Proliferative gingival lesion in a cat with disseminated cryptococcosis.
A case of disseminated cryptococcosis with oral, pulmonary, and cutaneous manifestations is described in an eleven-year-old Siamese cat. Marked clinical improvement was noted 2-months following appropriate antifungal therapy. A review of disseminated cryptococcosis and the oral manifestations of fungal disease are provided.


Vertebral artery ostial stenosis: prevalence by digital subtraction angiography, MR angiography, and CT angiography.
(1) To determine the prevalence of vertebral arterial ostial stenosis (VOS) as determined by the "gold standard" of digital subtraction angiography (DSA). (2) To learn the correlation between vertebral ostial stenosis and study indication. (3) To determine the ability of contrast-enhanced magnetic resonance angiography (CE MRA) and computed tomographic angiography (CTA) to reflect the true prevalence of vertebral ostial stenosis as determined by DSA. Three hundred and twenty-nine patients who underwent DSA had recorded evaluation of 443 vertebral artery origins. Cases were categorized by patient age and study indication. Similar numbers of CTA and MRA studies were assessed. The prevalence of VOS in the study population was 5.4%. VOS was not observed in patients under 40 years of age, and was seen in 12.5% of patients over 70 years. CE MRA demonstrated decreased signal at the vertebral origins consistent with stenosis in 20% of patients. CTA estimated VOS at .8%, and yielded 7.3% of studies, which were nondiagnostic for VOS. The prevalence of VOS as determined by DSA is low and increases with patient age and correlates with factors such as anterior infarct (18.4%), posterior infarct (33.3%), carotid atherosclerosis (30.8%), and vertebrobasilar insufficiency (33%). Patients being evaluated for reasons less closely correlated with atherosclerotic disease, such as arteriovenous malformation (AVM) or hemorrhage showed a lower prevalence of VA stenosis (brain aneurysm or AVM 5/121, 4.1%, brain hemorrhage 5/153, 3.3%). Routine clinical MRA significantly overestimates VOS prevalence, and findings suggest that CTA underestimates the degree and prevalence of VOS.


Mycobacterium avium subspecies paratuberculosis infects and multiplies in enteric glial cells.
To establish the role of enteric glial cells during infection with Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease. In order to establish the role of enteric glial cells during infection with M. avium subspecies paratuberculosis (MAP) in Crohn's disease, Map adhesion experiments on enteric glial cells were performed as well as expression analysis of Map sigma factors during infection. In this study, for the first time, we found a high affinity of MAP to enteric glial cells and we analyzed the expression of MAP sigma factors under different conditions of growth. The fact that Map showed a high affinity to the glial cells raises concerns about the complicated etiology of the Crohn's disease. Elucidation of the mechanisms whereby inflammation alters enteric neural control of gut functions may lead to novel treatments for Crohn's disease.


A Risk Assessment Model for Water Resources: releases of dangerous and hazardous substances.
Many dangerous and hazardous substances are used, transported and handled daily in diverse situations, from domestic use to industrial processing, and during those operations, spills or other anomalous situations may occur that can lead to contaminant releases followed by contamination of surface water or groundwater through direct or indirect pathways. When dealing with this problem, rapid, technically sound decisions are desirable, and the use of complex methods may not be able to deliver information quickly. This work describes a simple conceptual model established on multi-criteria based analysis involving a strategic appraisal for contamination risk assessment to support local authorities on rapid technical decisions. The model involves a screening for environmental risk sources, focussing on persistent, bioaccumulative and toxic (PBT) substances that may be discharged into water resources. It is a simple tool that can be used to follow-up actual accident scenarios in real time and to support daily activities, such as site-inspections.


Pretreatment of infant formula with sodium polystyrene sulfonate : focus on optimal amount and contact time.
In pediatric patients at risk of hyperkalemia there are limited treatment or preventive alternatives for this electrolyte imbalance. Oral or rectal sodium polystyrene sulfonate (SPS) has several potential adverse effects, and dietary potassium restriction may compromise nutrition. Pretreatment of infant formula with SPS has been previously studied with promising efficacy. The optimal dosing and contact time has not been fully elucidated for this practice, nor have brand and generic products been compared. The present study aimed to evaluate the effectiveness of varying amounts of brand and generic SPS for the removal of potassium from formula after 1 and 24 hours. SPS was added to infant formula in four different amounts measured in milliliters to reflect how a parent or caregiver would measure this product at home. After 1 and 24 hours samples were withdrawn and potassium and sodium levels were measured. Potassium decreased in all samples, with the greatest reduction after the addition of 10 mL of SPS. Sodium levels increased in all pretreated samples to a greater extent than the potassium reduction. Contact time of either 1 or 24 hours did not impact the amount of potassium removed or the increase in sodium concentration. There were also no differences found between generic and brand SPS products. The effectiveness of SPS for formula pretreatment appears to have a plateau effect beyond the addition of 20 mL (16.47 g of brand name product, 19.5 g of generic product). This study demonstrates an effective protocol for pretreatment of formula.


Experimental study on creep properties prediction of reed bales based on SVR and MLP.
Reed has high lignin content, wide distribution and low cost. It is an ideal raw material for replacing wood in the paper industry. Reeds are rich in resources, but the density of reeds is low, leading to high transportation and storage costs. This paper aims to study the compression process of reeds and the creep behaviour of compressed reeds, and provide theoretical guidance for the reed compressor management, bundling equipment and the stability of compressed reed bales. We have established a multi-layer perceptron network prediction model for the creep characteristics of reeds, and the prediction rate R2 of this model is greater than 0.997. The constitutive equation, constitutive coefficient and creep quaternary model of the reed creep process were established by using the prediction model. The creep behaviour of the reed bale is positively correlated with the initial maximum compressive stress (σ0). During the creep of the reed, the elastic power and the viscous resistance restrict each other. The results show that the proportion of elastic strain in the initial stage is the largest, and gradually decreases to 99.19% over time. The viscoelastic strain increases rapidly with time, then slowly increases, and finally stabilizes to 0.69%, while the plastic strain accounts for the proportion of the total strain. The specific gravity of the reed increases linearly with the increase of creep time, and finally accounts for 0.39%, indicating that as time increases, the damage of the reed's own structure gradually increases. We studied the relationship between the strain and time of the reed and the strain and creep behaviour of the reed bag under different holding forces under constant force. It is proved that the multi-layer perceptron network is better than the support vector machine regression in predicting the characteristics of reed materials. The three stages of elasticity, viscoelasticity and plasticity in the process of reed creep are analysed in detail. This article opens up a new way for using machine learning methods to predict the mechanical properties of materials. The proposed prediction model provides new ideas for the characterization of material characteristics.


Synthesis and evaluation of highly dispersible and efficient photocatalytic TiO2/poly lactic acid nanocomposite films via sol-gel and casting processes.
Using titanium teraisopropoxide (TTIP) as the hydrolysis material, titanium dioxide (TiO2) (6.3-11.1 nm) nanoparticles were synthesized via the sol-gel method and reinforced into poly lactic acid (PLA)/TiO2 nanocomposite films by casting. The effect of increasing amounts of TiO2 on the structure and properties of PLA/TiO2 nanocomposite films were evaluated. These results indicated that self-aggregation of TiO2 nanoparticles in PLA films could be avoided via sol-gel and casting processes. The presence of TiO2 significantly improved the tensile strength and thermal stability of films. The PLA/TiO2 (0.6 wt%) film exhibited the highest photocatalytic activity efficiency under UV irradiation and displayed high antibacterial activities with optimal inhibition zones of Staphylococcus aureus, followed by Escherichia dispersibility of TiO2 in films were responsible for those improvements. This study suggests that PLA/TiO2 nanocomposite films could be a promising antimicrobial alternative material to conventional plastic packages.


More realistic power estimation for new user, active comparator studies: an empirical example.
Pharmacoepidemiologic studies are often expected to be sufficiently powered to study rare outcomes, but there is sequential loss of power with implementation of study design options minimizing bias. We illustrate this using a study comparing pancreatic cancer incidence after initiating dipeptidyl-peptidase-4 inhibitors (DPP-4i) versus thiazolidinediones or sulfonylureas. We identified Medicare beneficiaries with at least one claim of DPP-4i or comparators during 2007-2009 and then applied the following steps: (i) exclude prevalent users, (ii) require a second prescription of same drug, (iii) exclude prevalent cancers, (iv) exclude patients age <66 years and (v) censor for treatment changes during follow-up. Power to detect hazard ratios (effect measure strongly driven by the number of events) ≥ 2.0 estimated after step 5 was compared with the naïve power estimated prior to step 1. There were 19,388 and 28,846 DPP-4i and thiazolidinedione initiators during 2007-2009. The number of drug initiators dropped most after requiring a second prescription, outcomes dropped most after excluding patients with prevalent cancer and person-time dropped most after requiring a second prescription and as-treated censoring. The naïve power (>99%) was considerably higher than the power obtained after the final step (~75%). In designing new-user active-comparator studies, one should be mindful how steps minimizing bias affect sample-size, number of outcomes and person-time. While actual numbers will depend on specific settings, application of generic losses in percentages will improve estimates of power compared with the naive approach mostly ignoring steps taken to increase validity.


The growth arrest-specific transcript 5 (GAS5): a pivotal tumor suppressor long noncoding RNA in human cancers.
Long noncoding RNAs (lncRNAs), which refer to a group of RNAs with length more than 200 nucleotides and limited protein-coding potential, play a widespread role in regulating biological processes, such as cell differentiation, proliferation, apoptosis, and migration. LncRNAs are dysregulated in multiple cancers, playing an either oncogenic or tumor-suppressive role. LncRNA GAS5 is a recently identified tumor suppressor involved in several cancers, like breast cancer, prostate cancer, lung cancer, and colorectal cancer. The low-expression pattern confers tumor cells elevated capacity of proliferation and predicts poorer prognosis. Existing studies mirror that lncRNA GAS5 promises to be a novel diagnostic biomarker, therapy target, as well as prognostic biomarker. In this review, we will summarize the current knowledge about this vital lncRNA, from its discovery, characteristics, and biological function to molecular mechanism in various neoplasms.


Landholder typologies illuminate pathways for social change in a deforestation hotspot.
Psychosocial factors determine individual and collective behaviours, and there is growing evidence of their influence on land management behaviours. Native vegetation management encompasses biophysical, economic, political, and cultural dimensions that are immensely complex, and a more thorough understanding of the personal and cultural dimensions of deforestation activity is required. We emphasise this interdisciplinary imperative using Queensland, Australia, as an exemplar case study, where the controversial Vegetation Management Act1999 has been met with significant scrutiny over its effects on private landholders and its ability to curb deforestation behaviours. We surveyed landholders across Queensland in order to identify different landholder typologies based upon (1) their recent tree clearing behaviours and (2) their psychosocial characteristics, mapped their distribution in the landscape, and determined the unique demographic and psychosocial factors associated with typology membership. We identified a heterogeneous mosaic of landholders in the clearing landscape, composed of four clearing typologies and five psychosocial typologies. Social norms, identity, trust, and security played crucial roles in distinguishing different types of landholders. The two most contrasting clearing typologies-active and inactive clearers-were primarily located in hot- and cold-spots of deforestation, respectively; in contrast, most psychosocial typologies could be found throughout the landscape, highlighting the potential benefit of complementing generalised state-wide psychosocial targets with localised behavioural targets. We discuss how conservation policy instruments can be regionally tailored, and relevant strategies for effective communication and engagement can be developed to create behaviour change by understanding the characteristics and distribution of these types of landholders. If modified top-down efforts (e.g. strategic messages, community-based communication) can be supplemented with more bottom-up approaches (e.g. collective learning, building network support), sustainable land management in deforestation hotspots around the world may be achievable.


STING promotes ferroptosis through NCOA4-dependent ferritinophagy in acute kidney injury.
Ferroptosis in tubules has been implicated in the pathogenesis of acute kidney injury (AKI), whereas the regulatory mechanism remains unclear. The stimulator of interferon genes (STING) is previously recognized as a critical mediator of innate immunity via a DNA-sensing pathway and has been increasingly linked to lipid peroxidation, a hallmark of ferroptosis. Herein we investigated the role and the underlying mechanism of STING in AKI models established by ischemia/reperfusion (IR) in C57BL mice. The expression level of STING was predominantly increased in tubules of kidney after IR treatment. Besides, STING deficiency markedly alleviated IR-induced lipid peroxidation, tissue damage and renal dysfunction. Consistently, in vitro experiments demonstrated that the increase in ferroptotic cell death, lipid ROS production and the decrease in GSH peroxidase 4 (GPX4) expression in renal tubular cells subjected to ferroptosis agonist or hypoxia/reoxygenation intervention were all mitigated by genetic deficiency or pharmacological inhibition of STING, while all exacerbated by STING overexpression. Further, these detrimental effects of STING overexpression relied on the induction of ferritinophagy, i.e. autophagic degradation of ferritin, leading to iron overload. Mechanistically, STING mediated the initiation of ferritinophagy through interacting with nuclear receptor coactivator 4 (NCOA4), a fundamental receptor for the transfer of ferritin into lysosome. Collectively, STING contributes to ferroptosis during ischemic AKI through facilitating NCOA4-mediated ferritinophagy and shows the potential as a promising therapeutic choice for AKI.


Demographic and clinical determinants of the quality of life in adults with inherited and acquired myopathies.
Measuring health-related quality of life (QOL) is vital for understanding the disease impact, but the complex relationship between clinical parameters and QOL remains unclear. The objective was to determine the demographic and clinical factors that influence the QOL in adults with inherited and acquired myopathies. The study was of cross-sectional design. Detailed demographic and clinical details were collected. Patients answered Neuro-QOL and Patient-Reported Outcomes Measurement Information System short-form questionnaires. Data was collected from 100 consecutive in-person patient visits. Mean age of the cohort was 49.5 ± 20.1 (18-85) years, and the majority were male (53, 53%). Bivariate analysis between the various demographic and clinical features with the QOL scales revealed single simple question (SSQ), handgrip strength, Medical Research Council (MRC) sum score, female gender, and age to be nonuniformly associated with the QOL scales. There was no difference between inherited and acquired myopathies for any of the QOL scores, except for the poorer lower limb function domain in inherited myopathies (36.7 ± 7.3 vs. 40.9 ± 11.2, p = 0.049). Linear regression models revealed lower SSQ, lower handgrip strength, and lower MRC sum score to independently predict poor QOL. Handgrip strength and SSQ serve as novel predictors of QOL in myopathies. Handgrip strength has a significant impact on physical, mental, and social domains and deserves special attention with respect to rehabilitation. SSQ correlates well with QOL and can be employed as a quick and global assessment of a patient's well-being. Differences in QOL scores between patients with inherited and acquired myopathies were minimal.


Measuring local context as context-word probabilities.
Context enables readers to quickly recognize a related word but disturbs recognition of unrelated words. The relatedness of a final word to a sentence context has been estimated as the probability (cloze probability) that a participant will complete a sentence with a word. In four studies, I show that it is possible to estimate local context-word relatedness based on common language usage. Conditional probabilities were calculated for sentences with published cloze probabilities. Four-word contexts produced conditional probabilities significantly correlated with cloze probabilities, but usage statistics were unavailable for some sentence contexts. The present studies demonstrate that a composite context measure based on conditional probabilities for one- to four-word contexts and the presence of a final period represents all of the sentences and maintains significant correlations (.25, .52, .53) with cloze probabilities. Finally, the article provides evidence for the effectiveness of this measure by showing that local context varies in ways that are similar to the N400 effect and that are consistent with a role for local context in reading. The Supplemental materials include local context measures for three cloze probability data sets.


Synthesis of novel N-diazeniumdiolates based on hyperbranched polyethers.
Novel N-diazeniumdiolate based on hyperbranched polyethers(HP-g-DACA/N(2)O(2)) were prepared through a two-step synthesized route. The alkyltrimethoxysilane containing secondary amine groups (DACA) was used to modify the hydroxyl end groups of hyperbranched polyethers (HP) to obtain the precursor hyperbranched diamine (HP-g-DACA). Then HP-g-DACA was reacted with NO at 80psi pressure to be converted into N-diazeniumdiolates. The structures were confirmed using (13)C NMR and IR spectra. UV-vis spectroscopy measurement indicated that the aqueous solution of obtained HP-g-DACA/N(2)O(2) had a characteristic absorption at 246nm. The final HP-g-DACA/N(2)O(2) product showed NO releasing within the prolonged periods of time, and the apparent half-life t(1/2) was more than 11min in phosphate buffer at 37 degrees C. The total amount of NO released from HP-g-DACA/N(2)O(2) could achieve to 0.43micromol/mg and was proportional to the modified degree of HP by DACA. In addition, the NO loading efficiency can be modulated by the modification degree of hyperbranched macromolecular end groups.


Structural abnormalities of the right inferior colliculus in schizophrenia.
Although structural and functional neuroimaging studies of schizophrenia have suggested that impaired connectivity in the extensive network of cortical and subcortical areas is involved in its pathophysiology, there were no studies have investigated the structural integrity of the lower sensory brain areas including the inferior (IC) and the superior (SC) colliculus. The IC plays an important role in mediating auditory gating processes and inhibitory neural transmission, while the SC is a key structure in a distributed network mediating saccadic eye movements and shifts of attention, both of which have been linked to the pathophysiology of schizophrenia. We compared the morphologies of the IC and SC, which are involved in the early stage processing of visual and auditory stimuli, in patients with schizophrenia (N=28) and healthy controls (N=34) using high-resolution magnetic resonance imaging. Subjects with schizophrenia had a significantly smaller right IC, compared with controls. The reduced IC volume suggests that a structural abnormality of the IC in patients with schizophrenia may be involved in the auditory cognitive dysfunction of schizophrenia.


Carcinoma of the colon presenting with dyspepsia.
Three patients with upper abdominal symptoms responding to anti-ulcer medication are reported who had negative upper gastrointestinal endoscopies. Subsequent barium enemas showed that each of the patients had either a carcinoma of the transverse colon or caecum. Investigation of the colon should be considered in all such cases.


Incidence and predictors of osteoporotic fractures in patients with Barrett's oesophagus: a population-based nested case-control study.
Proton pump inhibitors (PPI) are inconsistently associated with osteoporotic fractures. Barrett's oesophagus (BO) patients are treated with high PPI doses for prolonged periods, but there are limited data on the incidence of osteoporosis and fractures in this group pf patients. To estimate the incidence of (and risk factors for) low bone mass (osteoporosis and/or osteopenia) related fractures in a population-based BO cohort. All subjects with BO and a diagnosis of osteoporosis and fractures were identified using Rochester Epidemiology Project resources. The incidence rates of all and osteoporotic fractures in these subjects were compared to an age- and gender similar population in Olmsted County to determine standardised incidence ratios (SIR). Predictors were assessed using Cox proportional hazards models. Five hundred and twenty-one patients were included (median [IQR] age 61 [52, 72] years; 398 [76%] men) of whom 113 (21.7%) had fractures, and 46 (8.8%) had osteoporotic fractures. The incidence of all fractures and osteoporotic fractures was comparable to that of an age- and gender-matched population (SIR 1.09; 95% CI 0.92-1.29: SIR 1.05; 95% CI 0.85-1.29). PPI use, dose or duration of use was not associated with osteoporotic fracture risk (HR 0.87; 95% CI 0.12-6.39). Independent risk factors for osteoporotic fractures included older age, female gender and higher co-morbidity index. The incidence of osteoporotic fractures was not increased in BO patients compared to the general population. In addition, PPI use was not associated with increased fracture risk regardless of the duration of therapy or dose.


Antibody signatures in inflammatory bowel disease: current developments and future applications.
Adequate functioning of the intestinal barrier is required in order to repel invading pathogens while tolerating commensal microbiota and self-antigens. Inflammatory bowel diseases (IBDs), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are characterized by disrupted intestinal barrier integrity, resulting in excessive passage of luminal antigens and the activation of aberrant immune responses against otherwise unexposed antigens. A comprehensive overview of the exact antigens associated with IBD is still lacking, but recent innovative antibody profiling technologies have enabled systematic characterization of humoral immunity in health and disease. Here, we review established serological antibodies and novel high-throughput methods, such as protein arrays, phage-display immunoprecipitation sequencing (PhIP-Seq), and B cell receptor sequencing (BCRseq), and provide an outlook on their applications in disease diagnostics, therapeutic interventions, and opportunities for prevention in IBD.


Comparison of echocardiographic methods with magnetic resonance imaging for assessment of right ventricular function in children.
Assessment of right ventricular (RV) function is clinically relevant in the follow-up of various forms of congenital heart disease. Agreement on the value of different echocardiographic approaches for this purpose is lacking. Magnetic resonance imaging (MRI) provides dimensionally accurate RV volumes and ejection fraction. Transthoracic 2-dimensional echocardiography from 3 different views and gradient-echo tomographic MRI were performed in 16 children with congenital heart disease and 17 age-matched healthy children. RV volumes and ejection fraction were calculated with 5 mono- and biplane area-length and multiple-slice echocardiographic methods. Adequate MRI and echocardiographic apical 4-chamber images could be obtained in all 33 children. The best correlation between MRI and echocardiographic volumes was with the biplane pyramidal approximation method. End-diastolic volume by MRI was 92 +/- 27 ml: systematic difference with echocardiography was +14 +/- 16 ml (r = 0.86). End-systolic volume by MRI was 33 +/- 13 ml: systematic difference with echocardiography was -4 +/- 7 ml (r = 0.82). Ejection fraction by MRI was 65 +/- 8%: systematic difference with echocardiography was +5 +/- 7% (r = 0.72), using monoplane ellipsoid approximation. For all echocardiographic methods, significant effects of RV geometry were noted. Echocardiographic mono- and biplane area-length and multiple-slice calculations demonstrated moderate correlation and significant systematic errors compared with MRI-derived RV volumes. Echocardiographic results were influenced by RV geometry. The relatively simple monoplane area-length method provides ejection fraction results acceptable for clinical practice; results are not improved by more complex biplane and/or multislice methods.


DNase based therapeutic approaches for the treatment of NETosis related inflammatory diseases.
Neutrophils are the primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils limit pathogen transmission is NETosis, which includes releasing the nuclear content into the cytosol by forming pores in the plasma membrane. The extrusion of cellular deoxyribonucleic acid (DNA) results in neutrophil extracellular traps (NETs) composed of nuclear DNA associated with histones and granule proteins. NETosis is driven by the enzyme PAD-4 (Peptidylarginine deiminase-4), which converts arginine into citrulline, leading to decondensation of chromatin, separation of DNA, and eventual extrusion. DNase is responsible for the breakdown of NETs. On the one hand, the release of DNase may interfere with the antibacterial effects of NETs; further, DNase may protect tissues from self-destruction caused by the increased release of NET under septic conditions. NETs in physiological quantities are expected to have a role in anti-infectious innate immune responses. In contrast, abnormally high concentrations of NETs in the body that are not adequately cleared by DNases can damage tissues and cause inflammation. Through several novel approaches, it is now possible to avoid the adverse effects caused by the continued release of NETs into the extracellular environment. In this review we have highlighted the basic mechanisms of NETosis, its significance in the pathogenesis of various inflammatory disorders, and the role of DNase enzyme with a focus on the possible function of nanotechnology in its management.


Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells.
Recent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR inhibitors VE822 and AZD6738, by abrogating the G2 checkpoint, increase cGAS-mediated type I IFN response after irradiation in human lung cancer and osteosarcoma cell lines. Supporting that the checkpoint may prevent IFN induction, radiation-induced IFN signaling declined when the G2 checkpoint arrest was prolonged at high radiation doses. G2 checkpoint abrogation after co-treatment with radiation and ATR inhibitors was accompanied by increased radiation-induced IFN signaling in four out of five cell lines tested. Consistent with the hypothesis that the cytosolic DNA sensor cGAS may detect DNA from ruptured micronuclei after G2 checkpoint abrogation, cGAS co-localized with micronuclei, and depletion of cGAS or STING abolished the IFN responses. Contrastingly, one lung cancer cell line showed no increase in IFN signaling despite irradiation and G2 checkpoint abrogation. This cell line showed a higher level of the exonuclease TREX1 than the other cell lines, but TREX1 depletion did not enhance IFN signaling. Rather, addition of a pan-caspase inhibitor restored the IFN response in this cell line and also increased the responses in the other cell lines. These results show that treatment-induced caspase activation can suppress the IFN response after co-treatment with radiation and ATR inhibitors. Caspase activation thus warrants further consideration as a possible predictive marker for lack of IFN signaling.


Eosinophilic otitis media: a new middle ear disease entity.
Eosinophilic otitis media (EOM) is intractable otitis media characterized by the presence of a highly viscous yellow effusion containing eosinophils. It occurs mainly in patients with bronchial asthma and is resistant to conventional treatments for otitis media. Here we discuss the clinical features, pathogenesis, and management of EOM. EOM predominantly affects women and presents most often in patients in their 50s. The clinical features of the middle ear in EOM are roughly divided into the otitis media with effusion type and chronic otitis media type. The latter is further divided into two subtypes: simple perforation and granulation tissue formation. EOM is often complicated by rhinosinusitis (eosinophilic sinusitis). High-tone loss is more frequently found and more severe in EOM patients than in chronic otitis media control patients, and EOM patients sometimes become deaf suddenly. Systemic or topical steroid administration is the most effective treatment for patients with EOM. The instillation of triamcinolone acetonide, a suspension of steroids, into the middle ear is very effective for controlling eosinophilic inflammation. It is very important to explain to patients with EOM that the disease may last for a long period and that progressive and sudden hearing loss may occur.


Does psychosocial intervention improve survival in cancer? A meta-analysis.
There is growing evidence that positive psychosocial intervention improves the wellbeing of cancer patients. Two meta-analyses conducted to date confirmed a significant small-to-moderate effect on quality of life. Previous randomized trials reported that psychosocial intervention also improved survival. However, more recent trials failed to detect a difference in survival. A systematic review of randomized trials that have examined the effectiveness of psychosocial intervention in cancer patients in terms of survival prolongation was conducted. Randomized trials published between 1966 and June 2002 were identified through the databases of MEDLINE, EMBASE, CancerLit, CINAHL, Cochrane Library and reference lists of relevant articles. Relevant data were abstracted. The results of randomized trials were pooled using meta-analyses to estimate the effect of treatment on overall survival at one and four years in all cancer patients and also in breast cancer patients with metastases. Eight trials, which involved a total of 1062 patients (all cancer histologies), were identified. One- and four-year overall survival rates were obtained from eight trials and six trials, respectively. There was no statistically significant difference in the overall survival rates at one and four years [P = 0.6; RR 0.94 (95% CI 0.72, 1.22)] and [P = 0.5; RR 0.93 (95% CI 0.77, 1.13)], respectively. Four trials examined 511 metastatic breast cancer patients. Again, there was no statistically significant difference in the overall survival rates at one and four years [P = 0.3; RR 0.87 (95% CI 0.67, 1.14)] and [P = 0.3; RR 0.91 (95% CI 0.76, 1.10)], respectively. Psychosocial intervention does not prolong survival in cancer. This meta-analysis can not rule out small effect sizes because of the small number of trials and small trial sizes.


Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the Diabetic Retinopathy Screening Service for Wales: retrospective analysis.
To determine the incidence of any and referable diabetic retinopathy in people with type 2 diabetes mellitus attending an annual screening service for retinopathy and whose first screening episode indicated no evidence of retinopathy. Retrospective four year analysis. Screenings at the community based Diabetic Retinopathy Screening Service for Wales, United Kingdom. 57,199 people with type 2 diabetes mellitus, who were diagnosed at age 30 years or older and who had no evidence of diabetic retinopathy at their first screening event between 2005 and 2009. 49,763 (87%) had at least one further screening event within the study period and were included in the analysis. Annual incidence and cumulative incidence after four years of any and referable diabetic retinopathy. Relations between available putative risk factors and the onset and progression of retinopathy. Cumulative incidence of any and referable retinopathy at four years was 360.27 and 11.64 per 1000 people, respectively. From the first to fourth year, the annual incidence of any retinopathy fell from 124.94 to 66.59 per 1000 people, compared with referable retinopathy, which increased slightly from 2.02 to 3.54 per 1000 people. Incidence of referable retinopathy was independently associated with known duration of diabetes, age at diagnosis, and use of insulin treatment. For participants needing insulin treatment with a duration of diabetes of 10 years or more, cumulative incidence of referable retinopathy at one and four years was 9.61 and 30.99 per 1000 people, respectively. Our analysis supports the extension of the screening interval for people with type 2 diabetes mellitus beyond the currently recommended 12 months, with the possible exception of those with diabetes duration of 10 years or more and on insulin treatment.


Screening bioactivities of Caesalpinia pulcherrima L. swartz and cytotoxicity of extract synthesized silver nanoparticles on HCT116 cell line.
The extract of Caesalpinia pulcherrima (C. pulcherrima) is one of the common herbal drugs which have a key role in treating pyretic, microbial infections, cancer and for several other traditional systems of treatment. In our present work, we demonstrate the bioactivities of extracts and cytotoxicity of synthesized silver nanoparticles on HCT116 cell line. The qualitative phytochemical tests indicated the presence of some adequately required metabolites as follows; the total phenolic content in the aqueous extract contains a higher amount of phenolic compounds (815 ± 0.013 μgmg-1). The DPPH quenching activity of the aqueous extract showed an IC50 value of 18.7 μg which was equivalent to the IC50 value of ascorbic acid (15 μg) and methanolic extract (51 μg). The test extracts showed 4.6% haemolytic activity that attributes to its protective and non-toxic nature. The zone of inhibition of aqueous extract shown against the growth of E.coli was 25 mm. Further, silver nanoparticles synthesis was carried out with the extract and was characterized by X-ray diffraction, particle size analyzer, zeta potential, TEM- EDAX and UV spectroscopy. XRD analysis indicated the crystalline nature of silver nanoparticles with a face-centered cubic structure. The data obtained from the particle size analyzer demonstrated as 155.4 nm of the size of the synthesized silver nanoparticles. The values of zeta potential (-23.4 mV) revealed that the nanoparticles were extremely stable in colloidal form. SEM indicated the spherical shape of silver nanoparticles with the size range between 177.9 nm to 251.1 nm. Beside the efficient bioactivities, the synthesized C. pulcherrima silver nanoparticles showed significant cytotoxicity effect of 77.5% on a human colon cancer cell line. Therefore, along with antioxidant, antibacterial, haemolytic activity; C. pulcherrima also accomplished satisfactory cytotoxic property in anticancer mechanism as proven by this study.


Current advances in immune checkpoint inhibitor combinations with radiation therapy or cryotherapy for breast cancer.
Immune checkpoint inhibition (ICI) has demonstrated clinically significant efficacy when combined with chemotherapy in triple negative breast cancer (TNBC). Although many patients derived benefit, others do not respond to immunotherapy, therefore relying upon innovative combinations to enhance response. Local therapies such as radiation therapy (RT) and cryotherapy are immunogenic and potentially optimize responses to immunotherapy. Strategies combining these therapies and ICI are actively under investigation. This review will describe the rationale for combining ICI with targeted local therapies in breast cancer. A literature search was performed to identify pre-clinical and clinical studies assessing ICI combined with RT or cryotherapy published as of August 2021 using PubMed and ClinicalTrials.gov. Published studies of ICI with RT and IPI have demonstrated safety and signals of early efficacy. RT and cryotherapy are local therapies that can be integrated safely with ICI and has shown promise in early trials. Randomized phase II studies testing both of these approaches, such as P-RAD (NCT04443348) and ipilimumab/nivolumab/cryoablation for TNBC (NCT03546686) are current enrolling. The results of these studies are paramount as they will provide long term data on the safety and efficacy of these regimens.


Concentration-controlled use of sirolimus associated with reduced exposure of cyclosporine in black recipients of primarily living renal allograft donors: 12-month results.
This study was designed to identify optimal therapeutic sirolimus (SRL) concentrations in black kidney transplant recipients on reduced cyclosporine (CsA) exposure and prednisone. Seventy patients (64 living/six deceased) received CsA (8-10 mg/kg/d), prednisone, and 15 mg loading dose followed by 5-mg fixed doses of SRL till day 7 when they were randomized to maintain SRL trough concentrations (high-performance liquid chromatography) of 8-12 (GI = 34) or 15-20 (GII = 36) ng/mL. Mean CsA concentrations were 109 +/- 53 vs. 89 +/- 41 ng/mL and 75 +/- 54 vs. 60 +/- 35 ng/mL (ns) at 2 and 6 months. Accordingly, mean SRL trough concentrations were 12.4 +/- 6.1 vs. 20.0 +/- 9.5 ng/mL (p < 0.001) and 10.8 +/- 5.8 vs. 18.0 +/- 6.1 ng/mL (p < 0.001). The incidence of biopsy-proven acute rejection [13% (GI: 18% vs. GII: 8%, ns)], graft loss or death was 16% (GI: 21% vs. GII: 11%, ns]. There were no deaths and three graft losses (GI = 1; GII = 2). Creatinine clearance was higher in GI (64.5 +/- 17 vs. 54.4 +/- 14.7 mL/min, p = 0.011). The incidence of post-transplant diabetes mellitus was 13% and no CMV disease was observed. In black recipients of primarily living renal allograft donors reduced CsA exposure and SRL concentration-controlled regimens produced low incidences of acute rejection, post-transplant diabetes mellitus and CMV disease, with no significant impairment in graft function.


Histopathology of eye, optic nerve and brain in a case of dominant optic atrophy.
Histopathology of eye, optic nerve and brain was performed in a patient with typical signs and symptoms of dominant optic atrophy. He belonged to a previously-reported family of 152 members in which optic atrophy was demonstrable in 14 persons, and probably present in a further 8 cases. In the eyes, fibrosis of the retinal ganglion cell layer and disc was found. Ultrastructural examination showed a few remaining cells in this layer, heavy fibrosis and in particular a highly condensed inner limiting membrane. The optic nerves, the optic chiasm and optic tracts showed an increased content of collagen tissue and a decreased number of neurofibrils and myelin sheaths. In the lateral geniculate body there was massive loss of ganglion cells, fibrillary gliosis and a great quantity of fine granular lipid in the cytoplasm of the ganglion cells. No changes in the calcarine cortex were observed. Examination of the intracranial part of both vestibulocochlear nerves showed a decreased number of neurofibrils and myelin sheaths. It is concluded that the histopathological changes of the visual system are similar to those in Leber's disease, but less pronounced. The study confirms earlier theories that dominant optic atrophy is a primary degeneration of the ganglion cell layer in the retina, with ascending optic atrophy.


Cases from the aerospace medicine residents' teaching file. Case #22. An air traffic controller with syncope and accelerated idioventricular rhythm.
An 18-year-old air traffic controller fainted while running; an asymptomatic accelerated idioventricular rhythm was discovered in the ensuing aeromedical workup. The clinical presentation, ECG diagnosis, and aeromedical disposition of accelerated idioventricular rhythm are discussed.


The nucleotide sequence of the transforming HpaI-E fragment of adenovirus type 5 DNA.
The primary structure of the HpaI-E fragment of adenovirus type 5 (Ad5) DNA has been determined, mainly by the method of Maxam and Gilbert (1977). This fragment comprises the leftmost 4.5% of the Ad5 genome, and has been shown to be the shortest DNA fragment capable of transforming cells. The identification of potential initiation and termination codons in the determined sequence indicates that two small polypeptides consisting of 186, and 81 amino acids, respectively, could be synthesized. Taking into account recent data on RNA splicing, a possibility is considered that this DNA may code also for larger polypeptides.


Liver haemorrhage in haemophilia--a case report and review of the literature.
We present two patients with severe haemophilia A, who presented with haemorrhagic shock, secondary to a liver haematoma in the neonatal period. Both required emergency treatment and diagnosis of the hereditary coagulation defect. Major organ bleeding in severe haemophilia A in the newborn period is rare, and this unusual complication is not well recognized. Failure to recognize that the bleeding is due to a bleeding disorder, particularly in the absence of a family history, may lead to delay in appropriate management.


Ulnar nerve injuries in Guyon canal: a report of 32 cases.
In this study, the surgical outcomes of 32 patients with ulnar nerve injuries in the Guyon canal are presented. Outcomes were analyzed in relation to various factors such as age, surgical timing, zone of injury, and type of nerve reconstruction. Between 1990 and 2007, 32 patients with injury in Guyon canal were managed surgically. Twelve patients had ulnar nerve injury proximal to its bifurcation (zone I); 14 patients had isolated motor branch injury (zone II); and six patients had isolated sensory branch injury (zone III). End-to-end repair was achieved in 12 (38%) of 32 patients, while nerve grafting was performed in 20 (62%) cases. The mean follow-up period was 22 months. Good and excellent motor function was restored in 25 (96%) of 26 cases with motor branch injury. Good and excellent sensory results were achieved in 15 (83%) of 18 cases with sensory branch injury. Outcomes were significantly better for those who had early repair (<4 weeks) when compared with those who had repair 4 weeks after injury (P < 0.05). There were no significant differences between outcomes after end-to-end repair or nerve grafting (P > 0.05) and between outcomes from repair of injuries in different zone (P > 0.05). Early diagnosis and surgical treatment with careful dissection of the ulnar nerve branches within the canal is very important. Adequate exposure is usually required to repair the nerve in the Guyon canal. Nerve grafting in this level could give analogous results as the end-to-end repair.


Toward an understanding of the physiological function of Mammalian stem cells.
Stem cell biology has the potential to yield new therapies, new insights into disease, and a clearer understanding of tissue formation and maintenance. However, much of what we know about many stem cells is based upon experiments performed in culture. Stem cells sometimes exhibit critical differences in their properties or regulation between the culture and in vivo environments. Though cell lines with stem cell properties can be derived from the long-term culture of diverse tissues, it is not clear whether cells with similar properties exist in vivo. If the goal is to use differentiated cells for therapy or drug screening, it may not matter whether these stem cells exist in vivo. However, to understand tissue development/maintenance or the role of stem cells in disease, it is important to characterize progenitor function in vivo to evaluate physiological significance.


Assessment the flavor of soybean meal hydrolyzed with Alcalase enzyme under different hydrolysis conditions by E-nose, E-tongue and HS-SPME-GC-MS.
In the present study, E-nose, E-tongue, and headspace-solid phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) technology combined with Principal Component Analysis (PCA) were employed to evaluate the flavor characteristics of the volatile and the non-volatile substances generated during the enzymatic hydrolysis of the soybean meal by Alcalase. The results showed that the enzymatic hydrolysis effectively reduced the content of soybean odorous substance 1-octene-3-ol and led to better flavor. However, the excessive enzymatic hydrolysis resulted in the deterioration of the enzymatic hydrolysates flavor. In addition, both radar graph and PCA of E-tongue were able to provide the distribution of flavor substances during the enzymatic hydrolysis of the soybean meal. These results provided a theoretical basis for the improvement of the flavors of the soybean meal and its derived products.


Accuracy and resolution of in vitro imaging based porcine lens volumetric measurements.
There is considerable interest in determining lens volume in the living eye. Lens volume is of interest to understand accommodative changes in the lens and to size accommodative IOLs (A-IOLs) to fit the capsular bag. Some studies have suggested lens volume change during accommodation. Magnetic Resonance Imaging (MRI) is the only method available to determine lens volume in vivo. MRI is, by its nature, relatively low in temporal and spatial resolution. Therefore analysis often requires determining lens volume from single image slices with relatively low resolution on which only simple image analysis methods can be used and without repeated measures. In this study, 7 T MRI scans encompassing the full lens volume were performed on 19 enucleated pig eyes. The eyes were then dissected to isolate and photograph the lens in profile and the lens volumes were measured empirically using a fluid displacement method. Lens volumes were calculated from two- and three-dimensional (2D and 3D) MR and 2D photographic profile images of the isolated lenses using several different analysis methods. Image based and actual measured lens volumes were compared. The average image-based volume of all lenses varied from the average measured volume of all lenses by 0.6%-6.4% depending on the image analysis method. Image analysis methods that use gradient based edge detection showed higher precision with actual volumes (r(2): 0.957-0.990), while threshold based segmentation had poorer correlations (r(2): 0.759-0.828). The root-mean-square (RMS) difference between image analysis based volumes and fluid displacement measured volumes ranged from 8.51 μl to 25.79 μl. This provides an estimate of the error of previously published methods used to calculate lens volume. Immobilized, enucleated porcine eyes permit improved MR image resolution relative to living eyes and therefore improved image analysis methods to calculate lens volume. The results show that some of the accommodative changes in lens volume reported in the literature are likely below the resolution limits of imaging methods used. MRI, even with detailed image analysis methods used here, is unlikely to achieve the resolution required to accurately size an A-IOL to the capsular bag.


Impaired-driving recidivism among repeat offenders following an intensive court-based intervention.
Repeat impaired-drivers resist successful rehabilitation. This paper describes and evaluates an innovative court-based intervention for repeat impaired-driving offenders, the driving under the influence (DUI) Intensive Supervision Program (DISP) developed in Multnomah County, Oregon. The hazard of re-offending was compared between DISP participants (N=460) and a comparison group (N=497). The stratified Cox proportional hazards model was used to model the hazard of re-offense, adjusting for matching criteria and stratified by county of residence. Adjusted hazard of DUI re-offense for DISP participants was 0.52 that of comparison offenders (95% CI=0.36-0.76). DISP clients also had lower arrest rates for driving while revoked/suspended and for all other traffic offenses. Preliminary results suggest the DISP is an effective means of reducing recidivism among repeat impaired-driving offenders.


Development of a Stromal Microenvironment Experimental Model Containing Proto-Myofibroblast Like Cells and Analysis of Its Crosstalk with Melanoma Cells: A New Tool to Potentiate and Stabilize Tumor Suppressor Phenotype of Dermal Myofibroblasts.
Melanoma is one of the most aggressive solid tumors and includes a stromal microenvironment that regulates cancer growth and progression. The components of stromal microenvironment such as fibroblasts, fibroblast aggregates and cancer-associated fibroblasts (CAFs) can differently influence the melanoma growth during its distinct stages. In this work, we have developed and studied a stromal microenvironment model, represented by fibroblasts, proto-myofibroblasts, myofibroblasts and aggregates of inactivated myofibroblasts, such as spheroids. In particular, we have generated proto-myofibroblasts from primary cutaneous myofibroblasts. The phenotype of proto-myofibroblasts is characterized by a dramatic reduction of α-smooth muscle actin (α-SMA) and cyclooxygenase-2 (COX-2) protein levels, as well as an enhancement of cell viability and migratory capability compared with myofibroblasts. Furthermore, proto-myofibroblasts display the mesenchymal marker vimentin and less developed stress fibers, with respect to myofibroblasts. The analysis of crosstalk between the stromal microenvironment and A375 or A2058 melanoma cells has shown that the conditioned medium of proto-myofibroblasts is cytotoxic, mainly for A2058 cells, and dramatically reduces the migratory capability of both cell lines compared with the melanoma-control conditioned medium. An array analysis of proto-myofibroblast and melanoma cell-conditioned media suggests that lower levels of some cytokines and growth factors in the conditioned medium of proto-myofibroblasts could be associated with their anti-tumor activity. Conversely, the conditioned media of melanoma cells do not influence the cell viability, outgrowth, and migration of proto-myofibroblasts from spheroids. Interestingly, the conditioned medium of proto-myofibroblasts does not alter the cell viability of both BJ-5ta fibroblast cells and myofibroblasts. Hence, proto-myofibroblasts could be useful in the study of new therapeutic strategies targeting melanoma.


Peripheral blood inflammatory markers in predicting prognosis in patients with COVID-19. Some differences with influenza A.
To evaluate the ability of peripheral blood inflammatory markers in predicating the typing of COVID-19, prognosis, and some differences between COVID-19 and influenza A patients. Clinical data on 285 cases laboratory-confirmed as SARS-CoV-2 infection were obtained from a Wuhan local hospital's electronic medical records according to previously designed standardized data collection forms. Additional 446 Influenza A outpatients' hematologic data were enrolled for comparison. NLR, SII, RLR, PLR, HsCRP, and IL-6 were significant higher and LMR was lower in severe COVID-19 patients than in mild COVID-19 patients (p < .001). PLR and LMR were lower in the individuals with influenza A than those with COVID-19 (p < .01). COVID-19 patients with higher levels of NLR, SII, RLR, PLR, HsCRP, and IL-6 and lower LMR were significantly associated with the severe type. AUC of NLR (0.76) was larger while the specificity of IL-6 (86%) and sensitivity of HsCRP (89%) were higher than other inflammatory markers in predicating the typing of COVID-19. PT had obvious correlation with all the inflammatory markers except RPR. NLR showed positive correlations with AST, TP, BUN, CREA, PT, and D-dimer. Patients with high IL-6 levels have a relatively worse prognosis (HR = 2.30). Peripheral blood inflammatory markers reflected the intensity of inflammation and associated with severity of COVID-19.NLR was more useful to predict severity as well as IL-6 to predict prognosis of COVID-19. PLR and LMR were initially found to be higher in SARS-CoV-2 virus-infected group than in influenza A.


Pregnancy Complicated by the Most Frequent Forms of Maturity Onset Diabetes of the Young: A Narrative Review on Its Pharmacological Implications.
Monogenic Diabetes (MFD) represents close to 2% of all the cases of diabetes diagnosed in people younger than 45 years old. Maturity-Onset Diabetes of the Young (MODY), neonatal diabetes, and several syndromic forms of diabetes are included among the most accounts for about typical forms of MDF. MODY is the most frequent type of MFD, with MODY 1, 2, 3, and 5 being the most prevalent forms. The aim of this narrative review is to describe pregnancy associated changes in the pharmacological profile of the antidiabetic drugs used in women with the most frequent MODY subtypes. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/ PubMed, EMBASE, and SCIELO databases from 1970 to 2019 first semester. Pregnancy introduces changes in the pharmacodynamic and pharmacokinetic profile of some of the treatments used in MODY. MODY 3 (also known as HNF1-A MODY) is the most frequent MDF. MODY 3 patients are highly sensitive to Sulfonylureas (SU). This is also the case for MODY pregnant women. This high sensitivity to SU is also registered in patients with MODY 1 (HNF4-A MODY). Pharmacodynamic changes have been proposed to explain this behavior (Epac2 hyperactivity). However, changes in expression/activity of the metabolizing CYP2C9 cytochrome and/or alterations in the drug transporters oatp1 (Slc21a1), Lst-1 (Slc21a6), OATPD (SLC21A11), and oat2 may better explain, at least in part, this phenomenon by an increase in the concentration of the active drug. The impact of changes in the pharmacological behavior of drugs like SU and other metabolized/transported by mechanisms altered in a pregnancy complicated by MODY is unknown. However, switching-to-insulin recommendation formulated for MODY 1 and 3 seems to be justified. Further research in this field is needed for a better understanding of changes in drug activity associated with this particular subset of patients with MFD.


Transcriptional regulation of puc operon expression in Rhodobacter sphaeroides. Analysis of the cis-acting downstream regulatory sequence.
Both site-directed and spontaneous mutagenesis have been used to investigate the role of the cis-acting regulatory region between -92 and -1 base pair (bp) of the puc operon of Rhodobacter sphaeroides. The DNA sequence from -84 to -66 bp upstream of the 5' end of the start site of puc operon transcription is essential for normal puc operon expression. This regulatory effect was exerted irrespective of the presence or absence of additional upstream regulatory sequences extending from -629 to -93 bp. It is likely that this region is involved in activator binding. Additionally, two regions of dyad symmetry centered at -42 and -17 bp are shown to be involved in oxygen repression of puc operon expression. Mutations within these regions of dyad symmetry were further subdivided on the basis of whether or not the upstream regulatory region was required to observe the mutant phenotype. Based upon these observations we conclude that these regions of dyad symmetry possessing the motif TGT-N12-ACA (where N represents any nucleotide) are involved in repressor binding with the puc operon promoter overlapping each of these dyad symmetries.


Self-transcendence trait and its relationship with in vivo serotonin transporter availability in brainstem raphe nuclei: An ultra-high resolution PET-MRI study.
Self-transcendence is an inherent human personality trait relating to the experience of spiritual aspects of the self. We examined the relationship between self-transcendence and serotonin transporter (SERT) availability in brainstem raphe nuclei, which are collections of five different serotonergic nuclei with rostro-caudal extension, using ultra-high resolution magnetic resonance imaging (MRI) and positron emission tomography (PET) with (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([(11)C]DASB) to elucidate potential roles of serotonergic neuronal activities in this personality trait. Sixteen healthy subjects completed 7.0T MRI and High Resolution Research Tomograph (HRRT) PET. The regions of interest (ROIs) included the dorsal raphe nucleus (R1), median raphe nucleus (R2), raphe pontis (R3), and the caudal raphe nuclei (R4 and R5). For the estimation of SERT availability, the binding potential (BPND) was derived using the simplified reference tissue model (SRTM2). The Temperament and Character Inventory was used to measure self-transcendence. The analysis revealed that the self-transcendence total score had a significant negative correlation with the [(11)C]DASB BPND in the caudal raphe (R5). The subscale score for spiritual acceptance was significantly negatively correlated with the [(11)C]DASB BPND in the median raphe nucleus (R2). The results indicate that the self-transcendence trait is associated with SERT availability in specific raphe subnuclei, suggesting that the serotonin system may serve as an important biological basis for human self-transcendence. Based on the connections of these nuclei with cortico-limbic and visceral autonomic structures, the functional activity of these nuclei and their related neural circuitry may play a crucial role in the manifestation of self-transcendence.


Cloning of the mouse hypothalamic preprothyrotropin-releasing hormone (TRH) cDNA and tissue distribution of its mRNA.
A complementary DNA (cDNA) for mouse hypothalamic preprothyrotropin-releasing hormone (TRH) was isolated and characterized using three different combinations of the polymerase chain reaction (PCR). Using this cDNA, we examined the tissue distribution of expression of the mouse preproTRH gene and evaluated the evolutionary basis of the preproTRH gene by comparison of the cloned sequence with sequences of preproTRH in other species. The deduced protein sequence of the mouse preproTRH contained 256 amino acids featured by possessing an insertion of one amino acid as compared with that of rat preproTRH. Five repetitive copies of the TRH progenitor sequence (Lys-Arg-Gln-His-Pro-Gly-Arg/Lys-Arg) were found in the mouse preproTRH. Northern blot analysis showed an apparent single band of hypothalamic mRNA of approximately 1600 base pairs in length. The homology of the coding region of the mouse preproTRH with the rat and human preproTRH is 92 and 65% at the nucleic acid level, respectively, and 88 and 56% at the amino acid level, respectively. By means of the PCR procedure, a characteristic expression of the preproTRH mRNA was observed solely in the mouse hypothalamus and testis. Moreover, it was noteworthy to find that the degree of homology to the region containing the sixth TRH-coding sequence of the human preproTRH was higher in the mouse preproTRH than the rat counterpart.(ABSTRACT TRUNCATED AT 250 WORDS)


The dorsal lumbotomy incision in pediatric urological surgery.
Between January 1, 1983 and September 30, 1985, 42 upper urinary tract operations were performed using the dorsal lumbotomy incision, representing 28 per cent of all upper tract procedures performed. Operations included pyeloplasty, partial and total nephroureterectomy, pyelolithotomy, ureterolithotomy and renal exploration with cyst marsupialization. The major contraindications to lumbotomy were malignancy and malrotated or malpositioned kidneys. Patient age ranged from 1 month to 20 years. A modification of the Gil-Vernet vertical lumbotomy incision was used in all cases. This approach involves successive incisions through the layers of the lumbodorsal fascia to gain access to the kidney and ureter, and emphasizes a muscle-retracting technique. Incision of the costovertebral ligament allows 12th rib elevation and improves the exposure obtained. There were no postoperative complications related to the lumbotomy incision itself. Decreased surgical morbidity is suggested by our results. By 3 days postoperatively 64 per cent of our patients required no analgesic medication, 93 per cent were tolerating a regular diet and 83 per cent were evaluated as having a good appetite. Mean hospital length of stay for all lumbotomy patients was 5.6 days. We conclude that the dorsal lumbotomy incision can be used to perform a wide variety of upper tract operations in children, resulting in minimal morbidity and short hospital stays.


Hyperekplexia in Kurdish families: a possible GLRA1 founder mutation.
Autosomal recessive hyperekplexia is due to loss-of-function mutations in the GLRA1 gene. The authors describe six patients from two consanguineous families with a homozygous deletion of the first seven GLRA1 exons and provide evidence of a founder effect in Kurds from Turkey. Hyperekplexia may be misdiagnosed as epilepsy.


Evaluation of salmon calcitonin treatment in bone metastases from breast cancer--a controlled trial.
Salmon calcitonin 100 MRCU/day or a saline placebo were given in daily injections for at least three months to 49 patients with bone metastases from breast cancer in a randomized double-blind trial. All patients were normocalcemic, and most patients had stable or regressing disease at start of trial. No improvement in general performance or bone pain was detected as measured by a visual analogue scale, the daily duration of pain or consumption of analgetic drugs. Calcitonin had no effect on disease progression as judged by bone scans and radiographs. Calcitonin therapy did not affect serum calcium, alkaline phosphatase, bone gla-protein, or the urinary excretion of calcium and hydroxyproline. Serum phosphate and magnesium decreased significantly during calcitonin treatment (p = 0.01, and 0.00005, respectively). It was concluded that salmon calcitonin in this dosage has no discernible effect on skeletal pain, general performance, bone metabolism or disease progression in patients with breast cancer metastatic to bone. A significant decrease in serum phosphate and magnesium probably indicated an effect of calcitonin on the renal excretion of these ions.


Familial recurrent rhabdomyolysis due to carnitine palmityl transferase deficiency.
Muscle carnitine palmityltransferase (CPT) activity was very low (0 to 14 per cent of controls) in two brothers with a syndrome of recurrent rhabdomyolysis and myoglobulinuria. In isolated muscle mitochondria the majority (87.5 per cent) of total measurable CPT enzyme activity could be attributed to external membrane CPT with severe deficiency of inner membrane CPT. By contrast, control mitochondria demonstrated a 1:1 distribution of external membrane CPT to inner membrane CPT. Thus, myoglobinuria may be due to a genetic defect of lipid metabolism in skeletal muscle, with inner membrane CPT deficiency presenting the same clinical features as external membrane CPT deficiency.


[Plesiomonas shigelloides. 23 strains isolated from human stools in Madagascar].
Twenty-three strains of Plesiomonas shigelloïdes isolated from human stools in Antananarivo are studied. Ficklness of some biochemical characters is observed. Ability to pathogenicity is tested on animals (cornea of guinea pigs, intestinal ligatured loops of rabbits).


Predicting self-reported functional improvement one year after primary total knee arthroplasty using pre- and postoperative patient-reported outcome measures.
Approximately 20% of patients do not perceive functional improvement after a primary total knee arthroplasty (TKA). This study aims to assess which patient-related and clinical determinants at baseline and six months postoperative can predict lack of self-reported functional improvement at 12 months after primary TKA. In a retrospective cohort study of 569 patients who received a primary TKA between 2015 and 2018, self-reported functional improvement, measured as ≥7 points increase in Oxford Knee Score (OKS) from baseline to 12 months postoperative, was assessed. Patient characteristics and patient-reported variables at baseline and six months postoperative were entered in a logistic regression model with manual backward elimination. Incidence of functional improvement in this study was 73%. Preoperative variables were no strong predictors of the outcome. An increase in pain between baseline and six months postoperative was a risk factor for not functionally improving (odds ratio (OR) 1.13 (95% confidence interval (CI) 1.03-1.23)). An improvement in knee pain and function was a protective factor for lacking functional improvement (OR 0.78 (95% CI 0.74-0.82)). The prediction model explained 44% of variance and showed good calibration and discrimination. Sensitivity and specificity were 82% and 76%, respectively. Using pre- and postoperative variables, a prediction model for self-reported functional improvement one year after TKA was developed. This prediction tool was easy to use at six months postoperative and allowed identification of patients at high risk for not functionally improving one year after TKA. This could facilitate early interventions directed at functional improvement after TKA.


Vaginal erosion, sinus formation, and ischiorectal abscess following transobturator tape: ObTape implantation.
A 50-year-old woman was referred for evaluation with an 8-month history of intermittent malodorous vaginal discharge initially noted 2 months after placement of a transobturator tape for stress urinary incontinence. Evaluation revealed erosion of the tape through the vaginal wall with a sinus tract associated with an ischiorectal abscess. Surgical removal of the tape with excision of the sinus tract, drain placement, and antibiotic therapy was needed for complete resolution of the symptoms. Infectious complications need to be considered when counseling women prior to synthetic sling placement. A high index of suspicion, meticulous sub- and periurethral inspection, along with aggressive surgical management are required to treat an infected draining abscess following synthetic transobturator sling placement.


Survival of partially differentiated mouse embryonic stem cells in the scala media of the guinea pig cochlea.
The low regenerative capacity of the hair cells of the mammalian inner ear is a major obstacle for functional recovery following sensorineural hearing loss. A potential treatment is to replace damaged tissue by transplantation of stem cells. To test this approach, undifferentiated and partially differentiated mouse embryonic stem (ES) cells were delivered into the scala media of the deafened guinea pig cochlea. Transplanted cells survived in the scala media for a postoperative period of at least nine weeks, evidenced by histochemical and direct fluorescent detection of enhanced green fluorescent protein (EGFP). Transplanted cells were discovered near the spiral ligament and stria vascularis in the endolymph fluid of the scala media. In some cases, cells were observed close to the damaged organ of Corti structure. There was no evidence of significant immunological rejection of the implanted ES cells despite the absence of immunosuppression. Our surgical approach allowed efficient delivery of ES cells to the scala media while preserving the delicate structures of the cochlea. This is the first report of the survival of partially differentiated ES cells in the scala media of the mammalian cochlea, and it provides support for the potential of cell-based therapies for sensorineural hearing impairment.


YTHDC2 inhibits rat bone mesenchymal stem cells osteogenic differentiation by accelerating RUNX2 mRNA degradation via m6A methylation.
As the most abundant internal mRNA modification, N6-methyladenosine (m6A) RNA methylation has been found to influence many biological events including bone mesenchymal stem cells (BMSCs) osteogenic differentiation. YTH N6-methyladenosine RNA binding protein C2 (YTHDC2) is an m6A reading protein with the ability to mediate the decay of combined methylated mRNA, however its role in BMSCs osteogenic differentiation remains unknown. In this study, we first found an increase of RUNX family transcription factor 2 (RUNX2) expression and a decrease of YTHDC2 expression during the process of BMSCs osteogenic differentiation. Furthermore, we transfected BMSCs with YTHDC2 interference fragment, resulting in an increased content of RUNX2 mRNA and protein inside BMSCs. Finally, through RNA Immunoprecipitation experiments, we confirmed that YTHDC2 protein can bind to RUNX2 mRNA and accelerate its decomposition. Moreover, the immunofluorescence staining also showed a negative correlation between YTHDC2 and RUNX2. In conclusion, during BMSCs osteogenic differentiation, YTHDC2 protein showed decreased expression, resulting in a higher level of RUNX2 (mRNA and protein) expression inside cells, indicating YTHDC2 as a promising molecular target for the regulation of BMSCs osteogenic differentiation.


Identification of transcription factors dictating blood cell development using a bidirectional transcription network-based computational framework.
Advanced computational methods exploit gene expression and epigenetic datasets to predict gene regulatory networks controlled by transcription factors (TFs). These methods have identified cell fate determining TFs but require large amounts of reference data and experimental expertise. Here, we present an easy to use network-based computational framework that exploits enhancers defined by bidirectional transcription, using as sole input CAGE sequencing data to correctly predict TFs key to various human cell types. Next, we applied this Analysis Algorithm for Networks Specified by Enhancers based on CAGE (ANANSE-CAGE) to predict TFs driving red and white blood cell development, and THP-1 leukemia cell immortalization. Further, we predicted TFs that are differentially important to either cell line- or primary- associated MLL-AF9-driven gene programs, and in primary MLL-AF9 acute leukemia. Our approach identified experimentally validated as well as thus far unexplored TFs in these processes. ANANSE-CAGE will be useful to identify transcription factors that are key to any cell fate change using only CAGE-seq data as input.


Regional anesthesia is associated with improved metastasis free survival after surgical resection of bone sarcomas.
There is increasing evidence that perioperative factors, including type of anesthesia, may be an important consideration regarding oncological disease progression. Previous studies have suggested that regional anesthesia can improve oncological outcomes by reducing the surgical stress response that occurs during tumor resection surgery and that may promote metastatic progression. The purpose of this study is to provide the first robust investigation of the impact of adding regional anesthesia to general anesthesia on oncological outcomes following sarcoma resection. One hundred patients with bone sarcoma were retrospectively analyzed in this study. After adjusting for confounding variables such as age and grade of the tumor, patients with bone sarcoma receiving regional anesthesia in addition to general anesthesia during resection had improved metastasis free survival (multivariate hazard ratio of 0.47 and p = 0.034). Future studies are needed to confer the beneficial effect of regional anesthesia, and to further investigate the potential mechanism. Clinical significance: The results from this study provide evidence that regional anesthesia may be advantageous in the setting of bone sarcoma resection surgery, reducing pain while also improving oncological outcomes and should be considered when clinically appropriate.


The Modern Criteria for Medical Management of Acromegaly.
Acromegaly is an insidious disorder characterized by excess secretion of growth hormone (GH) and elevated circulating levels of insulin-like growth factor-I (IGF-I), generally caused by a pituitary adenoma. It is a rare disease associated with an average 10-year reduction in life expectancy due to metabolic, cardiovascular, and cerebrovascular comorbidities and reduced quality of life caused by paresthesias, fatigue, osteoarthralgia, or bone fractures. In 2000, Cortina Consensus Conference established general criteria for diagnosis and biochemical control of acromegaly, which have been revised in recent years, adapting them to emerging clinical evidences as well as the evolving assay techniques. Authors have proposed a binary definition of cure for acromegaly, where both GH and IGF-I are important determinants: the former is more linked to the presence of residual adenomatous tissue, while the latter to the peripheral activity of the disease. Control of tumor growth and complications is also an essential goal of treatment. Surgical, medical, and radiotherapy approaches are all valid alternatives. The surgical option is, however, unsuccessful in about 50% of patients. Somatostatin analogs (SRLs), octreotide LAR, and lanreotide ATG can inhibit cell growth, besides their beneficial effects on GH hypersecretion and on most comorbidities. Pasireotide is a new multireceptor-targeted SRL with reported superior biochemical efficacy to octreotide, due to higher affinity for SSTR-5, but potentially causing detrimental effects on glucose homeostasis. Pegvisomant could be a valid choice in all patients resistant to SRLs. It is a competitive GH antagonist, which efficaciously blocks IGF-I production, inhibiting the dimerization of GH receptor. Normal IGF-I levels represent, therefore, its only relevant efficacy endpoint, while only few cases of tumor growth on pegvisomant have been reported, so far.


The associations between exercise and lipid biomarkers.
Cardiovascular diseases (CVD) remain the leading cause of death globally, and further efforts are being undertaken to understand and modify CVD risk factors, such as dyslipidemia (DLD), hypertension, and diabetes. The sedentary lifestyle of most individuals today contributes to the prevalence of these conditions. Uncontrolled dyslipidemia serves as a fertile ground for atherosclerotic plaque formation, while lipoproteins (Lp) act as cofactors for inflammatory processes that cause plaque destabilization leading to subsequent CVD events. As such, many health experts and institutions continue to emphasize the importance of cardiorespiratory fitness (CRF) and muscular strength (MusS) with the intent to reduce atherogenic lipoproteins and proprotein convertase subtilisin kexin type 9 (PCSK-9) expression. Concordantly, the two modes of exercise training (ET), such as aerobic ET (aET) and resistance ET (rET) have both demonstrated to improve CRF and MusS, respectively. Although both modes of ET were shown to independently reduce mortality, participation in both forms resulted in a more pronounced improvement in cholesterol levels and CVD-related mortality. Though reduction of adiposity is not a pre-requisite to achieve better control of DLD through increased CRF and MusS, the beneficial effects of physical activity on the inflammatory processes linked to atherosclerosis are almost always associated with a simultaneous decrease in overall adiposity. It is therefore essential to promote both aET and rET, including weight loss in order to attenuate the risks stemming from atherosclerosis and its proinflammatory components.


Clinical information from medical images. A comparison of two types of ultrasonic image in the detection of focal intrahepatic lesions.
If the uncertainty in the diagnosis is measured before and after viewing a diagnostic image, the change in uncertainty is a measure of the information contributed by that image. The formal basis of information theory has been used to calculate the change in uncertainty. These analytical methods have been applied to assess two types of ultrasonic grey-scale image in the demonstration of possible focal intrahepatic lesions.


Astragalus regulates the intestinal immune response during sepsis by mediating ILC3 proliferation through RORγt.
Sepsis is a common complication of many diseases and is associated with high morbidity and mortality rates. Astragalus can improve humoral and innate immunity, inhibit inflammatory responses, and protect immune cells and organs from damage. However, to the best of our knowledge there are no reports on whether astragalus can regulate intestinal innate immune function during sepsis. In this study, a rat cecal ligation and puncture model of sepsis was used to investigate the effects of astragalus treatment, following which the apoptosis rate of lymphocytes from Peyer's patches (PP) was determined. Type 3 innate lymphoid cells (ILC3) were cultured in vitro to further evaluate the effects and mechanisms of astragalus. The apoptosis level of lymphocytes from PP in rats with sepsis was significantly increased, and the number of ILC3 was significantly reduced, compared with the sham operation group, which aggravated intestinal injury and ultimately led to the death of rats. Astragalus treatment significantly inhibited the apoptosis of lymphocytes from PP, increased the number of ILC3, and improved the intestinal inflammatory environment compared to the sepsis group. RT-PCR revealed that astragalus and the retinoic acid-related orphan receptor γt (RORγt) agonist LYC-55716 both promote the expression of interleukin (IL)-17A, IL-17F, IL-22, interferon-γ, and granulocyte-macrophage colony-stimulating factor mRNA. Mechanistically, astragalus promotes the proliferation of ILC3 through RORγt, thereby reducing intestinal inflammatory damage. Astragalus, via RORγt, promotes the generation of ILC3, improves the inflammatory environment in rats with sepsis.


A histochemical study of cholinesterases in arm and forearm muscles of the pigeon and fowl.
Various arm and forearm muscles of the pigeon and fowl were studied histochemically. Fibres of the muscles from both birds hydrolysed acetyl, butyryl and propionyl thiocholine iodide. With the exception of M. brachialis, all the fibres of the muscles had "en plaque" motor end plates. M. brachialis had "en grappe" endings on all its fibres. The possibility of M. brachialis being a physiologically "slow" muscle is discussed.


Accelerated and blast phase myeloproliferative neoplasms.
Myeloproliferative neoplasms (MPN) have an inherent risk of transformation into blast phase (MPN-BP) or accelerated phase (MPN-AP) which is characterized by presence of ≥20% or 10-19% peripheral blood or bone marrow blasts, respectively. Primary myelofibrosis (PMF) is associated with the highest risk of blastic transformation (14.2%), followed by polycythemia vera (PV) (6.8%) and essential thrombocythemia (ET) (3.8%). Risk of leukaemic transformation (LT) in PMF can be determined by a three-tiered model based on presence of IDH1 mutation, circulating blasts ≥3%, SRSF2 mutation, age >70 years, ASXL1 mutation, and moderate/severe anemia with high, intermediate, and low risk groups (LT incidence 57%, 17%, and 8%, respectively). Currently, treatment of MPN-AP/BP includes acute myeloid leukaemia (AML)-like induction chemotherapy or hypomethylating agents alone or in combination with venetoclax and/or ruxolitinib. In transplant-eligible patients, our goal is to achieve complete remission with or without count recovery, before proceeding with allogeneic stem cell transplantation, which is the only modality associated with long-term survival. In the current review, we discuss our diagnostic, prognostic, and therapeutic approach to patients with MPN-AP/BP.


ATP4- increases the intracellular calcium concentration in rat submandibular glands.
1. The intracellular calcium concentration of a crude suspension from rat submandibular glands was increased by extracellular ATP. 2. The stimulatory effect of ATP was favored by removal of magnesium from the extracellular medium. ADP and adenosine had no effect. ATP did not modify the concentration of calcium in isolated rat pancreatic acini. 3. It is concluded that ATP is a potential neurotransmitter regulating the submandibular gland function.


Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma.
Restylane (Q-Med, Uppsala, Sweden), a hyaluronic acid (HA) that is microbiologically produced and then cross-linked, is becoming popular as a dermal filler for improvement of facial lines and wrinkles. However, it is currently believed that the clinical and histologic persistence of this filler is from 6 to 9 months. We recently encountered Restylane in tissue where it had been implanted 23 months prior to removal of a basal cell carcinoma (BCC) on the lip, and its presence caused some confusion with HA that surrounds BCC nests. To show and to contrast the histologic dermal appearance of Restylane and its metachromatic staining characteristics with toluidine blue from those of HA that surrounds BCC nests. Toluidine blue staining at pH 7.07 was performed on excised tissue containing Restylane and BCC on the upper lip. Restylane appeared as reddish-purple amorphous masses, whereas the HA that frames BCC nests appeared redder and more well defined. The amorphous metachromatic reddish-purple color staining of Restylane with toluidine blue is due to its HA content. This staining pattern should be differentiated from the well-defined red color of HA that normally borders BCC nests. Restylane may persist in the dermis as long as 23 months after implantation.


Heart rhythm characterisation during unexplained transient loss of consciousness in dogs.
The identification of the heart rhythm during an episode of transient loss of consciousness (TLOC) is considered the reference standard method to elucidate the underlying aetiology. This study aimed to characterise heart rhythm in dogs during TLOC using Holter and external loop recorder monitoring. We retrospectively reviewed 24-h Holter monitoring and external loop recorder tracings from 8084 dogs. Heart rhythms from dogs that experienced TLOC during the recording was analysed to identify rhythm disturbances that occurred during episodes of TLOC. Electrocardiograms (ECGs) were subsequently categorised into Type 1 (ventricular arrest), Type 2 (sinus bradycardia), Type 3 (no/slight rhythm variations), and Type 4 (tachycardia). Transient LOC was documented in 92 dogs over 230 episodes of TLOC. Percentage of cases with ECGs compatible with each classification were as follows: 72.1%, Type 1; 6.1%, Type 2; 20.9%, Type 3; and 0.9%, Type 4. Cardiac rhythm during the TLOC could have been a consequence of a neurocardiogenic mechanism in 46.7% cases, while intrinsic rhythm disturbances of the sinus node or of the atrioventricular node were diagnosed in 31.5% cases. In two cases, tachycardia was the possible cause of the TLOC. ECG patterns in dogs presenting with multiple TLOC episodes were completely reproducible during each episode. TLOC in dogs was primarily caused by ventricular arrest. Most dogs with TLOC had electrocardiographic finding suggestive of a reflex or neurally-mediated syncope, but one third had an ECG more suggestive of a conduction disorder. Distinguishing these two entities could help inform diagnostic, therapeutic, and prognostic plans.


Healthcare Hackathons Provide Educational and Innovation Opportunities: A Case Study and Best Practice Recommendations.
Physicians and other healthcare professionals are often the end users of medical innovation; however, they are rarely involved in the beginning design stages. This often results in ineffective healthcare solutions with poor adoption rates. At the early design stage, innovation would benefit from input from healthcare professionals. This report describes the first-ever rehabilitation hackathon-an interdisciplinary and competitive team event aimed at accelerating and improving healthcare solutions and providing an educational experience for participants. Hackathons are gaining traction as a way to accelerate innovation by bringing together a diverse group of interdisciplinary professionals from different industries who work collaboratively in teams and learn from each other, focus on a specific problem ("pain point"), develop a solution using design thinking techniques, pitch the solution to participants, gather fast feedback and quickly alter the prototype design ("pivoting"). 102 hackers including 19 (18.6 %) physicians and other professionals participated, and over the course of 2 days worked in teams, pitched ideas and developed design prototypes. Three awards were given for prototypes that may improve function in persons with disabilities. 43 hackers were women (42.2 %) and 59 men (57.8 %); they ranged in age from 16 to 79 years old; and, of the 75 hackers who reported their age, 63 (84 %) were less than 40 years old and 12 (16 %) were 40 years or older. This report contributes to the emerging literature on healthcare hackathons as a means of providing interdisciplinary education and training and supporting innovation.


Presepsin as a diagnostic marker of sepsis in children and adolescents: a short critical update.
Sepsis is a potentially fatal condition which strikes 1.2 million children worldwide per year. New biomarkers have been proposed in the assessment of the risk of sepsis progression and in the identification of patients with the worst outcome. This review aims to assess the diagnostic value of presepsin, a promising new biomarker, in pediatric sepsis, with particular attention to its usefulness in emergency department. We performed a literature search of the last 10 years to find presepsin related studies and reports concerning pediatric population aged from 0 months to 18 years. We mainly focused on randomized placebo-control studies, followed by case-control studies, observational (both retrospective or prospective), and finally systematic reviews and meta-analysis. The article selection process was carried out independently by three reviewers. Results: A total of 60 records were identified in literature, 49 were excluded according to the exclusion criteria. The highest presepsin sensitivity value was 100%, with a high cut-off (800.5 pg/mL). The highest sensitivity-specificity ratio was 94% vs 100%, with a similar considered presepsin cut-off (855 ng/L). As regards the presepsin cut-offs reported in the various studies, several authors agree on a critical threshold of about 650 ng/L to guarantee a sensitivity> 90%. The analyzed studies show a wide variability for patients' age and presepsin risk cut-offs. Conclusions: Presepsin seems to be a new useful marker for early diagnosis of sepsis, even in a pediatric emergency setting. Being a new marker of sepsis, more studies are required to better understand its potential.


Glomerulotubular dimensional readjustments during compensatory renal hypertrophy in the hypothyroid rat.
Although growth of tubules is arrested and that of glomeruli retarded by hypothyroidism in rats, unilateral nephrectomy has been found to elicit a vigorous compensatory hypertrophy of the hypothyroid kidney. Microdissection and measurement of the dimensions of glomeruli and proximal convoluted tubules taken from the kidney removed first and from the hypertrophic contralateral organ removed two to three weeks later, disclosed a "normalization" of the typical glomerulotubular dimensional imbalance as a result of greater tubular than glomerular growth. A somewhat more striking but qualitatively identical response was observed in 9 euthyroid animals. Glomerular filtration rate and maximal glucose reabsorptive capacity (Tm(G)) increased in both euthyroid and hypothyroid animals in accord with the structural shifts.


Managing Geriatric Patients with Falls and Fractures.
Orthopedic fractures in adults 65 and older are common and can lead to functional decline and increased morbidity and mortality. Falls are often the precipitating event for fractures in this population, linked to common aging physiology with increasing comorbid conditions and advancing frailty. Managing falls and orthopedic fractures in the geriatric population is complex, requiring a systematic and collaborative approach spearheaded by a multidisciplinary team focused on improving patient outcomes.


Immediately loaded implant-supported full-arches: Peri-implant status after 1-9years in a private practice.
Evaluate the peri-implant status on the long-term (1-9years) of patients treated with immediately-loaded full-arch prostheses in a private practice. A retrospective cohort study was carried out in patients consecutively treated with immediately loaded full-arch restorations supported with a minimum of 4 implants (Replace® Tapered, Nobel Biocare AB) and Multi-Unit conical abutments (MUA®, Nobel Biocare AB) with a follow-up of over 12months after placement of the final prosthesis. A total of 378 implants were placed in 56 patients. Forty upper and 32 lower arches were restored, and 16 patients received bimaxillary rehabilitation. The mean duration of follow-up was 50 months, and the implant and patient peri-implantitis prevalences were 14.3% and 50%, respectively. Mucositis affected 56.9% of the implants and 50% of the patients. The survival rate was 96.4% by patient, but reached 99.5% in the implant-based analysis, and the success rate was 95.5% for implants and 80.4% for patients. Immediately-loaded full-arch restorations have an acceptable outcome after 1-9years of follow-up. However, the incidence of peri-implant diseases is high, and further research is needed to confirm whether these may compromise the predictability of the prostheses over the long-term. After a mean follow-up of 50months, the incidence of mucositis and peri-implantitis affected the 96.4% and 50% of patients, respectively. However, these results were reduced almost by half when the threshold of bleeding on probing and peri-implant bone loss applied was less strict.


Identification of Rho GEF and RhoA Activation by Pull-Down Assays.
The small GTPase RhoA participates in actin and microtubule machinery, cell migration and invasion, gene expression, vesicular trafficking and cell cycle, and its dysregulation is a determining factor in many pathological conditions. Similar to other Rho GTPases, RhoA is a key component of the wound-healing process, regulating the activity of different participating cell types. RhoA gets activated upon binding to guanine nucleotide exchange factors (GEFs), which catalyze the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). GTPase-activating proteins (GAPs) mediate the exchange of GTP to GDP, inactivating RhoA, whereas guanine nucleotide dissociation inhibitors (GDIs) preserve the inactive pool of RhoA proteins in the cytosol. RhoA and Rho GEF activation is detected by protein pull-down assays, which use chimeric proteins with Rhotekin and G17A mutant RhoA as "bait" to pull down active RhoA and RhoA GEFs, respectively. In this chapter, we describe an optimized protocol for performing RhoA and GEF pull-down assays.


Elevation of systolic and diastolic blood pressure associated with migration: the Tokelau island migrant study.
Cross-sectional univariate and multivariate analyses estimated differences between the blood pressure of adult Tokelauan migrants to New Zealand and non-migrants still living on three Polynesian atolls. Response rates were 97 and 99% in the two locations. Among males, the difference between migrants and non-migrants after adjustment for significant covariates was 7.2 mmHg systolic pressure (p less than 0.001) and 8.1 mmHg diastolic pressure (p less than 0.001). Among females, adjusted systolic pressure was not significantly higher in migrants compared to non-migrants (1.8 mmHg, p = 0.065) and diastolic pressure was only 3.0 mmHg higher (p less than 0.001). Body mass is significantly correlated with blood pressure in this study group; nonetheless, differences in body mass explain only a small proportion of the observed migrant/non-migrant differential in blood pressure. Estimates of blood pressure differences preceding migration are also reported. These indicate that blood pressure was neither consistently nor significantly higher among those who subsequently migrated. This report provides compelling evidence linking Westernization and the development of chronic disease.


Expression of TIP60 (tat-interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment-specific outcome of localised invasive bladder cancer.
What's known on the subject? and What does the study add? Several studies have shown that defects in DNA-damage response are associated with good survival after chemotherapy and radiotherapy. Furthermore, loss of cell cycle regulators may be prognostic indicators of poor survival after cystectomy. However, the potential clinical impact of previous findings is hampered by insufficient validation of significant results in suitable cystectomy and radiotherapy cohorts. Here we use a large cohort of patients receiving radiotherapy to successfully validate the importance of MRE11 as a predictive marker of disease-specific survival (DSS). Furthermore, using two independent patient cohorts we show for the first time that TIP60 is a predictive marker of DSS after cystectomy. We show that combined use of TIP60 and MRE11 may hold the potential to guide treatment decisions. • To determine the association between the proteins: tat-interactive protein 60 kDa (TIP60), p16, meiotic recombination 11 homolog (MRE11), phosphorylated ataxia telangiectasia mutated (ATM), retinoblastoma protein (Rb), Ki67, and p53 and clinical outcome in invasive lymph node-negative bladder cancer. • Protein expression was measured by immunohistochemistry in cancer specimens from two independent cohorts of patients with bladder cancer treated with cystectomy (162 patients and 273) and one cohort of patients receiving radiotherapy (148). • Disease-specific survival (DSS) was used as the outcome measure, and patients with no disease-specific death were followed for a minimum of 36 months. • TIP60 was significantly correlated with DSS in both cystectomy cohorts (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.26-0.68, P < 0.001 and HR 0.45, 95% CI 0.28-0.72, P = 0.001). • MRE11 was significantly correlated with DSS in the cohort receiving radiotherapy (HR 0.64, 95% CI 0.47-0.86, P = 0.005). • P16 was significantly correlated with DSS in all three cohorts (HR 0.46, 95% CI 0.30-0.75, P = 0.032; HR 0.60, 95% CI 0.37-0.97, P = 0.032; HR 0.52, 95% CI 0.28-0.96, P = 0.001). • Rb was significantly correlated with DSS in one cystectomy cohort (HR 1.71, 95% CI 1.13-2.75, P = 0.017). • Ki67, p53, and pATM were not significantly correlated with DSS in any of the cohorts. • TIP60 protein expression was a predictive marker for DSS after cystectomy in two independent cohorts. This novel marker was the strongest predictive factor in multivariate analysis in patients receiving cystectomy. • MRE11 was shown to be a predictive marker for DSS after radiotherapy. • We have shown that TIP60 and MRE11 hold the potential to guide patients with invasive bladder cancer to either cystectomy or radiotherapy. This study was based on retrospective material and consequently we suggest that these markers should be validated in a prospective study.


Long-term potentiation of evoked and spontaneous neuronal activity in the grafted hippocampus.
Adult rats with unilateral fimbria-fornix lesion received fetal hippocampal grafts into the lesion cavity. Seven to ten months after the transplantation the graft was examined for long-term potentiation (LTP) in response to host hippocampus and direct graft stimulation. High frequency tetanizing trains delivered to either the host hippocampus or the graft resulted in augmented field potentials and prolonged neuronal discharges in the graft lasting several hours. Very low currents (10-30 microA) were required to induce LTP by direct graft stimulation. In addition to the enhancement of evoked responses, the frequency of occurrence of spontaneously occurring EEG spikes and concurrent population neuronal bursts in the graft increased significantly after the tetanizing trains. These findings suggest that the physiological-biochemical mechanisms required for plastic changes of synaptic efficacy are present in the grafted hippocampus.