Clinical and genetic familial study of a large cohort of Italian children with idiopathic epilepsy.
Epilepsies are characterized by genetic heterogeneity and by the possible coexistence of different phenotypes in one family. Moreover, in different epilepsies, mutations in the same gene have been reported. We aimed to collect data in a large Italian cohort of 81 families with children affected by partial or generalized epilepsies and to evaluate the prevalence of several ion channel mutations. In particular, a clinical and genetic survey was performed and DNA regions known to be associated with several epilepsies were analysed by sequencing. We observed genetic complexity in all phenotype groups: any epileptic type may be transmitted as either autosomal dominant or recessive. No significant phenotype identity among generations and no differences among genders could be observed. Two missense mutations in SCN1A were identified in two GEFS+ probands confirming the importance of this channel for this epilepsy. Moreover, a previously unreported CLCN2 mutation was detected in a proband showing CAE. In conclusion, even in this highly heterogeneous cohort, the complexity of the epileptic condition was highlighted and mutations in the analysed candidate region of ion channel genes appear to explain only a minority of cases.


[Water jet cutting for bones and bone cement--parameter study of possibilities and limits of a new method].
Water jet techniques have been used in industrial cutting, drilling and cleaning applications for more than 30 years. Plain water is typically used for the cutting of non-metallic materials. The addition of abrasive substances to the stream allows almost any material to be cut. The first medical applications were reported in the early 1980s, when the water jet was used to cut organs. The present study investigates the use of water jet cutting technology for endoprosthesis revision surgery. Bone and PMMA (polymethylmethacrylate) samples were cut at different pressures using an industrial water jet cutting device. Using plain water at 400 bar, PMMA was cut selectively without damaging the bone; above 400 bar, bone was also cut, but the cutting depths in PMMA were significantly greater (p < 0.05). Adding a water-soluble abrasive disaccharide to the water results in a significantly higher removal rate for both materials (p < 0.05), but selectivity is lost, although the differences in cutting depth between the two materials was significant (p < 0.05). With an abrasive, the quality of the cut was better for both materials. The water jet technology--in particular the abrasive technique--can be used to cut biomaterials such as bone and bone cement. The diameter of the jet is a great advantage when working in the confined area at the prosthesis interface. The cutting process is essentially cold, thus eliminating a thermal effect, and the jet reaction forces are relatively low. Accurate manipulation of the hydro jet nozzle is possible both manually and by robot. The results obtained show that it is possible to remove prostheses with this cutting technique, rapidly and with little damage to the surrounding tissue. Problem areas are the development of sterile pumps and the "depth control" of the jet.


Autonomous Car Parking System through a Cooperative Vehicular Positioning Network.
The increasing development of the automotive industry towards a fully autonomous car has motivated the design of new value-added services in Vehicular Sensor Networks (VSNs). Within the context of VSNs, the autonomous car, with an increasing number of on-board sensors, is a mobile node that exchanges sensed and state information within the VSN. Among all the value added services for VSNs, the design of new intelligent parking management architectures where the autonomous car will coexist with traditional cars is mandatory in order to profit from all the opportunities associated with the increasing intelligence of the new generation of cars. In this work, we design a new smart parking system on top of a VSN that takes into account the heterogeneity of cars and provides guidance to the best parking place for the autonomous car based on a collaborative approach that searches for the common good of all of them measured by the accessibility rate, which is the ratio of the free parking places accessible for an autonomous car. Then, we simulate a real parking lot and the results show that the performance of our system is close to the optimum considering different communication ranges and penetration rates for the autonomous car.


Effect of influenza vaccines against mismatched strains: a systematic review protocol.
Influenza vaccines are most effective when the antigens in the vaccine match those of circulating influenza strains. The extent to which the vaccine is protective when circulating strains differ from vaccine antigens, or are mismatched, is uncertain. We propose to systematically review the cross-protection offered by influenza vaccines against circulating influenza A or B viruses that are not antigenically well-matched to vaccine strains. This is a protocol for a systematic review and meta-analysis. Placebo-controlled randomized clinical trials (RCTs) reporting laboratory-confirmed influenza among healthy participants vaccinated with antigens of influenza strains that differed from those circulating will be included. The primary outcome is the incidence of laboratory-confirmed influenza (polymerase chain reaction (PCR) or viral culture). The secondary outcome is the incidence of laboratory-confirmed influenza through antibody assay (a less sensitive test than PCR or viral culture) alone or combined with PCR, and/ or viral culture. The review will be limited to RCTs written in English.We will search MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, previous influenza reviews, and the reference lists of included studies to identify potentially relevant RCTs. Two independent reviewers will conduct all levels of screening, data abstraction, and quality appraisal (using the Cochrane risk of bias tool).If appropriate, random effects meta-analysis of vaccine efficacy will be conducted in SAS (version 9.2) by calculating the relative risk. Vaccine efficacy will be calculated using the following formula: (1 - relative risk × 100). The results will be analyzed by type of vaccine (live attenuated, trivalent inactivated, or other). Subgroup analysis will include the effects of age (children, adults, older participants), and influenza A versus influenza B on the results. For influenza B we will also consider variable degrees of antigenic mismatch (lineage and drift mismatch). Our results can be used by researchers and policy-makers to help predict the efficacy of influenza vaccines during mismatched influenza seasons. Furthermore, the review will be of interest to patients and clinicians to determine whether to get immunized or support immunization for a particular influenza season.


Experience-dependent plasticity of visual cortical microcircuits.
The recent decade testified a tremendous increase in our knowledge on how cell-type-specific microcircuits process sensory information in the neocortex and on how such circuitry reacts to manipulations of the sensory environment. Experience-dependent plasticity has now been investigated with techniques endowed with cell resolution during both postnatal development and in adult animals. This review recapitulates the main recent findings in the field using mainly the primary visual cortex as a model system to highlight the more important questions and physiological principles (such as the role of non-competitive mechanisms, the role of inhibition in excitatory cell plasticity, the functional importance of spine and axonal plasticity on a microscale level). I will also discuss on which scientific problems the debate and controversies are more pronounced. New technologies that allow to perturbate cell-type-specific subcircuits will certainly shine new light in the years to come at least on some of the still open questions.


Chromatin remodeling by ATP-dependent molecular machines.
The eukaryotic genome is packaged into a periodic nucleoprotein structure termed chromatin. The repeating unit of chromatin, the nucleosome, consists of DNA that is wound nearly two times around an octamer of histone proteins. To facilitate DNA-directed processes in chromatin, it is often necessary to rearrange or to mobilize the nucleosomes. This remodeling of the nucleosomes is achieved by the action of chromatin-remodeling complexes, which are a family of ATP-dependent molecular machines. Chromatin-remodeling factors share a related ATPase subunit and participate in transcriptional regulation, DNA repair, homologous recombination and chromatin assembly. In this review, we provide an overview of chromatin-remodeling enzymes and discuss two possible mechanisms by which these factors might act to reorganize nucleosome structure.


Hyperoxia induces inflammation and regulates cytokine production in alveolar epithelium through TLR2/4-NF-κB-dependent mechanism.
It has been reported that inflammation of lung could be induced by proinflammatory factor under hyperoxia, which may be attributed by increasing generation of reactive oxygen species (ROS). In the present study, with human epithelial lung cancer cell line A549 treated with hyperoxia as in vitro model, we found that hyperoxia stimulation induced TLR2/4 activity in A549 cells. ROS inhibitor NAC was used to investigate the role of ROS in hyperoxia-induced inflammatory cytokines secretion. Results of mRNA to protein level showed that elevated TLR2/4 activity and hyperoxia-induced inflammatory cytokines secretion could be significantly attenuated by NAC. EMSA results showed the activation of nuclear factor-κB (NF-κB) increased after 2-h hyperoxia stimulation, and the ROS inhibitor blocked TLR2/4 and NF-κB activity. Data suggested that the TLR2/4-NF-κB pathway is involved in hyperoxia-induced inflammatory cytokines secretion in A549 human type II alveolar epithelial cells.


Determination of free copper concentrations in natural waters by using supported liquid membrane extraction under equilibrium conditions.
A method is described for measurement of freely dissolved copper concentrations in natural water samples using supported liquid membrane (SLM) extraction under equilibrium conditions, a technique denoted "equilibrium sampling through membranes" (ESTM). For this purpose, 1,10-dibenzyl-1,10-diaza-18-crown-6 as neutral carrier and oleic acid were used in the membrane phase. The main variables optimised were the carrier used to form the metal complexes, the organic solvent used in the membrane, the countercation, pH, the ligand used in the acceptor phase, the extraction time, and the flow rate of the donor phase. After the optimisation process an enrichment factor of 18.5 was obtained. Equilibrium conditions were reached after extraction for 60 min if a flow rate of 1.0 mL min(-1) or greater was used. When different ligands such as humic acids, phthalic acid, and EDTA were added to the sample solution, and sample pH ranged from 6 to 8, the results obtained for freely dissolved copper concentrations were in a good agreement with results from speciation calculations performed with Visual Minteq V 2.30, Cheaqs V L20.1, and WinHumic V. The developed technique was applied to analysis of stream and leachate water.


Noise Annoyance Modelling using Fuzzy Rule Based Systems.
This paper presents a model that uses a fuzzy rule based engine to predict noise annoyance reported by individuals in a social survey. The rules are proposed by the human expert and are based on linguistic variables. The approach then adapts the sufficiency degree or certainty of a rule to tune the model to a particular survey. Although all possible relations between exposure, attitudinal, emotional, personal, environmental and social variables are not included in the model as yet, the benefits of the new approach are clearly demonstrated. A major limitation that remains is the varying theoretical and empirical basis of the expert for different subset of annoyance determinants. Future applications may include more accurate predictions of noise annoyance for policy support and extraction of knowledge concerning the construct of annoyance from surveys.


The Buffering Effect of Relationships on Combat Exposure, Military Performance, and Mental Health of U.S. Military Soldiers: A Vantage Point for CFTs.
This study examined the role of cumulative combat experiences with regard to military performance and conduct and mental health among a sample of young soldiers from the Army STARRS dataset (N = 5,283). Higher levels of cumulative combat experiences were directly related to poorer performance and conduct and a greater likelihood of anxiety, depression, and post-traumatic stress disorder (PTSD). Military performance and conduct served as a linking mechanism between combat experiences and mental health. Using moderated mediation structural equation modeling, relationship disruptions were found to exacerbate the adverse effects of combat experiences; conversely, unit cohesion buffered the impact of combat experiences. Implications for military helping professionals include identifying leverage points for intervention, particularly strengthening the social connections of service members within and outside the military.


Cellular and humoral anticorneal immune response in corneal transplantation.
Immunologic responses play a role in the rejection process of corneal transplants. Both histocompatibility antigens and tissue-specific antigens may be potential targets for such an immune response. To identify relevant responses, the humoral immune response against corneal tissue and the cellular immune response against one specific corneal protein were determined in patients before and after corneal transplantation. The results were compared with known risk factors for corneal transplantation, but no correlations were observed. A conversion from negative to positive in cellular immune response against the cornea-specific protein was seen in patients who had experienced an inflammatory episode during the time interval between measurements. The anticorneal protein response may therefore be the result of an intraocular inflammatory response, but not a prognostic factor to help predict the patients at risk for rejection.


Perceived discrimination is associated with reduced breast and cervical cancer screening: the Study of Women's Health Across the Nation (SWAN).
Racial disparities in breast and cervical cancer screening have been documented in African American, Hispanic, and Asian populations. Perceived discrimination may contribute to this disparity. The aim of this study was to understand the relationship between perceived everyday racial/ethnic and other discrimination and receipt of breast and cervical cancer screening in a multiethnic population of women. We analyzed data from 3,258 women participating in the Study of Women's Health Across the Nation (SWAN), a multiethnic/racial, longitudinal cohort study of the natural history of the menopausal transition conducted at seven U.S. sites. Participants completed a validated measure of perceived discrimination and reasons for believing that they were treated differently, along with Pap smears, clinical breast exams (CBE), and mammography at each follow-up period. We used multiple logistic regression for the binary outcomes of having a Pap smear, CBE, or mammogram in each of the two follow-up years, using self-reported "race discrimination" and "other discrimination" at baseline as the main predictors. African American women reported the highest percentage of racial discrimination (35%), followed by Chinese (20%), Hispanic (12%), Japanese (11%), and non-Hispanic white women (3%). Non-Hispanic white women reported the highest percentage of "other" discrimination (40%), followed by Chinese (33%), African American (24%), Japanese (23%), and Hispanic women (16%). Perceived racial discrimination was not associated with reduced receipt of preventive screening, except in one fully adjusted model. Reported discrimination owing to "other" reasons, such as age or gender, was associated with reduced receipt of Pap smear (odds ratio [OR] 0.85; 95% confidence interval [CI] 0.74-0.99), CBE (OR 0.78; 95% CI 0.67-0.91), and mammography (OR 0.80; 95% CI 0.69-0.92) regardless of patient race. Perceived discrimination is an important issue across racial/ethnic groups and is negatively associated with receipt of breast and cervical cancer screening. This is an important issue that needs to be further explored and addressed in efforts to improve the delivery of healthcare to all groups.


Changes in neutrophil deformability following in vitro smoke exposure: mechanism and protection.
We have previously demonstrated a reduction in the deformability of neutrophils, exposed to whole particulate cigarette smoke in vitro, by measuring their ability to filter through a micropore membrane with pore dimensions similar to those of the average pulmonary capillary segment. In this study, we exposed neutrophils to the vapor phase of cigarette smoke and investigated the mechanism of the reduction in neutrophil filterability. Although both stimulated neutrophils and smoke-exposed neutrophils demonstrated an increase in filtration pressures, and thus a reduction in cell deformability, compared with control untreated cells, the spontaneous release of the reactive oxygen intermediates hydrogen peroxide and the superoxide anion was depressed following in vitro smoke exposure and there was no shape change to suggest that smoke-exposed cells were activated. The presence of erythrocytes, plasma, or the antioxidants albumin and glutathione prevented the reduction in cell filterability following smoke exposure, suggesting that in vitro smoke exposure, in our system, was mediated by oxidants. Indeed, the increase in filtration pressures, produced by smoke, could be mimicked by the addition of the oxidant hypochlorous acid. The cytoskeletal inhibitors cytochalasin B and D improved the filterability of smoke-exposed cells, suggesting that smoke may change neutrophil deformability through an effect on the actin component of the cytoskeleton. By contrast, colchicine, a specific inhibitor of the microtubules, had no effect. Preincubation with a monoclonal antibody to the CD18 antigen, to block this major neutrophil adhesive glycoprotein, did not alter the filtration pressure developed by stimulated or smoke-exposed neutrophils, suggesting that increased adhesivity was not the mechanism of the increase in filtration pressures observed following smoke exposure.(ABSTRACT TRUNCATED AT 250 WORDS)


Self-supervised Signal Denoising for Magnetic Particle Imaging.
Magnetic particle imaging (MPI) is a medical imaging technology with high resolution and high sensitivity, which tracks the distribution of superparamagnetic iron oxide nanoparticles (SPIONs) in the nonlinear response to dynamic excitation at a field-free region. However, various noises distort the signals resulting in a decline in imaging quality. Traditional threshold-based methods cannot remove dynamic noise in MPI signals. Therefore, a self-supervised denoising method is proposed to denoise MPI signals in this study. The approach adopted U-net as the backbone and modified the network for MPI signals. The network is trained using two periods of noisy signals and the shape prior knowledge of the MPI signals is introduced for promoting the convergence of the self-supervised net. The experiments show that the learning-based method can still denoising the MPI signal without labeling data and eventually improve image quality, and our approach can achieve the best performance compared with other self-supervised methods in MPI signal denoising.


Airway remodeling: The Drosophila model permits a purely epithelial perspective.
Airway remodeling is an umbrella term for structural changes in the conducting airways that occur in chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). The pathobiology of remodeling involves multiple mesenchymal and lymphoid cell types and finally leads to a variety of hardly reversible changes such as hyperplasia of goblet cells, thickening of the reticular basement membrane, deposition of collagen, peribronchial fibrosis, angiogenesis and hyperplasia of bronchial smooth muscle cells. In order to develop solutions for prevention or innovative therapies, these complex processes must be understood in detail which requires their deconstruction into individual building blocks. In the present manuscript we therefore focus on the role of the airway epithelium and introduce Drosophila melanogaster as a model. The simple architecture of the flies' airways as well as the lack of adaptive immunity allows to focus exclusively on the importance of the epithelium for the remodeling processes. We will review and discuss genetic and environmentally induced changes in epithelial structures and molecular responses and propose an integrated framework of research for the future.


[Adenoid cystic cancer of the breast].
A case of a mammary adenoid cystic carcinoma in a female of 45, is described. The tumour was histologically identical to the salivary gland tumours of the same name.


Altered cortical thickness of the superior frontal gyrus and fusiform gyrus in individuals with subthreshold social anxiety.
Subthreshold social anxiety (SSA) is a condition in which individuals experience social anxiety that does not reach the threshold required for a clinical diagnosis of a social anxiety disorder (SAD). Although SSA may not impair lives as severely as SAD, it can affect social functioning. However, only a few studies focused on structural neural correlates of SSA. We recruited 65 individuals with SSA and used the Leibowitz Social Anxiety Scale to assess their social and performance anxiety levels and other relevant measures of social anxiety. Voxel-wise whole-brain correlational analyses showed a positive association between the cortical thickness (CT) of the superior frontal gyrus (SFG) and social anxiety levels and a negative correlation between the CT of the fusiform gyrus (FG) and performance anxiety levels in individuals with SSA. Exploratory Pearson's correlation analyses showed significant positive correlations between the CT of the SFG and Generalized Anxiety Disorder-7 total scores and negative associations between the CT of the FG and Beck Anxiety Inventory total scores. Our study provides insight into the neural basis of SSA, particularly performance anxiety, by highlighting the association between CT in specific brain regions and SSA characteristics.


Discordance rates between preliminary and final radiology reports on cross-sectional imaging studies at a level 1 trauma center.
The goal was to determine discordance rates between preliminary radiology reports provided by on-call radiology house staff and final reports from attending radiologists on cross-sectional imaging studies requested by emergency department staff after hours. A triplicate carbon copy reporting form was developed to provide permanent records of preliminary radiology reports and to facilitate communication of discrepant results to the emergency department. Data were collected over 21 weeks to determine the number of discordant readings. Patients' medical records were reviewed to show whether discrepancies were significant or insignificant and to assess their impact on subsequent management and patient outcome. The emergency department requested 2830 cross-sectional imaging studies after hours and 2311 (82%) had a copy of the triplicate form stored in radiology archives. Discrepancies between the preliminary and final report were recorded in 47 (2.0%), with 37 (1.6%) considered significant: 14 patients needed no change, 13 needed a minor change, and 10 needed a major change in subsequent management. Ten (0.43%) of the discordant scans were considered insignificant. A random sample of 104 (20%) of the 519 scans without a paper triplicate form was examined. Seventy-one (68%) did have a scanned copy of the triplicate form in the electronic record, with a discrepancy recorded in 3 (4.2%), which was not statistically different from the main cohort (P = .18). Our study suggests a high level of concordance between preliminary reports from on-call radiology house staff and final reports by attending subspecialty radiologists on cross-sectional imaging studies requested by the emergency department.


[Short history of L-Dopa].
The introduction of L-Dopa has been a landmark in Neuroscience. Before the use of L-Dopa, Parkinson's disease (PD) was considered a disabling disease with no effective treatment. The development of L-Dopa followed a rationale approach: first, the discovery of dopamine deficiency in the striatum of patients with PD; and then the use of precursor of dopamine. Overall, the whole process took less than 12 years; this is a remarkable short time taking into account that the development of a similar crucial drug such as insulin took 50 years. In addition, the success of L-Dopa stimulated the neurochemistry research for all neurodegenerative diseases.


A functional connectivity-based neuromarker of sustained attention generalizes to predict recall in a reading task.
Sustaining attention to the task at hand is a crucial part of everyday life, from following a lecture at school to maintaining focus while driving. Lapses in sustained attention are frequent and often problematic, with conditions such as attention deficit hyperactivity disorder affecting millions of people worldwide. Recent work has had some success in finding signatures of sustained attention in whole-brain functional connectivity (FC) measures during basic tasks, but since FC can be dynamic and task-dependent, it remains unclear how fully these signatures would generalize to a more complex and naturalistic scenario. To this end, we used a previously defined whole-brain FC network - a marker of attention that was derived from a sustained attention task - to predict the ability of participants to recall material during a free-viewing reading task. Though the predictive network was trained on a different task and set of participants, the strength of FC in the sustained attention network predicted reading recall significantly better than permutation tests where behavior was scrambled to simulate chance performance. To test the generalization of the method used to derive the sustained attention network, we applied the same method to our reading task data to find a new FC network whose strength specifically predicts reading recall. Even though the sustained attention network provided significant prediction of recall, the reading network was more predictive of recall accuracy. The new reading network's spatial distribution indicates that reading recall is highest when temporal pole regions have higher FC with left occipital regions and lower FC with bilateral supramarginal gyrus. Right cerebellar to right frontal connectivity is also indicative of poor reading recall. We examine these and other differences between the two predictive FC networks, providing new insight into the task-dependent nature of FC-based performance metrics.


Mating genes in Calonectria and evidence for a heterothallic ancestral state.
The genus Calonectria includes many important plant pathogens with a wide global distribution. In order to better understand the reproductive biology of these fungi, we characterised the structure of the mating type locus and flanking genes using the genome sequences for seven Calonectria species. Primers to amplify the mating type genes in other species were also developed. PCR amplification of the mating type genes and multi-gene phylogenetic analyses were used to investigate the mating strategies and evolution of mating type in a collection of 70 Calonectria species residing in 10 Calonectria species complexes. Results showed that the organisation of the MAT locus and flanking genes is conserved. In heterothallic species, a novel MAT gene, MAT1-2-12 was identified in the MAT1-2 idiomorph; the MAT1-1 idiomorph, in most cases, contained the MAT1-1-3 gene. Neither MAT1-1-3 nor MAT1-2-12 was found in homothallic Calonectria (Ca.) hongkongensis, Ca. lateralis, Ca. pseudoturangicola and Ca. turangicola. Four different homothallic MAT locus gene arrangements were observed. Ancestral state reconstruction analysis provided evidence that the homothallic state was basal in Calonectria and this evolved from a heterothallic ancestor.


Effect of prostaglandin I2 analogs on macrophage inflammatory protein 1α in human monocytes via I prostanoid receptor and cyclic adenosine monophosphate.
Inflammation plays critical roles in atherosclerosis. Chemokines are responsible for leukocyte trafficking and involve in inflammatory diseases. Macrophage inflammatory protein 1α (MIP-1α) has been implicated in atherosclerotic lesion formation. Prostaglandin I2 (PGI2) analog, used in pulmonary hypertension, has been reported to have anti-inflammatory functions. However, little is known about its role in the MIP-1α production in human monocytes. We investigated the effects of 3 conventional (iloprost, beraprost, and treprostinil) and 1 new (ONO-1301) PGI2 analogs, on the expression of MIP-1α expression in human monocytes. Human primary monocytes from control subjects and THP-1 cell line were treated with PGI2 analogs, with or without lipopolysaccharide (LPS) stimulation. Supernatants were harvested to measure MIP-1α levels by enzyme-linked immunosorbent assay. To explore which receptors involved the effects of PGI2 analogs on the expression of MIP-1α expression, I prostanoid (IP) and E prostanoid, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-r receptor antagonists were used to pretreat THP-1 cells. Forskolin, a cyclic adenosine monophosphate (cAMP) activator, was also used to further confirm the cAMP involvement on the effect of PGI2 analogs in MIP-1α production. Three PGI2 analogs could suppress LPS-induced MIP-1α production in THP-1 cells and human primary monocytes. ONO-1301 had a similar effect. CAY 10449, an IP receptor antagonist, could reverse the suppressive effects on MIP-1α production of iloprost. Forskolin, a cAMP activator, also suppressed MIP-1α production in THP-1 cells. Prostaglandin I2 analogs suppressed LPS-induced MIP-1α production in human monocytes via the IP receptor and cAMP pathway. The PGI2 analog may be potential in the treatment for atherosclerosis.


Identification and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the Alagille syndrome critical region at 20p12.
Notch proteins are a family of closely related transmembrane receptors proven to be instrumental in cell fate decisions. Recently, Notch ligands Delta and Jagged have been identified in Drosophila and rat, respectively. We have isolated the human homolog of the rat Jagged1 gene, JAG1, from a CpG island in a YAC clone covering the Alagille syndrome critical region at chromosome 20p12 (tel-SNAP-D20S186-cen). Alagille syndrome is an autosomal dominant disorder characterized by neonatal jaundice, paucity of intrahepatic bile ducts, and abnormalities of the heart, skeleton, and eyes. The human Jagged1 (JAG1), therefore, appears to be a strong candidate gene for this disease. Here we describe the identification, full-length cDNA cloning, expression patterns, and precise physical location of this gene within the Alagille syndrome critical region.


Hepatic zinc response via metallothionein induction after tumor transplantation.
Based on previous findings that liver zinc and metallothionein (MT) levels increase after tumor transplantation, zinc metabolism in tumor-bearing mice was studied to clarify the role of zinc-MT in host defense systems. Zinc in the hepatic cytosolic MT fraction did not increase in tumor-bearing mice fed a zinc-deficient diet, suggesting that dietary zinc is necessary for apo-MT induction in the liver after tumor transplantation and is then incorporated into the apo-MT. When (65)ZnCl(2) was intravenously injected, liver (65)Zn levels in the tumor-bearing mice were higher than those in control mice for 72 h after the injection. Pancreatic and blood (65)Zn levels in tumor-bearing mice were lower than those in controls for 24 h (pancreas) and 6 h (blood) after the injection. These findings indicate that the hepatic zinc response via MT induction influences zinc metabolism in the body after tumor transplantation. Moreover, (65)Zn uptake in the liver of MT-deficient tumor-bearing mice was lower than that in control tumor-bearing mice 1 h after injection. (65)Zn uptake in the tumor and blood (65)Zn levels in the MT-deficient tumor-bearing mice were higher than those in the control tumor-bearing mice. Tumor weight increased more in MT-deficient mice than in control mice. The formation of zinc-MT in the liver of tumor-bearing mice might decrease blood zinc availability for tumors and other tissues, such as the pancreas.


Changing patterns in women seeking terminations of pregnancy: a trend analysis of data from one service provider 1996-2006.
The purpose of this study was to assess emerging trends in five characteristics: age, first ever pregnancy, contraception at time of conception, contraception choices post-operatively and referral source of women presenting for a termination of pregnancy (1996-2006) from a southern service in Adelaide, South Australia. A time-series study, from 1996 to 2006, using 3,434 cases from a termination of pregnancy service provider. Five characteristics associated with women attending for a termination of pregnancy were examined. Data were analysed using simple linear regression analyses and one-way ANOVA. There was a significant increase in women aged 30-50 years having a pregnancy terminated (ANOVA F1,9 = 5.901, p=0.041), with 67% of women using contraception at the time of conception. An increasing percentage of women chose not to use any contraception post-operatively (ANOVA F1,9 = 14.409, p=0.006), although 90% of women left the service with contraception. Additionally, there was a significant decline in women using natural family planning methods (ANOVA F1,9 = 13.654, p=0.006). Referral patterns changed significantly over the ten years, with fewer women being referred by a general practitioner (ANOVA F1,9 = 46.492, p=0.000) and family planning clinics (ANOVA F1,9 = 13.011, p=0.007). Termination of pregnancy patterns from a hospital based regional termination service have changed over the past ten years in this study population. There are implications for policy, strategic plans and health promotion activities in the southern region of Adelaide.


Ciliary body and choroidal melanomas treated by proton beam irradiation. Histopathologic study of eyes.
Proton beam irradiation resulted in clinical and/or histopathological regression of large ciliary body and choroidal melanomas in three eyes. Enucleations were performed 6 1/2 weeks, five months, and 11 months after irradiation for angle-closure glaucoma from total retinal detachment, increase in retinal detachment, and neovascular glaucoma, respectively. A direct relationship was found between the length of the interval from irradiation to enucleation and the degree of histologic changes. Vascular changes in the tumors included endothelial cell swelling and decreased lumen size, basement membrane thickening, collapse of sinusoidal vessels, and thrombosis of vessels. Although apparently unaltered tumor cells remained, degenerative changes occurred in some melanoma cells, including lipid vacuoles in cytoplasm, pyknotic nuclei, and balloon cell formation. Patchy areas of necrosis and proteinaceous exudate were present. Pigment-laden macrophages were found near tumor vessels and all had a substantial chronic inflammatory infiltrate. The effect of proton beam irradiation on tumor vessels probably plays an important role in uveal melanoma regression.


Etiology- and region-specific characteristics of transependymal cerebrospinal fluid flow.
Transependymal flow (TEF) of CSF, often delineated as T2-weighted hyperintensity adjacent to the lateral ventricles on MRI, is a known imaging finding, usually in the setting of CSF flow disturbances. Specific radiological features of TEF and their relationships with clinical markers of hydrocephalus and underlying disease pathology are not known. Here, the authors describe the radiological features and clinical associations of TEF with implications for CSF circulation in the setting of intracranial pathology. After obtaining IRB review and approval, the authors reviewed the radiological records of all patients who underwent intracranial imaging with CT or MRI at St. Louis Children's Hospital, St. Louis, Missouri, between 2008 and 2019 to identify individuals with TEF. Then, under direct review of imaging, TEF pattern, degree, and location and underlying pathology and other radiological and clinical features pertaining to CSF circulation and CSF disturbances were noted. TEF of CSF was identified in 219 patients and was most prevalent in the setting of neoplasms (72%). In 69% of the overall cohort, TEF was seen adjacent to the anterior aspect of the frontal horns and the posterior aspect of the occipital horns of the lateral ventricles, and nearly half of these patients also had TEF dorsal to the third ventricle near the splenium of the corpus callosum. This pattern was independently associated with posterior fossa medulloblastoma when compared with pilocytic astrocytoma (OR 4.75, 95% CI 1.43-18.53, p = 0.0157). Patients with congenital or neonatal-onset hydrocephalus accounted for 13% of patients and were more likely to have TEF circumferentially around the ventricles without the fronto-occipital distribution. Patients who ultimately required permanent CSF diversion surgery were more likely to have the circumferential TEF pattern, a smaller degree of TEF, and a lack of papilledema at the time of CSF diversion surgery. CSF transmigration across the ependyma is usually restricted to specific periventricular regions and is etiology specific. Certain radiological TEF characteristics are associated with tumor pathology and may reflect impaired or preserved ependymal fluid handling and global CSF circulation. These findings have implications for TEF as a disease-specific marker and in understanding CSF handling within the brain.


Joint Modeling of Social Determinants and Clinical Factors to Define Subphenotypes in Out-of-Hospital Cardiac Arrest Survival: Cluster Analysis.
Machine learning clustering offers an unbiased approach to better understand the interactions of complex social and clinical variables via integrative subphenotypes, an approach not studied in out-of-hospital cardiac arrest (OHCA). We conducted a cluster analysis for a cohort of OHCA survivors to examine the association of clinical and social factors for mortality at 1 year. We used a retrospective observational OHCA cohort identified from Medicare claims data, including area-level social determinants of health (SDOH) features and hospital-level data sets. We applied k-means clustering algorithms to identify subphenotypes of beneficiaries who had survived an OHCA and examined associations of outcomes by subphenotype. We identified 27,028 unique beneficiaries who survived to discharge after OHCA. We derived 4 distinct subphenotypes. Subphenotype 1 included a distribution of more urban, female, and Black beneficiaries with the least robust area-level SDOH measures and the highest 1-year mortality (2375/4417, 53.8%). Subphenotype 2 was characterized by a greater distribution of male, White beneficiaries and had the strongest zip code-level SDOH measures, with 1-year mortality at 49.9% (4577/9165). Subphenotype 3 had the highest rates of cardiac catheterization at 34.7% (1342/3866) and the greatest distribution with a driving distance to the index OHCA hospital from their primary residence >16.1 km at 85.4% (8179/9580); more were also discharged to a skilled nursing facility after index hospitalization. Subphenotype 4 had moderate median household income at US $51,659.50 (IQR US $41,295 to $67,081) and moderate to high median unemployment at 5.5% (IQR 4.2%-7.1%), with the lowest 1-year mortality (1207/3866, 31.2%). Joint modeling of these features demonstrated an increased hazard of death for subphenotypes 1 to 3 but not for subphenotype 4 when compared to reference. We identified 4 distinct subphenotypes with differences in outcomes by clinical and area-level SDOH features for OHCA. Further work is needed to determine if individual or other SDOH domains are specifically tied to long-term survival after OHCA.


Heterogeneous response of subsarcolemmal heart mitochondria to calcium.
The Ca2+ -uptake capacity of two distinct populations of rat heart mitochondria was characterized by monitoring Ca2+ movements directly (using both 45Ca and dual-wavelength spectroscopy) and indirectly (monitoring effects of Ca2+ on respiration, enzyme release, and morphology). Interfibrillar mitochondria accumulated up to 930 nmol/mg protein, whereas the capacity of the subsarcolemmal mitochondria for Ca2+ uptake was limited to 620 nmol/mg protein. In both mitochondrial populations, uptake of the maximal amount of Ca2+ was accompanied by increased proton permeability and subsequent release of the accumulated Ca2+. Even when calcium was taken up and apparently retained by the subsarcolemmal mitochondria, resting respiratory rates increased. Morphological examination of these mitochondria revealed that, although the majority of mitochondria were in the aggregated, energized conformation, a considerable number were disrupted. These damaged mitochondria were probably responsible for the increased resting respiratory rates. No net release of calcium was observed, however, since the intact mitochondria could take up any calcium released by the damaged mitochondria. Morphological disruption of this subset of subsarcolemmal mitochondria was accompanied by release of not only cytochrome c but also of mitochondrial marker enzymes into the extramitochondrial milieu. In contrast, the interfibrillar mitochondria were relatively unaffected in terms of morphology and marker enzyme release, even when their capacity to retain calcium was exceeded.


Hydrodynamics Defines the Stable Swimming Direction of Spherical Squirmers in a Nematic Liquid Crystal.
We present a study of the hydrodynamics of an active particle-a model squirmer-in an environment with a broken rotational symmetry: a nematic liquid crystal. By combining simulations with analytic calculations, we show that the hydrodynamic coupling between the squirmer flow field and liquid crystalline director can lead to reorientation of the swimmers. The preferred orientation depends on the exact details of the squirmer flow field. In a steady state, pushers are shown to swim parallel with the nematic director while pullers swim perpendicular to the nematic director. This behavior arises solely from hydrodynamic coupling between the squirmer flow field and anisotropic viscosities of the host fluid. Our results suggest that an anisotropic swimming medium can be used to characterize and guide spherical microswimmers in the bulk.


[Physico-chemical characteristics of endogenous regulatory oligopeptides].
Analysis of amino acid residue content in endogenous regulatory oligopeptides possessing a preset spectrum of functional activity has been made. It has been shown that compared to proteins the oligopeptides contain a greater number of positively charged and cyclic radicals. All 525 oligopeptides with the preset spectrum of functional activity contained in EROP-Moscow data bank were found to have the same physicochemical characteristics.


Overexpression of SlCRF6 in tomato inhibits leaf development and affects plant morphology.
Cytokinin response factors (CRFs) are transcription factors (TFs) that are specific to plants and have diverse functions in plant growth and stress responses. However, the precise roles of CRFs in regulating tomato plant architecture and leaf development have not been comprehensively investigated. Here, we identified a novel CRF, SlCRF6, which is involved in the regulation of plant growth via the gibberellin (GA) signaling pathway. SlCRF6-overexpressing (SlCRF6-OE) plants displayed pleiotropic phenotypic changes, including reduced internode length and leaf size, which caused dwarfism in tomato plants. This dwarfism could be alleviated by application of exogenous GA3. Remarkably, quantitative real-time PCR (qRTPCR), a dual luciferase reporter assay and a yeast one-hybrid (Y1H) assay revealed that SlCRF6 promoted the expression of SlDELLA (a GA signal transduction inhibitor) in vivo. Furthermore, transgenic plants displayed variegated leaves and diminished chlorophyll content, resulting in decreased photosynthetic efficiency and less starch than in wild-type (WT) plants. The results of transient expression assays and Y1H assays indicated that SlCRF6 suppressed the expression of SlPHAN (leaf morphology-related gene). Collectively, these findings suggest that SlCRF6 plays a crucial role in regulating tomato plant morphology, leaf development, and the accumulation of photosynthetic products.


Accumulation and persistence of DNA adducts in respiratory tissue of rats following multiple administrations of the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone.
4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major nitrosamine formed in tobacco smoke, induces a high incidence of lung, liver, and nasal cavity tumors in rats. Since alpha-hydroxylation of NNK by target tissues can lead to the generation of a methylating agent, the formation and removal of 7-methylguanine and the promutagenic lesions O6-methylguanine (O6mGua) and O4-methyldeoxythymidine were determined over 12 days of NNK administration to rats (100 mg/kg/day). DNA alkylation was greatest in the nasal mucosa, followed by liver and lung after 1 dose of NNK. No DNA adducts were detected in kidney and brain under these conditions. The concentration of O6mGua increased steadily in lung throughout the treatment regimen, while O6-methylguanine-DNA methyltransferase decreased to less than 5% of control. The concentration of O4-methyldeoxythymidine in lung DNA reached a steady state after 4 days of carcinogen treatment. After NNK treatment was discontinued, O6mGua persisted, while O4-methyldeoxythymidine was removed rapidly in the lung, suggesting that different repair pathways exist for the removal of these adducts in vivo. In hepatocytes, nonparenchymal cells, and nasal mucosa, O6mGua concentrations were maximal after 1-2 days and declined by 50-80% during the remaining 10 days of treatment. The decrease in O6mGua levels in nasal mucosa paralleled a decline in O6-methylguanine-DNA methyltransferase activity and was associated with marked cytotoxicity to Bowman's glands, portions of the lateral nasal gland, and the olfactory and respiratory mucosa during carcinogen treatment. In contrast, the decline in O6mGua in hepatocytes was attributed to the induction of O6-methylguanine-DNA methyltransferase activity, since an 18-fold reduction in the ratio of O6mGua:7-methylguanine was observed over the 12 days of treatment. These studies have demonstrated a marked accumulation of promutagenic DNA adducts in target tissues during repeated exposure to NNK.


A review of osteoporosis management in younger premenopausal women.
The purpose of this review is to describe the available evidence for osteoporosis treatments in young and premenopausal women. A review of articles evaluating the treatment or prevention of osteoporosis in young (age less than 50 years) or premenopausal women was conducted. Several trials evaluating the treatment of anorexia nervosa and use of hormone therapy in those women, the use of bisphosphonates in women undergoing chemotherapy for breast cancer and the use of bisphosphonates, teriparatide and vitamin D in women with glucocorticoid-induced osteoporosis are described. Limited data were found to support the treatment of osteoporosis in women with idiopathic osteoporosis or cystic fibrosis, or after kidney transplant. The evidence for treatment of osteoporosis in premenopausal women is not nearly as robust as that for postmenopausal osteoporosis. Although fracture risk in the premenopausal population is low, women with secondary osteoporosis may benefit from treatment with various agents, depending upon the condition.


[Adult cardiopulmonary bypass in the twentieth century: science, art or empiricism?].
The aim of the present review is to highlight some less discussed aspects of the cardiopulmonary bypass (CPB), taking into consideration the physiology, physiopathology, and some new technologies of perfusion. Thus, some points, to a certain extent philosophical, have motivated this revision: a) To preserve and update the surgeon knowledge regarding CPB, even to keep his/her pedagogical leadership on his/her surgical team; b) To question if elderly and diabetic patients, as a result of their individual characteristics deserve more appropriate protocols similar to those adopted for children; c) One third aspect would be the questioning of the systemic inflammatory reaction caused by the blood exposure to CPB non-endothelized circuit surface, in face of the increasing importance of blood contact with the surgical wound; d) In relation to the treatment of the vasoplegic syndrome, methylene blue continues being the best therapeutical option, even so, many times are not efficient on account of a highly probable existence of a "therapeutical window" based on the guanylate cyclase dynamics of action (saturation and synthesis "de novo") and; finally, e) The reason of the title, highlighting that based on its current patterns, would the CPB be an outcome of empiricism, art, or science? The bottom line of this article carries the certainty of that as much as the empiricism, art, and science are highly related to CPB.


Production of 1,25-dihydroxyvitamin D3 by human T cell lymphotrophic virus-I-transformed lymphocytes.
The human T cell lymphotrophic virus type I (HTLV-I) has recently been identified in a T cell lymphoma associated with hypercalcemia and increased bone turnover. Since increased serum concentrations of 1,25-dihydroxyvitamin D have been reported in this disease, we have examined the capacity of HTLV-I-infected cord blood lymphocytes to metabolize 25-hydroxyvitamin D3. Our results demonstrate that HTLV-I-infected cells have the capacity to metabolize 25-hydroxyvitamin D3 to a substance that co-migrates with 1,25-dihydroxyvitamin D3 by high performance liquid chromatography over a silica column using either 12% isopropanol in hexane or 5% isopropanol in dichloromethane. The metabolite binds to the 1,25-dihydroxyvitamin D3 receptor in rat osteosarcoma cells and stimulates bone resorption in cultures of fetal rat long bones. Mass spectrometric analysis of the metabolite confirmed the presence of 1,25-dihydroxyvitamin D3. Production of 1,25-dihydroxyvitamin D by lymphoma cells may contribute to the pathogenesis of the hypercalcemia seen in patients with HTLV-I-associated T cell lymphomas.


Cloning and sequencing of the gene encoding a 125-kilodalton surface-layer protein from Bacillus sphaericus 2362 and of a related cryptic gene.
Using the vector pGEM-4-blue, a 4,251-base-pair DNA fragment containing the gene for the surface (S)-layer protein of Bacillus sphaericus 2362 was cloned into Escherichia coli. Determination of the nucleotide sequence indicated an open reading frame (ORF) coding for a protein of 1,176 amino acids with a molecular size of 125 kilodaltons (kDa). A protein of this size which reacted with antibody to the 122-kDa S-layer protein of B. sphaericus was detected in cells of E. coli containing the recombinant plasmid. Analysis of the deduced amino acid sequence indicated a highly hydrophobic N-terminal region which had the characteristics of a leader peptide. The first amino acid of the N-terminal sequence of the 122-kDa S-layer protein followed the predicted cleavage site of the leader peptide in the 125-kDa protein. A sequence characteristic of promoters expressed during vegetative growth was found within a 177-base-pair region upstream from the ORF coding for the 125-kDa protein. This putative promoter may account for the expression of this gene during the vegetative growth of B. sphaericus and E. coli. The gene for the 125-kDa protein was followed by an inverted repeat characteristic of terminators. Downstream from this gene (11.2 kilobases) was an ORF coding for a putative 80-kDa protein having a high sequence similarity to the 125-kDa protein. Evidence was presented indicating that this gene is cryptic.


Cryptococcal urease promotes the accumulation of immature dendritic cells and a non-protective T2 immune response within the lung.
Urease, a major virulence factor for Cryptococcus neoformans, promotes lethal meningitis/encephalitis in mice. The effect of urease within the lung, the primary site of most invasive fungal infections, is unknown. An established model of murine infection that utilizes either urease-producing (wt and ure1::URE1) or urease-deficient (ure1) strains (H99) of C. neoformans was used to characterize fungal clearance and the resultant immune response evoked by these strains within the lung. Results indicate that mice infected with urease-producing strains of C. neoformans demonstrate a 100-fold increase in fungal burden beginning 2 weeks post-infection (as compared with mice infected with urease-deficient organisms). Infection with urease-producing C. neoformans was associated with a highly polarized T2 immune response as evidenced by increases in the following: 1) pulmonary eosinophils, 2) serum IgE levels, 3) T2 cytokines (interleukin-4, -13, and -4 to interferon-gamma ratio), and 4) alternatively activated macrophages. Furthermore, the percentage and total numbers of immature dendritic cells within the lung-associated lymph nodes was markedly increased in mice infected with urease-producing C. neoformans. Collectively, these data define cryptococcal urease as a pulmonary virulence factor that promotes immature dendritic cell accumulation and a potent, yet non-protective, T2 immune response. These findings provide new insights into mechanisms by which microbial factors contribute to the immunopathology associated with invasive fungal disease.


Bacterial toxins and the nervous system: neurotoxins and multipotential toxins interacting with neuronal cells.
Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins) leading to characteristics neurological affections. But many other toxins are multifunctional and recognize a wider range of cell types including neuronal cells. Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins can pass the blood brain barrier and directly act on specific neurons.


[Bilateral obstruction of the ureters as a complication of iliac aneurysms].
A case of bilateral obstruction of the ureters secondary to iliac aneurysms is reported. While perianeurysmal fibrosis in so-called "inflammatory" aneurysms causes the obstruction in most cases, this is a report on a case of compression of both ureters by huge aneurysms without inflammatory reaction. Recurrent back pain of urinary type is the first symptom in 75% of the cases. Ultrasonography shows hydronephrosis and deviation of the ureters as well as the aneurysms. Intravenous pyelography, angiography and CT-scan are necessary to show the real size of the ureters and the aneurysm. Treatment of choice is resection of the aneurysm and replacement by a prosthesis. Ureterolysis may be necessary if the ureters are enveloped by perianeurysmal fibrosis.


Zinc toxicity with pancreatic acinar necrosis in piglets receiving total parenteral nutrition.
Two Hampshire-Duroc cross piglets maintained on 100% total parenteral nutrition (TPN) for 3 weeks developed pancreatic epithelial cell necrosis, diffuse acinar atrophy, and marked interstitial fibrosis. In addition, the piglets had severe villus atrophy in the small intestine as a result of TPN. Atomic absorption spectrophotometric analysis of liver samples revealed toxic hepatic zinc levels (513.5 and 491.2 ppm) in the TPN piglets (40-90 ppm in control piglets). Administering TPN bypasses homeostatic control mechanisms regulating zinc absorption at the gastrointestinal level and may reduce pancreatic secretion contributing to the accumulation of zinc in tissues. Intestinal villus atrophy, a sequela to TPN, may have also affected zinc excretion by impairing intestinal flux and desquamation. These factors should be considered in formulating TPN solutions and zinc levels administered must be reduced accordingly to avoid toxicity. Furthermore, sources and tissue levels of zinc should be investigated when necrosis, acinar atrophy, and fibrosis of the pancreas are encountered in young pigs.


Misdiagnosis of multiple sclerosis: Impact of the 2017 McDonald criteria on clinical practice.
Misdiagnosis of multiple sclerosis (MS) (the incorrect assignment of a diagnosis of MS) remains a problem in contemporary clinical practice. Studies indicate that misdiagnosed patients are often exposed to prolonged unnecessary health care risks and morbidity. The recently published 2017 revision of the McDonald criteria for the diagnosis of MS provides an opportunity to consider the effect of these revisions on the problem of MS misdiagnosis. The 2017 McDonald criteria include several new recommendations to reduce potential for misdiagnoses. The criteria should be used for the types of patients in which validation studies were performed, specifically those patients who present with typical demyelinating syndromes. MRI lesion characteristics were defined for which McDonald criteria would be expected to perform with accuracy. However, 2017 revisions, which now include assessment for cortical lesions, and the inclusion of symptomatic lesions and positive oligoclonal bands for the fulfillment of diagnostic criteria, may have the potential to lead to misdiagnosis of MS if not applied appropriately. While the 2017 McDonald criteria integrate issues relating to MS misdiagnosis and incorporate specific recommendations for its prevention more prominently than prior criteria, the interpretation of clinical and radiologic assessments upon which these criteria depend will continue to allow misdiagnoses. In patients with atypical clinical presentations, the revised McDonald criteria may not be readily applied. In those situations, further evaluation or monitoring rather than immediate diagnosis of MS is prudent.


Metal-organic frameworks for enzyme immobilization and nanozymes: A laccase-focused review.
Laccases are natural catalysts with remarkable catalytic activity. However, their application is limited by their lack of stability. Metal-organic frameworks (MOFs) have emerged as a promising alternative for enzyme immobilization. Enzymes can be immobilized in MOFs via two approaches: postsynthetic immobilization and in situ immobilization. In postsynthetic immobilization, an enzyme is embedded after MOF formation by covalent interactions or adsorption. In contrast, in in situ immobilization, a MOF is formed in the presence of an enzyme. Additionally, MOFs have exhibited intrinsic enzyme-like activity. These materials, known as nanozymes when they have the ability to replace enzymes in certain catalytic processes, have multiple key advantages, such as low cost, easy preparation, and large surface areas. This review presents a general overview of the most recent advances in both enzyme@MOF biocatalysts and MOF-based nanozymes in different applications, with a focus on laccase, which is one of the most widely investigated enzymes with excellent industrial potential.


DC-SIGN mediated internalisation of glycosylated extracellular vesicles from Schistosoma mansoni increases activation of monocyte-derived dendritic cells.
Helminths like Schistosoma mansoni release excretory/secretory (E/S) products that modulate host immunity to enable infection. Extracellular vesicles (EVs) are among these E/S products, yet molecular mechanisms and functionality of S. mansoni EV interaction with host immune cells is unknown. Here we demonstrate that EVs released by S. mansoni schistosomula are internalised by human monocyte-derived dendritic cells (moDCs). Importantly, we show that this uptake was mainly mediated via DC-SIGN (CD209). Blocking DC-SIGN almost completely abrogated EV uptake, while blocking mannose receptor (MR, CD206) or dendritic cell immunoreceptor (DCIR, CLEC4A) had no effect on EV uptake. Mass spectrometric analysis of EV glycans revealed the presence of surface N-glycans with terminal Galβ1-4(Fucα1-3)GlcNAc (LewisX) motifs, and a wide array of fucosylated lipid-linked glycans, including LewisX, a known ligand for DC-SIGN. Stimulation of moDCs with schistosomula EVs led to increased expression of costimulatory molecules CD86 and CD80 and regulatory surface marker PD-L1. Furthermore, schistosomula EVs increased expression of IL-12 and IL-10 by moDCs, which was partly dependent on the interaction with DC-SIGN. These results provide the first evidence that glycosylation of S. mansoni EVs facilitates the interaction with host immune cells and reveals a role for DC-SIGN and EV-associated glycoconjugates in parasite-induced immune modulation.


Finite-size effects in the static structure factor S(k) and S(0) for a two-dimensional Yukawa liquid.
Finite-size effects in the static structure factor S(k) are analyzed for an amorphous substance. As the number of particles is reduced, S(0) increases greatly, up to an order of magnitude. Meanwhile, there is a decrease in the height of the first peak S_{peak}. These finite-size effects are modeled accurately by the Binder formula for S(0) and our empirical formula for S_{peak}. Procedures are suggested to correct for finite-size effects in S(k) data and in the hyperuniformity index H≡S(0)/S_{peak}. These principles generally apply to S(k) obtained from particle positions in noncrystalline substances. The amorphous substance we simulate is a two-dimensional liquid, with a soft Yukawa interaction modeling a dusty plasma experiment.


In silico strategies to identify protein-protein interaction modulator in cell-to-cell transmission of SARS CoV2.
RNA sequence data from SARS CoV2 patients helps to construct a gene network related to this disease. A detailed analysis of the human host response to SARS CoV2 with expression profiling by high-throughput sequencing has been accomplished with primary human lung epithelial cell lines. Using this data, the clustered gene annotation and gene network construction are performed with the help of the String database. Among the four clusters identified, only 1 with 44 genes could be annotated. Interestingly, this corresponded to basal cells with p = 1.37e - 05, which is relevant for respiratory tract infection. Functional enrichment analysis of genes present in the gene network has been completed using the String database and the Network Analyst tool. Among three types of cell-cell communication, only the anchoring junction between the basal cell membrane and the basal lamina in the host cell is involved in the virus transmission. In this junction point, a hemidesmosome structure plays a vital role in virus spread from one cell to basal lamina in the respiratory tract. In this protein complex structure, different integrin protein molecules of the host cell are used to promote the spread of virus infection into the extracellular matrix. So, small molecular blockers of different anchoring junction proteins, such as integrin alpha 3, integrin beta 1, can provide efficient protection against this deadly viral disease. ORF8 from SARS CoV2 virus can interact with both integrin proteins of human host. By using molecular docking technique, a ternary complex of these three proteins is modelled. Several oligopeptides are predicted as modulators for this ternary complex. In silico analysis of these modulators is very important to develop novel therapeutics for the treatment of SARS CoV2.


Comparing in vitro affinity measurements of antibodies to TfR1: Surface plasmon resonance versus on-cell affinity.
Despite years of utilizing the transferrin receptor 1 (TfR1) to transport large biomolecules into the brain, there is no consensus on how to optimally measure affinity to it. The aim of this study was to compare different methods for measuring the affinities of anti-TfR1 antibodies. Antibodies 15G11, OX26 and 8D3 are known to successfully carry large biologics across the blood-brain barrier in humans, rats, and mice, respectively. The affinity to their respective species of TfR1 was measured with different surface plasmon resonance setups in Biacore and an on-cell assay. When the antibody was captured and TfR1 was the analyte, the dissociation in Biacore was very slow. The dissociation was faster when the antibody was the analyte and TfR1 was the ligand. The Biacore setup with capture of N-terminal FLAG-tag TfR1 yielded the most similar apparent affinities as the cell assay. In conclusion, it is important to evaluate assay parameters including assay orientation, surface capture method, and antibody-format when comparing binding kinetics for TfR1 antibodies. Although it seems possible to determine relative affinities of TfR1 antibodies using the methods described here, both the FLAG-tag TfR1 capture setup and cell assays likely yield apparent affinities that are most translatable in vivo.


Coiled-coil inspired functional inclusion bodies.
Recombinant protein expression in bacteria often leads to the formation of intracellular insoluble protein deposits, a major bottleneck for the production of soluble and active products. However, in recent years, these bacterial protein aggregates, commonly known as inclusion bodies (IBs), have been shown to be a source of stable and active protein for biotechnological and biomedical applications. The formation of these functional IBs is usually facilitated by the fusion of aggregation-prone peptides or proteins to the protein of interest, leading to the formation of amyloid-like nanostructures, where the functional protein is embedded. In order to offer an alternative to the classical amyloid-like IBs, here we develop functional IBs exploiting the coiled-coil fold. An in silico analysis of coiled-coil and aggregation propensities, net charge, and hydropathicity of different potential tags identified the natural homo-dimeric and anti-parallel coiled-coil ZapB bacterial protein as an optimal candidate to form assemblies in which the native state of the fused protein is preserved. The protein itself forms supramolecular fibrillar networks exhibiting only α-helix secondary structure. This non-amyloid self-assembly propensity allows generating innocuous IBs in which the recombinant protein of interest remains folded and functional, as demonstrated using two different fluorescent proteins. Here, we present a proof of concept for the use of a natural coiled-coil domain as a versatile tool for the production of functional IBs in bacteria. This α-helix-based strategy excludes any potential toxicity drawback that might arise from the amyloid nature of β-sheet-based IBs and renders highly active and homogeneous submicrometric particles.


The effect of polymorphisms in candidate genes on the long-term risk of lipodystrophy and dyslipidemia in HIV-infected white patients starting antiretroviral therapy.
We investigated whether polymorphisms in human candidate genes could be associated with a different risk of developing lipodystrophy and dyslipidemia in HIV-infected patients starting combination antiretroviral therapy (cART). Genomic DNA samples from white HIV-1-infected patients were analyzed for seven polymorphisms located in the MDR1, TNF-α, APM1, APOE, and LPL genes. Lipid data were retrospectively collected beginning with the initiation of cART. Lipodystrophy was assessed cross-sectionally and then prospectively. The association with lipodystrophy and National Cholesterol Evaluation Program Adult Treatment Panel III-defined lipid thresholds was analyzed using survival analysis and logistic regression. One-hundred and seventy-four patients were genotyped. In 151 patients assessed for lipodystrophy, MDR1 3435 T homozygosis was associated with a higher hazard (adjusted hazard ratio, aHR, versus CT 0.25; p=0.02) and tumor necrosis factor (TNF)-α 308 G homozygosis with a lower hazard (vs. AA aHR 2.14; p=0.04) of developing trunk fat accumulation after adjusting for gender and initial cART type. The TNF 238 GG genotype was associated with a higher risk of developing low HDL-cholesterol levels (adjusted odd ratio, aOR, 5.91; p=0.01) while patients carrying the LPL S477X mutation were at lower risk of reaching high non-HDL-cholesterol levels (aOR 0.39; p=0.05). The APOEe3/3 genotype patients were at lower risk (aOR 0.26, p=0.015), whereas the adiponectin 276 GT carriers were at higher risk of developing hypertriglyceremia (vs. GG aOR 3.10; p=0.04). Knowledge of the effect of genetic determinants on dyslipidemia and lipodystrophy may prompt the investigation of potential pathogenetic mechanisms and might eventually be used for guiding individualized treatment decisions.


Comparison of two caudolateral approaches to the scapulohumeral joint for treatment of osteochondritis dissecans in dogs.
Two caudolateral approaches to the canine scapulohumeral joint that do not require myotomy, tenotomy, or osteotomy were used to expose the humeral heads of both scapulohumeral joints in 10 clinically normal dogs. One approach (method 1) was used on the left shoulder of 5 dogs and on the right shoulder of the other 5 dogs. The other approach (method 2) was used on the opposite joints. The amount of humeral head articular cartilage that could be exposed with each approach was measured. The amount of articular cartilage exposed with method 1 was significantly greater than that exposed with method 2 (P less than 0.0001). Method 1 also provided for exposure of the caudomedial aspect of the scapulohumeral joint. Method 1 was used unilaterally in 20 dogs with osteochondritis dissecans. This approach provided excellent exposure of the humeral head and osteochondritis dissecans lesion. Of the 16 dogs that were available for follow-up evaluation, 1 developed a seroma after surgery. Other complications were not observed or reported.


Circuit resistance training in persons with complete paraplegia.
We assessed the metabolic and heart rate (HR) responses to a single session of circuit resistance training (CRT) in six subjects with complete paraplegia (T5-T12 levels) in order to determine the caloric cost of the exercise. Subjects underwent isoinertial weight training exercises with interspersed periods of high-cadence, low-resistance arm ergometry (AE). Following protocol familiarization, subjects completed one session of CRT during which continuous monitoring of HR, oxygen uptake (VO2), and respiratory exchange ratio (RER = VCO2/VO2) was performed. Caloric cost was calculated from the exercise VO2 values across the CRT session. A peak arm exercise test allowed data to be expressed as percentages of peak VO2 and HR. Subjects displayed mean VO2 values of 11.6 +/- 2.4 ml/kg/min (mean +/- SD) and a mean HR of 136 +/- 17 beats/min across the CRT session, corresponding with 49.0% of peak VO2 and 76.8% of peak HR. The RER values ranged from 0.96 to 1.19 and averaged above unity throughout the CRT session. Despite the modest absolute VO2 during exercise, CRT satisfies operational criteria developed for cardiorespiratory exercise prescriptions in persons without disability. The RER values recorded indicate that CRT is intense work that relies primarily on glycolytic metabolism.


The Genetic Puzzle of Familial Atrial Fibrillation.
Atrial fibrillation (AF) is the most common clinical tachyarrhythmia. In Europe, AF is expected to reach a prevalence of 18 million by 2060. This estimate will increase hospitalization for AF to 4 million and 120 million outpatient visits. Besides being an independent risk factor for mortality, AF is also associated with an increased risk of morbidities. Although there are many well-defined risk factors for developing AF, no identifiable risk factors or cardiac pathology is seen in up to 30% of the cases. The heritability of AF has been investigated in depth since the first report of familial atrial fibrillation (FAF) in 1936. Despite the limited value of animal models, the advances in molecular genetics enabled identification of many common and rare variants related to FAF. The importance of AF heritability originates from the high prevalence of lone AF and the lack of clear understanding of the underlying pathophysiology. A better understanding of FAF will facilitate early identification of people at high risk of developing FAF and subsequent development of more effective management options. In this review, we reviewed FAF epidemiological studies, identified common and rare variants, and discussed their clinical implications and contributions to developing new personalized therapeutic strategies.


An atlas of fish genome evolution reveals delayed rediploidization following the teleost whole-genome duplication.
Teleost fishes are ancient tetraploids descended from an ancestral whole-genome duplication that may have contributed to the impressive diversification of this clade. Whole-genome duplications can occur via self-doubling (autopolyploidy) or via hybridization between different species (allopolyploidy). The mode of tetraploidization conditions evolutionary processes by which duplicated genomes return to diploid meiotic pairing, and subsequent genetic divergence of duplicated genes (cytological and genetic rediploidization). How teleosts became tetraploid remains unresolved, leaving a fundamental gap in the interpretation of their functional evolution. As a result of the whole-genome duplication, identifying orthologous and paralogous genomic regions across teleosts is challenging, hindering genome-wide investigations into their polyploid history. Here, we combine tailored gene phylogeny methodology together with a state-of-the-art ancestral karyotype reconstruction to establish the first high-resolution comparative atlas of paleopolyploid regions across 74 teleost genomes. We then leverage this atlas to investigate how rediploidization occurred in teleosts at the genome-wide level. We uncover that some duplicated regions maintained tetraploidy for more than 60 million years, with three chromosome pairs diverging genetically only after the separation of major teleost families. This evidence suggests that the teleost ancestor was an autopolyploid. Further, we find evidence for biased gene retention along several duplicated chromosomes, contradicting current paradigms that asymmetrical evolution is specific to allopolyploids. Altogether, our results offer novel insights into genome evolutionary dynamics following ancient polyploidizations in vertebrates.


Chromium tolerance and accumulation in Aspergillus flavus isolated from tannery effluent.
Cr(VI) tolerance in Aspergillus flavus, strain SFL, isolated from tannery effluent was measured and compared with a reference strain of A. flavus, A1120. On solid medium, SFL had a high level of Cr(VI) tolerance (1,600 mg/L), which was 16 times that of A1120 and greater than most previously analyzed fungal strains. When in 100 mg/L of Cr(VI), SFL completely depleted Cr(VI) within 72 h while A1120 depleted 85% of Cr(VI). SFL was more effective in reducing extracellular Cr(VI) than A1120. While A1120 showed greater biosorption of Cr(VI) than SFL, intracellular accumulation was approximately 50% greater in SFL and was more energy-dependent than A1120. Cr(VI) modified the external surface of the hyphae. Cr speciation detected the presence of only Cr(III), corresponding to Cr(OH)3 , which precipitated on the hyphal surface. Cr(VI) bound to the functional groups carboxyl, amine, and hydroxyl in both SFL and A1120. Transmission electron microscopy energy-dispersive X-ray detected Cr on the fungal wall and within membrane-bound organelles of the cytoplasm. In conclusion, the greater tolerance of SFL to Cr(VI) relative to A1120 is due to more effective energy-dependant uptake of Cr(VI) into the cell and increased capacity of SFL to store Cr in intracellular vacuoles compared with A1120.


Communities' awareness, perception and participation in the Community-Based Medical Education of the University of Maiduguri.
Community-based medical education (CBME) is no longer a new innovation in medical education since the establishment of The Network: Towards Unity for Health (The Network: TUFH) 25 years ago. The CBME of the University of Maiduguri medical college is 14 years old and has never been assessed in terms of the population it serves. The study was conducted to determine the level of awareness, perception, and participation of the communities in CBME. A cross-sectional survey was carried out in 11 village units of three Local Government Areas (LGAs) using a 14-item structured questionnaire administered to adults in randomly selected households. The questionnaire was based on guide questions used for focus group discussions held earlier with community leaders. Awareness of students' visits among respondents was 73.7%. Knowledge of the frequency of presence of the students in the communities was 72.2%. "To examine and treat" (33.6%) and "to ask questions" (16.6%) were the most prominent reasons given for the visits. The majority of respondents perceived the visits as beneficial (72.2%). More frequent visits were requested by 54.4% of the respondents. The communities were willing to be more accessible and felt that the LGAs should provide more logistic support to the program. This study revealed that communities were aware of students' visits and knew reasons for the visits, thought visits were beneficial, and were willing to provide more support for these visits.


The physiopathologic background and standard technique of selective proximal vagotomy and pyloroplasty.
The observations collected on selective proximal vagotomy plus functionally and structurally appropriate pyloroplasty during a period of 13 years have demonstrated that inadequate selective proximal vagotomy results in an excessive rate of relapses and that adequate selective proximal vagotomy without drainage leads to stasis, resulting in retention difficulites or secondary gastric ulcers. In both instances, reoperations are to be expected. If complete healing without resection is what one wishes to accomplish, and who doesn't, adequate selective proximal vagotomy combined with structurally and functionally appropriate pyloroplasty is indicated. This combination can now be considered a reliable standardized procedure of curative nonresection surgical therapy for gastroduodenal ulcers.


[Pruritus: diagnostic strategy and therapeutic approach].
Pruritus, defined as an abnormal cutaneous sensation that will provoke the desire to scratch, is the leading symptom of cutaneous disorders. However, some pruritus will be the only sign of several internal pathologies. More than hundreds etiologies are possibles. That is why a diagnostic algorithm is necessary for an optimal care and to define which investigations to make. This algorithm will distinguish localized pruritus and diffuse pruritus. The presence of specifics cutaneous lesions will be constitute a great help for making diagnosis.


A critical evaluation of influence of ethanol and diet on salsolinol enantiomers in humans and rats.
(R/S)-Salsolinol (SAL), a condensation product of dopamine (DA) with acetaldehyde, has been speculated to have a role in the etiology of alcoholism. Earlier studies have shown the presence of SAL in biological fluids and postmortem brains from both alcoholics and nonalcoholics. However, the involvement of SAL in alcoholism has been controversial over several decades, since the reported SAL levels and their changes after ethanol exposure were not consistent, possibly due to inadequate analytical procedures and confounding factors such as diet and genetic predisposition. Using a newly developed mass spectrometric method to analyze SAL stereoisomers, we evaluated the contribution of ethanol, diet, and genetic background to SAL levels as well as its enantiomeric distribution. Simultaneous measurement of SAL enantiomers and DA were achieved by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). Plasma samples were collected from human subjects before and after banana (a food rich in SAL) intake, and during ethanol infusion. Rat plasma and brain samples were collected at various time points after the administration of SAL or banana by gavage. The brain parts including nucleus accumbens (NAC) and striatum (STR) were obtained from alcohol-non-preferring (NP) or alcohol-preferring (P) rats as well as P-rats which had a free access to ethanol (P-EtOH). Plasma SAL levels were increased significantly after banana intake in humans. Consistently, administration of banana to rats also resulted in a drastic increase of plasma SAL levels, whereas brain SAL levels remained unaltered. Acute ethanol infusion did not change SAL levels or R/S ratio in plasma from healthy humans. The levels of both SAL isomers and DA were significantly lower in the NAC of P rats in comparison to NP rats. The SAL levels in NAC of P rats remained unchanged after chronic free-choice ethanol drinking. There were decreasing trends of SAL in STR and DA in both brain regions. No changes in enantiomeric ratio were observed after acute or chronic ethanol exposure. SAL from dietary sources is the major contributor to plasma SAL levels. No significant changes of SAL plasma levels or enantiomeric distribution after acute or chronic ethanol exposure suggest that SAL may not be a biomarker for ethanol drinking. Significantly lower SAL and DA levels observed in NAC of P rats may be associated with innate alcohol preference.


Post splenectomy fatal pulmonary embolism in a patient with moderate hemophilia a.
Hemophilia A is a bleeding disorder caused by defective production of factor VIII. The main concern associated with the disease is bleeding, especially after trauma and surgeries. Factor VIII replacement therapy is associated with substantial decrease of bleeding events during surgery. However, there have been a number of reports of thromboemblic events in this situation. The present report describes a case of moderate hemophilia A in which splenectomy did lead to pulmonary embolism and subsequent death.The patient was a 25-year-old man with hemophilia A admitted after a car accident and trauma to left lower chest and abdomen. He received factor VIII concentrates for replacement therapy. He was hemodynamically stable on the first day, but on the second day his hemoglobin declined and he showed signs of abdominal tenderness. He, therefore, was subjected to laparatomy and splenectomy. After the operation, he suddenly developed dyspnea and decline in blood pressure, and death afterwards. Autopsy of the patient revealed massive pulmonary thromboembolism. The symptoms and outcome of the present case indicate that although pulmonary thromboembolism in the early postoperative period in patients with hemophilia A undergoing splenectomy and receiving factor VIII concentrate for replacement is rare, it should not be assumed a far-fetched event, and prophylactic measures to prevent thromboemboly must be considered.


Mechanical control of the time-course of contraction of the frog heart.
Changes in load during most phases of an isotonic contraction of the frog and turtle heart increased or decreased the duration of the twitch. It was abbreviated by a maintained increase or by a brief decrease in load. The relaxing effect of these procedures developed with a delay lasting more than a second under some conditions and will be called lengthening deactivation. The reverse procedures, a maintained diminution or a brief increase in load, increased the duration of the twitch. This effect will be called shortening activation. Although the termination of relaxation may be delayed or advanced by the mechanical interventions mentioned, the normal time-course of isotonic relaxation was always resumed later, regardless of the starting level of the load, making it possible to measure accurately changes in the duration of the twitch. The responses to changes in load produce positive feedback during the isotonic contraction and explain, at least in part, the difference in the time-course of isotonic and isometric contraction. The effects of changes in load were much smaller and briefer in the atrium than the ventricle.


Attentional biases toward threat: the concomitant presence of difficulty of disengagement and attentional avoidance in low trait anxious individuals.
Attentional biases toward threats (ABTs) have been described in high anxious individuals and in clinical samples whereas they have been rarely reported in non-clinical samples (Bar-Haim et al., 2007; Cisler and Koster, 2010). Three kinds of ABTs have been identified (facilitation, difficulty of disengagement, and avoidance) but their mechanisms and time courses are still unclear. This study aimed to understand ABTs mechanisms and timing in low trait anxiety (LTA) and high trait anxiety (HTA) anxious individuals. In particular, in an exogenous cueing task we used threatening or neutral stimuli as peripheral cues with three presentation times (100, 200, or 500 ms). The main results showed that HTA individuals have an attentional facilitation bias at 100 ms (likely automatic in nature) whereas LTA individuals show attentional avoidance and difficulty to disengage from threatening stimuli at 200 ms (likely related to a strategic processing). Such findings demonstrate that threat biases attention with specific mechanisms and time courses, and that anxiety levels modulate attention allocation.


A versatile approach to the synthesis of mannosamine glycosides.
O-Picoloyl protecting groups at remote positions can affect the stereoselectivity of glycosylation by means of the H-bond-mediated aglycone delivery (HAD) pathway. A new practical method for the stereoselective synthesis of β-glycosides of mannosamine is reported. The presence of the O-picoloyl group at the C-3 position of a mannosamine donor can provide high or complete stereocontrol. The method was also utilized for the synthesis of a biologically relevant trisaccharide related to the capsular polysaccharide of Streptococcus pneumoniae serotype 4. Also reported herein is a method to achieve complete α-manno stereoselectivity with mannosamine donors equipped with 3-O-benzoyl group.


Self-diffusion in core-shell composite 12CO2/13CO2 nanoparticles.
A new technique for the generation of multilayered molecular nanoparticles is presented. Core-shell composite nanoparticles of CO(2) with varied composition have been investigated by Fourier-transform infrared spectroscopy over 600 s at 78 K. The isotopically different zones of the particles turned out to have completely different spectra in the nu(3) region: a tub structure (mantle) and a head-and-shoulders structure (core). From the aggregation behavior of both components the particle formation time was found to be 0.1 s. Low-temperature self-diffusion of airborne molecular nanoparticles has been monitored for the first time. The self-diffusion coefficient for (12)CO(2)/(13)CO2 nanocomposites at 78 K was determined from the time evolution of the nu(1) + nu(3) combination band to about 7 x 10(-20) m(2)/s. The work represents a major advance toward nanoengineering of molecular nanoparticles at low temperatures.


Understanding acute burn injury as a chronic disease.
While treatment for burn injury has improved significantly over the past few decades, reducing mortality and improving patient outcomes, recent evidence has revealed that burn injury is associated with a number of secondary pathologies, many of which arise long after the initial injury has healed. Population studies have linked burn injury with increased risk of cancer, cardiovascular disease, nervous system disorders, diabetes, musculoskeletal disorders, gastrointestinal disease, infections, anxiety and depression. The wide range of secondary pathologies indicates that burn can cause sustained disruption of homeostasis, presenting new challenges for post-burn care. Understanding burn injury as a chronic disease will improve patient care, providing evidence for better long-term support and monitoring of patients. Through focused research into the mechanisms underpinning long-term dysfunction, a better understanding of burn injury pathology may help with the development of preventative treatments to improve long-term health outcomes. The review will outline evidence of long-term health effects, possible mechanisms linking burn injury to long-term health and current research into burns as a chronic disease.


Primary Pulmonary T-Cell Lymphoma Mimicking Asthma and Community-Acquired Pneumonia: A Rare Case Report.
Primary pulmonary T-cell lymphoma (PPTL) is a rare disease. Diagnosing PPTL is challenging due to non-specific clinical symptoms and imaging. A 32-year-old female presented with persistent fever, cough, and dyspnoea. The symptoms were initially treated as asthma and community-acquired pneumonia without improvement. Chest computed tomography (CT) revealed bilateral consolidations with a CT angiogram sign, and flexible bronchoscopy showed infiltrative lesions causing bronchial stenosis. Histopathological examination of the tissue biopsy identified T-cell lymphoma through immunohistochemical staining positive for CD3. This case highlights the importance of considering differential diagnoses such as PPTL in patients with atypical presentations of asthma or non-resolving pneumonia. This case also demonstrates the diagnostic utility of flexible bronchoscopy in identifying airway obstruction due to malignant cells, which can mimic asthma. Primary pulmonary T-cell lymphoma can manifest as atypical asthma and non-resolving pneumonia, making early diagnosis challenging.Malignant aetiologies, including primary pulmonary T-cell lymphoma, should be considered in cases of bilateral consolidations that do not respond to antibiotics and present CT angiogram signs.Histopathology remains the gold standard in primary pulmonary T-cell lymphoma diagnosis, wherein flexible bronchoscopy should be employed as a minimally invasive first-line approach for tissue biopsy.


BACE1 polymorphisms do not influence platelet membrane beta-secretase activity or genetic susceptibility for Alzheimer's disease in the Northern Irish population.
Beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer's disease (AD). BACE1 is a protease that catalyses APP cleavage at the beta-secretase site. We evaluated all common and putatively functional polymorphisms in the genomic region encompassing BACE1 for an association with AD, and for functional effects on platelet beta-secretase activity. Tag SNPs (n = 10) derived from phase II of the International HapMap Project, and a nonsynonymous variant, were successfully genotyped in 901 Caucasian individuals from Northern Ireland using Sequenom iPLEX and TaqMan technologies. APOE genotyping was performed by PCR-RFLP. Platelet membrane beta-secretase activity was assayed in a subset of individuals (n = 311). Hardy-Weinberg equilibrium was observed for all variants. Evidence for an association with AD was observed with multi-marker haplotype analyses (P = 0.01), and with rs676134 when stratified for APOE genotype (P = 0.02), however adjusting for multiple testing negated the evidence for association of this variant with AD. chi(2) analysis of genotype and allele frequencies in cases versus controls for individual SNPs revealed no evidence for association (5% level). No genetic factors were observed that significantly influenced platelet membrane beta-secretase activity. We have selected an appropriate subset of variants suitable for comprehensive genetic investigation of the BACE1 gene. Our results suggest that common BACE1 polymorphisms and putatively functional variants have no significant influence on genetic susceptibility to AD, or platelet beta-secretase activity, in this Caucasian Northern Irish population.


Abdominal compartment syndrome and acute pancreatitis.
Significant visceral edema associated with massive fluid resuscitation, paralytic ileus and formation of pancreatic ascites in patients with severe acute pancreatitis (SAP) can lead to abdominal compartment syndrome (ACS) that can contribute to the early development of multiple organ dysfunction syndrome (MODS), especially in the early stages of the disease. The prevalence of intra-abdominal hypertension (IAH) in SAP is about 40% and a manifest ACS occurs in about 10% of the patients warranting close monitoring of intra-abdominal pressure (IAP) in all patients with the severe form of the disease. Although nonsurgical management utilizing percutaneous drainage of ascites or continuous hemodiafiltration may decrease IAP, most patients require decompressive laparostomy and temporary abdominal closure. The primary aim in managing the ensuing open abdomen is delayed fascial closure during initial hospitalization. On many occasions a planned hernia approach, either with early skin grafting over the exposed bowel or managing the ASC primarily with a subcutaneous linea alba fasciotomy, is the only available option. The development of ACS in patients with SAP seems to be associated with increased mortality.


Epidemiologic trends of domestic violence-related ocular injuries among pediatric patients: data from the Nationwide Emergency Department Sample 2008-2017.
To study the epidemiology of all domestic violence (DV)-related ocular injuries among pediatric emergency department (ED) patients in the United States. This is a retrospective, cross-sectional study of isolated children (<18 years of age) with a diagnosis of DV and primary or secondary diagnosis of ocular injuries in the Nationwide Emergency Department Sample, 2008-2017. We calculated annual incidence of DV-related ocular injuries and prevalence by demographic variables, including age, sex, and income quartile. Median charges, median length of inpatient hospital stay, and factors associated with hospitalization were also measured. From 2008 to 2017, there were 4,125 ED encounters, with an average incidence of 0.56 per 100,000 population (males, 50.0%; mean age [SE], 9.2 [0.3]). Patients in the lowest income quartile (42.6%) and with Medicaid insurance (63.2%) were the most prevalent. The most common known perpetrator was a family member (29.4%). Most ED encounters took place at southern regional (28.6%), metropolitan teaching (67.1%) and designated trauma hospitals (57.8%). Contusion of the eye/adnexa and being struck by or against an object were the most common ocular diagnosis and known mechanism of injury, respectively. An estimated 12.4% of patients were admitted with a median hospital stay of 4 (IQR, 2-6). Median charges during the study period were $27,415.10 (IQR, $13,142.70-$54,454.90). DV-related ocular injuries were most prevalent among patients with a low socioeconomic status. Given the historical underreporting of DV, future studies are warranted to identify more specific social determinants of health that contribute to such presentations.


Catalytic roles of active-site amino acid residues of coenzyme B12-dependent diol dehydratase: protonation state of histidine and pull effect of glutamate.
The hydrogen abstraction and the OH migration processes catalyzed by diol dehydratase are discussed by means of a quantum mechanical/molecular mechanical method. To evaluate the push effect of His143 and the pull effect of Glu170, we considered three kinds of whole-enzyme model, the protonated and two unprotonated His143 models. A calculated activation energy for the hydrogen abstraction by the adenosyl radical is 15.6 (13.6) kcal/mol in the protonated (unprotonated) His143 model. QM/MM calculational results show that the mechanism of the OH migration is significantly changed by the protonation of His143. In the protonated His143 model, the OH group migration triggered by the full proton donation from the imidazolium to the migrating OH group occurs by a stepwise OH abstraction/re-addition process in which the water production reduces the barrier for the C-O bond cleavage. On the other hand, the OH migration in the unprotonated His143 model proceeds in a concerted manner, as we previously proposed using a simple model including only K+ ion and substrate. The latter mechanism seems to be kinetically more favorable from the calculated energy profiles and is consistent with experimental results. The activation barrier of the OH group migration step is only 1.6 kcal/mol reduced by the hydrogen-bonding interaction between the O2 of the substrate and unprotonated His143. Thus, it is predicted that His143 is not protonated, and therefore the main active-site amino acid residue that lowers the energy of the transition state for the OH group migration is determined to be Glu170.


The Mechanical, Thermal, and Chemical Properties of PLA-Mg Filaments Produced via a Colloidal Route for Fused-Filament Fabrication.
The effect of Mg particles on the thermal, chemical, physical, and primarily mechanical properties of 3D-printed PLA/Mg composites is studied in this paper. Recently, new colloidal processing has been proposed to introduce Mg particles into the PLA matrix, which ensures good dispersion of the particles and better thermal properties, allowing for thermal processing routes such as extrusion or 3D printing via fused-filament fabrication. The thermal and physical properties are here studied in 1D single-filament-printed PLA/Mg composites with 0 to 10 wt.% of Mg particles by Differential Scanning Calorimetry (DSC); we analyse the PLA chain modifications produced, the crystallinity fraction, and the different crystalline forms of the PLA after thermal processing. Fourier Transform Infrared Spectroscopy (FTIR) is used to confirm the influence of the PLA/Mg colloidal processing after printing. The mechanical properties are measured with a universal tensile test machine on the 1D single-printed filaments via fused-filament fabrication (FFF); the filaments were naturally aged to stable conditions. Filaments with and without a notch are studied to obtain the materials' tensile strength, elastic modulus, and fracture toughness. Different analytical models to explain the results of the PLA-Mg were studied, in which the minimum values for the interface strength of the PLA-Mg composites were calculated.