Small-for-gestational-age versus appropriate-for-gestational-age: Comparison of cord blood lipid profile & insulin levels in term newborns (SAGA-ACT study).
The genesis of atherosclerotic lesions, a major cardiovascular risk factor starts in the early stage of life. If the premature development of cardiovascular risk factors can be anticipated during childhood, cardiovascular events can be prevented effectively by taking appropriate measures. This study was carried out to assess the role of in utero malnutrition in cardiovascular disease development by comparing cord blood lipid profiles and serum insulin levels between small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) term newborns. Consecutive full-term infants who were born between June 20 and August 19, 2013, at the Obstetric Unit of a Hospital at Secunderabad, India, were enrolled in this study. Participating newborns were divided into SGA group (n = 51; test group) and AGA group (n = 52; control group) based on their gestational age and body weight. Cord blood lipid profile and insulin levels were compared between these two groups. As compared to the newborns in AGA group, SGA group of newborns had significantly (P<0.01) higher levels of cholesterol, triglyceride and low-density lipoprotein. No difference was observed between the groups for high-density lipoprotein and insulin levels. Mild and moderate anaemia was observed among mothers of both groups, while severe anaemia was seen in mothers of SGA group only. SGA newborns exhibited elevated lipid profiles as compared to AGA newborns. Hence, SGA newborns should be closely monitored for cardiovascular morbidities during childhood, adolescence and early adult life.


Evaluation of two surface sampling methods for the detection of Bacillus atrophaeus aerosolized in a test chamber.
In response to the airborne release of biothreat agents, surface sampling is often used to provide information on bioaerosol dispersal and deposition, to identify biocontaminant sources, and determine the effectiveness of decontamination. The objective of this project was to use aerosolization and deposition of dry spores to evaluate the efficiency of the cellulose sponge wipe and 37-mm cassette micro vacuum surface sampling methods for the collection of microorganisms from two contaminated surfaces, metal and concrete. Aerosolization trials were performed in a room-sized test chamber with known airborne concentrations of Bacillus atrophaeus spores serving as a surrogate for a bioterrorism agent. Following each aerosolization trial, the chamber heating, ventilation, air conditioning (HVAC) system was turned off to allow airborne spores to settle onto the test materials. Surface sampling was conducted and culture analysis was used to determine the concentration of B. atrophaeus on the surfaces. Results were compared with reference samples to determine the collection efficiency of the sampling methods. The sponge wipe sampling method was significantly more effective than the vacuum method for the collection of B. atrophaeus from both metal and concrete surfaces (P < 0.001). The collection efficiency of the sponge wipe method was 39.5% for metal and 26.5% for concrete, while the collection efficiency of the vacuum method was 7.6% for metal and 9.3% for concrete. The results of this study provided data on the collection efficiencies of two surface sampling methods for detection and enumeration of biocontaminants and can aid in selection of sampling methods.


Long-term risk of shunt failure after brain tumor surgery.
Long-term risks and survival times of ventriculoperitoneal (VP) shunts implanted due to hydrocephalus (HC) after craniotomy for brain tumors are largely unknown. The aim of this study was to establish the overall VP shunt survival rates during a decade after shunt insertion and to determine risks of shunt failure after brain tumor surgery in the long-term period. In this population-based cohort from a well-defined geographical region, all adult patients (> 18 years) from 2004 to 2013 who underwent craniotomies for intracranial tumors leading to VP shunt dependency were included. Our brain tumor database was cross-linked to procedure codes for shunt surgery (codes AAF) to extract brain tumor patients who became VP shunt dependent after craniotomy. The VP shunt survival time, i.e. the shunt longevity, was calculated from the day of shunt insertion after brain tumor surgery until the day of its failure. A total of 4174 patients underwent craniotomies, of whom 85 became VP shunt dependent (2%) afterwards. Twenty-eight patients (33%) had one or more shunt failures during their long-term follow-up, yielding 1-, 5-, and 10-year shunt success rates of 77%, 71%, and 67%, respectively. Patient age, sex, tumor location, primary/repeat craniotomy, placement of external ventricular drainage (EVD), ventricular entry, post-craniotomy hemorrhage, post-shunting meningitis/infection, and multiple shunt revisions were not statistically significant risk factors for shunt failure. Median shunt longevity was 457.5 days and 21.5 days for those with and without pre-craniotomy HC, respectively (p < 0.01). This study can serve as benchmark for future studies.


MicroRNA regulation of phenotypic transformations in vascular smooth muscle: relevance to vascular remodeling.
Alterations in the vascular smooth muscle cells (VSMC) phenotype play a critical role in the pathogenesis of several cardiovascular diseases, including hypertension, atherosclerosis, and restenosis after angioplasty. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs (approximately 19-25 nucleotides in length) that function as regulators in various physiological and pathophysiological events. Recent studies have suggested that aberrant miRNAs' expression might underlie VSMC phenotypic transformation, appearing to regulate the phenotypic transformations of VSMCs by targeting specific genes that either participate in the maintenance of the contractile phenotype or contribute to the transformation to alternate phenotypes, and affecting atherosclerosis, hypertension, and coronary artery disease by altering VSMC proliferation, migration, differentiation, inflammation, calcification, oxidative stress, and apoptosis, suggesting an important regulatory role in vascular remodeling for maintaining vascular homeostasis. This review outlines recent progress in the discovery of miRNAs and elucidation of their mechanisms of action and functions in VSMC phenotypic regulation. Importantly, as the literature supports roles for miRNAs in modulating vascular remodeling and for maintaining vascular homeostasis, this area of research will likely provide new insights into clinical diagnosis and prognosis and ultimately facilitate the identification of novel therapeutic targets.


Two cases of pregnant women with ovarian endometrioma mimicking a malignant ovarian tumor.
The detection of an ovarian mass during pregnancy is often a diagnostic challenge. We describe 2 cases of ovarian endometrioma during pregnancy with marked mural nodules on the cyst wall. The sonographic and MR imaging findings mimicked ovarian cancer. Surgical intervention may still be inevitable to exclude the possibility of malignancy.


Crosstalk between ROCK1 and PYROXD1 regulates CAFs activation and promotes laryngeal squamous cell carcinoma metastasis.
We previously found that the Rho-associated kinase 1 (ROCK1) activated Cancer-associated fibroblasts (CAFs) to promote LSCC metastasis. Accumulating evidence indicates that pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) is an oncogene; however, the crosstalk between ROCK1 and PYROXD1 in LSCC metastasis remains largely unknown. Here, we found that ROCK1 could target PYROXD1. The knockdown of ROCK1 expression reduces the expression of PYROXD1, while the knockdown of PYROXD1 expression did not alter the expression of ROCK1 indicating that ROCK1 is upstream of PYROXD1. Further, LSCC cells cocultured with PYROXD1 knocked-down CAFs exhibited lower proliferation, migration, invasion and metastasis abilities. Conversely, LSCC cells cocultured with PYROXD1-overexpressing CAFs showed opposite results. In conclusion, the crosstalk between ROCK1 and PYROXD1 regulated CAFs activation and promoted LSCC metastasis.


Oxidant-antioxidant imbalance in horses infected with equine infectious anaemia virus.
This study assesses the impact of equine infectious anaemia virus (EIAV) infection on the oxidant/antioxidant equilibrium of horses. Blood samples from 96 Romanian horses aged 1-25 years, were divided into different groups according to their EIAV-infection status, age, and time post-seroconversion. The effect of infection on oxidative stress was estimated by measuring enzymatic antioxidants (superoxide dismutase [SOD], glutathione peroxidase [GPx] and catalase), non-enzymatic antioxidants (uric acid and carotenoids), and lipid peroxidation (malondialdehyde [MDA]). Infection modified the oxidant/antioxidant equilibrium in the horses, influencing GPx and uric acid levels (P<0.05). Time post-seroconversion also contributed to oxidative stress imbalance, exhibiting a significant influence on both SOD and MDA concentrations in the blood (P<0.05). Animal age did not have a significant influence on oxidative stress. Recently infected horses (<1 year following seroconversion), and horses >5 years old, represented the most vulnerable category in terms of oxidative stress, followed by recently infected animals <5 years old. The results of this study are novel in implicating EIAV infection in the development of oxidative stress in horses.


Acyl-quinic acids from the root bark of Acanthopanax gracilistylus and their inhibitory effects on neutrophil elastase and cyclooxygenase-2 in vitro.
Eleven new acyl-quinic acids (AQAs) 1a-9, and 18 known AQAs 10-27 were isolated from the root bark of Acanthopanax gracilistylus W. W. Smith (Acanthopanacis Cortex). The planar structures of 1a-9 were determined based on their HR-ESIMS, IR, and NMR data. The absolute configurations of 1a-6 were identified by comparing the experimental and the calculated electronic circular dichroism (ECD) spectra. This is the first report of the isolation of AQAs from Acanthopanacis Cortex. Notably, 1a-6 were determined as unusual oxyneolignan-(-)-quinic acids heterodimers, representing a new class of natural products. The inhibitory activities of 1a-27 on neutrophil elastase (NE) and cyclooxygenase-2 (COX-2) were studied in vitro, and the results indicated they possessed significant inhibitory activities on COX-2. Among them, the IC50 values of 1a-9 were 0.63±0.014, 0.75±0.028, 0.15±0.023, 0.63±0.016, 0.30±0.013, 35.63±4.600, 8.70±1.241, 16.51±0.480, 0.69±0.049, 0.39±0.017, and 0.26±0.080 μM, respectively. This study represents the inaugural disclosure of the anti-COX-2 constituents found in Acanthopanacis Cortex, thereby furnishing valuable insights into the exploration of novel COX-2 inhibitors derived from natural reservoirs.


Singing Fish in an Ocean of Noise: Effects of Boat Noise on the Plainfin Midshipman (Porichthys notatus) in a Natural Ecosystem.
When it comes to hearing and vocal communication in fishes, the plainfin midshipman (Porichthys notatus) is perhaps best understood. However, distinctly lacking are studies investigating communication of P. notatus in its natural ecosystems and the effects of noise on wild fish populations. Here, an exploratory look into both is discussed. By monitoring a population of wild P. notatus off British Columbia, Canada, call patterns were distinguished, the function of communicative sounds was identified, and midshipman vocalizations in agonistic encounters with natural predators were evaluated. A preliminary investigation into the effects of boat noise on wild midshipman is also described.


[Educating health workers is key in congenital syphilis elimination in Colombia].
Colombia promotes the diagnosis and treatment of gestational syphilis in a single visit using rapid diagnostic tests to prevent mother-to-child transmission. Additionally, integrated health programs pursue the coordinated prevention of mother-to-child transmission of syphilis/HIV. To identify knowledge gaps among health workers in the prevention of mother-to-child transmission of syphilis/HIV and to provide recommendations to support these programs. We conducted a descriptive study based on 306 surveys of health workers in 39 health institutions in the city of Cali. Surveys inquired about planning, management and implementation of services for pregnant women, clinical knowledge of HIV/syphilis rapid diagnostic tests, and prior training. Knowledge deficits in the management of gestational syphilis were detected among the surveyed health workers, including physicians. Rapid tests for syphilis are currently used in clinical laboratories in Cali, however, procedural deficiencies were observed in their use, including quality control assurance. During the two years prior to the survey, training of health workers in the prevention of mother-to-child transmission of syphilis/HIV had been limited. Health workers are interested in identifying and treating gestational syphilis in a single event, in using rapid diagnostic tests and in receiving training. Intensive training targeting health workers, policy/decision makers and academic groups is needed to ensure adequate implementation of new strategies for the prevention of mother-to-child transmission of syphilis/HIV.


FAM3A attenuates ER stress-induced mitochondrial dysfunction and apoptosis via CHOP-Wnt pathway.
Endoplasmic reticulum (ER) stress is linked to several neurological disorders, and neuronal injury cascades initiated by excessive ER stress are mediated, in part, via mitochondrial dysfunction. In the present study, we identified FAM3A as an important regulator of ER stress-induced cell death in neuronal HT22 cells. The ER stress inductor tunicamycin (TM) significantly decreased the expression of FAM3A at both mRNA and protein levels, which was shown to be dependent on the induction of reactive oxygen species (ROS). Overexpression of FAM3A attenuated TM-induced apoptosis and activation of ER stress factors, but had no effect on ER calcium metabolism in HT22 cells. We also found decreased mitochondrial ROS generation, inhibited cytochrome c release and preserved mitochondrial membrane potential (MMP) in FAM3A overexpressed cells. In addition, the experiments using isolated mitochondria showed that overexpression of FAM3A attenuated mitochondrial swelling and loss of mitochondrial Ca(2+) buffering capacity after TM exposure. By using specific targeted small interfering RNA (siRNA) to knockdown the expression of the C/EBP homologous protein (CHOP), we found that FAM3A-induced protection and inhibition of ER stress was mediated by inverting TM-induced decrease of Wnt through the CHOP pathway. Our study demonstrates a pivotal role of FAM3A in protecting against TM-induced cytotoxicity via regulating CHOP-Wnt pathway, and suggests the therapeutic values of FAM3A overexpression against ER stress-associated neuronal injury.


Efficacy and safety of submucosal tunneling endoscopic resection for gastric submucosal tumors: a systematic review and meta-analysis.
submucosal tunneling endoscopic resection (STER) can be an effective treatment for submucosal tumors (SMTs) in the esophagus and cardia. However, STER may be more difficult to perform in the stomach than in the esophagus due to special anatomical and physiological features. The feasibility of STER to remove gastric STMs has not been systematically investigated. Therefore, this meta-analysis aimed to evaluate the safety and efficacy of STER for gastric SMTs. a comprehensive literature search of the Medline, Embase, PubMed, and Cochrane Library databases was conducted. Complete resection and en-bloc resection rates were considered as the primary outcome measures. The secondary outcome measure was the pooled estimate of complications. nine studies including 301 patients with 305 lesions were finally included. The pooled estimate of en-bloc resections was 95.1 % (95 % CI: 88.9-97.9 %), Cochran's Q-test, p = 0.151, and the weighted pooled rate (WPR) for complete resection was 97.9 % (95 % CI: 93.6-99.3 %), Cochran's Q-test, p = 0.778. In addition, the pooled estimate of gas-related complications was 8.7 % (95 % CI: 4.6-15.9 %), Cochran's Q-test, p = 0.057. The pooled estimate for mucosal laceration was 4.2 % (95 % CI: 2.2-7.9 %), Cochran's Q-test, p = 0.572. The pooled estimate for delayed bleeding was 2.1 % (95 % CI: 0.9-4.8 %), Cochran's Q-test, p = 0.985. The pooled estimate of inflammation-related complications was 8.6 % (95 % CI: 5.2-13.9 %), Cochran's Q-test, p = 0.308. STER is an effective and safe technique for removing gastric SMTs with low complications, and complications, when encountered, can be treated conservatively.


Recurrent adult nephroblastoma. Long-term remission after surgery plus adjuvant high-dose chemotherapy, radiation therapy, and allogeneic bone marrow transplantation.
The authors report a case of Stage IV, unfavorable histologic type adult nephroblastoma. The patient was treated with multimodal therapy: combination chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin, and etoposide succeeded by nephrectomy and radiation therapy. After a disease-free period of 27 months, a pararectal relapse was treated by surgery, high-dose chemotherapy, and allogeneic bone marrow transplantation (BMT). The patient is alive and disease-free 3.5 years after BMT.


The first transcriptome sequencing and data analysis of the Javan mahseer (Tor tambra).
The Javan mahseer (Tor tambra) is one of the most valuable freshwater fish found in Tor species. To date, other than mitogenomic data (BioProject: PRJNA422829), genomic and transcriptomic resources for this species are still lacking which is crucial to understand the molecular mechanisms associated with important traits such as growth, immune response, reproduction and sex determination. For the first time, we sequenced the transcriptome from a whole juvenile fish using Illumina NovaSEQ6000 generating raw paired-end reads. De novo transcriptome assembly generated a draft transcriptome (BUSCO5 completeness of 91.2% [Actinopterygii_odb10 database]) consisting of 259,403 putative transcripts with a total and N50 length of 333,881,215 bp and 2283 bp, respectively. A total count of 77,503 non-redundant protein coding sequences were predicted from the transcripts and used for functional annotation. We mapped the predicted proteins to 304 known KEGG pathways with signal transduction cluster having the highest representation followed by immune system and endocrine system. In addition, transcripts exhibiting significant similarity to previously published growth-and immune-related genes were identified which will facilitate future molecular breeding of Tor tambra.


Hybrid analogues of SFTI-1 modified in P₁ position by β- and γ-amino acids and N-substituted β-alanines.
A series of compounds containing either non-proteinogenic β-/γ-amino acids or N-substituted β-alanine residues (β-peptoid units) in P1 specificity position were synthesized based on the structure of sunflower trypsin inhibitor 1 (SFTI-1). The compounds were synthesized on a solid support; the N-substituted β-alanines (βNhlys and βNhphe) were introduced into a peptidomimetic chain via a two-step approach using acryloyl chloride and an appropriate primary amine. The inhibitory activities were characterized in vitro against bovine α-chymotrypsin or bovine β-trypsin. Three analogues displayed activity comparable to fully proteinogenic counterparts-monocyclic SFTI-1 and [Phe(5)]SFTI-1. Moreover, all active peptidomimetics were resistant toward proteolytic degradation, even after 24-h incubation at room temperature.


Hypogastric Artery Flow Interruption is Associated with Increased Mortality After Open Aortic Repair.
Potential complications of pelvic flow disruption during aortic aneurysm repair include buttock ischemia and mesenteric ischemia. Unilateral or bilateral hypogastric artery flow interruption, either from atherosclerosis or intentionally to facilitate aneurysm repair, is considered problematic in endovascular repair; however, it has not been well studied in open abdominal aortic aneurysm (AAA) repair (OAR). We sought to examine the effect of interruption of flow to one or both hypogastric arteries on outcomes after OAR. The Society for Vascular Surgery Quality Initiative database was queried for all patients undergoing elective open AAA repair between 2003 and 2020. (redundant) Patients with appropriate data on their hypogastric arteries postoperatively were stratified into two groups-patent bilaterally (normal pelvic perfusion, NPP) and unilateral or bilateral occlusion or ligation (compromised pelvic perfusion, CPP). Primary endpoints were 30-day major morbidity (myocardial infarction, respiratory complications, renal injury, and lower extremity or intestinal ischemia) and mortality. During the study period, 9.492 patients underwent elective open AAA repair-860 (9.1%) with compromised pelvic perfusion and 8,632 (90.9%) with patent bilateral hypogastric arteries. The groups had similar cardiac risk factors, including a history of coronary artery disease, prior coronary intervention, and the use of P2Y12 inhibitors and statins. A majority of patients in the CPP cohort had concurrent iliac aneurysms (63.3% vs. 24.8%; P < 0.001). The perioperative mortality was significantly higher in patients with compromised pelvic perfusion (5.5% vs. 3.1%; P < 0.001). Bilateral flow interruption had a trend toward higher perioperative mortality compared to unilateral interruption (7.1% vs. 4.7%; P < 0.147). The CPP group also had increased rates of myocardial injury (6.7% vs. 4.7%; P = 0.012), renal complications (18.9% vs. 15.9%; P = 0.024), leg and bowel ischemia (3.5% vs. 2.1%; P = 0.008; and 5.7% vs. 3.4%; P < 0.001, respectively). On multivariable analysis, CPP was associated with increased perioperative mortality (OR 1.47, CI 1.14-1.88, P = 0.003). On Kaplan-Meier analysis, there was no difference in survival at 2 years postdischarge between the NPP and CPP cohorts (86.1% vs. 87.5%, log-rank P = 0.275). Compromised pelvic perfusion is associated with increased perioperative complications and higher mortality in patients undergoing OAR. The sequelae of losing pelvic perfusion, in addition to the presence of more complex atherosclerotic and aneurysmal disease resulting in more difficult dissection, likely contribute to these findings. Thus, patients considered for OAR who have occluded hypogastric arteries or aneurysmal involvement of the hypogastric artery preoperatively may be candidates for more conservative management beyond traditional size criteria.


Treatment of waste stabilization pond effluent using natural zeolite for irrigation potential.
Direct utilization of treated effluent from natural treatment systems for irrigation can be challenging on sensitive plants due to high levels of salinity. Post-treatment of such an effluent prior to its applicability in irrigation can be of significant importance. In this study, the wastewater from a natural treatment plant was treated using a lab-scale filtration system with zeolite as a filter material. Three different column depths (0.5 m, 0.75 m, and 1 m) were used to investigate the effect of column depth on the treatment efficiency of the media. The suitability of the raw wastewater and the treated effluent from each column for irrigation purposes was investigated. The water quality parameters investigated were; electrical conductivity (EC), total dissolved solids (TDS), sodium (Na+), calcium (Ca2+), and magnesium (Mg2+). From the analysis results, it was observed that the column depth had a significant influence on the removal efficiency of the pollutants. The highest removal efficiency (94.58%) was achieved from the combination of electrical conductivity and 1 m column depth, while the lowest removal efficiency (10.05%) was observed from the combination of calcium and 0.5 m column depth. The raw wastewater fell mostly into a "very high" hazard, which is class four (C4) based on electrical conductivity and class four (S4) based sodium adsorption ratio; making it unsuitable for irrigation purposes. However, when the wastewater was subjected to 1 m column depth, the quality of the treated effluent improved significantly which in turn also improved the suitability of the effluent for irrigation purposes, with percent compliance ranging from 20.19% to 97.54%.


Ultrastructural features of the Purkinje cell damage caused by acrylamide in the rat: a new phenomenon in cellular neuropathology.
Dosing rats with acrylamide leads to the formation in Purkinje cells of juxtanuclear clusters of tubular and vesicular smooth endoplastic reticulum (SER). A microtubule organizing centre forms in relation to these clusters and together they appear to move to the cell surface, where protrusions of plasmalemma form, often with overlying synaptic attachments, containing densely packed tubular and vesicular SER membranes. Usually the microtubule organizing centre immediately underlies this. Subsequently, appearances suggest that astroglial intrusions occur internal to the protrusions described above to which the tubulo-vesicular material appears to be transferred. During these events the organization of the cytoplasm of the Purkinje cell is grossly disturbed with apparent loss and disarray of rough endoplasmic reticulum (RER) and of polyribosomes. This temporal sequence of events can be followed after a single dose of acrylamide. In chronically intoxicated animals vacuolation and swelling of dendrites takes place and the Purkinje cell may die after all stages of the cellular transformations have been present. These unique events appear to be confined to Purkinje cells and are considered probably to be the result of a primary disturbance to SER synthesis caused by acrylamide. It is argued that the changes taking place in acrylamide intoxication in neurons that lead to degeneration in long axons are probably of the same general kind.


Differential risk reclassification improvement by exercise testing and myocardial perfusion imaging in patients with suspected and known coronary artery disease.
The objective of this study is to compare the incremental prognostic and net risk reclassification value of exercise testing alone vs exercise myocardial perfusion imaging (MPI) for estimating the risk of death in patients with suspected and known coronary artery disease (CAD). 6702 patients with suspected CAD and 2008 with known CAD had treadmill exercise MPI and were followed for 2.5 ± 0.9 years for the occurrence of all-cause death. The estimation of risk of death and net reclassification improvement (NRI) were examined in three models. Model 1: clinical variables; Model 2: model 1+Duke Treadmill Score; and Model 3: model 2+ MPI variables. Risk estimates were categorized as <1%, 1-3%, and >3% risk of death per year. In patients with suspected CAD, the global Chi-square for predicting risk of death increased significantly for Model 2 compared to Model 1 (74.78 vs 63.86 to (P = .001). However, adding MPI variables in Model 3 did not further improve predictive value (Chi-square 79.38, P = .10). In patients with suspected CAD risk, reclassification improved significantly in Model 2 over Model 1 (NRI = 0.12, 95% CI 0.02 to 0.22, P = .019), but not in Model 3 (NRI = 0.0009, 95% CI -0.072 to 0.070; P = .98). In contrast, in patients with known CAD Model 2 did not yield significant improvements for predicting risk and risk reclassification compared to Model 1. However, global Chi-square of Model 3 was significantly higher than that of Model 2 (30.03 vs 6.56, P < .0001) with associated significant reclassification improvement (NRI = 0.26 95% CI 0.067 to 0.46. P = .0084). Risk reclassification by diagnostic testing is importantly influenced by baseline characteristics of patient cohorts. In patients with suspected CAD, NRI is predominately achieved by exercise variables, whereas in patients with known CAD, greatest NRI is obtained by MPI variables.


Treatment with biologic DMARDs may not adversely affect lung nodules in rheumatoid arthritis patients.
Lung nodules (LNs) impose diagnostic and therapeutic challenges in patients with rheuma- toid arthritis (RA) due to unpredictable outcomes. Potential induction of nodulosis with the use of con- ventional synthetic DMARDs (csDMARD) and lack of knowledge regarding the effect of biologic disease-modifying anti-rheumatic drugs (bDMARDs)/tofacitinib on the LN raise concerns and have an impact on treatment decisions. This study aims to evaluate the possible effects of the bDMARDs/tofa- citinib and csDMARDS on LNs observed in RA patients. Electronic health records of RA patients who had LNs detected on computed tomography (CT) between January 2015 and December 2020 were evaluated retrospectively. Patients with follow- up CT images were included in the study. Baseline and follow-up images were meticulously examined for the number, size, attenuation, and cavity formation. Clinical, histopathologic, and laboratory find- ings were analyzed. Forty-two RA patients with LNs were studied, 21 were on bDMARDs/tofacitinib (11 females, mean age: 59.7 6 8.4) and 21 were on csDMARDs (12 females, mean age: 71.4 6 8.3). The proportion of patients with progressed nodules during follow-up was comparable between groups (six patients in bDMARDs/tofacitinib vs seven patients in csDMARDs). Progression of LNs was observed in six patients in the bDMARDs/tofacitinib group: three in anti-TNFa, two in rituximab, and one in abatacept users and none in tofacitinib users. Our results suggest that the risk of progression in LNs in RA patients with use of bDMARDs/tofacitinib might not impose a higher risk compared to csDMARDs. Moreover, bDMARDs/ tofacitinib might result in regression in LNs.


Magnetization transfer ratio measurements of the brain in children with tuberous sclerosis complex.
Magnetization transfer contrast and magnetization transfer ratio (MTR) in brain are mainly related to the presence of myelin. Neuropathological studies of brain lesions in tuberous sclerosis complex (TSC) have demonstrated disordered myelin sheaths. To evaluate the MTR of the brain in children with TSC and to compare with that in controls. Four patients (aged 0.41-8.4 years, mean 2.5 years) with TSC and four age- and sex-matched controls were evaluated with classic MR sequences and with a three-dimensional gradient-echo sequence without and with magnetization transfer pre-pulse. The MTR was calculated as: (SI(0)-SI(m))/SI(0)x100%, where SI(m) refers to signal intensity from an image acquired with a magnetization transfer pre-pulse and SI(0) the signal intensity from the image acquired without a magnetization transfer pre-pulse. The MTR values of cortical tubers (44.1+/-4.1), of subependymal nodules (51.6+/-4.8) and of white matter lesions (52.4+/-1.8) were significantly lower than those of cortex (58.7+/-3.53), of basal ganglia (caudate nucleus 58.2+/-2.8, putamen 59.6+/-2.5, thalamus 61.3+/-2.4) and of white matter (64.2+/-2.5) in controls (P<0.001). The MTR of normal-appearing white matter (61.2+/-3.0) in patients was lower than that of white matter in controls (P<0.01). The MTR of cortex and basal ganglia in patients was not significantly different from that in controls. MTR measurements not only provide semiquantitative information for TSC lesions but also reveal more extensive disease.


GRP78 facilitates M2 macrophage polarization and tumour progression.
This study investigated the regulation of GRP78 in tumour-associated macrophage polarization in lung cancer. First, our results showed that GRP78 was upregulated in macrophages during M2 polarization and in a conditioned medium derived from lung cancer cells. Next, we found that knocking down GRP78 in macrophages promoted M1 differentiation and suppressed M2 polarization via the Janus kinase/signal transducer and activator of transcription signalling. Moreover, conditioned medium from GRP78- or insulin-like growth factor 1-knockdown macrophages attenuated the survival, proliferation, and migration of lung cancer cells, while conditioned medium from GRP78-overexpressing macrophages had the opposite effects. Additionally, GRP78 knockdown reduced both the secretion of insulin-like growth factor 1 and the phosphorylation of the insulin-like growth factor 1 receptor. Interestingly, insulin-like growth factor 1 neutralization downregulated GRP78 and suppressed GRP78 overexpression-induced M2 polarization. Mechanistically, insulin-like growth factor 1 treatment induced the translocation of GRP78 to the plasma membrane and promoted its association with the insulin-like growth factor 1 receptor. Finally, IGF-1 blockade and knockdown as well as GRP78 knockdown in macrophages inhibited M2 macrophage-induced survival, proliferation, and migration of lung cancer cells both in vitro and in vivo.


Photodynamic therapy in the management of resistant lower urinary tract carcinoma.
Twenty-three patients with resistant transitional cell carcinoma (TCC) of the bladder and posterior urethra had photodynamic therapy (PDT). Seventy-two hours after an intravenous injection with 2 mg/kg of the photosensitizer dihematoporphyrin ether (DHE) (Photofrin II, Photomedica, Raritan, NJ), each patient received cystoscopic light treatment. The light dose to the whole bladder using the bulb diffuser ranged from 5 to 60 J/cm2; power density ranged from 9 to 22 mW/cm2. The focal light dose ranged from 100 to 200 J/cm2 at a power density from 100 to 200 mW/cm2. To treat the urethra, a diffuser fiber was used to deliver 200 to 400 J/linear cm at a power of 110 to 300 mW/cm. In the 19 of 23 patients who were treated for resistant superficial TCC, 83.3% of the tumors had responded at the initial follow-up evaluation. Seven patients had a complete response and 10 had a partial response. Three of 19 patients who received inadequate light treatment failed to respond. Control of intractable gross hematuria was the only benefit for patients with locally invasive disease (greater than or equal to T2). Irritating lower urinary tract symptoms that varied in severity and duration occurred in all patients. Four patients experienced bladder shrinkage, which did not resolve. Although the light and drug doses remain to be determined, a whole bladder light dose of 15 to 20 J/cm2 with a drug dose of 2 mg/kg seems to be effective enough without producing permanent adverse effects in the bladder.


Clinical Implications of the STAR*D Trial.
This chapter provides a synopsis of the clinically relevant findings derived from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and selected ancillary studies appended to the primary trial. The chapter describes the participants, their recruitment and treatment, and the study design, primary outcomes, and clinically informative results. In particular, the chapter describes acute phase response and remission rates from each of the five treatment steps which entail antidepressant monotherapies and combinations, and psychotherapy alone or in combination with an antidepressant. In addition, longer-term outcomes beyond the 12 week acute trial are described for each treatment step. The treatment challenges described include patient retention and relapse, and longer-term follow-up. The chapter discusses the use of measurement-based care for delivering high-quality care, describes "treatment-resistant" depression and discusses its implications for clinical practice, and discusses the contributions of STAR*D to patient-oriented research and patient care.


Mechanism of relaxant action of prostaglandin F2alpha on the guinea-pig isolated trachea.
Prostaglandin F2alpha consistently produced a dose-related triphasic response in guinea-pig isolated tracheal chain preparations. The response consisted of an initial transient contraction followed by a transient relaxation, followed by a further contraction. The relaxant action was not due to adrenergic or histaminergic transmission, but might be due to a PG-like material released by the PGF 2alpha-induced contraction.


Downregulation of MicroRNA-130a Inhibits Oral Squamous Cell Carcinoma Proliferation and Metastasis via the Hippo-YAP Pathway [Retraction].
[This retracts the article DOI: 10.2147/CMAR.S287575.].


Initial Dosage Optimization of Tacrolimus in Pediatric Patients With Thalassemia Major Undergoing Hematopoietic Stem Cell Transplantation Based on Population Pharmacokinetics.
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with β-thalassemia major (β-TM) undergoing HSCT are insufficient. To establish a PPK model of tacrolimus in children with β-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. Data on patients aged <18 years were retrospectively collected from January 2017 to December 2018. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed-effects modeling. A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy.


Differential effects of elevated potassium ion concentration and of theophylline on growth hormone release by rat adenohypophyses in vitro.
The effects of 27 mM K+ and of 6.7 mM theophylline on the release of growth hormone (GH) by rat hemipituitaries in vitro were investigated using bioassay (rat tibia test) and radioimmunoassay (RIA). Both agents markedly increased the release of immunoreactive GH. High K+ also promoted the release of bioactive GH but to a much lesser degree than RIA-GH. Theophylline did not consistently affect the release of bioassay-detectable GH. The results suggest that these agents promote massive release of a form of immunoreactive GH (possibly "immature") that has little or no activity in the bioassay. Theophylline is relatively more effective in this regard than is elevated K+.


[In vitro development of murine embryos using different types of microinjections].
We studied the effects of different types of microinjections, such as the mechanical damage to cytoplasmic and nuclear membranes of the zygote and the injection of various gene-engineering constructs or buffer solutions into the cytoplasm or the pronucleus, on the preimplantation of murine embryos (CBA x x C57BL)F1. The survival rate of the embryos was estimated by their capacity to develop in vitro to the blastocyst or hatched blastocyst stages. Puncture of the cytoplasm using a microneedle and injection of buff or foreign DNA did not affect the zygotes capacity for further in vitro development. But, the puncture of the pronucleus and microinjection of gene-engineering constructs or buffer into it reliably decreased the survival rate of embryos, as compared to the control. The differences were found in the capacity of murine zygotes for in vitro development after injection with gene-engineering constructs.


ROCK, PAK, and Toll of synapses in Alzheimer's disease.
Alzheimer's disease is a neurodegenerative disorder where the cognitive deficit is the hallmark symptom reflecting the progression of the disease. Synaptic dysfunction is a sensitive parameter of the AD pathology. Rho GTPases and the Rho kinases, ROCK1/2, and PAK1-3, are important regulators of synaptic plasticity, especially in maintaining the actin cytoskeleton of dendritic spines. Recent studies have revealed that beta-amyloid oligomers can inhibit PAK and stimulate ROCK-mediated signaling. Both of these effects enhance the disassembly of synaptic actin filaments and ultimately evoke synaptic loss. Brain tissue in AD recognizes the beta-amyloid peptide oligomers as foreign protein particles and mounts an inflammatory defense via Toll-like receptor (TLR) signaling which causes synaptic impairment. We will review here the dysfunction of ROCK, PAK, and Toll signaling associated with AD pathology. The protection of synapses in AD may provide new therapeutic approaches to combatting the cognitive impairment in AD.


Prognostic implications of left ventricular hypertrophy defined by the thresholds from the international and Chinese guidelines.
To compare the predictive value of mortality between left ventricular hypertrophy (LVH) defined by Chinese thresholds and defined by international guidelines in hypertension individuals and investigate better indexation methods for LVH in Chinese population. We included 2454 community hypertensive patients with Left ventricular mass (LVM) and relative wall thickness. LVM was indexed to body surface area (BSA), height2 7 and height 1 7 . The outcomes were all-cause and cardiovascular mortality. Cox proportional hazards models were used to explore the association between LVH and the outcomes. C-statistics and time-dependent receiver operating characteristic curve (ROC) was used to evaluate the value of those indicators. During a median follow-up of 49 months (interquartile range 2-54 months), 174 participants (7.1%) died from any cause (n = 174), with 71 died of cardiovascular disease. LVM/BSA defined by the Chinese thresholds was significantly associated with cardiovascular mortality (HR: 1.63; 95%CI: 1.00-2.64). LVM/BSA was significantly associated with all-cause mortality using Chinese thresholds (HR: 1.56; 95%CI: 1.14-2.14) and using Guideline thresholds (HR: 1.52; 95%CI: 1.08-2.15). LVM/Height1.7 was significantly associated with all-cause mortality using Chinese thresholds (HR: 1.60; 95%CI: 1.17-2.20) and using Guideline thresholds (HR: 1.54; 95%CI: 1.04-2.27). LVM/Height2.7 was not significantly associated with all-cause mortality. C-statistics indicated that LVM/BSA and LVM/Height1.7 by Chinese thresholds had better predictive ability for mortality. Time-ROC indicated that only LVM/Height1.7 defined by Chinese threshold had incremental value for predicting mortality. We found that in community hypertensive populations, race-specific thresholds should be used to classify LV hypertrophy related to mortality risk stratification. LVM/BSA and LVM/Height1.7 are acceptable normalization method in Chinese hypertension.


Neuropeptidergic inhibitory regulation of Met-enkephalin immunoreactive material release from rat spinal cord in vitro.
The release of Met-enkephalin immunoreactive material (ME-IR) from rat spinal slices was measured in vitro. This release increased about 4 fold in response to the addition of K+ ions. K+-evoked release of ME-IR was Ca++ dependent. Veratridine, a depolarizing agent, also stimulated the release of ME-IR. Veratridine-induced ME-IR release was completely prevented by tetrodotoxin (TTX), a Na+ channel blocker. Somatostatin (SRIF) inhibited both basal and K+-evoked release of ME-IR at 10(-7) M. Substance P had a similar effect although higher concentrations were needed. gamma-Aminobutyric acid (GABA) and neurotensin (NT) did not affect the basal release but slightly decreased K+-evoked release at 10(-5) M. Serotonin (5-HT) and noradrenaline (NA), did not affect ME-IR release. These results suggest that some of the neuropeptides present in the spinal cord, especially SP and SRIF, may be potent modulators of ME-IR release at the spinal level.


Gas exchange and water balance of a mistletoe species and its mangrove hosts.
The gas exchange and water relations of the hemiparasite Pthirusa maritima and two its mangrove host species, Conocarpus erectus and Coccoloba uvifera, were studied in an intertidal zone of the Venezuelan coast. Carbon uptake and transpiration, leaf osmotic and total water potential, as well as nutrient content in the xylem sap and leaves of mistletoes and hosts were followed through the dry and wet season. In addition, carbon isotope ratios of leaf tissue were measured to further evaluate water use efficiency. Under similar light and humidity conditions, mistletoes had higher transpiration rates, lower leaf water potentials, and lower water use efficiencies than their hosts. Potassium content was much higher in mistletoes than in host leaves, but mineral nutrient content in the xylem sap of mistletoes was relatively low. The resistance of the liquid pathway from the soil to the leaf surface of mistletoes was larger than the total liquid flow resistance of host plants. Differences in the daily cycles of osmotic potential of the xylem sap also indicate the existence of a high resistance pathway along the vascular connection between the parasite pathway along the vascular connection between the parasite and its host. P. maritima mistletoes adjust to the different physiological characteristics of the host species which it parasitizes, thus ensuring an adequate water and carbon balance.


Molecular basis of homocysteine toxicity in humans.
Because of its similarity to the protein amino acid methionine, homocysteine (Hcy) can enter the protein biosynthetic apparatus. However, Hcy cannot complete the protein biosynthetic pathway and is edited by the conversion to Hcy-thiolactone, a reaction catalyzed by methionyl-transfer RNA synthetase in all organisms investigated, including human. Nitrosylation converts Hcy into a methionine analogue, S-nitroso-Hcy, which can substitute for methionine in protein synthesis in biological systems, including cultured human endothelial cells. In humans, Hcy-thiolactone modifies proteins posttranslationally by forming adducts in which Hcy is linked by amide bonds to epsilon-amino group of protein lysine residues (Hcy-epsilonN-Lys-protein). Levels of Hcy bound by amide or peptide linkages (Hcy-N-protein) in human plasma proteins are directly related to plasma 'total Hcy' levels. Hcy-N-hemoglobin and Hcy-N-albumin constitute a major pool of Hcy in human blood, larger than 'total Hcy' pool. Hcy-thiolactone and Hcy-thiolactone-hydrolyzing enzyme, a product of the PON1 gene, are present in human plasma. Modification with Hcy-thiolactone leads to protein damage and induces immune response. Autoantibodies that specifically recognize the Hcy-epsilonN-Lys-epitope on Hcy-thiolactone-modified proteins occur in humans. The ability of Hcy to interfere with protein biosynthesis, which causes protein damage, induces cell death and elicits immune response, is likely to contribute to the pathology of human disease.


Differential autoreceptor control of extracellular 5-HT in guinea pig and rat: species and regional differences.
Central 5-hydroxytryptamine (5-HT) release is regulated by inhibitory 5-HT autoreceptors, including 5-HT(1A) and 5-HT(1B) receptors. The purpose of this study was to use combinations of selective autoreceptor antagonists to elucidate the role of these receptors in controlling extracellular 5-HT in terminal areas. METHODS. Microdialysis was carried out in awake rats and guinea pigs to measure extracellular 5-HT in the frontal cortex and dentate gyrus. Using the selective 5-HT(1A) receptor antagonist, WAY-100635, and the selective 5-HT(1B) receptor antagonist, SB-224289, we have compared the roles of 5-HT(1A) and 5-HT(1B) autoreceptors in controlling extracellular 5-HT. SB-224289 (4 mg/kg i.p.) alone produced a significant 50% increase in extracellular 5-HT in the dentate gyrus of guinea pigs, but not in the frontal cortex of the same animals. Co-administration of WAY-100635 (0.3 mg/kg s.c.), did not change the SB-224289-induced increase in dentate gyrus 5-HT but did produce a significant augmentation (60% increase) of guinea pig frontal cortex 5-HT. In contrast, neither autoreceptor antagonist, alone or in combination, affected extracellular 5-HT in the frontal cortex or dentate gyrus of rats. These data indicate that there is a species difference in the autoreceptor control of 5-HT release. Furthermore, in the guinea pig there is a divergence between dorsal and median raphe innervated brain regions. On the basis that antagonism of 5-HT(1A) and 5-HT(1B) receptors produced an immediate increase in extracellular 5-HT in multiple brain regions in the guinea pig, it is suggested that this might be a novel mechanism for achieving antidepressant efficacy.


New colored and fluorescent amine substrates for activated fibrin stabilizing factor (Factor XIIIa) and for transglutaminase.
Two fluorescent (FITC and 6-chloro-2-methoxyacridine) and an intensely colored (dabsyl) derivative of cadaverine were synthesized, following earlier work from this laboratory with dansyl-cadaverine, in order to enlarge the scope of possibilities for labeling some gamma-glutamine sites in proteins. Enzyme affinities of the amine substrates for human Factor XIIIa and for guinea pig liver transglutaminase were measured. The utility of dabsylcadaverine was further demonstrated by activity staining of these enzymes, following electrophoresis in agarose, and by measuring the Factor XIII zymogen of human plasma colorimetrically.


Decrease in cognitive performance and increase of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios with higher doses of antipsychotics in women with schizophrenia: a cross-sectional study.
We explored the relationship between symptoms, cognitive performance, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) (three markers of inflammation), and antipsychotic dose (in chlorpromazine units) in male and female patients with schizophrenia. We conducted a cross-sectional analysis in patients with schizophrenia of the complete blood count and the results of neuropsychological testing, using the Welch t-test to compare groups and the Pearson test for correlations. We found that the NLR and the PLR are higher among women with schizophrenia when compared with men. In women, the NLR and the PLR correlate positively with antipsychotic drug dose and inversely with a working memory test (Direct Digit Span). Higher doses of antipsychotics are associated with worse working and semantic memory and mental flexibility in the women in our sample. Higher doses of antipsychotics were associated with worse working and semantic memory and mental flexibility in women with schizophrenia. No such correlations were present in men, suggesting that, in female patients, cognitive performance deteriorates as the antipsychotic dose is increased, a finding that could be mediated by inflammatory mechanisms, given the demonstrated relationship to biomarkers of inflammation - e.g., the NLR and the PLR. NCT03788759 (ClinicalTrials.gov).


Distribution of endogenous and exogenous carnitine in rats with sepsis and acute liver failure.
The distribution of carnitine was investigated in male Wistar rats with sepsis or acute liver failure. Sepsis was produced by cecal ligation and puncture, while acute liver failure was induced by intraperitoneal injection of carbon tetrachloride. Then 14C-carnitine or L-carnitine was injected intravenously. In healthy control rats and rats with sepsis, both 14C-radioactivity and carnitine were increased in the liver and kidneys. When the carnitine fractions were investigated, it was found that free carnitine and short-chain acylcarnitine were increased. In the rats with acute liver failure, 14C-radioactivity decreased in the liver, but carnitine increased, with free carnitine and short-chain acylcarnitine levels rising. These findings suggested that exogenous free carnitine accumulated directly in the organs with carnitine deficiency in rats with sepsis and acute liver failure. In addition, there was differential regulation of the fractions of both exogenous and endogenous carnitine (free carnitine, short-chain acylcarnitine, and long-chain acylcarnitine). Furthermore, the distribution of exogenous carnitine differed between sepsis and acute liver failure.


A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy.
Although several prospective studies have reported the efficacy of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC), treatment-related toxicity varies and has not been determined. Therefore, the authors evaluated the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus-endemic area. This multicenter phase 2 trial enrolled patients with unresectable HCC. Patients received SBRT with 45 to 60 Gy in 3 fractions. To evaluate gastroduodenal toxicity, esophagogastroduodenoscopy (EGD) was performed before and 2 months after SBRT. The primary endpoint was treatment-related severe toxicity at 1 year after SBRT. The secondary endpoints were the 2-year local control, progression-free survival, and overall survival rates. In total, 74 patients were enrolled between January 2012 and April 2015, and 65 eligible patients were analyzed. One patient experienced radiation-induced liver disease with acute grade ≥3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment-related severe toxicity at 1 year was 3%. The pre-SBRT and post-SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2-year and 3-year local control rates were 97% and 95%, respectively. The progression-free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively. With a median follow-up of 41 months, this prospective multicenter study demonstrated that SBRT for patients with HCC is well tolerated and is an effective treatment modality.


Development and validation of a hydrophilic interaction liquid chromatography-tandem mass spectrometry method for the quantification of lipid-related extracellular metabolites in Saccharomyces cerevisiae.
A highly sensitive hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed and validated for the quantification of glycerophosphoinositol (GroPIns), glycerophosphocholine (GroPCho), glycerol 3-phosphate (GroP), inositol, and choline in the extracellular medium of Saccharomyces cerevisiae. The media samples were pretreated with a single two-phase liquid extraction. Chromatographic separation was achieved on a Waters Xbridge HILIC (150 mm × 4.6 mm, 5 μm) column under isocratic conditions using a mobile phase composed of acetonitrile/water, 70:30 (v/v) with 10mM ammonium acetate (pH adjusted to 4.5) at a flow-rate of 0.5 mL/min. Using a triple quadrupole tandem mass spectrometer, samples were detected in multiple reaction monitoring (MRM) mode via an electrospray ionization (ESI) source. The calibration curves were linear (r² ≥ 0.995) over the range of 0.5-150 nM, with the lower limit of quantitation validated at 0.5 nM for all analytes. The intra- and inter-day precision (calculated by coefficient of variation, CV%) ranged from 1.24 to 5.88% and 2.46 to 9.77%, respectively, and intra- and inter-day accuracy (calculated by relative error, RE%) was between -8.42 to 8.22% and -9.35 to 6.62%, respectively, at all quality control levels. The extracellular metabolites were stable throughout various storage stability studies. The fully validated method was successfully applied to determine the extracellular levels of phospholipid-related metabolites in S. cerevisiae.


Morphology and transcriptional activity of mouse oocyte chromosomes.
Lampbrush chromosomes of growing amphibian oocytes carry thousands of lateral loops each of which consists of a chromatin fiber heavily encrusted with nascent ribonucleoprotein fibrils. These are believed to be responsible for the accumulation and maintenance of RNA transcripts found stored in the egg. In the case of mammalian oocytes, lampbrush chromosomes are most likely to occur during the major growth phase and also possibly during pachytene-early diplotene stages of meiosis. We have examined pachytene and early diplotene mouse oocyte chromosomes through the light microscope using sections of plastic-embedded material and air dried spreads stained with either silver nitrate or methyl green pyronin. Our results indicates that the projections radiating from the chromosomal axis are bundles of chromatin fibers rather than single fibers covered with an ribonucleoprotein matrix. These bundles may represent partially unfolded chromomeres. The axis itself could be partially dispersed revealing threads surrounding a fine linear element. -- Little is known about chromosome structure in growing mammalian oocytes, the stage when transcriptional activity is likely to be most rapid. In our preparations chromosomes at this stage appear as partially condensed fuzzy threads of relatively uniform width. In some cases, the fuzzy thread is seen to contain a dense linear core in the center. Thus, during the growth phase, the chromosomes retain a relatively condensed axis, a characteristic of meiotic chromosomes in general. RNA-containing material is found diffusely spread within the nucleus but not specifically associated with the chromosomes. Electron microscopic analysis of spread chromatin from growing oocytes demonstrates that most transcription units possess only one or two nascent ribonucleoprotein fibrils while a few have more. These and other published data indicate that mouse oocytes do not have true lampbrush chromosomes at any stage of their development.


Experiences and Perceptions of Patients with Oxaliplatin-Induced Cold Sensitivity in Turkey: A Qualitative Study.
This study aimed to explore and describe the impact on patients with oxaliplatin-induced cold sensitivity in the early stages. An inductive design was used for this qualitative study, which included open-ended, and in-depth interviews with 18 cancer patients. Throughout the study, the authors followed the COREQ checklist. The interviews were audiorecorded and listened to multiple times. Observation notes were also recorded following each interview. Thematic analysis developed six main themes and 13 subthemes. The first theme concerns changing habits, including changes in fluid intake and clothing choice, changes in bathing and eating habits, and changes in caregiver roles. The second theme includes changes in daily routine behaviors that are perceived as difficulties with changing routines. The third theme is avoiding triggers; the fourth theme is anxiety about self-care. The fifth theme includes a subtheme of difficulty in contact. The final theme includes adaptation to life, caring responsibilities, changes in sexual functions, the performance of religious activities, and social activities IMPLICATIONS FOR NURSING PRACTICE: This study provides an overview of the lived experiences of oxaliplatin-induced cold sensitivity among cancer patients. Patients faced fewer adverse events by avoiding initiators from the first treatment. They changed their eating and drinking habits owing to difficulties. The findings of this study can be used to better understand oxaliplatin-induced cold sensitivity, identify patients needs based on their experience, and develop interventions to improve patient outcomes.


Influence of toxic cyanobacteria on community structure and microcystin accumulation of freshwater molluscs.
Community structure and microcystin accumulation of freshwater molluscs were studied before and after cyanobacterial proliferations, in order to assess the impact of toxic blooms on molluscs and the risk of microcystin transfer in food web. Observed decrease in mollusc abundance and changes in species richness in highly contaminated waters were not significant; however, relative abundances of taxa (prosobranchs, pulmonates, bivalves) were significantly different before and after cyanobacterial bloom. Pulmonates constituted the dominant taxon, and bivalves never occurred after bloom. Microcystin accumulation was significantly higher in molluscs from highly (versus lowly) contaminated waters, in adults (versus juveniles) and in pulmonates (versus prosobranchs and bivalves). Results are discussed according to the ecology of molluscs, their sensitivity and their ability to detoxify.


Dexmedetomidine versus propofol: An effective combination with ketamine for adult procedural sedation: A randomized clinical trial.
Recently, drug combination protocols have been preferred over single drugs in procedural sedation and analgesia (PSA). This study aimed to compare the effectiveness and hemodynamic profile of ketamine-dexmedetomidine (ketodex) and ketofol as drug combinations with ketamine as a single medication for PSA in the emergency department (ED). This prospective, randomized, double-blind clinical trial was performed among adult patients (≥18 years) requiring PSA for a painful procedure in the ED. 135 patients were enrolled and assigned into three equal groups to receive either ketodex, ketofol, or ketamine. Additional ketamine was used as a rescue agent for inadequate sedation in three groups. Oxygen saturation, heart rate, and blood pressure were recorded from baseline until 120 min after induction of PSA. Adverse events, hemodynamic variables, induction, and recovery time were recorded and compared between groups. The mean age of the patients was 38.16 ± 19.09 years and no differences were observed between the three groups in terms of demographic variables, pain scores, and procedures between the three groups. Respiratory events had similar incidences between the three groups. The O2 reduction was less in the Ketodex group in comparison with Ketofol and Ketamine groups (1.9%, 6.5%, and 3.8%, P = 0.015). No patient needed endotracheal intubation. Changes in mean arterial pressure from the baseline in Ketamine and Ketofol groups compared to Ketodex was higher (difference was 12.9 mmHg [95% CI, 9.5 to 20.3] and 8.6 mmHg [95% CI, 3.4 to 13.7]. Tachycardia in the Ketamine group had a significantly higher incidence. The recovery time was statistically shorter in the Ketofol group in comparison with other groups. The differences between Ketofol with Ketamine and Ketodex groups were 9.8 min (95% CI, [2.5 to 17.1]) and 8.3 min (95% CI, [1.5 to 15.1]). Ketodex, as well as ketofol, were effective and safe combinations with good recovery profiles and hemodynamic stability for adult PSA in ED.


Choice of the first anti-epileptic drug in elderly patients with newly diagnosed epilepsy: A Finnish retrospective study.
The choice of initial anti-epileptic drug (AED) for elderly and younger adult patients with newly diagnosed epilepsy was assessed. The pattern of initial prescription of AEDs between 2000 and 2013 was retrospectively studied in two community-dwelling cohorts, identified from the case records of Kuopio University Hospital (KUH): elderly subjects (aged 65 or above at the time of diagnosis; n = 529) and a random sample of younger adults (16-64 years old at the time of diagnosis; n = 201). Furthermore, nationwide register data from the Social Insurance Institution of Finland were included in the analysis, from the years 2004 and 2012. Valproic acid (VPA) and carbamazepine (CBZ) were the most common initial AEDs both among the elderly (49% and 31% of prescriptions, respectively) and for the patients in the younger-adults group (19% and 61%, respectively) in the KUH data. In the nationwide register data, the most frequently used initial AEDs for the elderly were VPA and oxcarbazepine. The selection of VPA was associated with higher age (P < 0.001), myocardial infarction (P = 0.003), and stroke (P = 0.013). Lower probability of receiving CBZ was observed with more advanced age (P < 0.001) and myocardial infarction (P = 0.002), whereas diabetes (P = 0.018) and atrial fibrillation (P = 0.045) predicted a higher probability. First-generation AEDs are still the most commonly employed first drugs for elderly patients with newly diagnosed epilepsy in Finland. Age and comorbid conditions have an effect in the choice of the initial AED treatment.


Age-related changes in normal adult pancreas: MR imaging evaluation.
To investigate age-related changes in normal adult pancreas as identified by magnetic resonance imaging (MRI). We examined 115 patients without pancreatic diseases (21-90 years) who underwent upper abdominal MRI to evaluate the normal pancreatic MRI findings related to aging. The parameters examined were the pancreatic anteroposterior (AP) diameter, pancreatic lobulation, pancreatic signal intensity (SI), depiction of the main pancreatic duct (MPD), grade of the visual SI decrease on the opposed-phase T1-weighted images compared with in-phase images, and enhancement effect of the pancreas in the arterial phase of dynamic imaging. The pancreatic AP diameter significantly reduced (head, p=0.0172; body, p=0.0007; tail, p<0.0001), and lobulation (p<0.0001) and parenchymal fatty change (p<0.0001) became more evident with aging. No significant correlation was observed between aging and pancreatic SI, however the SI on the in-phase T1-weighted images tended to decrease with aging. No significant correlation was observed between aging and the depiction of the MPD as well as aging and contrast enhancement. MRI findings of pancreatic atrophy, lobulation, and fatty degeneration are characteristic changes related to aging, and it is necessary to recognize these changes in the interpretation of abdominal MRI in patients with and without pancreatic disease.


Improvement of osteoporosis Care Organized by Nurses: ICON study - Protocol of a quasi-experimental study to assess the (cost)-effectiveness of combining a decision aid with motivational interviewing for improving medication persistence in patients with a recent fracture being treated at the fracture liaison service.
Given the health and economic burden of fractures related to osteoporosis, suboptimal adherence to medication and the increasing importance of shared-decision making, the Improvement of osteoporosis Care Organized by Nurses (ICON) study was designed to evaluate the effectiveness, cost-effectiveness and feasibility of a multi-component adherence intervention (MCAI) for patients with an indication for treatment with anti-osteoporosis medication, following assessment at the Fracture Liaison Service after a recent fracture. The MCAI involves two consultations at the FLS. During the first consultation, a decision aid is will be used to involve patients in the decision of whether to start anti-osteoporosis medication. During the follow-up visit, the nurse inquires about, and stimulates, medication adherence using motivational interviewing techniques. A quasi-experimental trial to evaluate the (cost-) effectiveness and feasibility of an MCAI, consisting of a decision aid (DA) at the first visit, combined with nurse-led adherence support using motivational interviewing during the follow-up visit, in comparison with care as usual, in improving adherence to oral anti-osteoporosis medication for patients with a recent fracture two Dutch FLS. Medication persistence, defined as the proportion of patients who are persistent at one year assuming a refill gap < 30 days, is the primary outcome. Medication adherence, decision quality, subsequent fractures and mortality are the secondary outcomes. A lifetime cost-effectiveness analysis using a model-based economic evaluation and a process evaluation will also be conducted. A sample size of 248 patients is required to show an improvement in the primary outcome with 20%. Study follow-up is at 12 months, with measurements at baseline, after four months, and at 12 months. We expect that the ICON-study will show that the MCAI is a (cost-)effective intervention for improving persistence with anti-osteoporosis medication and that it is feasible for implementation at the FLS. This trial has been registered in the Netherlands Trial Registry, part of the Dutch Cochrane Centre (Trial NL7236 (NTR7435)). Version 1.0; 26-11-2020.


Synergistic combinations of antimicrobial peptides against biofilms of methicillin-resistant Staphylococcus aureus (MRSA) on polystyrene and medical devices.
Antimicrobial research is being focused to look for more effective therapeutics against antibiotic-resistant infections such as those caused by methicillin-resistant Staphylococcus aureus (MRSA). In this regard, antimicrobial peptides (AMPs) appear to be a promising solution. The aim of the present study was to investigate the potential activity of temporin A, citropin 1.1, CA(1-7)M(2-9)NH2 and Pal-KGK-NH2 in synergistic activity against MRSA biofilms developed on polystyrene surface (PSS) and central venous catheter (CVC). The study was subdivided into distinct phases to assess the ability of AMPs to inhibit biofilm formation, to identify possible synergy between AMPs, and to eradicate preformed biofilms on PSS and CVC using AMPs alone or in combination. Activity of the AMPs was particularly evident in the inhibition of biofilm formation on PSS and CVC, whilst the eradication of preformed biofilms was more difficult and was reached only after 24h of contact. The synergistic activity of AMP combinations, selected by their fractional inhibitory concentration index (FICI), led to an improvement in the performance of all of the molecules in the removal of different biofilms. Overall, AMPs could represent the next generation of antimicrobial agents for a prophylactic or therapeutic tool to control biofilms of antibiotic-resistant bacteria and/or biofilm-associated infections on different medical devices.


Using resource use logs to reduce the amount of missing data in economic evaluations alongside trials.
Economic evaluations alongside randomized controlled trials that collect data using patient-completed questionnaires are prone to missing data. Our objective was to determine whether giving patients a resource use log (RUL) at baseline would improve the odds of completing questions in a follow-up resource use questionnaire (RUQ) and to identify patients' views on RUL's usefulness and acceptability. The RUL study was a randomized controlled trial and qualitative study nested within a larger randomized controlled trial (the Arthroplasty Pain Experience Study trial). Eighty-five patients were randomized at baseline to receive or not receive an RUL. At 3-month follow-up, all participants received a postal RUQ. We created dummy variables for 13 resource use categories indicating whether complete information had been given for each category. We compared the completion rates between arms by using descriptive statistics and logistic regression. We explored patients' experience of using the RUL by interviewing a different subsample of Arthroplasty Pain Experience Study patients (n = 24) at 2- to 4-week follow-up. At 3 months, 74 of the 85 (87% in each arm) patients returned the RUQ. Patients in the RUL arm were 3.5 times more likely to complete the National Health Service community-based services category (P = 0.08). The RUL was positively received by patients and was generally seen as a useful memory aid. The RUL is a useful and acceptable tool in reducing the amount of missing data for some types of resource use.


Surveillance and Genomic Characterization of Influenza A and D Viruses in Swine, Belgium and the Netherlands, 2019-2021.
During 2019-2021, we isolated 62 swine influenza A viruses in Belgium and the Netherlands. We also detected influenza D in pigs in the Netherlands. The ever-changing diversity of influenza viruses and the identification of influenza D emphasize the need for more virus surveillance.


Tumour-infiltrating lymphocytes in canine melanocytic tumours: An investigation on the prognostic role of CD3+ and CD20+ lymphocytic populations.
The study of the immune response in several types of tumours has been rapidly increasing in recent years with the dual aim of understanding the interactions between neoplastic and immune cells and their importance in cancer pathogenesis and progression, as well as identifying targets for cancer immunotherapy. Despite being considered one of the most immunogenic tumour types, melanoma can progress in the presence of abundant lymphocytic infiltration, therefore suggesting that the immune response is not able to efficiently control tumour growth. The purpose of this study was to investigate whether the density, distribution and grade of tumour-infiltrating lymphocytes (TILs) in 97 canine melanocytic tumours is associated with histologic indicators of malignancy and can be considered a prognostic factor in the dog. As a further step in the characterization of the immune response in melanocytic tumours, an immunohistochemical investigation was performed to evaluate the two main populations of TILs, T-lymphocytes (CD3+ ) and B-lymphocytes (CD20+ ). The results of our study show that TILs are present in a large proportion of canine melanocytic tumours, especially in oral melanomas, and that the infiltrate is usually mild. The quantity of CD20+ TILs was significantly associated with some histologic prognostic factors, such as the mitotic count, the cellular pleomorphism and the percentage of pigmented cells. Remarkably, a high infiltration of CD20+ TILs was associated with tumour-related death, presence of metastasis/recurrence, shorter overall and disease-free survival, increased hazard of death and of developing recurrence/metastasis, hence representing a potential new negative prognostic factor in canine melanocytic tumours.


Activity and safety of topical pimecrolimus in patients with early stage mycosis fungoides (PimTo-MF): a single-arm, multicentre, phase 2 trial.
The calcineurin pathway is often activated in mycosis fungoides. We aimed to assess the activity and safety of topical pimecrolimus, a calcineurin inhibitor, in patients with early mycosis fungoides. PimTo-MF was a single-arm, multicentre, phase 2 trial done at six medical centres in Spain. Patients (aged ≥18 years) had histologically confirmed early mycosis fungoides (stages IA-IIA) and an Eastern Cooperative Oncology Group performance status of 0-1. Key exclusion criteria included the use of concurrent treatments for mycosis fungoides, including sunbathing, topical or systemic corticosteroids, and other calcineurin inhibitors. Patients applied topical pimecrolimus 1% cream on their skin lesions twice daily for 16 weeks (1 g per 2% of body surface), with subsequent follow-up of 12 months. Dosage modifications were not allowed. To evaluate adherence to the treatment, patients were instructed to return all empty tubes to the hospital (as per drug accountability protocols). The primary endpoint was the overall response ratein the intention-to-treat population. PimTo-MF is registered with EudraCT, 2014-001377-14, and is complete. Between March 1, 2015, and Sept 30, 2016, 39 patients were enrolled. All patients were assessable, with a median age of 51·5 years (IQR 45-62), and the population was predominantly male (24 male [62%], 15 female [38%]). Median follow-up after baseline was 5·7 years (IQR 5·7-6·2). 22 (56%) of 39 patients had an overall response (one complete response, 21 partial responses). Responses were observed across IA (14 [54%] of 26 patients) and IB (eight [73%] of 11 patients) clinical stages, but not IIA. Topical pimecrolimus was well tolerated and no patient required a dose reduction or discontinued treatment because of unacceptable drug-related toxicity. No patients were lost to follow-up or discontinued treatment. 13 (33%) of 39 patients reported adverse events; transitory mild burning or pruritus (grade 1) was the most common, seen in eight (21%) patients. In three (8%) of these patients, the burning or pruritus was considered related to treatment. No grade 4 or 5 adverse events were observed. Pimecrolimus 1% cream seems active and safe in patients with early stage mycosis fungoides. Our findings should be taken with caution until long-term follow-up data are obtained that confirm the safety of this treatment. Further controlled clinical trials are warranted to confirm these results. Instituto de Salud Carlos III and the European Regional Development Fund. For the Spanish translation of the abstract see Supplementary Materials section.


Human Plasmacytoid Dendritic Cells Elicited Different Responses after Infection with Pathogenic and Nonpathogenic Junin Virus Strains.
The arenavirus Junin virus (JUNV) is the etiologic agent of Argentine hemorrhagic fever. We characterized the JUNV infection of human peripheral blood-derived plasmacytoid dendritic cells (hpDC), demonstrating that hpDC are susceptible to infection with the C#1 strain (attenuated) and even more susceptible to infection with the P (virulent) JUNV strain. However, hpDC elicited different responses in terms of viability, activation, maturation, and cytokine expression after infection with both JUNV strains.


Mechanical properties and biocompatibility of titanium with a high oxygen concentration for dental implants.
In order to improve the strength of commercially pure Ti (CP-Ti) for oral implants, the high oxygen content Ti (HOC-Ti) was prepared via powder metallurgy. Its composition and mechanical properties were then characterized. After surface treatment by sandblasting and acid etching (SLA), the surface morphology, wettability and roughness of the HOC-Ti and CP-Ti sample were examined. In an in vitro test that followed an evaluation of the protein adsorption capacity of HOC-Ti, the mouse preosteoblast cells were inoculated onto the specimens to evaluate their biocompatibility, in comparison with those of CP-Ti. The oxygen concentration of the HOC-Ti increased to 0.62 wt%, which is higher than the 0.26 wt% of the CP-Ti, while their compositions and microstructures were very similar. The tensile and compressive yield strength of the HOC-Ti (800 MPa) was improved significantly in comparison to that of the CP-Ti (530 MPa). After surface treatment, a unique structure of micropores with a diameter of 380 nm was observed on the entire surface of the HOC-Ti that facilitates cell adhesion and proliferation. The wettability of the HOC-Ti was obviously superior (p < 0.05). The in vitro study showed that the MC3T3-E1 cells inoculated on the surface of HOC-Ti exhibited a homogeneous microstructure, and the viability was higher than that of the control group on days 4 and 7 (p < 0.05). In addition, the number and differentiation activity of cells that adhered to the surface of the HOC-Ti increased significantly on day 7 (p < 0.05). The experimental results showed that, in view of its mechanical properties and biocompatibility, HOC-Ti is superior to CP-Ti and is promising for oral implant applications.


Association between serum levels of organochlorine pesticides and sex hormones in adults living in a heavily contaminated area in Brazil.
Several studies have investigated the effects of organochlorine (OC) pesticides on adverse reproductive outcomes. However, few previous studies explored their effects on sex hormones. To examine the association between serum concentrations of OC pesticides and levels of sex hormones in adult population in a rural area in Brazil heavily contaminated with these pesticides. A cross-sectional study with 304 men and 300 women was undertaken. Wet weight serum concentrations of 19 OC pesticides (dichloro-diphenyl-trichloroethane [DDT] and hexachlorocyclohexane [HCH], among others) were determined in all participants. Testosterone levels were obtained for men and estradiol, progesterone, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) for women. Associations between OC pesticides and sex hormones were evaluated using linear regression models. Prevalence of women with non-physiological hyperprolactinemia was 4%. After adjusting for serum lipids and confounders, heptachlor and o,p'-DDT concentrations in men were associated with lower testosterone levels, while peri- and postmenopausal women (N=77) showed inverse associations between LH and hexachlorobenzene (HCB), p,p'-DDT, p,p'-DDD (dichloro-diphenyl-dichloroethane), endosulfan 1 and 2, aldrin and mirex, as well as between FSH and p,p'-DDD, endosulfan 1 and aldrin. Premenopausal women (N=210) did not show statistically significant associations between OC pesticides and sex hormones. Inverse associations between OC pesticide concentrations and testosterone in men and LH and FSH in peri-/postmenopausal women, together with the high proportion of women with elevated prolactin, suggest that these OC compounds may have triggered anti-androgenic effects in men and estrogenic effects in women in this population.


EGR1 Overexpression Inhibits the Occurrence of Preeclampsia by Binding to MicroRNA-574 Promoter and Upregulating GAB1.
Early growth response protein 1 (EGR1) is potent in modulating placental trophoblast cell growth and shows a differential expression in preeclampsia (PE). We aimed to identify the downstream mechanism of EGR1 in PE. RT-qPCR showed EGR1 was significantly decreased in PE placenta. Overexpression of EGR1 facilitated the proliferation and invasion of HTR-8/Svneo cells, and reduced the concentration of human chorionic gonadotrophin (HCG) in the supernatant. Bioinformatics prediction, ChIP, and luciferase reporter experiments revealed that EGR1 inhibited miR-574 expression by binding to miR-574 promoter and that miR-574 targeted GAB1. Furthermore, overexpression of miR-574 inhibited the proliferation and invasion of HTR-8/Svneo cells. GAB1 was downregulated in placenta of PE patients, which was positively correlated with EGR1 and negatively correlated with miR-574. Inhibition of GAB1 attenuated the effect of EGR1 overexpression on the proliferation and invasion of HTR-8/Svneo cells. All in all, EGR1 upregulated GAB1 by inhibiting miR-574, thus contributing to trophoblast cell proliferation and invasion.


Comparative pharmacokinetics of ceftazidime in young, healthy and elderly, acutely ill males.
The pharmacokinetics of ceftazidime have been investigated after single and multiple i.v. doses in 9 young healthy male volunteers and 15 elderly male patients with acute bacterial infections. All subjects had normal, age-correlated glomerular function. Distribution and elimination in young volunteers were unaffected by posture and were similar to what has been reported earlier. In contrast, elderly patients had longer t1/2 beta (3.1 vs 1.9 h), larger AUC (414.0 vs 276.6 h.mg/l), lower total and renal clearances, reduced urinary recovery over 12 h and enlarged Vss. Total serum clearance of ceftazidime was closely correlated with the 51Cr-EDTA clearance. There was no significant change in 51Cr-EDTA clearance after seven days of treatment. A reduction in the dose of beta-lactam antibiotics eliminated by the kidney is advisable in elderly patients with an acute bacterial infection.


Cross-cultural adaptation and validation of the Spanish version of the Anesthetists' Non-Technical Skills (ANTS) assessment tool.
Establish the transcultural validity of Anesthetists Non-Technical Skills (ANTS) in a Spanish-speaking country. Prospective cohort. Clinical simulation center. Forty-two Anesthesia PY2 and PY3 residents participated in the study. Four clinical scenarios simulating anesthesia crises were assessed with a Spanish version of ANTS. Every simulated scenario was run twice with a time span of 3 to 4 months between them. Two anesthesiologists independently assessed all simulated sessions using ANTS. The ANTS indicators of construct validity were obtained by confirmatory factor analysis. Various goodness-of-fit indices of the factorial model were calculated: Comparative Fit Index (CFI); Tucker-Lewis Adjustment Index (TLI) and Root Mean Square Error of Approximation (RMSEA). The standardized factor loadings and the determination coefficient (R2) was also estimated. A total of 212 clinical scenarios were analyzed. The specified factorial model had the same grouping of elements in four domains as the original version of ANTS. The CFI index and the TLI were 0.99 and the RMSEA reached 0.07 (95% CI 0.06-0.08). All the standardized factor loadings were found to be >0.4. Also, the elements obtained an R2 value that fluctuated between 0.54 and 0.92. The Spanish version of ANTS is a valid, reliable and a useful tool to assess non-technical skills in Spanish-speaking countries. The applicability of the instrument was comparable to the original setting. The high reliability of ANTS in our setting allows us to propose its use not just in an educational and research setting; it can be used as an assessment tool of non-technical skills.


The role of biogenic amines in the modulation of monocytes in autoimmune neuroinflammation.
Multiple sclerosis (MS) is inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) with autoimmune mechanism of development. The study of the neuroimmune interactions is one of the most developing directions in the research of the pathogenesis of MS. The influence of biogenic amines on the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and MS was shown by the modulation of subsets of T-helper cells and B-cells, which plays a crucial role in the autoimmunity of the CNS. However, along with T- and B-cells the critical involvement of mononuclear phagocytes such as dendritic cells, macrophages, and monocytes in the development of neuroinflammation also was shown. It was demonstrated that the activation of microglial cells (resident macrophages of the CNS) could initiate the neuroinflammation in the EAE, suggesting their role at an early stage of the disease. In contrast, monocytes, which migrate from the periphery into the CNS through the blood-brain barrier, mediate the effector phase of the disease and cause neurological disability in EAE. In addition, the clinical efficacy of the therapy with depletion of the monocytes in EAE was shown, suggesting their crucial role in the autoimmunity of the CNS. Biogenic amines, such as epinephrine, norepinephrine, dopamine, and serotonin are direct mediators of the neuroimmune interaction and may affect the pathogenesis of EAE and MS by modulating the immune cell activity and cytokine production. The anti-inflammatory effect of targeting the biogenic amines receptors on the pathogenesis of EAE and MS by suppression of Th17- and Th1-cells, which are critical for the CNS autoimmunity, was shown. However, the latest data showed the potential ability of biogenic amines to affect the functions of the mononuclear phagocytes and their involvement in the modulation of neuroinflammation. This article reviews the literature data on the role of monocytes in the pathogenesis of EAE and MS. The data on the effect of targeting of biogenic amine receptors on the function of monocytes are presented.


Origin of the selectivity for trans-to-cis isomerization in 2-butene on Pt(111) single crystal surfaces.
DFT calculations were performed to explain the preference for the conversion of trans-2-butene to its less stable cis isomer on Pt(111) surfaces reported previously. The results indicate that the main factors controlling the direction of this reaction are the lesser degrees of molecular rearrangement and surface reconstruction required in the adsorption of the cis isomer on the hydrogen-covered Pt surface. This is a case where hydrogen coverage and atomic restructuring not only dominate the energetics of adsorption but also define reaction selectivity.


Complete Genome Sequences of Allofrancisella inopinata SYSU YG23 and Allofrancisella frigidaquae SYSU 10HL1970, Isolated from Water from Cooling Systems in China.
Near neighbors to the causative agent of tularemia, Francisella tularensis, isolated from diverse sources, have been reported in recent years. In this announcement, we present the complete sequences of circular chromosomes of one of the closest neighboring genera of Francisella (i.e., the type strains of Allofrancisella inopinata and Allofrancisella frigidaquae).


Purinergic signaling in diabetes and metabolism.
Purinergic signaling, a concept originally formulated by the late Geoffrey Burnstock (1929-2020), was found to modulate pathways in every physiological system. In metabolic disorders there is a role for both adenosine receptors and P2 (nucleotide) receptors, of which there are two classes, i.e. P2Y metabotropic and P2X ionotropic receptors. The individual roles of the 19 receptors encompassed by this family have been dissected - and in many cases the effects associated with specific cell types, including adipocytes, skeletal muscle, liver cells and immune cells. It is suggested that ligands selective for each of the four adenosine receptors (A1, A2A, A2B and A3), and several of the P2 subtypes (e.g. P2Y6 or P2X7 antagonists) might have therapeutic potential for treating diabetes and obesity. This is a developing story with some conflicting conclusions relevant to drug discovery, which we summarize here.


Acral verruca-like presentation of chronic graft-vs.-host disease.
Chronic graft-vs.-host disease (GVHD) is a severe and potentially fatal complication in patients after undergoing allogeneic stem cell transplant. This disease may be hard to diagnose as it has numerous cutaneous presentations. We report four cases of patients seen at Stanford Hospital between January 2013 to December 2014 with hematologic malignancy who developed hyperkeratotic papules and plaques on the palms and soles after allogeneic hematopoietic stem cell transplant. In all four cases, standard treatments for verruca vulgaris failed. Histopathology uniformly showed basal vacuolar alteration at the dermal-epidermal junction and necrotic keratinocytes around the eccrine glands, consistent with GVHD. Interestingly, all four patients responded to topical immunosuppression. Acral verrucous lesions represent an underrecognized presentation of chronic GVHD. We describe four patients with verruca-like lesions on the palms and soles following allogeneic HSCT. Histopathology confirmed GVHD, and lesions improved with immunosuppression. It is important for dermatologists and dermatopathologists to recognize this rare presentation of cutaneous GVHD.


An actualized catalogue of the Psychodidae (Diptera) of Mexico and their known distribution by state.
A catalogue of Psychodidae of Mexico is presented. A total of 99 species in 30 genera of the subfamilies Bruchomyiinae, Phlebotominae, Psychodinae, and Trichomyiinae are listed, with bibliographic citations and distributional data by country and in the case of Mexico by states.


[Prophylactic bedrest against post-lumbar puncture headache should not be routinely used in all patients].
Headache after lumbar puncture (PPH) is a common clinical problem, and occurs more frequently in patients with prepuncture headache. Bedrest after extraction of the needle has been recommended as prophylaxis for over a century. In a nation-wide survey, it was found that a majority of Swedish clinics kept all patients in a recumbent position for 30-90 minutes or longer. Many patients find enforced bedrest after lumbar puncture disagreeable, and every second person does not follow the recommendation. There is no good evidence from randomised trials to suggest that routine bedrest after dural puncture is beneficial. On the contrary, there are data in support of an increase of PPH after prolonged recumbency. Presumably, all cases should not be handled similarly. Based on present knowledge, it is suggested that patients free of headache during the last week before lumbal puncture are to be mobilised immediately.


Nanobody-Based GFP Traps to Study Protein Localization and Function in Developmental Biology.
Synthetic protein-binding tools based on anti-green fluorescent protein (GFP) nanobodies have recently emerged as useful resources to study developmental biology. By fusing GFP-targeting nanobodies to well-characterized protein domains residing in discrete sub-cellular locations, it is possible to directly and acutely manipulate the localization of GFP-tagged proteins-of-interest in a predictable manner. Here, we describe a detailed protocol for the application of nanobody-based GFP-binding tools, namely Morphotrap and GrabFP, to study the localization and function of extracellular and intracellular proteins in the Drosophila wing imaginal disc. Given the generality of these methods, they are easily applicable for use in other tissues and model organisms.


The Q-type C2H2 zinc finger subfamily of transcription factors in Triticum aestivum is predominantly expressed in roots and enriched with members containing an EAR repressor motif and responsive to drought stress.
Q-type C2H2 zinc finger proteins (ZFPs) form a subfamily of transcription factors that contain a plant-specific QALGGH amino acid motif. A total of 47 expressed Q-type C2H2 zinc finger genes in bread wheat (Triticum aestivum) (designated TaZFP) were identified from the current databases. Protein sequence analysis for the presence of ERF-associated amphiphilic repressor (EAR) motif sequences from known transcriptional repressors revealed that 26% of the TaZFP subfamily members contain an EAR motif. Quantitative RT-PCR analysis of the mRNA distribution of 44 TaZFP genes in various organs revealed that 30 genes were predominantly expressed in the roots. The majority of the TaZFP genes showed significant changes in their mRNA levels during leaf development and aging. Expression of 37 TaZFP genes in the leaves and roots responded to drought stress at least in one organ with 74% of the drought-responsive TaZFP genes being down-regulated in the drought-stressed roots. In contrast, only 6 out of the 44 TaZFP genes showed expression changes in the leaves with sucrose treatment. Expression of 50% of the drought-responsive TaZFP genes in the leaves (16 genes analysed) did not respond to ABA treatment, indicating that some TaZFP genes are involved in ABA-independent signalling pathways. These results indicate that the Q-type TaZFP subfamily is likely to have an important role in wheat roots and is enriched with members that are potentially involved in regulating cellular activities during changes of the physiological status of plant cells, as it occurs during drought stress or leaf development/aging.


Community structure of yeast in fermented soy sauce and screening of functional yeast with potential to enhance the soy sauce flavor.
Yeast plays an important role in the formation of desirable aroma during soy sauce fermentation. In this study, the structure and diversity of yeast communities in seven different soy sauce residues were investigated by ITS sequencing analysis, and then the aroma characteristics of selected yeast species were examined by a combination of gas chromatography-mass spectrometry (GC-MS), headspace solid-phase microextraction (SPME) and liquid-liquid extraction (LLE). A total of 18 yeast genera were identified in seven soy sauce residues. Among them, Candid and Zygosaccharomyces were detected in all samples, followed by Millerozyma, Wickerhamiella, Meyerozyma, Trichosporon and Wickerhamomyces, which were found in more than two-thirds of the samples. Subsequently, eight representative species, isolated from soy sauce residues, were subjected to environmental stress tolerance tests and aroma production tests. Among them, three isolated species were regarded as potential aroma-enhancing microbes in soy sauce. Wickerhamiella versatilis could increase the contents of ethyl ester compounds and alcohols, thereby improving the fruity and alcoholic aroma of soy sauce. Candida sorbosivorans enhanced sweet and caramel-like aroma of soy sauce by producing 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) and 3-hydroxy-2-methyl-4h-pyran-4-one (maltol). Starmerella etchellsii could enhance the contents of 2,6-dimethylpyrazine, methyl pyrazine and benzeneacetaldehyde. This study is of great significance for the development and application of flavor functional yeasts in soy sauce fermentation.


Dry facts are not always inviting: a content analysis of Korean videos regarding Parkinson's disease on YouTube.
This study aimed to evaluate the accuracy of Korean videos regarding Parkinson's disease (PD) on YouTube and viewers' responses to them. YouTube search was performed using the search term "Parkinson disease" in Korean language on March 28, 2017. Two independent neurologists categorized the videos into "reliable", "misleading" or "patient experiences". The number of views, days since upload, video length, number of "likes" and "dislikes", and upload source were collected for each video. A total of 138 videos were included in this study. Of these, 91 videos (65.9%) were reliable; 31 (22.5%) were misleading, and 16 (11.6%) were of patient experiences. The videos with patient experiences had the highest number of mean views with 9710.4±3686.9, followed by misleading videos with 5075.0±1198.6, and reliable videos with 2146.8±353.4 (ANOVA, p<0.001). The number of mean views per day was 4.0±0.6 for the reliable videos, which was significantly lower than the misleading videos (9.7±3.4, p=0.020) and the videos of patient experiences (11.3±4.6, p=0.023). The reliable videos were mostly uploaded by university hospitals (46.2%) and misleading videos by health-related commercial entities (74.2%). The misleading videos as well as the videos of patient experiences advocated "diet" asa treatment of PD. The current study found that only two-thirds of the Korean videos regarding PD on YouTube provide reliable information. More importantly, the videos with reliable contents were less popular than videos with misleading contents. Further efforts are warranted to effectively increase the dissemination of accurate and scientifically proven PD information to YouTube users.