit scored higher for professionalism than uniforms with small print, bold print, or solid colour, and most patients preferred that the RN dress in white. Our preliminary findings suggest that RN attire warrants further investigation, and we are planning a large-scale, fully powered study to inform patient-driven change to existing uniform policies.


The effect of fasting month of Ramadan on the abdominal fat distribution: assessment by computed tomography.
The aim of this study was to evaluate the changes in abdominal fat distribution in the fasting month of Ramadan. Thirty-eight healthy volunteers (17 women and 21 men) who fasted in the month of Ramadan in 2002 were included in this prospective study. Waist, hip and thigh circumferences, weight and height of all subjects were measured. Waist-to-hip ratio (WHR), waist-to-thigh ratio (WTR) and body mass index (BMI) were calculated for each subject. For assessing the fat distribution in the abdomen, computed tomography (CT) was performed. Both subcutaneous and visceral fat areas were calculated by the CT scanning technique. All of the calculations were done before (first measurement) and after (second measurement) Ramadan fasting and the changes were evaluated. No statistically significant differences were found in all subjects between the first and second measurements, which include total, subcutaneous and visceral fat areas, waist, hip and thigh circumferences, weight, BMI, WHR, and WTR (p > 0.05). In females and the individuals in their twenties, there was a significant decrease in visceral fat area (p < 0.05). Despite of the general opinion that supposes the change of weight during the fasting month of Ramadan, there were no significant differences in weight and abdominal fat distribution. However in female and young individuals, there was a reduction in visceral fat compartment. This could be due to fat redistribution, because they have more physical activity than males and older individuals.


Modified Marshall, Marchetti and Krantz operation.
A modification of the Marshall, Marchetti and Krantz procedure is described that uses the Babcock clamp for exposure and the rectus muscle for suspension in order to reduce the complications and technical difficulties. The procedure was utilized for 30 patients, and in the same period 27 patients were treated with the nonmodified procedure. A follow-up from one to six years resulted in one patient with a complete failure and another with a partial failure in the modified group and five patients with complete failure in the nonmodified group. The complications rates were essentially the same. However, in the nonmodified group there was one patient with osteitis pubis, one patient with urethral stenosis and two patients with prolonged urinary retention. The results suggest that the modified technique is simple and successful in correcting stress urinary incontinence in women if coupled with adequate study of the patient and careful selection of the treatment.


Baicalin Inhibits Haemophilus Parasuis-Induced High-Mobility Group Box 1 Release during Inflammation.
Haemophilus parasuis (H. parasuis) can cause Glässer's disease in pigs. However, the molecular mechanism of the inflammation response induced by H. parasuis remains unclear. The high-mobility group box 1 (HMGB1) protein is related to the pathogenesis of various infectious pathogens, but little is known about whether H. parasuis can induce the release of HMGB1 in piglet peripheral blood monocytes. Baicalin displays important anti-inflammatory and anti-microbial activities. In the present study, we investigated whether H. parasuis can trigger the secretion of HMGB1 in piglet peripheral blood monocytes and the anti-inflammatory effect of baicalin on the production of HMGB1 in peripheral blood monocytes induced by H. parasuis during the inflammation response. In addition, host cell responses stimulated by H. parasuis were determined with RNA-Seq. The RNA-Seq results showed that H. parasuis infection provokes the expression of cytokines and the activation of numerous pathways. In addition, baicalin significantly reduced the release of HMGB1 in peripheral blood monocytes induced by H. parasuis. Taken together, our study showed that H. parasuis can induce the release of HMGB1 and baicalin can inhibit HMGB1 secretion in an H. parasuis-induced peripheral blood monocytes model, which may provide a new strategy for preventing the inflammatory disorders induced by H. parasuis.


Pyrosequencing Analysis of APC Methylation Level in Human Prostate Tissues: A Molecular Marker for Prostate Cancer.
Epigenetic alterations such as abnormal DNA methylation are associated with many human cancers. Differences in methylation patterns between neoplastic and normal cells can be used to detect cancer. The aim of the present study was to evaluate the effectiveness of detecting Adenomatous polyposis coli (APC) hypermethylation by quantitative pyrosequencing for discriminating between normal and prostate cancer (PCa) cells and for predicting tumor behaviors. A total of 218 human prostate tissues obtained from our institute were assessed: 106 specimens of benign prostatic hyperplasia (BPH) and 112 specimens of PCa. The methylation status of APC was analyzed by quantitative pyrosequencing. The association between the APC methylation level and clinicopathological parameters was explored. The level of APC methylation was significantly higher in PCa specimens than in BPH specimens (33.3%±20.7% vs. 1.3%±1.8%, p<0.001). The sensitivity and specificity of APC methylation status in discriminating between PCa and BPH reached 89.3% and 98.1%, respectively. Similar results were obtained after stratification by stage, Gleason score, and prostate-specific antigen level. The APC methylation level correlated positively with Gleason score (p trend=0.016). There was no association between the APC methylation level and the PSA level or staging. Our results demonstrate that APC methylation is associated with PCa and its aggressive tumor features.


Chromium isotopic insights into the origin of chondrite parent bodies and the early terrestrial volatile depletion.
Chondrites are meteorites from undifferentiated parent bodies that provide fundamental information about early Solar System evolution and planet formation. The element Cr is highly suitable for deciphering both the timing of formation and the origin of planetary building blocks because it records both radiogenic contributions from 53Mn-53Cr decay and variable nucleosynthetic contributions from the stable 54Cr nuclide. Here, we report high-precision measurements of the massindependent Cr isotope compositions (ε53Cr and ε54Cr) of chondrites (including all carbonaceous chondrites groups) and terrestrial samples using for the first time a multi-collection inductively-coupled-plasma mass-spectrometer to better understand the formation histories and genetic relationships between chondrite parent bodies. With our comprehensive dataset, the order of decreasing ε54Cr (per ten thousand deviation of the 54Cr/52Cr ratio relative to a terrestrial standard) values amongst the carbonaceous chondrites is updated to CI = CH ≥ CB ≥ CR ≥ CM ≈ CV ≈ CO ≥ CK > EC > OC. Chondrites from CO, CV, CR, CM and CB groups show intra-group ε54Cr heterogeneities that may result from sample heterogeneity and/or heterogeneous accretion of their parent bodies. Resolvable ε54Cr (with 2SE uncertainty) differences between CV and CK chondrites rule out an origin from a common parent body or reservoir as has previously been suggested. The CM and CO chondrites share common ε54Cr characteristics, which suggests their parent bodies may have accreted their components in similar proportions. The CB and CH chondrites have low-Mn/Cr ratios and similar ε53Cr values to the CI chondrites, invalidating them as anchors for a bulk 53Mn-53Cr isochron for carbonaceous chondrites. Bulk Earth has a ε53Cr value that is lower than the average of chondrites, including enstatite chondrites. This depletion may constrain the timing of volatile loss from the Earth or its precursors to be within the first million years of Solar System formation and is incompatible with Earth's accretion via any of the known chondrite groups as main contributors, including enstatite chondrites.


Development of horizontal tooth wear in maxillary anterior teeth from five to 18 years of age.
Sizes of horizontal wear facets of maxillary anterior teeth were studied longitudinally from the primary dentition at age five to the young adult dentition at the age of 18 years. By a planimetric method, we calculated the wear areas on dental casts taken at the ages of five, ten, 14, and 18 years from the dentition of 39 healthy, orthodontically untreated subjects with good morphological occlusion. For young adults, we also studied the association between the amount of wear and reported parafunctions, maximal bite force, salivary buffer capacity, salivary flow rate, and some cephalometric variables. Size of wear facets on all anterior teeth increased with age. Significant correlations were found between the total wear areas of the six anterior primary teeth at five years of age and those of their permanent successors at age 14 (r = 0.44) and 18 (r = 0.39). For an individual, tooth wear at five years of age was, however, of low predictive value for tooth wear in young adulthood, whereas tooth wear at 14 years of age predicted it well (r = 0.89). Highest correlations between tooth wear and background factors at 18 years of age were found for maximal anterior bite force (r = 0.44) and for the size of the gonial angle (r = -0.31). Wear of anterior teeth was not associated with reported parafunctions in young adulthood.


Elevated cyclin D1 expression is predictive for a benefit from TPF induction chemotherapy in oral squamous cell carcinoma patients with advanced nodal disease.
Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients with cancer with biomarker detection. To investigate the prognostic and predictive values of cyclin D1 expression in patients with oral squamous cell carcinoma (OSCC) who were treated in a prospective, randomized, phase III trial evaluating standard treatment with surgery and postoperative radiotherapy preceded or not by induction docetaxel, cisplatin, and 5-fluorouracil (TPF), immunohistochemical staining for cyclin D1 was conducted in pretreatment biopsy specimens of 232 out of 256 clinical stage III/IVA OSCC patients randomized to the clinical trial. Cyclin D1 index was estimated as the proportion of tumor cells with cyclin D1 nuclear staining. A low cyclin D1 expression predicted significantly better overall survival (OS; P = 0.001), disease-free survival (P = 0.005), locoregional recurrence-free survival (P = 0.003), and distant metastasis-free survival (DMFS; P = 0.002) compared with high cyclin D1 expression. Cyclin D1 expression levels were not predictive of benefit from induction TPF in the population overall. However, patients with nodal stage cN2 whose tumors had high cyclin D1 expression treated with TPF had significantly greater OS (P = 0.025) and DMFS (P = 0.025) when compared with high cyclin D1 cN2 patients treated with surgery upfront. Patients with low cyclin D1 level or patients with cN0 or cN1 disease did not benefit from induction chemotherapy. This study indicates that cN2 OSCC patients with high cyclin D1 expression can benefit from the addition of TPF induction chemotherapy to standard treatment. Cyclin D1 expression could be used as a biomarker in further validation studies to select cN2 patients that could benefit from induction therapy.


[Studies on the glycopeptides of canine prothrombin].
After degradation of canine prothrombin by the complex of Streptomyces griseus proteases four glycopeptides were obtained. Each of them contained aspartic acid, hexosamines, mannose, galactose and sialic acids. Canine prothrombin contains two or three carbohydrate chanins, which are bound to aspartic (asparagine) residues. Microheterogenity of the carbohydrate chains of canine prothrombin was found.


The effect of hypoxia on in vitro prevascularization of a thick soft tissue.
Prevascularizing an implantable tissue is one strategy to improve oxygen (O(2)) transport throughout larger tissues upon implantation. This study examined the role of hypoxia both during (i.e., as a stimulus) and after (i.e., mimicking implant conditions) vascularization of an implantable tissue. Tissues consisted of microcarrier beads coated with human umbilical vein endothelial cells embedded in fibrin. The fibrin was covered with a monolayer of normal human lung fibroblasts (NHLFs), or exposed to conditioned media from NHLFs. Capillary networks developed at 20% or 1% O(2) tension for 8 days. In some experiments, tissues were supplemented with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, whereas in others the tissues prevascularized at 20% O(2) were transferred to 1% O(2) for 8 additional days. Maximal capillary formation occurred in media conditioned by NHLFs at 20% O(2), supplemented with VEGF (concentration >10 pM). Hypoxia (1% O(2)) did not stimulate basic fibroblast growth factor production and decreased in vitro angiogenesis, despite an increase in endogenous VEGF production. Hypoxia also degraded a preformed capillary network within 4 days. Hence, strategies to prevascularize implantable tissues may not require the physical presence of stromal cells, but will likely require fibroblast-derived growth factors in addition to VEGF to maintain capillary growth.


Terahertz active spatial filtering through optically tunable hyperbolic metamaterials.
We theoretically consider infrared-driven hyperbolic metamaterials able to spatially filter terahertz (THz) radiation. The metamaterial is a slab made of alternating semiconductor and dielectric layers whose homogenized uniaxial response, at THz frequencies, shows principal permittivities of different signs. The gap provided by metamaterial hyperbolic dispersion allows the slab to stop spatial frequencies within a bandwidth tunable by changing the infrared radiation intensity. We numerically prove the device functionality by resorting to full wave simulation coupled to the dynamics of charge carries photoexcited by infrared radiation in semiconductor layers.


Systematic review of multiple versus single device closure of Secundum atrial septal defects in adults.
Multiple device closure (MDC) strategy has been used in treating of complex Atrial septal defects (ASDs) in adults. The safety profile of MDC compared to conventional single device closure (SDC) is unknown in this population. This report represents the first review examining the outcomes of single versus multiple device ASD closure in adults with ostium secundum defects. Literature databases and manual search from their inception until June 30th, 2017 followed the Preferred Reporting Items of Systemic Review and Meta-Analysis (PRISMA) guideline. Main outcomes are 1) overall complication incidence, 2) arrhythmia incidence, 3) residual shunt rate. Each outcome profile was pooled by MDC and SDC, respectively and chi-square analysis was applied to examine statistical significance between MDC and SDC strategies (two-sided and p < .050). A total of 1806 + studies were initially screened, and 20 studies were finally selected (MDC group, 147 patients; SDC group, 1706 patients). There was no difference in overall complication incidence (χ2 = 1.269; p = .259) and arrhythmia incidence (χ2 = 0.325; p = .568) between MDC and SDC. There was no difference in residual shunt rate between the SDC (4.10 %; 70/1706) and MDC groups (6.80 %; 10/147; χ2 = 2.387; p = .122). The outcomes of percutaneous multiple ASD closure (MDC) seem to be safe and effective as compared to conventional single ASD (SDC) closure in terms of device - related complications and technical success of the procedure. Prospective registry data and randomized trials are needed to determine the long-term outcomes of percutaneous ASD closure using MDC.


Influence of phase function on modeled optical response of nanoparticle-labeled epithelial tissues.
Metal nanoparticles can be functionalized with biomolecules to selectively localize in precancerous tissues and can act as optical contrast enhancers for reflectance-based diagnosis of epithelial precancer. We carry out Monte Carlo (MC) simulations to analyze photon propagation through nanoparticle-labeled tissues and to reveal the importance of using a proper form of phase function for modeling purposes. We first employ modified phase functions generated with a weighting scheme that accounts for the relative scattering strengths of unlabeled tissue and nanoparticles. To present a comparative analysis, we repeat our MC simulations with simplified functions that only approximate the angular scattering properties of labeled tissues. The results obtained for common optical sensor geometries and biologically relevant labeling schemes indicate that the exact form of the phase function used as model input plays an important role in determining the reflectance response and approximating functions often prove inadequate in predicting the extent of contrast enhancement due to labeling. Detected reflectance intensities computed with different phase functions can differ up to ∼60% and such a significant deviation may even alter the perceived contrast profile. These results need to be taken into account when developing photon propagation models to assess the diagnostic potential of nanoparticle-enhanced optical measurements.