Chromatin modification: how to put a HAT on the histones.
Specific patterns of acetylation of the core histones are associated with specific structures and functions of chromatin. A basis for the specificity of acetylation is now apparent in the recent crystal structures of two acetyltransferases.


Bacterial adhesion on amorphous and crystalline metal oxide coatings.
Several studies have demonstrated the influence of surface properties (surface energy, composition and topography) of biocompatible materials on the adhesion of cells/bacteria on solid substrates; however, few have provided information about the effect of the atomic arrangement or crystallinity. Using magnetron sputtering deposition, we produced amorphous and crystalline TiO2 and ZrO2 coatings with controlled micro and nanoscale morphology. The effect of the structure on the physical-chemical surface properties was carefully analyzed. Then, we studied how these parameters affect the adhesion of Escherichia coli and Staphylococcus aureus. Our findings demonstrated that the nano-topography and the surface energy were significantly influenced by the coating structure. Bacterial adhesion at micro-rough (2.6 μm) surfaces was independent of the surface composition and structure, contrary to the observation in sub-micron (0.5 μm) rough surfaces, where the crystalline oxides (TiO2>ZrO2) surfaces exhibited higher numbers of attached bacteria. Particularly, crystalline TiO2, which presented a predominant acidic nature, was more attractive for the adhesion of the negatively charged bacteria. The information provided by this study, where surface modifications are introduced by means of the deposition of amorphous or crystalline oxide coatings, offers a route for the rational design of implant surfaces to control or inhibit bacterial adhesion.


Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma.
Immunohistochemical analysis of erbB3, as the third member of epidermal growth factor receptor gene family, was performed on 41 cases of oral squamous cell carcinoma, correlating the staining pattern with clinical outcome. High expression of erbB3 protein (ERBB3) was significantly associated with lymph node metastasis (P < 0.05), survival rate (P < 0.05) and mode of invasion (P < 0.01) in this series. These results demonstrated that ERBB3 expression may be helpful in identifying those oral squamous cell carcinomas with higher malignant potential.


Insulin gene expression and insulin synthesis in mammalian neuronal cells.
To demonstrate the presence of de novo synthesis in central mammalian neurons, we cloned and sequenced a rabbit insulin cDNA from pancreas and used it to define sequences encoding insulin mRNA from postnatal rabbit brain. We observed transcription/elongation of nascent insulin transcripts, characterized the size of these transcripts, and localized them to specific neurons in certain catecholaminergic-rich areas of the central nervous system. RNase protection assays using a rabbit probe spanning a region from 14 bases 5' to the translation start site through all but 18 bases of the sequence encoding the A-chain of insulin showed two bands in rabbit brain RNA and only one band in pancreas. The larger band in brain was the same size as that in pancreatic RNA; the other was approximately 10 bases shorter. Because the sequence of a reverse transcription-polymerase chain reaction product from brain RNA was identical to pancreatic RNA sequence in the region corresponding to the 3' region of the probe, the smaller band in brain is most consistent with a sequence mismatch in some brain mRNA in the region corresponding to the 5'-end of the probe. In situ hybridization localized insulin mRNA to anatomical regions involved with olfaction and higher association of the limbic system. High performance liquid chromatography, radioimmunoassay, and [35S]cysteine metabolic labeling of cultured neuronal and glial cells indicated extracellular secretion of immunoprecipitable insulin by neurons only. Presence of insulin transcripts within specific neurons with extracellular secretion of the peptide suggests a specialized biological role.


Managing Gallstone Disease in the Elderly.
Geriatric patients tend to have subtle presentations of biliary disorders and, if untreated, can decompensate acutely. Each biliary disorder warrants formulation of an individualized treatment plan with a multidisciplinary approach. Acute cholecystitis, a common complication of gallstones, is initially managed by conservative measures and subsequently, among patients with optimal surgical risk, through laparoscopic or open cholecystectomy. High-risk patients undergo temporization, percutaneous or endoscopic, followed by definitive intervention. Acute cholecystitis with complications (ie, perforation, gangrene, or small bowel obstruction) warrants emergent cholecystectomy. Gallstone migration into the biliary system can cause choledocholithiasis, often complicated by biliary pancreatitis or cholangitis if not intervened. Therapy for choledocholithiasis is based on biliary clearance through endoscopic and, infrequently, surgical approaches.


Humoral response after a third and fourth dose of mRNA-based SARS-CoV-2 vaccine in previously seronegative kidney transplant recipients.
Growing evidence shows diminished response to mRNA-based SARS-CoV‑2 vaccination in kidney transplant recipients. We aimed to investigate the seroconversion rate after a 3rd and 4th dose of mRNA vaccination in kidney transplant recipients without prior antibody response to two or three vaccination doses.This retrospective study included 324 prevalent kidney transplant recipients of a single tertiary transplantation center of which 157 remained seronegative, defined as anti-spike-RBD-IgG antibody titer < 7.1 BAU/ml, after two doses of mRNA-based SARS-CoV‑2 vaccination. Maintenance immunosuppression was not changed. The median patient age was 60.6 years (IQR 51.4-68.1 years), 66.9% were male. Positivity for anti-spike-RBD-IgG (≥ 7.1 BAU/ml) was measured 4-5 weeks after administration of a 3rd and 4th vaccine dose.Seroconversion rates were 63.9% after a 3rd dose and 29.3% after a 4th dose of vaccine. Cumulative prevalence of seropositivity was 51.5% after 2 doses, 80.5% after 3 doses and 84.2% after 4 doses.In conclusion, seroconversion can be achieved in the majority of the kidney transplant recipients by administrating three or four doses of mRNA vaccine without changing maintenance immunosuppression.


Biotinylated RNA probes for the detection of potato spindle tuber viroid (PSTV) in plants.
Diseases caused by potato spindle tuber viroid (PSTV) are of significant agronomic importance, and early detection is vital. The objective of this paper was to synthesize biotinylated RNA probes in order to develop a specific, sensitive, and reliable assay system for detection of PSTV in infected plants. RNA probes were prepared by in vitro transcription of cloned PSTV, and were labelled with either biotin-11-UTP or [32P]UTP. Partially purified total RNAs from healthy and from PSTV-infected plants were spotted onto nitrocellulose filters and hybridized with either biotin-labelled or 32P-labelled probes. Our results showed that the sensitivity of biotinylated probes was similar to that for the 32P-labelled probes.


Anti-parasitic activity of a chimeric peptide Cecropin A (2-8)-Melittin (6-9) (CM11) against tachyzoites of Toxoplasma gondii and the BALB/c mouse model of acute toxoplasmosis.
Toxoplasmosis is a zoonotic disease that infects most animals, including humans. Pyrimethamine/sulfadiazine is the standard treatment for toxoplasmosis. Although this treatment has been successful, it is often associated with side effects that cannot be tolerated. Therefore, various compounds have been proposed as alternative treatments for toxoplasmosis. Antimicrobial peptides (AMPs) act on various pathogens, from viruses to protozoa. The purpose of the present study was to evaluate the effects of CM11 on in vitro and in vivo Toxoplasma gondii infection. For in vitro experiments, VERO cells were treated with different concentrations of CM11 (1-128 μg/ml) compared to sulfadiazine (SDZ) (0.78-100 μg/ml). MTT and lactate dehydrogenase (LDH) assays evaluated the cell viability and plasma membrane integrity. Then, the inhibitory concentration (IC50) values were determined for treating tachyzoites of T. gondii before or on cells previously infected. Annexin V-FITC/propidium iodide (PI) staining was used to distinguish viable and apoptotic cells. The effect of CM11, SDZ, and a combination of CM11 and SDZ was evaluated in the BALB/c mouse model of acute toxoplasmosis. CM11 was effective on tachyzoites of T. gondii and had a time and dose-dependent manner. The results of the MTT assay showed that the CC50 values of CM11 and SDZ were estimated at 17.4 µg/ml and 62.3 µg/ml after 24-h, respectively. The inhibitory concentration (IC50) of CM11 and SDZ on infected cells was estimated at 1.9 µg/ml and 1.4 µg/ml after 24-h, respectively. The highest rate of apoptosis (early and late) in high concentrations of SDZ and CM11 was determined for tachyzoites (2.13 % and 13.88 %), non-infected VERO cells (6.1 % and 19.76 %), and infected VERO cells (7.45 % and 29.9 %), respectively. Treating infected mice with CM11 and a combination of CM11 and SDZ had increased survival time. Based on the mentioned results, it can be concluded that CM11 has a beneficial effect on tachyzoites of T. gondii in vitro. The result of the mouse model suggests that CM11, either alone or in combination with other chemotherapeutic agents, could be a potential therapeutic for toxoplasmosis. Hence, antimicrobial peptides could be applied as promising anti-toxoplasma agents for treating toxoplasmosis.


Constraints from protein structure and intra-molecular coevolution influence the fitness of HIV-1 recombinants.
A major challenge for developing effective treatments for HIV-1 is the viruses' ability to generate new variants. Inter-strain recombination is a major contributor to this high evolutionary rate, since at least 20% of viruses are observed to be recombinant. However, the patterns of recombination vary across the viral genome. A number of factors influence recombination, including sequence identity and secondary RNA structure. In addition the recombinant genome must code for a functional virus, and expressed proteins must fold to stable and functional structures. Any intragenic recombination that disrupts internal residue contacts may therefore produce an unfolded protein. Here we find that contact maps based on protein structures predict recombination breakpoints observed in the HIV-1 pandemic. Moreover, many pairs of contacting residues that are unlikely to be disrupted by recombination are coevolving. We conclude that purifying selection arising from protein structure and intramolecular coevolutionary changes shapes the observed patterns of recombination in HIV-1.


Mechanisms of tolerance to inhalant allergens: the relevance of a modified Th2 response to allergens from domestic animals.
Subjects can be "non-allergic" because (1) they are not exposed, (2) they fail to make an immune response, or (3) they make an immune response that does not include IgE antibodies (Ab). The recent observation that children raised in a house with a cat are less likely to become allergic to cat allergen than those who only get indirect exposure provides a model to investigate the factors controlling allergic responses. Many of these highly exposed children have made an IgG and IgG4 Ab response to Fel d 1 without IgE Ab, i.e., a "modified Th2 response". In countries where cats are a major cause of asthma, the presence of a cat may decrease the risk of asthma. By contrast, in countries with high exposure to dust mites, cats can induce specific tolerance to Fel d 1 without influencing asthma or the IgE Ab response to dust mites. Using overlapping peptides to investigate T cell responses to Fel d 1 suggests that the structure of the molecule plays a special role in inducing the T cell responses that can "control" the immune response to cat allergens. This T cell response is characterized by high levels of IL-10 production, but this is not restricted to those who have made a modified Th2 response. The results suggest that there are major differences in the immune response to different allergens that profoundly affect their role in allergic disease. Dust mite and cockroach differ from cat (and rat) allergens not only in the quantity inhaled and the particles' sizes but also in the biochemistry of the molecule.


Do Racial Differences in Orbital Volume Influence the Reconstruction of Orbital Trauma.
Successful orbital reconstruction relies on an accurate restoration of orbital volume (OV). The purpose of this study was to determine if the OV of African American (AA) subjects differs from that of Caucasian subjects. The authors implemented a retrospective observational study of successive subjects who received a maxillofacial computed tomography (CT) scan at a level I trauma center between 2017 and 2020. The primary predictor variable was race (AA/Caucasian). The primary outcome variable was orbital volume. Two independent examiners calculated OV with an open access OsiriX MD software version 10.0.5 (Pixmeo, Switzerland). Inter-rater reliability was calculated. Differences between races, genders, and sides were tested using independent samples t test with a significance of P < .05. Sixty subjects (120 orbits) were included in the study. The mean age was 36.7 (SD ± 13.2) years with a range of 22 to 78 years. Gender distribution was equal with 30 male (50%) and 30 female (50%) subjects. Inter-examiner reliability was 0.973. The mean OV of AA and Caucasians was 22.38 and 23.23 cm3, respectively (P = .07). The mean OV of AA and Caucasian males was 23.92, and 24.17cm3, respectively (P = .71). The mean OV in AA and Caucasian females was 20.84 and 22.28cm3, respectively (P = .013). African-American female subjects appear to have a smaller OV when compared with Caucasians which may influence orbital reconstruction. Laterality does not appear to be associated with any differences in OV.


Mujeres que Consumen Sustancias y su Vulnerabilidad frente al VIH en Santiago de Chile (Women Who Consume Substances and Their Vulnerability to HIV in Santiago of Chile).
Women represent 15% of the people living with HIV in Chile. Risk behaviors for HIV are: multiple partners, unsafe sex, and exchange of sex for drugs/money. A correlational design was used. A sample of 203 women who were sexually active and consumed substances within the last 3-months were selected for this study. The average age of the participants was 32.4 years (SD = 9.2) and 68.1% were housewives. The substance most commonly used was alcohol (95.1%) and marijuana (49.8%); 23.7% of the women were drunk or drugged before having sex; 74.4% had multiple sexual partners and 95.6% had unprotected sex. There is a significant correlation (p < 0.05) between substance abuse and HIV risk behaviors. It is necessary to develop more research to understand in depth the relationship between substance use and HIV risk among Chilean women. It is important to consider the use of substances to develop and implement HIV prevention programs in the Chilean community.


Metrics-based assessments of research: incentives for 'institutional plagiarism'?
The issue of plagiarism--claiming credit for work that is not one's own, rightly, continues to cause concern in the academic community. An analysis is presented that shows the effects that may arise from metrics-based assessments of research, when credit for an author's outputs (chiefly publications) is given to an institution that did not support the research but which subsequently employs the author. The incentives for what is termed here "institutional plagiarism" are demonstrated with reference to the UK Research Assessment Exercise in which submitting units of assessment are shown in some instances to derive around twice the credit for papers produced elsewhere by new recruits, compared to papers produced 'in-house'.


Extensive tissue-specific transcriptomic plasticity in maize primary roots upon water deficit.
Water deficit is the most important environmental constraint severely limiting global crop growth and productivity. This study investigated early transcriptome changes in maize (Zea mays L.) primary root tissues in response to moderate water deficit conditions by RNA-Sequencing. Differential gene expression analyses revealed a high degree of plasticity of the water deficit response. The activity status of genes (active/inactive) was determined by a Bayesian hierarchical model. In total, 70% of expressed genes were constitutively active in all tissues. In contrast, <3% (50 genes) of water deficit-responsive genes (1915) were consistently regulated in all tissues, while >75% (1501 genes) were specifically regulated in a single root tissue. Water deficit-responsive genes were most numerous in the cortex of the mature root zone and in the elongation zone. The most prominent functional categories among differentially expressed genes in all tissues were 'transcriptional regulation' and 'hormone metabolism', indicating global reprogramming of cellular metabolism as an adaptation to water deficit. Additionally, the most significant transcriptomic changes in the root tip were associated with cell wall reorganization, leading to continued root growth despite water deficit conditions. This study provides insight into tissue-specific water deficit responses and will be a resource for future genetic analyses and breeding strategies to develop more drought-tolerant maize cultivars.


A streptomycin-dependent live pasteurella multocida type-3 vaccine for the prevention of fowl cholera in turkeys.
A live streptomycin-dependent Pasteurella multocida (Serotype 3) vaccine was found to protect turkeys orally and parenterally against homologous challenge.


Cardiac surgery in the first year of life: the effect on weight gains of infants with congenital heart disease.
Forty-seven infants with ventricular septal defect (n = 17), tetralogy of Fallot (n = 7) and transposition of the great arteries (n = 23) who had 'corrective' surgery in the first year of life were reviewed with respect to birthweight and pre- and postoperative growth. The mean birthweight for each group was below that of the standard population. There was an overall decrease in growth velocity pre-operatively which was reversed after surgery. At follow up, 12-18 months later (means), most infants had regained at least their birthweight percentile, while the group with ventricular septal defect exceeded it. Consideration is given to the pathophysiological mechanisms contributing to these observations.


hnRNPL expression dynamics in the embryo and placenta.
Heterogeneous nuclear ribonucleoprotein L (hnRNPL) is a conserved RNA binding protein (RBP) that plays an important role in the alternative splicing of gene transcripts, and thus in the generation of specific protein isoforms. Global deficiency in hnRNPL in mice results in preimplantation embryonic lethality at embryonic day (E) 3.5. To begin to understand the contribution of hnRNPL-regulated pathways in the normal development of the embryo and placenta, we determined hnRNPL expression profile and subcellular localization throughout development. Proteome and Western blot analyses were employed to determine hnRNPL abundance between E3.5 and E17.5. Histological analyses supported that the embryo and implantation site display distinct hnRNPL localization patterns. In the fully developed mouse placenta, nuclear hnRNPL was observed broadly in trophoblasts, whereas within the implantation site a discrete subset of cells showed hnRNPL outside the nucleus. In the first-trimester human placenta, hnRNPL was detected in the undifferentiated cytotrophoblasts, suggesting a role for this factor in trophoblast progenitors. Parallel in vitro studies utilizing Htr8 and Jeg3 cell lines confirmed expression of hnRNPL in cellular models of human trophoblasts. These studies [support] coordinated regulation of hnRNPL during the normal developmental program in the mammalian embryo and placenta.


Reductive transformation of 2,4,6-trinitrotoluene, hexahydro-1,3,5-trinitro-1,3,5-triazine, and nitroglycerin by pyrite and magnetite.
Reductive transformation of 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and nitroglycerin (NG) by pyrite (FeS(2)) and magnetite (Fe(3)O(4)) was investigated to determine the role of Fe(II)-bearing minerals on the fate of toxic explosives in Fe/S-rich natural environment. Results from batch experiments showed that 65% of TNT and 45% of RDX were transformed from solution in the presence of pyrite under pH 7.4 buffered conditions within 32 days. Without a buffered solution, transformation of TNT and RDX decreased. NG was continuously and rapidly transformed by pyrite under both conditions. Complete removal of NG was achieved in 32 days under buffered conditions. NH(4)(+) was identified as a reduction product for RDX and NG in the pyrite-water system. Reductive transformation of RDX and NG by magnetite was slower than that by pyrite. The results suggest that abiotic transformation of the explosives by pyrite and magnetite may be considered when determining the fate of explosives in Fe/S-rich subsurface environments.


Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality.
SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.


End-of-Life Care for Persons Under Guardianship.
Guardians are surrogate decision makers appointed by a court when other health care decision-makers are unable, unwilling, or unavailable to make decisions. Prior studies suggest that persons under guardianship may experience delays in transitions of care. To compare quality of end-of-life care for persons under guardianship to a matched group on objective indicators and to identify narrative themes characterizing potential obstacles to quality end-of-life care. One hundred sixty-seven persons under guardianship who died between 2003 and 2019 within the Veterans Healthcare Administration in Massachusetts and Connecticut matched on a 1:1 basis to persons without guardians. The groups were compared on treatment specialty at death, days of hospice and intensive care unit care, and receipt of palliative care consultation. Additionally, patient narratives for those under guardianship with extended lengths in intensive care unit were subjected to qualitative analysis. Overall, <1% were under guardianship. Within this sample of persons who died within the Veterans Health Administration, persons under guardianship were as likely as patients in the comparison group to receive palliative care consultation (odds ratio [CI] = 0.93 [.590-1.46], P = .359), but were more likely to have ethics consultation (odds ratio [CI] = 0.25 [0.66-0.92], P = .036) and have longer lengths of ICU admission (β = -.34, t = -2.70, P = .009). Qualitative findings suggest that issues related to family conflict, fluctuating medical course, and limitations in guardian authority may underlie extended lengths of stay. Guardianship appears to be rare, and as a rule, those under guardianship have equal access to hospice and palliative care within Veterans Health Administration. Guardianship may be associated with health-care challenges in a small number of cases, and this may drive perceptions of adverse outcomes.


Effect of drying method on volatile compounds, phenolic profile and antioxidant capacity of guava powders.
We studied the chemical composition of oven and freeze dried guava powders for future use as antioxidant-rich flavour enhancers. Among thirty-one volatiles in guava powders, terpenes were predominant, even after both drying processes. In contrast, esters and aldehydes, volatiles characteristic of fresh guava fruit, appeared to have been decreased by drying. Insoluble phenolics were predominant and among the sixteen compounds identified, quercetin-3-O-rutinoside and naringenin corresponded to 56% of total phenolics. Drying processes decreased total phenolics contents by up to 44%. Oven drying promoted the release of insoluble flavonoids, generating mainly quercetin. Antioxidant capacity also decreased due to both drying processes, but guava powders still presented similar antioxidant capacity in comparison to other tropical fruit powders. Our results suggest that oven drying is a viable option for the production of a functional ingredient that would improve the phenolic content of cereal foods while adding desirable guava flavour.


Orientation independence of single-vacancy and single-ion permeability ratios.
Single-vacancy models have been proposed as open channel permeation mechanisms for K+ channels. Single-ion models have been used to describe permeation through Na+ channels. This paper demonstrates that these models have a distinctive symmetry property. Their permeability ratios, measured under biionic conditions, are independent of channel orientation when the reversal potential is zero. This symmetry is a property of general m-site single-vacancy channels, m-site shaking-stack channels, as well as m-site single-ion channels. An experimental finding that the permeability ratios of a channel did not have this symmetry would provide evidence that a single-vacancy or single-ion model is an incorrect or incomplete description of permeation.


Screening for post-traumatic stress disorders in 1017 cancer patients and correlation with anxiety, depression, and distress.
Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder, which might develop after a traumatic event, like cancer diagnosis, and threatens the patient's psychological and/or physiological integrity. Anxiety, depression, and mental distress are known to be common in cancer patients; however, the frequency of PTSD was not investigated thoroughly in this patient group so far. Here, we aim to screen cancer patients for PTSD symptoms and determine a possible correlation with anxiety, depression, and distress. The study was performed at the Divisions of Hematology and Oncology of the Medical University of Vienna from 2010 to 2018. Following written consent, patients were asked to fill out the validated self-assessment questionnaire for PTSS-10 and HADS. The study was approved by the institutional ethics committee of the Medical University of Vienna (EC Nr: 2255/2016). A total of 1017 adult cancer patients (513 male, 504 female) were included in a cross-sectional single-center study. Mean age was 57.6 years (SD 14.4 years); 31.7%, 14.6%, 13.2%, and 27.4% of patients outscored the predefined thresholds for self-assessed cases of PTSD, anxiety, depression, and distress, respectively. Compared with men, women showed a higher prevalence of symptoms for PTSD (38.9% vs 24.5%; P < .001) and anxiety (20.4% vs 8.6%; P < .001). The scores of HADS-A, HADS-D, and the combined HADS score (distress) were significantly correlated with PTSS-10 scores (P < .01). No differences in age were observed among the different score groups. The study shows a significant prevalence as well as a correlation of PTSD symptoms with anxiety, depression, and distress among cancer patients. Findings underscore the necessity of a serious screening for psychiatric disorders, especially in female patients. In order to enable multidisciplinary care for cancer patients and to reduce the burden for psychiatric disorders, interdisciplinary screening and treatment concepts, which take into account gender aspects, are urged.


Montmorillonite clay-based heterogenous catalyst for the synthesis of nitrogen heterocycle organic moieties: a review.
The use of montmorillonite clay as solid catalyst has grabbed much attention in the liquid phase reactions for organic synthesis. In recent years, there has been a lot of interest in organic synthesis using montmorillonite-based composites, especially in the synthesis of heterogeneous nanoparticles. Due to the robust and green nature of montmorillonite-based nanocatalysts, it has been widely used in N-heterocyclic reactions. In this review, we have concentrated on the reports pertaining the use of montmorillonite-based nanocatalyst in the synthesis of N-heterocycles, a category of organic compounds with excellent biological properties. This manuscript is arranged by the types of N-containing heterocycles synthesized using montmorillonite-based composite as catalysts including polycyclic spirooxindoles, heterocyclic propargylamine, indole-based heterocycles, quinoline and its derivatives, six-membered N-heterocyclic-based compounds and five-membered N-heterocyclic-based compounds. Special attention was given to the structural stability under experimental parameters of the montmorillonite-based composite with the incidence of metal leaching and reusability. Finally, along with recent developments, new findings in heterogeneous montmorillonite (Mt)-based catalysis have also been addressed.


Order-Order Morphological Transitions for Dual Stimulus Responsive Diblock Copolymer Vesicles.
A series of non-ionic poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer vesicles has been prepared by reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of HPMA at 70 °C at low pH using a carboxylic acid-based chain transfer agent. The degree of polymerization (DP) of the PGMA block was fixed at 43, and the DP of the PHPMA block was systematically varied from 175 to 250 in order to target vesicle phase space. Based on our recent work describing the analogous PGMA-PHPMA diblock copolymer worms [Lovett J. R.; Angew. Chem.2015, 54, 1279-1283], such diblock copolymer vesicles were expected to undergo an order-order morphological transition via ionization of the carboxylic acid end-group on switching the solution pH. Indeed, irreversible vesicle-to-sphere and vesicle-to-worm transitions were observed for PHPMA DPs of 175 and 200, respectively, as judged by turbidimetry, transmission electron microscopy (TEM), and dynamic light scattering (DLS) studies. However, such morphological transitions are surprisingly slow, with relatively long time scales (hours) being required at 20 °C. Moreover, no order-order morphological transitions were observed for vesicles comprising longer membrane-forming blocks (e.g., PGMA43-PHPMA225-250) on raising the pH from pH 3.5 to pH 6.0. However, in such cases the application of a dual stimulus comprising the same pH switch immediately followed by cooling from 20 to 5 °C, induces an irreversible vesicle-to-sphere transition. Finally, TEM and DLS studies conducted in the presence of 100 mM KCl demonstrated that the pH-responsive behavior arising from end-group ionization could be suppressed in the presence of added electrolyte. This is because charge screening suppresses the subtle change in the packing parameter required to drive the morphological transition.


Roles of vitamins in stem cells.
Stem cells can differentiate to diverse cell types in our body, and they hold great promises in both basic research and clinical therapies. For specific stem cell types, distinctive nutritional and signaling components are required to maintain the proliferation capacity and differentiation potential in cell culture. Various vitamins play essential roles in stem cell culture to modulate cell survival, proliferation and differentiation. Besides their common nutritional functions, specific vitamins are recently shown to modulate signal transduction and epigenetics. In this article, we will first review classical vitamin functions in both somatic and stem cell cultures. We will then focus on how stem cells could be modulated by vitamins beyond their nutritional roles. We believe that a better understanding of vitamin functions will significantly benefit stem cell research, and help realize their potentials in regenerative medicine.


The seminal vesicle in eight and 16 week streptozotocin-induced diabetic rats: adrenergic, cholinergic and peptidergic innervation.
The autonomic innervation of the seminal vesicle from 8 and 16 week streptozotocin-induced diabetic rats and age-matched controls was studied by pharmacological, histochemical and immunohistochemical methods. Contractions in response to electrical field stimulation, which were abolished using prazosin (2 microM) or tetrodotoxin (one to 1.6 microM), and to noradrenaline were significantly increased in both eight and 16 week diabetic animals. The contractile response to acetylcholine was significantly increased in the 16 week diabetic rats only, when compared with controls. Although these responses were significantly increased, no difference was found in ED50 and EF50 values between control and diabetic rats. Vasoactive intestinal polypeptide (0.3 microM) had no effect on resting tension or nerve-mediated responses. In seminal vesicles from control animals, both vasoactive intestinal polypeptide-immunoreactive and acetylcholinesterase-containing nerves were localised around the folds of the columnar epithelium of secretory cells, in contrast to neuropeptide Y-immunoreactive and catecholamine-containing nerves which were found in the smooth muscle layers. In seminal vesicles from both eight and 16 week diabetic animals no difference was seen in distribution or density of acetylcholinesterase-containing nerves; there was an increase in density and fluorescence intensity of vasoactive intestinal polypeptide- and neuropeptide Y-immunoreactive nerves and a decrease in catecholamine-containing nerves compared with controls. The results are discussed in relation to autonomic neuropathy in diabetes.


Blockade of intercostobrachial nerve by an erector spinae plane block at T2 level: a case report.
The intercostobrachial nerve blockade is required, in addition to brachial plexus block, to anesthetize the entire upper arm. No studies have described the use of erector spinae plane (ESP) block for an intercostobrachial nerve block. A 72-year-old man was scheduled to undergo left brachial vein transposition-arteriovenous fistula creation for hemodialysis access. An ultrasound-guided infraclavicular brachial plexus block was performed using a mixture of 0.5% levobupivacaine (12.5 ml) and 2% lidocaine (12.5 ml). An ESP block was implemented using 10 ml of the same local anesthetic at the T2 level. A pinprick test showed that the entire upper arm and lateral aspect of the left upper chest wall were anesthetized 20 min after the blocks. Surgery was successfully performed without the need for general anesthesia. In the present case, an ESP block performed at the T2 level provided sensory loss of the area innervated by the intercostobrachial nerve.


Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors.
Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia.


Follicular lymphoma and marginal zone lymphoma: how many diseases?
Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent mature B-cell neoplasms with variable clinical presentation and distinct histopathologic features. Recent advances in the biology and molecular characteristics of these lymphomas have further expanded our understanding of the heterogeneous nature of these lymphomas, with increasing recognition of specific disease entities within the broader categories of FL and MZL. Here, we discuss the conclusions of the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC) dealing with FL, and review differences with the proposed WHO 5th Edition classification. We review issues related to grading and alternative forms of FL especially those lacking the genetic hallmark of FL, the t(14;18) chromosomal alteration. Among them, t(14;18)-negative CD23+ follicle center lymphoma has been proposed by the 2022 ICC as a provisional entity. Other follicle center-derived lymphomas such as pediatric-type follicular lymphoma, testicular follicular lymphoma, primary cutaneous follicle center lymphoma, and large B-cell lymphoma with IRF4 rearrangement are considered distinct entities separate from conventional FL. Importantly, large B-cell lymphoma with IRF4 rearrangement introduced as a provisional entity in the WHO 2017 is upgraded to a definite entity in the 2022 ICC. We also discuss diagnostic strategies for recognition of MZLs including splenic MZL, extranodal MZL (MALT lymphoma), and primary nodal MZL. The importance of molecular studies in the distinction among marginal zone lymphoma subtypes is emphasized, as well as their value in the differential diagnosis with other B-cell lymphomas.


Clinical and genetic features of myoclonus-dystonia in 3 cases: a video presentation.
Many cases of myoclonus-dystonia (M-D) are caused by mutations in the epsilon-sarcoglycan (SGCE) gene. We describe 3 children with a similar clinical picture of autosomal dominant M-D and an SGCE mutation in only one of them, suggesting that M-D is genetically heterogeneous.


Placental soluble aconitase: population studies in Italy.
Human placental soluble aconitase (ACONs) polymorphism was studied in two samples from continental Italy and Sardinia. The ACONs3 allele was found with a frequency of 0.01 in the Sardinian sample.


Effects of ultrasound on the degradation kinetics, physicochemical properties and prebiotic activity of Flammulina velutipes polysaccharide.
The controllable ultrasonic modification was hindered due to the uncertainty of the relationship between ultrasonic parameters and polysaccharide quality. In this study, the ultrasonic degradation process was established with kinetics. The physicochemical properties and prebiotic activity of ultrasonic degraded Flammulina velutipes polysaccharides (U-FVPs) were investigated. The results showed that the ultrasonic degradation kinetic models were fitted to 1/Mt-1/M0 = kt. When the ultrasonic intensity increased from 531 to 3185 W/cm2, the degradation proceeded faster. The decrease of polysaccharide concentration contributed to the degradation of FVP, and the fastest degradation rate was at 60 °C. Ultrasound changed the solution conformation of FVP, and partially destroyed the stability of the triple helix structure of FVP. Additionally, the viscosity and gel strength of FVP decreased, but its thermal stability was improved by ultrasound. Higher ultrasonic intensity led to larger variations in physicochemical properties. Compared with FVP, U-FVPs could be more easily utilized by gut microbiota. U-FVPs displayed better prebiotic activity by promoting the growth of Bifidobacterium and Brautella and inhibiting the growth of harmful bacteria. Ultrasound could be effectively applied to the degradation of FVP to improve its physicochemical properties and bioactivities.


Comprehensive Bioinformatics Analysis of Lipopolysaccharide-Induced Altered Autophagy in Acute Lung Injury and Construction of Underlying Competing Endogenous RNA Regulatory Mechanism.
Acute lung injury (ALI) is a fatal syndrome frequently induced by lipopolysaccharide (LPS) released from the bacterial cell wall. LPS could also trigger autophagy of lung bronchial epithelial cell to relieve the inflammation, while the overwhelming LPS would impair the balance of autophagy consequently inducing serious lung injury. We observed the autophagy variation of 16HBE, human bronchial epithelial cell, under exposure to different concentrations of LPS through western blot, immunofluorescence staining, and electron microscopy. Eight strands of 16HBE were divided into two groups upon 1000 ng/ml LPS stimulation or not, which were sent to be sequenced at whole transcriptome. Subsequently, we analyzed the sequencing data in functional enrichment, pathway analysis, and candidate gene selection and constructed a hsa-miR-663b-related competing endogenous RNA (ceRNA) network. We set a series of concentrations of LPS to stimulate 16HBE and observed the variation of autophagy in related protein expression and autophagosome count. We found that the effective concentration of LPS was 1000 ng/ml at 12 hours of exposure and sequenced the 1000 ng/ml LPS-stimulated 16HBE. As a result, a total of 750 differentially expressed genes (DEGs), 449 differentially expressed lncRNAs (DElncRNAs), 76 differentially expressed circRNAs (DEcircRNAs), and 127 differentially expressed miRNAs (DEmiRNAs) were identified. We constructed the protein-protein interaction (PPI) network to visualize the interaction between DEGs and located 36 genes to comprehend the core discrepancy between LPS-stimulated 16HBE and the negative control group. In combined analysis of differentially expressed RNAs (DERNAs), we analyzed all the targeted relationships of ceRNA in DERNAs and figured hsa-miR-663b as a central mediator in the ceRNA network to play when LPS induced the variation of autophagy in 16HBE. Our research indicated that the hsa-miR-663b-related ceRNA network may contribute to the key regulatory mechanism in LPS-induced changes of autophagy and ALI.


Prognostic Role of Early and End-of-Neoadjuvant Treatment 18F-FDG PET/CT in Patients With Breast Cancer.
To determine the use of early and final treatment F-FDG PET/CT in the prediction of response to neoadjuvant chemotherapy (NAC) and its role in the prognosis of patients with locally advanced breast cancer (LABC). One hundred thirty-two patients underwent a baseline FDG PET/CT (PET-1) after the second course of chemotherapy (PET-2) and after the last course (PET-3). Breast tumors were categorized into molecular phenotypes and risk categories according to the biological prognostic factors obtained by immunohistochemistry. PET/CT scans were semiquantitatively evaluated, obtaining the Δ% SUV1-2 and SUV1-3 in primary tumor and axillary lymph nodes to establish response groups attending to EORTC criteria. Moreover, a binary assessment was obtained classifying the studies as positive or negative. Histopathological response was obtained in breast and lymph node specimens. Overall survival (OS) and disease-free survival (DFS) were obtained after the follow-up. ROC analysis was performed to determine a cutoff value of Δ% SUV1-2 and SUV1-3 for the prediction of response and prognosis. Relations between phenotypes, metabolic behavior, final histopathological response, OS, and DFS were evaluated. In binary analysis, only PET-3 was able to predict histopathological response in lymph nodes. The cutoff values of %Δ SUV1-2 and %Δ SUV1-3 with the best sensitivity and specificity in the prediction of response in breast tumor were 62% (Se: 70% and Sp: 69%) and 84% (Se: 70% and Sp: 88%). A %ΔSUV1-3 of 74% in breast tumor was a predictor of DFS (AUC = 0.647; P = 0.037, Se: 52% and Sp: 66%). Kaplan-Meier analysis revealed significant relations between the binary lymph node assessment of PET-3 with OS (P = 0.016, χ = 5.78) and DFS (P = 0.003, χ = 9.10). End-of-treatment F-FDG PET/CT was a predictor of lymph node response and prognosis. Most of metabolic response variables related to histopathological response showed association with the prognosis.


Acute and chronic viral infections.
A large number of viruses belonging to various families are able to cause central nervous system (CNS) infections and contribute significantly to burden of disease in humans globally. Most viral CNS infections are benign and self-limiting, and most remain undiagnosed. However, some viruses can cause severe inflammation, leading to morbidity and mortality, and result in severe long-term residual damage and neurologic dysfunction in patients. The potential of viruses to cause CNS inflammation greatly varies depending on host factors, such as age, sex, and genetic background, as well as viral factors. Despite the need for protection against viral invasion and replication, the extent of the immune response in the CNS is carefully regulated to prevent excessive inflammation and tissue destruction leading to irretrievable loss of neurons. Direct cytopathology is for many virus infections a major cause of neurologic symptoms; however, the antiviral immune response can in some instances contribute substantially to pathology. This chapter highlights a selection of clinically important neurotropic viruses that infect the CNS and cause neurologic diseases such as meningitis, encephalitis, and myelitis in humans, with a focus on neuropathologic findings.


Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits.
Atrial fibrillation (AF) leads to electrical atrial remodeling including alterations of various ion channels early after arrhythmia onset. The beneficial effects of statins in AF treatment due to their influence on oxidative stress and inflammation are discussed. Our hypothesis was that statins might also alter atrial ion currents and their early tachycardia-induced remodeling. Effects of an atorvastatin treatment (7 days) on atrial ion currents and their tachycardia-induced alterations were studied in a rabbit model of tachycardia-induced electrical remodeling (rapid atrial pacing (600 min) for 24 and 120 h). Ion currents (L-type calcium channel [I(Ca,L)], transient outward current [I(to)]) were measured using whole cell patch clamp method and were compared with previous experiments in untreated but also tachypaced animals. Atorvastatin treatment alone decreased I(Ca,L) similar to rapid atrial pacing alone, currents were also further reduced by additional atrial tachypacing. I(to) and its pacing-induced down-regulation after 24 h were not influenced by atorvastatin treatment. However, I(to) was still reduced after 120 h in atorvastatin-treated animals and did not return to control values as expected. The present study establishes that an atorvastatin treatment can affect atrial ion currents and their tachycardia-induced remodeling in a rabbit model. These results show that-amongst other positive effects on oxidative stress and inflammation-the impact of statins on ion currents and their tachycardia-induced alterations might also play a role in "upstream" treatment of AF with HMG-CoA reductase inhibitors.


Hemodynamic mechanisms of emerging portal hypertension caused by schistosomiasis in the hamster.
A hamster model of schistosomiasis has provided the first opportunity to sequentially examine the early phases of the development of portal hypertension in a natural model of chronic liver disease. Groups of hamsters were infected with 50 cercariae of Schistosoma mansoni and underwent hemodynamic evaluation at intervals of 5, 8, 12 and 20 wk after infection. A progressive rise in intrahepatic resistance (from 4.0 +/- 0.4 to 8.4 +/- 1.0 mm Hg min.ml-1.gm liver weight [p less than 0.01]) appeared to play a major role in the initial stages of evolving portal hypertension. A gradual decline in portal blood flow (from 2.1 +/- 0.3 to 1.3 +/- 0.1 ml.min-1.gm-1 liver weight [p less than 0.01]) was only partially compensated for by an increase in hepatic arterial flow. Accordingly, by week 20, total hepatic blood flow decreased 23%. Liver weight that increased markedly between 5 and 12 wk after infection, as a result of the acute accumulation of obstructing granulomas, stabilized between wk 12 and 20, while a gradual but progressive rise in hepatic collagen content was seen. Portal pressure increased 75% during the study period. Chronic examination of this natural model should help define the pathogenesis of the complications of portal hypertension and contribute to the basis for effective intervention in this disease process.


Depth dose measurements in water for 11C and 10C beams with therapy relevant energies.
Owing to the favorable depth-dose distribution and the radiobiological properties of heavy ion radiation, ion beam therapy shows an improved success/toxicity ratio compared to conventional radiotherapy. The sharp dose gradients and very high doses in the Bragg peak region, which represent the larger physical advantage of ion beam therapy, make it also extremely sensitive to range uncertainties. The use of β +-radioactive ion beams would be ideal for simultaneous treatment and accurate online range monitoring through PET imaging. Since all the unfragmented primary ions are potentially contributing to the PET signal, these beams offer an improved image quality while preserving the physical and radiobiological advantages of the stable counterparts. The challenging production of radioactive ion beams and the difficulties in reaching high intensities, have discouraged their clinical application. In this context, the project Biomedical Applications of Radioactive ion Beams (BARB) started at GSI (Helmholtzzentrum für Schwerionenforschung GmbH) with the main goal to assess the technical feasibility and investigate possible advantages of radioactive ion beams on the pre-clinical level. During the first experimental campaign 11C and 10C beams were produced and isotopically separated with the FRagment Separator (FRS) at GSI. The β +-radioactive ion beams were produced with a beam purity of 99% for all the beam investigated (except one case where it was 94%) and intensities potentially sufficient to treat a small animal tumors within few minutes of irradiation time, ∼ 106 particle per spill for the 10C and ∼ 107 particle per spill for the 11C beam, respectively. The impact of different ion optical parameters on the depth dose distribution was studied with a precision water column system. In this work, the measured depth dose distributions are presented together with results from Monte Carlo simulations using the FLUKA software.


Semi-automated scoring of pulmonary emphysema from X-ray CT: trainee reproducibility and accuracy.
We developed a semi-automated tool to quantify emphysema from thoracic X-ray multi-detector (64-slice) computed tomography (CT) for training purposes and multi-reader studies. Thoracic X-ray CT was acquired in 93 ex-smokers, who were evaluated by six trainees with little or no expertise (trainees) and a single experienced thoracic radiologist (expert). A graphic user interface (GUI) was developed for emphysema quantification based on the percentile of lung where a score of 0=no abnormalities, 1=1-25%, 2=26-50%, 3=51-75% and 4=76-100% for each lung side/slice. Trainees blinded to subject characteristics scored randomized images twice; accuracy was determined by comparison to expert scores, density histogram 15th percentile (HU 15), relative area at -950 HU (RA(950)), low attenuation clusters at -950 HU (LAC(950)), -856 HU (LAC(856)) and the diffusing capacity for carbon monoxide (DL(CO%pred)). Intra- and inter-observer reproducibility was evaluated using coefficients-of-variation (COV), intra-class (ICC) and Pearson correlations. Trainee-expert correlations were significant (r=0.85-0.97, p<0.0001) and a significant trainee bias (0.15 ± 0.22) was observed. Emphysema score was correlated with RA(950) (r=0.88, p<0.0001), HU 15 (r=-0.77, p<0.0001), LAC(950) (r=0.76, p<0.0001), LAC(856) (r=0.74, p=0.0001) and DLCO%pred (r=-0.71, p<0.0001). Intra-observer reproducibility (COV=4-27%; ICC=0.75-0.94) was moderate to high for trainees; intra- and inter-observer COV were negatively and non-linearly correlated with emphysema score. We developed a GUI for rapid and interactive emphysema scoring that allows for comparison of multiple readers with clinical and radiological standards.


Molecular diagnosis of canine visceral leishmaniasis: a comparative study of three methods using skin and spleen from dogs with natural Leishmania infantum infection.
Polymerase chain reaction (PCR) and its variations represent highly sensitive and specific methods for Leishmania DNA detection and subsequent canine visceral leishmaniasis (CVL) diagnosis. The aim of this work was to compare three different molecular diagnosis techniques (conventional PCR [cPCR], seminested PCR [snPCR], and quantitative PCR [qPCR]) in samples of skin and spleen from 60 seropositive dogs by immunofluorescence antibody test and enzyme-linked immunosorbent assay. Parasitological analysis was conducted by culture of bone marrow aspirate and optical microscopic assessment of ear skin and spleen samples stained with Giemsa, the standard tests for CVL diagnosis. The primers L150/L152 and LINR4/LIN17/LIN19 were used to amplify the conserved region of the Leishmania kDNA minicircle in the cPCR, and snPCR and qPCR were performed using the DNA polymerase gene (DNA pol α) primers from Leishmania infantum. The parasitological analysis revealed parasites in 61.7% of the samples. Sensitivities were 89.2%, 86.5%, and 97.3% in the skin and 81.1%, 94.6%, and 100.0% in spleen samples used for cPCR, snPCR, and qPCR, respectively. We demonstrated that the qPCR method was the best technique to detect L. infantum in both skin and spleen samples. However, we recommend the use of skin due to the high sensitivity and sampling being less invasive.


Feasibility study of utilizing Sphinx Compact for quality assurance in uniform scanning proton therapy.
To investigate the feasibility of utilizing the Sphinx Compact detector for quality assurance in a uniform scanning proton therapy system. The Sphinx Compact detector was used to measure various dosimetric parameters of uniform scanning proton beam at the Oklahoma Proton Center: distal range, distal-fall-off, collinearity, field symmetry, flatness, and field size for four different beams. A specially designed brass aperture was used to perform the required measurements. The Sphinx Compact measurement results were validated against the measurement results from the well-established detectors in proton therapy: IBA Zebra, IBA MatriXX-PT, EBT3 films, and Logos XRV-124. The data collected using the Sphinx Compact was analyzed in myQA software. Based on the data analysis performed, the Sphinx Compact measurements were within acceptable accuracy to the results from the detectors mentioned in the Method section. Specifically, the lateral penumbra was within ±0.4 mm, collinearity was within ± 0.5 mm, flatness was within ±0.6 %, symmetry within ±1.6 %, distal range was within ±0.5 mm, distal-fall-off was <0.9 mm, and field size was within ±1 mm. The reproducibility of the Sphinx Compact was tested for range and collinearity, and the results were within ±0.1 mm. The sphinx Compact detector could potentially replace multiple detectors utilized for monthly QA in uniform scanning proton therapy. In a multi-room center, performing the QA with one detector compared to using multiple detectors dramatically reduces total QA time and the complexity of the QA process.


Hippocampal lesions and trace conditioning in the rabbit.
Trace conditioning of the nictitating membrane response (NMR) was examined in rabbits with lesions of the dorsal hippocampus and fimbria-fornix. Using a white noise conditional stimulus and an electrical shock unconditional stimulus, the number and amplitude of conditional responses (CRs) was similar in hippocampus-lesioned and control subjects. At some stages of conditioning, the latencies of CRs from hippocampus-lesioned subjects were slightly shorter than those of the controls. We suggest that the hippocampus is not essential for trace conditioning but may exert a modulatory influence on the timing of the CR.


Cultural behaviour and the invention of traditions: music and musical practices in the early concentration camps, 1933-6/7.
This article investigates music in the concentration camps before the second world war. For the camp authorities, ordering prisoners to sing songs or play in orchestras was an instrument of domination. But for the prisoners, music could also be an expression of solidarity and survival: inmates could retain a degree of their own agency in the pre-war camps, despite the often unbearable living conditions and harsh treatment by guards. The present article emphasizes this ambiguity of music in the early camps. It illustrates the emergence of musical traditions in the pre-war camps which came to have a significant impact on everyday life in the camps. It helps to overcome the view that concentration camp prisoners were simply passive victims.


The effect of transferring weekend physical therapy services from the acute to sub-acute setting in patients following hip and knee arthroplasty: a quasi-experimental study.
Weekend physical therapy services in the acute and/or sub-acute setting may optimize postoperative recovery following hip and knee arthroplasty, though evidence supporting these services is limited. To explore the change in patient and service outcomes of transferring a weekend physical therapy service from the acute to the sub-acute setting following hip and knee arthroplasty. This was a quasi-experimental research design nested within two stepped-wedge cluster randomized controlled trials. Acute weekend physical therapy services were sequentially discontinued and reallocated to the sub-acute setting in a random order from one ward at a time within the broader trial. Patient and service outcomes for participants 6 weeks following hip and knee arthroplasty (N = 247) were compared during 6 months of acute weekend physical therapy services (Phase 1, n = 117) followed by 6 months of sub-acute services (Phase 2, n = 130). Intention-to-treat statistical analyses were conducted. The intervention had a negligible effect on medium-term outcomes. The only statistically significant difference observed was slightly higher ratings of "worst pain experienced over the past week" [coefficient 0.865 (0.123 to 1.606), p = .022] during Phase 2. No interaction effects were observed despite a 2.4-day reduction in length of stay amongst complex patients during Phase 2 (18.28 and 15.86 days in Phase 1 and 2, respectively). No comparative advantage or disadvantage was observed by reallocating a weekend physical therapy budget from the acute to sub-acute setting following hip and knee arthroplasty. Further research investigating the cost-effectiveness of these services in the sub-acute setting may be warranted for complex patients.


Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib.
To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists' Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined. Separate analyses were performed for all patients and for those not taking aspirin. Data from all controlled, completed arthritis trials of > or =4 weeks duration, including 13 new drug application studies and 2 large post-marketing trials (CLASS and SUCCESS) were included for analyses. Patients were randomized to celecoxib at doses from 100 to 400 mg twice daily (18,942 patients; 5,668.2 patient-years of exposure), diclofenac 50 to 75 mg twice daily, ibuprofen 800 mg thrice daily, naproxen 500 mg twice daily (combined NSAID exposure of 11,143 patients; 3,612.2 patient-years), or placebo (1,794 subjects; 199.9 subject-years). Data from a long-term uncontrolled trial with 5,209 patients (6,950 patients-years) treated with celecoxib were included in a supplemental analysis. The entire 15-trial database was searched for possible serious thrombotic events as well as to identify all deaths. For these patients, detailed clinical data were obtained and reviewed by 2 of the investigators (WBW and JSB), who were independently and blinded to exposure, to classify the event as primary, secondary, or neither. All analyses were done using the intent-to-treat population, and time-to-event analyses were performed using per-patient data. To examine heterogeneity of results among studies, tests of interaction were performed using the Cox model. Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups, nor for the celecoxib group compared with the NSAIDs group, regardless of aspirin use and NSAID type. The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 (95% confidence interval 0.70 to 1.61, p = 0.79) for all patients, and 0.86 (95% confidence interval 0.48 to 1.56, p = 0.62) for the subgroup not taking aspirin. Similarly, for secondary cardiovascular end points, all relative risks were < or =1 for celecoxib compared with either placebo or NSAIDs. These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo.


Structural characterization of phosphatidylcholines by atmospheric pressure photoionization mass spectrometry.
The potential of atmospheric pressure photoionization was investigated for the structural analysis of phosphatidylcholine lipids (PCs). [M+H]+ ions of high abundance were obtained, along with several fragment ions. Three of these dissociation products corresponded to quite unusual fragmentation pathways but allowed the determination of both the nature and the position on the glycerol backbone (sn-1 or sn-2) of the fatty acyl chains. The loss of a methyl group from the choline head was also observed. These results suggest a complex ionization mechanism in APPI. However, this method proved to be very powerful for the rapid structural analysis of PC species without using MS/MS experiments.


A rapid and sensitive method for the quantification of dopamine and serotonin metabolites in cerebrospinal fluid based on UHPLC with fluorescence detection.
Inborn errors of dopamine and serotonin metabolism are diseases caused by deficiencies in enzymes belonging to metabolic pathways. The specific diagnosis of these inborn illnesses is based on the identification and quantification of biomarkers in cerebrospinal fluid (CSF), especially: 5-hydroxy-tryptophane (5-HTP), 5-hydroxy-indol-acetic acid (5-HIAA), 3-ortho-methyl-DOPA (3-OMD), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG). In the present work, we propose a novel ultrahigh performance liquid chromatography (UHPLC) method coupled to fluorescence detection (FD) to quantify simultaneously the five dopamine and serotonin metabolites. This method efficiently separates the five molecules in less than 10 min. A complete validation of the proposed method was performed in terms of accuracy, linearity, precision, and lower limit of quantification (LLOQ). Depending on the compound, the obtained LLOQs are between 1 nM and 5 nM, thus allowing to measure concentrations as low as in CSF samples. We also verified the method applicability by analyzing 10 CSF samples in triplicates. The obtained results showed satisfactory repeatability and an ability of this method to clearly distinguish healthy samples from pathologic samples, hence, demonstrating, the method suitability for diagnosing inborn errors of dopamine and serotonin metabolism. Therefore, the proposed UHPLC-FD method appears as a reliable alternative to the current gold standard for the quantification of these biomarkers, which is based on UHPLC coupled to electrochemical detection (ECD).


Progression of mild ureteropelvic junction obstruction in infancy.
Mild and clinically silent ureteropelvic junction obstruction was observed to progress in severity in 2 infants. Diuretic renography was useful in serial evaluation and documentation of progression. The possible mechanism for such progression of obstruction is proposed. Although mild obstruction in the older child and adult can be followed successfully without surgery, it appears that close follow-up of mild obstruction during the first year of life is necessary to detect and assure treatment of progressive obstruction at an optimum age.


The organic solvents acetone, ethanol and dimethylformamide potentiate the mutagenic activity of N-methyl-N'-nitro-N-nitrosoguanidine, but have no effect on the mutagenic potential of N-methyl-N-nitrosourea.
The frequency of recessive chlorophyll and embryonic lethals included by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Arabidopsis thaliana was markedly increased when exposure of the seeds to MNNG (3 h) was carried out in the presence of 4-12% acetone, 4-16% ethanol or 8-32% dimethylformamide. The enhancement of MNNG mutagenicity was proportional to the concentrations of these organic solvents. In contrast, neither of them, applied at the same conditions and doses, influenced the mutagenic activity of N-methyl-N-nitrosourea. The solvents without mutagens did not influence the spontaneous rate of mutations and revealed no or very weak toxic effect as measured by the seed germination.


Vocalization and stapedius muscle activity evoked by local electrical stimulation of midbrain in the chicken (Gallus gallus).
The organization of chicken mesencephalic areas from which stapedius muscle activity and vocalization can be differently elicited was studied. Our results show the existence of an area, around the mesencephalic 'calling area', from which stapedius muscle activity can be evoked independently of vocalization. Furthermore, low threshold 'vocalization loci' stimulation evokes field potentials in the stapedius-controlling area, due to the activation of stapedius-controlling neurons by vocalization neurons.


Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations. Although the approval of new therapies includes only one agent in 50 years, a number of promising new drugs are in development. Lupus nephritis is a dreaded complication of SLE as it is associated with significant morbidity and mortality. Advancing the treatment of lupus nephritis requires well-designed clinical trials and this can be challenging in SLE. The major obstacles involve identifying the correct population of patients to enroll and ensuring that a clinically appropriate and patient-centered endpoint is being measured. In this review, we will first discuss the clinical utility of endpoints chosen to represent lupus nephritis in global disease activity scales. Second, we will review completed and active trials focused on lupus nephritis and discuss the endpoints chosen. There are many important lessons to be learned from existing assessment tools and clinical trials. Reviewing these points will help ensure that future efforts will yield meaningful disease activity measures and well-designed clinical trials to advance our understanding of lupus management.


CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activity.
Esketamine, the S-stereoisomer of (R,S)-ketamine was recently approved by drug agencies (FDA, EMA), as an antidepressant drug with a new mechanism of action. (R,S)-ketamine is a N-methyl-d-aspartate receptor (NMDA-R) antagonist putatively acting on GABAergic inhibitory synapses to increase excitatory synaptic glutamatergic neurotransmission. Unlike monoamine-based antidepressants, (R,S)-ketamine exhibits rapid and persistent antidepressant activity at subanesthetic doses in preclinical rodent models and in treatment-resistant depressed patients. Its major brain metabolite, (2R,6R)-hydroxynorketamine (HNK) is formed following (R,S)-ketamine metabolism by various cytochrome P450 enzymes (CYP) mainly activated in the liver depending on routes of administration [e.g., intravenous (largely used for a better bioavailability), intranasal spray, intracerebral, subcutaneous, intramuscular or oral]. Experimental or clinical studies suggest that (2R,6R)-HNK could be an antidepressant drug candidate. However, questions still remain regarding its molecular and cellular targets in the brain and its role in (R,S)-ketamine's fast-acting antidepressant effects. The purpose of the present review is: 1) to review (R,S)-ketamine pharmacokinetic properties in humans and rodents and its metabolism by CYP enzymes to form norketamine and HNK metabolites; 2) to provide a summary of preclinical strategies challenging the role of these metabolites by modifying (R,S)-ketamine metabolism, e.g., by administering a pre-treatment CYP inducers or inhibitors; 3) to analyze the influence of sex and age on CYP expression and (R,S)-ketamine metabolism. Importantly, this review describes (R,S)-ketamine pharmacodynamics and pharmacokinetics to alert clinicians about possible drug-drug interactions during a concomitant administration of (R,S)-ketamine and CYP inducers/inhibitors that could enhance or blunt, respectively, (R,S)-ketamine's therapeutic antidepressant efficacy in patients.


Investigating tubulin posttranslational modifications with specific antibodies.
Microtubules play highly diverse and essential roles in every eukaryotic cell. While built from conserved dimers of α- and β-tubulin, microtubules can be diversified by posttranslational modifications in order to fulfill specific functions in cells. The tubulin posttranslational modifications: acetylation, detyrosination, polyglutamylation, and polyglycylation play important roles in microtubule functions; however, only little functional and mechanistic insight has been gained so far. The modification state of microtubules can be visualized with specific antibodies. A drawback is that detailed information about the specificities and limitations of these antibodies are not easily accessible in the literature. We provide here a comprehensive description of the currently available set of antibodies specific to tubulin modifications. Focusing on glutamylation antibodies, we discuss specific protocols that allow using these antibodies to gain semi-quantitative information on the levels and distribution of tubulin modifications in immunocytochemistry and immunoblot.


Erythrocyte as a potential model for study of lifelong somatic mutations.
The detection and measurement of somatic cell mutation in vivo is an important subject of research for the assessment of human cancer risk induced by various environmental genotoxic factors. The possible mechanisms which influence the persistence of mutant cells of the hematoimmune system in the peripheral blood are presented. The erythroid system is a system which accumulates mutational lesions and so stably generates red blood cells with various phenotypic changes.


Aciduric microbial taxa including Scardovia wiggsiae and Bifidobacterium spp. in caries and caries free subjects.
Actinobacteria came into focus of being potential caries-associated pathogens and could, together with the established Streptococcus mutans and lactobacilli thus function as caries indicator species. Here we analyzed the role and diagnostic predictive value of the acidogenic-aciduric species Scardovia wiggsiae and Bifidobacterium dentium together with S. mutans, lactobacilli and bifidobacteria in biofilm of non-cavitated (n = 20) and cavitated (n = 6) caries lesions versus controls (n = 30). For the genus Bifidobacterium and for B. dentium new sets of primers were designed. Based on real-time quantitative PCR and confirmed by DNA sequencing we found a higher prevalence (61.5%) of S. wiggsiae in caries lesions than in controls (40%). However, among the controls we found three individuals with both the highest absolute and relative S. wiggsiae numbers. Testing for S. mutans revealed the same prevalence as S. wiggsiae in caries lesions (61.5%) but in controls its prevalence was only 10%. B. dentium was never found in healthy plaque but in 30.8% of clinical cases, with the highest numbers in cavitated lesions. The Bifidobacterium-genus specific PCR had less discriminative power as more control samples were positive. We calculated the relative abundances and applied receiver operating characteristic analyses. The top results of specificity (93% and 87%) and sensitivity (100% and 88%) were found when the constraint set was "Lactobacillus relative abundance ≥0.02%" and "two aciduric species with a relative abundance of each ≥0.007%". Combinatory measurement of several aciduric taxa may be useful to reveal caries activity or even to predict caries progression.


A method for the direct evaluation of the fatty acid status in a drop of blood from a fingertip in humans: applicability to nutritional and epidemiological studies.
Several studies have shown that the fatty acid composition of circulating lipids reflects dietary fat intake, in turn being related to health status. The fatty acid composition of plasma lipids is therefore an important parameter in studies on dietary interventions. The aim of our study was to develop a rapid and inexpensive method for the analysis of circulating fatty acids applicable to large population groups. Drops of blood collected from fingertips have been directly subjected to transmethylation for gas chromatography analysis. This new method, validated for reproducibility, has been compared with the conventional method, based on withdrawal of blood from the antecubital vein followed by lipid extraction, and identical data have been obtained with the two techniques. Observed and predicted differences between blood and plasma fatty acids are related to the contribution of circulating cell membranes in blood. Finally the application of the methods to samples from 100 healthy subjects and the assessed correlation between dietary habits and blood fatty acid profiles demonstrate the validity of the new method and its applicability to nutritional and epidemiological studies.


A theory for cursive handwriting based on the minimization principle.
We propose a trajectory planning and control theory which provides explanations at the computation, algorithm, representation, and hardware levels for continuous movement such as connected cursive handwriting. The hardware is based on our previously proposed forward-inverse-relaxation neural network. Computationally, the optimization principle is the minimum torque-change criterion. At the representation level, hard constraints satisfied by a trajectory are represented as a set of via-points extracted from handwritten characters. Accordingly, we propose a via-point estimation algorithm that estimates via-points by repeating trajectory formation of a character and via-point extraction from the character. It is shown experimentally that for movements with a single via-point target, the via-point estimation algorithm can assign a point near the actual via-point target. Good quantitative agreement is found between human movement data and the trajectories generated by the proposed model.


Effects of test anxiety and sex of subject on neuropsychological test performance: Finger Tapping, Trail Making, Digit Span and Digit Symbol tests.
To determine the effects of anxiety and sex on various neuropsychological tests, 28 male and 28 female non-impaired, high and low test-anxious subjects were given the Finger Tapping, Trail Making (Forms A and B), Digit Span, and Digit Symbol tests. Sex significantly affected only the Finger Tapping Test; females made significantly fewer taps. High test-anxious subjects reported an increase in posttest state anxiety. However, test anxiety did not significantly affect performance.


[Thirty years of tuberculosis control in Cameroon: alternating "vertical" and "horizontal" health care delivery systems].
In sub-Saharan Africa, tuberculosis remains endemic despite reforms of health systems and the tuberculosis control organization carried out in the last decades. We conducted a retrospective study of tuberculosis control in Cameroon from the period 2009 back to 1980. Data were collected from documents and activity reports of tuberculosis control, and interviews with managers of the National tuberculosis control program. The history of tuberculosis control in Cameroon from 2009 back to 1980 can be divided into three main periods. The first period, from 1980 to 1994, corresponded to the implementation of the 'primary health care' policy. At that time, tuberculosis case management was delivered free of charge, but centralized in specialized services with a gradual and mild increase in new cases detected. The second period, from 1995 to 2000, was characterized by the implementation of the 'primary health care reorientation' policy that decentralized tuberculosis care to all health facilities, but introduced cost recovery --which came along with a dramatic drop in the number of tuberculosis cases detected. The National tuberculosis control program, established in 1996, entrusted health facilities--especially hospitals--with the responsibility of tuberculosis diagnosis and treatment, and referred to them as tuberculosis diagnosis and treatment centers. During the third period, from 2001 to 2009, owing to major support from global health initiatives, the number of tuberculosis diagnosis and treatment centers was increased (reaching 216 centers in 2009), with a significant increase of new cases detected that peaked in 2006, from where the situation started declining till 2009. Tuberculosis control indicators have never been optimal in Cameroon, despite the generally positive trend from 1980 to 2009. The strategy of tuberculosis diagnosis and treatment centers, which are essentially nested within hospitals, seems to have reached its intrinsic limitations. Better performance in tuberculosis control will henceforth require greater decentralization of tuberculosis detection and treatment to health centers. This careful decentralization will improve access for tuberculosis patients and lead to a comprehensive use of hospital technical expertise for tuberculosis care.


A stranger in the heart: LRV stent migration.
We present a case of migration of the left renal vein (LRV) stent into the right ventricle in a patient with nutcracker syndrome. After a failed attempt of percutaneous endovascular removal of the stent, the stent in the heart was removed by open cardiac surgery, another stent was placed into the LRV via a puncture in the inferior vena cava (IVC) under direct vision, and the patient had an uneventful postoperative recovery. At 3 years follow-up, the patient was asymptomatic and Doppler ultrasonography demonstrated the stent to be patent and well-positioned.


Functional Bioinformatics Analyses of the Matrisome and Integrin Adhesome.
The extracellular matrix (ECM) is the noncellular compartment of living organisms and is formed of a complex network of cross-linked proteins, which is collectively known as the matrisome. Apart from providing the structure for an organism, cells interact and thereby communicate with the ECM. Cells interact with their surrounding ECM using cell-surface receptors, such as integrins. Upon integrin engagement with the ECM, cytoskeletal proteins are recruited to integrins and form a molecular protein complex known as the integrin adhesome. Global descriptions of the matrisome and integrin adhesome have been proposed using in silico bioinformatics approaches, as well as through biochemical enrichment of matrisome and adhesome fractions coupled with mass spectrometry-based proteomic analyses, providing inventories of their compositions in different contexts. Here, methods are described for the computational downstream analyses of matrisome and adhesome mass spectrometry datasets that are accessible to wet lab biologists, which include comparing datasets to in silico descriptions, generating interaction networks and performing functional ontological analyses.


Mechanism for improving coconut milk emulsions viscosity by modifying coconut protein structure and coconut milk properties with monosodium glutamate.
In this study, monosodium glutamate (MSG) was used to improve the viscosity of coconut milk and the underlying mechanism was explored by investigating the changes in structures of coconut milk protein and physicochemical properties of coconut milk. Firstly, the effect of MSG on the properties of coconut milk was studied. The results showed that MSG increased the pH and zeta potential, reduced the particle size, thus enhancing the droplet interaction and increasing the viscosity of coconut milk. Subsequently, the effects of MSG on the structure and properties of coconut proteins (CP) were investigated. FTIR spectroscopy and circular dichroism spectroscopy showed that MSG was able to change the secondary structure of CP. The results of SDS-PAGE showed that MSG was able to bind to CP to form a larger molecular weight protein, thus improving the viscosity of coconut milk. Moreover, MSG was also able to increase the water-binding capacity of CP. In addition, molecular docking and driving force analysis revealed that hydrogen bonds, electrostatic forces, disulfide bonds, and hydrophobic interactions are the main interactions between MSG and CP. Studying the effect of MSG on the viscosity of coconut milk provides theoretical support to improve the viscosity of other plant protein emulsions.


Carboxymethyl cellulose-human hair keratin hydrogel with controlled clindamycin release as antibacterial wound dressing.
This study offers a new antibacterial wound dressing from carboxymethyl cellulose (CMC)-human hair keratin with topical clindamycin delivery. Keratin was successfully extracted from human hair. Different sponges fabricated by changing CMC to keratin ratio were characterized and compared. Halloysite nanotubes were used as carriers to control the clindamycin release. Various characterization techniques were used to determine the effects of keratin addition on the structure, morphology, physical properties, drug release, antibacterial activity, and cellular behavior of CMC hydrogels. As proved by SEM and EDS, porous structure with interconnected pores was successfully formed and clindamycin-loaded HNTs were uniformly dispersed within the porous structures. Increasing the keratin in CMC hydrogel not only lowered its water vapor transmission rate to a suitable range for wound healing but also improved the water stability of CMC hydrogel. The in vitro release study indicated that clindamycin was released slower in samples containing higher keratin and the Fickian diffusion mechanism controlled their release profile. The fabricated dressing effectively inhibits S. aureus bacterial colonies growth after 24 h. Fibroblast culturing on the fabricated sponges indicated that cellular attachment, proliferation, and spreading were significantly enhanced with increasing the keratin amount.


Bispecific antibodies and dual-targeting CAR-T cells for multiple myeloma: latest updates from the 2023 ASCO annual meeting.
Bispecific antibodies (BsAbs) and dual-targeted chimeric antigen receptor T (CAR T) cells have been employed in relapsed/refractory multiple myeloma (RRMM) patients over the past few years, as an increasing number of patients were ineffectively treated by ≥ 3 prior lines of therapy. BCMA/CD3 and GPRC5D/CD3 are the most popular combinations. Clinical findings indicated that patients exhibit a greater susceptibility to stronger and more enduring responses. Here, we summarize the latest data from the 2023 ASCO annual meeting on BsAbs targeting BCMA/CD3, GPRC5D/CD3 and BCMA/CD19 CAR T cells.


Chylous ascites after liver transplantation with mesentero-portal jump graft.
Chylous effusions and lymphatic leaks occur after trauma, malignant disease, primary lymphatic disorders, and parasitosis, and rarely after abdominal surgery. Chylous ascites after orthotopic liver transplantation is a rare complication. We report a case of chylous ascites occurring after hepatic transplantation with a mesentero-portal venous jump graft, successfully treated with conservative management.


Falciparum malaria molecular drug resistance in the Democratic Republic of Congo: a systematic review.
Malaria cases were estimated to 207 million in 2013. One of the problems of malaria control is the emergence and spread of Plasmodium falciparum strains that become resistant to almost all drugs available. Monitoring drug resistance is essential for early detection and subsequent prevention of the spread of drug resistance by timely changes of treatment policy. This review was performed to gather all data available on P. falciparum molecular resistance in DR Congo, as baseline for future assessments. The search for this review was undertaken using the electronic databases PubMed and Google Scholar using the terms "malaria", "Congo", "resistance", "molecular", "antimalarial", "efficacy". Articles were classified based on year of collecting, year of publication, sample size and characteristics, molecular markers analysed and polymorphisms detected. Thirteen articles were included and five genes have been analysed in these studies: pfcrt, pfdhps, pfdhfr, pfmdr1 and K13-propeller. The majority of studies included were not representative of the whole country. This systematic review demonstrates the lack of molecular resistance studies in DRC. Only 13 studies were identified in almost 15 years. The MOH must implement a national surveillance system for monitoring malaria drug resistance and this surveillance should be conducted frequently and country-representative.


Neuron-specific enolase as a novel biomarker reflecting tuberculosis activity and treatment response.
It is not clear which tests are indicative of the activity and severity of tuberculosis (TB). This study aimed to investigate the predictive value of neuron-specific enolase (NSE) and to determine the origin of NSE in TB patients. A single-center retrospective analysis was conducted on newly diagnosed TB patients between January and December 2010. Patients were categorized into one of two disease groups (focal segmental or extensive) based on chest X-ray. Pre- and post-treatment NSE concentrations were evaluated. To determine the origin of serum NSE concentration, NSE staining was compared with macrophage-specific CD68 staining in lung tissues and with a tissue microarray using immunohistochemistry and immunofluorescence. A total of 60 newly diagnosed TB patients were analyzed. In TB patients, NSE serum concentration was significantly increased and NSE level decreased after treatment (p < 0.001). In proportion to serum high-sensitivity C-reactive protein concentration, the mean serum concentration of NSE in the extensive group (25.12 ng/mL) was significantly higher than that in the focal segmental group (20.23 ng/mL, p = 0.04). Immunohistochemical staining revealed a large number of macrophages that stained positively for both NSE and CD68 in TB tissues. In addition, NSE signals mostly co-localized with CD68 signals in the tissue microarray of TB patients. Our results suggest that NSE may be a practical parameter that can be used to monitor TB activity and treatment response. Elevated serum NSE level originates, at least in part, from macrophages in granulomatous lesions.


Anti-IL-23 and Anti-IL-17 Biologic Agents for the Treatment of Immune-Mediated Inflammatory Conditions.
Advancements in the immunopathogenesis of psoriasis have identified interleukin (IL)-23 and IL-17 as fundamental contributors in the immune pathways of the disease. Leveraging these promising therapeutic targets has led to the emergence of a number of anti-IL-23 and -17 biologic agents with the potential to treat multiple conditions with common underlying pathology. The unprecedented clinical efficacy of these agents in the treatment of psoriasis has paved way for their evaluation in diseases such as psoriatic arthritis, Crohn's disease, rheumatoid arthritis, in addition to other immune-mediated conditions. Here we review the IL-23/IL-17 immune pathways and discuss the key clinical and safety data of the anti-IL-23 and anti-IL-17 biologic agents in psoriasis and other immune-mediated diseases.


Azidothymidine (AZT) leads to arterial stiffening and intima-media thickening in mice.
HIV positive patients on highly active antiretroviral therapy (HAART) have shown elevated incidence of a number of non-AIDS defining co-morbidities, including cardiovascular disease. Given that HAART regimens contain a combination of at least three drugs, that disease management often requires adjustment of these regimens, and HIV, independent of HAART, also plays a role in development of co-morbidities, determining the role of specific HAART drugs and HIV infection itself from clinical data remains challenging. To characterize specific mediators and underlying mechanisms of disease, in vitro and in vivo animal models are required, in parallel with clinical data. Given its low cost azidothymidine (AZT) contributes to the backbone of a large proportion of HAART treated patients in the developing world where much of the global burden of HIV resides. The goal of this study was to test the hypothesis that AZT can lead to proatherogenic changes including the subclinical markers of arterial stiffening and intima-media thickening in mice. AZT (100mg/kg) or vehicle was administered to wild-type FVB/N mice via oral gavage for 35 days. Cylindrical biaxial biomechanical tests on the common carotid arteries and suprarenal aortas exhibited arterial stiffening in AZT mice compared to controls. Multiphoton microscopy and histology demonstrated that AZT led to increased intima-media thickness. These data correlated with decreased elastin content and increased protease activity as measured by cathepsin zymography; no differences were observed in collagen content or organization, in vivo axial stretch, or opening angle. Thus, this study suggests the drug AZT has significant effects on the development of subclinical markers of atherosclerosis.


Impaired fasting glucose and cardiogenic shock in patients with acute myocardial infarction.
In-hospital outcome after acute myocardial infarction (MI) has not yet been evaluated with regard to the new category of Impaired Fasting Glucose level (IFG) patients defined by the American Diabetes Association (ADA). Nine hundred and ninety-nine patients with acute MI from the RICO survey were included in the study. Fasting blood glucose was measured after admission. Patients were grouped according to ADA definitions: Diabetes Mellitus (DM) (FG >/=7mmol/l or personal history of DM); IFG (FG 6.1 to 7mmol/l); NFG (normal FG <6.1mmol/l). Three hundred and eighty-one patients (38%) had DM, 145 (15%) IFG and 473 (47%) NFG. Mortality in the IFG group was twice that of the NFG group (8% vs 4%, P=0.049). A significant increase in cardiogenic shock (12% vs 6%, P=0.011) and ventricular arrhythmia (15% vs 9%, P=0.035) was observed in the IFG vs NFG group. IFG, after adjustment for confounding factors (age, sex, anterior location, and LVEF), was a strong independent predictive factor for cardiogenic shock (P=0.005). MI patients with IFG had an overall worse outcome, characterized by a higher risk of developing cardiogenic shock during their hospital stay.


Child and adolescent depression: psychotherapeutic, ethical, and related nonpharmacologic considerations for general psychiatrists and others who prescribe.
Depression is a common, recurring disorder affecting millions of youth at some point before they reach mature adulthood. Given the shortage of and uneven distribution of psychiatrists who have completed specialized fellowships in child and adolescent psychiatry, a significant number of depressed youth will receive their pharmacotherapy from general psychiatrists and other prescribers with varying degrees of interest, training, and even willingness to treat children and adolescents. For general psychiatrists who will prescribe antidepressants for minors, knowledge of the training and expertise of nonphysician mental health professionals, the psychotherapies they may employ, and familiarity with school services are essential. Physicians who typically work only with adults will also need familiarity with differing ethical, legal, and regulatory issues and standards applicable to pediatric psychopharmacology. General psychiatrists, pediatricians, family physicians, nurse practitioners, and others contribute greatly to the care of depressed children, adolescents, and their families, and many find this work to be a very rewarding part of their professional practices.


Physical Activity Participation in People With an Active Diabetic Foot Ulceration: A Scoping Review.
Being physically active on a regular basis has a favourable impact on diabetes-related complications. With the exception of evidence advising individuals with an active diabetic foot ulceration (DFU) to avoid weight-bearing activity, no physical activity (PA) recommendations are currently provided for this population. The aim of this scoping review was to examine and map the existing research evidence of PA participation for individuals with an active DFU. A scoping review using the Arksey and O'Malley framework was conducted in electronic databases and grey literature from inception to June 2020 to identify publications that investigated individuals with type 1 or type 2 diabetes and an active DFU at enrolment in relation to a PA intervention. Reported outcomes had to inform on effects of PA on any health or wound parameters. Nineteen articles from 17 distinct studies met inclusion criteria. Fourteen of the included studies were published in the last 10 years. Types of exercises and materials used, duration of studies, offloading considerations and provision of wound care varied greatly between studies. Included studies are heterogenous in methodological designs and aims, and reporting was often lacking important components of wound care and PA interventions. A discussion based on descriptive statistics and narrative analysis is provided. It is not possible from this scoping review to determine what would be the ideal components of a PA program for this specific population. Conclusions are limited by the quality and design of the included studies. No articles evaluated quality of life, mortality or cardiorespiratory capacity, nor were adverse effects routinely reported.


Perceptions of the medical relevance of patients` stories of painful and adverse life experiences: a focus group study among Norwegian General Practitioners.
Adverse life experiences increase the risk of health problems. Little is known about General Practitioners' (GPs') thoughts, clinical concepts, and work patterns related to eliciting, including, or excluding their patients' stories of painful and adverse life experiences. We wanted to explore GPs' perceptions of the medical relevance of stories of painful and adverse life experiences, and to focus on what hinders or facilitates working with such stories. Eighteen Norwegian GPs participated in three focus group interviews. The interviews were analysed using reflexive thematic analysis. The participating GPs' views on the clinical relevance of patients' painful and adverse experiences varied considerably. Our analysis revealed two distinct stances: a confident-accepting stance, and an ambivalent-conditional stance. GPs encountered barriers to exploring such stories: scepticism on behalf of the medical discipline; scepticism on behalf of the patients; and, uncertainty regarding how to address stories of painful and adverse experiences in consultations. Work with painful stories was best facilitated when GPs manifested personal openness and prepared availability, within the context of a doctor-patient relationship based on trust. Clearer processes for handling biographical information and life experiences that affect patients' health are needed to facilitate the work of primary care physicians.


Experimental evaluation of mimosa tenuiflora (willd.) poir. (Tepescohuite) I. Screening of the antimicrobial properties of bark extracts.
Mimosa tenuiflora (Willd.) Poir, is a tree from the south areas of Mexico. This bark is popularly used as remedy to treat different skin lesions. The present study demonstrates the in vitro antimicrobial properties of the water and ethanolic extracts prepared with the dried and powdered bark of this plant. A clear inhibition growth effect was observed in all the gram positive and gram negative organisms, yeasts and dermatophytes used.