Differences in relative growth rate in 11 grasses correlate with differences in chemical composition as determined by pyrolysis mass spectrometry.
Eleven grass species varying in potential relative growth rate (RGR) were investigated for differences in chemical composition by pyrolysis mass spectrometry. The spectral data revealed correlations between RGR and the relative composition of several biopolymers. Species with a low potential RGR contained relatively more cell wall material such as lignin, hemicellulose, cellulose, polysaccharide-bound ferulic acid and hydroxyproline-rich protein, whereas species with a high potential RGR showed relatively more cytoplasmic elements such as protein (other than those incorporated in cell walls) and sterols.


Role of autophagy in diabetes and endoplasmic reticulum stress of pancreatic β-cells.
Type 2 diabetes mellitus is characterized by insulin resistance and failure of pancreatic β-cells producing insulin. Autophagy plays a crucial role in cellular homeostasis through degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER). Here we discussed the role of β-cell autophagy in development of diabetes, based on our own studies using mice with β-cell-specific deletion of Atg7 (autophagy-related 7 ), an important autophagy gene, and studies by others. β-cell-specific Atg7-null mice showed reduction in β-cell mass and pancreatic insulin content. Insulin secretory function ex vivo was also impaired, which might be related to organelle dysfunction associated with autophagy deficiency. As a result, β-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia. However, diabetes never developed in those mice. Obesity and/or lipid are physiological ER stresses that can precipitate β-cell dysfunction. Our recent studies showed that β-cellspecific Atg7-null mice, when bred with ob/ob mice, indeed become diabetic. Thus, autophagy deficiency in β-cells could be a precipitating factor in the progression from obesity to diabetes due to inappropriate response to obesity-induced ER stress.


Feto-pelvic disproportion of mimicking placental abruption.
An unbooked patient presented with severe eclampsia and sudden onset of abdominal pain, uterine tenderness and fresh vaginal bleeding. Unsuspected macrosomia and multiple congenital fetal malformation were discovered at delivery and a neonate weighing 7.545 kg was delivered. The infant died shortly afterwards.


NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia.
Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.


Trends in Delirium and New Antipsychotic and Benzodiazepine Use Among Hospitalized Older Adults Before and After the Onset of the COVID-19 Pandemic.
The COVID-19 pandemic caused large disruptions to health care for hospitalized older adults. The incidence and management of delirium may have been affected by high rates of COVID-19 infection, staffing shortages, overwhelmed hospital capacity, and changes to visitor policies. To measure changes in rates of delirium and related medication prescribing during the COVID-19 pandemic among hospitalized older adults. This population-based, repeated cross-sectional study used linked databases to measure rates of delirium and related medication prescriptions among adults aged 66 years or older hospitalized before and during the COVID-19 pandemic (January 1, 2017, to March 31, 2022) in Ontario, Canada. The first 2 years of the COVID-19 pandemic (March 1, 2020, to March 31, 2022). The main outcomes were weekly rates of delirium per 1000 admitted population and monthly rates of new antipsychotic and benzodiazepine prescriptions per 1000 discharged population. Observed rates were compared with projected rates based on modeling from 3 years before pandemic onset. Among 2 128 411 hospitalizations of older adults over the 5-year study period (50.7% female; mean [SD] age, 78.9 [8.3] years), absolute rates of delirium increased from 35.9 per 1000 admitted population during the prepandemic period to 41.5 per 1000 admitted population throughout the pandemic. The adjusted rate ratio (ARR) of delirium during the pandemic compared with the projected rate was 1.15 (95% CI, 1.11-1.19). Monthly rates of new antipsychotic prescriptions increased from 6.9 to 8.8 per 1000 discharged population and new benzodiazepine prescriptions from 4.4 to 6.0 per 1000 discharged population and were significantly higher during the pandemic compared with projected rates (antipsychotics: ARR, 1.28; 95% CI, 1.19-1.38; benzodiazepines: ARR, 1.37; 95% CI, 1.20-1.57). Rates were highest during pandemic waves 1 (March to June 2020), 3 (March to June 2021), and 5 (December 2021 to February 2022) and remained elevated above projected levels throughout the first 2 years of the pandemic. In this repeated cross-sectional study of hospitalized older adults, there was a temporal association between COVID-19 pandemic onset and significant increases in rates of delirium in the hospital and new antipsychotic and benzodiazepine prescriptions after hospital discharge. Rates remained elevated over 2 years. Pandemic-related changes such as visitor restrictions, staff shortages, isolation practices, and reduced staff time at the bedside may have contributed to these trends.


Er:YAG laser ablation of tissue: measurement of ablation rates.
The ablation of both soft and hard tissue using the normal-spiking-mode Er:YAG laser has been quantified by measuring the number of pulses needed to perforate a measured thickness of tissue. Bone is readily ablated by 2.94 microns radiation; however, at per pulse fluences greater than 20 J/cm2, plasma formation decreases ablation efficiency. At low fluence, desiccation can prevent efficient ablation of bone. The ablation efficiency for aorta and skin is higher than for bone. The ablation efficiency, 540 micrograms/J, and the ablation depth per pulse, greater than 400 microns, for skin are too high to be readily explained by simple models of ablation and thus provide evidence for a more complex explosive removal process.


Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation.
Extracellular vesicles can cross the blood-brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system.


The prognosis of bodily distress syndrome: a cohort study in primary care.
Bodily distress syndrome (BDS) is a newly proposed diagnosis for functional disorders. The diagnosis is based on empirical research, but little is known about the course of the disease. We aimed to study the prognosis in terms of diagnosis stability over time. A longitudinal study of 1356 primary care patients with 2-year follow-up was conducted in the Central Denmark Region. Data were obtained from family physician registration forms, patient questionnaires (including a BDS checklist) and nationwide registries. Complete data were available for 1001 patients (73.8%). Overall, 146 persons [14.6%, 95% confidence interval (CI): 12.5-16.9] fulfilled the criteria for BDS at baseline and 142 persons (14.2%, CI: 12.1-16.5) at follow-up. Among study participants with BDS at baseline, 56.8% (CI: 48.4-65.0) also had BDS at follow-up. Multiorgan BDS tended to be more persistent (81.8%, CI: 48.2-97.7) than single-organ BDS (54.8%, CI: 46.0-63.4). Patients with BDS had fewer socioeconomic resources, experienced more emotional distress, and used more opioids and medical services. BDS is a common clinical condition being prone to chronicity; one in seven primary care patients met the criteria for BDS, and more than half of these patients still suffered from BDS 2 years later.


Vapor generation - atomic spectrometric techniques. Expanding frontiers through specific-species preconcentration. A review.
We review recent progress in preconcentration strategies associated to vapor generation techniques coupled to atomic spectrometric (VGT-AS) for specific chemical species detection. This discussion focuses on the central role of different preconcentration approaches, both before and after VG process. The former was based on the classical solid phase and liquid-liquid extraction procedures which, aided by automation and miniaturization strategies, have strengthened the role of VGT-AS in several research fields including environmental, clinical, and others. We then examine some of the new vapor trapping strategies (atom-trapping, hydride trapping, cryotrapping) that entail improvements in selectivity through interference elimination, but also they allow reaching ultra-low detection limits for a large number of chemical species generated in conventional VG systems, including complete separation of several species of the same element. This review covers more than 100 bibliographic references from 2009 up to date, found in SCOPUS database and in individual searches in specific journals. We finally conclude by giving some outlook on future directions of this field.


Retrospective analysis of exploratory laparotomies in 192 Andalusian horses and 276 horses of other breeds.
The medical records of 468 horses that underwent 490 exploratory laparotomies for the correction of gastrointestinal diseases were reviewed to search for differences between Andalusian horses and other breeds. The seasonal distribution of surgical colics and their outcome and complications were also investigated. Bivariant analysis was used to compare the horses' age, gender and breed with the type of surgery, the bowel affected and the type of colic, and all these variables were compared in relation to euthanasia during surgery, complications, short-term survival and seasonal distribution. A total of 405 horses survived the surgery and 329 were discharged from the hospital. Horses less than one year old had better short-term survival than older horses. Andalusian horses suffered more inguinal hernias than the other breeds and were more prone to suffer laminitis as a complication. Colic surgery and inguinal hernias were also more common in the summer.


Differences in the constitutive and SIV infection induced expression of Siglecs by hematopoietic cells from non-human primates.
The expression of the Siglec family of molecules by hematopoietic cells from uninfected and SIV infected disease susceptible rhesus macaques (RM) and SIV infected disease resistant sooty mangabeys (SM) and for comparison humans was carried out. The predominant cell lineage in all three species expressing Siglec's was monocytes. The major finding by both a cross sectional and a prospective SIV infection study showed that, whereas monocytes from RM show marked increase in each Siglec constitutively expressed, monocytes from SM showed marked decreases in Siglec-1 expression. While monocytes from all three species constitutively expressed Siglec-3, human monocytes in addition expressed Siglec-5 and -9 and to a lower density 7, monocytes from RM expressed Siglec-7 and those from SM expressed Siglec-1. Monocytes from all three species, however, expressed mRNA for Siglec-1, -5, -7 and -9. The reasons for the failure to detect these molecules at the protein level and the mechanisms for such distinct effects of SIV infection on Siglec expression are discussed.


Present status of vaccination against HIV-1 infection.
The development of an effective vaccine against the acquired immunodeficiency syndrome (AIDS) is a formidable task. The absence of any documented case of natural recovery from the disease raises the question of whether any vaccine against human immunodeficiency virus (HIV) could possibly be effective in preventing natural transmission of the virus. It also raises the issue of which type of immune response a vaccine should elicit to be protective. Many obstacles have to be overcome, including the considerable antigenic variability of the virus, its intracellular mode of transmission, its mucosal port of entry, and the persistent nature of the infection. The only animal model available for the development of prototype HIV-1 vaccines is the chimpanzee model. Chimpanzees infected with HIV-1 do not develop AIDS but remain persistently infected. This model, therefore, allows one to test for protection from infection, but not for protection from disease.


Seasonal patterns of CO2 and water vapor exchange of three salt marsh succulents.
Diurnal carbon dioxide exchange patterns of three salt marsh succulents, Borrichia frutescens, Batis maritima and Salicornia virginica, were determined on a seasonal basis in the marsh at Sapelo Island, Georgia. Year-round photosynthetic activity was observed in these species though winter rates of CO2 exchange were reduced. Net primary productivity, estimated using gas exchange techniques, agreed with previously reported harvest data. The role of light and temperature in the control of seasonal photosynthetic changes was investigated. A similar variation in light utilization with season was found in all three species, while seasonal temperature acclimation was species dependent. Less than 20% of fixed CO2 was lost through dark respiration in any of the species.Water use in the salt marsh succulents was found to be relatively inefficient. High rates of transpiration were observed both summer and winter in the succulents.The succulents were judged to be C3 plants on the basis of several criteria.


Dynamics of AQP4 upon exposure to seropositive patient serum before and after Rituximab therapy in Neuromyelitis Optica: A cell-based study.
Neuromyelitis Optica (NMO) is an autoimmune inflammatory disease that affects the optic nerves and spinal cord. The autoantibody is generated against the abundant water channel protein of the brain, Aquaporin 4 (AQP4). Of the two isoforms of AQP4, the shorter one (M23) often exists as a supramolecular assembly known as an orthogonal array of particles (OAPs). There have been debates about the fate of these AQP4 clusters upon binding to the antibody, the exact mechanism of its turnover, and the proteins associated with the process. Recently several clinical cases of NMO were reported delineating the effect of Rituximab (RTX) therapy. Extending these reports at the cell signaling level, we developed a glioma based cellular model that mimicked antibody binding and helped us track the subsequent events including a variation of AQP4 levels, alterations in cellular morphology, and the changes in downstream signaling cascades. Our results revealed the extent of perturbations in the signaling pathways related to stress involving ERK, JNK, and AKT1 together with markers for cell death. We could also decipher the possible routes of degradation of AQP4, post-exposure to antibody. We further investigated the effect of autoantibody on AQP4 transcriptional level and involvement of FOXO3a and miRNA-145 in the regulation of transcription. This study highlights the differential outcome at the cellular level when treated with the serum of the same patient pre and post RTX therapy and for the first time mechanistically describes the effect of RTX.


Anesthesia for mandibular yolk sac tumor in children after radiotherapy and chemotherapy: A case report.
Yolk sac tumor (YST), also known as endodermal sinus tumor, is a malignant germ cell tumor that usually affects children aged >3 years. It is commonly observed in the gonadal sites (testis or ovary) but is extremely rare in the mandibular regions. This study describes the anesthesia process for spontaneous ventilation bronchoscope intubation in the rare case of a 7-year-old child with extragonadal primary YST of the face, refractory to radiotherapy, and chemotherapy.


Method for determination of sodium, potassium, calcium, magnesium, chloride, and phosphate in the rat choroid plexus by flame atomic absorption and visible spectroscopy.
A rapid simple technique for the measurement of Na+, K+, Mg2+, Ca2+, PO4(3-), and Cl- was developed to analyze ion contents in the choroid plexus of the rat. The technique involves digestion in piperidine, precipitation of proteins with HClO4, and analysis of Na+, K+, Ca2+, and Mg2+ by atomic absorption spectroscopy and Cl- and PO4(3-) by visible spectroscopy. The coefficient of variation for the measurement of eight replicates was 1-3% for all ions. Analysis of choroid plexuses from eight rats yielded coefficients of variation of about 6% and the values for Na+, K+, and Cl- compared favorably to previous works. The analytical procedure described in this paper allows the determination of six major physiologic ions in rat choroid plexus (4 mg wet wt).


Suppression of invasion by inducible expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in B16-F10 melanoma cells.
We have previously shown that down-modulation (i.e., by antisense expression vector) of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a noninvasive, nontumorigenic cell line led to an acquisition of an invasive, tumorigenic, and metastatic ability in these cells. Our purpose was to examine whether increased levels of murine TIMP-1 can directly suppress the invasive ability of malignant cells. Murine B16-F10 melanoma cells were transfected with an expression vector to overproduce TIMP-1. Among these transfectants, we isolated five clonal cell lines (2-5, 2-8, 2-10, 6-5, and 6-9) that showed upregulation (i.e., overexpression) of TIMP-1. These cell lines had an increased basal level of TIMP-1 messenger RNA. TIMP-1 expression was under the control of the mouse metallothionein-I promoter, and four of these five clones (2-5, 2-8, 6-5, and 6-9) showed a threefold to 10-fold induction of TIMP-1 message when they were treated with 20 microM cadmium for 4 hours. An increase in TIMP-1 message led to an increase in TIMP-1 protein activity measured in the conditioned medium of clones 2-10 and 6-5. The invasive ability of the TIMP-1-upregulated cells was tested in a matrigel transwell invasion assay. All of the upregulated clones showed a significant reduction in their invasive ability, relative to the invasive ability of parental B16-F10 and the control 1-2 cell line; this reduction correlated with the level of TIMP-1 overexpression. Cadmium induction of TIMP-1 messenger RNA resulted in a further suppression of the invasive ability of the two inducible cell lines tested (i.e., 2-8 and 6-5). Our data demonstrate that a specific upregulation of murine TIMP-1 expression in B16-F10 melanoma cells directly suppresses their invasive ability.


Modified thyroplasty for unilateral vocal fold paralysis using an adjustable titanium implant.
This study aimed to describe a new titanium thyroplasty implant that can be adjusted with a screw. Six Beagle dogs were randomly divided into experimental and control groups (n = 3). The titanium screw was implanted in the experimental group after the left recurrent laryngeal nerve was cut off under general anaesthesia. This procedure caused arytenoid cartilage internal shift, allowing the vocal cord to locate at the median and the glottis to close during phonation. No other operation was conducted in the control group. Each group, respectively, underwent video laryngoscopy, CT scan and histopathology before and after operation. After 4 months of follow-up, the video laryngoscopy results showed that the left arytenoid cartilage in the experimental group underwent internal adduct and shift, whereas the left vocal cords in the control group located at the paramedian position and exhibited fissure during phonation. CT scan results showed that the adjustable titanium screw was in proper position. Postoperative pathological examination showed that, in addition to early local inflammation, the laryngeal muscle may atrophy. The adjustable titanium screw requires a simple operation and can be significantly adjusted. The effect of the operation can be immediately observed without rejection. Therefore, this method is an efficient treatment for unilateral vocal cord paralysis.


Standardization of 32P/33P and 204Tl by liquid scintillation counting.
Two solutions, one of 32P with a significant contribution of 33P, and another one of 204Tl were standardized by liquid scintillation counting in the frame of two intercomparison exercises organized by the BIPM in 2002. For the 32P solution, the counting efficiencies for 32P and 33P were obtained by the CIEMAT/NIST method. The individual contributions of 32P and 33P were determined by fitting a set of measurements to a function of the half-lives and counting efficiencies of both component nuclides. 204Tl was also standardized by the CIEMAT/NIST method using two counters, three scintillators, HiSafe 3, Insta-Gel Plus and Ultima-Gold, and two different kinds of samples. A total of 480 samples were measured over 45 days with results in full agreement within the uncertainties considered. The efficiency values are also compared to those used in the previous 204Tl intercomparison (1997).


Ethane: a marker of lipid peroxidation during cardiopulmonary bypass in humans.
The goals of this study were to (1) determine the utility of quantification of ethane as a marker of ischemia-reperfusion during human cardiopulmonary bypass (CPB); and (2) determine, using an animal model for this surgical procedure, whether the mode of surgical approach produced increases the quantity of exhaled ethane. Human CPB was initiated following standard anesthetic and monitoring regimens. Samples of gas were collected at baseline and at multiple defined time points throughout the studies. Ethane was determined using cryogenic concentration and gas chromatography. Sternotomy increased exhaled ethane compared to baseline (p < .007; 5.8 +/- 1.7 vs. 3.0 +/- 0.7 nmol/m2 x min); ethane returned to baseline levels prior to the initiation of CPB. Aortic unclamping produced ethane elevation (p < .05; 2.3 +/- 0.8 vs. 1.5 +/- 0.4 nmol/m2 x min) with the levels being related to a lower cardiac index and a higher systemic vascular resistance post aortic unclamping. Termination of CPB significantly increased ethane levels compared to baseline (p < .002; 4.8 +/- 1.7 vs. 3.0 +/- 0.7 nmol/m2 x min). Independent variables that correlated with increased ethane measurements included a higher arterial blood pH on bypass and the change in hemoglobin pre- and post-CPB. Electrocautery, but not scalpel, incision of the porcine abdominal wall increased ethane levels significantly (p < .02). These results indicate that exhaled ethane may be a valuable marker of lipid peroxidation during and following CPB.


Raccoon epithelium--a new allergen source.
We report the case of a 39-year-old asthmatic patient who developed acute rhinoconjunctivitis, Quincke's edema, and asthma after repeated exposure to a raccoon (Procyon lotor) which a friend kept at home. Skin prick and scratch tests with native raccoon hair and epithelium, as well as RAST, were clearly positive. Elimination of contact with the raccoon and avoiding the home of his friend led to a cessation of the patient's acute exacerbations.


Genome-Wide Mapping of DNA Methylation 5mC by Methylated DNA Immunoprecipitation (MeDIP)-Sequencing.
Methylated DNA immunoprecipitation is a large scale purification technique. It enables the isolation of methylated DNA fragments for subsequent locus-specific or genome-wide analysis. Here we describe an immunoprecipitation protocol using a monoclonal mouse anti 5-methyl-cytidine antibody followed by next-generation sequencing (MeDIP-Seq).


Bleeding and thrombosis in acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) has evolved from being a deadly to a highly curable disease, due to targeted molecular therapy with all-trans retinoic acid (ATRA). As a result, the incidence of early hemorrhagic deaths for which APL is notorious has reduced to 5-10% as reported in clinical trials. These results are not replicated outside of clinical trials as is evident from recent population-based registries. High incidence of early hemorrhagic deaths remains the greatest contributor to treatment failure in this otherwise curable leukemia. Additionally, thrombosis is now being increasingly recognized in APL patients and may be associated with ATRA usage.


Retention of bioprosthetic valve annulus in mitral prosthetic replacement.
Mitral valve prosthetic replacement carries high mortality rates by modern standards, and mitral bioprostheses are particularly prone to degeneration. Bioprosthetic replacement may be technically difficult when there is calcification of the tissue ingrowth, strut incorporation, or valve-to-annulus size mismatch at the primary operation. A "valve-in-valve" technique is described where the mechanical prosthesis is implanted in the bioprosthetic annulus in order to avoid such difficulties. The results in the first eight patients are presented, showing post-operative Doppler-derived transvalvar mean gradients between 3.9 mmHg and 7.5 mmHg, and estimated valve areas between 1.9 cm2 and 3.5 cm2. All patients are alive at between 20 and 30 months (mean 23.6 months) after operation, they are without serious post-operative morbidity and are in functional class I or II (NYHA classification).


Rheumatoid arthritis macrophages are primed for inflammation and display bioenergetic and functional alterations.
Myeloid cells with a monocyte/macrophage phenotype are present in large numbers in the RA joint, significantly contributing to disease; however, distinct macrophage functions have yet to be elucidated. This study investigates the metabolic activity of infiltrating polarized macrophages and their impact on pro-inflammatory responses in RA. CD14+ monocytes from RA and healthy control (HC) bloods were isolated and examined ex vivo or following differentiation into 'M1/M2' macrophages. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT-PCR, western blot, Seahorse XFe technology, phagocytosis assays and transmission electron microscopy along with RNA-sequencing (RNA-seq) transcriptomic analysis. Circulating RA monocytes are hyper-inflammatory upon stimulation, with significantly higher expression of key cytokines compared with HC (P < 0.05) a phenotype which is maintained upon differentiation into mature ex vivo polarized macrophages. This induction in pro-inflammatory mechanisms is paralleled by cellular bioenergetic changes. RA macrophages are highly metabolic, with a robust boost in both oxidative phosphorylation and glycolysis in RA along with altered mitochondrial morphology compared with HC. RNA-seq analysis revealed divergent transcriptional variance between pro- and anti-inflammatory RA macrophages, revealing a role for STAT3 and NAMPT in driving macrophage activation states. STAT3 and NAMPT inhibition results in significant decrease in pro-inflammatory gene expression observed in RA macrophages. Interestingly, NAMPT inhibition specifically restores macrophage phagocytic function and results in reciprocal STAT3 inhibition, linking these two signalling pathways. This study demonstrates a unique inflammatory and metabolic phenotype of RA monocyte-derived macrophages and identifies a key role for NAMPT and STAT3 signalling in regulating this phenotype.


A randomized double-blind trial of iseganan in prevention of ventilator-associated pneumonia.
Iseganan, an antimicrobial peptide, is active against aerobic and anaerobic gram-positive and gram-negative bacteria as well as fungi and yeasts. The drug has shown little resistance in vitro and to be safe and well tolerated in 800 patients with cancer treated for up to 6 wk. To determine the efficacy of iseganan for the prevention of ventilator-associated pneumonia (VAP). Mechanically ventilated patients in the United States and Europe were randomized to oral topical iseganan or placebo (1:1) and treated six times per day while intubated for up to 14 d. Patients were eligible if randomized within 24 h of intubation and estimated to survive and remain mechanically ventilated for 48 h or more. The primary efficacy endpoint of the study was VAP measured among survivors at Day 14. A total of 709 patients were randomized and received at least one dose of study drug. The two groups were comparable at baseline except iseganan-treated patients were, on average, 3 yr older. The rate of VAP among survivors at Day 14 was 16% (45/282) in patients treated with iseganan and 20% (57/284) in those treated with placebo (p = 0.145). Mortality at Day 14 was 22.1% (80/362) in the iseganan group compared with 18.2% (63/347) in the placebo group (p = 0.206). No pattern of excess adverse events in the iseganan group compared with placebo was observed. Iseganan is not effective in improving outcome in patients on prolonged mechanical ventilation.


Cellular distribution of prostanoid EP receptors mRNA in the rat gastrointestinal tract.
The inhibition of PGE(2) synthesis resulting from sustained NSAIDs therapy has been linked to gastrointestinal irritations and ulceration. The multiple physiological effects of PGE(2) in the gut are mediated through the activation of four receptors termed EP(1-4). The aim of the study was to determine the precise distribution of the four prostaglandin E(2) receptors in the rat stomach, small intestine, and colon. We used non-radioactive in situ hybridization techniques on paraffin-embedded tissue. Mucous cells of the stomach and goblet cells of the small intestine and colon were found to express mRNA for all four EP subtypes. A positive hybridization signal for EP(1), EP(3), and EP(4) was detected in the parietal cells of the stomach whereas the chief cells expressed low levels of EP(1) and EP(3). The EP(1) and EP(3) receptor mRNA could also be detected in the muscularis mucosa, longitudinal muscle and enteric ganglias of the stomach and small intestine. However, close examination of the enteric ganglias indicated that most of the positive labeling was localized to the glial cells, although some neurons did express EP(3). In conclusion, we have detailed the distribution of prostanoid EP receptors in the gut at the cellular level, giving new insights to the role of prostaglandins in gastrointestinal functions.


Mammary Paget Disease With Melanocytic Proliferation Mimicking Malignant Melanoma in situ: A Case Report.
Several cases of pigmented mammary Paget's disease (PMPD) mimicking cutaneous malignant melanoma have been reported. In these cases, the tumor cells are colonized by melanocytes, particularly with the presence of a population of melanocytes staining for HMB-45 and S100. Here, we report a case of mammary Paget disease (MPD) which was misdiagnosed as melanoma in situ due to the interpretation of the staining of melanocytic markers S-100, Melan-A, and HMB-45. The tumor cells strongly expressed CK7 and GATA3, and a dual-labeling showed negative PHH3 labeling for the melanocytes. Pathologists need to be aware of the caveat of colonization of melanocytes in Paget disease.


Combined B- and A-scan ultrasonography in the management and preoperative assessment of vitreo retinal pathology.
Newer surgical techniques such as vitrectomy instrumentation and microsurgery now allow us to take a full advantage of ultrasonic evaluation of vitreal-retinal pathology. The ultrasonic techniques of A- and B-scan as well as M-scan allow us to more adequately evaluate the opaque vitreous, retinal detachment, traumatic changes to the globe, thus directing the newer surgical techniques to achieve therapeutic results never previously possible.


Children with psychiatric disorders: the A1 Ain Community Psychiatric Survey.
The prevalence of child psychiatric morbidity in the community is unknown in most developing countries, including those in the Arab region. An epidemiologic study was carried out to estimate the prevalence of psychiatric morbidity and to determine the sociodemographic correlates in a sample of children in the community, aged 6 to 18 years, in A1 Ain, United Arab Emirates (UAE). We obtained a prevalence rate of 22.2% for overall morbidity, as classified in the DSM-1V, and 14.3% for those with significant dysfunction, with the most common diagnosis being mood disorders. Female sex, large family size, chronic life difficulties, family history of psychiatric disorder, and alcohol-related problems in a family member were significantly associated with DSM-IV diagnosis. Although the prevalence and symptomatology in this Middle East community are similar to those in Western studies, none of these children had received professional help, suggesting serious deficiencies in mental health care services in the country.


AMPK α1 mediates the protective effect of adiponectin against insulin resistance in INS-1 pancreatic β cells.
The fat-derived protein adiponectin is known to reverse the effects of insulin resistance and to lower blood glucose levels. The AMP-activated protein kinase (AMPK) signalling pathway plays a central role in metabolism and energy homeostasis. Here, to investigate the role of AMPK in the protective effect of adiponectin against insulin resistance, we established the model of high-glucose (HG)- and high-lipid (HL)-induced insulin resistance in INS-1 pancreatic β cells. We found that 25mM of glucose and 0.4mM of palmitic acid treatment significantly increased cell apoptosis and impaired insulin secretion in INS-1 cells. However, recombinant human adiponectin dramatically reduced HG- and/or HL-induced cell apoptosis and greatly improved insulin secretion. Interestingly, adiponectin treatment also activated AMPK signalling pathway by increasing the phosphorylation of Thr172 in the AMPK α subunit; 10μM of compound C, a potent AMPK inhibitor, blocked the protective effects of adiponectin against HG/HL-induced insulin resistance. Furthermore, knockout experiments by CRISPR/Cas9 technology showed that AMPK α1, but not AMPK α2, is involved in the protective effects of adiponectin. Taken together, adiponectin reversed the effects of insulin resistance via AMPK α1, which provides a novel insight into the protective mechanism of adiponectin and may be used as a new strategy for the treatment of type 2 diabetes. SIGNIFICANCE OF THE STUDY: Adiponectin can reverse the effects of insulin resistance and lower blood glucose levels. Here, adiponectin reduced HG/HL-induced cell apoptosis and greatly improved insulin secretion. These effects were blocked by AMPK inhibitor, compound C. Specifically, we found that AMPK α1, but not AMPK α2, mediates the protective effects of adiponectin, which provides a novel insight into the protective mechanism of adiponectin against insulin resistance.


Unusual renal pseudotumor (cloison) in a young woman with chronic rejection of a transplanted kidney.
Localized nontumorous conditions may simulate renal neoplasms. A case is described in which a cloison was observed in conjunction with chronic rejection of a renal transplant.


Oxytocin in the rat caudate nucleus influences pain modulation.
Our previous studies have demonstrated that oxytocin (OXT) in the central nervous system plays a role in pain modulation. Many studies have found that caudate nucleus (CdN) enriches OXT and OXT receptors by the methods of historadioautograph and gene expression. The communication was designed to investigate OXT effect in the rat CdN on pain modulation. The results showed that (1) intra-CdN microinjection of OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold, whereas the local administration of OXT increased the pain threshold in a dose-dependent manner; (2) OXT receptor antagonist can attenuate the analgesic role induced intra-CdN administration of OXT; and (3) pain stimulation could increase OXT concentration in the CdN perfusion liquid. The data suggested that OXT in the CdN was involved in this pain process via OXT receptors.


Ultrasound as a new tool in the assessment of airway difficulties: An observational study.
Prediction of difficult mask ventilation (DMV) is as challenging as difficult laryngoscopy. Ultrasound could be a helpful tool in the prediction of these difficulties. The purpose of this study was to evaluate the ability of pre-operative ultrasound assessment of neck anatomy in predicting DMV and difficult laryngoscopy in patients undergoing during elective surgery requiring tracheal intubation. Prospective, single blind, observational study. Operating theatre of a teaching hospital in Italy from April 2018 to July 2018. A total of 194 patients aged more than 18 years, without neck masses, previous thyroid surgery or tracheotomy undergoing general anaesthesia and tracheal intubation for elective ear, nose and throat-surgery were included in the study. Ultrasound distances were recorded with a linear 6 to 13 MHz ultrasound transducer: measurements included the minimum distance from the thyroid isthmus to skin surface, the minimum distance from the hyoid bone to skin surface (DSHB), the minimum distance from skin to anterior commissure of the vocal cords, the minimum distance from skin to trachea at the level of the jugular notch and the distance from skin to epiglottis midway. The degree of DMV and difficult laryngoscopy was quantified. The mean (SD) of DSHB was 0.88 (0.3) cm in the easy mask ventilation group, 1.4 (0.19) cm in DMV group. The mean of DSHB and of the other ultrasound distances increased according to the DMV and difficult laryngoscopy level. The DSHB was correlated with an increase in the risk for DMV (0.61 [IQR 0.5 to 0.69]). DMV groups were associated with a greater ultrasound-measured DSHB. The prospective observational study confirms the relationship between ultrasound assessment of the anterior soft tissues of the neck and difficult laryngoscopy and DMV. DSHB and the other distances extend the available evidence, not only for difficult laryngoscopy but also for DMV. Clinicaltrials.gov. identified NCT03592758.


Increasing the efficiency of traveling wave ultrasonic motor by modifying the stator geometry.
Current traveling wave ultrasonic motor (TWUSM) utilizes comb-teeth structure as deflection amplifier. The position of the stator neutral axis to the stator contact surface is one of the factors that influences the deflection amplifier. Stator deflection directly effects on motor performance. In this study, the modification of the comb-teeth stator design is proposed to see its effect on motor efficiency. The modification is done so that the neutral axis position is further distance from the stator top contact surface. The proposed solution is to remove a selected mass element from the comb-teeth structure. Modeling, simulation and experimental work of the proposed concept is carried out utilizing Shinsei USR60 as the chosen TWUSM. The modeling and analyses are conducted through multi-physic finite element simulation MSC Marc Mentat. The results of the analyses and experimental work reveal that the modified comb-teeth stator increases the position of the neutral axis from the stator top surface. Due to the neutral axis shifting, the results also confirm that the proposed modified motor has higher efficiency compared to the non-modified motor.


A community survey of the potential use of thrombolytic agents for acute myocardial infarction.
We surveyed all patients admitted to nine community hospital coronary care units to determine what proportion could be candidates for thrombolytic therapy. During the 12-month study period, there were 4,115 admissions for possible acute myocardial infarction, and 1,076 (26%) had a discharge diagnosis of myocardial infarction. Patients with myocardial infarction had the following characteristics: 60% had ST elevation seen on the first ECG, 17% had ST depression without ST elevation, 75% were less than 75 years old, 75% had no contraindications to thrombolytic therapy, 78% arrived at hospital within six hours of onset of symptoms, and 94% arrived within 24 hours of symptoms. Criteria for administration of thrombolytic therapy can be grouped as restrictive (arrival within six hours of symptoms and ST elevation) or liberal (arrival within 24 hours of symptoms and ST elevation or ST depression). Applying these characteristics, 26% met restrictive criteria for treatment with thrombolytic therapy, and 36% met liberal criteria. Until liberal criteria (therapy up to 24 hours and ST depression) are convincingly shown to be of benefit, we believe clinicians should apply restrictive criteria to potential candidates for thrombolytic therapy.


Object formation in visual working memory: Evidence from object-based attention.
We report on how visual working memory (VWM) forms intact perceptual representations of visual objects using sub-object elements. Specifically, when objects were divided into fragments and sequentially encoded into VWM, the fragments were involuntarily integrated into objects in VWM, as evidenced by the occurrence of both positive and negative object-based attention effects: In Experiment 1, when subjects' attention was cued to a location occupied by the VWM object, the target presented at the location of that object was perceived as occurring earlier than that presented at the location of a different object. In Experiment 2, responses to a target were significantly slower when a distractor was presented at the same location as the cued object (Experiment 2). These results suggest that object fragments can be integrated into objects within VWM in a manner similar to that of visual perception.


A simple approach to the determination of the crystallographic orientation: applications and accuracy.
A simple analytical solution for the crystallographic orientation is described. This method is based on one indexed Kikuchi pair in a known zone rather than the corresponding diffraction spots. The accuracy of this method is shown to be better than 0.1 degrees even for cases in which a zone axis deviates by a large angle (e.g. 10 degrees ) from the centre of the beam direction. This approach simplifies experiments because only one pair of Kikuchi lines and a zone axis are needed, and is especially suited when it is difficult or cumbersome to resolve a second pair of Kikuchi lines with sufficient accuracy.


Ecotoxicity Evaluation of Industrial Waste and Construction Materials: Comparison Between Leachates from Granular Steel Slags and Steel Slags-Containing Concrete Through a Plant-Based Approach.
Steel slags, the main waste product from the steel industry, may have several reuse possibilities. Among others, building applications represent a crucial field. However, the potential impact of harmful substances on the environment should be assessed. The aim of this study was to assess the phytotoxicity of steel slags (SS) and concrete mixtures cast with a partial replacement of SS (CSS). Leaching tests were carried out on four SS and four CSS according to EN 12457-2 and UNI EN 15863, respectively. Each leachate was assayed using root elongation tests on 30 seeds of Allium cepa, Cucumis sativus, and Lepidium sativum, respectively, and on 12 bulbs of A. cepa. The latter also allowed the analysis of other macroscopic parameters of toxicity (turgidity, consistency, colour change and root tip shape) and the evaluation of the mitotic index on 20,000 root tip cells per sample. None of the samples induced phytotoxic effects on the organisms tested: all samples supported seedlings emergence, verified by root elongation comparable to, or even greater than, that of the negative controls, and did not affect cell division, as evidenced by mitotic index values. The absence of phytotoxicity demonstrated by the leachates allows SS and SS-derived concrete to be considered as reliable materials suitable for use in civil constructions or in other engineering applications, with economic and environmental advantages, such as the reduction of the final disposal in landfills as well as the consumption of natural resources.


Alternative routes for 64Cu production using an 18 MeV medical cyclotron in view of theranostic applications.
Radiometals play a fundamental role in the development of personalized nuclear medicine. In particular, copper radioisotopes are attracting increasing interest since they offer a varying range of decay modes and half-lives and can be used for imaging (60Cu, 61Cu, 62Cu and 64Cu) and targeted radionuclide therapy (64Cu and 67Cu), providing two of the most promising true theranostic pairs, namely 61Cu/67Cu and 64Cu/67Cu. Currently, the most widely used in clinical applications is 64Cu, which has a unique decay scheme featuring β+-, β--decay and electron capture. These characteristics allow its exploitation in both diagnostic and therapeutic fields. However, although 64Cu has extensively been investigated in academic research and preclinical settings, it is still scarcely used in routine clinical practice due to its insufficient availability at an affordable price. In fact, the most commonly used production method involves proton irradiation of enriched 64Ni, which has a very low isotopic abundance and is therefore extremely expensive. In this paper, we report on the study of two alternative production routes, namely the 65Cu(p,pn)64Cu and 67Zn(p, α)64Cu reactions, which enable low and high 64Cu specific activities, respectively. To optimize the 64Cu production, while minimizing the mass of copper used as a target in the first case, or the co-production of other copper radioisotopes in the second case, an accurate knowledge of the production cross sections is of paramount importance. For this reason, the involved nuclear reaction cross sections were measured at the Bern medical cyclotron laboratory by irradiating enriched 65CuO and enriched 67ZnO targets. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. Several production tests were performed to confirm these findings.


The Critical Role of the Antimicrobial Peptide LL-37/ CRAMP in Protection of Colon Microbiota Balance, Mucosal Homeostasis, Anti-Inflammatory Responses, and Resistance to Carcinogenesis.
Mouse cathelin-related antimicrobial peptide (CRAMP) and its homologue human cathelicidin (LL-37) play active roles in innate immune responses, angiogenesis, and wound healing. In addition, LL-37/CRAMP fends off microbes and protects against infections in the colon, where the epithelium is exposed to myriad of enteric pathogens. It is increasingly recognized that LL-37/CRAMP maintains colon mucosal barrier integrity, shapes the composition of microbiota, and protects the host from tumorigenesis. In this review, we discuss the importance of LL-37/CRAMP in the homeostasis of the host, with novel findings derived from mice deficient in CRAMP that support the proposition for this natural antimicrobial peptide and an immune modulator as a drug lead for therapeutic development.


Future therapeutic targets for the treatment and prevention of cholesterol gallstones.
The formation of cholesterol gallstones involves very complex imbalances, such as alterations in the secretion of biliary lipids (which involves the ABCG5, ABCG8, ABCB4 and ABCB11 transporters), biochemical and immunological reactions in the gallbladder that produce biliary sludge (mucins), physicochemical changes in the structure of cholesterol (crystallization), alterations in gallbladder motility, changes in the intestinal absorption of cholesterol (ABCG5/8 transporters and Niemann-Pick C1L1 protein) and alterations in small intestine motility. Some of these proteins have been studied at the clinical and experimental levels, but more research is required. In this review, we discuss the results of studies on some molecules involved in the pathophysiology of gallstones that may be future therapeutic targets to prevent the development of this disease, and possible sites for treatment based mainly on the absorption of intestinal cholesterol (Niemann-Pick C1L1 and ABCG5/8 proteins).


Chinese herbal medicine reduces mortality in patients with severe and critical Coronavirus disease 2019: a retrospective cohort study.
This study aimed to evaluate the efficacy of Chinese herbal medicine (CHM) in patients with severe/critical coronavirus disease 2019 (COVID-19). In this retrospective study, data were collected from 662 patients with severe/critical COVID-19 who were admitted to a designated hospital to treat patients with severe COVID-19 in Wuhan before March 20, 2020. All patients were divided into an exposed group (CHM users) and a control group (non-users). After propensity score matching in a 1:1 ratio, 156 CHM users were matched by propensity score to 156 non-users. No significant differences in seven baseline clinical variables were found between the two groups of patients. All-cause mortality was reported in 13 CHM users who died and 36 non-users who died. After multivariate adjustment, the mortality risk of CHM users was reduced by 82.2% (odds ratio 0.178, 95% CI 0.076-0.418; P < 0.001) compared with the non-users. Secondly, age (odds ratio 1.053, 95% CI 1.023-1.084; P < 0.001) and the proportion of severe/critical patients (odds ratio 0.063, 95% CI 0.028-0.143; P < 0.001) were the risk factors of mortality. These results show that the use of CHM may reduce the mortality of patients with severe/critical COVID-19.


Attitudes toward dating violence among Turkish university students: The relationships with self-esteem level and gender roles.
The current study aimed to determine the relationships between attitudes toward dating violence, self-esteem, and gender roles. Men supported dating violence more than women, and the attitudes toward gender roles and self-esteem level were found to have a significant positive correlation with attitudes toward dating violence. For women, attitudes toward gender roles and levels of self-esteem predicted attitudes toward dating violence. The only significant variable in predicting attitudes toward dating violence in men was their attitude toward gender roles. The prevention activities should begin with identifying the risk factors.


Giant Posterior Communicating Artery Aneurysm Presenting as Trigeminal Neuralgia.
We report an extremely rare case of trigeminal neuralgia (TN) caused by a giant posterior communicating artery aneurysm. We describe the case of a 73-year-old man who suffered disabling TN, which was deeply exacerbated when he laid down. Computed tomography angiography and digital angiography revealed an unruptured giant posterior left communicating artery aneurysm projecting to the posterior fossa and contacting the trigeminal root. The size and projection of the aneurysm seemed responsible for both the neuralgia itself and its peculiar clinical characteristic of exacerbation when the patient laid down. The aneurysm was surgically clipped, then opened and emptied to decompress the trigeminal root. The patient reported an immediate complete remission of the neuralgia. The finding of TN secondary to aneurysms is rare but even more in the case of a posterior communicating aneurysm. The clinical clue that should alert physicians about the presence of an aneurysm as the cause of TN is exacerbation of pain by adopting a supine position. Due to the high risk of rupture associated with giant and symptomatic aneurysms, we believe that treatment should be aggressive in this case, not only to solve the symptomatic TN but also to avoid the risk of aneurysm rupture in the future. The treatment selection between surgical clipping or endovascular coiling with or without stenting, depends on patient's clinical condition and the size and shape of the aneurysm.


A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes.
Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron-sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death. We generated neuron-specific Isca1 knockout rat (Isca1flox/flox -NeuN-Cre) using CRISPR-Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons. This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis. This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.


Clinical Outcomes Following Therapeutic Endoscopic Retrograde Cholangiopancreatography in Children With Pancreas Divisum.
Pancreas divisum (PD) is a risk factor in children for the development of acute pancreatitis. Endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (mPES) may be of clinical benefit, however, the clinical outcomes from endotherapy remain unclear. We sought to review the outcomes and safety of therapeutic ERCP in children with PD. We performed a retrospective chart of children with PD who underwent an ERCP between February 2012 and December 2018. Pertinent patient, clinical and procedure information was collected including procedure-related adverse events. A follow-up questionnaire of the parent was conducted to determine the clinical impact from endotherapy. Fifty-eight ERCPs were performed in 27 patients (14 boys; mean age: 9.7 years, range 2-19) with PD. All patients underwent a successful mPES. A genetic variant was identified in 19/26 (73%) tested patients. Post-ERCP pancreatitis (PEP) was the only observed adverse event; 21% (12/58). Median follow-up interval from first ERCP intervention to questionnaire completion was 31.5 months (range: 4--72 months). Of the 20 questionnaire responders, 13 reported clinical improvement from endotherapy. The majority of children from our PD cohort possessed at least 1 genetic variant. Most questionnaire responders had a favorable response to endotherapy. PEP rate was comparable with that of prior reports in adult patients.


eQED: an efficient method for interpreting eQTL associations using protein networks.
Analysis of expression quantitative trait loci (eQTLs) is an emerging technique in which individuals are genotyped across a panel of genetic markers and, simultaneously, phenotyped using DNA microarrays. Because of the spacing of markers and linkage disequilibrium, each marker may be near many genes making it difficult to finely map which of these genes are the causal factors responsible for the observed changes in the downstream expression. To address this challenge, we present an efficient method for prioritizing candidate genes at a locus. This approach, called 'eQTL electrical diagrams' (eQED), integrates eQTLs with protein interaction networks by modeling the two data sets as a wiring diagram of current sources and resistors. eQED achieved a 79% accuracy in recovering a reference set of regulator-target pairs in yeast, which is significantly higher than the performance of three competing methods. eQED also annotates 368 protein-protein interactions with their directionality of information flow with an accuracy of approximately 75%.


Maternal rubella and the congenital rubella syndrome.
The major goal of rubella immunization is the prevention of the congenital rubella syndrome. As many as 20 per cent of women in the reproductive age group in the United States continue to be susceptible to rubella despite the immunization programs currently in place. Intensified efforts are therefore needed to identify persons at risk for infection and to vaccinate them. Women who develop a rubella-like illness during pregnancy should have the diagnosis confirmed serologically because a diagnosis based on clinical criteria alone is unreliable and because of the serious implications of gestational rubella infection. The rubella virus can infect the fetus at any stage of pregnancy, but defects are rarely noted when this occurs after the 16th week of gestation. The most common abnormalities in the congenital rubella syndrome are hearing loss, mental retardation, cardiac malformations, and eye defects. Diabetes mellitus, thyroid disease, glaucoma, and other delayed manifestations of congenital rubella syndrome are common, thereby necessitating long-term followup of these patients. The detection of rubella-specific IgM antibodies in fetal blood is helpful in establishing the diagnosis prenatally and can aid in the management of pregnancies complicated by this infection. Susceptible women identified through screening during pregnancy should be immunized in the immediate postpartum or postabortion period. Although the live, attenuated rubella vaccine is contraindicated during pregnancy, pregnant women who are inadvertently immunized are not candidates for pregnancy termination because no defects consistent with congenital rubella have been reported to date in the offspring of other similarly vaccinated women.


Delivering on NIH data sharing requirements: avoiding Open Data in Appearance Only.
Introduction In January, the National Institutes of Health (NIH) implemented a Data Management and Sharing Policy aiming to leverage data collected during NIH-funded research. The COVID-19 pandemic illustrated that this practice is equally vital for augmenting patient research. In addition, data sharing acts as a necessary safeguard against the introduction of analytical biases. While the pandemic provided an opportunity to curtail critical research issues such as reproducibility and validity through data sharing, this did not materialise in practice and became an example of 'Open Data in Appearance Only' (ODIAO). Here, we define ODIAO as the intent of data sharing without the occurrence of actual data sharing (eg, material or digital data transfers).Objective Propose a framework that states the main risks associated with data sharing, systematically present risk mitigation strategies and provide examples through a healthcare lens.Methods This framework was informed by critical aspects of both the Open Data Institute and the NIH's 2023 Data Management and Sharing Policy plan guidelines.Results Through our examination of legal, technical, reputational and commercial categories, we find barriers to data sharing ranging from misinterpretation of General Data Privacy Rule to lack of technical personnel able to execute large data transfers. From this, we deduce that at numerous touchpoints, data sharing is presently too disincentivised to become the norm.Conclusion In order to move towards Open Data, we propose the creation of mechanisms for incentivisation, beginning with recentring data sharing on patient benefits, additional clauses in grant requirements and committees to encourage adherence to data reporting practices.


Three additional examples of anti-Xga and Xg blood groups among the Japanese.
Three examples of anti-Xga identified in Japanese donors are reported. Two of these were stimulated by pregnancy, while the antibody stimulation of the other one remains unknown. All of these antibodies had the ability to bind complement. A dosage effect was observed in an anti-Xga serum. The Xga gene frequency for 529 unrelated Japanese was 0.681, similar to that for Caucasians. Tests on 125 Japanese families with 242 offspring for Xga antigen are also reported.


Topical application of a cream containing nanoparticles with vitamin E for radiodermatitis prevention in women with breast cancer: A randomized, triple-blind, controlled pilot trial.
Most topical agents for radiodermatitis prevention are not based on its pathophysiology, mainly caused by the indirect effects of radiation from reactive oxygen species release. Therefore, this study aimed to evaluate the effect of vitamin E-containing nanoparticle cream as an antioxidant for radiodermatitis prevention. A randomized, triple-blind, parallel pilot study conducted in an Oncology Hospital including 40 adult women with breast cancer, and healthy skin, submitted to radiotherapy, divided into three groups: Intervention (12; 30%) receiving cream with nanoparticles containing vitamin E; Control 1 (14; 35%) cream without nanoparticles or vitamin E; Control 2 (14; 35%) cream with nanoparticles without vitamin E. Incidence, grade and time to onset of radiodermatitis were primary outcomes; health-related quality of life, reported symptoms, and breast temperature were secondary outcomes. All patients were followed until the end of the study. All had radiodermatitis. There were no significant differences between the study groups regarding radiodermatitis grade, health-related quality of life, and breast temperatures. A protective effect of vitamin E-containing nanoparticle cream was identified regarding the onset time of radiodermatitis in patients who did not receive a boosted radiation dose (p = .03) and the occurrence of mild inframammary erythema (p = .04). Itching was reported by 90% of the women. The definitive calculated sample is 108 volunteers. There were no identified side effects. A potential protective effect of a cream containing vitamin E nanoparticles was observed. This pilot study presents initial evidence about the role of a nanoencapsulated antioxidant in preventing radiodermatitis. No. RBR-784F3Y; UTN-U1111-1201-5923.


Linoleic acid peroxidation--the dominant lipid peroxidation process in low density lipoprotein--and its relationship to chronic diseases.
Modern separation and identification methods enable detailed insight in lipid peroxidation (LPO) processes. The following deductions can be made: (1) Cell injury activates enzymes: lipoxygenases generate lipid hydroperoxides (LOOHs), proteases liberate Fe ions--these two processes are prerequisites to produce radicals. (2) Radicals attack any activated CH2-group of polyunsaturated fatty acids (PUFAs) with about a similar probability. Since linoleic acid (LA) is the most abundant PUFA in mammals, its LPO products dominate. (3) LOOHs are easily reduced in biological surroundings to corresponding hydroxy acids (LOHs). LOHs derived from LA, hydroxyoctadecadienoic acids (HODEs), surmount other markers of LPO. HODEs are of high physiological relevance. (4) In some diseases characterized by inflammation or cell injury HODEs are present in low density lipoproteins (LDL) at 10-100 higher concentration, compared to LDL from healthy individuals.


A Rare Case of Congenital Plunging Ranulas: Diagnosis With Intraoral and Extraoral Ultrasound and Magnetic Resonance Imaging.
Ranulas are cystic lesions located in the floor of the mouth. These are "pseudocysts" and are developed due to an obstruction in the sublingual gland. Congenital variants of plunging ranulas are very rare. Here, we report a case of an eight-year-old male child presenting with congenital swelling with an intraoral component as well as extension to the submandibular gland region. The swelling was painless and gradually growing in size.


Serum lipoprotein changes after prolonged intralipid infusion in malnourished haemodialysis patients.
Fat emulsions have been shown to be on efficient source of energy support in malnourished haemodialysis patients. This work was conducted in order to study the effect of prolonged intralipid infusion, during dialysis, on lipid metabolism. The following fasting serum parameters were measured before and after a 1 month infusion of 20% Intralipid (67 kJ/kg body wt/dialysis) in 10 malnourished patients undergoing dialysis: total cholesterol, triglycerides, phospholipids, HDL-cholesterol, LDL-cholesterol, HDL2-cholesterol, HDL3-cholesterol, apolipoproteins A-I, A-II, A-IV, C-II, C-III, and lipoproteins A-I, A-I A-II, EB and (a). After prolonged lipid infusion, the apoprotein B (p < 0.05) and C-II (p < 0.005) increased suggesting a triglyceride transport activation. Apolipoprotein A-I (p < 0.05) and lipoprotein A-I (p < 0.05) decreased without a change in total cholesterol. Lipoprotein (a) decreased in each case (p < 0.005), suggesting a reduction of its related risk of atherogenesis.


Differentiation between canine cutaneous and visceral leishmaniasis by the detection of immunoglobulin G specific for Leishmania (Viannia) braziliensis and Leishmania (Leishmania) chagasi antigens using flow cytometry.
Flow cytometry employing Leishmania (L.) chagasi (Lc) and L. (Viannia) braziliensis (Lb) antigen was used to establish the differential diagnosis between visceral (VL) and cutaneous leishmaniasis (CL) in dogs. Flow cytometry permitted the detection of Leishmania-specific immunoglobulin G in sera from 19 dogs: nine with CL and 10 with VL. A significant difference in the percentage of positive staining was observed in sera from dogs with CL between the homologous antigen (69% for Lb) and the heterologous antigen (42% for Lc). However, this difference was not significant in sera from dogs with VL (61% for Lb and 73% for Lc). No significant staining was observed in control sera (0.6% for Lb and 0.4% for Lc) consisting of samples from healthy dogs, or in the group with sporotrichosis (1.8% for Lb and 1.5% for Lc), a differential diagnosis of CL. The results suggest that flow cytometry might be useful for the differentiation between CL and VL in dogs, with practical applications in areas where the two infections overlap.


A cell kinetic model to explain the time of appearance of skin reaction after X-rays or ultraviolet light irradiation.
Skin reactions to various doses of X-rays (300 and 10 kV) and ultraviolet light (u.v.) have been compared using hairless mice. Two regions of epidermis with widely differing cell kinetics and gross structure have been compared. Little evidence could be found to support the idea that the early phases of the reaction are dependent on cell cycle time. The data can be explained by a model based on the assumption that epidermis contains only a small fraction of clonogenic (stem) cells and this fraction may vary in different epidermal regions. X-rays appear to exert their greatest destructive action on these clonogenic cells while u.v. is more indiscriminate in its action, killing both clonogenic and non-clonogenic cells.


Assessment of radial glia in the frontal lobe of fetuses with Down syndrome.
Down syndrome (DS) occurs with triplication of human chromosome 21 and is associated with deviations in cortical development evidenced by simplified gyral appearance and reduced cortical surface area. Radial glia are neuronal and glial progenitors that also create a scaffolding structure essential for migrating neurons to reach cortical targets and therefore play a critical role in cortical development. The aim of this study was to characterise radial glial expression pattern and morphology in the frontal lobe of the developing human fetal brain with DS and age-matched controls. Secondly, we investigated whether microstructural information from in vivo magnetic resonance imaging (MRI) could reflect histological findings from human brain tissue samples. Immunohistochemistry was performed on paraffin-embedded human post-mortem brain tissue from nine fetuses and neonates with DS (15-39 gestational weeks (GW)) and nine euploid age-matched brains (18-39 GW). Radial glia markers CRYAB, HOPX, SOX2, GFAP and Vimentin were assessed in the Ventricular Zone, Subventricular Zone and Intermediate Zone. In vivo diffusion MRI was used to assess microstructure in these regions in one DS (21 GW) and one control (22 GW) fetal brain. We found a significant reduction in radial glial progenitor SOX2 and subtle deviations in radial glia expression (GFAP and Vimentin) prior to 24 GW in DS. In vivo, fetal MRI demonstrates underlying radial projections consistent with immunohistopathology. Radial glial alterations may contribute to the subsequent simplified gyral patterns and decreased cortical volumes observed in the DS brain. Recent advances in fetal MRI acquisition and analysis could provide non-invasive imaging-based biomarkers of early developmental deviations.


Sensitive and quantitative, 10-min immunofluorometric assay for D-Dimer in whole blood.
Normal concentrations of D-Dimer can be used to exclude venous thromboembolism (VTE). However, methods for sensitive and quantitative D-Dimer measurements at the point-of-care (POC) are still limited. We developed a 10-min, non-competitive immunofluorometric assay for D-Dimer in citrated whole blood and plasma using pre-dispensed reagents dried in single assay wells. The simple, automated assay procedure comprises a 1:50 sample dilution, one-step incubation, washing, and time-resolved fluorometric measurement directly from the wet well surface. The limits of detection (background + 3SD) and quantification (CV <15%) were 0.05 and 0.2 mg/L D-Dimer, respectively, and the assay was linear up to 400 mg/L. Correlations to Roche TinaQuant (r=0.726, n=200) and Biopool Auto.Dimer (r=0.190, n=149) were carried out using citrated plasma. Diagnostic sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values were 98.7%, 64.4%, 99.1% and 55.1%, and 92.2%, 81.0%, 95.9% and 68.3%, respectively, using cut-off values of 0.6 and 1.0 mg/L, respectively, in outpatients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (n=77) compared with outpatients with various other diseases (n=174). The within- and between-run CVs near the cut-off values were < or =10% in both whole blood and plasma. The 95th percentile upper range in apparently healthy individuals was 0.68 mg/L of whole blood (n=101). The high sensitivity and NPV suggest that the rapid immunofluorometric assay could be valuable for rapid exclusion of VTE in outpatients. With appropriate cut-offs, the assay could potentially be used as a stand-alone test or combined with clinical probability assessment, but further studies are required.


Development of vaccine delivery vehicles based on lactic acid bacteria.
Live recombinant bacteria represent attractive antigen delivery systems able to induce both mucosal and systemic immune responses against heterologous antigens. The first live recombinant bacterial vectors developed were derived from attenuated pathogenic microorganisms. In addition to the difficulties often encountered in the construction of stable attenuated mutants of pathogenic organisms, attenuated pathogens may retain a residual virulence level that renders them unsuitable for the vaccination of partially immunocompetent individuals such as infants, the elderly or immunocompromised patients. As an alternative to this strategy, non-pathogenic food-grade lactic acid bacteria (LAB) maybe used as live antigen carriers. This article reviews LAB vaccines constructed using antigens other than tetanus toxin fragment C, against bacterial, viral, and parasitic infective agents, for which protection studies have been performed. The antigens utilized for the development of LAB vaccines are briefly described, along with the efficiency of these systems in protection studies. Moreover, the key factors affecting the performance of these systems are highlighted.


Construction and characterization of recombinant flaviviruses bearing insertions between E and NS1 genes.
The yellow fever virus, a member of the genus Flavivirus, is an arthropod-borne pathogen causing severe disease in humans. The attenuated yellow fever 17D virus strain has been used for human vaccination for 70 years and has several characteristics that are desirable for the development of new, live attenuated vaccines. We described here a methodology to construct a viable, and immunogenic recombinant yellow fever 17D virus expressing a green fluorescent protein variant (EGFP). This approach took into account the presence of functional motifs and amino acid sequence conservation flanking the E and NS1 intergenic region to duplicate and fuse them to the exogenous gene and thereby allow the correct processing of the viral polyprotein precursor. YF 17D EGFP recombinant virus was grew in Vero cells and reached a peak titer of approximately 6.45 +/- 0.4 log10 PFU/mL at 96 hours post-infection. Immunoprecipitation and confocal laser scanning microscopy demonstrated the expression of the EGFP, which was retained in the endoplasmic reticulum and not secreted from infected cells. The association with the ER compartment did not interfere with YF assembly, since the recombinant virus was fully competent to replicate and exit the cell. This virus was genetically stable up to the tenth serial passage in Vero cells. The recombinant virus was capable to elicit a neutralizing antibody response to YF and antibodies to EGFP as evidenced by an ELISA test. The applicability of this cloning strategy to clone gene foreign sequences in other flavivirus genomes was demonstrated by the construction of a chimeric recombinant YF 17D/DEN4 virus. This system is likely to be useful for a broader live attenuated YF 17D virus-based vaccine development for human diseases. Moreover, insertion of foreign genes into the flavivirus genome may also allow in vivo studies on flavivirus cell and tissue tropism as well as cellular processes related to flavivirus infection.


Exploring syndemic vulnerability across generations: A case study of a former fishing village in the Netherlands.
This qualitative case study uses a life-course approach to explore syndemic vulnerability in a former fishing village in the Netherlands. Building on four years of fieldwork in a low-income neighborhood, we explored salient themes between and across families and generations. Elderly community members (>65 years) were interviewed to map village history and explore how contextual factors have affected family life, health, and wellbeing since the 1940s. We systematically traced and compared processes leading to or from syndemic vulnerability by studying seven families across three generations. Adults with at least one of clustering diseases, their parents (when possible), and their children participated in semi-structured life-course interviews. A complex interaction of endemic social conditions, sociocultural normative processes, learned health behaviors, and disheartening life events shaped families' predispositions for a syndemic of psychological distress, cardiometabolic conditions, and musculoskeletal pain. Educational attainment, continued social support, and aspirational capabilities emerged as themes related to decreasing syndemic vulnerability. This study demonstrates that syndemic vulnerability is potentially intergenerational and reveals the need for culturally sensitive and family-focused syndemic interventions. Future longitudinal research should focus on unravelling the pathogenesis of the clustering of psychological distress, cardiometabolic conditions, and musculoskeletal pain among young people.


DHPC: a new tool to express genome structural features.
The DHPC (DNA Hilbert-Peano curve) is a new tool for visualizing large-scale genome sequences by mapping sequences into a two-dimensional square. It utilizes the space-filling function of Hilbert-Peano mapping. By applying a Gauss smoothing technique and a user-defined color function, a large-scale genome sequence can be mapped into a two-dimensional color image. In the calculated DHPCs, many genome characteristics are revealed. In this article we introduce the method and show how DHPCs may be used to identify regions of different base composition. The power of the method is demonstrated by presenting multiple examples such as repeating sequences, degree of base bias, regions of homogeneity and their boundaries, and mark of annotated segments. We also present several genome curves generated by DHPC to demonstrate how DHPC can be used to find previously unidentified sequence features in these genomes.


The effects of self-instruction training on a deaf child's semantic and pragmatic production.
Effects of self-instruction training on the communication skills of a profoundly hearing-impaired child were studied. Self-instruction training included modeling a series of problem-solving steps in order to direct communication production. Communication production was operationalized as signed semantic and pragmatic functions. A multiple baseline was used to assess treatment and generalization (treatment variations of person and setting) effects. There was evidence to suggest that self-instruction was immediately effective on pragmatic behaviors but such behaviors were reduced when another person administered treatment. In contrast, self-instruction training had a gradual influence on semantic behaviors and those effects were maintained when treatment included a different person and setting. Implications of the clinical study were discussed.


Radiology of wrist and hand injuries in athletes.
Traumatic injuries are a major cause of hand and wrist pain in athletes. Wrist injuries include fractures, dislocations, and instability patterns. Hand injuries include tendon injuries, ligamentous injuries, and fractures. In this article we have presented the radiographic appearance of the more common of these injuries.


Double outlet left ventricle associated with situs inversus and atrioventricular concordance.
A case is described in which the ventriculo-arterial connection of double-outlet left ventricle was associated with situs inversus and atrioventricular concordance. The case additionally exhibited l-malposition of the aorta, a subaortic ventricular septal defect, and valvar and subvalvar pulmonary stenosis. Originally diagnosed as transposition of the great arteries, a Rastelli type correction was attempted. This was not successful, owing to hypoplasia of the morphological tricuspid valve orifice.


Health consequences of intimate partner violence.
Intimate partner violence, which describes physical or sexual assault, or both, of a spouse or sexual intimate, is a common health-care issue. In this article, I have reviewed research on the mental and physical health sequelae of such violence. Increased health problems such as injury, chronic pain, gastrointestinal, and gynaecological signs including sexually-transmitted diseases, depression, and post-traumatic stress disorder are well documented by controlled research in abused women in various settings. Intimate partner violence has been noted in 3-13% of pregnancies in many studies from around the world, and is associated with detrimental outcomes to mothers and infants. I recommend increased assessment and interventions for intimate partner violence in health-care settings.


The molecular basis of neutral aminoacidurias.
Recent success in the molecular cloning and identification of apical neutral amino acid transporters has shed a new light on inherited neutral amino acidurias, such as Hartnup disorder and Iminoglycinuria. Hartnup disorder is caused by mutations in the neutral amino acid transporter B(0) AT1 (SLC6A19). The transporter is found in kidney and intestine, where it is involved in the resorption of all neutral amino acids. The molecular defect underlying Iminoglycinuria has not yet been identified. However, two transporters, the proton amino acid transporter PAT1 (SLC36A1) and the IMINO transporter (SLC6A20) appear to play key roles in the resorption of glycine and proline. A model is presented, involving all three transporters that can explain the phenotypic variability of iminoglycinuria.


Effect of beta-lactoglobulin polymorphism and seasonality on bovine milk composition.
The objective was to evaluate the effect of beta-lactoglobulin (beta-lg) polymorphism and seasonality on milk composition (fat, lactose, total solids, milk urea nitrogen, total protein, true protein, casein and somatic cell counts) of Holstein and Girolando cows. Milk and blood samples from 278 Holsteins cows and 156 Girolando cows were taken during two dry seasons and two rainy seasons, for milk composition analysis and to determine beta-lg genotypes, respectively. BB genotype was the most frequent for both breeds, followed by AA genotype for Holstein (BB>AA>AB) and by AB for Girolando cows (BB>AB>AA). No differences were found in milk compositional characteristics among genetic variants of beta-lg (AA, AB and BB) either between Holstein or Girolando cows. No association between milk composition and beta-lg genetic polymorphism was observed. During the dry season, independently of the breed considered, higher contents of lactose, true protein, casein and casein:true protein ratio were found.


An alternate method for posterior fixation in anterior and inferior atlanto-axial dislocation.
A modification of common methods is described for fixation of anterior and inferior atlanto-axial dislocation (AAD and IAD). In AAD a wire is passed around the atlas arch and knotted around the spinous process of the axis in a way that a figure 8 arrangement is achieved as seen in the lateral view. In IAD a wire is passed through holes in the occiput and knotted around the spinous process of the axis. A rectangular bone graft is inserted between the occiput and the spinous process of the axis, thus preventing further inferior dislocation. In both methods methyl methacrylate and bone grafts are as a rule added for further long-time stabilization. The methods have been used in 15 cases of AAD and in three cases of IAD. On radiologic examination with attention focused on the immediate postoperative fixation the follow-up time has been three months. The long-time results of fixation have been recorded with a follow-up time of six years. The fixation proved to be satisfactory in 14 patients with AAD and in the three patients with IAD. The clinical results were good in the 14 patients with AAD and in the three with IAD.


Intermittent positive pressure ventilation by nasal mask: technique and applications.
Intermittent positive pressure ventilation delivered non-invasively through a well-fitting nasal mask has been used to control nocturnal hypoventilation in three patients with severe, combined cardiorespiratory and skeletal disease. The advantages of this approach to domiciliary ventilation are described and the requirements of the ventilator are defined.


Analysing the association between two variables.
Techniques of linear regression and correlation analysis are discussed and illustrated by means of dentally-related examples.


Enzyme kinetic properties of human recombinant arylamine N-acetyltransferase 2 allotypic variants expressed in Escherichia coli.
Arylamine N-acetyltransferase (NAT2) catalyses the N-acetylation of primary arylamine and hydrazine drugs and chemicals. N-Acetylation is subject to polymorphism, and humans can be categorized as either fast or slow acetylators according to their ability to N-acetylate certain arylamine substrates in vivo. Genetic variants at the polymorphic NAT2 locus have been described. We expressed five of the most common NAT2 variants (NAT2 4, NAT2 5A, NAT2 5B, NAT2 6A and NAT2 7B) in Escherichia coli as a convenient source of the human variants. The apparent Km values (at 100 microM acetyl CoA as co-substrate) of the different NAT2 variants for sulphamethazine, dapsone, p-anisidine, 2-aminofluorene, procainamide and isoniazid were determined. Data show that the apparent Km of the slow variant NAT2 7B for the arylamine sulphamethazine was 10-fold lower than all the other allotypes. The apparent Km for the structurally related sulphone antibiotic dapsone was 5-fold lower for the slow variant NAT2 7B when compared with the wild-type NAT2 4. These results indicate that the NAT2 7B specific amino acid substitution, Gly286-Glu, is important in promoting the binding of sulphamethazine and dapsone to the active site.


Questionnaire results on exposure characteristics of pregnant women participating in the Japan Environment and Children Study (JECS).
The Japan Environment and Children's Study (JECS) is a nation-wide birth cohort study investigating environmental effects on children's health and development. In this study, the exposure characteristics of the JECS participating mothers were summarized using two questionnaires administered during pregnancy. Women were recruited during the early period of their pregnancy. We intended to administer the questionnaire during the first trimester (MT1) and the second/third trimester (MT2). The total number of registered pregnancies was 103,099. The response rates of the MT1 and MT2 questionnaires were 96.8% and 95.1%, respectively. The mean gestational ages (SDs) at the time of the MT1 and MT2 questionnaire responses were 16.4 (8.0) and 27.9 (6.5) weeks, respectively. The frequency of participants who reported "lifting something weighing more than 20 kg" during pregnancy was 5.3% for MT1 and 3.9% for MT2. The Cohen kappa scores ranged from 0.07 to 0.54 (median 0.31) about the occupational chemical use between MT1 and MT2 questionnaires. Most of the participants (80%) lived in either wooden detached houses or steel-frame collective housing. More than half of the questionnaire respondents answered that they had "mold growing somewhere in the house". Insect repellents and insecticides were used widely in households: about 60% used "moth repellent for clothes in the closet," whereas 32% applied "spray insecticide indoors" or "mosquito coil or an electric mosquito repellent mat." We summarized the exposure characteristics of the JECS participants using two maternal questionnaires during pregnancy.


Variation in use of non-surgical treatments among osteoarthritis patients in orthopaedic practice in the Netherlands.
National and international evidence-based guidelines for hip and knee osteoarthritis (OA) recommend to start with non-surgical treatments, followed by surgical intervention if a patient does not respond sufficiently to non-surgical treatments, but there are indications that these are not optimally used. The aim of this study was to assess the extent to which all recommended non-surgical treatments were used by patients with hip or knee OA who receive(d) a total hip or knee replacement, as reported by patients and orthopaedic surgeons. We performed two cross-sectional internet-based surveys among patients and orthopaedic surgeons throughout the Netherlands. 195 OA patients either have undergone total knee arthroplasty or total hip arthroplasty no longer than 12 months ago or being on the waiting list for surgery with a confirmed date within 3 months and 482 orthopaedic surgeons were invited to participate. The use of recommended non-surgical treatments including education about OA/treatment options, lifestyle advice, dietary therapy, physical therapy, acetaminophen, NSAIDs and glucocorticoid injections. 174 OA patients (93%) and 172 orthopaedic surgeons (36%) completed the surveys. Most recommended non-surgical treatments were given to the majority of patients (eg, 80% education about OA, 73% physical therapy, 72% acetaminophen, 80% NSAIDs). However, only 6% of patients and 10% of orthopaedic surgeons reported using a combination of all recommended treatments. Dietary therapy was used least frequently. Only 11% of overweight and 30% of obese participants reported having received dietary therapy and 28% of orthopaedic surgeons reported to prescribe dietary therapy to overweight patients. While most recommended non-surgical treatments were used frequently as single therapy, the combination is used in only a small percentage of OA patients. Especially, use of dietary therapy may be improved to help patients manage their symptoms, and potentially delay the need for joint arthroplasty.


Discovery of SHR5428 as a selective and noncovalent inhibitor of CDK7.
Cyclin dependent kinase 7 (CDK7) is an attractive target in tumor indications via regulating both cell cycle and transcription. Here, SHR5428 was discovered as a selective and noncovalent CDK7 inhibitor with highly potent CDK7 enzymatic activity and triple negative breast cancer cellular activity on MDA-MB-468 cell. SHR5428 also displayed favorable pharmacokinetic properties in different preclinical species such as mouse, rat and dog, and showed high selectivity over CDK1, CDK2, CDK4, CDK6, CDK9, CDK12 in CDK family. Furthermore, the computational modeling has shed some light on this mechanism. Additionally the in vivo efficacy study in a breast cancer cell line (HCC70 cell) derived xenograft mouse model proved SHR5428 to be orally efficacious with dose-dependent tumor growth inhibition.


The use of FT-IR for quantitative studies of the apparent pKa of lipid carboxyl groups and the dehydration degree of the phosphate group of phospholipids.
Fourier-transform infrared spectroscopy (FT-IR) has been applied to the quantitative study of the dehydration of the phosphatidylserine phosphate group in the presence of Ca2+ exerted by different molecules, such as diacylglycerol, sphingosine and stearylarnine, by using a partial least-squares statistical procedure. By using this method it was observed that diacylglycerol enhanced the dehydration of this PO2- group produced by Ca2+ whereas the amino-bases sphingosine and stearylamine protected the phosphate group from the dehydration produced by Ca2+ due to the very strong electrostatic interaction established. The apparent pKa of lipid carboxyl groups can also be estimated by using FTIR. The method consisted in quantifying the absorbance intensities due to the protonated and the unprotonated forms of the specific group being studied. The pKa of the carboxyl group of [1-13C]-palmitic acid included in dipalmitoylphosphatidylcholine membranes was found to be 8.7, a value much higher than that estimated from a molecular solution of the fatty acid. It was observed using the same method that the pKa of free fatty acids in model stratum corneum lipid mixtures was in the range 6.2-7.3 increasing with the preponderance of oleic acid over palmitic acid. Finally the pKa of the carboxyl group of phosphatidylserine was shifted from 4.6 in the pure phospholipid to 2.1 and 2.2 in the presence of equimolar sphingosine and stearylamine, respectively, as a consequence of electrostatic interactions.


Beneficial effect of amrinone on the size of acute regional ischemia in isolated rabbit hearts.
The effect of inotropes on myocardial ischemia is difficult to predict because they may influence the determinants of myocardial O2 demand and O2 supply differently. Several PDE-inhibitors have been reported to possess antiischemic properties related to their hemodynamic and O2-sparing effects. To assess whether PDE-inhibitors also possess direct cardioprotective properties, the effects of amrinone (2.5 x 10(-5) mol/L) in comparison to isoproterenol (5 x 10(-9) mol/L) and ouabain (1.5 x 10(-7) mol/L) were studied in isolated rabbit hearts perfused according to Langendorff at a constant pressure (70 cmH2O) and electrically driven at a constant pacing rate. Regional ischemia was induced by coronary artery ligation and quantified by epicardial NADH fluorescence. All substances significantly increased the actively developed left ventricular pressure to a similar extent (+20%) (P < 0.05). Coronary flow was significantly decreased by ouabain (-15%) and significantly increased by isoproterenol (+25%) and particularly by amrinone (+50%) (P < 0.05). Neither ouabain nor isoproterenol significantly changed the intensity or the distribution pattern of NADH fluorescence, whereas the size of the ischemic zone was significantly reduced by amrinone (-25%) (P < 0.05). The PDE-inhibitor amrinone was shown to possess a direct cardioprotective effect by improving myocardial perfusion and O2 supply in isolated rabbit hearts.


Fatty liver: The metabolic syndrome increases major hepatectomy mortality.
As the obesity epidemic worsens, the prevalence of fatty liver disease has increased. However, minimal data exist on the impact of combined fatty liver and metabolic syndrome on hepatectomy outcomes. Therefore, the aim of this analysis is to measure the outcomes of patients who do and do not have a fatty liver undergoing hepatectomy in the presence and absence of the metabolic syndrome. Patients with fatty and normal livers undergoing major hepatectomy (≥3 segments) were identified in the 2014 to 2018 American College of Surgeon National Surgical Quality Improvement Program database. Patients undergoing partial hepatectomy and those with missing liver texture data were excluded. Propensity matching was used and adjusted for multiple variables. A subgroup analysis stratified by the metabolic syndrome (body mass index ≥30 kg/m2, hypertension and diabetes) was performed. Demographics and outcomes were compared by χ2 and Mann-Whitney tests. Of 2,927 hepatectomies, 30% of patients (N = 863) had a fatty liver. The median body mass index was 28.6, and the metabolic syndrome was present in 6.3% of patients (N = 184). After propensity matching, 863 patients with fatty and 863 with normal livers were compared. Multiple outcomes were significantly worse in patients with fatty livers (P <.05), including serious morbidity (32% vs 24%), postoperative invasive biliary procedures (15% vs 10%), organ space infections (11% vs 7.8%), and pulmonary complications. Patients with fatty livers and the metabolic syndrome had significantly increased postoperative cardiac arrests, pulmonary embolisms, and mortality (P < .05). Fatty liver disease is associated with significantly worse outcomes after major hepatectomy. The metabolic syndrome confers an increased risk of postoperative mortality.


Biomedical Sensors for Functional Mapping: Techniques, Methods, Experimental and Medical Applications.
The rapid advancement of biomedical sensor technology has revolutionized the field of functional mapping in medicine, offering novel and powerful tools for diagnosis, clinical assessment, and rehabilitation [...].


[Transcriptional coactivator SAYP can suppress transcription in heterochromatin].
The new transcriptional coactivator SAYP binds at many sites to transcriptionally active chromatin of polytene chromosomes, colocalizes with RNA polymerase II, and coactivates transcription. On the other hand, SAYP is present in heterochromatic regions of chromosome IV and in the chromocenter and suppresses transcription of transgenes located in heterochromatin. The conserved SAY domain of SAYP is involved in transcription activation, while its PHD domains are responsible for gene silencing in heterochromatin. Thus, SAYP plays a dual role in regulating transcription in euchromatic and heterochromatic regions.


Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: Prospective cohort study.
While systemic inflammation has been implicated in the etiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS), a condition with high case-fatality, is untested. Accordingly, we quantified the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with subsequent ALS occurrence. We used data from UK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centers between 2006 and 2010. Venous blood was collected at baseline in the full cohort and assayed for CRP, and repeat measurement was made 3-7 years later in a representative subgroup (N = 14,514) enabling correction for regression dilution. ALS was ascertained via national hospitalization and mortality registries until 2021. We computed multivariable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles. In an analytical sample of 400,884 initially ALS-free individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalizations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviors, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalizations (1.20; 1.00, 1.39). There was evidence of dose-response effects across tertiles of CRP for both outcomes (p for trend ≤ 0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalizations (1.37; 1.05, 1.76). Higher levels of CRP, a blood-based biomarker widely captured in clinical practice, is associated with moderately increased future risk of amyotrophic lateral sclerosis.