Strong adherence to a healthy dietary pattern is associated with better semen quality, especially in men with poor semen quality.
To study associations between periconceptional dietary patterns and semen quality parameters. Prospective periconception cohort study. Tertiary hospital. One hundred and twenty-nine male partners of pregnant women who participated in the Rotterdam Periconception Cohort (Predict study). None. Semen quality parameters-ejaculate volume, sperm concentration, total sperm count, progressive motility, immotile sperm, and total motile sperm count (TMSC). Men included in our study were on average 35 (±6 standard deviation) years old and had a body mass index of 26.4 ± 4 kg/m2. Two dietary patterns were identified using principle component analysis, which were labeled as "healthy" and "unhealthy." An increase of one factor score (stated as β) represented an increase of 1 standard deviation. Sperm concentration (β = 0.278; 95% CI, 0.112-0.444), total sperm count (β = 1.369; 95% CI, 0.244-2.495), progressive motility (β = 4.305; 95% CI, 0.675-7.936), and TMSC (β = 0.319; 95% CI, 0.113-0.526) were all positively associated with a strong adherence to the healthy dietary pattern. Subgroup analysis showed that these associations were mainly present in men with a TMSC <10 million spermatozoa. Although there was a trend toward a diminution in semen quality, we found no statistically significant associations with strong adherence to the unhealthy dietary pattern. The positive associations between strong adherence to a healthy dietary pattern and semen parameters in men with poor semen quality support the importance of preconceptional tailored nutritional counseling and coaching of couples who are trying to conceive.


Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets.
Platelets are specialized hemostatic cells that circulate in the blood as anucleate cytoplasts. We report that platelets unexpectedly possess a functional spliceosome, a complex that processes pre-mRNAs in the nuclei of other cell types. Spliceosome components are present in the cytoplasm of human megakaryocytes and in proplatelets that extend from megakaryocytes. Primary human platelets also contain essential spliceosome factors including small nuclear RNAs, splicing proteins, and endogenous pre-mRNAs. In response to integrin engagement and surface receptor activation, platelets precisely excise introns from interleukin-1beta pre-mRNA, yielding a mature message that is translated into protein. Signal-dependent splicing is a novel function of platelets that demonstrates remarkable specialization in the regulatory repertoire of this anucleate cell. While this mechanism may be unique to platelets, it also suggests previously unrecognized diversity regarding the functional roles of the spliceosome in eukaryotic cells.


QuickStats: Age-Adjusted Rate* for Suicide,† by Sex - National Vital Statistics System, United States, 1975-2015.
There was an overall decline of 24% in the age-adjusted suicide rate from 1977 (13.7 per 100,000) to 2000 (10.4). The rate increased in most years from 2000 to 2015. The 2015 suicide rate (13.3) was 28% higher than in 2000. The rates for males and females followed the overall pattern; however, the rate for males was approximately 3-5 times higher than the rate for females throughout the study period.


MicroRNA-374b mediates the initiation of non-small cell lung cancer by regulating ITGB1 and p53 expressions.
Previous studies have shown that microRNAs (miRNAs) play important roles in the pathogenesis of human cancers. This study aims to clarify the role of miR-374b in non-small cell lung cancer (NSCLC). In this study, RT-qPCR and western blot analysis were used to measure mRNA and protein expression. The regulatory mechanism of miR-374b/ITGB1 was investigated by dual-luciferase reporter, CCK-8, and transwell assays. MiR-374b expression was reduced in NSCLC tissues and associated with lymph node metastasis, tumor stage and prognosis in NSCLC patients. Functionally, overexpression of miR-374b inhibited cell viability and metastasis in NSCLC. In addition, miR-374b blocked EMT and promoted p53 expression in NSCLC. MiR-374b was found to directly target ITGB1. Furthermore, upregulation of ITGB1 weakened the antitumor effect of miR-374b in NSCLC. MiR-374b inhibits the tumorigenesis of NSCLC by downregulating ITGB1 and upregulating p53.


Amiodarone-mediated increase in intracellular free Ca2+ associated with cellular injury to human pulmonary artery endothelial cells.
The cardiac antidysrrhythmic drug amiodarone can give rise to potentially fatal pulmonary toxicity in large numbers of patients. The effect of amiodarone on Ca2+ homeostasis and cell injury has been studied using human pulmonary artery endothelial (HPAE) cells in vitro. Amiodarone produced a concentration-dependent increase in intracellular free Ca2+ concentration ( [Ca2+]i) to micromolar levels that are similar to those seen with physiological stimuli that increase [Ca2+]i. Unlike physiological stimuli, the rise in [Ca2+]i produced by amiodarone developed slowly and was maintained over at least 30 min. Omitting Ca2+ from the external medium reversibly prevented the amiodarone-induced rise in [Ca2+]i. Amiodarone treatment increased the apparent first order rate constants for 45Ca2+ influx and efflux in intact HPAE cells. 45Ca2+ accumulation into the endoplasmic reticulum of saponin-permeabilized HPAE cells was decreased by amiodarone treatment. The release of 45Ca2+ from the endoplasmic reticulum stores by the putative intracellular second messengers inositol-1,4,5-trisphosphate, arachidonic acid, and Ca2+ was blocked by amiodarone treatment. The changes in Ca2+ homeostasis coincide with an increase in [3H]deoxyglucose release as a measure of early cell injury by amiodarone. It is concluded that amiodarone can produce an increase in [Ca2+]i by an action on the plasma membrane that allows the influx of external Ca2+. This increase in [Ca2+]i, together with other changes in Ca2+ homeostasis, may be responsible for the early cell injury associated with amiodarone toxicity.


Measurement of blood flow in the dental pulp of dogs with the 133xenon washout method.
Following rapid injection of 133Xe into the maxillary artery, the radioactivity from a dog canine tooth was monitored with a specially-designed scintillation probe connected to a multichannel analyser. With a PDP 11/10 minicomputer, the semilogarithmic radioactivity-time curve was resolved into a fast component and a slow component using best fit least-square lines and the exponential rate constant (k) was determined for each component. The blood flow per unit of pulp mass (Q, in ml/min per 100 g) was obtained using the equation: Q = k X lambda tb, where lambda tb is the tissue-blood partition coefficient of 133Xe in the pulp determined for the haematocrit value of the individual experiments. The fast-component blood flow was 53.12 +/- 3.12 and the slow-component blood flow was 8.86 +/- 0.53 ml/min per 100 g (mean +/- SEM, n = 21). Although the exact anatomical areas for the fast and slow components are yet to be determined, the results show heterogeneity of blood flow in the pulp. The study showed that pulp blood flow in an intact tooth can be measured with the 133Xe washout method; the method enables study of circulatory physiology of the pulp in health and disease.


Transhiatal esophagectomy for benign disease.
Transhiatal esophagectomy without thoracotomy has been performed in 65 adult patients with dysphagia from benign esophageal disease: strictures (30), neuromotor dysfunction (24), acute iatrogenic perforation (five), acute caustic injury (four), and recurrent gastroesophageal reflux (two). Nearly 70% (45) had undergone at least one prior esophageal operation, and 26% (17) had a history of between two and four esophageal operations. The esophagus was replaced with stomach in 53 patients (82%), colon being used only when there was a history of either prior gastric resection or caustic injury to the stomach (10 patients). Intraoperative blood loss averaged 1,050 ml. Intraoperative complications included pneumothorax in 38 patients (58%) and a tracheal laceration in one patient. Postoperative complications included transient recurrent laryngeal nerve paresis (11 patients, 17%), chylothorax (four patients, 6%), anastomotic leak (four patients, 6%), and small bowel obstruction (two patients). There were five hospital deaths (8% mortality), none related to the technique of esophagectomy. Follow-up ranges from 1 to 84 months (average 28 months). Of 46 patients with a cervical esophagogastric anastomosis in the original esophageal bed, 42 have had an excellent functional result although 17 have required at least one postoperative esophageal dilation. Two have developed true anastomotic strictures. Clinically significant gastroesophageal reflux has not occurred. Transhiatal esophagectomy for benign disease is feasible and safe, even after multiple previous esophageal operations. The stomach appears to be a better visceral esophageal substitute than colon, because it allows an initially easier technical operation and superior long-term functional results.


Dengue virus: epidemiology, biology, and disease aetiology.
Dengue is a vector-borne viral disease caused by the flavivirus dengue virus (DENV). Approximately 400 million cases and 22 000 deaths occur due to dengue worldwide each year. It has been reported in more than 100 countries in tropical and subtropical regions. A positive-stranded enveloped RNA virus (DENV) is principally transmitted by Aedes mosquitoes. It has four antigenically distinct serotypes, DENV-1 to DENV-4, with different genotypes and three structural proteins and seven non-structural proteins. Clinical symptoms of dengue range from mild fever to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), with thrombocytopenia, leucopenia, and increased vascular permeability. Although primary infection causes activation of immune responses against DENV serotypes, the severity of the disease is enhanced via heterotypic infection by various serotypes as well as antibody-dependent enhancement (ADE). The first licensed DENV vaccine was tetravalent CYD Denvaxia, but it has not been approved in all countries. The lack of a suitable animal model, a proper mechanistic study in pathogenesis, and ADE are the main hindrances in vaccine development. This review summarizes the current knowledge on DENV epidemiology, biology, and disease aetiology in the context of prevention and protection from dengue virus disease.


Binding strength and activation state of single fibrinogen-integrin pairs on living cells.
Integrin activation states determine the ability of these receptors to mediate cell-matrix and cell-cell interactions. The prototypic example of this phenomenon is the platelet integrin, alphaIIbbeta3. In unstimulated platelets, alphaIIbbeta3 is inactive, whereas exposing platelets to an agonist such as ADP or thrombin enables alphaIIbbeta3 to bind ligands such as fibrinogen and von Willebrand factor. To study the regulation of integrin activation states at the level of single molecules, we developed a model system based on laser tweezers, enabling us to determine the rupture forces required to separate single ligand-receptor pairs by using either purified proteins or intact living cells. Here, we show that rupture forces of individual fibrinogen molecules and either purified alphaIIbbeta3 or alphaIIbbeta3 on the surface of living platelets were 60 to 150 pN with a peak yield strength of 80-100 pN. Platelet stimulation using either ADP or the thrombin receptor-activating peptide enhanced the accessibility but not the adhesion strength of single alphaIIbbeta3 molecules, indicating that there are only two states of alphaIIbbeta3 activation. Thus, we found it possible to use laser tweezers to measure the regulation of forces between individual ligand-receptor pairs on living cells. This methodology can be applied to the study of other regulated cell membrane receptors using the ligand-receptor yield strength as a direct measure of receptor activation/inactivation state.


[How frequent are poor prognostic markers in rheumatoid arthritis? : An estimate based on three epidemiologic cohorts].
Unfavorable prognostic factors-high disease activity, early erosions, and autoantibodies-should be considered when making treatment decisions in rheumatoid arthritis (RA). There are little data on the frequency of individual poor prognostic factors among RA patients in daily care. Disease activity (Disease Activity Score, DAS28), erosions, antibodies against citrullinated peptides or rheumatoid factor (ACPA/RF+), previous treatment failure, inflammation markers, and functional disability (FFbH < 70) were defined as prognostic factors. Different treatment decision making situations were evaluated in disease-modifying antirheumatic drug (DMARD)-naïve patients from the early RA CAPEA cohort (n = 1059), and in patients from the biologics register RABBIT after failure of one (n = 2217) or more (n = 3280) conventional synthetic (cs)DMARDs or one (n = 1134) or more (n = 795) biologic (b)DMARDs. With the national database of German arthritis centers (NDB), the frequency of these factors was analyzed according to treatment strata (no/1st/2nd/3rd DMARD; n = 5707). In DMARD-naïve patients (CAPEA), 50% presented with DAS28 > 5.1, 64% were ACPA/RF+, 13% had erosions, and 37% functional disability (FFbH < 70). In RABBIT, 63 (1st csDMARD failure) to 81% (≥2 bDMARD failures) were ACPA/RF+, 29 to 70% had erosions, 33 to 52% DAS28 > 5.1, and 41 to 66% had FFbH < 70, respectively. In the NDB, between 47 (DMARD-naïve) and 82% (≥2 previous DMARDs) were ACPA/RF+, 5 to 11%, had high disease activity under treatment (DAS28 > 5.1), and 26 to 50% had functional disability (FFbH < 70), respectively. With growing numbers of previous DMARD therapies, increasing proportions of patients have poor prognostic factors. This underlines the importance of these factors for a difficult-to-treat disease course.


Single-cell segmentation in bacterial biofilms with an optimized deep learning method enables tracking of cell lineages and measurements of growth rates.
Bacteria often grow into matrix-encased three-dimensional (3D) biofilm communities, which can be imaged at cellular resolution using confocal microscopy. From these 3D images, measurements of single-cell properties with high spatiotemporal resolution are required to investigate cellular heterogeneity and dynamical processes inside biofilms. However, the required measurements rely on the automated segmentation of bacterial cells in 3D images, which is a technical challenge. To improve the accuracy of single-cell segmentation in 3D biofilms, we first evaluated recent classical and deep learning segmentation algorithms. We then extended StarDist, a state-of-the-art deep learning algorithm, by optimizing the post-processing for bacteria, which resulted in the most accurate segmentation results for biofilms among all investigated algorithms. To generate the large 3D training dataset required for deep learning, we developed an iterative process of automated segmentation followed by semi-manual correction, resulting in >18,000 annotated Vibrio cholerae cells in 3D images. We demonstrate that this large training dataset and the neural network with optimized post-processing yield accurate segmentation results for biofilms of different species and on biofilm images from different microscopes. Finally, we used the accurate single-cell segmentation results to track cell lineages in biofilms and to perform spatiotemporal measurements of single-cell growth rates during biofilm development.


Amelioration of reperfusion injury following hypothermic, ischemic cardioplegia in isolated, infarcted rat hearts.
The left coronary artery was ligated and myocardial infarction developed in 28 rats. Three weeks later, the hearts were excised and mounted in an apparatus for perfusion of non-working isolated hearts (Langendorff). Hypothermic (15 degrees C), ischemic cardioplegia was induced for either 2 or 3 1/2 h followed by reperfusion for 45 min. Half of the hearts were reperfused with an initially gradual rise in temperature and pressure of the perfusion fluid, whereas the other half was reperfused directly with the perfusate at 37 degrees C and 100 cm H2O pressure. The hearts were examined by transmission electron microscopy and randomized for stereological analysis based on point counting on electron micrographs. Cardioplegia of 2 h duration was tolerated better than cardioplegia for 3 1/2 h (interstitial edema; P = 0.03, fraction of altered mitochondria; P = 0.001). Particularly in the hearts undergoing the longest cardioplegia, myocardial injury was less severe following a gentle reperfusion as compared with those exposed to the clinically common abrupt technique (fraction of mitochondria in the myocyte; P = 0.03, fraction of altered mitochondria; P = 0.008). In the interstitium, the luminal area of capillaries was significantly increased and the endothelial swelling less pronounced in the groups undergoing the gentle reperfusion technique, (luminal/endothelial fraction; P = 0.01). The study shows that previously infarcted hearts are susceptible to ischemic damage even after 2 h of regular hypothermic, ischemic cardioplegia and that a gentle reperfusion technique significantly ameliorates reperfusion injury.


Forceps delivery as a risk factor in epilepsy: some further observations.
A total of 381 children born with forceps delivery and 372 with normal delivery were followed up for 4-7 years. More children in the forceps group developed seizures than in the normal group, i.e. 22:10. This was statistically significant (P < 0.05). There was no neurological deficit in any child who had seizures. Both partial and generalized seizures were seen but partial seizures were more frequent.


Transpetrosal approach: an anatomical study of temporal bone.
Resection of the petrous temporal bone to various degrees provides different levels of access to lesions of the posterior fossa. However, regarding the numerous variations, precise distances of petrosal bone are not still clearly described. This may lead to serious complications during transpetrosal surgeries. Our objective was to evaluate different distances of temporal bone landmarks in order to assess their variations and the possible correlations between them. This anatomical study was performed on 60 temporal bones from 60 human cadavers in the years 2006 and 2007. All the bones contained an adequate portion of the petrous apex and attached fossa dura. Twelve landmarks were defined and 27 different distances were measured for each temporal bone using two-point caliper. Less variation was observed in the superoinferior diameter of horizontal carotid canal with the less coefficient of variation (CV) of 9.29; whereas, the most variation was detected in the inferior (axial) plane of posterior semicircular canal to superior plane of jugular bulb (CV = 57.65). There was a significant correlation between vertical intratemporal diameter of carotid in pyramidal direction, and superior-inferior diameter of horizontal carotid canal (r (Pearson) = 0.500, P < 0.001). Other significant correlations were also found between other distances. The variations of different distances and landmarks were evaluated and many significant correlations were demonstrated between them which could potentially aid ENT specialists and neurosurgeons in order to approach anatomical landmarks and cranial fossas more safely during otologic and neurotologic surgeries. It could also help the design of middle ear prosthesis.


Urinary retention during the second trimester of pregnancy: a rare cause.
Acute urinary retention during pregnancy is rare. Retention secondary to an impacted, gravid uterus is an emergency. Retroversion of the uterus, a history of pelvic inflammatory disease, and large fibroids are predisposing factors. The enlarging gravid uterus and uterine fibroids may trap the uterus inside the pelvic ring, preventing it from ascending into the abdominal cavity; furthermore, a history of inflammatory disease may trap the fundus of the uterus within scar tissue that also may prevent the enlarging, gravid uterus from ascending into the abdominal cavity. The impacted uterus should be manually replaced in the anterior position. Clean intermittent catheterization and placement of a vaginal pessary are temporizing measures. A knowledge of the causes of urinary retention during pregnancy can help prevent spontaneous abortion and other devastating consequences that can arise as a result of a delay in the diagnosis.


A standardized glucose-insulin-potassium infusion protocol in surgical patients: Use of real clinical data from a clinical data warehouse.
We evaluated the clinical usefulness of a new unified glucose-insulin-potassium (GIK) regimen in a general surgical department. Surgical patients treated under the previous diverse GIK regimens (September 2016 to August 2017) and the new unified GIK regimen (September 2017 to August 2018) were identified in records of the Clinical Data Warehouse of Seoul National University Bundang Hospital. Serial and area under the curve (AUC) glucose levels, and percentages of time within the target glucose levels were compared in propensity score matched patients in the diverse GIK regimen and in the unified GIK regimen (n = 227 in each group). The AUC of glucose at 6 h and 12 h was lower under the unified GIK regimen than the diverse GIK regimen. The percentage of target glucose levels was higher in the unified GIK regimen compared to the diverse GIK regimen (81.5% vs. 75.0%, P = 0.026), but the occurrence of hypoglycaemia did not differ significantly between groups. The unified GIK regimen was more effective than the diverse GIK regimen for glycaemic control and did not increase the number of patients developing hypoglycaemia. This validated written GIK regimen can be safely used in a general surgical department.


Characteristics and predictors of post-transplant-associated hemophagocytic lymphohistiocytosis in adults.
Hemophagocytic lymphohistiocytosis (HLH) is an uncontrolled hyperinflammatory disorder driven by an overactive immune system that results in high mortality. Post-transplant-associated hemophagocytic lymphohistiocytosis (PT-HLH) is a type of secondary HLH that occurs following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical features of PT-HLH remain unclear and diagnostic and prognostic tools have not yet been established. Here, we retrospectively evaluated the clinical manifestations and outcomes of PT-HLH in 94 patients who underwent allo-HSCT. According to our PT-HLH criteria (hyperferritinemia and increased macrophage count in bone marrow), PT-HLH occurred in 12 patients (12.8%). The PT-HLH patients showed splenomegaly (P = .001), a higher risk of engraftment failure (P = .013), and an increased percentage of macrophages and hemophagocytes in bone marrow aspirates (P = .0009 and P = .0006, respectively). Moreover, univariate and multivariate analyses revealed that the survival rate was lower in PT-HLH patients than non-PT-HLH patients (P = .0017 and P = .034, respectively). This study defines the clinical features of PT-HLH and PT-HLH criteria that could be useful tools for diagnosing PT-HLH.


The Boscombe Valley mystery: A lesson in the perils of dogmatism in science.
The central dogma enunciated by Francis Crick and the postulate that sequence defines protein structure and function put forth by Christian Anfinsen (also referred to as the Thermodynamics Hypothesis) are some of the most fundamental tenets of molecular biology that have had very profound influences and implications. They were formulated based on observations (evidence) that was obvious to the preceptors. However, as is well known, exception is the rule in biology and several works in the literature cite examples that appear to challenge these dogmas suggesting that being dogmatic can be perilous. In this perspective, using the Boscombe Valley Mystery from Sir Arthur Conan Doyle's fabled Sherlock Holmes stories as a paradigm, I ponder the necessity to revise the two dogmas in light of new evidence, especially concerning prions and intrinsically disordered proteins, much like the call for revising the Modern Synthesis to enunciate the Extended Evolutionary Synthesis.


Asthma symptom utility index: reliability, validity, responsiveness, and the minimal important difference in adult asthmatic patients.
The evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess the frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized, and a minimal important difference (MID) is not established. We assessed the reliability, validity, and responsiveness to change of the ASUI in a population of adult asthmatic patients. We also sought to determine the MID for the ASUI. Adult asthmatic patients (n = 1648) from 2 previously completed multicenter randomized trials were included. Demographic information, spirometric results, ASUI scores, and other asthma questionnaire scores were obtained at baseline and during follow-up visits. Participants also kept a daily asthma diary. The internal consistency reliability of the ASUI was 0.74 (Cronbach α). Test-retest reliability was 0.76 (intraclass correlation). Construct validity was demonstrated by significant correlations between ASUI scores and Asthma Control Questionnaire scores (Spearman correlation r = -0.79; 95% CI, -0.85 to -0.75; P < .001) and Mini Asthma Quality of Life Questionnaire scores (r = 0.59; 95% CI, 0.51-0.61; P < .001). Responsiveness to change was demonstrated, with significant differences between mean changes in ASUI scores across groups of participants differing by 10% in percent predicted FEV(1) (P < .001) and by 0.5 points in Asthma Control Questionnaire scores (P < .001). Anchor-based and statistical methods support an MID for the ASUI of 0.09 points. The ASUI is reliable, valid, and responsive to changes in asthma control over time. The MID of the ASUI (range of scores, 0-1) is 0.09.


Anisotropic damage of soft tissues in supra-physiological deformations.
Soft tissues may undergo mechanical damage under supra-physiological deformations caused by medical treatments such as balloon-angioplasty and stent deployment. This damage is exhibited as a softening in the mechanical behavior of tissues. In this work, alteration of the collagen network is treated as the origin of damage and loss of stiffness. Inspired by the hierarchical structure of the collagen network, the mechanical properties of collagenous tissues are connected to model parameters. Softening of esophageal and arterial tissues under directional cyclic loading is investigated to determine evolution of the associated material parameters through damage progress. An evolution law is proposed which predicts the mechanical behavior of tissues after excessive deformations. Various deformation measures are examined as the damage parameter to determine the most appropriate one for general 3D loading. It is observed that, if the Green-Lagrange strain in the direction of the fibers is used as the damage parameter, the proposed law well describes the evolution of the collagen network's stiffness. The results not only facilitate prediction of the deformation-induced damage under supra-physiological deformations but also are useful for surgeons in better planning of surgical procedures and stents design.


Effect of treatment on serum glial cell line-derived neurotrophic factor in bipolar patients.
Post-mortem studies have demonstrated various glial deficits in different brain areas of patients diagnosed with bipolar disorder (BD). Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor beta family which has been implicated in the pathophysiology of BD. This study aimed to determine whether GDNF in serum was abnormal in BD, and how it responded to drug treatment of BD. Serum GDNF concentrations were measured in BD patients before treatment, after 8 weeks of drug treatment, and in control subjects using a sandwich ELISA method. Before treatment, serum GDNF was significantly lower in BD patients during both manic (P<0.001) and depressive (P<0.001) episodes than in control subjects. From baseline to remission after 8 weeks of treatment, the increase in serum GDNF was statistically significant (P<0.001). The present study suggests that lower GDNF levels might be involved in the pathophysiology of BD and drug treatment increases the GDNF in BD.


Anomalous Aortic Origin of the Coronary Arteries: A Novel Unroofing Technique in an Adult Cohort.
Anomalous aortic origin of the coronary arteries (AAOCA) is associated with sudden cardiac death and frequently treated with unroofing of an intramural segment. Most reports on AAOCA are of patients less than 30 years of age. We have reviewed our "older" patients who have undergone surgical repair and report a novel unroofing technique. A retrospective review was conducted of 40 adult patients who underwent surgery for AAOCA from June 2005 to June 2016. Our surgical approach changed from traditional sharp excision to electrical fulguration of the shared intramural wall segment. We assessed our population for symptom relief, resolution of ischemia, and reintervention. More than 6 months of follow-up was available for 34 patients. Mean age was 47.1 ± 11.6 years (range, 19 to 67); 17 patients were female. The coronary anomaly was right from left in 35 patients, left from right 4, and left coronary from noncoronary sinus in 1 patient. Thirty-nine of 40 patients were symptomatic, with two prior sudden cardiac arrests. Preoperatively, 22 of 31 patients tested positive for ischemia, including the asymptomatic. The operation was unroofing in 37 of 40 patients, 17 by sharp excision and 20 by electrical fulguration. There were no 30-day deaths or complications and no reinterventions. Isolated unroofing by fulguration required shorter cardiopulmonary bypass and cross-clamp times than excision: 39 versus 62 minutes (p = 0.02) and 28 versus 42 minutes (p = 0.02), respectively. At an average follow-up of 5.0 years, 28 of 34 patients reported symptomatic improvement. There were two unrelated late deaths. Unroofing by sharp excision and by electrical fulguration were equally safe in the short term. Fulguration is technically easier and faster while still equally effective.


Long-term outcome of peanut oral immunotherapy-Real-life experience.
Oral immunotherapy (OIT) is currently recommended as a treatment option for peanut-allergic patients. Data regarding its long-term compliance and efficacy in real life are required. Peanut-allergic patients aged ≥4 years were enrolled in a single-center clinical OIT program. Buildup to 3000 mg peanut protein was performed. Patients reaching this dose before or after 12/2014 were instructed to consume 3000 or 1200 mg daily, respectively. Patients were followed ≥6 months after reaching maintenance and rechallenged to 3000 mg. Of the 145 patients studied, 113 (77.9%) were fully desensitized to 3000 mg and 133 (91.7%) were desensitized to ≥300 mg. 21/145 patients (14.5%) required adrenaline for home-dose reactions during buildup. Non-anaphylactic gastrointestinal symptoms, experienced by 9 patients (6.2%), reversed with dose reduction. Of the 111 patients available for analysis 6 months after reaching 3000 mg, 97 (87.4%) continued regular peanut consumption. Only 2/111 patients (1.8%) required adrenaline over the long-term (median, range; 18, 6-75 months) follow-up. Adherence to treatment was significantly higher in patients consuming 1200 mg (73/76, 96.1%) vs those consuming 3000 mg (24/35, 72.2%), (P = .001). A higher maintenance dosage and home adrenaline requirement during buildup predicted adherence cessation (OR 12.5, P = .001; and OR 7.8, P = .02, respectively). 63/64 patients (98.4%) consuming 1200 mg maintenance dose were successfully rechallenged to 3000 mg. This real-life experience demonstrates the efficacy of peanut OIT long-term. A lower maintenance dose minimized treatment cessation while maintaining desensitization. OIT should be performed in qualified centers given the prevalence of adverse reactions, particularly during buildup.


Jarid2 links MicroRNA and chromatin in Th17 cells.
In this issue of Immunity, Escobar et al. (2014) bring microRNAs and chromatin together by showing how activation-induced miR-155 targets the chromatin protein Jarid2 to regulate proinflammatory cytokine production in T helper 17 cells.


Older adults' prevention and communication to beat anxiety: the diminishing utility of proactive coping actions.
This study aims to investigate older adults' psychological reactions when facing changes in daily life caused by the COVID-19 pandemic and anti-epidemic measures. Specifically, this study investigated the impacts of communication types (i.e., electronic and face-to-face communication) and frequency during the pandemic and the kinds of proactive coping actions taken by older adults on their anxiety. A total of 43,019 respondents were included in this study by merging two longitudinal databases. One is the seventh wave of the Survey of Health, Ageing and Retirement in Europe (SHARE) conducted in 2017, and the other is the COVID-19 Survey of SHARE, which was conducted between June and August 2020. This study found that one third of older adults reported anxiety symptoms during the COVID-19 pandemic and one fifth reported increased anxiety than before the pandemic. Anxiety symptoms seem somewhat prevalent among older adults during the COVID-19 pandemic. During the pandemic, the more kinds of proactive coping actions taken by older adults, the more likely they felt anxious. As the pandemic continues and develops, taking proactive coping actions might no longer alleviate anxiety in older adults, showing a diminishing utility. In addition, face to face communication was found to decrease the likelihood of anxiety symptoms in older adults, whereas the opposite impact of electronic communication was found. For older adults, contacting others by electronic means may increase their anxiety feeling during the COVID-19 pandemic.


Prevalence of antibodies against Entamoeba histolytica in Mexico measured by ELISA.
The prevalence of antibodies against Entamoeba histolytica was studied in the Mexican population using an immunoenzyme assay in solid phase (ELISA) and semiautomatic equipment. The antigen was a mixture of membrane proteins obtained by Triton X-100 extraction from an axenic culture of Entamoeba histolytica HM1-IMSS. The method was standardized by comparing serum samples from amoebic liver abscess patients with healthy volunteers. From the 60,538 samples supplied by the National Seroepidemiology Survey, antibodies were found in 4.49% (4.32-4.65% at 95% confidence limit). More significant titres occurred in the central region of the country. The ratio female to male was 1.25:1. The population living in metropolitan areas had probably been infected at a younger age than those living in the country. Important differences were found in the seroprevalence obtained by ELISA compared with a study which used indirect haemagglutination (IHA) in the same sample frame.


Decreased expression of the SIN3A gene, a candidate tumor suppressor located at the prevalent allelic loss region 15q23 in non-small cell lung cancer.
To identify the tumor suppressor genes (TSG) associated with non-small cell lung cancers (NSCLC), we performed the loss of heterozygosity (LOH) analysis in NSCLC samples from 66 patients. We focused on the novel hot spot region on 15q14-24 with eight polymorphic microsatellite markers. Frequent allelic loss was detected in 33 of 48 informative cases (69%) at D15S984 on 15q23. We defined the fine map on the region and identified the SIN3A gene as a candidate TSG. The SIN3A gene product is a component of the histone deacetylase (HDAC) complex and plays essential roles in early embryonic development and the proliferation and survival of a variety of cells through the repression of diverse signaling pathways. Our expression analysis revealed more frequent down-regulation of the SIN3A mRNA in 19 of 31 cases (61%) of NSCLCs in comparison to those of other flanking genes (16-42%), albeit the correlation of the decreased expression with the LOH did not attain statistic significance. These results suggest that the attenuated function of SIN3A due to a decreased level of expression may result in epigenetic de-regulation of growth-related genes through histone acetylation, which leads to the tumorigenesis of lung cancer cells. To our knowledge, this is the first evidence of the down-regulation of the SIN3A gene in human cancer.


Convergent olfactory trace amine-associated receptors detect biogenic polyamines with distinct motifs via a conserved binding site.
Biogenic amines activate G-protein-coupled receptors (GPCRs) in the central nervous system in vertebrate animals. Several biogenic amines, when excreted, stimulate trace amine-associated receptors (TAARs), a group of GPCRs in the main olfactory epithelium, and elicit innate behaviors. How TAARs recognize amines with varying numbers of amino groups is largely unknown. We reasoned that a comparison between lamprey and mammalian olfactory TAARs, which are thought to have evolved independently but show convergent responses to polyamines, may reveal structural determinants of amine recognition. Here, we demonstrate that sea lamprey TAAR365 (sTAAR365) responds strongly to biogenic polyamines cadaverine, putrescine, and spermine, and shares a similar response profile as a mammalian TAAR (mTAAR9). Docking and site-directed mutagenesis analyses show that both sTAAR365 and mTAAR9 recognize the two amino groups of cadaverine with the conserved Asp3.32 and Tyr6.51 residues. sTAAR365, which has remarkable sensitivity for cadaverine (EC50 = 4 nM), uses an extra residue, Thr7.42, to stabilize ligand binding. These cadaverine recognition sites also interact with amines with four and three amino groups (spermine and spermidine, respectively). Glu7.36 of sTAAR365 cooperates with Asp3.32 and Thr7.42 to recognize spermine, whereas mTAAR9 recognizes spermidine through an additional aromatic residue, Tyr7.43. These results suggest a conserved mechanism whereby independently evolved TAAR receptors recognize amines with two, three, or four amino groups using the same recognition sites, at which sTAAR365 and mTAAR9 evolved distinct motifs. These motifs interact directly with the amino groups of the polyamines, a class of potent and ecologically important odorants, mediating olfactory signaling.


Eveningness chronotype preference among individuals at clinical high risk for psychosis.
Circadian rhythm disturbances are frequently implicated in psychosis. Indeed, research has suggested several avenues by which circadian rhythms may play a mechanistic role as well as contribute to clinical outcomes. Despite its potential role as a risk factor, little is known about circadian rhythm disruption among individuals at clinical high risk (CHR) for psychosis, clinical correlates, or specificity to the psychosis risk syndrome. Eighty-four CHR, 74 individuals with depressive disorders (DD), and 101 non-psychiatric controls (NPC) participated in structured clinical interviews and provided self-reports of chronotype preference. Clinical (positive, negative, anxious, and depressive symptoms) and social functioning outcomes were self-reported and/or clinician-rated. Analyses of covariance controlling for demographics examined group differences in chronotype preference, and partial Pearson correlations evaluated associations with clinical/functional outcomes. Group differences were observed (F(11, 246) = 8.05, p < .001) with CHR and DD individuals indicating greater eveningness preference compared to NPC. A follow-up sensitivity analysis examining CHR participants with (n = 25) and without (n = 59) depressive disorders indicated no difference in chronotype preference (F(10,72) = 0.00, p = .99). Greater eveningness preference was related to greater negative symptoms (i.e., avolition; r = -0.25) and anxiety (r = -0.34) among CHR individuals. CHR and DD display greater preference for eveningness chronotype compared to NPC indicating the disruption is associated with a range of mental health concerns, and not specific to the psychosis-risk syndrome. However, comorbidity with DD did not appear to be driving the finding in the CHR group. Further research may examine shared versus non-shared underlying mechanisms contributing to chronotype preference across psychiatric presentations.


In vivo biological effects of foam sclerotherapy.
This study aims to assess by biological markers the in vivo consequences of foam sclerotherapy (FS) of saphenous veins. The secondary objective of this randomised controlled trial (RCT) is to compare results of two randomised groups: with or without post-treatment compression. Forty patients with incompetent great or small saphenous veins underwent ultrasound-guided FS. Randomisation was conducted immediately after sclerotherapy to two parallel groups, one (CG) with compression stockings and the other (WCG) without compression. A laboratory work-up was done on days 0 (before sclerotherapy), 1, 7, 14 and 28. The studied markers were: fibrinogen, factor VIII, thrombomodulin, thrombin-antithrombin complex, D-dimers, platelet factor 4 and troponin. General data repartition was homogenous for CG and WCG. Twenty patients were included in each group (females 90%; mean age 58 years). On day 28 (D28), the occlusion rate of the veins was 100% in both groups. In all the samples (D0-D28), apart from a moderate D-dimers' increase at D1-D14, no significant biological change was observed in either the WCG or the CG groups. In terms of inflammation and coagulation, FS seems to have a minimal effect on peripheral blood, either with or without post-treatment compression and does not appear to have an effect on the myocardial risk.


Plasmodium spp.: an experimental study on vertebrate host susceptibility to avian malaria.
The interest in experimental studies on avian malaria caused by Plasmodium species has increased recently due to the need of direct information about host-parasite interactions. Numerous important issues (host susceptibility, development of infection, the resistance and tolerance to avian malaria) can be answered using experimental infections. However, specificity of genetically different lineages of malaria parasites and their isolates is largely unknown. This study reviews recent experimental studies and offers additional data about susceptibility of birds to several widespread cytochrome b (cyt b) lineages of Plasmodium species belonging to four subgenera. We exposed two domesticated avian hosts (canaries Serinus canaria and ducklings Anas platyrhynchos) and also 16 species of common wild European birds to malaria infections by intramuscular injection of infected blood and then tested them by microscopic examination and PCR-based methods. Our study confirms former field and experimental observations about low specificity and wide host-range of Plasmodium relictum (lineages SGS1 and GRW11) and P. circumflexum (lineage TURDUS1) belonging to the subgenera Haemamoeba and Giovannolaia, respectively. However, the specificity of different lineages and isolates of the same parasite lineage differed between species of exposed hosts. Several tested Novyella lineages were species specific, with a few cases of successful development in experimentally exposed birds. The majority of reported cases of mortality and high parasitaemia were observed during parasite co-infections. Canaries were susceptible mainly for the species of Haemamoeba and Giovannolaia, but were refractory to the majority of Novyella isolates. Ducklings were susceptible to three malaria infections (SGS1, TURDUS1 and COLL4), but parasitaemia was light (<0.01%) and transient in all exposed birds. This study provides novel information about susceptibility of avian hosts to a wide array of malaria parasite lineages, outlining directions for future experimental research on various aspects of biology and epidemiology of avian malaria.


[Dopaminergic receptors].
The functions of multiple brain dopamine receptors are discussed in relation to the physiological role of dopamine in CNS.


Printing and mounting digital casts in the centric relation position for use on an analog articulator: A dental technique.
A technique for recording, printing, and mounting digital casts in centric relation is described. Combining elements of analog and digital workflows, centric relation records can be transferred by digital scanning and used to align casts for articulation. This method is useful to the clinician adapting to digital workflow or preferring a physical semiadjustable articulator in conjunction with digital scans.


Purification of the insulin-like growth factor II (IGF-II) receptor from an IGF-II-producing cell line, and generation of an antibody which both immunoprecipitates and blocks the type 2 IGF receptor.
18,54-SF cells, which secrete rat insulin-like growth factor II (rIGF-II), have abundant type 2 IGF receptors. We have purified the type 2 receptor from these cells by solubilization of crude membranes in Triton X-100, followed by chromatography on agarose-immobilized rIGF-II. A partially purified receptor preparation, obtained by chromatography of solubilized membranes over wheat germ agglutinin, was used to immunize a rabbit. The antibody generated both immunoprecipitates the type 2 receptor, and specifically inhibits IGF-II binding to a variety of rat tissues, including 18,54-SF cells, BRL-3A cells and placenta. The presence of abundant type 2 receptors on an rIGF-II-secreting cell line is consistent with an autocrine role for IGF-II in select cells.


Design of nanoemulgel using Argania spinosa microfibrillated cellulose and natural emulsifiers foreseeing melanogenesis enhancement.
Nanotechnology is a route of choice that improves administration and efficacy of bioactive compounds. In this study, nanoemulgels were prepared using microfibrillated cellulose from Argania spinosa shell (AS-MFC) and Argan shell (ASE) or Argan press cake extracts (APC) as natural emulsifiers. Oil-in-water (O/W) nanoemulsions were prepared using different natural emulsifiers or synthetic emulsifiers and presented a nano size (d3,2 < 140 nm). Following that, the nanoemulsions were incorporated within AS-MFC matrix and rheological properties confirmed a shear thinning behavior. Confocal micrographs of nanoemulgels confirmed the dispersion of nanoemulsions in the AS-MFC network without affecting the nanoemulsions stability. Finally, in vitro bioassay on B16F10 using ASE or APC nanoemulsions was conducted. This study confirmed cell permeation in B16F10 cells of formulated nanoemulsions and the upregulation of melanin content up to 30% more that the untreated cells. This study designed novel MFC nanoemulgel with high potential application in healthcare and cosmetic field.


Polyurethane-functionalized starch nanocrystals as anti-tuberculosis drug carrier.
Studies related to loading ability and delivery of clinically used first-line anti-tuberculosis drugs (ATDs) such as isoniazid, rifampicin, pyrazinamide and streptomycin on the surface of starch-derived bulk and nanopolyurethanes (SBPUs and SNPUs) as drug delivery systems (DDS) have been focused to minimise or remove the drug-associated adverse effects. The efficiencies of nanopolyurethanes obtained from the differently substituted cyclic aliphatic and aromatic isocyanates have been studied for drug loading and release purposes. Different advanced instrumental techniques analysed the structural and morphological properties, thermal stability and crystallinity of the starch nanopolyurethans. Average particle sizes ranging from 27.35-42.38 nm to 126.89-218.60 nm for starch nanopolyurethans, SNPU3i and SNPU4i, respectively, were determined by high-resolution transmission electron microscopy. Similarly, the loading efficiency of ATDs to the surfaces of SNPUs and SBPUs was observed in the range of 60-97% while ATDs-loaded SNPUs showed a sustainable release profile for all ATDs except for streptomycin. However, most SBPUs provided burst-release for all the above-mentioned ATDs in pH-dependent studies. The anti-tuberculosis assay against the Mycobacterium tuberculosis H37Rv strain revealed that streptomycin-loaded SNPU4i and isoniazid-loaded SNPU7i are approximately 42 and 7 times more active than the native streptomycin and isoniazid, respectively.


Quantitative EEG effects of topiramate.
The study is to invesigate the effect of topiramate (TPM) on EEG by means of quantitative pharmacoelectroencephalography (QPEEG). One dose of TPM was administrated to epileptics and healthy adults. The EEG samples were obtained prior to and at regular intervals within the 24 hours following the administration of TPM. The EEG activity was processed with power spectral analysis. The power of slow wave, alpha 1 bands and total power increased after the administration of TPM, the power or slow wave in both occipital areas, and the total power of all scalp areas also increased. The percent of power increased at the theta band and alpha 1 band (healthy adults) or delta band, theta band (patients). TPM can change the EEG background activity. These changes are different from other antiepileptic drugs.


Perioperative respiratory management with fiberoptic bronchoscopy in pediatric living-related liver transplantation.
Perioperative respiratory complications have been one of the largest obstacles to pediatric management of pediatric liver The roles of fiberoptic bronchoscopy in perioperative respiratory management of pediatric liver transplantation were studied retrospectively. In a group of 162 children who underwent pediatric living-related liver transplantation, 44 underwent 222 bronchoscopic procedures for diagnostic and therapeutic purposes during the perioperative period. Major indications for bronchoscopy were atelectasis/retention of airway secretion (n = 27), pneumonia (n = 19), pulmonary edema (n = 8), airway stenosis (n = 7), and airway bleeding (n = 6). Visualization of the airway was helpful in diagnosing respiratory complications; in seven infants, bronchoscopy revealed tracheobronchial stenosis that other diagnostic modalities failed to detect. In 16 of 19 patients with pneumonia, specimens taken by bronchoscopy were positive for specific pathogens. Bronchoscopy also proved to have significant therapeutic value, especially in airway cleaning; bronchial suctioning resulted in immediate reexpansion of the collapsed lung in 16 of 20 cases of atelectasis. No complications were noted other than severe hypoxia and bradycardia in one infant. Fiberoptic bronchoscopy is a safe and useful modality for perioperative respiratory management in pediatric liver transplantation.


Associations of the pre-pregnancy weight status with anaemia and the erythropoiesis-related micronutrient status.
The coexistence of underweight (UW) and overweight (OW)/obese (OB) at the population level is known to affect iron deficiency (ID) anaemia (IDA), but how the weight status affects erythropoiesis during pregnancy is less clear at a population scale. This study investigated associations between the pre-pregnancy BMI (pBMI) and erythropoiesis-related nutritional deficiencies. Anthropometry, blood biochemistry and 24-h dietary recall data were collected during prenatal care visits. The weight status was defined based on the pBMI. Mild nutrition deficiency-related erythropoiesis was defined if individuals had an ID, folate depletion or a vitamin B12 deficiency. The Nationwide Nutrition and Health Survey in Taiwan (Pregnant NAHSIT 2017-2019). We included 1456 women aged 20 to 45 years with singleton pregnancies. Among these pregnant women, 9·6 % were UW, and 29·2 % were either OW (15·8 %) or OB (13·4 %). A U-shaped association between the pBMI and IDA was observed, with decreased odds (OR; 95 % CI) for OW subjects (0·6; 95 % CI (0·4, 0·9)) but increased odds for UW (1·2; 95 % CI (0·8, 2·0)) and OB subjects (1·2; 95 % CI (0·8, 1·8)). The pBMI was positively correlated with the prevalence of a mild nutritional deficiency. Compared to normal weight, OB pregnant women had 3·4-fold (3·4; 95 % CI (1·4, 8·1)) higher odds for multiple mild nutritional deficiencies, while UW individuals had lowest odds (0·3; 95 % CI (0·1, 1·2)). A dietary analysis showed negative relationships of pBMI with energy, carbohydrates, protein, Fe and folate intakes, but positive relationship with fat intakes. The pre-pregnancy weight status can possibly serve as a good nutritional screening tool for preventing IDA during pregnancy.


Late side effects of radioactive iodine on salivary gland function in patients with thyroid cancer.
The purpose of this study was to assess the late side effects of radioiodine therapy (RIT) on salivary gland function. One hundred eighty two patients were evaluated. Assessment of salivary gland function was performed with salivary gland scintigraphy (SGS), sialometry, and subjective open questions to determine common side effects of RIT on salivary gland function. RIT had a strong association with decreased elimination counts by SGS. Patient age was the only variable associated with sialometry; age and the use of xerostomic drugs were strongly associated with decreased mean values of salivary flow. Dysphagia was strongly associated with RIT. Using multiple logistic regression analysis, age was determined to be an important factor associated with salivary gland dysfunction, and RIT was associated with impairment of saliva excretion. These results show that patients subjected to RIT have more difficulty in draining saliva, mainly from the parotid glands, which is associated with clinical dysphagia in this subset of patients.


Burns as a result of domestic accidents and their prevention.
Over a 1-year period (October 1990 to October 1991), 100 patients with burns due to domestic accidents have been admitted to our Burn Unit. The total number of burn admissions was 238. There is a relative abundance of data in the burn literature, clearly depicting local characteristics and peculiarities in different countries or societies. Our purpose is to present some statistical, epidemiological and socioeconomic data from Greek society, as well as to compare data from other countries.


Sex differences in growth performance are related to cecal microbiota in chicken.
In poultry industry, male chickens have a better growth performance than female ones under the same genetic background and diet. Emerging evidences proposed an important role of intestinal microbiota in chicken's growth performance. This study aimed to determine gut microbiota related gender based differences in the growth performance of chickens. Therefore, male and female chickens (n = 20) at 7-week age were used to carry out histomorphological, molecular, gene expression analysis with their liver, chest and leg muscle, as well as 16S rRNA sequencing analysis for gut microbiota. The results revealed that Bacteroides and Megamonas genera were more prominently colonized in the cecum of male chickens. The male chicken's cecal microbiota indicated a closer relation with glycan metabolism, while in the female chickens it was more related with lipid metabolism. Gene expression levels associated with glycan and lipid metabolism were different between male and female chickens. Further, using Spearman correlation analysis, we found a positive correlation between glycan and lipid metabolism, and the relative abundance of Bacteroides, Megamona and Lactobacillus in male chickens. Similarly, we also found a positive correlation between the lipid metabolism and the relative abundance of Ruminococcaceae and Enterococcus in female chickens. These findings revealed the association of chicken growth performance with cecal microbiota that contributed to the metabolism of glycan and lipid in a sex-dependent manner.


Consensus Molecular Subtypes Efficiently Classify Gastric Adenocarcinomas and Predict the Response to Anti-PD-1 Immunotherapy.
Background: Gastric adenocarcinoma (GAC) is highly heterogeneous and closely related to colorectal cancer (CRC) both molecularly and functionally. GAC is currently subtyped using a system developed by TCGA. However, with the emergence of immunotherapies, this system has failed to identify suitable treatment candidates. Methods: Consensus molecular subtypes (CMSs) developed for CRC were used for molecular subtyping in GAC based on public expression cohorts, including TCGA, ACRG, and a cohort of GAC patients treated with the programmed cell death 1 (PD-1) inhibitor pembrolizumab. All aspects of each subtype, including clinical outcome, molecular characteristics, oncogenic pathway activity, and the response to immunotherapy, were fully explored. Results: CMS classification was efficiently applied to GAC. CMS4, characterized by EMT activation, stromal invasion, angiogenesis, and the worst clinical outcomes (median OS 24.2 months), was the predominant subtype (38.8%~44.3%) and an independent prognostic indicator that outperformed classical TCGA subtyping. CMS1 (20.9%~21.5%) displayed hypermutation, low SCNV, immune activation, and best clinical outcomes (median OS > 120 months). CMS3 (17.95%~25.7%) was characterized by overactive metabolism, KRAS mutation, and intermediate outcomes (median OS 85.6 months). CMS2 (14.6%~16.3%) was enriched for WNT and MYC activation, differentiated epithelial characteristics, APC mutation, lack of ARID1A, and intermediate outcomes (median OS 48.7 months). Notably, CMS1 was strongly correlated with immunotherapy biomarkers and favorable for the anti-PD-1 drug pembrolizumab, whereas CMS4 was poorly responsive but became more sensitive after EMT-based stratification. Conclusions: Our study reveals the practical utility of CMS classification for GAC to improve clinical outcomes and identify candidates who will respond to immunotherapy.


[Severe coarctation of the aorta in children revealed by high blood pressure: a case report].
Coarctation of the aorta is an obstructive aortic lesion that causes secondary hypertension. Diagnosis is sometimes difficult because patients could present no other symptom. An asymptomatic 20-month-old child was referred in the context of isolated high blood pressure. Echocardiography was not effective, but CT scan established the diagnosis of coarctation. This case report underlines the importance of blood pressure measurement in the detection of aortic obstructions in the pediatric population.


Smartphone photography for smart assessment of post-surgical wounds - an experience during the COVID-19 pandemic.

Aim: This study was undertaken with an aim to assess the feasibility of monitoring of wound healing by replacement of the traditional real-life clinical follow-up with a review of smartphone-captured digital photographs of post-surgical wounds by a clinician.

Method: The postoperative patients who understood the objectives got enrolled in the prospective study and were followed up. They were requested to capture digital photographs of the wounds using smartphones and send them through WhatsApp on postoperative days 3, 5, 7, 15 and 30 or else whenever they felt need for review due to symptoms like fever, pain, redness or swelling.

Results: 24 abdominal, 2 extremity and 1 neck wounds were followed up in 27 patients. Three patients developed complications and all were detected with 100% accuracy. As many as 81% of the patients were satisfied with this mode of postoperative wound assessment.

Conclusion: The experience shows that in the follow-up of postsurgical wounds, there is a good correlation between real-life clinical and remote photographic review. Incorporating photographic wound assessment into the postoperative follow-up care pathway can potentially decrease the number of postoperative hospital visits and decrease the burden on healthcare facilities.</br&gt.


Effects of Mediterranean diet on hospital length of stay, medical expenses, and mortality in elderly, hospitalized patients: A 2-year observational study.
The Mediterranean diet (MedDiet) has been related to reduced overall mortality and improved disease outcome. The aim of this study was to estimate the effects of the MedDiet on hospital length of stay (LOS), financial cost, and mortality (from hospitalization up to 24 mo afterward) in hospitalized patients >65 y of age. Participating in this observational study were 183 patients >65 y of age, who were urgently admitted for any cause to the Internal Medicine Department of Argolidos General Hospital. Hospital LOS and its financial cost, mortality (during hospitalization, 6 and 24 mo after discharge), physical activity, and medical and anthropometric data were recorded and correlated with the level of adherence to the MedDiet (MedDiet score). In multivariate analyses, hospital LOS decreased by 0.3 d for each unit increase of MedDiet score (P < 0.0001), 2.1 d for each 1 g/dL increase of albumin (P = 0.001) and increased 0.1 d for each day of previous admissions (P < 0.0001). Extended hospitalization (P < 0.0001) and its interaction with MedDiet score (P = 0.01) remained the significantly associated variables for financial cost. Mortality risk increased 3% per each year increase of age (hazard ratio [HR], 1.03; P = 0.02) and 6% for each previous admission (HR, 1.06; P = 0.04); whereas it decreased 13% per each unit increase of MedDiet score (HR, 0.87; P < 0.0001). Adoption of the MedDiet decreases duration of admission and long-term mortality in hospitalized patients >65 y of age, with parallel reduction of relevant financial costs.


[Dwarfism due to deprivation associated with deep sleep deficiency (author's transl)].
The authors report sleep disturbances in a case of dwarfism due to deprivation. Polygraphic recording of sleep showed a deficiency in deep sleep which is the normal stimulus for hgH secretion. This might explain the deficiency of hgH frequently encountered in this form of dwarfism.


[Benign pleural mesothelioma. Report of 2 cases].
We report two cases of benign pleura mesothelioma. We compare our pre-, intra- and postoperative findings with other reports in the literature. This tumor is rare. The patients have few symptoms. Large tumors may cause hypoglycemia. The treatment of choice is complete resection of the tumor. The prognosis is good.


The effect of prophylactic ampicillin on pelvic infection following vaginal hysterectomy.
One hundred patients undergoing vaginal hysterectomy at the University of Kentucky Medical Center were given prophylactic ampicillin and compared to one hundred control patients. The use of prophylactic ampicillin caused significant reduction in both postoperative pelvic infection and hospital stay. However, two patients in the prophylactic antibiotic group later required readmission for infections resistant to ampicillin. Prophylactic antibiotics are beneficial in vaginal hysterectomy, but careful follow-up of all patients is mandatory.


The application of post-market monitoring to novel foods.
The role of post-market monitoring (PMM) in the safety assessment of novel foods is critically discussed in order to derive guidelines as to in which situations the application of PMM might be warranted. Available data sources on food consumption and health status, and the methodologies for generating such data are reviewed. The paper suggests improvements to make them more applicable for PMM purposes. It is concluded that any PMM programme must be a hypothesis-driven scientific exercise. PMM can have a role as a complement to, but not as a replacement for, a comprehensive pre-market safety assessment. Its use may be appropriate to confirm that product use is as predicted in the pre-market assessment; to provide reassurance that effects observed in the pre-market assessment occur with no greater frequency or intensity in the post-market phase than anticipated; and to investigate the significance of any adverse effects reported by consumers after market-launch. However PMM is insufficiently powerful to test the hypothesis that any effects seen in the pre-market assessment are absent in the post-market phase. Current methodologies place limitations on what PMM can achieve. PMM should only be used when triggered by or when the focus is on specific evidence-based questions.


Assessing the Individual Interviewer Rapport-Building and Supportive Techniques of the R-NICHD Protocol.
The use of the rapport-building and supportive techniques formulated by the R-NICHD protocol is intended to support children and increase the quality of their statements as well as disclosures without possessing suggestive potential. While the effectiveness of the entire R-NICHD protocol for children who have actually experienced child sexual abuse (CSA) has been supported by research, to date no study assessed the effect of each individual socio-emotional interview technique in both interviewees with and without CSA experiences. The current study aimed to address this gap in research by means of an online vignette-study, asking participants to rate the identified rapport-building and supportive techniques on the scales well-being, willingness to talk, and perceived pressure. A total of 187 participants were randomly assigned to either a hypothetical "abused" or a hypothetical "not abused" group by means of a vignette-manipulation. The results suggest that many socio-emotional interview techniques were perceived as supportive and non-suggestive, while a number of techniques were perceived as not supportive but suggestive. Few differences emerged between the hypothetical "abused" group and the hypothetical "not abused" control group. To conclude, most but not all rapport-building and supportive techniques proposed by the R-NICHD protocol had a positive effect on interviewees.


Ascending colon cancer accompanied by tumor thrombosis in the superior mesenteric vein: A case report.
Venous tumor thrombosis occasionally accompanies renal cancer, liver cancer, and pancreatic cancer. Colorectal cancer is seldom accompanied by venous tumor thrombosis in the portal vein or the superior or inferior mesenteric veins (SMV, IMV), and little is known about its features. We report a case of ascending colon cancer with tumor thrombosis in the SMV treated with right hemicolectomy and combined resection of the SMV. An 82-year-old man with chief complaints of loss of appetite was admitted to our hospital. He was diagnosed with ascending colon cancer accompanied with tumor thrombosis extending to the SMV. He underwent right hemicolectomy and combined resection of the tumor thrombosis and the SMV. Intestinal blood flow was evaluated by intraoperative indocyanine green (ICG) fluorography. He continued to recover well from surgery. No adjuvant chemotherapy was employed because of the patient's advanced age and his own will. He was transferred to another hospital on postoperative day 39. Six months after surgery, abdominal CT showed multiple liver metastases. He died 8 months after surgery. Radical resection of the primary tumor and surgical thrombectomy should be considered for the treatment of colorectal cancer without distant metastasis accompanied by tumor thrombosis. However, venous tumor thrombosis is representative of an aggressive cancer and that may be a strong risk factor for the development of liver metastasis. Adjuvant systematic chemotherapy in addition to complete surgical resection may be one of the treatment strategies.


Comparison of sister-chromatid exchange induced by photoactivated 3-carbethoxypsoralen and 8-methoxypsoralen in human blood lymphocytes.
The induction of sister-chromatid exchange (SCE) by a photoactivated monofunctional derivative of psoralen, 3-carbethoxypsoralen (3-CPs) was compared with that of the bifunctional compound, 8-methoxypsoralen (8-MOP). Lymphocytes were exposed in vitro to a series of equimolar concentrations of the drugs as well as to increasing doses of long-wave ultraviolet light (UVA) and second-division metaphases examined for SCE. The drugs or UVA per se did not influence the incidence of SCE. However, combination of the drug and UVA exposure resulted in a dose-dependent increase in SCE and such elevation was less pronounced with 3-CPs as compared to 8-MOP. This difference between 3-CPs and 8-MOP could be due to the difference in the types of lesions induced/repaired in DNA.


Formation of lipid-bound oligosaccharides in yeast.
Incubation of a membrane fraction from Saccharomyces cerevisiae with UDP-N-acetyl [14C]glucosamine catalyzes the transfer of N-acetylglucosamine to an endogenous lipid fraction as well as a methanol-insoluble polymer. The glycolipid was shown to separate into three compounds by thin-layer chromatography. The biosynthesis of two of them could clearly be stimuated by the addition of dolichol monophosphate to the incubation mixture. Evidence is presented that the substances are dolichol pyrophosphate derivatives: dolichol pyrophosphate N-acetylglucosamine and dolichol pyrophosphate di-N-acetylchitobiose. The formation of the chitobiose-containing lipid was increased by reincubation of the glycolipid with non-radioactive UDP-N-acetylglucosamine. The same particulate preparation transferred mannose from GDPmannose to dolichol pyrophosphate di-N-acetylchitobiose, giving rise to a lipid-bound oligosaccharide. Molecular weight determination of the oligosaccharide moiety gave a value of 780, which is consistent with a tetrasaccharide containing two mannose subunits attached to di-N-acetylchitobiose. The methanol-insoluble radioactive product obtained in the presence of UDP-N-acetyl[14C]glucosamine was transformed by pronase treatment to a large extent into dialyzable material. It is suggested that the glycolipids described serve as intermediates in the glycosylation of yeast mannoproteins.


Immunohistochemical expression of MAM-3 and MAM-6 antigens in salivary gland tumours.
MAM-3 and MAM-6 antigens of human milk fat globule membrane were detected immunohistochemically in 93 cases of salivary gland tumours as well as in normal glands. The antigens were visualized in 10% formalin-fixed paraffin sections. MAM-3 (MoAbs 115G3, 67D11) antigen was distributed in intercalated and striated duct cells of the normal salivary glands, and in luminal tumour cells and squamous metaplastic cells of pleomorphic adenomas. In pleomorphic adenomas the frequency of positive staining with MoAb 67D11 (54/67; 80.6%) was higher than that with MoAb 115G3 (36/67; 53.7%). MAM-6 (MoAbs 115D8, 115F5) antigen was expressed in luminal and lateral borders of serous acinar cells and ductal of the normal glands, and also in luminal borders of tubulo-ductal and glandular structures of salivary gland tumours. Ductal basal cells were characterized by existence of positive staining for MAM-6 antigen, in adenolymphomas MAM-6 antigen was restricted to the basal tumour cells. Some mucous cells of mucoepidermoid tumours were stained specifically with MoAb 115G3, and epidermoid cells of mucoepidermoid carcinomas manifested MAM-6 antigen staining. Immunohistochemical localization of MAM-6 antigen resembled that of epithelial membrane antigen (EMA) detected with MoAb.


Delayed presentation of ilio-iliac arteriovenous fistula following laparoscopic cholecystectomy treated with percutaneous graft-covered stent placement.
Major vascular injuries during laparoscopic cholecystectomy are rare, usually readily apparent, and immediately treated. We report a case of delayed presentation of a retroperitoneal vascular injury. The patient presented with abdominal pain and increasing edema of the lower extremities 1 year after laparoscopic cholecystectomy and was found to have an ilio-iliac arteriovenous fistula. Endovascular treatment was accomplished using a graft-covered polytetrafluoroethylene stent. The patient remained free of symptoms at 1-year follow-up.


Arteriographic and tomodensitometric pictures in three cases of popliteal artery entrapment.
CT could be an effective diagnostic modality of "popliteal artery entrapment". The authors present three cases of this pathology, studied with CT and arteriography.


Asymmetric synthesis of γ-chiral borylalkanes via sequential reduction/hydroboration using a single copper catalyst.
The synthesis of γ-chiral borylalkanes through copper-catalyzed enantioselective SN2'-reduction of γ,γ-disubstituted allylic substrates and subsequent hydroboration was reported. A copper-DTBM-Segphos catalyst produced a range of γ-chiral alkylboronates from easily accessible allylic acetate or benzoate with high enantioselectivities up to 99% ee. Furthermore, selective organic transformations of the resulting γ-chiral alkylboronates generated the corresponding γ-chiral alcohol, arene and amine compounds.


Preparation and corrosion resistance of magnesium phytic acid/hydroxyapatite composite coatings on biodegradable AZ31 magnesium alloy.
In this work, a magnesium phytic acid/hydroxyapatite composite coating was successfully prepared on AZ31 magnesium alloy substrate by chemical conversion deposition technology with the aim of improving its corrosion resistance and bioactivity. The influence of hydroxyapatite (HA) content on the microstructure and corrosion resistance of the coatings was investigated. The results showed that with the increase of HA content in phytic acid solution, the cracks on the surface of the coatings gradually reduced, which subsequently improved the corrosion resistance of these coated magnesium alloy. Electrochemical measurements in simulated body fluid (SBF) revealed that the composite coating with 45 wt.% HA addition exhibited superior surface integrity and significantly improved corrosion resistance compared with the single phytic acid conversion coating. The results of the immersion test in SBF showed that the composite coating could provide more effective protection for magnesium alloy substrate than that of the single phytic acid coating and showed good bioactivity. Magnesium phytic acid/hydroxyapatite composite, with the desired bioactivity, can be synthesized through chemical conversion deposition technology as protective coatings for surface modification of the biodegradable magnesium alloy implants. The design idea of the new type of biomaterial is belong to the concept of "third generation biomaterial". Corrosion behavior and bioactivity of coated magnesium alloy are the key issues during implantation. In this study, preparation and corrosion behavior of magnesium phytic acid/hydroxyapatite composite coatings on magnesium alloy were studied. The basic findings and significance of this paper are as follows: 1. A novel environmentally friendly, homogenous and crack-free magnesium phytic acid/hydroxyapatite composite coating was fabricated on AZ31 magnesium alloy via chemical conversion deposition technology with the aim of enhancing its corrosion resistance and bioactivity. The chemical conversion coatings, which are formed through the reaction between the substrate and the environment, have attracted increasing attention owing to the relative low treatment temperature, favorable bonding to substrate and simple implementation process. 2. With the increasing of hydroxyapatite (HA) content, the crack width in the composite coatings and the thickness of the coatings exhibit obviously decreased. The reason is probably that when adding HA into the phytic acid solution, the amount of active hydroxyl groups in the phytic acid are reduced via forming the coordination bond between P-OH groups from phytic acid and P-OH groups from the surface of HA, thus decreasing the coating thickness and hydrogen formation, as well as avoiding coating cracking. 3. By adjusting the HA content to 45 wt.%, a dense and relatively smooth composite coating with ~1.4 μm thickness is obtained on magnesium alloy, and exhibits high corrosion resistance and good bioactivity when compared with the single phytic acid conversion coating.


Assessment of Lipotoxic Endoplasmic Reticulum (ER) Stress in Nonalcoholic Steatohepatitis (NASH).
Hepatocyte lipotoxicity is a hallmark of nonalcoholic steatohepatitis (NASH), and lipid induced liver injury occurs, in part, via activation of endoplasmic reticulum (ER) stress. Consequently, the unfolded protein response (UPR) is initiated, driven by three key ER transmembrane proteins, resulting in downstream responses that are dynamic and interconnected. Thus, careful interrogation of these pathways is required to investigate the complex role of ER stress in NASH. Herein, we describe different mechanisms of, and in vitro assays for assessment of lipotoxic ER stress in mouse hepatocytes.


Establishment of three Joubert syndrome-derived induced pluripotent stem cell (iPSC) lines harbouring compound heterozygous mutations in CC2D2A gene.
We have developed Joubert syndrome (JS)-derived induced pluripotent stem cell (iPSC) lines from dermal fibroblasts biopsied from a female patient harbouring novel compound heterozygous mutations in CC2D2A gene. The newly established iPSC lines provide tremendous promises for development of JS-derived neuronal cell lines to uncover the molecular and cellular mechanisms underlying the pathogenesis of JS and to develop therapeutic interventions for treatment of JS.


Comparison of Indocyanine Green Angiography and Fluorescein Angiography for Imaging of Central Serous Chorioretinopathy Patients as Candidates for Photodynamic Therapy.
To compare fluorescein angiography (FA) and indocyanine green angiography (ICGA) for imaging of central serous chorioretinopathy (CSC) patients. The observational cross-sectional clinical study was conducted on 131 eyes of 131 patients with CSC who were candidates for photodynamic therapy (PDT). An experienced ophthalmologist marked the leakage sites and choroidal hyperpermeability sites that needed PDT. For each eye, simultaneous FA and ICGA imaging with the maximum leakage area was selected for comparison regarding the site and size. The mean±standard deviation age of patients was 44.53±9.03 years. Of 226 leakage points, 177 (78.32%) points were in the same site, and 168 (74.34%) points were in the same size on FA. No statistical difference was found between age (P=0.45), sex (P=0.32), and chronicity (P=0.11) of the disease in comparing the ICGA images to the FA images regarding leakage at the same site. A statistically significant difference was also found regarding size of leakage and chronicity (P<0.001). The current results suggested that FA could be considered an alternative ocular imaging technology as a guide for PDT in CSC patients.


Live three-dimensional transthoracic echocardiographic assessment of transcatheter closure of atrial septal defect and patent foramen ovale.
We report the usefulness of live three-dimensional transthoracic echocardiography in the accurate assessment of the morphology and efficacy of Amplatzer transcatheter devices used for closure of atrial septal defect and patent foramen ovale.


Spino-cerebellar tDCS modulates N100 components of the P300 event related potential.
To evaluate the role of the cerebellum and spinal cord in cognitive processes, we assessed changes in event-related potentials (ERPs), before and after different combinations of spinal and cerebellar direct current stimulation (tDCS) in healthy subjects. We enrolled 37 volunteers (11 males and 26 females, aged 20-50 years), who were subsequently randomly assigned to one of four stimulation conditions: i) anodal cerebellar tDCS, with the reference electrode over the right shoulder; ii) anodal spinal tDCS, with the reference electrode over the right shoulder; iii) anodal spinal tDCS with cathodal cerebellar tDCS, and iv) sham stimulation. Stimulation intensity was set at 2 mA and delivered for 20 min. ERPs were assessed in an auditory oddball task before (T0) and 5 (T1) and 30 min (T2) after tDCS offset. In condition iii, spino-cerebellar tDCS, the N100 component at T2 increased in amplitude by 60% (p = 0.019), whereas the sham stimulation left the N100 amplitude unchanged (p > 0.05). The N100 wave reflects pre-attentive processes and correlates with arousal due to a specific stimuli and selective attention. Because spino-cerebellar tDCS induces electric fields in the brainstem, the facilitation of the N100 may be due to the modulation of the reticular formation. Regardless of the underlying mechanism, spino-cerebellar tDCS can help patients with deficits at the pre-attentive or selective attentional level.


Discovering novel direct acting antiviral agents for HBV using in silico screening.
The treatments for chronic hepatitis B (CHB) are interferon and nucleoside analogues reverse transcriptase (RT) inhibitors. Because both treatments are less than ideal, we conducted to identify novel anti-viral agents for HBV-reverse transcriptase (HBV-RT). We determined the ligand-binding site of the HBV-RT by conducting a homological search of the amino acid sequence and then we also determined not only structural arrangement of the target protein but the target protein-binding site of the ligand using known protein-ligand complexes in registered in the protein data bank (PDB). Finally we simulated binding between the ligand candidates and the HBV-RT and evaluated the degree of binding (in silico screening). PXB cells derived from human-mouse chimeric mouse liver, infected with HBV were administrated with the candidates, and HBVDNA in the culture medium was monitored by realtime qPCR. Among compounds from the AKosSamples database, twelve candidates that can inhibit RT were also identified, two of which seem to have the potential to control HBV replication in vitro.


Variations of meal-to-meal liver glycogen in rats.
Liver glycogen content was determined in free feeding rats sacrificed at the beginning of nocturnal meals or 60 min later. It was found that the glycogen content at the beginning of meals and 60 min later was highly correlated with the cumulative food intake since the beginning of the dark cycle, and therefore, increased from meal to meal. The comparison of these correlations between the cumulative food intake and the liver glycogen at the beginning of the meal and 60 min after ruled out the possibility that a constant decrement of glycogen might be involved in both meal onset and prandial periodicity of feeding. Rather the results are consistent with the view that the glycogen load during the night is a minute carbohydrate store which, like the fat store, is involved in the diurnal 12/12 hr feeding periodicity.


Aripiprazole causing false positive urine amphetamine drug screen in an adult patient with bipolar disorder.
There has been only a few reports regarding aripiprazole causing false positive urine amphetamine drug screens, exclusively on children accidently ingesting aripiprazole. Herein, we present the first reported case of a 40 year old woman affected by Bipolar I Disorder, treated with aripirazole at therapeutic oral dose ranging from 15 mg/day to 30 mg/day, in the context of a depressive episode with mixed and psychotic features, showing a false positive urine amphetamine drug screen. We document the relationship between aripiprazole-dose, plasma concentration and amphetamines values in toxicologic urine examinations over time. Awareness of potential false positive urine amphetamine drug screens during aripiprazole treatment can condition therapeutic choices and prevent legal implications.


Complications in cerebral angiography. A comparison between the non-ionic contrast medium iohexol and meglumine metrizoate (Isopaque Cerebral).
Cerebral angiography was performed in 100 patients in order to study the frequency of adverse effects and complications with a new non-ionic contrast medium, iohexol, compared with an ionic medium, meglumine metrizoate. The study was performed as a double blind clinical trial. Iohexol was better tolerated than meglumine metrizoate, since more patients experienced the injections as painful and unpleasant with metrizoate than with iohexol. However, the subjective adverse effects were minor with both contrast media. There was no statistically significant difference in the frequency of more serious side effects. Transient hemiparesis was seen in two patients who prior to the angiography had suffered from numerous similar attacks per day and in one patient in whom a nearly occluded internal carotid artery was occluded during the examination. These complications occurred in the iohexol group, but are more likely to be due to thromboembolism than to contrast medium toxicity.


A technique for the purification of immune complexes using rheumatoid factor.
A method for the purification of immune complexes (IC) from human serum is described, using as a model complexes of tetanus toxoid with human antitoxoid antibodies (TAT). The technique is based on the ability of IC to bind to tubes coated with rheumatoid factor (RF). Small amounts of TAT IC were added to human serum and the mixtures were rotated overnight in tubes coated with RF. The tubes were then washed and the bound material was eluted with sodium dodecyl sulphate and iodinated with 125I. Analysis of the labeled preparation by electrophoresis in polyacrylamide gels revealed the presence of the toxoid component. The technique should be useful in isolating small amounts of IC for analytical purposes.


Changes in Monoamine Levels in BALB/c and 57Bl/6N Mice in Response to Acute Stress with Different Controllability.
The severity and specificity of CNS disturbances resulting from negative psychoemotional experience are determined by not only genetically determined stress sensitivity, but also epigenetic factors; among the latter, the context of stress exposure, e.g. stress controllability is considered. We examined the effect of controllability factor on behavioral and neurochemical parameters of acute stress in the elevated plus maze test. The situations of controllable and uncontrollable stress were modeled by allowing or restricting mice in their choice for closed arms during testing in the maze. The anxiety level of inbred BALB/c and C57Bl/6N mice was assessed and the levels and monoamine turnover in the medial prefrontal cortex, hippocampus, amygdala, and hypothalamus were measured. It was found that the decrease in stress controllability suppresses explorative activity in mice; the behavioral and neurochemical differences between the two strains are not constant feature and depend on stress controllability; serotoninergic and dopaminerigic neurotransmission in the hypothalamus can be a signal to discriminate stress controllability in the brain.


Current Resources for Evidence-Based Practice, November 2019.
A review of new resources to support the provision of evidence-based care for women and infants.


Mixed carbon substrates: a necessary nuisance or a missed opportunity?
Although fermentation with single carbon sources is the preferred mode of operation in current industrial biotechnology, the use of multiple substrates has been continuously investigated throughout the years. Generally, microbial metabolism varies significantly when cells are presented with mixed carbon substrates compared to a single carbon-energy source, as different nutrients interact in complex ways within the metabolic network. By exploiting these distinct modes of interaction, researchers have identified unique opportunities to optimize metabolism using mixed carbon sources. Here we review situations where process yield and productivity are markedly improved through the judicious introduction of substrate mixtures. Our goal is to illustrate that with proper design of the choice of substrates and the way they are introduced to cultures, metabolic optimization with mixed substrates can be a unique strategy that complements genetic engineering techniques to enhance cell performance beyond what is accomplished in single substrate fermentations.


Plasma lipoproteins affect platelet malondialdehyde and thromboxane B2 production.
Platelet interaction with plasma lipoproteins was studied using gel-filtered platelets free of plasma constituents and purified lipoproteins. On incubation of gel-filtered platelets with plasma lipoproteins at 30 degrees C for 30 min, 100 micrograms of protein/ml of very-low as well as low-density lipoprotein caused 10% increment in platelet aggregation and [14C]serotonin release in parallel to elevation of around 15% of malondialdehyde and thromboxane B2 production. High-density lipoprotein showed the opposite effect and reduced platelet aggregation as well as thromboxane B2 synthesis by 17 and 32%, respectively. Lipoprotein-deficient plasma enhanced platelet function. Preincubation of the platelet suspension with prostacyclin did not prevent the effect of the lipoproteins on the in vitro platelet response as well as on the platelet prostaglandin pathway. Our results suggest that the formation of thromboxane B2 and malondialdehyde is influenced by plasma lipoproteins and that these, in turn, affect platelet aggregation and the release reaction. The possible significance of these results to platelet function in hyperlipidemic patients is discussed.


Processed meat products with added plant antioxidants affect the microbiota and immune response in C57BL/6JRj mice with cyclically induced chronic inflammation.
Epidemiological studies have found that there is a correlation between red and processed meat consumption and an increased risk of colorectal cancer. There are numerous existing hypotheses on what underlying mechanisms are causative to this correlation, but the results remain unclear. A common hypothesis is that lipid oxidation, which occurs in endogenous lipids and phospholipids in consumed food, are catalyzed by the heme iron in meat. In this study, five pre-selected plant antioxidant preparations (sea buckthorn leaves and sprouts, summer savory leaves, olive polyphenols, onion skin and lyophilized black currant leaves) were added to a meatball type prone to oxidize (pork meat, 20 % fat, 2% salt, deep-fried and after 2 weeks of storage). Pro-inflammatory markers, neutrophil infiltration and microbiota composition were studied after four months in a chronic inflammation model in C57BL6/J female mice. We found that the bacterial diversity index was affected, as well as initial immunological reactions.


JKAP, Th1 cells, and Th17 cells are dysregulated and inter-correlated, among them JKAP and Th17 cells relate to cognitive impairment progression in Alzheimer's disease patients.
JNK pathway-associated phosphatase (JKAP) is engaged in Alzheimer's disease (AD) pathology via regulating immune response, cluster of differentiation 4 positive (CD4+) T cell differentiation, inflammation, and phosphorylated tau (p-tau). This study aimed to investigate its clinical value serving as a biomarker for AD. Fifty AD patients, 50 Parkinson's disease (PD) patients, and 50 controls (patients with non-degenerative neurological diseases with normal cognition) were enrolled. Their β-protein 42 (Aβ42), total tau (t-tau), p-tau, and Mini-Mental State Examination (MMSE) scale were assessed. Furthermore, JKAP in serum and T-help type 1 (Th1) and T-help type 17 (Th17) cells in CD4+ T cells were measured. JKAP level was lower, while Th17 cell proportion (but not Th1 cell proportion) was higher in AD patients compared with PD patients and controls (all P < 0.01). Besides, JKAP level negatively correlated with both Th1 (r = - 0.306, P = 0.030) and Th17 (r = - 0.380, P = 0.006) cell proportions in AD patients but not PD patients and controls. Furthermore, in AD patients, JKAP positively correlated with Aβ42 (r = 0.307, P = 0.030) and MMSE score (r = 0.350, P = 0.013) while negatively correlated with p-tau (r = - 0.280, P = 0.048); Th17 cell proportion negatively associated with Aβ42 (r = - 0.281, P = 0.048) and MMSE score (r = - 0.366, P = 0.009). Notably, JKAP was negatively related to 1-year (r = - 0.297, P = 0.038) and 2-year MMSE decline (r = - 0.304, P = 0.048); Th17 cell proportion was positively linked with 1-year (r = 0.392; P = 0.008), 2-year (r = 0.482, P = 0.001), and 3-year (r = 0.365, P = 0.013) MMSE decline. JKAP, Th1 cells, and Th17 cells are dysregulated and inter-correlated; among them, JKAP and Th17 cells relate to cognitive impairment progression in AD patients.


2,4,6-Trimethyl-pyridinium dihydrogen phosphate.
The asymmetric unit of the title compound, C(8)H(12)N(+)·H(2)PO(4) (-), contains two H(2)PO(4) (-) anions and two 2,4,6-trimethyl-pyridinium cations. In the crystal, the anions are linked by O-H⋯O hydrogen bonds, forming supra-molecular chains running along the a axis; the cations are connected to the anion chains by N-H⋯O hydrogen bonds. Weak inter-molecular C-H⋯O hydrogen bonding is also present in the crystal structure.


The Parkinson's disease-associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2.
Parkinson disease-associated mutations within the GTPase domain Ras of complex proteins (ROC) of leucine rich repeat kinase 2 (LRRK2) result in an abnormal over-activation of its kinase domain. However, the mechanisms involved remain unclear. Recent study has shown that LRRK2 G-domain cycles between monomeric and dimeric conformations upon binding to GTP or guanosine diphosphate, and that the Parkinson's disease (PD)-associated R1441C/G/H mutations impair the G-domain monomer-dimer dynamics and trap the G-domain in a constitutive monomeric conformation. That led us to question whether other disease-associated mutations in G-domain would also affect its conformation. Here, we report that another PD-associated N1437H mutation also impairs its monomer-dimer conformational dynamics and GTPase activity. In contrast with mutations at R1441, ROCN1437H was found to be locked in a stable dimeric conformation in solution and its GTPase activity was ∼4-fold lower than that of the wild-type. Furthermore, the N1437H mutation reduced the GTP binding affinity by ∼2.5-fold when compared with other pathogenic G-domain mutations. Moreover, ROCN1437H was found to have a slower GTP dissociation rate, indicating that N1437H might interrupt the nucleotide exchange cycle. Taken together, our data support that conformational dynamics is important for LRRK2 GTPase activity and that the N1437H mutation impairs GTPase activity by locking the ROC domain in a persistently dimeric state.-Huang, X., Wu, C., Park, Y., Long, X., Hoang, Q. Q., Liao, J. The Parkinson's disease-associated mutation N1437H impairs conformational dynamics in the G domain of LRRK2.


Ultrastructural and immunocytochemical study of P1 protamine localization in human testis.
Two monoclonal antibodies (MAbs) directed against human protamine P1 were realized. Anti-P1 specificity was assessed by western-blot and confirmed by ELISA. Monoclonal antibody 97-3 was selected. Protamine P1 was specifically demonstrated in human testis by immunoelectron microscopy, using 97-3 MAb and an indirect post-embedding immunogold technique. Our results clearly demonstrated the precise time of appearance of P1 protamine in the nuclei of human spermatids. P1 first appeared in the nucleus of step 5 spermatids and its concentration was increased in steps 6-8 spermatids, cytoplasm was not labelled.


N-Acetyl-L-tyrosine ethyl ester (ATEe) hydrolytic activities of diseased human palatine tonsils. Possible pathogenesis of recurrent acute tonsillitis.
The N-acetyl-L-tyrosine ethyl ester (ATEe)-hydrolysing activities of tonsillar extracts in cases of recurrent acute tonsillitis decreased more than those in less severe cases of chronic tonsillitis and in cases of obstructive enlargement of the palatine tonsil. Since ATEe is hydrolysed by C1-esterase, the ATEe hydrolytic activity of the tonsil might be related to the C1-activating system of the tonsil. This indicates that tonsils in which ATEe hydrolytic activities are low, repeatedly and severely, become infected, possibly due to easy invasion of micro-organisms.


Infectious encephalitis in elderly patients: a prospective multicentre observational study in France 2016-2019.
Data on encephalitis in elderly patients are scarce. We aimed to describe the characteristics, aetiologies, management, and outcome of encephalitis in patients older than 65 years. We performed an ancillary study of ENCEIF, a prospective cohort that enrolled all cases of encephalitis managed in 46 clinical sites in France during years 2016-2019. Cases were categorized in three age groups: (1) 18-64; (2) 65-79; (3) ≥ 80 years. Of the 494 adults with encephalitis enrolled, 258 (52%) were ≥ 65 years, including 74 (15%) ≥ 80 years. Patients ≥ 65 years were more likely to present with coma, impaired consciousness, confusion, aphasia, and rash, but less likely to present with fever, and headache (P < 0.05 for each). Median cerebrospinal fluid (CSF) white cells count was 61/mm3[13-220] in 65-79 years, 62 [17-180] in ≥ 80 years, vs. 114 [34-302] in < 65 years (P = 0.01). The proportion of cases due to Listeria monocytogenes and VZV increased after 65 years (P < 0.001), while the proportion of tick-borne encephalitis and Mycobacterium tuberculosis decreased with age (P < 0.05 for each). In-hospital mortality was 6/234 (3%) in < 65 years, 18/183 (10%) in 65-79 years, and 13/73 (18%) in ≥ 80 years (P < 0.001). Age ≥ 80 years, coma on admission, CSF protein ≥ 0.8 g/L and viral encephalitis were independently predictive of 6 month mortality. Elderly patients represent > 50% of adults with encephalitis in France, with higher proportion of L. monocytogenes and VZV encephalitis, increased risk of death, and sequels. The empirical treatment currently recommended, aciclovir and amoxicillin, is appropriate for this age group.