Real Time 3D Representation and Tracking of Guidewire for Image Guided Cardiovascular Interventions.
Visual tracking and 3D representation of guidewire in fluoroscopic image sequence for beating heart image guided interventions is very challenging task. The degraded image quality due to low dose fluoroscopy further complicates the problem. In this paper a robust guidewire tracking is proposed for mean shift algorithm using integrated colour, texture and depth features. The target colour, texture and depth features are encoded into gray level intensity histogram, filtered local binary pattern histogram and filtered local depth pattern histograms respectively. For depth features a 3D image acquisition system for C-Arm, X-Ray imaging system is simulated for real time three dimensional shape recovery of guidewire and associated vessels for vertical beating heart motion using shape from focus technique. The proposed technique provides 3D visualization of guide wire and vessels to the physician as well as real time robust guidewire tip tracking. Experimental results of guidewire tip tracking and 3D shape recovery on image sequence acquired through beating heart simulated phantom show the significance of the proposed technique.


Co-localization of cyclic GMP in superior cervical ganglion with peptide neurotransmitters.
The immunofluorescent localization of cyclic 3',5'-guanosine monophosphate (cyclic GMP) in rat superior cervical ganglion has been compared to postganglionic neurons having immunoreactivity to neuropeptides. Cyclic GMP-positive somata are equally distributed among cell bodies fluorescent for substance P, somatostatin, and methionine-enkephalin. 40% of the total number of cells stained for each peptide demonstrate co-incident cyclic GMP localization, suggesting a large majority of the neurons employ non-cyclic GMP mechanisms.


Influence of dissolved oxygen tension and agitation speed on alginate production and its molecular weight in cultures of Azotobacter vinelandii*
The alginate production by Azotobacter vinelandii, as well as the molecular weight of the polymer, are strongly influenced by the dissolved oxygen tension (DOT) and stirring speed of the culture. Under high DOT (5% of air saturation), the bacteria produced more alginate (4.5 g/l) than that obtained at low (0.5%) oxygen tension (1.0 g/l) in cultures conducted at 300 rpm. On the other hand, under constant DOT (3%), the higher the stirring speed (from 300 to 700 rev./min), the higher the specific growth rate and the alginate production rate. However, low agitation speed (300 rev./min) lead the culture to produce a polymer of high molecular weight (680 000 g/g mol) whereas a low molecular weight (352 000 g/g mol) alginate was isolated from cultures conducted at high (700 rev./min) stirring speed. At 700 rev./min, the MMW increased to a plateau between 1 and 3% DOT and then decreased to a minimum of 0.11 x 10(6) g/g mol at 7%. Microscopic observations revealed the presence of cell aggregates (one order of magnitude larger than individual cells) when the culture was conducted at 300 rev./min. Oxygen gradients occurring within the aggregates could be responsible of this phenomenon. At high agitation rate, the MMW of the alginate dropped towards the end of the culture in all conditions evaluated. Alginase activity was detected, which would be responsible for this phenomenon.


Fetal movements associated with fetal heart rate accelerations and decelerations.
In normal pregnant women, the relationship between the FHR and fetal movements (FM) was evaluated during 1,541 consecutive observed FM of at least 1 second's duration. Two observed FHR changes were: (1) accelerations and (2) accelerations followed by decelerations. An acceleration in FHR was observed in association with 91.2 per cent of all FM of 1 to 3 seconds' duration and with 99.8 per cent of FM of longer than 3 seconds' duration. FM were associated with an acceleration followed by a deceleration 66.7 per cent of the time. FM lasting longer than 1 second and associated with neither accelerations nor decelerations were seen 1.8 per cent of the time.


Over expression of mTOR gene predicts overall survival in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) is defined as heterogenous disease, it contains heterogenous leukemic stem cells with various degree of cell differentiation. The perturbation of genes involved in myeloid progenitor cell growth, differentiation and proliferation lead to morphologic dysplasia, maturation arrest, ineffective hematopoiesis hence the cytopenias and propensity to develop into acute myeloid leukemia (AML). Heterogeneous subsets of MDS patients have been defined by their clinical and biologic abnormalities. These different features lead to the development of different prognostic system; however, these approaches are limited in predicting clinical course, and management of patients remains challenging given the uncertainty of the time course of disease progression. It is of importance to identify transcriptomic marker causing maturational and differentiation arrest which could help in understanding the pathogenesis of disease. We have studied differential gene expression profiles (GEPs) in CD34 + marrow cells from myelodysplastic syndrome (MDS) patients (n = 14) and control CD34 + cells using Affymetrix Human Clariom S microarray with 20,000 well annotated genes. We found 4165 genes significantly (p < 0.05) differentially expressed in MDS. Using stringent bioinformatics analyses, we were able to identify few genes (MAPK8, JUNB, mTOR) which were differentially upregulated i.e. 5.39, 73.61 and 2.7 fold change observed in MDS than control and also validated (n = 60) these genes by RT - qPCR. Kaplan - Meier survival analysis indicated that MAPK8 and JUNB could be poor prognostic marker as patients with increased expression showed poor survival, whereas surprisingly mTOR increased expression proved to be good prognostic marker. The correlation analysis showed that the level of gene (MAPK8, JUNB, mTOR) expression was significantly (p ≤ 0.05) associated with frequency of genetic lesions. Interestingly the increased expression of MAPK8 was significantly accompanied with ASXL1 gene mutation. Our study showed an elevation of TNF and AMPK signalling pathways in MDS. TNF signalling might be mediating the proliferative advantage to myeloid clonal cells (mutation carrying cells) over normal cells, whereas, AMPK signalling could be acting as protector against it (favouring normal cells). Hence it would be interesting to explore the functions and pathways associated with mTOR, AMPK, MAPK8 and JUNB in myelopoiesis related diseases like MDS.


Activity of the alpha-1 antitrypsin deficiency registry in Belgium.
A Belgian alpha-1-antitrypsin (AAT) deficiency registry has been established in 2003. Currently 55 patients are included. At the same time, a working group has been set up for publishing national guidelines. In 2014, several Belgian patients founded Alpha-1 Global. We hope that the integrated activities of all the stakeholders involved in AAT deficiency will permit a high quality care for all patients suffering from this disabling disease.


[Determination of urinary lead through optic emission spectrography using the double-arch method].
A new method for the determination of urinary lead by means of the emission spectroscopy is described. The sample is concentrated by lyophilization and the homogeneous dust obtained is analysed using the "double arc" method. The matrix effects and the source unstability are compensated by the use of the internal standard. The influence of the volatilization of the elements of the analytical pairs are studied and the pair thallium-lead is selected. The method is reproducible and the detection limit is 5 microgram/l of urinary lead.


Safety of direct oral anticoagulant exposure during pregnancy: a retrospective cohort study.
Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in many indications for anticoagulation. Prescribed to millions of patients, including women of reproductive age, exposure to DOACs in early pregnancy is not uncommon, but data on the embryotoxic risks are scarce. We aimed to assess the risk of DOAC embryotoxicity in a large sample of reported cases. In this retrospective cohort study, we collected individual case reports of DOAC exposure in pregnancy from gynaecologists, haematologists, and vascular specialists starting from May, 2015. We obtained exports in April and October, 2017, August, 2018, and December, 2019, from the pharmacovigilance databases of the DOAC manufacturers, the European Medicines Agency (EMA), the German drug authority, and searched the homepage of the US Food and Drug Administration (FDA) for pregnancy exposure reports. Data from the International Society of Thrombosis and Haemostasis (ISTH) registry were obtained in August, 2018, and on July 21, 2020; data from the Teratology Information Service in Ulm, Germany, were received July 22, 2020. We also ran a systematic literature search on July 22, 2020, for cases of DOAC exposure. These data were compiled with those from our 2016 risk assessment and duplicate reports were excluded. Fetal or neonatal abnormalities were classified as a major birth defect according to the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) classification and adjudicated into four categories: relation to DOAC exposure likely, possible, unlikely, or unrelated. We identified 1193 reports of DOAC exposure during pregnancy: 49 from physicians, 48 from the ISTH registry, 29 from the Teratology Information Service, 62 from the German drug authority, 536 from Bayer (extracted from the Bayer pharmacovigilance system, the WHO VigiBase, and from the FDA Adverse Event Reporting System), 87 from Boehringer Ingelheim, 16 from Daiichi Sankyo, 98 from the literature search, two from the FDA homepage search, ten from the Risk Evaluation and Mitigation Strategy Review, and 256 from the EMA reports. After excluding potential duplicates, we identified 614 unique cases of DOAC exposure in pregnancy occurring between Feb 1, 2007, and July 9, 2020, that consisted of rivaroxaban in 505 (82%) pregnancies, dabigatran in 36 (6%), apixaban in 50 (8%), and edoxaban in 23 (4%). The median duration of DOAC exposure was 5·3 weeks (IQR 4·0-7·0) into pregnancy. Information on pregnancy outcome was available in 336 (55%) of 614 pregnancies: 188 (56%) livebirths, 74 (22%) miscarriages, and 74 (22%) elective pregnancy terminations. 21 (6%; 95% CI 4-9) of 336 showed fetal abnormalities, of which 12 (4%; 2-6) were adjudicated as major birth defects potentially related to DOAC exposure. Although reports of pregnancy outcomes after DOAC exposure are missing important details and predominantly describe rivaroxaban exposures, the available data do not suggest that DOAC exposure in pregnancy carries a high risk of embryopathy. The 2016 ISTH guidance against elective pregnancy termination for fear of DOAC embryotoxicity and the recommendation in favour of close pregnancy surveillance is still valid. Pregnancy outcome data are inconsistently captured in pharmacovigilance databases, indicating a strong need for a more robust system of reporting. None.


Familial prevalence among first-degree relatives of celiac disease in North India.
Prevalence of celiac disease is increased in first-degree relatives with reported prevalence rates in the west between 2.8 and 10%. Paucity of similar data from Asia and the Indian subcontinent prompted us to determine the familial prevalence of celiac disease in first-degree relatives of patients diagnosed with this disorder in Northern India. One hundred sixty-nine first-degree relatives (66 parents, 71 siblings and 32 children) of 53 probands were screened by using anti tissue transglutaminase antibodies. Duodenal biopsy was performed in all seropositive relatives and graded as per Marsh classification. Patients with both positive serology and biopsy suggestive of celiac disease were classified as typical celiac disease whereas those with only positive serology were classified as potential celiacs. The prevalence of celiac disease among first-degree relatives was 8.2% (14/169). The prevalence of celiac disease among siblings (15.6%) was much higher as compared to that in parents (3.5%) and offspring (3%). More than one family member was affected in 23% (12/53) of families. Of 14 new cases detected by targeted screening, 11 (78%) were overtly symptomatic with either chronic diarrhoea (8) or easy fatiguability (3). Growth retardation was seen in all six newly diagnosed children, three of whom (22%) were otherwise asymptomatic. Eight members detected to be seropositive had minimal changes on duodenal biopsy (Marsh I and II) suggesting that they have potential celiac disease. Familial prevalence of celiac disease in North India is similar to the data from the West. However unlike the situation in the West, the overwhelming majority of first-degree relatives in India are overtly symptomatic with majority having chronic diarrhoea. Since gluten restriction is a highly effective treatment modality, early detection of these patients would result in significant improvement in quality of life as manifested by cessation of diarrhoea and improvement in growth and lab parameters. Our data strongly supports the targeted screening of all first-degree relatives of celiac disease patients in north India.


FTY720-Mitoxy reduces synucleinopathy and neuroinflammation, restores behavior and mitochondria function, and increases GDNF expression in Multiple System Atrophy mouse models.
Multiple system atrophy (MSA) is a fatal disorder with no effective treatment. MSA pathology is characterized by α-synuclein (aSyn) accumulation in oligodendrocytes, the myelinating glial cells of the central nervous system (CNS). aSyn accumulation in oligodendrocytes forms the pathognomonic glial cytoplasmic inclusions (GCIs) of MSA. MSA aSyn pathology is also associated with motor and autonomic dysfunction, including an impaired ability to sweat. MSA patients have abnormal CNS expression of glial-cell-line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Our prior studies using the parent compound FTY720, a food and drug administration (FDA) approved immunosuppressive for multiple sclerosis, reveal that FTY720 protects parkinsonian mice by increasing BDNF. Our FTY720-derivative, FTY720-Mitoxy, is known to increase expression of oligodendrocyte BDNF, GDNF, and nerve growth factor (NGF) but does not reduce levels of circulating lymphocytes as it is not phosphorylated so cannot modulate sphingosine 1 phosphate receptors (S1PRs). To preclinically assess FTY720-Mitoxy for MSA, we used mice expressing human aSyn in oligodendrocytes under a 2,' 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter. CNP-aSyn transgenic (Tg) mice develop motor dysfunction between 7 and 9 mo, and progressive GCI pathology. Using liquid chromatography-mass spectrometry (LC-MS/MS) and enzymatic assays, we confirmed that FTY720-Mitoxy was stable and active. Vehicle or FTY720-Mitoxy (1.1 mg/kg/day) was delivered to wild type (WT) or Tg littermates from 8.5-11.5 mo by osmotic pump. We behaviorally assessed their movement by rotarod and sweat production by starch‑iodine test. Postmortem tissues were evaluated by qPCR for BDNF, GDNF, NGF and GDNF-receptor RET mRNA and for aSyn, BDNF, GDNF, and Iba1 protein by immunoblot. MicroRNAs (miRNAs) were also assessed by qPCR. FTY720-Mitoxy normalized movement, sweat function and soleus muscle mass in 11.5 mo Tg MSA mice. FTY720-Mitoxy also increased levels of brain GDNF and reduced brain miR-96-5p, a miRNA that acts to decrease GDNF expression. Moreover, FTY720-Mitoxy blocked aSyn pathology measured by sequential protein extraction and immunoblot, and microglial activation assessed by immunohistochemistry and immunoblot. In the 3-nitropropionic acid (3NP) toxin model of MSA, FTY720-Mitoxy protected movement and mitochondria in WT and CNP-aSyn Tg littermates. Our data confirm potent in vivo protection by FTY720-Mitoxy, supporting its further evaluation as a potential therapy for MSA and related synucleinopathies.


Instability of protease production in a rel+/rel- -pair of Bacillus licheniformis and associated morphological and physiological characteristics.
A naturally occurring relaxed/protease-producing (A-type) versus stringent/not protease-producing (B-type) pair of an industrial Bacillus licheniformis has been characterized; either of the two types can convert into the other. Both types can sporulate, grow anaerobically, grow at 56 degrees C and reduce nitrate; morphologically, they can easily be distinguished by cell- and colony-shape. They differ in the ability to use 12 substrates, as determined in API-tests. The two types are remarkably different in their content of extrachromosomal elements (A-type: 2; B-type: 4); furthermore, they differ in their rel-status (A-type: relaxed; B-type: stringent). We propose that the differences in the ability of the two types to use different substrates probably are due to integration/extrusion of the extrachromosomal elements in and out of the chromosome, distorting or restoring a number of genes, together with induction of certain catabolic genes that are under control of the rel-system.


The differential effect of stress on natural killer T (NKT) and NK cell function.
When C57Bl/6 mice were exposed to restraint stress for 12 h or 24 h, lymphocytopenia was induced in the liver, spleen, and thymus. We examined which types of lymphocytes were sensitive or resistant to such stress by a immunofluorescence test. T cells of thymic origin were sensitive while NKT and NK cells were resistant. In contrast to the increase in the proportion of NK cells, NK activity of liver lymphocytes against YAC-1 targets decreased at 24 h after stress. On the other hand, their NKT cytotoxicity against syngeneic thymocytes increased in parallel with an increase in their proportion. In perforin -/- B6 mice and B6-gld/gld (Fas ligand-) mice, NK cells were found to mediate cytotoxicity through perforin while NKT cells mediated self-reactive cytotoxicity through Fas ligand. These results suggest that stress increases the proportion of both NK and NKT cells, but that NK cytotoxicity is suppressed while self-reactive NKT cytotoxicity is not, due to a diversity of their functional mechanisms.


Malocclusion and Scoliosis: Is There a Correlation?
Scoliosis is a complex three-dimensional malformation of the spine. Although its etiology is still being investigated, it is clear that a number of factors can influence this syndrome. The spinal deformity of idiopathic scoliosis can be viewed from an etiopathogenetic perspective as a symptom of a complicated condition with a multifactorial etiology. Numerous studies have established its relationship with malocclusion, but it is still unclear how these factors interact. Malocclusion is a change in the physiological alignment of the upper and lower teeth that can be either dental or skeletal in origin. This study's objective is to assess the relationship between scoliosis and malocclusion. A total of 646 patients were enrolled (554 females and 92 males), 447 with scoliosis and 199 without, from private dental and orthopedic practices, to answer an anonymous questionnaire. They were selected in private dental and orthopedic practices where they had dental and orthopedic examinations. Twenty-two patients were excluded because of a lack of answers. Participants were given a bilingual survey, in English and Italian, composed of 13 questions formulated specifically for this study, using Google Forms (Google LLC, Mountain View, CA, USA). Univariate analysis of the question "Do you have scoliosis?" shows a significant correlation with the following questions: "Was scoliosis a family issue?" (p < 0.05 OR 7.30 IC: 3.05-17.46) "Do you have malocclusion?" (p < 0.05, OR: 1.19 IC:1.0-1.34) and "Was mal-occlusion a family issue?" (p < 0.01, OR: 1.39 IC 1.10-1.77). Performing a multivariate analysis for the same variables, the best predictors of scoliosis were "Was scoliosis a family issue?" (p < 0.001) and "Was malocclusion a family issue?" (p < 0.05), while the question "Do you have malocclusion" lost significance. This study adds further confirmation that there might be an important connection between malocclusion and scoliosis; it suggests that dentists and orthopedists have to check, as early as possible, for the probable presence of both pathologies to avoid a severe progression which, in most cases, may require significant therapy and even surgery.


Patterns of vasopressor utilization during the resuscitation of massively transfused trauma patients.
The use of vasopressors (VP) in the resuscitation of massively transfused trauma patients might be considered a marker of inadequate resuscitation. We sought to characterize the utilization of VP in patients receiving massive transfusion and examine the association of their use with mortality. Trauma patients admitted from January 2011 to October 2016 receiving massive transfusion, defined as 3 units of pRBC within the first hour from admission, were selected for analysis. Demographics, admission vital signs and labs, use of VP, surgical interventions and outcomes were collected. Standard statistical tools were utilized. Over the 5-year study period, 120 trauma patients met inclusion criteria. The median age was 39 years with 77% being male and 41% sustaining a penetrating injury. Patients who received VP [VP (+)] were more likely to have a lower admission GCS (median 4.5 vs. 14.0, p <0.01) and less likely to have a penetrating injury (31% vs. 54%, p=0.02). The overall mortality was 49% and significantly higher in the VP (+) cohort (60% vs. 34%, AHR: 9.9, adjusted p=0.03). Mortality increased in a stepwise fashion with increasing number of VP utilized, starting at 34% for no VP, to 78% for 3 VP, and 100% for 5 or more. The majority of deaths in the VP (-) group (88%) occurred within one day from admission. For the VP (+) group, 57% of deaths occurred within one day, with the remaining 43% occurring at a later time. In the era of massive transfusion protocols, vasopressors are commonly utilized in exsanguinating trauma patients and their use is associated with a higher mortality risk. Deaths in patients receiving vasopressors are more likely to occur later compared to those in patients who do not receive vasopressors. Further research to characterize the role of these agents in the resuscitation of trauma patients is required.


Value of the compressive technique associated with pharmacological hypotonia in the diagnosis of erosive gastritis.
The double-contrast method and the compressive technique associated with pharmacological hypotonia of the stomach were compared in 13 cases and found to be equally valuable in the diagnosis of erosive gastritis.


On the meaning and measurement of nestedness of species assemblages.
Nestedness of species assemblages occurs when thebiotas of sites with lower numbers of species tend to be subsets of the biotas at richer sites. We develop new quantitative and statistical techniques for measuring, testing, and comparing nestedness, and apply these methods to data from the literature. Significantly nonrandom nestedness was present in all 27 assemblages examined, and tended to be stronger in systems dominated by extinction, such as landbridge islands. Sets of assemblages that were very strongly nested were more likely to have greater species richness on one or a few large sites than on several smaller sites of equivalent total area - that is, to fall toward the "single large" side of the "Single Large Or Several Small" (SLOSS) continuum. Our analysis indicates that nestedness, when quantified as a single number for a presence-absence matrix, measures community-wide differences in incidence (the frequency of occurrence or "distribution" of species). Factors that lead to consistent differences among species in immigration or extinction rates cause strong patterns of nestedness of species assemblages. Nestedness is negatively related to beta diversity: nestedness is low when beta diversity is high, and vice versa. Conservation managers will thus seek to minimize nestedness and the development of nested structure in systems of nature reserves.


Predicting incomplete basal cell carcinoma excisions - a large multidisciplinary retrospective analysis in a tertiary center.
Introduction: Surgical treatment of basal cell carcinomas is often performed by physicians with different surgical backgrounds. Collecting data from different surgical departments would better reflect their real-life surgical management.Objectives: To identify the rate, recurrence risk, and predictive factors accordingly to their relative contribution for an incomplete basal cell carcinoma excision in a large multidisciplinary real-life settingMethods: Retrospective cohort study of 2305 surgically treated lesions in different departments of a tertiary center.Results: There was a rate of incomplete excisions (15%) and a recurrence rate (35.5% vs. 6.8% in incomplete vs. complete excisions (p < .001)). A third of incompletely excised basal cell carcinoma (BCC) will recur over time. Stratified by relevancy, high-risk histological subtypes (micronodular (OR 5.10 - p < .001) and morpheaform (OR 5.42 - p < .001), smaller specimen sizes ( <0.5 cm or 0.5-1 cm, OR 3.99 and 2.49, respectively, p < .001) high-risk locations (OR 3.06 on the nose, OR 2.77 on the eyelids, p < .001), and recurrent BCCs (OR 1.72, p < .001). are the best predictors of an incomplete excision.Conclusions: Acknowledging the rate, recurrence risk and predictive factors for incomplete excisions may be beneficial for optimal preoperative planning and to prevent unwarranted re-interventions, morbidity, and healthcare costs.


A MYC-controlled redox switch protects B lymphoma cells from EGR1-dependent apoptosis.
Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma.


Ramipril Enhances Autonomic Control in Essential Hypertension: A Study Employing Spectral Analysis of Heart Rate Variation.
We estimated the effect of an angiotensin-converting enzyme inhibitor, ramipril, on the sympathetic and parasympathetic input to the sinoatrial node of hypertensive patients using spectral and time domain analysis of heart rate variation (HRV). The heart rate of patients with essential hypertension was recorded during spontaneous breathing at rest and during controlled deep breathing. The periodic HRV was quantified at low-frequency (0.025--0.075 Hz), mid-frequency (0.075--0.125 Hz) and high-frequency (0.15--0.40 Hz) bands. Ramipril changed the balance of autonomic nervous system assessed by spectra: the parasympathetic tone increased (p < 0.05) and the sympathetic tone decreased (p < 0.01). There was an inverse correlation between the decrease in diastolic blood pressure and increase in the mid-frequency HRV, which is connoted with resetting of the baroreceptor reflex by ramipril. Thus, ramipril treatment was associated with improved autonomic control of the circulatory system.


Azathioprine hypersensitivity. Case report and review of the literature.
Fever in a transplant recipient is an important sign of graft rejection or infection. Rarely, fever may result from an immunosuppressive agent used to prevent graft rejection. A case of fever, rigors, arthralgias, and myalgias is reported in a cardiac transplant recipient in whom azathioprine therapy was recently begun. These findings resolved on discontinuation of the azathioprine, recurred on rechallenge, and were most consistent with a hypersensitivity reaction. The clinical spectrum of reported azathioprine hypersensitivity reactions is reviewed.


Neurosyphilis in HIV-infected patients: clinical manifestations, serum venereal disease research laboratory titers, and associated factors to symptomatic neurosyphilis.
To describe clinical and laboratory features of human immunodeficiency infection (HIV)-infected patients with neurosyphilis. Retrospective study of 27 consecutive cases of HIV-infected patients with a positive Venereal Disease Research Laboratory (VDRL) in cerebrospinal fluid (CSF). Median of age was 36 years and 89% were men. Ten (37%) patients had previous nonneurologic syphilis treatment. At the time of neurosyphilis diagnosis, 10 (37%) patients had early syphilis, and 6 of them were neurologically asymptomatic. Nine (33%) patients had symptomatic neurosyphilis. Twenty-six (96%) patients were classified with early neurosyphilis. The medians of serum VDRL and CD4 T cell counts were 1:128 and 182 cell/muL, respectively. Twenty five (93%) patients presented serum VDRL titers > or =1:16. Five of 6 patients with early syphilis and asymptomatic neurosyphilis, presented serum VDRL > or =1:16. Symptomatic patients showed lower CD4 T cell counts (59 cell/muL vs. 208 cell/muL, P = 0.03) and higher protein concentration on CSF (118 mg/dL vs. 39 mg/dL, P <0.001) than asymptomatic patients. Most patients had early and asymptomatic neurosyphilis, and more than one third had early syphilis. Patients with symptomatic neurosyphilis showed lower CD4 T cell counts and higher protein concentration on CSF than those asymptomatic. Most patients had serum VDRL titers > or =1:16, regardless of syphilis stage.


Staphylococcus aureus strains of the 94/96 complex isolated in the German Democratic Republic: incidence and discrimination of strain clones.
The incidence of S. aureus with a phage pattern of 94/96 rose from 9% in 1979 to 18% in 1985. The frequency of occurrence not only increased among isolates from inpatients and outpatients but also among those from healthy carriers. All of the 504 investigated strains of different origin exhibited a uniform pattern of biochemical characteristics. In each of 40 investigated strains, a plasmid with a molecular mass of 16 Md was found. Elimination experiments indicated that these plasmids determined resistance to penicillin and/or cadmium. Resistance to chloramphenicol was found to be determined by plasmids of 2.0 Md, resistance to oxytetracycline by plasmids of 2.7 Md. Clones could be discriminated by means of 7 experimental phages. The application of these phages for typing strains from infections in hospitals is demonstrated.


Grouping in auditory temporal perception and vocal production is mutually adapted: the case of wriggling calls of mice.
Auditory Gestalt perception by grouping of species-specific vocalizations to a perceptual stream with a defined meaning is typical for human speech perception but has not been studied in non-human mammals so far. Here we use synthesized models of vocalizations (series of wriggling calls) of mouse pups (Mus domesticus) and show that their mothers perceive the call series as a meaningful Gestalt for the release of instinctive maternal behavior, if the inter-call intervals have durations of 100-400 ms. Shorter or longer inter-call intervals significantly reduce the maternal responsiveness. We also show that series of natural wriggling calls have inter-call intervals mainly in the range of 100-400 ms. Thus, series of natural wriggling calls of pups match the time-domain auditory filters of their mothers in order to be optimally perceived and recognized. A similar time window exists for the production of human speech and the perception of series of sounds by humans. Neural mechanisms for setting the boundaries of the time window are discussed.


Global food security: the impact of veterinary parasites and parasitologists.
Global food security will require the production of more food using resources including land more efficiently, and with less waste. This goal must be achieved within the context of climate change and while ensuring minimal adverse environmental impact from both crop and livestock production. Disease, especially infectious disease, is a main constraint of biologically efficient livestock production and both endemic and exotic disease results in mortality and morbidity and hence less food than should ideally be available in current farming systems. A significant proportion of diseases affect the safety of food supplies, in addition to or instead of, their effect on volume and quality of food products. Parasitological diseases including those caused by nematodes, trematodes, protozoa and ectoparasites, have widely differing effects on meat, milk and fibre production and many new technologies have been developed in order to prevent or treat them. Approaches to developing better control of parasites have included livestock breeding strategies, improved nutrition and management, and the development of new drugs, diagnostic tests and vaccines. Some of the most important examples include both the development of new anthelmintic products, and better means of using existing drugs in order to maximise their effectiveness in the face of rapidly increasing parasite resistance; diagnostic tests which are able to detect low levels of nucleic acids or proteins from infectious agents rapidly; and vaccines derived from either native or recombinant proteins and designed to stimulate the most appropriate protective response from livestock species. Some of the parasitic diseases affect restricted regions around the world, however most affect very large global populations. The development of technologies of suitable and affordable livestock products for use in developing countries where most pressure on increased production for food will occur, provides a particular challenge. Most if not all new technologies form part of integrated management schemes on farms and these vary hugely in differing systems and geographical regions of the world. If the benefit of improved technologies for optimal health, welfare and biological efficiency of livestock is to be realised, then the veterinary, farming, commercial animal health and public service communities need to learn lessons from past successes and failures in the delivery of newly developed technologies to the farmer. The combination of technology and rural development in the veterinary parasitological field has played a key role in current food production and is well placed to continue this trend to help in ensuring future food requirements for the world.


Gene signature reveals decreased SOX10-dependent transcripts in malignant cells from immune checkpoint inhibitor-resistant cutaneous melanomas.
Evidence is mounting for cross-resistance between immune checkpoint and targeted kinase inhibitor therapies in cutaneous melanoma patients. Since the loss of the transcription factor, SOX10, causes tolerance to MAPK pathway inhibitors, we used bioinformatic techniques to determine if reduced SOX10 expression/activity is associated with immune checkpoint inhibitor resistance. We integrated SOX10 ChIP-seq, knockout RNA-seq, and knockdown ATAC-seq data from melanoma cell models to develop a robust SOX10 gene signature. We used computational methods to validate this signature as a measure of SOX10-dependent activity in independent single-cell and bulk RNA-seq SOX10 knockdown, cell line panel, and MAPK inhibitor drug-resistant datasets. Evaluation of patient single-cell RNA-seq data revealed lower levels of SOX10-dependent transcripts in immune checkpoint inhibitor-resistant tumors. Our results suggest that SOX10-deficient melanoma cells are associated with cross-resistance between targeted and immune checkpoint inhibitors and highlight the need to identify therapeutic strategies that target this subpopulation.


Oxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells.
The flavin-containing monooxygenases (FMOs) are important for the oxidation of a variety of endogenous compounds and xenobiotics. The hepatic expression of FMO3 is highly variable and until recently, it was thought to be uninducible. In this study, human FMO3 gene regulation by the oxidative stress transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2) was examined. Constitutive FMO3 gene expression is repressed in HepG2 cells, thus this cell can be a good model for FMO3 gene regulation studies. Over-expression of NRF2 in HepG2 cells increased NRF2 target gene expression, heme oxygenase-1 (HMOX1) and quinone oxidoreductase-1 (NQO1), but did not alter FMO3 gene expression. Co-transfection studies with NRF2 or its cytosolic regulatory protein, Kelch-like ECH-associated protein 1 (KEAP1), expression vectors, along with FMO3 promoter luciferase reporter constructs of various lengths (5kb or 6kb), did not change FMO3 reporter gene activity significantly. Furthermore, treatment with tert-butyl hydroperoxide (tBHP) and tert-butyl hydroquinone (tBHQ) did not alter FMO3 reporter construct activity. In summary, in vitro results suggest that the transcriptional regulation of FMO3 might not involve the NRF2-KEAP1 regulatory pathway.


Identification of patatin as a novel allergen for children with positive skin prick test responses to raw potato.
Peeling of raw potatoes may cause allergic symptoms, such as sneezing, wheezing, and contact urticaria, for adults. For children, potatoes as food may cause various allergic reactions. However, the identity and molecular structure of the putative allergens in potato have remained unknown. The aim of our study was to identify possible major allergens in potato by using sera of atopic children suspected of having food allergy and having positive skin prick test responses to raw potato. Potato proteins were purified by standard methods of protein chemistry and characterized with amino-terminal sequencing and mass spectrometry. The IgE-binding ability of the purified proteins was verified by immunoblotting and ELISA with IgE antibodies from the sera of atopic children having positive skin prick test responses to raw potato. Immunoblotting showed strong IgE binding to a 43-kd protein, identified as patatin, the main storage protein of potato tubers. In ELISA, 20 of 27 (74%) children with positive skin prick test responses to potato and none of the control subjects showed specific binding of IgE antibodies to purified patatin. A positive wheal-and-flare reaction was seen in 8 of 14 children prick tested with purified patatin. These results show that patatin in potatoes is a significant, previously unrecognized,IgE-binding protein for children with a positive skin prick test response to raw potato. Further studies are needed to confirm the clinical importance of potatoes, and especially patatin, as a food allergen.


Dexamethasone - PAMAM dendrimer conjugates for retinal delivery: preparation, characterization and in vivo evaluation.
Ocular diseases affecting retina, such as diabetic retinopathy (DR), age-related macular degeneration (AMD) and glaucoma are the major causes of blindness, and their treatment is still a challenge due to the special structure of the eye. The purpose of this study was to prepare a sustained release DEX conjugate formulation with enhanced ocular permeation using poly(amidoamine) (PAMAM) dendrimers and to evaluate the effects of conjugation on DEX release and ocular residence time. PAMAM G3.5 and PAMAM G4.5 dendrimers were used to prepare DEX conjugates, and conjugation was confirmed using (1) H-NMR. Formulations were evaluated in terms of drug release in the presence of ocular enzymes and cytotoxicity on ARPE19 cell lines. Fluorotron analysis was performed and ocular pharmacokinetic properties of DEX-PAMAM conjugates were studied in Sprague Dawley rats following intravitreal and subconjunctival applications. The results indicated that DEX-PAMAM conjugates were able to enhance ocular permeability and ocular tissue levels of DEX following subconjunctival injection, and results were encouraging when compared to the literature that has reported DEX getting cleared from vitreous in 3 h. Current studies are focused on formulation improvement to enhance hydrolysis and clearance time.


Insight on physicochemical properties governing peptide MS1 response in HPLC-ESI-MS/MS: A deep learning approach.
Accurate and absolute quantification of peptides in complex mixtures using quantitative mass spectrometry (MS)-based methods requires foreground knowledge and isotopically labeled standards, thereby increasing analytical expenses, time consumption, and labor, thus limiting the number of peptides that can be accurately quantified. This originates from differential ionization efficiency between peptides and thus, understanding the physicochemical properties that influence the ionization and response in MS analysis is essential for developing less restrictive label-free quantitative methods. Here, we used equimolar peptide pool repository data to develop a deep learning model capable of identifying amino acids influencing the MS1 response. By using an encoder-decoder with an attention mechanism and correlating attention weights with amino acid physicochemical properties, we obtain insight on properties governing the peptide-level MS1 response within the datasets. While the problem cannot be described by one single set of amino acids and properties, distinct patterns were reproducibly obtained. Properties are grouped in three main categories related to peptide hydrophobicity, charge, and structural propensities. Moreover, our model can predict MS1 intensity output under defined conditions based solely on peptide sequence input. Using a refined training dataset, the model predicted log-transformed peptide MS1 intensities with an average error of 9.7 ± 0.5% based on 5-fold cross validation, and outperformed random forest and ridge regression models on both log-transformed and real scale data. This work demonstrates how deep learning can facilitate identification of physicochemical properties influencing peptide MS1 responses, but also illustrates how sequence-based response prediction and label-free peptide-level quantification may impact future workflows within quantitative proteomics.


Thinking biases and their role in persecutory delusions: A systematic review.
Thinking biases are posited to be involved in the genesis and maintenance of delusions. Persecutory delusions are one of the most commonly occurring delusional subtypes and cause substantial distress and disability to the individuals experiencing them. Their clinical relevance confers a rationale for investigating them. Particularly, this review aims to elucidate which cognitive biases are involved in their development and persistence. MEDLINE, Embase, PsycINFO and Global Health were searched from the year 2000 to June 2020. A formal narrative synthesis was employed to report the findings and a quality assessment of included studies was conducted. Twenty five studies were included. Overall, 18 thinking biases were identified. Hostility and trustworthiness judgement biases appeared to be specific to persecutory delusions while jumping to conclusions, self-serving attributional biases and belief inflexibility were proposed to be more closely related to other delusional subtypes. While the majority of the biases identified were suggested to be involved in delusion maintenance, hostility biases, need for closure and personalizing attributional biases were believed to also have aetiological influences. These findings show that some cognitive biases are specific to paranoid psychosis and appear to be involved in the formation and/or persistence of persecutory delusions.


Management of hip involvement in ankylosing spondylitis.
Ankylosing spondylitis (AS) is an inflammatory rheumatologic disease characterized by inflammation and progressive structural damage of the affected joints. Hip involvement often results in severe deformities and significant impairment on function. Although, tremendous progress has been made in conservative management for AS, effective prevention strategies for hip involvement and long-term need for total hip arthroplasty (THA) remain indefinite. When hip involvement has progressed to intractable pain and disability, THA is still the most effective treatment strategy to relieve pain and restore function. However, certain AS-specific problems regarding "preoperative preparation," "intraoperative difficulties," "perioperative pharmacological management," "postoperative physiotherapy," "operation benefits," and "operation complications" need more concern and further discussion.


Success of blinding a procedural intervention in a randomised controlled trial in preterm infants receiving respiratory support.
Blinding of treatment allocation from treating clinicians in neonatal randomised controlled trials can minimise performance bias, but its effectiveness is rarely assessed. To examine the effectiveness of blinding a procedural intervention from treating clinicians in a multicentre randomised controlled trial of minimally invasive surfactant therapy versus sham treatment in preterm infants of gestation 25-28 weeks with respiratory distress syndrome. The intervention (minimally invasive surfactant therapy or sham) was performed behind a screen within the first 6 h of life by a 'study team' uninvolved in clinical care including decision-making. Procedure duration and the study team's words and actions during the sham treatment mimicked those of the minimally invasive surfactant therapy procedure. Post-intervention, three clinicians completed a questionnaire regarding perceived group allocation, with the responses matched against actual intervention and categorised as correct, incorrect, or unsure. Success of blinding was calculated using validated blinding indices applied to the data overall (James index, successful blinding defined as > 0.50), or to the two treatment allocation groups (Bang index, successful blinding: -0.30 to 0.30). Blinding success was measured within staff role, and the associations between blinding success and procedural duration and oxygenation improvement post-procedure were estimated. From 1345 questionnaires in relation to a procedural intervention in 485 participants, responses were categorised as correct in 441 (33%), incorrect in 142 (11%), and unsure in 762 (57%), with similar proportions for each of the response categories in the two treatment arms. The James index indicated successful blinding overall 0.67 (95% confidence interval (CI) 0.65-0.70). The Bang index was 0.28 (95% CI 0.23-0.32) in the minimally invasive surfactant therapy group and 0.17 (95% CI 0.12-0.21) in the sham arm. Neonatologists more frequently guessed the correct intervention (47%) than bedside nurses (36%), neonatal trainees (31%), and other nurses (24%). For the minimally invasive surfactant therapy intervention, the Bang index was linearly related to procedural duration and oxygenation improvement post-procedure. No evidence of such relationships was seen in the sham arm. Blinding of a procedural intervention from clinicians is both achievable and measurable in neonatal randomised controlled trials.


Long-term population spike-timing-dependent plasticity promotes synaptic tagging but not cross-tagging in rat hippocampal area CA1.
In spike-timing-dependent plasticity (STDP), the direction and degree of synaptic modification are determined by the coherence of pre- and postsynaptic activities within a neuron. However, in the adult rat hippocampus, it remains unclear whether STDP-like mechanisms in a neuronal population induce synaptic potentiation of a long duration. Thus, we asked whether the magnitude and maintenance of synaptic plasticity in a population of CA1 neurons differ as a function of the temporal order and interval between pre- and postsynaptic activities. Modulation of the relative timing of Schaffer collateral fibers (presynaptic component) and CA1 axons (postsynaptic component) stimulations resulted in an asymmetric population STDP (pSTDP). The resulting potentiation in response to 20 pairings at 1 Hz was largest in magnitude and most persistent (4 h) when presynaptic activity coincided with or preceded postsynaptic activity. Interestingly, when postsynaptic activation preceded presynaptic stimulation by 20 ms, an immediate increase in field excitatory postsynaptic potentials was observed, but it eventually transformed into a synaptic depression. Furthermore, pSTDP engaged in selective forms of late-associative activity: It facilitated the maintenance of tetanization-induced early long-term potentiation (LTP) in neighboring synapses but not early long-term depression, reflecting possible mechanistic differences with classical tetanization-induced LTP. The data demonstrate that a pairing of pre- and postsynaptic activities in a neuronal population can greatly reduce the required number of synaptic plasticity-evoking events and induce a potentiation of a degree and duration similar to that with repeated tetanization. Thus, pSTDP determines synaptic efficacy in the hippocampal CA3-CA1 circuit and could bias the CA1 neuronal population toward potentiation in future events.


Thrombin-mediated proteoglycan synthesis utilizes both protein-tyrosine kinase and serine/threonine kinase receptor transactivation in vascular smooth muscle cells.
G protein-coupled receptor signaling is mediated by three main mechanisms of action; these are the classical pathway, β-arrestin scaffold signaling, and the transactivation of protein-tyrosine kinase receptors such as those for EGF and PDGF. Recently, it has been demonstrated that G protein-coupled receptors can also mediate signals via transactivation of serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Atherosclerosis is characterized by the development of lipid-laden plaques in blood vessel walls. Initiation of plaque development occurs via low density lipoprotein retention in the neointima of vessels due to binding with modified proteoglycans secreted by vascular smooth muscle cells. Here we show that transactivation of protein-tyrosine kinase receptors is mediated by matrix metalloproteinase triple membrane bypass signaling. In contrast, serine/threonine kinase receptor transactivation is mediated by a cytoskeletal rearrangement-Rho kinase-integrin system, and both protein-tyrosine kinase and serine/threonine kinase receptor transactivation concomitantly account for the total proteoglycan synthesis stimulated by thrombin in vascular smooth muscle. This work provides evidence of thrombin-mediated proteoglycan synthesis and paves the way for a potential therapeutic target for plaque development and atherosclerosis.


Mechanisms and Functions of Activity-Regulated Cytoskeleton-Associated Protein in Synaptic Plasticity.
Activity-regulated cytoskeleton-associated protein (Arc) is one of the most important regulators of cognitive functions in the brain regions. As a hub protein, Arc plays different roles in modulating synaptic plasticity. Arc supports the maintenance of long-term potentiation (LTP) by regulating actin cytoskeletal dynamics, while it guides the endocytosis of AMPAR in long-term depression (LTD). Moreover, Arc can self-assemble into capsids, leading to a new way of communicating among neurons. The transcription and translation of the immediate early gene Arc are rigorous procedures guided by numerous factors, and RNA polymerase II (Pol II) is considered to regulate the precise timing dynamics of gene expression. Since astrocytes can secrete brain-derived neurotrophic factor (BDNF) and L-lactate, their unique roles in Arc expression are emphasized. Here, we review the entire process of Arc expression and summarize the factors that can affect Arc expression and function, including noncoding RNAs, transcription factors, and posttranscriptional regulations. We also attempt to review the functional states and mechanisms of Arc in modulating synaptic plasticity. Furthermore, we discuss the recent progress in understanding the roles of Arc in the occurrence of major neurological disorders and provide new thoughts for future research on Arc.


Contribution of myeloperoxidase to coronary artery vasculitis associated with MPO-ANCA production.
The role of myeloperoxidase (MPO) in the pathogenesis of vasculitis associated with MPO-specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) was examined in a murine animal model. Coronary artery vasculitis was induced in C57BL/6 mice with and without endogenous MPO by intraperitoneal injection of Candida albicans-derived substances (CADS). The corresponding levels of MPO-ANCA in sera of mice with and without vasculitis were measured and compared in both wild-type and MPO-deficient animals. The MPO-ANCA titers in sera were significantly higher in mice with vasculitis than in vasculitis-negative mice, indicating that MPO-ANCA correlated with vasculitis formation. However, the increase of MPO-ANCA titers observed in sera of wild C57BL/6 mice were strongly suppressed in MPO-deficient C57BL/6 mice, accompanied with prevention of vasculitis formation. These results show that MPO acted as an antigen for MPO-ANCA production by CADS and was followed by the vasculitis formation. Vasculitis did develop in a few MPO-deficient mice, though the incidence of vasculitis was much lower in MPO-deficient mice than in C57BL/6 mice.


Post-traumatic stress disorder is associated with a higher rate of polypectomy independent of an increased frequency of colonoscopy in Australian veterans: a retrospective review.
Post-traumatic stress disorder (PTSD) is associated with extensive physical comorbidities, including lower gastrointestinal symptoms. Diagnostic uncertainty and poor therapeutic responses may result in more frequent colonoscopies than clinically necessary. Polypectomy is standard practice when polyps are identified, and if PTSD is a risk factor for polyp formation, one would expect a higher rate of polyp detection and removal in veterans with PTSD than those without PTSD. To determine the association between PTSD and the rate of colonoscopy and polypectomy in Australian veterans. Diagnostic and therapeutic colonoscopy rates in Australian male Veterans aged ≥50 years were examined by reviewing case records of veterans who accessed Department of Veterans' Affairs funded health services between 1 January 2013 and 31 December 2018. A total of 138 471 veterans was included, of whom 28 018 had a diagnosis of PTSD; 56.4% were aged ≥65 years. Twenty-one percent of the entire cohort underwent at least one colonoscopy during the study period. Increased rates of diagnostic colonoscopy and polypectomy were associated with the presence of PTSD across all age brackets. The effect was empirically large as veterans with PTSD experience colonoscopy rates 76-81% greater than those without PTSD. Similarly, veterans with PTSD experienced polypectomy rates 76-81% greater than veterans without PTSD, and this increase persisted when controlling for the increased number of diagnostic colonoscopies they undergo. The presence of PTSD has a marked impact on colonoscopy rates in Australian veterans. The increased polypectomy rate independent of increased colonoscopy rate suggests that PTSD is a risk factor for colonic polyp formation.


Maleic acid-induced impaired conversion of 25(OH)D3 to 1,25(OH)2D3: implications for Fanconi's syndrome.
Conversion of 25-hydroxyvitamin D3 [25(OH)D3] to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] occurs exclusively in the renal cortex. To determine whether a disorder of the renal cortical tubule capable of causing Fanconi's syndrome can also impair the synthesis of 1,25(OH)2D3, we investigated whether conversion of 25(OH)D3 to 1,25(OH)2D3 was reduced by maleic acid. In vitamin D-deficient rats, maleic acid was administered i.v. over two hours. Thirty minutes after its initiation, when the complex renal tubule dysfunction had occurred, 3H-25(OH)D3 was administered i.v. as a bolus. Five hours afterwards, the amount of 3H-1,25(OH)2D3 recovered in the kidney, small intestine mucosa, and blood was one-third to one-half that in tissues of control rats that received acetazolamide or only saline or were subjected only to the surgical procedure. The glomerular filtration rate, as measured by inulin clearance, did not decrease significantly with maleic acid. In intact vitamin D-deficient chicks, 24 and 22 hr after i.p. administration of maleic acid and 14C-vitamin D3, respectively, the amount of 14C-1,25(OH)2D3 recovered in small intestine mucosa was reduced by one-half when compared to saline-treated controls. In kidney homogenates and isolated renal tubules of vitamin D-deficient chicks, activity of 25-hydroxyvitamin D3-1-hydroxylase was diminished immediately after maleic acid was administered in vivo or added in vitro to the incubation medium, respectively. These data provide the first demonstration that the renal capacity to convert 25(OH)D3 to 1,25(OH)2D3 can be substantially impaired in vivo by a renal disorder in which the glomerular filtration rate is not reduced.


Malignant epidural spinal cord compression associated with a paravertebral mass: its radiotherapeutic outcome on radiosensitivity.
To evaluate clinical characteristics and functional outcome of malignant epidural spinal cord compression associated with a paravertebral mass. Between 1987 and 1990, 136 patients with epidural spinal cord compression were treated with irradiation. Of these, 25 patients (18%) had epidural spinal cord compression associated with a paravertebral mass. This report is based on analysis of these 25 patients. Fourteen patients received 3000 cGy in 10 fractions. Seven received 4000 cGy in 16 fractions. Four received 2000 cGy in 5 fractions. Motor function was evaluated by five grades. Lung cancer accounted for the majority of epidural spinal cord compression with a paravertebral mass (60%) followed by lymphoma (8%) and kidney tumor (8%). This pattern of epidural spinal cord compression has a longer duration of pain before developing neurologic symptoms and has a high propensity of the upper thoracic spine involvement by an apical lung cancers. The functional outcome of radiation treatment reveals a significant difference between moderately radiosensitive tumors (lung, prostate, cervix, esophagus) and very radiosensitive tumor (lymphoma). None of the nonambulatory patients became ambulatory following radiotherapy except for the very radiosensitive tumors. Higher doses of radiation treatment (4000 cGy in 16 fractions) did not improve functional outcome. Due to the larger tumor burden, radiation treatment for epidural spinal cord compression associated with a paravertebral mass is not as effective as treatment of epidural spinal cord compression without a paravertebral mass except for the very radiosensitive tumor. Therefore, combined treatment modality might be beneficial for improving functional outcome.


Dysregulation of RNA interference components in COVID-19 patients.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus causing severe respiratory illness (COVID-19). This virus was initially identified in Wuhan city, a populated area of the Hubei province in China, and still remains one of the major global health challenges. RNA interference (RNAi) is a mechanism of post-transcriptional gene silencing that plays a crucial role in innate viral defense mechanisms by inhibiting the virus replication as well as expression of various viral proteins. Dicer, Drosha, Ago2, and DGCR8 are essential components of the RNAi system, which is supposed to be dysregulated in COVID-19 patients. This study aimed to assess the expression level of the mentioned mRNAs in COVID-19patients compared to healthy individuals. Our findings demonstrated that the expression of Dicer, Drosha, and Ago2 was statistically altered in COVID-19 patients compared to healthy subjects. Ultimately, the RNA interference mechanism as a crucial antiviral defense system was suggested to be dysregulated in COVID-19 patients.


Short-term effects of air pollutants on hospital admissions for acute bronchitis in children: a multi-city time-series study in Southwest China.
Few studies have investigated the effects of air pollutants on children with acute bronchitis. This study aimed to explore the acute effects of four air pollutants [fine particulate matter (PM2.5), inhalable particulate matter (PM10), sulfur dioxide (SO2), and nitrogen dioxide (NO2)] on the daily number of children admitted to the hospital for acute bronchitis in Sichuan Province, China. The 49,975 records of hospitalized children with acute bronchitis from medical institutions in nine cities/prefectures, Sichuan Province, China, as well as the simultaneous meteorological data and air pollution data from 183 monitoring sites, were collected from 1 January 2017 to 31 December 2018. A generalized additive model was adopted to analyze the exposure-response and lag effects of hospitalizations of children with acute bronchitis to air pollutants. Stratified analyses were conducted based on sex, age, and season. The single-pollutant model showed that a 10 µg/m3 increase at lag07 of PM2.5, PM10, SO2, and NO2 corresponded to an increase of 1.23% [95% confidence interval (CI) 0.21-2.26%], 1.33% (95% CI 0.62-2.05%), 23.52% (95% CI 11.52-36.81%), and 12.47% (95% CI 8.46-16.64%) in daily hospitalizations for children with acute bronchitis, respectively. Children aged 0-2 were more prone to PM2.5 (P < 0.05). Interestingly, the effects were stronger in the warm season than in transition seasons and the cool season for PM2.5 and PM10 (P < 0.05). The higher daily average concentrations of four pollutants in Sichuan Province can result in an increased number of children hospitalized for acute bronchitis.


Rare Variant Double-Layered Lateral Meniscus Detected During Arthroscopy in a Young Gymnast After a Hyperextension Knee Injury: A Case Report.
A 15-year-old high-level gymnast sustained a hyperextension knee injury and was diagnosed with a lateral meniscus tear on advanced imaging. During arthroscopy, a redundant meniscus was encountered overlying an otherwise normal, intact lateral meniscus, consistent with a double-layer lateral meniscus. The redundant meniscus was resected, and the patient was able to return to gymnastics at her previous high level of competition. Abnormalities of the lateral meniscus may be poorly characterized or undetected on preoperative imaging studies. When the decision is made to proceed with surgery, a vigilant diagnostic arthroscopic examination can facilitate the detection and treatment of unanticipated pathology.


Changes in fluid compartments in hamster renal papilla due to peristalsis in the pelvic wall.
The pelvic peristalsis "milks" the renal papilla in rodents. This study investigates the effect of the pelvic contractions upon the fluid in papillary loops of Henle (LH) and capillaries (cap) and on the volume of collecting duct (CD) cells, papillary epithelial (PE) cells and interstitium. In the anesthetized antidiuretic hamsters the urine was made green by an intravenous infusion of lissamine green. A snare was placed loosely around the papilla. The peristalsis was recorded on a Grass recorder using a fiberoptic light signal which changed intensity with the events in the pelvis and papilla. In one group of hamsters the snare was tightened during the contraction and in another group at the beginning of the relaxation. The papilla within the pelvis was then fixed immediately. It was epon-embedded for light and electron microscopy. In the group with contracted pelvis CD, LH, and cap were all closed and empty; the papilla was elongated. In the group with relaxed pelves these structures were full and open spaces were seen between the cells of CD and PE. Morphometric measurements showed that the intercollecting duct volume was larger in the papillae with relaxed pelvis, but that cell volume of PE was larger in the papillae with contracted pelvis. It is suggested that fluid moves into the cells during contraction when urine flows through the CD and into the interstitium during relaxation.


Electrocardiography for the detection of left ventricular hypertrophy in an elderly population with long-standing hypertension in primary care: a secondary analysis of the CHELLO cohort study.
To investigate: (1) the prevalence of left ventricular hypertrophy (LVH) in elderly primary care patients with long-standing asymptomatic hypertension, and (2) the diagnostic value of ECG as a screening tool in the detection of LVH compared with echocardiography in this specific patient population. A cross-sectional study in five general practices in the south-east of the Netherlands. Patients with primary care-managed hypertension, aged between 60 and 85 years, without known heart failure. Between June 2010 and January 2013, the patients underwent structured interviews, blood pressure assessment, laboratory testing, ECGs and echocardiograms. The primary outcome was to investigate the ability of ECG to detect LVH, compared with echocardiography as a reference test (gold standard). Four hundred and twenty-two patients (44% male; ages 70±7 years) who underwent ECG and echocardiographic assessment to determine LVH were included. The median duration of hypertension was 10 (4-15) years. The overall prevalence of LVH was 44%, which increased with age (p<0.001); up to 60% of patients were ≥75 years. ECG intimated LVH in 47 patients (11%) but in only 26 of those (55%) was LVH confirmed by echocardiography. The sensitivity of ECG for detecting LVH was poor (14%). Asymptomatic primary care patients with long-standing hypertension have a high prevalence of previously undetected LVH, which increases with age. ECG is inadequate for detecting LVH in these patients. Early detection of LVH could potentially create more awareness for the optimal regulation of hypertension and compliance to therapy. Therefore, echocardiography should be considered a screening device for the detection of LVH in this population.


The quantification of circular RNA 0007841 during induction therapy helps estimate the response and survival benefits to bortezomib-based regimen in multiple myeloma.
Circular RNA_0007841 (Circ_0007841) facilitates multiple myeloma (MM) progression and resistance of the bortezomib by experimental studies, while its clinical implication in MM patients is still unclear. This study intended to evaluate the longitudinal change and prognostic role of circ_0007841 expression in MM patients receiving bortezomib-based induction therapy. In this prospective study, bone marrow plasma cell (BMPC) samples were gained from 97 MM patients at diagnosis and after bortezomib-based induction therapy, and from 30 healthy controls (HCs) proposing BM donation. Then, circ_0007841 expression in BMPC samples was measured by reverse transcription-quantitative polymerase chain reaction. Additionally, MM patients were followed up for a median of 29.4 months. Circ_0007841 expression was increased in MM patients compared to HCs (P < 0.001), but it was decreased after bortezomib-based induction therapy in MM patients (P < 0.001). Moreover, circ_0007841 expression at diagnosis was associated with the presence of t (4; 14) (P = 0.034), while its expression after bortezomib-based induction therapy was linked with higher revised international staging system stage (P = 0.025) in MM patients. Interestingly, circ_0007841 expression after bortezomib-based induction therapy was lower in MM patients who achieved complete remissions (P = 0.001) and overall responses (P = 0.002) compared to those who did not. Prognostically, circ_0007841 expression after bortezomib-based induction therapy (over the median vs. below the median) independently predicted shorter progression-free survival (hazard ratio (HR): 2.497, P = 0.002) and overall survival (HR: 3.107, P = 0.008) in MM patients. Circ_0007841 quantification during induction therapy may reflect the response and survival benefits to bortezomib-based regimen in MM patients.


Association of postural balance and falls in adult patients receiving haemodialysis: A prospective cohort study.
Static postural balance performance is often impaired in people receiving haemodialysis (HD) for the treatment of stage-5 chronic kidney disease (CKD-5). However, the question as to whether lower postural balance is associated with adverse clinical outcomes such as falls has not been addressed yet. We conducted a prospective cohort study to explore the association between static postural balance and falls in people receiving HD. We hypothesised that higher postural sway would be associated with increased odds of falling. Seventy-five prevalent CKD-5 patients receiving HD (age: 61.8 ± 13.4 years) from three Renal Units were enrolled in this prospective cohort study. At baseline, postural balance was assessed with a force platform in eyes open (EO) and eyes closed (EC) conditions. Centre of pressure (CoP) measures of range, velocity and area were taken for the analysis. Falls experienced by study participants were prospectively recorded during 12 months of follow-up. Secondary outcomes included timed-up and go, five-repetition sit-to-stand test and the Tinetti falls efficacy scale (FES). In multivariable logistic regression analysis, higher CoP range in medial-lateral direction during EC was associated with increased odds of falling (OR: 1.04, 95 %CI: 1.00-1.07, p = 0.036). In ROC curve analysis, CoP velocity in EO exhibited the greatest prognostic accuracy (AUC: 0.69, 95 %CI: 0.55-0.82), however this was not statistically different from CoP measures of area and range. None of the postural balance measures exceeded the prognostic accuracy of the FES (AUC: 0.70, 95 %CI: 0.58-0.83, p = 0.005). This prospective cohort study showed that higher postural sway in medial-lateral direction was associated with increased odds of falling in people receiving HD. CoP measures of range, velocity and area displayed similar prognostic value in discriminating fallers from non-fallers. The overall utility of static posturography to detect future fall-risk may be limited in a clinical setting.


Trigeminal P2X3 receptor expression differs from dorsal root ganglion and is modulated by deep tissue inflammation.
The distribution and modulation of the P2X(3) receptor was studied in trigeminal ganglion neurons to provide insight into the role of ATP in craniofacial sensory mechanisms. Binding to the d-galactose specific lectin IB4 was found in 73% of P2X(3)-positive neurons while only 16% of IB4 neurons expressed P2X(3). Neurons expressing P2X(3) alone were significantly larger than IB4-or IB4/P2X(3)-positive neurons. Investigation of target-specificity revealed that 22% of trigeminal ganglion muscle afferent neurons were positive for P2X(3) versus 16% of cutaneous afferent neurons. Muscle P2X(3) afferents were significantly smaller than the overall muscle afferent population while P2X(3) cutaneous afferent neurons were not. Presumptive heteromeric (P2X(2/3)) muscle afferent neurons were also identified and comprised 77% of the P2X(3) muscle afferent population. Muscle afferent neurons co-expressed P2X(3) with either calcitonin gene-related peptide (15%) or substance P (4%). The number of P2X(3)-positive muscle afferent neurons significantly increased one and four days following complete Freund's adjuvant-induced masseter muscle inflammation, but significantly decreased after 12 days. These results indicate that within trigeminal ganglia: (1) the P2X(3) receptor is expressed in both small and medium-sized neurons; (2) the P2X(3) receptor is not exclusively expressed in IB4 neurons; (3) P2X(3) is co-expressed with neuropeptides; (4) differences in the proportion of cutaneous versus muscle P2X(3) afferents are not apparent. Trigeminal P2X(3) neurons therefore differ markedly from dorsal root ganglion P2X(3) afferents. This study also shows that deep tissue inflammation modulates expression of the P2X(3) receptor and thus may warrant exploration as a target for therapeutic intervention.


Delirium Assessment and Management in Geriatric Psychiatry under Prevailing Indian Laws (MHCA 2017).
The Indian Mental Health Care Act of 2017 (the Act) focuses on the human rights of persons with mental illness. It is based on the individual's dignity, autonomy, and independence with a client-centered approach. Delirium is frequently seen in the hospitalized geriatric population, more commonly in medical and surgical wards, and much less frequently in psychiatry wards. Delirium is covered under the Act as a "substantial disturbance of thinking, mood, perception, orientation or memory that grossly impairs judgment, behavior, (and) capacity to recognize reality or ability to meet the ordinary demands of life." The Act provides provisions for capacity assessment, emergency treatment, supported admission, advance directive, and the role of nominated representative in such cases.


Altered spontaneous brain activity pattern in cognitively normal young adults carrying mutations of APP, presenilin-1/2 and APOE ε4.
To explore genetic effects of amyloid precursor protein (APP), presenilin-1/2 and apolipoprotein E (APOE) ε4 on brain structural and functional alterations in cognitively normal young adults. Eighty healthy adults (mean age 24.0±2.5years; n=18, APP/presenilin-1/2 group; n=31, APOE ε4 group; n=31, control group [without above-mentioned gene mutation]) underwent high-resolution T1-weighted 3D anatomical imaging, resting-state functional MR imaging and neuropsychological assessments. We used voxel-based morphometry and regional homogeneity (ReHo) algorithms to investigate brain structural and functional changes among three groups, and performed correlation analyses between the brain regions with statistically significant difference and neuropsychological results. No brain structural changes were found, however, ReHo values were increased in right parietal-frontal lobes in APOE ε4 group, and decreased in the left middle temporal gyrus in APP/presenilin-1/2 group compared with controls (all P<0.05). Compared with APOE ε4 group, decreased ReHo values of bilateral temporal lobes were shown in APP/presenilin-1/2 group (P<0.05). ReHo values of right superior frontal gyrus in APOE ε4 group positively correlated with neuropsychological tests scores(P<0.05). Cognitively normal young adults carrying APOE ε4 or APP/presenilin-1/2 had different spontaneous brain activity patterns without cerebral structural differences.


A case of penile tumor: combination of leiomyosarcoma and squamous cell carcinoma.
Leiomyosarcoma of the penis is a very rare malignant tumor. We describe a patient with a combination of leiomyosarcoma and squamous cell carcinoma, apparently the first case in the world, and review previous cases of leiomyosarcoma.


Small particulate gadolinium oxide and gadolinium oxide albumin microspheres as multimodal contrast and therapeutic agents.
To prepare and characterize new particulate contrast media, small particulate gadolinium oxide (SPGO) and gadolinium oxide albumin microspheres (GOAM), as prototype multimodal imaging and therapeutic agents. SPGO was purchased from Alfa Aesar Inc. (Ward Hill, MA). GOAM were synthesized via ultrasonic irradiation using SPGO and 5% bovine serum albumin in aqueous solution. SPGO and GOAM were characterized by size, concentration, structure, and gadolinium content. Their relaxivity at high magnetic field strength and x-ray attenuating abilities were evaluated in 0.4% agar gel at room temperature. SPGO were confirmed to be 20-40 nm in diameter. GOAM have an average size of 2 to 5 microm and show a relatively homogeneous distribution of SPGO within the albumin microspheres. T1 and T2 relaxivity of GOAM was 6.7 seconds(-1) mmol/L(-1) and 38.5 seconds(-1) mmol/L(-1), respectively, while that of SPGO was 0.2 seconds(-1) mmol/L(-1) and 6.8 seconds(-1) mmol/L(-1), respectively. At 0, 0.004, 0.16, 4.0, and 16.0 mmol/L SPGO, x-ray attenuation values were measured at 2.11, 3.48, 7.06, 39.83, and 187.33 Hounsfield units, respectively. Use of SPGO and SPGO encapsulated in non-heat-hardened albumin microspheres (GOAM) represents a new approach. SPGO and GOAM have suitable physicochemical properties to warrant further biophysical and animal studies and reevaluation of toxicity limitations.


Genomic variations and transcriptional regulation of the human mu-opioid receptor gene.
The mu-opioid receptor (MOR1) is a target of endogenous and exogenous opioids and plays a pivotal role for anesthesia and analgesia. Variations in the 5' flanking sequence of the mu-opioid receptor gene may influence transcriptional regulation and ultimately alter protein expression of MOR1. In the present study we investigated the influence of eight single nucleotide polymorphisms (SNP) within the mu-opioid receptor promoter on promoter activity and evaluated the frequencies of the relevant SNPs in 700 patients under opioid medication. Reporter-gene-constructs were created by means of PCR and site directed mutagenesis, testing eight SNPs previously described. The neuroblastoma cell line SHSY5Y was used for transfection and promoter activity was estimated by luciferase activity. Of the eight reporter gene constructs employed to test genomic variations, two produced a significant change in luciferase activity when compared to wild-type constructs. The G-554A variation located within a known NFkB binding element resulted in a decreased activity whereas the A/G base exchange at position -1320 showed an increased luciferase activity. This particular variant generated a myeloid zinc finger (MZF1) cis-acting element known to impact transcription. The allele frequency of the -1320G variant was 0.21% in 700 Caucasian patients under opioid medication in contrast to 9.1% reported previously in drug addicted African Americans. Because of this unexpected low frequency an association analysis to opioid requirements and effects of mu-opioid receptor agonists was not feasible. In conclusion, transcriptional regulation of MOR1 is modified by two genetic variations at positions -554 and -1320 of the mu-opioid receptor promoter. Individuals presenting these variations may have an altered level of MOR expression. A possible association of these genomic variants on efficacy and side effects of opioid treatment in different ethnic groups has to be elucidated.


Clinical Routine Application of the Second-generation Neuroendocrine Markers ISL1, INSM1, and Secretagogin in Neuroendocrine Neoplasia: Staining Outcomes and Potential Clues for Determining Tumor Origin.
Neuroendocrine neoplasms (NENs) have traditionally been identified via expression of proteins associated to the regulation of secretory vesicles and granules. We report the clinical usage of the "second-generation" proteins ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), and secretagogin (SECG) as immunohistochemical markers of neuroendocrine differentiation since their introduction in clinical routine and compare the results with the established proteins chromogranin A (CGA) and synaptophysin (SYP). In total, 161 tumors, including 139 NENs and 22 "non-NENs" (unrelated tumors with an initial suspicion of NEN), were informatively stained for ISL1, and subsets were also interrogated for INSM1 and/or SECG. Diffuse or focal positive immunoreactivity was noted for ISL1 in 91/139 NENs (65%) and in 6/22 (27%) non-NENs, for INSM1 in 76/85 NENs (89%) and in 2/5 (40%) non-NENs, and for SECG in 49 out of 64 NENs (77%) and in 0/5 non-NENs (0%). Generally, ISL1, INSM1, and SECG exhibited sensitivities in line with or slightly below that of CGA and SYP-largely attributable to tissue-specific patterns regarding tumoral origin. Moreover, for pancreatic and small intestinal NENs, the two largest subgroups, ISL1 staining results were consistent irrespectively of tumor source and WHO grade. We verify previously suggested immunohistochemical schemes of neuroendocrine markers of first- and second-generations to facilitate the diagnostic process for NENs and confirm that the second-generation neuroendocrine markers display tissue-specific patterns. We therefore recommend their implementation in tertiary endocrine pathology centers, not least to aid in the identification of primary tumors when analyzing metastases.


Effect of ammonium acetate on alcohol fermentation in cassava-alcohol fermentation process.
The cassava-alcohol fermentation process employing cassava requires nitrogen source to maximize yields by a commercial strain of S. cerevisiae TG1348. In this study, a factorial experimental design was used to assess a suitable nitrogen source for growth and fermentative performance of S. cerevisiae in cassava-ethanol fermentation. The alcohol fermentation time was about 39 h for urea and ammonium acetate, which was 48 h for ammonium chloride and ammonium sulphate. The fermentation time was reduced by 19 % when using urea and ammonium acetate as nitrogen source. Ammonium acetate leaded to the highest alcohol yield, which was 4% higher than for ammonium sulphate. In addition, byproduct formation differed obviously between the nitrogen sources. The glycerol yields were similar for urea, ammonium sulphate and ammonium chloride but were 24 % lower for ammonium acetate. However, glycerol yield for ammonium carbonate was higher than for other nitrogen sources. Clearly, in batch cultures the ammonium acetate not only increased ethanol generation, but also decreased glycerol generation. In order to understand why ammonium acetate promotes alcohol fermentation, acetic acid was added to different nitrogen sources. The weight loss effect of ammonium sulphate adding acetic acid and ammonium acetate as nitrogen source was the same. The fermentation time was shortened by adding acetic acid. And pH was increased by addition of acetic acid when ammonium sulfate and urea were used as nitrogen sources. The results showed that the acetate root plays an important role in ammonium acetate. The results of this study could facilitate the development of new strategies to control fermentation performance.


Centrally mediated antinociceptive effects of cannabinoid receptor ligands in rat models of nociception.
The endogenous nonapeptide hemopressin (HE) demonstrates potent block of the cannabinoid subtype-1 (CB1) receptor in vitro and robust antinociception in vivo. The current study evaluated the effects of centrally administered HE in mechanistically distinct pre-clinical rat models of pain-the hot plate test and the hind paw formalin test. The non-subtype selective CB receptor agonist WIN 55,212-2 was tested concurrently as a positive control. In the hot plate test, neither intrathecal (i.t.) HE nor WIN 55,212-2 significantly altered the latency to respond to noxious heat. By contrast, i.t. HE and WIN 55,212-2 significantly reduced pain-related behaviors in the formalin test. Possible HE functionality as a CB1 receptor antagonist at the spinal level was evaluated in the formalin test. Intrathecal pretreatment with HE did not attenuate the antinociceptive effect of i.t. WIN 55,212-2. However, pretreatment with the CB1 receptor antagonist rimonabant did; i.t. rimonabant pretreatment was not antinociceptive. Potential supraspinal antinociceptive activity of HE was also evaluated. Whereas intracerebroventricular (i.c.v.) injection of WIN 55,212-2 reduced pain-related behaviors in the formalin test, interestingly, i.c.v. HE increased behaviors. In the current study, an antinociceptive effect with the CB receptor ligand HE was obtained under the specific condition of tissue injury and not in the uninjured state. Thus, HE could be a useful analgesic peptide with a novel spinal mechanism of action.


Correction to: Bayesian approach to investigate a two-state mixed model of COPD exacerbations.
The article [Bayesian approach to investigate a two-state mixed model of COPD exacerbations], written by [Anna Largajolli, Misba Beerahee, Shuying Yang], was originally published electronically on the publisher's internet portal (currently SpringerLink) on [13 June 2019] without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on [November 2019] to © The Author(s) [2019] and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.


The Effect of CoAl2O4 as a Nucleating Agent and Pouring Temperature on the Microstructure and Properties of Inconel 713C® Nickel-Based Superalloy Castings.
In this work, three melt-pouring temperatures (1450 °C, 1480 °C, 1520 °C) and CoAl2O4 inoculant contents in the shell mold's primary coating (0 wt%, 5 wt%, and 10 wt%) were selected to study microstructural and mechanical property changes of the Inconel 713C® nickel-based superalloy. The castings' phase transformation temperatures, phase constitution, microstructure, and mechanical properties at room and elevated temperatures were investigated via thermodynamical simulations, differential thermal analysis, light and scanning electron microscopy, energy-dispersive X-ray spectroscopy, and tensile and stress-rupture tests. The pouring temperature and inoculant content strongly influenced the mean equiaxed grain size, which ranged between 2.36 and 6.55 mm. The primary microstructure of Inconel 713C® castings, owing to its complex chemical composition, comprised multiple phases, including γ, γ', MC, M3B2, and Ni7Zr2. The mean size of γ' was in the 0.446-0.613 μm range, depending on the casting variant. Grain refinement with CoAl2O4 at ambient temperature for each melt-pouring temperature led to increased yield strength (YS) and ultimate tensile strength (UTS). YS was in the range of 775-835 MPa, while UTS was in the range of 868-1010 MPa. A reverse trend was observed in samples that crept in 982 °C/152 MPa, while for each variant, the time to rupture exceeded 30 h. The maximum time to rupture was 46.1 h obtained in the unmodified casting poured at 1480 °C.


Advocacy for Unaccompanied Migrant Children in US Detention.
During 2021, nearly 150,000 unaccompanied children (UCs) were apprehended at the US-Mexican border. Most are leaving Guatemala, Honduras, and El Salvador, motivated by poverty, climate change, and violence. UCs are most often apprehended by the Border Patrol and then transferred to the Office of Refugee Resettlement (ORR), the Department of Health and Human Services. ORR is responsible for ensuring that the child is released to a parent or sponsor in the United States capable of providing an adequate home. Advocacy must not only address a complex system of legal and custodial care but also confront a troubled political environment.


Neuregulin-1 type III knockout mice exhibit delayed migration of Schwann cell precursors.
In an embryonic developmental stage of the peripheral nervous system (PNS), Schwann cell precursors migrate along neuronal axons to their final destinations. After birth, they eventually wrap around individual axons to form myelin sheaths, which insulate axons to increase the nerve conduction velocity. Some growth factors and adhesion molecules are known to control these developmental stages from in the fish to in the mammal. Neuregulin-1 (NRG1), which is composed of many alternative splicing variants, is such a growth factor. Among these variants, the type III isoform of NRG1, interacting with ErbB2 and ErbB3 receptors on Schwann cells, plays an essential role in myelination in the fish and the mammal. NRG1 type III is also known to promote migration of fish Schwann cell precursors; however, it still remains to be clarified whether mammalian type III isoform does it. We have therefore generated type III isoform-specific knockout mice in inbred strain. The mice result in delayed migration of the precursors from the dorsal to ventral root via a peripheral ganglion, comparing littermate controls. Similar results are observed in an in vitro migration assay using reaggregated Schwann cell precursors. Furthermore, the knockout mice exhibit reduced myelin thickness, consistent with the established role of NRG1 type III in myelination. These results indicate that in mice, NRG1 type III plays a key role not only in myelination but also in migration.


Incidental findings detected with panoramic radiography: prevalence calculated on a sample of 2017 cases treated at a major Italian trauma and cancer centre.
This study aimed to assess the prevalence of incidental findings, not strictly related to dentistry, viewed with panoramic radiography. Panoramic radiographs performed between December 2013 and June 2016 were retrospectively collected. These images were analyzed, searching for incidental findings. All the information collected was statistically analysed RESULTS: A total of 2307 Panoramic Radiograph were analyzed and 2017 of them were included in the study. 529 incidental findings were seen: 255 (48.2%) were ESP (Elongation of Styloid Process), 167 were CAC (Carotid Artery Calcification) (31.57%), 36 were maxillary sinus pathologies (6.8%) and 71 were other incidental findings (13.42%). The total prevalence of IF was 26, 23%., CAC was 8.28% in the total population, and it was higher in women (9.82%) than men (6.54%). 48.5% of CAC were bilateral. When unilateral, the right side showed a higher right side prevalence. The prevalence of ESP was 12.64% in total population (men: 13.82%; women: 11.60%). 84.71% of ESP were bilateral and, when present unilaterally, no side difference was seen. 13.33% of the ESP appeared segmented. The prevalence of maxillary sinus pathologies was 1.78% (men: 2.32%; women: 1.31%). Only 8.33% of these pathologies were bilateral, and, when unilateral, they were mostly present on the right side. Between the 71 other IF (prevalence: 3.52%), sialoliths and tonsilloliths were assessed most frequently. Due to the high prevalence of incidental findings detected with panoramic radiography, dental practitioners should be aware of the various pathologic conditions seen on the panoramic radiographs.


Differences in long-term survival outcomes after coronary artery bypass grafting using single vs multiple arterial grafts: a meta-analysis with reconstructed time-to-event data and subgroup analyses.
We reviewed the available literature on patients with coronary artery disease undergoing isolated coronary artery bypass grafting (CABG) with either single (SAG) or multiple arterial grafting (MAG). Original research studies that evaluated the long-term survival of MAG versus SAG were identified, from 1995 to 2022. The median overall survival (OS) and event-free OS were the primary endpoints. Comparison of median OS between the right internal mammary artery (RIMA) and radial artery (RA) as a second arterial conduit was the secondary endpoint. Subgroup analyses were performed regarding patients older than 70 years, with diabetes mellitus, and females. A sensitivity analysis was performed with the leave-one-out method. Forty-four studies were included in the qualitative and thirty-nine in the quantitative synthesis. After pooling data from 180 to 459 patients, the MAG group demonstrated a higher OS (HR, 0.589; 95% CI, 0.58-0.60; p < 0.0001) and event-free OS compared with the SAG group (HR, 0.828; 95% CI, 0.80-0.86; p < 0.0001). In addition, RITA was associated with superior OS compared with RA as a second arterial conduit (HR, 0.936; 95% CI, 0.89-0.98; p = 0.009). MAG was also superior to SAG in patients over 70 years, females, and patients with diabetes mellitus. Sensitivity analysis demonstrated a small-size study effect on the female subgroup analysis. The present meta-analysis indicates that MAG is associated with enhanced survival outcomes compared to SAG for patients undergoing isolated CABG.


MiR-192/NKRF axis confers lung cancer cell chemoresistance to cisplatin via the NF-κB pathway.
Chemoresistance influences the therapeutic effect of cisplatin and remains a major obstacle to its clinical use. MicroRNAs are associated with drug resistance of various tumors. However, the association between microRNAs and cisplatin in lung cancer remains largely unclear. MicroRNA expression profile was identified by microRNA microarray between the lung cancer cisplatin-sensitive cell line A549 (A549) and cisplatin-resistant cell line A549/DDP (A549/DDP) and confirmed by quantitative real-time-PCR (qRT-PCR). In vitro loss- and gain-of-function studies were performed to reveal the biological function of miR-192 and related mechanism of the microRNA-192/NKRF axis in lung cancer cell cisplatin resistance. Increased miR-192 expression was detected in A549/DDP cells compared to A549. High miR-192 expression significantly suppressed apoptosis, enhanced proliferation, and conferred resistance to cisplatin in lung cancer cells. NF-κB repressing factor (NKRF), which is involved in the regulation of the NF-κB signaling pathway, was identified as a direct target of miR-192. Overexpression of miR-192 significantly increased the nuclear protein amount and transcriptional activation of NF-κB and expression of cIAP1, cIAP2, Bcl-xl and XIAP, whereas decreased miR-192 expression did the opposite. Inhibition of the NF-κB signal pathway by curcumin reversed the effect of upregulation of miR-192 on proliferation, apoptosis and cisplatin-resistance in lung cancer cells. These results indicated that miR-192/ NKRF axis enhances the cisplatin resistance of lung cancer cells through activating the NF-κB pathway in vitro. MiR-192 plays a crucial role in cisplatin-resistance of lung cancer cells. Thus, MiR-192 may represent a therapeutic target for overcoming resistance to cisplatin-based chemotherapy in lung cancer.


Immunogenicity of subcellular fractions and molecular species of MuLV-induced tumors. III. Stimulation of syngeneic antitumor responses by subcellular fractions and molecular species of Moloney virus-induced tumors in CBA and A mice.
YBA, a Moloney virus-induced leukemia in CBA mice, and a relatively weak immunogenic tumor, was screened for the presence of immunogenic antigens. The tumor was subjected to homogenization and subcellular fractionation on sucrose gradients; the immunogenic subcellular fractions underwent further separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The immunogenicity of the subcellular fractions and the SDS-PAGE-isolated molecular species were tested by (their) subcutaneous injection into syngeneic mice and examination of their splenocytes examined against tumor cell and normal cell targets by the chromium release cell-mediated lympholysis assay. Tumor cell homogenates were also separated by SDS-PAGE and tested for immunogenicity without prior fractionation. Splenocytes from mice that had received injections of certain SDS-PAGE-isolated epitopes derived from YBA tumor homogenate or its light and heavy subcellular fractions generated effective cytotoxic responses against YBA target cells after 6 days in vitro cultivation. In contrast, intact YBA tumor cells or non-separated tumor homogenates failed to induce an efficient cytotoxic response. The effector cells induced with the immunogenic SDS-PAGE-isolated epitopes of YBA tumor were specific, since they cytolysed the homologous target cells more efficiently than unrelated target cells or syngeneic normal cells. The activity of these effector cells was affected by varying the effector: target ratio. Augmentation of the cytotoxic responses was obtained when the splenocytes of mice immunized with SDS-PAGE-isolated epitopes of YBA tumor were restimulated in vitro, with the homologous neoplastic cells. Immunogenic SDS-PAGE epitopes were isolated from YAC tumor also (YAC is a Moloney-induced tumor of A mice). The effector cells induced with these separated epitopes were characterized as thymus-derived cells and not as natural killer cells. The results suggest that (1) the molecular repertoire of YBA and YBA tumors contain immunogens that can induce a specific antitumor cell-mediated response; (2) the isolated molecular species injected are more efficient immunogens than the entire, unseparated homogenate sample or a dose of 10(8) intact inactivated tumor cells; and (3) the gel matrix may be responsible for the enhanced cell-mediated response induced against the weakly immunogenic tumor.


Effect of adjunctive single high-dose vitamin D3 on outcome of community-acquired pneumonia in hospitalised adults: The VIDCAPS randomised controlled trial.
Low vitamin D status is associated with increased risk of pneumonia, greater disease severity and poorer outcome. However, no trials have examined the effect of adjunctive vitamin D therapy on outcomes in adults with community-acquired pneumonia (CAP). We conducted a randomised, double-blind, placebo-controlled trial examining the effects of adjunctive vitamin D in adults hospitalised with CAP. Participants were randomised to either a single oral dose of 200,000 IU vitamin D3 or placebo. The primary outcome was the complete resolution of chest radiograph infiltrate at 6 weeks post-study treatment. Secondary outcomes included length of hospital stay, intensive care admission and return to normal activity. Only participants who completed the study or died within the 6 week period were included in the analysis (n = 60 vitamin D, n = 57 placebo). Adjunctive vitamin D did not have any effect on the primary outcome (OR 0.78, 95% CI 0.31 to 1.86, p = 0.548). However, there was evidence it increased the complete resolution of pneumonia in participants with baseline vitamin D levels <25 nmol/L (OR 17.0, 95% CI 1.40-549.45, P = 0.043), but this did not reach statistical significance using exact methods (OR 13.0, 95%CI 0.7-960.4, P = 0.083). There were no significant effects for any secondary outcome.