Improved understanding of human anatomy through self-guided radiological anatomy modules.
To quantifiably measure the impact of self-instructed radiological anatomy modules on anatomy comprehension, demonstrated by radiology, gross, and written exams. Study guides for independent use that emphasized structural relationships were created for use with two online radiology atlases. A guide was created for each module of the first year medical anatomy course and incorporated as an optional course component. A total of 93 of 96 eligible students participated. All exams were normalized to control for variances in exam difficulty and body region tested. An independent t-test was used to compare overall exam scores with respect to guide completion or incompletion. To account for aptitude differences between students, a paired t-test of each student's exam scores with and without completion of the associated guide was performed, thus allowing students to serve as their own controls. Twenty-one students completed no study guides; 22 completed all six guides; and 50 students completed between one and five guides. Aggregate comparisons of all students' exam scores showed significantly improved mean performance when guides were used (radiology, 57.8% [percentile] vs. 45.1%, P < .001; gross, 56.9% vs. 46.5%, P = .001; written, 57.8% vs. 50.2%, P = .011). Paired comparisons among students who completed between one and five guides demonstrated significantly higher mean practical exam scores when guides were used (radiology, 49.3% [percentile] vs. 36.0%, P = .001; gross, 51.5% vs. 40.4%, P = .005), but not higher written scores. Radiological anatomy study guides significantly improved anatomy comprehension on radiology, gross, and written exams.


In silico analysis and molecular docking studies of natural compounds of Withania somnifera against bovine NLRP9.
NLRP9 is a member of nucleotide-binding domain leucine-rich repeat-containing receptors and is found to be associated with many inflammatory diseases. In the current scenario, the identification of promising anti-inflammatory compounds from natural sources by repurposing approach is still relevant for the early prevention and effective management of the disease. In the present study, we docked bioactives of Ashwagandha (Withanoside IV, Withanoside V, Withanolide A, Withanolide B, and Sitoindoside IX) and two control drugs against bovine NLRP9 protein. ADME/T analysis was used to determine the physiochemical properties of compounds and standard drugs. Molecular modeling was used to evaluate the correctness and quality of protein structures. In silico docking analysis revealed Withanolide B had the highest binding affinity score of -10.5 kcal/mol, whereas, among control drugs, doxycycline hydrochloride was most effective (-10.3 kcal/mol). The results of this study revealed that bioactives of Withania somnifera could be promising inhibitors against bovine NLRP9. In the present study, molecular simulation was used to measure protein conformational changes over time. The Rg value was found to be 34.77A°. RMSD and B-factor were also estimated to provide insights into the flexibility and mobile regions of protein structure. A functional protein network interaction was constructed from information collected from non-curative sources as protein-protein interactions (PPI) that play an important role in determining the function of the target protein and the ability of the drug molecule. Thus, in the present situation, it is important to identify bioactives with the potential to combat inflammatory diseases and provide strength and immunity to the host. However, there is still a need to study in vitro and in vivo to further support these findings.


Changes in L-selectin expression on CD34-positive cells upon cryopreservation of peripheral blood stem cell transplants.
Several studies have pointed out that L-selectin on CD34-positive cells plays a role in haematopoietic reconstitution after peripheral blood stem cell (PBSC) transplantation. Since it is known that a decrease in L-selectin expression in lymphocytes and granulocytes can be induced by a variety of stress situations, we have investigated in this study whether the freeze-thawing procedure, used in PBSC transplantation, would affect L-selectin expression on CD34+ stem cells. Flow cytometry was performed by labelling the cells with anti-CD34 (HPCA2 PE) and anti-CD62L (FMC46 FITC). The leucapheresis procedure itself caused a slight decrease of L-selectin expression on CD34 cells in 11 out of 12 cases (mean decrease of the percentage of positive cells 11.9; range 6-23). A much larger decrease was found upon freeze-thawing: a mean of 39% (range 4-78% in 27 cases) compared to fresh material. To determine if L-selectin expression might be up-regulated after cryopreservation, thawed transplant samples (n = 11) were incubated at 37 degrees C in RPMI with 10% FCS at 5% CO2. Already early in the course of incubation two CD34-positive populations appeared in the blast region, characterized by either a low or high forward scatter. Simultaneous viability staining with the DNA dye 7-Amino Actinomycin D and the DNA/RNA dye Syto16 revealed that the population with low forward scatter was apoptotic while the population with the high forward scatter was non-apoptotic. The latter population is considered to be most relevant for transplantation. In this population an increase of L-selectin expression after overnight incubation was observed in 8/11 samples up to values of 46-120% of the values of the fresh nonfrozen samples. In addition, the mean fluorescence intensity was significantly increased in 10/11 cases. Kinetic experiments with shorter incubation times revealed that only part of the leucapheresis samples (two out of 8) showed an increase of L-selectin expression within 4 h. In addition, a decrease of L-selectin expression was found upon CD34 purification from fresh leucapheresis material by magnetic isolation (decrease ranging from 59 to 92%, n = 5). In contrast to frozen samples, L-selectin reappearance was seen already within 4 h of incubation in all samples. Both the loss of L-selectin expression on CD34 cells occurring upon freeze-thawing, the emergence of apoptosis, as well as the recovery of L-selectin expression on non-apoptotic cells varies largely between individual leucapheresis samples, and therefore it is concluded that such processes should be considered when correlations with clinical outcome after transplantation are made.


A split-face comparison of low-fluence Q-switched Nd: YAG laser plus 1550 nm fractional photothermolysis vs. Q-switched Nd: YAG monotherapy for facial melasma in Asian skin.
Melasma is a common pigmentary disorder which poses substantial therapeutic challenge. Combined therapy may be beneficial in Asians, where mixed type melasma is dominant. We sought to assess the efficacy and safety of a 1064 nm Q-switched Nd: YAG (1064 QSNY) and a nonablative 1550 nm erbium-doped fractional photothermolysis (NFP) treatment in Asian melasma. This was a split face study, in which 26 patients were treated with the 1064 QSNY (6 mm spot size, 1.2-1.4 J/cm(2) fluence) for 10 sessions at 2-week intervals to the entire face, and with the NFP (dynamic mode, pulse energy 6-8 mJ/microthermal zone (MTZ); total density 300 MTZs/cm(2)) for five sessions at 4-week intervals to the experimental side of the face. Efficacy variables were modified Melasma Area and Severity Index (mMASI), the physician's global assessment (PhGA), and patient's subjective global assessment (PGA). Safety was evaluated through the reporting of adverse events. The percentage of subjective improvement was virtually identical on both sides. The mMASI corroborated the patients' subjective estimate, both in terms of the degree of improvement and the lack of difference between the 1064 QSNY + NFP and the 1064 QSNY treated sides. No serious side effects were reported in either side. Our findings do not support the hypothesis of NFP providing a substantial benefit in treating the melasma when compared with the lone treatment of the 1064 QSNY.


Patterns of six behaviors and psychosomatic symptoms in adolescents: A six-province study in China.
Psychosomatic symptoms are often related with behaviors. However, the association between different behaviors and their latent patterns and psychosomatic health status is unclear. Current study aimed to identify the patterns of six behaviors and explore the association between different patterns and psychosomatic symptoms in a school-based sample of Chinese adolescents. From November 2015 to January 2016, the study enrolled 22,628 students from six cities in China (15.36 ± 1.79 years). Six behaviors [unintentional injury (UI), non-suicidal self-injury (NSSI), suicidal behaviors (SB), drinking, smoking, screen time (ST)] and psychosomatic symptoms (psychological and physical symptoms) were measured by self-report validated questionnaires. Six behaviors were all related to psychosomatic symptoms, among which SB was the strongest. Four patterns of behaviors were be identified as follows: low-risk pattern (64.0%), substance use pattern (4.5%), injury pattern (28.8%) and high-risk pattern (2.7%). Logistic regression analysis of psychological symptoms indicated that compared with low-risk pattern, high-risk pattern had the highest risk, followed by injury pattern, substance use pattern showed the lowest risk. Compared with low-risk pattern, the results of physical symptoms suggested the degree of risk was high-risk pattern, injury pattern and substance use pattern, respectively. Cross-sectional data were used in the study that could not evaluate causal relationships between six behaviors and psychosomatic symptoms. Six behaviors and their latent patterns are related to psychosomatic symptoms among Chinese adolescents differently, so different intervention and prevention protocol need to be taken for different patterns of adolescents.


Muscle sonography in six patients with hereditary inclusion body myopathy.
To evaluate the morphological changes of muscle with sonography in six patients affected by hereditary inclusion body myopathy (HIBM). We studied a group of six Persian Jews diagnosed with HIBM. All were homozygous for the GNE mutation M712T. Ultrasonographic examinations of the quadriceps femoris and hamstring muscle groups were performed. A follow-up ultrasound examination was performed, after an interval of 3 years, in four of these patients. Muscles were assessed subjectively as to echogenicity, determined by gray-scale assessment, and loss of normal muscle morphology. Power Doppler sonography (PDS) was used to assess vascularity. A sonographic finding of central atrophy and peripheral sparing resulting in a target-like appearance was noted in the hamstring compartment of all six patients. The quadriceps compartment also showed involvement of the rectus femoris of all patients, which, in some cases, was the only muscle involved in the quadriceps. Vascularity was markedly reduced in the affected areas, with blood flow demonstrated in the peripherally spared areas. The severity of atrophy increased with disease duration. In this case series, we describe a new sonographic finding as well as document progression of HIBM disease, which has generally been described as quadriceps sparing. The myopathic target lesion, as well as isolated rectus femoris atrophy, may provide a useful adjunct to disease diagnosis.


Are click-evoked BAEPs useful in case of neonate hyperbilirubinemia?
There is still controversy about the usefulness of click-evoked brainstem auditory evoked potentials (BAEPs) for the investigation of neonatal hyperbilirubinemia. The present work concerns the study of click-evoked BAEP responses in a population of 72 hyperbilirubinemic children (conceptional age between 33 and 42 weeks). Their bilirubinemia rates were between 219 and 600 mumol/l. The waves I, III and V were always present, and click BAEP thresholds were normal in all subjects. Latency anomalies were found only for 8 of the 72 subjects. The comparison of subjects having the higher (greater than 307 mumol/l) bilirubin levels with the group having the lower ones failed to show any significant differences for the I-III and I-V intervals. The influence of prematurity in BAEP alteration has not been demonstrated in this study. These data show, on the one hand, normal click-BAEP thresholds but, on the other hand, alterations of central conduction time in some hyperbilirubinemic newborns. It seems that other factors than hyperbilirubinemia might be operating.


BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia.
Mitophagy is an important metabolic mechanism that modulates mitochondrial quality and quantity by selectively removing damaged or unwanted mitochondria. BNIP3 (BCL2/adenovirus e1B 19 kDa protein interacting protein 3), a mitochondrial outer membrane protein, is a mitophagy receptor that mediates mitophagy under various stresses, particularly hypoxia, since BNIP3 is a hypoxia-responsive protein. However, the underlying mechanisms that regulate BNIP3 and thus mediate mitophagy under hypoxic conditions remain elusive. Here, we demonstrate that in hypoxia JNK1/2 (c-Jun N-terminal kinase 1/2) phosphorylates BNIP3 at Ser 60/Thr 66, which hampers proteasomal degradation of BNIP3 and drives mitophagy by facilitating the direct binding of BNIP3 to LC3 (microtubule-associated protein 1 light chain 3), while PP1/2A (protein phosphatase 1/2A) represses mitophagy by dephosphorylating BNIP3 and triggering its proteasomal degradation. These findings reveal the intrinsic mechanisms cells use to regulate mitophagy via the JNK1/2-BNIP3 pathway in response to hypoxia. Thus, the JNK1/2-BNIP3 signaling pathway strongly links mitophagy to hypoxia and may be a promising therapeutic target for hypoxia-related diseases.


Facile synthesis of hydroxyapatite/yeast biomass composites and their adsorption behaviors for lead (II).
For the first time, the hydroxyapatite (HAp)/yeast biomass composites were successfully synthesized through a facile alkaline ultrasound cavitation method, and used as a novel sorbent for removal of Pb(2+) from aqueous solution. The obtained HAp/yeast biomass composites were characterized by various techniques, including SEM, EDX, XRD, TGA, FTIR, XPS and fluorescence detection, respectively. It was found that the yeast cells were wrapped by the well-dispersed HAp, and more functional groups (such as carboxyl, hydroxyl and amino) on yeast surface were exposed. Also, varying factors that may affect the adsorption efficiency of HAp/yeast biomass composites, such as solution pH, reaction temperature and time, have been carefully investigated respectively. Remarkably, more than 99% of Pb(2+) can be removed by the HAp/yeast biomass composites. Evidence from FTIR and XPS analysis revealed that the higher removal efficiency should be ascribed to the synergetic effect of synthesized HAp and more functional groups exposed on yeast surface.


Low Healthy Diet Self-Efficacy and Intentions Associated with High Sweet Snacks and Sugar Sweetened Beverages Consumption among African American Adolescents Recruited from Low-Income Neighborhoods in Baltimore.
Psychosocial factors may influence consumption patterns of sweet snacks and sugar sweetened beverages (SSB), which are potential risk factors for obesity among African American (AA) adolescents. We used multivariable linear and logistic regression models to examine cross-sectional associations among psychosocial factors, sweet snacks and SSB consumption, and BMI z-scores in 437 AA adolescents aged 9-14 years living in low-income neighborhoods in Baltimore City, U.S.A. Mean caloric intake from sugar was 130.64 ± 88.37 kcal. Higher sweet snacks consumption was significantly associated with lower self-efficacy (adjusted Odds Ratio (aOR) = 0.81; 95% CI = 0.71 to 0.93) and lower food intentions scores (0.43; 0.30 to 0.61). Higher SSB consumption was associated with lower outcome expectancies (aOR = 0.98; 95% CI = 0.96-0.99), lower self-efficacy (0.98; 0.96 to 0.99), and lower food intentions (0.91; 0.87 to 0.95). No significant association was found between SSB and sweet snacks consumption and weight status. Psychosocial factors may play a role in sugar consumption behaviors among AA adolescents in low-income neighborhoods. Further studies are needed to improve our understanding of causal mechanisms of this association.


Examination of Statistical Instability of Electroencephalograms.
The study examined stochastic stability of EEG samples recorded in succession from the same healthy volunteer at unchanged state. The absence of statistical repetitions not only for EEG samples, but also for the corresponding spectral densities was proven. A method to calculate the pairwise comparison matrices of ECG samples and quasi-attractors was proposed. The diagnostic effectiveness of these calculations was demonstrated during photostimulation, when successive EEG samples chaotically changed under overall homeostatic conditions.


Adult respiratory distress syndrome following closure of a chronic ventricular septal defect: possible relationship to the use of intracardiac gelatin-resorcin-formaldehyde glue.
Gelatin-resorcin-formaldehyde glue is now widely used in cardiac surgery, particularly in Europe. A case is reported where its use may have contributed to the pulmonary dysfunction seen postoperatively after elective closure of a postinfarct ventricular septal defect. It is believed that this is a result of a relatively high exposure of the pulmonary circulation to the glue, in particular to formalin. Although not proven, the authors advise caution when using the glue within the cardiac chambers.


Mycotic femoral artery aneurysm due to Salmonella oranienburg. A case report.
A case of mycotic aneurysm in the superficial femoral artery due to Salmonella infection is described. The important features and clinical presentation of such aneurysms are described and the principles of surgical management are reviewed.


Capacitively coupled contactless conductivity detection to account for system-induced gradient deformation in liquid chromatography.
The time required for method development in gradient-elution liquid chromatography (LC) may be reduced by using an empirical modelling approach to describe and predict analyte retention and peak width. However, prediction accuracy is impaired by system-induced gradient deformation, which can be especially prominent for steep gradients. As the deformation is unique to each LC instrument, it needs to be corrected for if retention modelling for optimization and method transfer is to become generally applicable. Such a correction requires knowledge of the actual gradient profile. The latter has been measured using capacitively coupled "contactless" conductivity detection (C4D), featuring a low detection volume (approximately 0.05 μL) and compatibility with very high pressures (80 MPa or more). Several different solvent gradients, from water to acetonitrile, water to methanol, and acetonitrile to tetrahydrofuran, could be measured directly without the addition of a tracer component to the mobile phase, exemplifying the universal nature of the approach. Gradient profiles were found to be unique for each solvent combination, flowrate, and gradient duration. The profiles could be described by convoluting the programmed gradient with a weighted sum of two distribution functions. Knowledge of the exact profiles was used to improve the inter-system transferability of retention models for toluene, anthracene, phenol, emodin, sudan-I and several polystyrene standards.


Chronological improvement of pancreatectomy for resectable but advanced pancreatic neuroendocrine neoplasms.
Progress of non-surgical treatments in the last decade has improved the prognosis of pancreatic neuroendocrine neoplasms (PanNEN). However, the improvement of surgery for advanced PanNEN remains unknown. This study aimed to investigate the chronological changes of the clinical impact of pancreatectomy for PanNEN. Patients undergoing curative-intent pancreatectomy for PanNEN between 1991 and 2010 were categorized into the earlier period group, and those between 2011 and 2021 were into the later period group. Advanced PanNEN was defined as showing resectable synchronous liver metastases or invasion to portal venous systems or adjacent organs. The recurrence-free survival (RFS) and overall survival (OS) were analyzed among patients with non-advanced and advanced PanNENs. The independent prognostic risk factors were identified using a Cox proportional hazard model. A total of 189 patients (n = 54 in the earlier period and n = 135 in the later period) were included. The proportion of advanced PanNEN increased from 15% to 30% (P = 0.027). The RFS and OS of non-advanced PanNEN were similar between the periods. Whereas, among patients with advanced PanNEN, the later period group showed improved prognosis; The 5-year RFS of the earlier period vs. the later period was 0% vs. 27%, and the 5-year OS was 38% vs. 82% (p = 0.013). A radical surgical treatment for advanced PanNEN has shown prognostic improvement in this decade. However, more careful perioperative examinations and possibly, additional treatments are required for PanNEN with portal vein invasion.


A Novel Mechanism for NF-κB-activation via IκB-aggregation: Implications for Hepatic Mallory-Denk-Body Induced Inflammation.
Mallory-Denk-bodies (MDBs) are hepatic protein aggregates associated with inflammation both clinically and in MDB-inducing models. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-κB activation. However, the precise mechanism that links protein aggregation to NF-κB-activation and inflammatory response remains unclear. Herein we find that treating primary hepatocytes with MDB-inducing agents (N-methylprotoporphyrin (NMPP), protoporphyrin IX (PPIX), or Zinc-protoporphyrin IX (ZnPP)) elicited an IκBα-loss with consequent NF-κB activation. Four known mechanisms of IκBα-loss i.e. the canonical ubiquitin-dependent proteasomal degradation (UPD), autophagic-lysosomal degradation, calpain degradation and translational inhibition, were all probed and excluded. Immunofluorescence analyses of ZnPP-treated cells coupled with 8 M urea/CHAPS-extraction revealed that this IκBα-loss was due to its sequestration along with IκBβ into insoluble aggregates, thereby releasing NF-κB. Through affinity pulldown, proximity biotinylation by antibody recognition, and other proteomic analyses, we verified that NF-κB subunit p65, which stably interacts with IκBα under normal conditions, no longer binds to it upon ZnPP-treatment. Additionally, we identified 10 proteins that interact with IκBα under baseline conditions, aggregate upon ZnPP-treatment, and maintain the interaction with IκBα after ZnPP-treatment, either by cosequestering into insoluble aggregates or through a different mechanism. Of these 10 proteins, the nucleoporins Nup153 and Nup358/RanBP2 were identified through RNA-interference, as mediators of IκBα-nuclear import. The concurrent aggregation of IκBα, NUP153, and RanBP2 upon ZnPP-treatment, synergistically precluded the nuclear entry of IκBα and its consequent binding and termination of NF-κB activation. This novel mechanism may account for the protein aggregate-induced inflammation observed in liver diseases, thus identifying novel targets for therapeutic intervention. Because of inherent commonalities this MDB cell model is a bona fide protoporphyric model, making these findings equally relevant to the liver inflammation associated with clinical protoporphyria.


CXCL12 induces migration of oligodendrocyte precursor cells through the CXCR4‑activated MEK/ERK and PI3K/AKT pathways.
Demyelination is a nervous system disease in which the myelin sheaths of neurons are damaged due to inflammatory reactions, inherited abnormalities or trauma. This damage impairs the conduction of signals in the affected nerves, which in turn causes deficiencies in sensation, movement and cognition. Oligodendrocyte precursor cells (OPCs) are able to induce remyelination. However, the remyelination is suboptimal due to the limited migration of OPCs. In the present study, neonatal OPCs were isolated from rats for the investigation of the role of C‑X‑C motif chemokine ligand 12 (CXCL12), an important chemokine, in mediating the migration ability of OPCs. The present results demonstrated that CXCL12 stimulation markedly promoted the migration of OPCs and activated the dual specificity mitogen‑activated protein kinase kinase 1 (MEK)/extracellular signal‑regulated kinase (ERK) and phosphoinositide 3‑kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (AKT) pathways. Knockdown of C‑X‑C motif chemokine receptor 4 (CXCR4; a receptor of CXCL12) reversed the CXCL12‑induced migration of OPCs and blocked the MEK/ERK and PI3K/AKT pathways. In addition, specific inhibitors of the MEK/ERK and PI3K/AKT pathways significantly reduced the migration of OPCs. Based on these findings, it was concluded that CXCL12 may induce the migration of OPCs through the CXCR4‑activated MEK/ERK and PI3K/AKT pathways. The results of the present study support the manipulation of CXCL12‑mediated OPC migration to improve remyelination.


When to refer a child to an otolaryngologist.
While children commonly present with acute or chronic upper respiratory tract disorders in general practice, in the majority of cases these problems are seasonal, self limiting and/or unlikely to cause long term disability. However, assessment may be difficult, and on occasions, surgical referral and treatment should be considered. This article provides a general approach in determining when to refer a child to an otolaryngologist. Chronic conditions should be considered for surgical management when the pattern of illness in the child is such that significant morbidity is being experienced and this is thought likely to continue for an unacceptable period of time. The need to refer for assessment or treatment of an acute condition is often self evident. In particular, a suppurative complication of a common infection should be considered in an unwell child with upper respiratory tract symptoms.


Influence of fluoride on the uptake of 51Cr-chromate by human erythrocytes.
Uptake of 51Cr-chromate by freshly collected human erythrocytes was inhibited by 90 mM sodium fluoride only in cells preincubated with fluoride. In vitro storage also increased the sensitivity of the cells: 90 mM NaF clearly inhibited the uptake of chromate in cells stored in vitro for 5 weeks. Gel chromatography revealed two forms of 51Cr within the cells, one of small molecular weight, which thin layer chromatography indicated was unchanged chromate; the other form was apparently bound to macromolecules such as hemoglobin.


Human neutrophils exhibit disparate chemotactic factor gene expression.
The evolution of acute inflammation from initiation through resolution is associated with the changing character of the infiltrating leukocytes. Recruitment of these leukocytes is dependent upon the generation of chemotactic factors that have either global or specific activity for a particular leukocyte. In this manuscript we present data demonstrating that human neutrophils can express mRNA for neutrophil chemotactic factor/interleukin 8 (IL-8), but fail to express mRNA for monocyte chemotactic protein (MCP-1). The expression of IL-8 was observed upon adherence or in response to stimulation with lipopolysaccharide. Maximal IL-8 antigenic production was noted at 24 hrs. These studies demonstrate a disparate expression of chemotactic cytokines by neutrophils.


Effect of environmental temperature on thermal response to chlorpromazine. I. Simulation of temperature regulation in rats.
Using the basic equations for heat balance, a compartment model was constructed to simulate the physiological responses to heat and cold in rats. The model predicted steady-state situations of rectal temperature, skin temperature (pelt and tail), metabolic rate and evaporative heat loss.


Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome.
Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders, and accumulating evidence gained in both preclinical and clinical studies indicate the involvement of enteric microbiota in its pathogenesis. Gut resident microbiota appear to influence brain activity through the enteric nervous system, while their composition and function are affected by the central nervous system. Based on these results, the term "brain-gut-microbiome axis" has been proposed and enteric microbiota have become a potential therapeutic target in IBS cases. However, details regarding the microbe-related pathophysiology of IBS remain elusive. This review summarizes the existing knowledge of molecular mechanisms in the pathogenesis of IBS as well as recent progress related to microbiome-derived neurotransmitters, compounds, metabolites, neuroendocrine factors, and enzymes.


Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma.
The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd. The median number of prior therapies was 3 (range 1-8). The best response was complete response (CR) in one (4.2%), very good partial response (VGPR) in one (4.2%) and partial response in eight (33.3%) patients. Ten patients, 41.7% (95% CI: 22.1, 63.4), achieved ≥PR. The median time to response was 4.4 months (range 1-13.6 months) and the median duration of response was 6.9 months (range 3-52.2 months). The clinical benefit rate (CR + VGPR + PR + MR) was 45.8% (95% CI 25.6, 67.2). The median progression-free survival was 4 months. Median overall survival was 25 months with a median follow-up of 27.5 months. The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. Addition of clarithromycin to Rd can overcome resistance to Rd in a subset of patients and lead to durable clinical responses.


[Immunochemical identification and physico-chemical characteristics of specific proteins of seminal plasma].
Two specific antigens of human spermatic plasma have been identified: thermostable alpha 1-globulin and alpha 2-microglobulin of fertility. The thermostable alpha 1-globulin presents a glycoprotein containing sialic acids with a molecular weight of 60000 +/- 7000. In addition to the sperm, it has been also identified in the saliva of men and women. Alpha 2-microglobulin of fertility is identical to placental alpha 2-microglobulin. This protein is specific for the reproductive system of men and women. The physicochemical properties of the test antigens are described.


Enhancing immunogenicity and reducing dose of microparticulated synthetic vaccines: single intradermal administration.
Our purpose was to evaluate the ability of a polymeric vehicle to release a model synthetic vaccine to the skin in order to reach a potent activation of the specific immune response. The peptide-loaded poly-D,L-lactide-co-glycolide acid (PLGA) microparticles were prepared by a double emulsion technique and administered to Balb/c mice. The immune response (antibody and T cell activation) obtained by the intradermal (i.d.) and the subcutaneous (s.c.) routes was tested. When similar doses of peptide-loaded microparticles were injected s.c. or i.d. in mice, the antipeptide IgG antibody immune response was found to be significantly higher after i.d. injection into the skin. We could also reduce the dose of antigen 10 times by the i.d. route and find a similar antibody response to that obtained by the s.c. immunization. At the lowest i.d. dose level, the IgG2a/IgG1 ratio was also incremented and the IgE production decreased. The i.d. microparticles induced, at both dose levels, a marked IFN-gamma secretion by peptide-stimulated splenocytes and lymph node cells and a significant T cell proliferation in spleen cell cultures. The results demonstrate that peptide-loaded microparticles were efficiently administered by the i.d. route because lower doses were required and powerful antibody and T cell responses were obtained compared to the conventional s.c. administration.


A double-blind trial of clonazepam in the treatment of parkinsonian dysarthria.
We studied the effect of clonazepam in a double-blind trial on 12 parkinsonian patients with hypokinetic dysarthria. Speech samples were judged on 14 of the dimensions used in the Mayo Clinic dysarthria study. Of the 11 patients who completed the study, 10 showed improvement. The effective dosage of clonazepam was 0.25 to 0.5 mg/d with higher dosage than that less effective. Clonazepam has a definite role in the management of parkinsonian dysarthria.


Influence of anti-interleukin (IL)-5/anti-IL-5 receptor-α treatment on work productivity in patients with severe eosinophilic asthma.
This retrospective study shows that treatment with anti-eosinophilic antibodies in patients with severe eosinophilic asthma is associated with an increase in work productivity and a decrease in missed days at work https://bit.ly/3IIPppR.


Carotid arterial hemorrhage after radical head and neck surgery.
From 1960 to 1974, 63 patients treated by the Head and Neck Service of Memorial Hospital underwent carotid arterial ligation for control of actual or threatened carotid rupture. Twenty-one of these patients died without leaving the hospital. Fourteen of these deaths were the direct result of carotid ligation or hemorrhage. Five of the surviving patients suffered permanent neurologic damage. Factors predisposing to carotid rupture included a history of radiation, advanced disease, the presence of an oral or pharyngeal suture line in continuity with a dissected neck, and the postoperative development of skin necrosis or fistulas. Because elective carotid ligation did not prevent the consequences of carotid rupture and because reestablishment of vascular continuity is almost never possible, all attempts should be made to avoid the conditions that are precursors to this most serious complication of radical head and neck surgery.


Reexamining the phonological similarity effect in immediate serial recall: the roles of type of similarity, category cuing, and item recall.
Study of the phonological similarity effect (PSE) in immediate serial recall (ISR) has produced a conflicting body of results. Five experiments tested various theoretical ideas that together may help integrate these results. Experiments 1 and 2 tested alternative accounts that explain the effect of phonological similarity on item recall in terms of feature overlap, linguistic structure, or serial order. In each experiment, the participants' ISR was assessed for rhyming, alliterative, and similar nonrhyming/nonalliterative lists. The results were consistent with the predictions of the serial order account, with item recall being higher for rhyming than for alliterative lists and higher for alliterative than for similar nonrhyming/nonalliterative lists. Experiments 3 and 4 showed that these item recall differences are reduced when list items repeat across lists. Experiment 5 employed rhyming and dissimilar one-syllable and two-syllable lists to demonstrate that recall for similar (rhyming) lists can be better than that for dissimilar lists even in a typical ISR task in which words are used, providing a direct reversal of the classic PSE. These and other previously published results are interpreted and integrated within a proposed theoretical framework that offers an account of the PSE.


Post-mortem viral dynamics and tropism in COVID-19 patients in correlation with organ damage.
The persistence of SARS-CoV-2 after death of infected individuals is unclear. The aim of this study was to investigate the presence of SARS-CoV-2 RNA in different organs in correlation with tissue damage and post-mortem viral dynamics in COVID-19 deceased. Twenty-eight patients (17 males, 11 females; age 66-96 years; mean 82.9, median 82.5 years) diagnosed with COVID-19 were studied. Swabs were taken post-mortem during autopsy (N = 19) from the throat, both lungs, intestine, gallbladder, and brain or without autopsy (N = 9) only from the throat. Selective amplification of target nucleic acid from the samples was achieved by using primers for ORF1a/b non-structural region and the structural protein envelope E-gene of the virus. The results of 125 post-mortem and 47 ante-mortem swabs were presented as cycle threshold (Ct) values and categorized as strong, moderate, and weak. Viral RNA was detected more frequently in the lungs and throat than in the intestine. Blood, bile, and the brain were negative. Consecutive throat swabs were positive up to 128 h after death without significant increase of Ct values. All lungs showed diffuse alveolar damage, thrombosis, and infarction and less frequently bronchopneumonia irrespective of Ct values. In 30% the intestine revealed focal ischemic changes. Nucleocapsid protein of SARS-CoV-2 was detected by immunohistochemistry in bronchial and intestinal epithelium, bronchial glands, and pneumocytes. In conclusion, viral RNA is still present several days after death, most frequently in the respiratory tract and associated with severe and fatal organ damage. Potential infectivity cannot be ruled out post-mortem.


Label-free dendrimer-like silica nanohybrids for traceable and controlled gene delivery.
To create advanced functional nanocarriers for achieving excellent gene delivery performance, fluorescence label-free hybridized dendrimer-like silica nanocarriers (HPSNs-AC-PEI) were developed by using the endosomal pH and cytoplasmic glutathione (GSH) responsive autofluorescent acetaldehyde-modified-cystine (AC) to link non-toxic low molecular weight branched polyethyleneimine (PEI) onto amino-functionalized dendrimer-like silica nanoparticles with hierarchical pores (HPSNs-NH2). The specific microstructure of this hybridized nanocarrier makes it not only show low cytotoxicity and high gene loading capability, but also display high gene transfection efficiency. The cleavage of disulfide bonds caused by GSH facilitates plasmid DNA (pDNA) release. Moreover, the pH and GSH controlled gene delivery profile can be real-time tracked using the autofluorescence of HPSNs-AC-PEI.


Dataset on causality analysis of chilling process in beef and pork carcasses using graphical modeling.
Appropriate control of carcass temperatures in slaughterhouses requires an accurate understanding of extrinsic and intrinsic factors present after slaughter and dressing. Therefore, we use large amounts of data required under the hazard analysis and critical control point system that are accumulated in daily business reports compiled by food business operators. This data aims to clarify the influencing factors or affectors of the chilling processes for beef and pork carcasses in a slaughterhouse using graphical modeling (GM), which is an explorative method in multivariate data analysis. GM has been widely used for statistical causality analysis in visual and flexible modeling. GM is carried out using the following parameters: outside temperature and humidity, number of carcasses in a chilling room on each operating day and during every afternoon of operation, time of sealing a chilling room, pre-set temperature in a chilling room, chilling room temperature at 16:30 on the day of slaughter and dressing and at 8:00 on the next day, and surface and core temperatures of carcasses. These parameters are set in a three-layered structure comprising (1) cause, (2) intermediate effect, and (3) effect. Covariance selection is performed to statistically eliminate spurious correlation. Path diagrams are drawn for beef and pork in GM for visualization. The data herein has contributed to the first attempt at the use of GM to statistically verify causality in the food manufacturing process. These data can be used to determine causality between carcass temperature and affectors in the chilling process via GM and thus minimize bias. Analyses of the present data are reported in the article "Chilling control of beef and pork carcasses in a slaughterhouse based on causality analysis by graphical modeling" [1].


Vitamin D deficiency in non-alcoholic fatty liver disease: The chicken or the egg?
Serum vitamin D concentration is reduced in patients with non-alcoholic fatty liver disease (NAFLD). Although the mechanism of vitamin D deficiency in liver disease is not fully understood, a few reports have suggested the beneficial effects of vitamin D supplements. The present study investigated changes in serum 25-hydroxy vitamin D level and clinical parameters after total calorie restriction with vitamin D intake reduction in NAFLD patients. Newly diagnosed NAFLD patients with elevated aminotransferase levels were chosen for a calorie restriction and weight-reduction program. A total of 82 patients received nutritional education from nutritionists every 2 weeks for 2 months. Serum 25-hydroxy vitamin D level, amount of vitamin D intake, and physical activity were thoroughly investigated. The mean serum 25-hydroxy vitamin D concentration was 13.0 ng/ml. Twenty-nine patients (35.4%) had severe vitamin D deficiency. Patients with a 25-hydroxy vitamin D concentration <10 ng/ml had an increased risk of abdominal obesity (72.4% vs. 47.2%, P = 0.023) and a higher prevalence of metabolic syndrome (69% vs. 42.2%, P = 0.015) compared with patients with 25-hydroxy vitamin D levels >10 ng/ml. Although total energy and vitamin D intake were reduced during the program, serum 25-hydroxy vitamin D levels increased in patients with NAFLD (P < 0.001). Liver enzymes and metabolic parameters also improved, even as vitamin D intake decreased. Serum vitamin D concentration increased with body weight and intrahepatic fat reduction, independent of decreases in vitamin D intake. Weight loss per increased serum vitamin D level without vitamin D supplementation and improved metabolic parameters in NAFLD.


"Paradoxical" reduction in postexercise ejection time and increased transthoracic impedance.
Despite decreasing heart rate, left ventricular ejection time (LVET) transiently falls immediately following bicycle exercise. In seven normal, untrained subjects LVET decreases at 15 s postexercise corresponded (r = 0.78) with an increase in transthoracic electrical impedance (Z) consistent with decreased venous return to the thorax. Because the determinants of LVET are stroke volume (SV) and ejection rate, the deltaZ implies that decreased SV contributed to the "paradoxical" fall in LVET.


Galectin fingerprinting detects differences in expression profiles between bovine endometrium and placentomes as well as early and late gestational stages.
The concept of a network within the family of adhesion/growth regulatory galectins implies distinct spatio-temporal expression profiles. To test this assumption immunohistochemically for bovine placenta, placentomal (P) and interplacentomal tissues (IP) were collected at a slaughterhouse from the three stages of pregnancy (early gestation = day 30-130; mid gestation = day 130-220; late gestation = day 220-275). The specimens were snap-frozen or fixed in Bouin's solution, then embedded in paraffin. Gene expression for galectins-1, -3, -4 and -9 in P and IP of late gestational stages was monitored by RT-PCR. Galectin-type-specific antibodies were used for immunohistochemical localization. In IP, galectin-1 was present in stroma cells and early gestational trophoblast giant cells (TGC), whereas galectin-3 was confined to uterine epithelial cells. In contrast, both galectins were found in epithelia of P tissue. Uterine epithelial cells and blood vessel walls were positive for galectin-4, while galectin-9 was detected predominantly in uterine epithelial cells and late gestational TGC. Our study thus reveals individual profiles among the galectins tested, an indication for specific functions exerted by each protein in the bovine endometrium and placenta.


[The primary inflamed and primary degeneratively changed joint from the viewpoint of physical therapy].
The author emphasizes the interdisciplinary approach that is necessary to rheumatic arthropathies. The pain, inflammation and disturbance of movement must be seen as requiring physiotherapy, while a degree of differentiation is necessary in thermotherapy.


Tissue carnitine in Reye syndrome.
Skeletal muscle carnitine palmityltransferase and muscle or liver carnitine content were determined in biopsies from children during and after attacks of Reye syndrome. No consistent abnormality of enzyme or cofactor was found. Reye syndrome is biochemically distinct from the clinically similar syndrome of systemic carnitine deficiency.


Impacts of some clinicopathodemography and colorectal tissues key cell cycle and mucin stabilizing molecules on the metastasis trend in colorectal cancer patients.
We aimed to evaluate the various clinicopathodemographical, epidemiological, and molecular contributors to cumulatively worldwide metastatic colorectal cancer (CRC) in CRC patients from a highly populated area in northeastern Iran to pinpoint metastasis risk. A retrospective clinical material-based cohort including a total of 6260 registered CRC patients, of whom 3829 underwent surgery, from regional university hospitals, during 2006-2016, were analyzed for the clinicopathodemographical aspects of age, sex, stage of CRC, history of smoking, type 2 diabetes (T2D), hypertension, body mass index (BMI), familial/occupational status, post-surgery survival period and mRNA/protein expression of mucin stabilizer (B3GALNT2), mucin I (MUC1), key cell cycle molecules (i.e., P53 and Ki67), and MMR-related genes. Factors were set to estimate the risk of metastatic CRC and mortality. Predominant adenocarcinomatous CRCs were found in colon. Post-surgery survival period of metastatic CRC patients was remarkably longer in patients aged > 50 compared to those aged < 50 years, and worse in females than males. B3GALNT2high, MUChigh, P53low, and Ki67high mRNA/protein expression in the metastatic stage III CRC along with T2D and hypertension were associated with increased metastasis/mortality, with more worsening in males, older, BMI > 25, urban residing, and employed individuals, indicative of non-genetic attributable factors. B3GALNT2, MUC1, and "Ki67" can be used as promising biomarkers for prognosis and early diagnosis of increasingly/predominantly non-genetic/environmental originated metastatic CRCs.


Cross-cultural adaptation of the Brazilian-Portuguese version of the chronic urticaria quality-of-life questionnaire - CU-Q2oL.
Chronic urticaria (CU) is a debilitating skin disorder that affects patients' health related quality of life and the only questionnaire prepared specifically to CU is the Chronic Urticaria Quality of Life Questionnaire (CU-Q(2)oL). The purpose of this study was to cross-culturally adapt and validate the CU-Q(2)oL Brazilian-Portuguese version. Forward and back translation by three bilingual translators followed by pre-test was used to adapt the questionnaire. The CU-Q(2)oL was self-administered along with the Dermatology Life Quality Index (DLQI) in 112 patients with CU. Disease activity was assessed using the Urticaria Activity Score. Factor analysis was used to identify scales of the Brazilian portuguese CU-Q(2)oL. Internal consistency, convergent validity and known-group validity was determined. Reproducibility was evaluated by interclass correlation coefficient (ICC). Multiple linear regression was used to determine the predicting factors of CU-Q(2)oL results. Factor analysis revealed a three-dimensional structure: sleep/mental status/eating (I), pruritus/impact on life activities (II) and swelling/limits/look (III), which explained 52.49% of the total variance. All scales showed excellent internal consistency. External construct validity was supported by correlations between the CU-Q(2)oL and DLQI. The tool was found to be able to differentiate between patients with high and low levels of urticaria activity. Test-retest reliability was good to excellent (ICC = 0.69-0.86). Disease severity and urticaria type were the only factors predicting results. The CU-Q(2)oL Brazilian portuguese version was easily filled out, well accepted by the patients, demonstrated an acceptable validity and reliability and might be used to evaluate treatment outcomes and in clinical research.


An exceptionally well-preserved monodominant fossil forest of Wataria from the lower Miocene of Japan.
Byttneriophyllum tiliifolium is a leaf fossil-species of the family Malvaceae that was distributed widely throughout Eurasia from the Miocene to the Pliocene. An affinity to some Malvadendrina subfamilies has been suggested for Byttneriophyllum-bearing plants, but remains to be clarified due to insufficient information on other organs. Here, we report an exceptional lower Miocene fossil locality in Japan where a monodominant forest of the wood fossil-species Wataria parvipora flourished. Notably, the forest floor was covered by a bed consisting almost exclusively of B. tiliifolium. We observed occurrence modes of B. tiliifolium in this bed that confirmed that these leaves were deposited parautochthonously. These observations imply a biological connection between B. tiliifolium and W. parvipora. The wood and leaf characters together might narrow the affinity of Byttneriophyllum-bearing plants down to Helicterioideae within the Malvadendrina, although it is also possible that Byttneriophyllum-bearing plants constitutes an extinct lineage which is characterized by a combination of morphological traits found in several extant lineages. Our results suggest that Byttneriophyllum-bearing plants started to inhabit swamps no later than the end of the early Miocene when the global temperature was getting warmer.


Nonuniformity in the linear network model of the oculomotor integrator produces approximately fractional-order dynamics and more realistic neuron behavior.
The oculomotor integrator is a network that is composed of neurons in the medial vestibular nuclei and nuclei prepositus hypoglossi in the brainstem. Those neurons act approximately as fractional integrators of various orders, converting eye velocity commands into signals that are intermediate between velocity and position. The oculomotor integrator has been modeled as a network of linear neural elements, the time constants of which are lengthened by positive feedback through reciprocal inhibition. In this model, in which each neuron reciprocally inhibits its neighbors with the same Gaussian profile, all model neurons behave as identical, first-order, low-pass filters with dynamics that do not match the variable, approximately fractional-order dynamics of the neurons that compose the actual oculomotor integrator. Fractional-order integrators can be approximated by weighted sums of first-order, low-pass filters with diverse, broadly distributed time constants. Dynamic systems analysis reveals that the model integrator indeed has many broadly distributed time constants. However, only one time constant is expressed in the model due to the uniformity of its network connections. If the model network is made nonuniform by removing the reciprocal connections to and from a small number of neurons, then many more time constants are expressed. The dynamics of the neurons in the nonuniform network model are variable, approximately fractional-order, and resemble those of the neurons that compose the actual oculomotor integrator. Completely removing the connections to and from a neuron is equivalent to eliminating it, an operation done previously to demonstrate the robustness of the integrator network model. Ironically, the resulting nonuniform network model, previously supposed to represent a pathological integrator, may in fact represent a healthy integrator containing neurons with realistically variable, approximately fractional-order dynamics.


Fish cell lines: establishment and characterization of three new cell lines from grass carp (Ctenopharyngodon idella).
Three new cell lines were established from tissues of the grass carp, Ctenopharyngodon idella. Derived from the fin, snout, and swim bladder of two apparently healthy diploid fry, these cell lines have been designated GCF, GCS-2, and GCSB, respectively. The cells grew at temperatures between 24 degrees and 36 degrees C with optimal growth at 32 degrees C and have been subcultured more than 50 times since their initiation in August 1986. Two of the lines remained diploid or pseudodiploid after 38 passages. The cells were tested for microbial contamination, and plating efficiencies were determined. The three cell lines were sensitive to Rhabdovirus carpio (RVC), infectious hematopoietic necrosis virus (IHNV), golden shiner virus (GSV), chum salmon virus (CSV), and infectious pancreatic necrosis virus serotype VR299 IPNV). They were refractory to channel catfish virus (CCV), channel catfish reovirus (CRV), chinook salmon paramyxovirus (CSP), and an Ab serotype of IPNV.


Comparison of angular and combined automatic tube current modulation techniques with constant tube current CT of the abdomen and pelvis.
The objective of our study was to compare image quality and radiation dose associated with abdominopelvic CT using combined modulation, angular modulation, and constant tube current. Compared with using a constant tube current to scan the abdomen and pelvis, the use of a combined modulation technique results in a substantial reduction (42-44%) in radiation dose with acceptable image noise and diagnostic acceptability.


[Work-related stress in the indoor environment: how might we assess it?].
The periodic medical examination at the workplace should be an opportunity to monitor the health of workers. Psychological well-being and work-related stress are part of health, and therefore the occupational physician is required to control these parameters during his examinations. 29 companies with a total of 4069 workers were monitored by the Italian version of the questionnaire on air quality MMO40/IAQ, which contains a section on work-related stress based on the demand/control/support model of Karasek, and by Goldberg's scales of anxiety and depression. Work-related stress was significantly correlated with the number of symptoms reported by workers (p < 0.001) and with levels of anxiety and depression (p < 0.001). Despite its extreme simplicity, the scale of stress included in the questionnaire allows effective monitoring of the work-related stress.


Updated spatio-temporal distribution of Aedes (Stegomyia) albopictus in Brazil.
Aedes albopictus is native to Asia and is ranked among the top 100 invasive species worldwide, with vector competence for dengue, Zika, and chikungunya viruses. Understanding Ae. albopictus dispersal is essential for effective monitoring and vector control strategies. In this study, we analysed and updated the distribution of Ae. albopictus in Brazil using data available from the Ministry of Health through the Rapid Index Survey for Aedes (LIRA) for the years 2015-2020. The results of this research were mapped to visually represent the current distribution of Ae. albopictus in Brazil. In 2015, the presence of the vector was confirmed in 271 of the 1,820 Brazilian municipalities sampled (14.9%), and in 2020 it was detected in 728 of the 2,937 municipalities sampled (24.8%). In 2020, all Brazilian states had recorded the presence of this critical vector with a broader geographic distribution in the Southeast and Midwest regions as compared to the North, Northeast, and South regions. It was possible to note some stabilization of dispersion of this species in the Brazilian territory. The record of Ae. albopictus distribution advanced in Brazilian states and municipalities from 2015 to 2020; it is suggested that surveys of this vector be conducted periodically in all Brazilian municipalities and authorities should developing control strategies for this species together with Ae. aegypti.


Comparison of ST segment depression in upright treadmill and supine bicycle exercise testing.
Significant differences in the hemodynamic response to upright and supine exercise have been reported in patients with coronary artery disease. The purpose of the present study was to compare the degree of myocardial ischemia as assessed by ST segment depression during upright treadmill and supine bicycle exercise in 98 patients with coronary artery disease and in 34 patients with normal coronary arteries. The amount of ST segment depression at maximal exercise in patients with coronary artery disease was 0.90 +/- 0.80 mm for treadmill and 1.34 +/- 1.09 mm for supine bicycle (p less than 0.001). The amount of ST segment depression during treadmill and supine bicycle exercise tests was also compared at highest similar heart rates (0.68 +/- 0.77 versus 1.17 +/- 1.01, p less than 0.001), at highest similar rate-pressure products (0.71 +/- 0.77 versus 1.08 +/- 1.04, p less than 0.001), at highest similar metabolic equivalents of oxygen consumption (MET) levels (0.69 +/- 0.75 versus 1.20 +/- 1.05 mm, p less than 0.001) and at the onset of angina (0.84 +/- 0.73 versus 1.18 +/- 0.88 mm, p less than 0.001). The rate-pressure product achieved at maximal exercise was similar in both tests (18.74 +/- 5.80 x 10(3) versus 18.81 +/- 5.17 x 10(3), p = NS). The occurrence of angina during treadmill and supine bicycle exercise tests was similar (47 of 98 versus 48 of 98, respectively, p = NS). For the detection of coronary artery disease, the sensitivity was 50.0% for treadmill and 63.3% for supine bicycle (p less than 0.05) and the specificity was 73.5 versus 70.6%, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)


Pulse-shape discrimination against low-energy Ar-39 beta decays in liquid argon with 4.5 tonne-years of DEAP-3600 data.
The DEAP-3600 detector searches for the scintillation signal from dark matter particles scattering on a 3.3 tonne liquid argon target. The largest background comes from 39 Ar beta decays and is suppressed using pulse-shape discrimination (PSD). We use two types of PSD estimator: the prompt-fraction, which considers the fraction of the scintillation signal in a narrow and a wide time window around the event peak, and the log-likelihood-ratio, which compares the observed photon arrival times to a signal and a background model. We furthermore use two algorithms to determine the number of photons detected at a given time: (1) simply dividing the charge of each PMT pulse by the mean single-photoelectron charge, and (2) a likelihood analysis that considers the probability to detect a certain number of photons at a given time, based on a model for the scintillation pulse shape and for afterpulsing in the light detectors. The prompt-fraction performs approximately as well as the log-likelihood-ratio PSD algorithm if the photon detection times are not biased by detector effects. We explain this result using a model for the information carried by scintillation photons as a function of the time when they are detected.


Chol understandings of suicide and human agency.
According to ethnographic material collected since 2003, the Chol Mayan indigenous people in southern Mexico have different causal explanations for suicide. It can be attributed to witchcraft that forces victims to take their lives against their own will, to excessive drinking, or to fate determined by God. However, it can also be conceived of as a conscious decision made by a person overwhelmed by daily problems. Drawing from the theoretical framework developed by Laura M. Ahearn, inspired by practice theory, the paper contends that these different explanations operate within two different logics or understandings of human agency. The first logic attributes responsibility to supernatural causes such as witchcraft or divine destiny, and reflects Chol notions of personhood. The second logic accepts personal responsibility for suicide, and is related to processes of social change such as the introduction of wage labor, education and a market economy. The contemporary Chol resort to both logics to make sense of the human drama of suicide.


Sintering densification mechanism and mechanical properties of the 3D-printed high-melting-point-difference magnesium oxide/calcium phosphate composite bio-ceramic scaffold.
Over the past few years, biodegradable ceramic scaffolds have gained significant attention in the field of bone repair. Calcium phosphate (Ca3(PO4)2)- and magnesium oxide (MgO)-based ceramics are biocompatible, osteogenic, and biodegradable, making them attractive for potential applications. However, the mechanical properties of Ca3(PO4)2 are limited. We developed a magnesium oxide/calcium phosphate composite bio-ceramic scaffold characterized by a high melting point difference, using vat photopolymerization (VP) technology to address this issue. The primary goal was to fabricate high-strength ceramic scaffolds using biodegradable materials. In this study, we investigated ceramic scaffolds with varying MgO contents and sintering temperatures. We also discussed the co-sintering densification mechanism of high and low melting-point materials associated with composite ceramic scaffolds. During sintering, a liquid phase was generated, which filled up the pores generated during the vaporization of additives (such as resin) under the influence of capillary force. This led to an increase in the extent of ceramic densification realized. Moreover, we found ceramic scaffolds with 80 wt% MgO exhibited the best mechanical performance. This kind of composite scaffold performed better than pure MgO scaffold. The results reported herein highlight that high-density composite ceramic scaffolds can be potentially used in the field of bone repair.


Organization and expression of three genes from the silkmoth early chorion locus.
Chorion genes in the silkmoth Bombyx mori are clustered in a small region of one chromosome. Genes are grouped within this locus according to their expression in either early, middle, or late stages of choriogenesis. The entire set of late genes and a large fraction of the middle genes have been cloned and extensively characterized. We report here the first molecular characterization of a set of early chorion genes clustered within a 22.5-kb region. Transcripts homologous to these genes appear in the very first choriogenic follicle but disappear with different kinetics. One of the three early genes, 5H4, is the first example of a chorion gene which is not a member of a multigene family, or divergently paired with another chorion gene. The other two early genes, (ErA.1 and ErB.1) are divergently paired with each other in the manner of the middle and late chorion genes. The common 5' region between ErA.1 and ErB.1 is significantly shorter and does not contain certain sequence elements shared by the highly conserved 5' regions of middle and late chorion gene pairs. This evidence taken together with the fact that 5H4 is unpaired indicates that the early genes may utilize a regulatory mechanism somewhat different from the middle and late gene families.


Theileria and Babesia infection in cattle - First molecular survey in Kazakhstan.
Central Asia, including Kazakhstan, is an endemic area of Theileria and Babesia infections in cattle. Current data on the geographic distribution, prevalence, and genetic diversity of these pathogens in vertebrate hosts are lacking in Kazakhstan. The present study aimed to fill this gap, using molecular techniques for the first time. A cross-sectional survey was performed on adult cattle from 40 villages in nine administrative districts of the provinces of Turkistan and Zhambyl, southern Kazakhstan, in summer 2020. A total of 766 blood samples were screened for Theileria annulata (enolase gene), Theileria orientalis (major piroplasm surface protein gene, MPSP) and Babesia spp. (18 S ribosomal RNA gene) using polymerase chain reaction. The genetic variability of Theileria spp. was assessed by sequencing one amplicon from each village. All Babesia spp. positive amplicons were sequenced to identify the species involved. The overall prevalence of infections with T. annulata, T. orientalis and Babesia spp. was 83.0% (40 villages positive), 33.3% (31 villages) and 13.5% (36 villages), respectively. Co-infections with two or three species were present in 48.9% of all positive cattle. Theileria annulata showing a high polymorphism of the enolase gene occurred with similar frequency in both provinces. Theileria orientalis was detected for the first time in Kazakhstan being significantly (P = 0.014) more prevalent in Zhambyl than in Turkistan. Fourteen genotypes of T. orientalis were identified; two belonged to the moderately virulent MPSP-type 1 ('Chitose') and the others to MPSP-type 3 ('Buffeli') which is considered avirulent. The prevalence of Babesia infection was significantly (P < 0.000) higher in Turkistan than in Zhambyl. An unequivocal identification of the species involved was possible in 127 sequenced samples: Babesia occultans was the most common species, followed by Babesia bigemina and Babesia major, the latter being the first record in the country. The results show that Theileria and Babesia infections in cattle are widespread and occur with remarkably high prevalence in the southern Kazakhstan. They also provide first data on the genetic diversity of the species involved.


The cytonucleus test in the rat: a combined metaphase and micronucleus assay.
The suitability of the rat as a species choice for the micronucleus assay and the possibility of combining both metaphase and micronucleus analysis using one set of animals were investigated. Cyclophosphamide, trenimon, vinblastine sulphate and dimethyl benzanthracene were used to optimise the study design and experimental procedures. The sample times ranged from 12 to 72 h after a single dose of the compound. A maximal response in both micronucleus and chromosome aberration induction was observed 24 h after dosing. This sample time is recommended as the single sample time for the screening of all classes of compound. Using the optimal conditions, a number of different mutagens/carcinogens were then analysed for the induction of both micronuclei and chromosome aberrations in the same animal. The compounds selected were mitomycin C, methotrexate, 5-fluorouracil, hexamethyl phosphoramide, benzo[a]pyrene, benzidine and diaminoterphenyl. The results show that the rat is a responsive test species and that it is possible to combine both metaphase and micronucleus analysis in the same animal.


Levels of L-carnitine and L-O-acetylcarnitine in normal and infertile human semen: a lower level of L-O-acetycarnitine in infertile semen.
The level of total L-carnitine was determined in normal human seminal plasma and sperm. Most of the L-carnitine is concentrated in the seminal plasma and its level is about 10 times higher than that in blood plasma. About 50% of total L-carnitine in normal human seminal plasma exists in the form of acetylcarnitine. Similar studies were also carried out in oligospermic and azoospermic human seminal plasma. The level of L-O-acetylcarnitine in both types of infertile samples is significantly lower than that in normal samples. On the other hand, the level of free L-carnitine is the same in fertile and infertile seminal plasma.


Lymphocytes of the intestinal mucosa of chickens.
Examination, by light and electron microscopy, of the morphology and the staining properties of intraepithelial lymphocytes from the intestine of the chicken revealed a population of lymphoid cells, of which a proportion (up to 20%) is granulated. The majority of cells were immunoreactive with anti-T cell serum and can therefore be considered to be related to T-lymphocytes, but they did not proliferate when cultured with phytohaemagglutinin. The granulated cells were identical to those previously designated globule-containing leukocytes, but were distinct from mast cells in their morphology, staining reactions and the stability of the granules in different fixatives and buffers.


The anatomy of the calcaneus and surrounding structures.
Appreciation of the normal anatomy of the calcaneus is significant for various reasons. Restoration of normal anatomy has been of particular interest for fracture care. In addition, knowledge of surrounding structures is important when planning surgical approaches and vital when performing percutaneous procedures. Understanding of anatomic relationships allows discernment of the pathophysiology that is related to chronic conditions. The biomechanics of normal structures provides a theoretic basis for reconstruction and rehabilitation, and individual variations in calcaneal anatomy can be a predisposition for pathology.


Developing online training in using music for carers of people with dementia: A focus group study.
This study aimed to identify the core content and design issues in developing an online training course in the effective use of music for people with dementia. A co-design approach was taken in which focus groups were conducted with aged care staff and family caregivers (n = 17; 76.5% female). A general inductive approach was taken to data analysis. The consolidated criteria for reporting qualitative research (COREQ) guidelines were followed to ensure rigour in this study. Participants identified five core concepts for inclusion in the training program including the benefits of music, the need to assess for vulnerability to negative responses, music selection strategies, timing of use and equipment selection. Themes on design and implementation such as the need for role-specific content for care staff at all levels and scenario-based learning were identified. The development of online training in music use for carers of people with dementia needs to consider the demands on carers and develop training that is informative and engaging without placing large time demands on the user. Support at a management and executive level will be important to the implementation of such training in residential aged care contexts.


Identification of overlengthening after replacement of the radial head with a bipolar prosthesis.
Overlengthening of the radial column leads to insufficient functionality and increased capitellar wear. Methods to detect or prevent overlengthening have been described for monopolar prostheses. The aim of this study was to evaluate whether one such method described by Athwal et al. is also applicable for a bipolar prosthesis. The radial heads of six fresh frozen upper extremities were resected. A bipolar radial head prosthesis was implanted in each, and the effects of sequential overlengthening on the alignment of the radiocapitellar and ulnohumeral joint line were recorded by fluoroscopic images. Digital image analysis and estimation of overlengthening followed according to the method described by Athwal et al. Statistical analysis of the estimated and actual differences between the native state and bipolar replacement of the radial head with stepwise overlengthening of 1.5, 3, 4.5, and 6 mm showed a specificity of 86 % but consistently underestimated the amount of overlengthening with a sensitivity of only 61 %. The method described by Athwal et al. for the identification of overlengthening by a monopolar prosthesis was not found to be reliable for ruling out or quantifying overlengthening of the tested bipolar prosthesis. However, the use of the method to detect (rule in) overlengthening may be acceptable in certain circumstances. A reliable method for postoperative quantification of overlengthening by bipolar prostheses has still to be found.


Morphometric analysis of sparse capillary networks.
Two methods were used to assess the heterogeneity of capillary supply to muscles of widely differing metabolic capacity and fibre size. Using the method of capillary domains (DOM; Hoofd et al., 1985) and the closest-individual method (CI; Kayar et al., 1981) radii of Kroghian cylinders (R) can be calculated, and the heterogeneity of their lognormal distribution represented by the logarithmic standard deviation (Log SD). Both methods yield similar values for mean R in a tissue. DOM is more direct and quicker than CI, and may be particularly useful in the analysis of capillary oxygen supply during functional hypertrophy and in muscle regeneration where a broad distribution of fibre areas may be found. Despite a 500-fold range of capillary density, to a minimum of 20 capillaries mm-2, heterogeneity of capillary supply was similar in all muscles, indicating a functionally homologous spatial distribution. The relationship between number of fibres overlapped by a capillary domain, and domain area has zero correlation in most tissues but shows a negative trend in fish fast muscle, reflecting hyperplastic and hypertrophic growth. Capillary/fibre ratio is inappropriate for sparse networks whereas the cumulative fraction of domains vs fibre area shows a strong correlation, suggesting that maximal oxygen supply to muscle fibres is not restricted to contiguous capillaries, but also involves those remote from the fibre surface.


Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?
Evidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs. A systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19. Eight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42-0.94, P = 0.02, I2 = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB. MSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.


Current legal developments in medical staff credentialing disputes.
Credentialing of hospital staff has become an important method by which to ensure and to monitor the quality of clinical practice.


Dehalogenase-producing halophiles and their potential role in bioremediation.
This review aims to briefly describe the potential role of dehalogenase-producing halophilic bacteria in decontamination of organohalide pollutants. Hypersaline habitats pose challenges to life because of low water activity (water content) and is considered as the largest and ultimate sink for pollutants due to naturally and anthropogenic activities in which a substantial amount of ecological contaminants are organohalides. Several such environments appear to host and support substantial diversity of extremely halophilic and halotolerant bacteria as well as halophilic archaea. Biodegradation of several toxic inorganic and organic compounds in both aerobic and anaerobic conditions are carried out by halophilic microbes. Therefore, remediation of polluted marine/hypersaline environments are the main scorching issues in the field of biotechnology. Although many microbial species are reported as effective pollutants degrader, but little has been isolated from marine/hypersaline environments. Therefore, more novel microbial species with dehalogenase-producing ability are still desired.


Single-reflection regime of X rays that travel into a monocapillary.
We present an analysis of the transmission of x rays through a single monocapillary under the single-reflection regime. Because ray tracing does not provide an explanation for experimental data, we give a qualitative interpretation of the observed behavior within the framework of wave theory.


Therapeutic drug monitoring of posaconazole delayed release tablet while managing COVID-19-associated mucormycosis in a real-life setting.
Along with COVID-19 pandemic, India has faced an outbreak of COVID-19-associated mucormycosis (CAM). Due to restricted availability of amphotericin B during this outbreak, clinicians were forced to use posaconazole or isavuconazole preparations as first-line or alternate therapy in many patients. We planned an early monitoring of posaconazole trough level while using delayed release (DR) tablet as first-line or alternate therapy. Primary objective of the study was to determine percentage of patients achieving arbitrarily decided therapeutic posaconazole levels (≥1.2 μg/ml) after using standard dosages of posaconazole. Secondary objective was to identify potential factors associated with sub-therapeutic posaconazole levels. We performed retrospective chart review of the hospitalised patients, who received posaconazole DR tablet as first-line or alternate therapy to treat CAM during outbreak period (March 1 to May 31, 2021). High-performance liquid chromatographic (HPLC) method was used to measure trough level of posaconazole. Posaconazole serum levels of 29 patients were analysed, who received posaconazole DR tablet. Majority (n = 23) were male with the median (range) age 53 (24-86) years. The mean (SD) posaconazole level was 1.66 (0.76) μg/ml. Sub-therapeutic posaconazole trough level was observed in 7 (24.1%) patients. Relatively younger patients were associated with lower posaconazole level (p = .046). Except two patients, all the patients tolerated posaconazole well. The study supports the posaconazole trough level measurement on day 4 while using posaconazole DR tablet as first-line or alternate therapy to treat mucormycosis during limited supply of amphotericin B.


Regional cerebral blood flow measurement in rats with radioactive microspheres.
The effect of the method of heart catheterization on the measurement of cerebral blood flow (CBF) with radioactive microspheres was evaluated during various experimental procedures in male Sprague-Dawley rats. Catheters were inserted into the left ventricle via the right carotid or right subclavian artery or directly into the left atrium for microsphere injections. CBF was measured in cerebral cortical and subcortical tissues under control anesthetized (70% N2O, 30% O2), hypoxic or hypercapnic test conditions. Under control conditions, CBF was similar in the right vs the left cerebral hemisphere in subclavian artery and atrial catheterized rats but was greater in the left vs the right cortex in carotid catheterized animals (p less than .05). During hypoxia and hypercapnia CBF increased equally in both cerebral hemispheres in atrial catheterized rats. The increase in CBF was significantly attenuated in the cerebral hemisphere ipsilateral to carotid catheterization during hypoxia and hypercapnia, although the percentage increase in flow was similar in both hemispheres. The results indicate the limitations of measuring regional CBF changes under experimental test conditions in rats with a ligated carotid artery and suggest that atrial catheterization is the method of choice when comparable changes in CBF are desired in both cerebral hemispheres.


Development and application of a dot-ELISA test for the detection of serum antibodies to Fasciola hepatica antigens in llamas.
A microenzyme-linked immunosorbent assay (dot-ELISA) was developed to detect serum antibodies against Fasciola hepatica antigens in llamas. Sera from five F. hepatica-infected and 11 non-infected llamas were used in initial test development. Nitrocellulose filter disks containing F. hepatica excretory-secretory product were placed in 96-well microtiter plates, washed, blocked with Tween-20, then incubated with four-fold serial dilutions of llama sera. After incubation with rabbit anti-llama IgG followed by peroxidase-conjugated goat anti-rabbit IgG, addition of precipitable substrate resulted in purple dots on white background (positives) easily read by eye. The technique was further evaluated at titers of 1:512 using an additional six known positive and eight known negative llamas. Test results showed 6/6 known positive as positive and 8/8 known negative as negative. Sera were collected, at approximately weekly intervals, from three llamas experimentally infected with F. hepatica. The dot-ELISA detected antibodies to F. hepatica as early as the second week post-infection in all llamas. In a serologic survey of 256 llamas from an F. hepatica endemic area, the dot-ELISA detected antigen-specific serum antibodies to F. hepatica in 42 (16%) of the llamas. Although no difference was noted in antibody prevalence between sexes, prevalence increased in llamas over 6 months of age.


Interferons and bacterial infections.
Viruses have been established initially as interferon inducers and interferons have been considered to be antiviral proteins only. By our article we wish to draw attention to two observations: a) bacteria and derivatives thereof also are inducing the production of interferon b) interferons activate a number of defense mechanisms that are of potential relevance in antibacterial resistance. These two observations are not new. However, we believe, they deserve renewed attention within the framework of the pleiotropism of interferon effects and of the complexity of antibacterial defense mechanisms.


The genome of Brugia malayi - all worms are not created equal.
Filarial nematode parasites, the causative agents of elephantiasis and river blindness, undermine the livelihoods of over one hundred million people in the developing world. Recently, the Filarial Genome Project reported the draft sequence of the ~95 Mb genome of the human filarial parasite Brugia malayi - the first parasitic nematode genome to be sequenced. Comparative genome analysis with the prevailing model nematode Caenorhabditis elegans revealed similarities and differences in genome structure and organization that will prove useful as additional nematode genomes are completed. The Brugia genome provides the first opportunity to comprehensively compare the full gene repertoire of a free-living nematode species and one that has evolved as a human pathogen. The Brugia genome also provides an opportunity to gain insight into genetic basis for mutualism, as Brugia, like a majority of filarial species, harbors an endosybiotic bacterium (Wolbachia). The goal of this review is to provide an overview of the results of genomic analysis and how these observations provide new insights into the biology of filarial species.


Change in the body temperature of healthy term infant over the first 72 hours of life.
To determine the range of body temperature in a group of healthy Chinese term neonates over the first 72 hours of life and to assess the influence of body weight, gestational age and route of delivery. All 200 consecutive cases of neonates delivered at our hospital from March to August 2001 were included in this retrospective study. Temperatures were measured immediately after delivery, after 30 minutes, 1 hour, 2 hours, 8 hours and 15 hours and on the 2nd and 3rd day. Axillary temperatures ranging from 36.5 degrees C to 37 degrees C were regarded as normal. No cases of maternal fever or systemic infection of the newborns were discovered. All infants were discharged in good general condition. The mean rectal temperature at birth was 37.19 degrees C. The lowest average temperature was reached at 1 hour after delivery (36.54 degrees C) with a significant difference between natural delivery (36.48 degrees C) and section (36.59 degrees C) (P<0.05). Temperature subsequently rose to 36.70 degrees C at 8 hours and 36.78 degrees C at 15 hours (P<0.05). Hypothermia was seen in 51.8% and hypothermia in 42.5% of the patients. On the 3rd day after delivery, 96% of all temperatures were in the normal range. A significant relation was found between hypothermia and both low birth weight (P<0.001) and low gestational age (P<0.05). The reference range presently used did not include all physiological temperatures in the first 72 hours of life. Considering other factors, such as birth weight, route of delivery, gestational age and body temperature on the 2nd and 3rd day of life, may help to correctly assess the significance of temperatures beyond the reference range.


Predicting drug hydrolysis based on moisture uptake in various packaging designs.
An attempt was made to predict the stability of a moisture sensitive drug product based on the knowledge of the dependence of the degradation rate on tablet moisture. The moisture increase inside a HDPE bottle with the drug formulation was simulated with the sorption-desorption moisture transfer model, which, in turn, allowed an accurate prediction of the drug degradation kinetics. The stability prediction, obtained by computer simulation, was made in a considerably shorter time frame and required little resources compared to a conventional stability study. The prediction was finally upgraded to a stochastic Monte Carlo simulation, which allowed quantitative incorporation of uncertainty, stemming from various sources. The resulting distribution of the outcome of interest (amount of degradation product at expiry) is a comprehensive way of communicating the result along with its uncertainty, superior to single-value results or confidence intervals.


Targeted next-generation sequencing in the detection of mismatch repair deficiency in endometrial cancers.
Mismatch repair deficiency represents a biomarker of immunotherapy response and a phenotypic feature of Lynch syndrome-associated endometrial cancers. Using a targeted next-generation sequencing assay, we identified molecular features of mismatch repair deficiency, specifically insertion and deletion mutations in mononucleotide repeats, and established thresholds for the number of such mutations to classify endometrial cancers as mismatch repair deficient, proficient, or indeterminate. Sequencing classification was compared to the loss of MLH1, MSH2, MSH6, or PMS2 expression by immunohistochemistry. A total of 259 endometrial cancers were classified by sequencing as mismatch repair deficient (n = 48, 19%), proficient (n = 199, 77%), or indeterminate (n = 12, 5%). Sequencing findings were concordant with loss of expression of at least one mismatch repair protein in 47 of 48 (98%) cases classified as deficient and retained expression of all four proteins in 190 of 199 (95%) cases classified as proficient. Of the 12 cases classified as indeterminate, 7 (58%) demonstrated mismatch repair protein loss. Overall, targeted next-generation sequencing exhibited a high rate of concordance with immunohistochemistry for mismatch repair deficiency; however, sequencing was indeterminate in a few cases and demonstrated a false negative rate of 5%. Although we recommend implementation of a mismatch repair deficiency algorithm for laboratories performing next-generation sequencing cancer panels, immunohistochemistry remains a cost-effective screening method for mismatch repair deficiency in endometrial cancer.


Free-electron interactions with van der Waals heterostructures: a source of focused X-ray radiation.
The science and technology of X-ray optics have come far, enabling the focusing of X-rays for applications in high-resolution X-ray spectroscopy, imaging, and irradiation. In spite of this, many forms of tailoring waves that had substantial impact on applications in the optical regime have remained out of reach in the X-ray regime. This disparity fundamentally arises from the tendency of refractive indices of all materials to approach unity at high frequencies, making X-ray-optical components such as lenses and mirrors much harder to create and often less efficient. Here, we propose a new concept for X-ray focusing based on inducing a curved wavefront into the X-ray generation process, resulting in the intrinsic focusing of X-ray waves. This concept can be seen as effectively integrating the optics to be part of the emission mechanism, thus bypassing the efficiency limits imposed by X-ray optical components, enabling the creation of nanobeams with nanoscale focal spot sizes and micrometer-scale focal lengths. Specifically, we implement this concept by designing aperiodic vdW heterostructures that shape X-rays when driven by free electrons. The parameters of the focused hotspot, such as lateral size and focal depth, are tunable as a function of an interlayer spacing chirp and electron energy. Looking forward, ongoing advances in the creation of many-layer vdW heterostructures open unprecedented horizons of focusing and arbitrary shaping of X-ray nanobeams.


Green and rapid and instrumental one-pot method for the synthesis of imidazolines having potential anti-SARS-CoV-2 main protease activity.
The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is responsible for ongoing epidemics in humans and some other mammals and has been declared a public health emergency of international concern. In this project, several small non-peptide molecules were synthesized to inhibit the major proteinase (Mpro) of SARS-CoV-2 using rational strategies of drug design and medicinal chemistry. Mpro is a key enzyme of coronaviruses and plays an essential role in mediating viral replication and transcription in human lung epithelial and stem cells, making it an attractive drug target for SARS-CoV. The antiviral potential of imidazoline derivatives as inhibitors of (SARS-CoV-2) Mpro was evaluated using in-silico techniques such as molecular docking simulation, molecular dynamics (MD), and ADMET prediction. The docking scores of these imidazoline derivatives were compared to that of the N3 crystal inhibitor and showed that most of these compounds, particularly compound E07, interacted satisfactorily in the active site of the coronavirus and strongly interacted with the residues (Met 165, Gln 166, Met 165, His 41, and Gln 189). Furthermore, the results were confirmed by MD simulations after exposure to long-term MD simulations and ADMET predictions.


Primary hyperoxaluria Type 1: A case report in an extended family with a novel AGXT gene mutation.
Primary hyperoxaluria type 1 (PH1) is a genetic autosomal recessively inherited disorder due to mutation in the alanine-glyoxylate aminotransferase (AGXT) gene. It usually presents in children with nephrolithiasis and/or nephrocalcinosis and progressive renal function impairment and end stage renal disease (ESRD). A 13 years old Saudi boy with history of recurrent urolithiasis since the age of 2 years presented to us with picture of ESRD. He has strong family history of urolithiasis. Working up the patient suggested the diagnosis of PH1 based on the typical clinical, laboratory, and imaging findings which was genetically proved by positive AXGT gene mutation. The mutation detected was not previously reported in literature. The mutation detected was not previously reported in literature. The novel mutation c. 799A>T p. (IIe267Phe) detected in our patient extend the spectrum of the known AGXT gene mutations. Hemodialysis as a temporary step followed by renal transplantation which is the only cure. High index of suspicion of PH1 before ESRD should be considered in any patient who has recurrent urolithiasis since early life especially in presence of strong family history.


The relationship between brain-derived neurotrophic factor, irisin and cognitive skills of endurance athletes.
The objective of this study was to assess the cognitive performance of endurance athletes and its relation with circulating brain-derived neurotrophic factor (BDNF) and irisin levels. 26 endurance athletes (14 elite orienteers (mean ± SD: age = 26.33 ± 4.08, body weight = 70.33 ± 4.64, body height = 177.7 ± 6.1), 12 pentathletes (mean ± SD: age = 29.42 ± 5.32, body weight = 74.77 ± 6.59, body height = 180.8 ± 3.8)) and ten sedentary (mean ± SD: age = 27.30 ± 2.06, body weight = 76.65 ± 12.50, body height = 176.9 ± 5.2) men at almost same ages and educational levels participated in this study. Cognitive functions were analyzed with mini-mental-state examination (MMSE) and Isaacs' Set Test of Verbal Fluency (IST) tests. Insulin-like growth factor-1 (IGF-1), BDNF and irisin levels were measured in the blood samples. The MSSE and IST scores of the endurance athletes were higher than that of the sedentary control group (P < 0.05). Serum IGF-1 levels were higher in the pentathletes (111.18 ± 22.26 ng mL(-1)) than the orienteers (85.89 ± 19.32 ng mL(-1)) (P < 0.05). Plasma BDNF (2.78 ± 0.81, 4.28 ± 1.03, and 3.93 ± 0.77 ng mL(-1) in the sedentary, orienteers and pentathletes, respectively) and irisin (3.25 ± 0.70, 6.16 ± 0.99, and 6.58 ± 1.09 µg mL(-1) in the sedentary, orienteers and pentathletes, respectively) concentrations of the endurance trained athletes were higher than that of the sedentary control group (P < 0.05). Positive correlation between the cognitive function test results and BDNF and irisin concentrations were observed (P < 0.05). There was also a positive correlation between the circulating irisin and BDNF concentrations (P < 0.05). These results suggested that irisin and BDNF levels positively correlated with cognition in the endurance trained athletes.


Meta-analysis: remission and response from control arms of randomized trials of biological therapies for active luminal Crohn's disease.
Remission and response are the main outcomes to evaluate the efficacy of new treatments for Crohn's disease (CD). To explain variation of remission and response rates in active luminal CD. We studied control patients from trials of biological therapies through articles retrieved by MEDLINE search (from 1997 to 2007) and by bibliography review. Thousand nine hundred and thirteen control patients from 28 trials were identified; data were extracted by three independent observers and pooled by DerSimonian and Laird random effect model; factors influencing remission and clinical response were explored by metaregression for aggregated data. The pooled control rates of remission and response were 17% and 33%, respectively, both with significant heterogeneity among studies (P < 0.0001). At metaregression, the time of primary outcome evaluation was associated with remission, whereas the trial's criteria for defining response and publication year were predictors of response. CDAI score, CRP levels or other clinical variables related with disease activity or concomitant medications were not significant factors. Populations used as 'add-on' treatment comparator in trials of biological therapies for active luminal CD are poorly characterized and outcomes are heterogeneous. Planning of future trials will require better description of patients and concomitant therapies, blinding of outcome assessors and homogeneous criteria of outcome definition.


Increased Response to 3,4-Methylenedioxymethamphetamine (MDMA) Reward and Altered Gene Expression in Zebrafish During Short- and Long-Term Nicotine Withdrawal.
An interactive effect between nicotine and 3,4-methylenedioxymethamphetamine (MDMA) has been reported but the mechanism underlying such interaction is not completely understood. This study used zebrafish to explore gene expression changes associated with altered sensitivity to the rewarding effects of MDMA following 2-week exposure to nicotine and 2-60 days of nicotine withdrawal. Reward responses to MDMA were assessed using a conditioned place preference (CPP) paradigm and gene expression was evaluated using quantitative real-time PCR of mRNA from whole brain samples from drug-treated and control adult zebrafish. Zebrafish pre-exposed for 2 weeks to nicotine showed increased conditioned place preference in response to low-dose, 0.1 mg/kg, MDMA compared to un-exposed fish at 2, 7, 30 and 60 days withdrawal. Pre-exposure to nicotine for 2 weeks induced a significant increase of c-Fos and vasopressin receptor expression but a decrease of D3 dopaminergic and oxytocin receptor expression at 2 days of withdrawal. C-Fos mRNA increased also at 7, 30, 60 days of withdrawal. Nicotine pre-exposed zebrafish submitted to MDMA-induced CPP showed an increase in expression of p35 at day 2, α4 at day 30, vasopressin at day 7 and D3 dopaminergic receptor at day 7, 30 and 60. These gene alterations could account for the altered sensitivity to the rewarding effects of MDMA in nicotine pre-exposed fish, suggesting that zebrafish have an altered ability to modulate behaviour as a function of reward during nicotine withdrawal.


Use of an oncolytic vaccinia virus for the treatment of canine breast cancer in nude mice: preclinical development of a therapeutic agent.
Mammary cancers together with cancers of the skin account for about 60% of the total cancers occurring in dogs. The veterinary options for therapeutic management of canine mammary cancer are limited and prognosis for such patients is poor. In this study, we analyzed the functionality of the oncolytic vaccinia virus strain GLV-1h68 as a possible therapeutic agent for canine mammary cancer. Cell culture data demonstrated that GLV-1h68 efficiently infected and destroyed cells of the canine mammary adenoma cell line ZMTH3. Furthermore, after systemic administration this attenuated vaccinia virus strain primarily replicated in canine tumor xenografts in nude mice. The efficient tumor colonization process resulted in inhibition of tumor growth and drastic reduction of tumor size. This is the first report demonstrating that vaccinia virus is an effective tool for the therapy of canine mammary cancers, which might next be applied to dogs with breast tumors.