Life history of oysters influences Vibrio parahaemolyticus accumulation in Pacific oysters (Crassostrea gigas).
Vibrio parahaemolyticus infection in humans is associated with raw oyster consumption. Evaluation of V. parahaemolyticus presence in oysters is of most interest because of the economic and public health issues that it represents. To explore V. parahaemolyticus accumulation and depuration in adult Crassostrea gigas, we developed a GFP-tagged V. parahaemolyticus strain (IFVp201-gfp+ ), as well as a rapid and efficient quantification method in C. gigas oysters haemolymph by flow cytometry. Impact of the life history of C. gigas on accumulation and depuration of V. parahaemolyticus IFVp201 was subsequently investigated. We found that naive oysters, i.e. grown in controlled facilities with UV treated seawater, accumulated significantly more IFVp201 than environmental oysters, i.e. grown in intertidal environment. We hypothesized that environmental oysters could have been immune primed, thus could limit V. parahaemolyticus accumulation. Meanwhile, both naive and environmental oysters had similar depuration rates.


Profiling the Essential Nature of Lipid Metabolism in Asexual Blood and Gametocyte Stages of Plasmodium falciparum.
During its life cycle, Plasmodium falciparum undergoes rapid proliferation fueled by de novo synthesis and acquisition of host cell lipids. Consistent with this essential role, Plasmodium lipid synthesis enzymes are emerging as potential drug targets. To explore their broader potential for therapeutic interventions, we assayed the global lipid landscape during P. falciparum sexual and asexual blood stage (ABS) development. Using liquid chromatography-mass spectrometry, we analyzed 304 lipids constituting 24 classes in ABS parasites, infected red blood cell (RBC)-derived microvesicles, gametocytes, and uninfected RBCs. Ten lipid classes were previously uncharacterized in P. falciparum, and 70%-75% of the lipid classes exhibited changes in abundance during ABS and gametocyte development. Utilizing compounds that target lipid metabolism, we affirmed the essentiality of major classes, including triacylglycerols. These studies highlight the interplay between host and parasite lipid metabolism and provide a comprehensive analysis of P. falciparum lipids with candidate pathways for drug discovery efforts.


Do HER-2 positive metastatic breast cancer patients benefit from the use of trastuzumab beyond disease progression? A mono-institutional experience and systematic review of observational studies.
Though preclinical evidence supports the protracted use of trastuzumab to reach sustained anti-tumor activity, the activity of trastuzumab beyond disease progression remains controversial in HER-2 over-expressing (HER-2+) metastatic breast cancer (MBC) patients. We retrospectively evaluated a total of 59 patients with HER-2 + MBC treated at our institution with trastuzumab-based therapies. Our results were added to those obtained in similar observational studies and summary estimates for overall response (OR) and clinical benefit (CB) to first and second trastuzumab-based lines were calculated. In our series of patients we observed an OR of 59.3% and 27% for first and second trastuzumab-based lines, respectively, with a corresponding CB of 83% and 62.2%, respectively. Time to first and second progression were 9.5 months and 6.7 months, respectively. The combined analysis showed an OR of 50% for first trastuzumab-based regimen and 21.2% for second trastuzumab-based line. The corresponding values for CB were 77.6% and 42.6%, respectively. A second trastuzumab-containing regimen beyond progression yields a considerable rate of OR and CB in HER-2 + MBC patients. Randomized trials are warranted.


Ultrastructural pathology of lymphocytes in neuronal ceroid-lipofuscinoses.
Lymphocytes were studied by electron microscopy in five cases of neuronal ceroid-lipofuscinoses (NCL), one of infantile, three of late infantile and one of juvenile types. Each type of NCL revealed specific cytoplasmic inclusions, namely, granular bodies in the infantile form, curvilinear profiles in the late infantile form and fingerprint profiles within vacuoles in the juvenile type. Survey of the literature also confirmed the high correlation between subtype of NCL and type of lymphocytic inclusion. The electron microscopic examination lymphocytes offers easily available diagnostic informations.


Cytotoxicity of 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) and analogues in wild type and CYP3A4 stably transfected HepG2 cells.
The thiazolidinedione (TZD) ring is a constituent of the glitazones that are used to treat type II diabetes. Liver injury has been reported following chronic glitazone use; however, they do not produce hepatic damage in common laboratory animal species. In contrast, 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) causes hepatotoxicity in rats. DCPT toxicity is dependent upon the presence of an intact TZD ring and cytochrome P450 (CYP)-mediated biotransformation. To further investigate TZD ring-induced toxicity, DCPT and several structural analogues or potential metabolites were tested in vitro using wild type human hepatoma HepG2 and HepG2 cells stably transfected with the CYP3A4 isozyme. CYP3A4 activity was confirmed by measuring testosterone 6β-hydroxylation. Both cell lines were treated with 0-250 μM of the compounds in Hanks' balanced salt solution. Cell viability was measured after 24 h. DCPT and S-(3,5-dichlorophenyl)aminocarbonyl thioglycolic acid (DCTA) were the most toxic compounds of the series. Furthermore, DCPT was significantly more toxic in transfected cells (LC50=160.2±5.9 μM) than in wild type cells (LC50=233.0±19.7 μM). Treatment with a CYP3A4 inhibitor or inducer attenuated or potentiated DCPT cytotoxicity, respectively. These results suggest that DCPT-induced cytotoxicity in the transfected HepG2 cells is partially dependent on CYP3A4.


Quality of recovery and safety of deep intravenous sedation compared to general anesthesia in facial plastic surgery: A prospective cohort study.
Facial plastic surgical procedures are performed under either general anesthesia (GA) or sedation. GA is often associated with post-operative nausea and longer recovery, while deep sedation is thought to greatly facilitate perioperative patient comfort and expedite recovery. The objective of this study was to compare these two anesthetic techniques in a relatively healthy patient population undergoing facial plastic surgery and to discuss optimizing patient safety with a deep sedation technique. A non-randomized, prospective cohort study was conducted to evaluate patients undergoing facial plastic surgery with a focus on rhinoplasty under either deep intravenous sedation (DIVS) in an ambulatory surgery center or under GA in a community hospital. Patients were between ages 18-65 and agreed to participate in the study and complete a quality of recovery (QoR-40) survey. Two-tailed Student's t-test was done for numerical data and Chi-squared test for categorical data. Twenty-three patients and 16 patients had surgery under DIVS and GA, respectively. Compared to the GA group, the DIVS group had less post-operative nausea and vomiting (21.7% vs 50%, P = 0.04; 4.3% vs 37.5%; P = 0.004, respectively), shorter emergence time (4 vs 13 min, P < 0.001), and higher QoR-40 scores for almost all the categories except for physical independence. There were no post-operative medical or surgical complications. DIVS appeared to be safe in the office-based setting and provided a higher quality recovery after a predominantly rhinoplasty-based practice compared to the GA group. Vigilant monitoring of the patient is crucial for careful titration of sedation to avoid respiratory depression and possible compromise of the surgical result from having to rescue the airway.


Circular RNA circ_0061140 accelerates hypoxia-induced glycolysis, migration, and invasion in lung adenocarcinoma through the microRNA-653/hexokinase 2 (HK2) axis.
Circular RNA (circRNA) is considered to be an essential regulator of multiple human malignancies. However, the role and molecular mechanism of circ_0061140 in lung adenocarcinoma ((LUAD) remain elusive. The levels of circ_0061140, microRNA (miR)-653 and hexokinase 2 (HK2) were examined by RT-qPCR. Downstream targets of circ_0061140 were predicted by circinteractome website and verified by luciferase reporter and RIP assays. HK2 protein level was assessed via Western blotting. The migratory and invasive abilities of LUAD cells were assessed via wound healing and transwell assays. It was uncovered that circ_0061140 level was elevated in LUAD samples, and the high level of circ_0061140 was related to poor survival rate of LUAD patients. Circ_0061140 deletion inhibited glycolysis, migration and invasion of hypoxia-treated LUAD cells. Moreover, circ_0061140 could modulate HK2 level by absorbing miR-653. Furthermore, miR-653 silence or HK2 addition neutralized the effects of circ_0061140 knockdown on LUAD progression under hypoxia. This study elaborated that circ_0061140 accelerated hypoxia-triggered glycolysis, migration and invasion in LUAD cells via downregulating miR-653 and increasing HK2 expression.


Technical skills assessment in a coronary angiography simulator for construct validation.
The aim of this study was to evaluate technical skills in a coronary angiography (CA) simulator to establish the performance level of trainees and experts in virtual CA.The traditional master-apprentice way of learning CA is by practicing on patients despite a known risk for complications during training. Safe CA training is warranted, and simulators might be one possibility. Simulators used must be validated regarding their ability to separate trainees from experts. Construct validation of a CA simulator, to our knowledge, has not yet been published. Ten cardiology residents without experience in CA, 4 intermediate, and 10 CA experts performed 5 CAs in the Mentice VIST (Vascular Intervention Simulation Trainer). Metrics reflecting proficiency skills such as total procedure time, fluoroscopy time, and contrast volume were extracted from the simulator computer and compared between the groups. All examinations were videotaped, and the number of handling errors was examined. The videos were evaluated by 2 experts blinded to the test object's performance level. Experts outperformed trainees in all metrics measured by the simulator. Improvement was demonstrated in all metrics through all 5 CAs. Furthermore, beginners had more handling errors compared with experts. Mentice VIST simulator can distinguish between trainees and experts in CA in the metrics extracted from the computer and therefore prove the concept of construct validity.


Biradicals by triplet recombination of radical ion pairs.
Radical ion pairs generated by photoinduced electron transfer may undergo return electron transfer (RET) in pairs of singlet or triplet multiplicity. RET efficiencies are determined by the free energy of RET and the topologies of the potential surfaces of parent molecule, radical ion and triplet state. If radical ion geometries are different from the corresponding triplet states, RET occurs either with cleavage ("dissociative" RET; 1,2-diphenylcyclopropane radical cations) or formation of C-C bonds ("associative" RET; norbornadiene radical cation). Radical ions of some strained ring compounds spontaneously undergo ring-opening; RET to such species form ring-opened triplets without major geometry changes. CIDNP spectroscopy offers unique insights into triplet RET.


Changes in angiogenesis-related factors in serum following autologous bone marrow cell implantation for severe limb ischemia.
Bone marrow mononuclear cell (BM-MNC) implantation (BMI) for critical severe limb ischemia especially for Buerger's disease shows excellent clinical results but the mechanism of this treatment is still unknown. In this study, we investigated the changes in serum levels of angiogenesis-related factors after BMI treatment. Twelve patients whose BMI treatments were clinically very effective was selected out of ninteen cases, nine patients had Buerger's disease, two patients had arteriosclerosis obliterans and one had systemic sclerosis. Venous bood from femoral vein or brachial vein of the recipient limbs of these patients. Adrenomedulin (AM), soluble vascular cell adhesion molecule-1 (sVCAM-1), and C-reactive protein (CRP) serum levels 24 h after BMI treatment were significantly increased compared with those before BMI treatment (p < 0.05). Vascular endothelial growth factor (VEGF) serum levels after BMI treatment significantly increased between 1 week and 3 months after BMI treatment (p < 0.05). Nitric oxide (NO) serum levels after BMI treatment increased significantly 2 weeks after BMI treatment (p < 0.05). There was no correlation between the numbers of implanted cells and serum levels of measured angiogenesis-related factors that were significantly increased after BMI treatment. It was concluded that the mechanism underlying BMI treatment consists of early and late phases. The early phase involves the direct action by implanted cells, and the late phase involves indirect paracrine action. In addition, it was considered that BMI treatment is effective when we implant a sufficient level of bone marrow (600 ml) to treat severe limb ischemia.


Novel naturally occurring autoantibodies attenuate α-synuclein pathology in a mouse model of Parkinson's disease.
Accumulation and propagation of pathological α-synuclein (α-Syn) are the major contributing factors to the pathogenesis of Parkinson's disease (PD). Therapy to halt the spreading of α-Syn pathology needs to be established. After phage display and affinity maturation, human-derived anti-α-Syn autoantibodies were selected and applied to biochemical, cellular and animal models of PD. The novel naturally occurring anti-α-Syn autoantibodies (α-Syn-nAbs), P21 and P22, selectively bind α-Syn preformed fibrils (PFFs), recognise Lewy bodies (LBs) and Lewy neurites (LNs) in human PD brains, block α-Syn fibrillization and inhibit the seeding of α-Syn PFFs. Moreover, systematic administration of P21 and P22 attenuates α-Syn pathology, degeneration of the nigrostriatal pathway and motor deficits in mice injected with α-Syn PFFs. P21 and P22 attenuate α-synuclein pathology and are promising candidates for PD treatment.


Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor.
In aggressive, rapidly growing solid tumors such as glioblastoma multiforme (GBM), cancer cells face frequent dynamic changes in their microenvironment, including the availability of glucose and other nutrients. These challenges require that tumor cells have the ability to adapt in order to survive periods of nutrient/energy starvation. We have identified a reciprocal negative feedback loop mechanism in which the levels of microRNA-451 (miR-451) are negatively regulated through the phosphorylation and inactivation of its direct transcriptional activator OCT1 by 5' AMP-activated protein kinase (AMPK), which is activated by glucose depletion-induced metabolic stress. Conversely, in a glucose-rich environment, unrestrained expression of miR-451 suppresses AMPK pathway activity. These findings uncover miR-451 as a major effector of glucose-regulated AMPK signaling, allowing tumor cell adaptation to variations in nutrient availability in the tumor microenvironment.


Genetic aetiology of ophthalmological manifestations in children - a focus on mitochondrial disease-related symptoms.
To investigate the association of mutations in the mitochondrial DNA (mtDNA) or nuclear candidate genes with mitochondrial disease-related ophthalmic manifestations (nystagmus, ptosis, ophthalmoplegia, optic neuropathy and retinopathy) in children. A retrospective cohort of children (n = 98) was identified from the medical record files of a tertiary care hospital. The entire mtDNA and nuclear genes POLG1, OPA1 and PEO1 were analysed from the available DNA samples (n = 38). Furthermore, some nuclear candidate genes were investigated based on family history and phenotype. Rare mtDNA mutations were evaluated using in silico predictors and sequence alignment. Three patients had previously identified mutations in mtDNA that are associated with optic neuropathy (in MT-ND6 and MT-ND1) and nystagmus (in tRNA Arg). Nine rare mutations in MT-ATP6 were identified in seven patients, of whom four manifested with retinopathy and three had clusters of MT-ATP6 mutations. Nuclear PEO1 and OPA1 were unchanged in all samples, but a patient with nystagmus had a heterozygous POLG1 mutation. The analysis of nuclear candidate genes revealed mutations in NDUF8 (patient with nystagmus), TULP1 (patient with optic neuropathy, nystagmus and retinopathy) and RP2 (patient with retinopathy) genes. Children with retinopathy, nystagmus or optic neuropathy, especially together with developmental delay or positive family history, should be considered for mitochondrial disease. MT-ATP6 should be taken into account for children with retinopathy of unknown aetiology.


A case of holoprosencephaly and cebocephaly associated to torch infection.
Cebocephaly is a very rare congenital anomaly combining a severe midline facial malformation and holoprosencephaly. Here we report on first case of cebocephaly with semilobar holoprosencephaly, hypotelorism, and a single nostril due to intrauterine TORCH infection (Toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus [CMV], and Herpes infections) in the English language literature. Chromosomal analysis showed normal karyotyping.


Management-related risk factors for M. paratuberculosis infection in Michigan, USA, dairy herds.
A cross-sectional study was conducted from June through December 1996 to identify management-related risk factors for herd-level M. paratuberculosis infection. Data were collected from 121 participating herds. A two-part questionnaire was administered to gather data on current and previous management practices and herd productivity. A random sample of cows aged > or = 24 months was selected from each herd and tested for antibodies to M. paratuberculosis using the IDEXX Antibody ELISA (sensitivity 64%, specificity 96%). A positive herd was one in which > or = 2 animals tested positive for antibodies to M. paratuberculosis. A negative herd was one in which no animal tested positive. Herds in which only one animal tested positive were dropped from statistical analysis to reduce the risk of including false-positive herds in the statistical analyses. There were 80 herds with one or more positive animals and 41 herds with no positive animals in the sample (66% herd-level prevalence). Twenty-six herds (21%) were dropped from further analyses because they had only one positive cow. Twelve herds (10%) were dropped from analysis because of missing data. The resulting sample used for statistical modeling included 46 positive herds and 37 negative herds (55% herd-level prevalence). A multi-variable logistic-regression model was used to evaluate the results. The variable 'use of an exercise lot for lactating cows' was associated with a three-fold increase in odds of a herd being positive for M. paratuberculosis infection (O.R. = 3.01, C.I. = 1.03-8.80); 'cleaning of maternity pens after each use' was associated with a three-fold reduction in odds of a herd being positive for M. paratuberculosis infection (O.R. = 0.28, C.I. = 0.08-0.89); 'application of lime to pasture areas in 1993' resulted in a ten-fold decrease in odds of a herd being positive for M. paratuberculosis infection (O.R. = 0.10, C.I. = 0.02-0.56).


Comparison of atypical furunculosis vaccines in spotted wolffish (Anarhicas minor O.) and Atlantic halibut (Hippoglossus hippoglossus L.).
Atypical furunculosis caused by atypical Aeromonas salmonicida is a problem in farming of Atlantic halibut (Hippoglossus hippoglossus) and spotted wolffish (Anarhicas minor) in Norway, and vaccines for marine fish species are not available. Susceptibility to atypical A. salmonicida infection and efficacy of furunculosis vaccines in various fish species indicate that the host responses differ. Here, spotted wolffish was shown to be highly susceptible to intraperitoneal challenge with atypical A. salmonicida compared to halibut, and the two species appeared to respond differently to identical vaccines. Grouping of the atypical A. salmonicida isolates used as vaccines was based on a variable region in the surface A-layer protein, but no clear correlation between vaccine efficacy and A-protein group was found.


Classification and Analysis of Multiple Cattle Unitary Behaviors and Movements Based on Machine Learning Methods.
The behavior of livestock on farms is the primary representation of animal welfare, health conditions, and social interactions to determine whether they are healthy or not. The objective of this study was to propose a framework based on inertial measurement unit (IMU) data from 10 dairy cows to classify unitary behaviors such as feeding, standing, lying, ruminating-standing, ruminating-lying, and walking, and identify movements during unitary behaviors. Classification performance was investigated for three machine learning algorithms (K-nearest neighbors (KNN), random forest (RF), and extreme boosting algorithm (XGBoost)) in four time windows (5, 10, 30, and 60 s). Furthermore, feed tossing, rolling biting, and chewing in the correctly classified feeding segments were analyzed by the magnitude of the acceleration. The results revealed that the XGBoost had the highest performance in the 60 s time window with an average F1 score of 94% for the six unitary behavior classes. The F1 score of movements is 78% (feed tossing), 87% (rolling biting), and 87% (chewing). This framework offers a possibility to explore more detailed movements based on the unitary behavior classification.


Increased carbonyl content of proteins in synovial fluid from patients with rheumatoid arthritis.
The carbonyl content of proteins in the synovial fluid (SF) of patients with rheumatoid arthritis was significantly (p less than or equal to 0.10) elevated over levels in the SF of patients with osteoarthritis (OA). Other indicators of oxidative damage including catalse, ceruloplasmin, ferritin and superoxide dismutase also showed statistically significant differences (p less than or equal to 0.05) compared to patients with OA.


Association between procrastination, white-collar work and obesity in Japanese male workers: a cross-sectional study.
To investigate the associations among procrastination (time inconsistency), work environment and obesity-related factors in Japanese male workers. Cross-sectional study. Data were collected at two work sites of Japanese electronics manufacturing company in 2015. 795 full-time male workers in a Japanese electric company, aged 35-64 years, who underwent health checkups in 2015. Body mass index (BMI), adult weight change, obesity (BMI ≥25 kg/m2), adult weight gain over 10 kg (AWG10) and metabolic syndrome (MetS). Multivariable linear and logistic regression analyses were performed to assess the associations of procrastination assessed by using a one-item questionnaire and white-collar and blue-collar work with obesity-related factors. White-collar workers with high procrastination levels showed positive associations with BMI (B: 0.75, 95% CI 0.06 to 1.44) and adult weight change (B: 1.77, 95% CI 0.26 to 3.29), and had increased odds of AWG10 (OR: 1.85, 95% CI 1.04 to 3.29) and MetS (OR: 2.29 95% CI 1.18 to 4.44) after adjustment for age, education, work-related factors and lifestyle factors. However, such positive associations were not observed among blue-collar workers. Procrastination and white-collar work might have a joint effect on weight gain during adulthood and consequential obesity.


Erythropoietin-stimulated erythropoiesis in long-term bone marrow culture.
The proliferation of multipotential haematopoietic stem cells (CFU-S) is possible in some long-term bone marrow cultures. Granulocyte and macrophage progenitor (CFU-C) and megakaryocyte precursor cells (CFU-M) are present in these cultures and undergo full development into mature cells. In contrast, while immature erythroid progenitors ('early' BFU-E) are maintained in long-term culture, none of the more differentiated progeny (CFU-E) have been detected, and no morphologically recognisable erythroid cells have been observed. We now describe a modified culture system in which the 'early' BFU-E develop into 'late' BFU-E in response to added erythropoietin. Further maturation of these cells into CFU-E and non-nucleated erythrocytes can be achieved by mechanical agitation of the long-term cultures or by transferring the cells into dishes which do not allow cell attachment to occur.


Alterations in the water intake caused by central inhibition of angiotensin-converting enzyme in the rat.
In the present study we investigated the effects of central (i.c.v.) and subcutaneous (s.c.) injections of a 2 micrograms dose of lisinopryl, an inhibitor of angiotensin I(ANGI)-converting enzyme (CE), on water intake. I.c.v. but not s.c. injection of lisinopryl abolished drinking in response to s.c. isoprenaline (100 micrograms/kg) and significantly reduced drinking in response to 24 h water deprivation or s.c. polyethylene glycol (30% w/v, 10 ml/kg). Lisinopryl had no effect on water intake induced by cellular dehydration (s.c. injection of hypertonic saline (2 M NaCl)). These results are consistent with the hypothesis that lisinopryl acts as a CE blocking agent in the brain. The thrist challenge induced by hypotension using isoprenaline acts primarily by generating ANGII systemically and centrally. The other thirst challenges such as cellular dehydration are independent of the ANGII in the brain. This conclusion was made possible by utilizing a new CE blocking agent at a smaller dose than normally used for other ANG I-CE inhibitors.


Noninvasive detection of risk for emotion-provoked myocardial ischemia.
To test an easily administered, noninvasive technology to identify vulnerability to mental stress ischemia. Myocardial ischemia provoked by emotional stress (MSI) in patients with stable coronary artery disease (CAD) predicts major adverse cardiac events. A clinically useful tool to risk stratify patients on this factor is not available. Patients with documented CAD (n = 68) underwent single photon emission CT myocardial perfusion imaging concurrent with pulse wave amplitude assessment by peripheral arterial tonometry (PAT) during a mental stress protocol of sequential rest and anger stress periods. Heart rate and blood pressure were assessed, and blood was drawn for catecholamine assay, during rest and stress. MSI was defined by the presence of a new perfusion defect during anger stress (n = 26) and the ratio of stress to rest PAT response was calculated. Patients with MSI had a significantly lower PAT ratio than those without MSI (0.76 +/- 0.04 versus 0.91 +/- 0.05, p = .03). An ROC curve for optimum sensitivity/specificity of PAT ratio as an index of MSI produced a sensitivity of 0.62 and a specificity of 0.63. Among patients taking angiotensin converting enzyme (ACE) inhibitors, the sensitivity and specificity of the test increased to 0.86 and 0.73, respectively; 90% of patients without MSI were correctly identified. PAT in concert with ACE inhibition may provide a useful approach to assess risk for MSI. Future studies should help determine how best to utilize this approach for risk assessment in the clinical setting.


The epidemic of non-Hodgkin lymphoma in the United States: disentangling the effect of HIV, 1992-2009.
For decades, non-Hodgkin lymphoma (NHL) incidence has been increasing worldwide. NHL risk is strongly increased among HIV-infected people. Our understanding of trends in NHL incidence has been hampered by difficulties in separating HIV-infected NHL cases from general population rates. NHL incidence data during 1992-2009 were derived from 10 U.S. SEER cancer registries with information on HIV status at NHL diagnosis. The CDC estimated the number of people living with HIV in the registry areas. The proportion of NHL cases with HIV and NHL rates in the total and the HIV-uninfected populations were estimated. Time trends were assessed with Joinpoint analyses. Of 115,643 NHL cases diagnosed during 1992-2009, 5.9% were HIV-infected. The proportions of NHL cases with HIV were highest for diffuse large B-cell (DLBCL; 7.8%), Burkitt (26.9%), and peripheral T-cell lymphomas (3.2%) with low proportions (≤1.1%) in the other subtypes. NHL rates in the total population increased 0.3% per year during 1992-2009. However, rates of NHL in HIV-uninfected people increased 1.4% per year during 1992-2003, before becoming stable through 2009. Similar trends were observed for DLBCLs and follicular lymphoma in HIV-uninfected people; rates increased 2.7% per year until 2003 and 1.7% per year until 2005, respectively, before stabilizing. NHL incidence rates in the United States have plateaued over the last 5-10 years, independent of HIV infection. Although the causes of the long-term increase in NHL incidence rates in the United States remain unknown, general population rates of NHL have stabilized since the early 2000s, independent of HIV.


Functional outcome of bone marrow stem cells (CD45(+)/CD34(-)) after cell therapy in acute spinal cord injury: in exercise training and in sedentary rats.
Cell therapy and exercise training may be options for spinal cord regeneration. Our objective was to evaluate the functional effects of autologous bone marrow stem cell (CD45(+)/CD34(-)) transplantation in acute spinal cord injury in exercise training and in sedentary rats. Fifty-five adult male Wistar rats underwent spinal cord contusion by Impactor (NYU). Locomotor rating scale was performed every 48 hours for 48 days. Animals with scores < or = 12 were randomly divided into 4 groups: sedentary without parenchymal cell infusion; sedentary with parenchymal cell infusion; swimming training without parenchymal cell infusion; and swimming training with parenchymal cell infusion. Bone marrow stem cells were isolated by puncture-aspiration of the bone marrow and density gradient (d = 1.077). The animals underwent a 60-minute swimming session 6 times/week supporting an overload of 3% of body weight for 6 consecutive weeks. Comparisons between the groups in relation to differences between the beginning to the end of scores used the nonparametric Bonferroni test and post-hoc Mann-Whitney U test to identify significance. Forty-two rats that obtained scores < or = 12 underwent therapy with 9 animals in each of the 4 groups as completors (n = 36). There was significance (P < or = .008) for sedentary without parenchymal cell infusion vs swimming training with parenchymal cell infusion. The combination of bone marrow stem cell therapy (CD45(+)/CD34(-)) and exercise training resulted in significant functional improvement in acute spinal cord injury.


Changes in subcellular distribution of ependymins in goldfish brain induced by learning.
Goldfish were trained for 4 h to swim with an attached polystyrene foam float and tested for retention 3 days later. Intracerebroventricular injection of anti-ependymin antisera was shown to prevent long-term memory formation of this vestibulomotor learning task, as reported previously. In further experiments, fish were killed 4-14 h after the start of training. The brains were dissected, incubated in an isoosmolar solution for collection of proteins of the brain extracellular fluid (ECF), homogenized, and fractionated by differential centrifugation. The ECF, a supernatant fraction enriched in cytoplasmic constituents (S3), and various particulate subcellular fractions were analyzed for their ependymin contents by radioimmunoassay. No statistically significant changes that might be induced by the learning were revealed in any of the particulate fractions. Steady-state concentrations of ependymins in the cytoplasm, however, increased temporarily by 39% in fish that had mastered the training task as compared with nonlearning animals (passive and active controls). In the ECF, the specific concentration of ependymins first decreased to 88% of control levels (4-5 h after the start of training), but later on, it increased to 138% (8-14 h). Apparently, ependymins present in the ECF are used during biochemical reactions of memory consolidation. The resulting decrease in extracellular ependymin concentrations might trigger their resynthesis in the cytoplasm and lead to an increased release of these glycoproteins into the ECF.


Vector affinity and diversity of Geosmithia fungi living on subcortical insects inhabiting Pinaceae species in central and northeastern Europe.
Fungi from the genus Geosmithia (Ascomycota: Hypocreales) are associated with bark beetles (Coleoptera: Scolytinae), though little is known about ecology, diversity, and distribution of these fungi across beetle and its host tree species. This study surveyed the diversity, distribution and vector affinity of Geosmithia isolated from subcortical insects that colonized trees from the family Pinaceae in Central and Northeastern Europe. Twelve Geosmithia species were isolated from 85 plant samples associated with 23 subcortical insect species (including 14 bark beetle species). Geosmithia community composition was similar across different localities and vector species; although the fungal communities associated with insects that colonized Pinus differed from that colonizing other tree species (Abies, Larix, and Picea). Ten Geosmithia species from four independent phylogenetic lineages were not reported previously from vectors feeding on other plant families and seem to be restricted to the vectors from Pinaceae only. We conclude that presence of such substrate specificity suggests a long and stable association between Geosmithia and bark beetles.


[Effect of soybean trypsin inhibitor and chicken ovomucoid on the immunogenic and sensitizing properties of various dietary proteins].
Adult male guinea pigs were sensitized by intragastric administration of bovine serum albumin (BSA) and chick ovalbumin (OA) and their mixtures with soybean Kunitz trypsin inhibitor (SBTI) and chick ovomucoid (OM). Sensitization of the animals was evaluated by the anaphylactic shock reaction and also by the levels of serum specific IgG antibodies against BSA and OA as measured in the solid phase radioimmunoassay. The experiment revealed pronounced desensitizing properties of SBTI combined both with OA and BSA. OM produced no effect on the animal sensitization caused by OA and enhanced the BSA-induced sensitization. The results obtained demonstrate the necessity of differential approach to the evaluation of the action of varying trypsin inhibitors on food sensitization.


Smoking-Attributable mortality in Spain in 2016.
Smoking-attributable mortality (SAM) is a valuable indicator that can be used to characterize the course and health burden of the smoking epidemic. The aim of this paper was to estimate SAM in Spain in 2016 in the population aged 35 and over, using the best available evidence. A smoking prevalence-dependent analysis based on the estimation of population-attributable fractions was performed. Smoking prevalence (never, former, and current smokers) was calculated from a combination of the Spanish Health Survey (2016) and the European Health Survey (2014); the relative risk of death among current and former smokers was taken from the follow-up of various cohorts; and mortality rates were obtained from National Center for Statistics data. SAM estimates are presented globally, and by sex, age groups, and major disease categories: cancer, cardiometabolic diseases and respiratory diseases. In 2016, 56,124 deaths were attributed to tobacco consumption, 84% in men (47,000), and 50% in the population aged over 74 (27,795). Overall, 50% of SAM was due to cancer (28,281), 65% of which was lung cancer. One in 4 attributable deaths (13,849) occurred before the age of 65. One in 7 deaths in Spain in 2016 were attributable to smoking. This estimation of SAM clearly highlights the great impact of smoking on mortality in Spain, mainly due to lung cancer and chronic obstructive pulmonary disease.


Hormonal regulation of hypothalamic gene expression: identification of multiple novel estrogen induced genes.
Estrogen (E) has been shown to play a major role in hypothalamic function and is a prerequisite for progesterone (P) induced sexual behavior in female rats. In the course of studies in search of steroid induced hypothalamic genes, we discovered a surprisingly large number of E-induced genes (21 mRNAs in total). This is the largest number of E-induced genes ever identified in a single organ. Many of these mRNAs exhibit considerable magnitudes of induction and their levels were maintained typically during subsequent P treatment. Among the induced genes, several encode metabolic enzymes and may account for some of the morphological changes observed in hypothalamic neurons in response to E. Since E appears to play a major role in defining the pattern of hypothalamic gene expression in conjunction with its capacity for behavioral modulation, these newly identified cDNAs may serve as genetic markers for correlative studies of E-induced central nervous system behavior.


High-Performing Self-Powered Photosensing and Reconfigurable Pyro-photoelectric Memory with Ferroelectric Hafnium Oxide.
With highly diverse multifunctional properties, hafnium oxide (HfO2 ) has attracted considerable attention not only because of its potential to address fundamental questions about material behaviors, but also its potential for applied perspectives like ferroelectric memory, transistors, and pyroelectric sensors. However, effective harvesting of the pyro-photoelectric effect of HfO2 to develop high-performing self-biased photosensors and electric writable and optical readable memory has yet to be developed. Here, a proof-of-concept HfO2 -based self-powered and ultrafast (response time ≈ 60 µs) infrared pyroelectric sensor with a responsivity of up to 68 µA W-1 is developed. In particular, temporal infrared light illumination induced surface heating and, in turn, change in spontaneous polarization are attributed to robust pyro-photocurrent generation. Further, controllable suspension and reestablishment of the self-biased pyro-photocurrent response with a short electric pulse are demonstrated, which offers a conceptually new kind of photoreadable memory. Potentially, the novel approach opens a new avenue for designing on-demand pyro-phototronic response over a desired area and offers the opportunity to utilize it for various applications, including memory storage, neuromorphic vision sensors, classification, and emergency alert systems.


Oral administration of carvedilol and prazosin inhibits the prostaglandin F2 alpha- and noradrenaline-induced contraction of human hand veins in vivo.
Carvedilol is a beta-blocker with additional vasodilating activity. This study was performed in order to determine whether the vasodilator action of orally administered carvedilol in man is based upon an alpha-adrenoceptor antagonism exclusively or if evidence for an additional mechanism could be confirmed. The influence of carvedilol (50 mg p.o.) and prazosin (2 mg p.o.) upon the vasoconstrictor effect of noradrenaline and prostaglandin F2 alpha, infused into superficial hand veins, was established in 8 healthy male volunteers. Increasing dosages of the vasoconstrictors below their threshold of systemic activity were employed in order to obtain dose-response curves of the hand veins congested at a venous occlusion pressure of 40 mmHg. These dose-response curves were repeated 1 and 3.5 h after oral administration of either carvedilol, prazosin, or placebo. The ex vivo, in vitro alpha 1-receptor occupancy in plasma was measured before and after each vasoconstrictor dose-response curve, using an alpha 1-radioreceptor binding assay. Washout periods of 48 h were kept between study days, investigating the influence of one orally administered drug upon one of the local vasoconstrictor dose-response curves at a time. In the alpha 1-radioreceptor assay, plasma concentrations from 0.9- to 1.7-fold the equilibrium dissociation constant (Ki) of carvedilol could be evaluated 1 as well as 3.5 h after medication, corresponding with a receptor occupancy of 44%-63%. After prazosin, 9-13 times the Ki values were determined, which amounts to an alpha 1-adrenoceptor occupation of about 90%-93%.(ABSTRACT TRUNCATED AT 250 WORDS)


Estimated weight of the term fetus. Accuracy of ultrasound vs. clinical examination.
A prospective analysis was done of the accuracy of fetal weight estimation comparing clinical and ultrasound estimation with actual birth weight in 100 women at term. The mean error of clinical estimation was 277 g, or 79.4 g/kg, for a 7.9% error. The error of ultrasound in the same population was 286 g, or 81.7 g/kg, for an 8.2% error. Analysis of these data revealed no statistical difference between clinical estimation and ultrasound estimation of birth weight in the term fetus, even at the extremes of birth weight.


In-vitro and in-vivo activity of antimicrobial-coated prosthetic heart valve sewing cuffs.
Prosthetic valve endocarditis (PVE) is a relatively uncommon but very serious condition. As bacterial colonization of the prosthetic heart valve sewing cuff can be a prelude to the clinical occurrence of PVE, antimicrobial coating of the sewing cuff may be beneficial. The study aims were to examine the antimicrobial activity in vitro and anti-infective efficacy in vivo of prosthetic heart valve sewing cuffs coated with minocycline and rifampin. Zones of inhibition by antimicrobial-coated sewing cuffs were assessed in vitro against Staphylococcus epidermidis, S. aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans. The ability of subcutaneously implanted devices coated with minocycline and rifampin to resist colonization and infection by P. aeruginosa was also examined in a rabbit model. Antimicrobial-coated sewing cuffs produced zones of inhibition against all tested organisms. Coated devices were significantly less likely than uncoated devices to become colonized (2/24; 8% versus 20/24; 83%; p <0.001) or to cause device-related infection (0/24; 0% versus 18/24; 75%; p <0.001) and device-related abscess (0/24; 0% versus 10/24; 42%; p <0.001) due to P. aeruginosa. Prosthetic heart valve sewing cuffs coated with minocycline and rifampin provide broad-spectrum antimicrobial activity in vitro, and are anti-infective in vivo against P. aeruginosa. These results encourage the clinical evaluation of these sewing cuffs.


Flooding-induced inorganic phosphorus transformations in two soils, with and without gypsum amendment.
Anaerobic conditions developed during flooding can increase phosphorus (P) losses from soils to waterways. Soil amendment with gypsum (CaSO4 ·2H2 O) can effectively reduce flooding-induced P release, but its effectiveness is soil dependent, and the reasons are poorly understood. The objectives of this study were to reveal the possible inorganic P transformations during flooding of two soils (acidic-Neuenberg sandy loam [NBG-SL] and alkaline-Fyala clay [FYL-Cl]), with and without gypsum amendment prior to flooding. Porewater samples collected at 0, 35, and 70 d after flooding (DAF) from soils incubated in vessels were analyzed for dissolved reactive P (DRP); pH; and concentrations of calcium (Ca), magnesium, iron (Fe), manganese, chloride, nitrate, sulfate, and fluoride. Thermodynamic modeling using Visual MINTEQ software and chemical fractionation of soil P were used to infer P transformations. Soil redox potential (Eh) decreased with flooding and favored reductive dissolution of Fe-associated P increasing porewater DRP concentrations. Greater solubility of Ca-P under acidic pH maintained a higher DRP concentration in NBG-SL during early stages of flooding. A subsequent increase in pH with flooding and higher Ca concentration with added gypsum enhanced the stability of Ca-P (β-tricalcium phosphate and octacalcium phosphate), reducing the DRP concentration in gypsum-amended NBG-SL. Stability of Ca-P was less affected with flooding and gypsum amendment in FYL-Cl soil because it had an alkaline pH and inherently higher Ca concentration. The FYL-Cl, with a more rapid decrease in Eh than NBG-SL, became severely reduced, releasing more P and Fe by 70 DAF. These conditions favored vivianite formation in FYL-Cl but not in NBG-SL.


Developing the Low-Temperature Oxidation Mechanism of Cyclopentane: An Experimental and Theoretical Study.
At present, the reactivity of cyclic alkanes is estimated by comparison with acyclic hydrocarbons. Due to the difference in the structure of cycloalkanes and acycloalkanes, the thermodynamic data obtained by analogy are not applicable. In this study, a molecular beam sampling vacuum ultraviolet photoionization time-of-flight mass spectrometer (MB-VUV-PI-TOFMS) was applied to study the low-temperature oxidation of cyclopentane (CPT) at a total pressure range from 1-3 atm and low-temperature range between 500 and 800 K. Low-temperature reaction products including cyclic olefins, cyclic ethers, and highly oxygenated intermediates (e. g., ketohydroperoxide KHP, keto-dihydroperoxide KDHP, olefinic hydroperoxides OHP and ketone structure products) were observed. Further investigation of the oxidation of CPT - electronic structure calculations - were carried out at the UCCSD(T)-F12a/aug-cc-pVDZ//B3LYP/6-31+ G(d,p) level to explore the reactivity of O2 molecules adding sequentially to cyclopentyl radicals. Experimental and theoretical observations showed that the dominant product channel in the reaction of CPT radicals with O2 is HO2 elimination yielding cyclopentene. The pathways of second and third O2 addition - the dissociation of hydroperoxide - were further confirmed. The results of this study will develop the low-temperature oxidation mechanism of CPT, which can be used for future research on accurately simulating the combustion process of CPT.


Numerical analysis of pore-scale CO2-EOR at near-miscible flow condition to perceive the displacement mechanism.
Gas flooding through the injection of [Formula: see text] is generally performed to achieve optimum oil recovery from underground hydrocarbon reservoirs. However, miscible flooding, which is the most efficient way to achieve maximum oil recovery, is not suitable for all reservoirs due to challenge in maintaining pressure conditions. In this circumstances, a near-miscible process may be more practical. This study focuses on pore-scale near-miscible [Formula: see text]-Oil displacement, using available literature criteria to determine the effective near-miscible region. For the first time, two separate numerical approaches are coupled to examine the behavior of [Formula: see text]-oil at the lower-pressure boundary of the specified region. The first one, the Phase-field module, was implemented to trace the movement of fluids in the displacement [Formula: see text]-Oil process by applying the Navier-Stokes equation. Next is the TDS module which incorporates the effect of [Formula: see text] mass transfer into the oil phase by coupling classical Fick's law to the fluids interface to track the variation of [Formula: see text] diffusion coefficient. To better recognize the oil recovery mechanism in pore-scale, qualitative analysis indicates that interface is moved into the by-passed oil due to low interfacial tension in the near-miscible region. Moreover, behind the front ahead of the main flow stream, the [Formula: see text] phase can significantly displace almost all the bypassed oil in normal pores and effectively decrease the large amounts in small pores. The results show that by incorporating mass transfer and capillary cross-flow mechanisms in the simulations, the displacement of by-passed oil in pores can be significantly improved, leading to an increase in oil recovery from 92 to over 98%, which is comparable to the result of miscible gas injection. The outcome of this research emphasizes the significance of applying the [Formula: see text]-EOR process under near-miscible operating conditions.


Fluorophore labeling of native FKBP12 by ligand-directed tosyl chemistry allows detection of its molecular interactions in vitro and in living cells.
Introducing synthetic fluorophores into specific endogenous proteins and analyzing their function in living cells are a great challenge in chemical biology. Toward this end, we demonstrate the target-selective and site-specific fluorescent labeling of native FKBP12 (FK506-binding protein 12) in vitro and in living cells using ligand-directed tosyl (LDT) chemistry. The LDT-mediated labeling yielded a semisynthetic FKBP12 containing the Oregon green (OG) dye near the catalytic pocket. The OG-labeled FKBP12 (OG-FKBP12) acted as a fluorescent reporter that allows monitoring of its interaction with rapamycin and FRB (FKBP-rapamycin-binding domain) in vitro. We also successfully demonstrated the visualization of the rapamycin-mediated complexation of the OG-FKBP12 and FRB inside of living cells by the combined use with fluorescent protein-tag technology and Förster resonance energy-transfer imaging.


Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review.
Vaccines are critical cost-effective tools to control the coronavirus disease 2019 (COVID-19) pandemic. However, the emergence of variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may threaten the global impact of mass vaccination campaigns. The objective of this study was to provide an up-to-date comparative analysis of the characteristics, adverse events, efficacy, effectiveness and impact of the variants of concern for 19 COVID-19 vaccines. References for this review were identified through searches of PubMed, Google Scholar, BioRxiv, MedRxiv, regulatory drug agencies and pharmaceutical companies' websites up to 22nd September 2021. Overall, all COVID-19 vaccines had a high efficacy against the original strain and the variants of concern, and were well tolerated. BNT162b2, mRNA-1273 and Sputnik V after two doses had the highest efficacy (>90%) in preventing symptomatic cases in phase III trials. mRNA vaccines, AZD1222, and CoronaVac were effective in preventing symptomatic COVID-19 and severe infections against Alpha, Beta, Gamma or Delta variants. Regarding observational real-life data, full immunization with mRNA vaccines and AZD1222 seems to effectively prevent SARS-CoV-2 infection against the original strain and Alpha and Beta variants but with reduced effectiveness against the Delta strain. A decline in infection protection was observed at 6 months for BNT162b2 and AZD1222. Serious adverse event rates were rare for mRNA vaccines-anaphylaxis 2.5-4.7 cases per million doses, myocarditis 3.5 cases per million doses-and were similarly rare for all other vaccines. Prices for the different vaccines varied from $2.15 to $29.75 per dose. All vaccines appear to be safe and effective tools to prevent severe COVID-19, hospitalization, and death against all variants of concern, but the quality of evidence greatly varies depending on the vaccines considered. Questions remain regarding a booster dose and waning immunity, the duration of immunity, and heterologous vaccination. The benefits of COVID-19 vaccination outweigh the risks, despite rare serious adverse effects.


Assessment of mesoscale and microscale simulations of a NO2 episode supported by traffic modelling at microscopic level.
The aim of this work is to simulate with high accuracy an episode of high NO2 pollution during December 2016 in the city of Madrid (Spain). For this purpose, a multiscale modelling system has been implemented that includes a mesoscale model (WRF/Chem) up to a horizontal resolution of 1 km and a computational fluid dynamics model (CFD; MICROSYS) with a resolution of 5 m. For the calculation of traffic emissions, a traffic simulation has been previously conducted with the SUMO microscopic model, calibrated from data measured with traffic counters. We show a substantial improvement in the results obtained with 5 m resolution with respect to those of 1 km, reproducing very closely the daily peaks of NO2 concentrations since a very detailed traffic emission source is being used and the CFD reproduces the interactions between the air flow and the buildings. The modelling system presented can be used as a tool to evaluate different emission reduction strategies at street level, as it would allow to have an orientation on their effectiveness without having to implement them.


Health workforce policy and Turkey's health care reform.
The health care industry is labor intensive and depends on well-trained and appropriately deployed health professionals to deliver services. This article examines the health workforce challenges in the context of Turkey's recent health reform initiative, Health Transformation Program (HTP). Reformers identified shortages, imbalances in the skills-mix, and inequities in the geographical distribution of health professionals as among the major problems. A comprehensive set of policies was implemented within the HTP framework to address these problems. The article argues that these policies addressed some of the health workforce challenges, while on the other hand exacerbating others and hence may have resulted in increasing the burden on the workforce. So far HTP's governance reforms and health human resource policy have not encouraged meaningful participation of other key stakeholders in the governance of the health care system. Without effective participation of health professionals, the next stages of HTP implementation that focus on managerial reforms such as restructuring public hospitals, improving the primary care system and implementing new initiatives on quality improvement could be very difficult.


A new isoxazol from Glehnia littoralis.
A new isoxazol derivative, 9,9a-dihydro-naphtho [2, 3-c] isoxazol-3(1H)-one (Naphthisoxazol A) (1, Fig. 1) was isolated from the roots of the traditional Chinese medicine Glehnia littoralis. The structure has been elucidated on the basis of MS and extensive NMR analysis.


Systematic screening of the cellular uptake of designed alpha-helix peptides.
The cellular penetration (CP) activity of functional molecules has attracted significant attention as one of the most promising new approaches for drug delivery. In particular, cell-penetrating peptides (CPPs) have been studied extensively in cellular engineering. Because there have been few large-scale systematic studies to identify peptide sequences with optimal CP activity or that are suitable for further applications in cell engineering, such as cell-specific penetration and cell-selective culture, we screened and compared the cellular uptake (CU) activity of 54 systematically designed α-helical peptides in HeLa cells. Furthermore, the CU activity of 24 designed peptides was examined in four cell lines using a cell fingerprinting technique and statistical approaches. The CU activities in various cells depended on amino acid residues of peptide sequences as well as charge, α-helical content and hydrophobicity of the peptides. Notably, the mutation of a single residue significantly altered the CU ability of a peptide, highlighting the variability of cell uptake mechanisms. Moreover, these results demonstrated the feasibility of cell-selective culture by conducting cell-selective permeation and death in cultures containing two cell types. These studies may lead to further peptide library design and screening for new classes of CPPs with useful functions.


[The phytoclimates of France: probabilistic classification of 1874 bio-indicators of the climate].
This article presents a synthesis of the relationships between plants and climates at the scale of France, based on a probabilistic classification of 1874 bio-indicators. This classification defines plants groups that indicate the climate, named phytoclimates, expressing the climatic gradients in France. This classification shows 210 phytoclimatic groups distributed into ten cluster levels. The analysis of the various hierarchical levels shows two main phytoclimates testifying the importance of the marine masses and the altitude. The analysis of the third hierarchical level underlines particular phytoclimates which would not be easily recognizable by only analysing the overlapping of floristic and climatic territories. This classification allows one to select taxa that are indicators of the climate. The distribution monitoring or modeling of these taxa should show the effects of the global change on the ecosystems.


Not choosing pathology: An essay-based survey of first-year clinical residents.
Health care systems worldwide are facing a shortage in the pathology workforce that could negatively affect health care services, particularly oncology. To address this potential shortfall, the pathology community must identify the reasons why graduating students are not choosing pathology as a specialty. We analyzed 226 free-text essay responses submitted by nonpathology residents at a teaching hospital. We used a general inductive approach and quantitative analysis to identify the barriers that prevent medical college graduates from choosing pathology as a specialty. Residents at our institution view pathology similar to residents from other countries, with the main obstacles to choosing pathology as a specialty being a perception that it lacks practical application to patient care or provides "no real help" and has a lack of patient interaction. In Russia specifically, there is a focus on the perceived negative aspects of autopsy as a barrier to selecting pathology. Less significant factors that may be based more on stereotypes than reality include the expectation that the work is not engaging, the emotional burden, and the occupational risks. For medical students who place less importance on patient interaction, addressing these secondary factors could help select potential pathologists during students' undergraduate years.


Increasing the accuracy of peanut allergy diagnosis by using Ara h 2.
Measurement of whole peanut-specific IgE (sIgE) is often used to confirm sensitization but does not reliably predict allergy. Ara h 2 is the dominant peanut allergen detected in 90% to 100% of patients with peanut allergy and could help improve diagnosis. We sought to determine whether Ara h 2 testing might improve the accuracy of diagnosing peanut allergy and therefore circumvent the need for an oral food challenge (OFC). Infants from the population-based HealthNuts study underwent skin prick tests to determine peanut sensitization and subsequently underwent a peanut OFC to confirm allergy status. In a stratified random sample of 200 infants (100 with peanut allergy and 100 with peanut tolerance), whole peanut sIgE and Ara h 2 sIgE levels were quantified by using fluorescence enzyme immunoassay. By using the previously published 95% positive predictive value of 15 kU(A)/L for whole peanut sIgE, a corresponding specificity of 98% (95% CI, 93% to 100%) was found in this study cohort. At the equivalent specificity of 98%, the sensitivity of Ara h 2 sIgE is 60% (95% CI, 50% to 70%), correctly identifying 60% of subjects with true peanut allergy compared with only 26% correctly identified by using whole peanut sIgE. We report that when using a combined approach of plasma sIgE testing for whole peanut followed by Ara h 2 for the diagnosis of peanut allergy, the number of OFCs required is reduced by almost two thirds. Ara h 2 plasma sIgE test levels provide higher diagnostic accuracy than whole peanut plasma sIgE levels and could be considered a new diagnostic tool to distinguish peanut allergy from peanut tolerance, which might reduce the need for an OFC.


Long-Term Surgical Outcome of Indirect Bypass Surgery in Young Children With Moyamoya Disease.
The prognosis of moyamoya disease (MMD) in young children (younger than 4 years) is worse than that of older adults. The effectiveness of surgery is still inconclusive. To evaluate long-term outcomes after indirect bypass in young children with MMD. A total of 1417 MMD children underwent indirect bypass from August 1988 to October 2020. This study included 135 patients who were younger than 4 years at the time of surgery. The clinical features and surgical outcomes of these patients were assessed. We analyzed the long-term outcome of 102 children who were followed up for more than 5 years (mean: 18.8 years, range: 5-27.3 years). Cross-sectional analysis was performed to evaluate overall outcomes based on the Lansky Play Performance Scale (LPS). The annual risk of symptomatic stroke after surgery was calculated with a person-year method, and the event-free survival rate was evaluated using the Kaplan-Meier method. The overall clinical outcome was favorable (LPS ≥ 80) in 88% of the patients. The overall postoperative adverse event rate was 15%, including 1 death. At the last follow-up, 86% of patients who had seizures at diagnosis were seizure-free. During the follow-up, there were 3 symptomatic infarctions on the operated hemisphere (postoperative 3, 3, and 10 months each). There was no hemorrhagic event. The annual infarction rate was 0.16% per person-year. The 20-year event-free survival rates for symptomatic infarction were 97%. Indirect bypass could provide a satisfactory long-term outcome and prevent recurrent stroke in young children with MMD.


The hyperthermophilic bacterium Aquifex aeolicus: from respiratory pathways to extremely resistant enzymes and biotechnological applications.
Aquifex aeolicus isolated from a shallow submarine hydrothermal system belongs to the order Aquificales which constitute an important component of the microbial communities at elevated temperatures. This hyperthermophilic chemolithoautotrophic bacterium, which utilizes molecular hydrogen, molecular oxygen, and inorganic sulfur compounds to flourish, uses the reductive TCA cycle for CO(2) fixation. In this review, the intricate energy metabolism of A. aeolicus is described. As the chemistry of sulfur is complex and multiple sulfur species can be generated, A. aeolicus possesses a multitude of different enzymes related to the energy sulfur metabolism. It contains also membrane-embedded [NiFe] hydrogenases as well as oxidases enzymes involved in hydrogen and oxygen utilization. We have focused on some of these proteins that have been extensively studied and characterized as super-resistant enzymes with outstanding properties. We discuss the potential use of hydrogenases in an attractive H(2)/O(2) biofuel cell in replacement of chemical catalysts. Using complete genomic sequence and biochemical data, we present here a global view of the energy-generating mechanisms of A. aeolicus including sulfur compounds reduction and oxidation pathways as well as hydrogen and oxygen utilization.


Antigen-Specific Peptide Immunotherapy for Type 1 Diabetes: Proof of Safety, Hope for Efficacy.
Antigen-specific immunotherapy has long been hailed as the ideal disease-modifying approach for type 1 diabetes, both for disease prevention and reversal. A small phase 1 trial now demonstrates safety of a peptide-based treatment in recently diagnosed adults.


Are Magnetic Resonance Imaging-Generated 3Dimensional Models Comparable to Computed Tomography-Generated 3Dimensional Models for Orbital Fracture Reconstruction? An In-Vitro Volumetric Analysis.
Magnetic resonance imaging (MRI) is being increasingly considered as an alternative for the evaluation and reconstruction of orbital fractures. No previous research has compared the orbital volume of an MRI-imaged, three-dimensional (3D), reconstructed, and virtually restored bony orbit to the gold standard of computed tomography (CT). To measure the orbital volumes generated from MRI-based 3D models of fractured bony orbits with virtually positioned prebent fan plates in situ and compare them to the volumes of CT-based virtually reconstructed orbital models. This retrospective in-vitro study used CT and MRI data from adult patients with orbital trauma assessed at the Royal Brisbane and Women's Hospital Outpatient Maxillofacial Clinic from 2011 to 2012. Only those with orbital blowout fractures were included in the study. The primary predictor variable was imaging modality, with CT- and MRI-based 3D models used for plate bending and placement. The primary outcome variable was the orbital volume of the enclosed 3D models. Additional data collected was age, sex, and side of fractured orbit. The effect of operator variability on plate contouring and orbital volume was quantified. The Wilcoxon signed rank test was used to assess differences between orbital volumes with a significance level P < .05. Of 11 eligible participants, six patients (four male and two female; mean age 31 ± 8.6 years) were enrolled. Two sets of six CT-based virtually restored orbits were smaller than the intact contralateral CT models by an average of 1.02 cm3 (95% CI -0.07 to 2.11 cm3; P = .028) and 0.99 cm3 (95% CI 0.07 to 1.91 cm3; P = .028), respectively. The average volume difference between the MRI-based virtually restored orbit and the intact contralateral MRI model was 0.97 cm3 (95% CI -1.08 to 1.94 cm3; P = .75). Imaging modality did affect orbital volume difference for 1 set of CT and MRI models (0.63 cm3; 95% CI -0.11 to 1.29 cm3; P = .046) but not the other (0.69 cm3; 95% CI -0.11 to 1.23 cm3; P = .075). Single operator variability in plate bending did not result in significant (P = .75) volume differences. MRI can be used to reconstruct orbital volume with a clinically acceptable level of accuracy.


The effects of Coronavirus disease-2019 (COVID-19) pandemic on routine antenatal care visits and complications of pregnancy.
Routine follow-up of pregnancy is a comprehensive care process starting from planning of pregnancy that involves rational and careful use of medical, psychological, and social support. In this study, our objective was to compare the adherence rate to routine antenatal follow-up program during the COVID-19 pandemic with that of previous years among pregnant women, in an effort to shed light on health policies to be developed similar events in the future. This retrospective cross-sectional study was carried out between March 11, 2019, when isolation measures were initiated in the context of precautionary steps taken in Turkey against the COVID-19 pandemic, and June 1, 2020, when the "normalization" was initiated. During the study period in 2020, the proportion of cesarean sections were higher, 61.1%, as compared to previous years (p=0.27). The stillbirths were numerically lower (1.2%, p=0.77), but the rate of spontaneous abortions was significantly higher (19.6%, p=0.009). The number of follow-up visits per pregnancy was lower than in previous years (3.8, p=0.02), although the proportion of patients visiting the outpatient units for regular controls to the overall patient group increased as compared to previous years (52.0%). During the flare-up of the COVID-19 pandemic (i.e. between March and June 2020), the rate of obstetric/neonatal morbidity and mortality except spontaneous abortion was not significantly higher as compared to the corresponding period in previous years. However, considering the potential increase in the risk of obstetric complications during a pandemic, specialized management programs targeting basic pregnancy follow-up services should be developed.


Kinetics of 7-hydroxy-methotrexate after high-dose methotrexate therapy.
Kinetics of 7-hydroxy-methotrexate (7-OH-MTX) excretion after high-dose methotrexate (MTX) (12 g/m2) therapy were monitored in 93 consecutive drug cycles of 19 adolescent patients with osteosarcoma. A reversed-phase HPLC method was used. Serum elimination was found to be monophasic with a mean half-life of 5.5 h. Shortly after the 4-h MTX infusion period 7-OH-MTX levels exceeded those of the parent compound. By 12 h after MTX infusion 7-OH-MTX levels were 16.5 times higher than those of MTX itself. Autostimulation of MTX metabolism leading to enhanced 7-OH-MTX production after repeated drug cycles was not observed. The production of 7-OH-MTX decreased significantly from the first to the last high-dose MTX cycle of the adjuvant chemotherapy protocol.


Different manifestation of irradiation induced coronary artery disease detected with coronary computed tomography compared with matched non-irradiated controls.
Patients who received chest irradiation for treatment of a malignancy are at increased risk for the development of coronary artery atherosclerosis. Little is known about the anatomical coronary artery plaque characteristics of irradiation induced coronary artery disease (CAD). This study aimed to evaluate potential differences in the presence, extent, severity, composition and location of CAD in patients treated with mediastinal irradiation compared with non-irradiated controls matched on age, gender and cardiovascular risk factors. Seventy-nine asymptomatic Hodgkin and non-Hodgkin lymphoma survivors, all treated with mediastinal irradiation with or without chemotherapy, who underwent coronary computed tomography angiography (CTA) to exclude or detect CAD were included. Patients were 1:3 matched with non-irradiated controls (n=237) for age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD and currently smoking. Mean age at cancer diagnosis was 26±9years and age at the time of coronary CTA was 45±11years. More patients had an abnormal CTA (defined as any coronary artery atherosclerosis): 59% vs. 36% (P<0.001) and significantly more patients had two vessel CAD: 10% vs. 6% and three vessel/left main CAD: 24% vs. 9% compared with controls (overall P<0.001). The maximum stenosis severity among patients was less often <30% (53% vs. 68%) and more often >70% (7% vs. 0%) (overall P=0.001). Patients had more coronary artery plaques in proximal coronary artery segments: left main (17% vs. 6%, P=0.004), proximal left anterior descending artery (30% vs. 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001) and proximal left circumflex artery (14% vs 6%, P=0.022), whereas the number of plaques in non-proximal segments did not differ between groups. Hodgkin and non-Hodgkin lymphoma survivors treated with mediastinal irradiation with or without chemotherapy showed a higher presence, greater severity, larger extent and more proximally located CAD compared with age, gender and risk factor matched non-irradiated controls. These findings represent features of higher risk CAD and may explain the worse cardiovascular outcome after chest irradiation.


Synthesis of praziquantel derivatives and their in vitro activity against adult Clonorchis sinensis.
Several praziquantel derivatives have been prepared by the acylation of compound 5, and examined on their biological activity in vitro a against adult Clonorchis sinensis collected from rabbits infected with metacercariae which was isolated from Pseudorasbora parva, a second intermediate host, captured in Nakdong river in Korea.


Simultaneous determination of hydrogen cyanide and volatile aliphatic nitriles by headspace gas chromatography, and its application to an in vivo study of the metabolism of acrylonitrile in the rat.
A method for the simultaneous determination of hydrogen cyanide (HCN) and aliphatic nitriles using manual headspace (HS) gas chromatography (GC) with a capillary porous polymer column GS-Q and a nitrogen-phosphorus detector is described. With a HS incubation at 50 degrees C for 30 min and a GC temperature at 180 degrees C, HCN and volatile nitriles [acetonitrile, acrylonitrile (VCN), propionitrile, isobutyronitrile] were well separated and could be detected within 7 min with a detection limit of 0.7-2.4 ng/ml in blood samples. The HS-GC method was used in an in vivo study of VCN metabolism. VCN was administered orally (at nearly one-half its LD(50)) to rats, and heart blood and urine were sampled. Blood concentrations of HCN and VCN were measured by HS-GC, and plasma and urinary thiocyanate concentrations were measured by the König colorimetric method. Blood levels of HCN and VCN peaked 1.5 h after VCN administration, at which time the cyanide level (about 0.7 microg/ml) is close to the fatal level. HCN levels were observed to be at almost background levels at 10 h, although 50 ng/ml VCN was still detectable. The plasma thiocyanate level increased, reaching a peak (about 30 microg/ml) at 5 h. The cumulative urinary thiocyanate amount gradually increased, and at 10 h more than 1 mg thiocyanate was excreted into the urine. It is therefore possible to clarify the cause of cyanide poisoning using HS-GC analysis, when someone has taken volatile nitriles.


Muscle mass is more strongly related to hip bone mineral density than is quadriceps strength or lower activity level in adults over age 50 year.
This cross-sectional study examined whether reduced hip bone mineral density (BMD) is better explained by isokinetic knee extensor strength (KES), lower limb lean body mass (L-LBM), or Physical Activity Scale for the Elderly (PASE). Through population-based recruitment, 1543 adults without knee osteoarthritis were recruited. For men and women respectively, means+/-SD were age 60.8+/-8.0 and 61.1+/-7.9 yr; body mass index 29.6+/-4.6 and 29.1+/-5.4 kg/m(2); hip BMD 1.025+/-0.138 and 0.895+/-0.128 g/cm(2); KES 124.9+/-41 and 72.7+/-22.9 N.m; L-LBM 10.3+/-1.5 and 7.0+/-1.2 kg; and PASE 206.4+/-99.7 and 163.8+/-77.0. The relationship between BMD and KES in men (r(2)=0.21, p> or =0.002) and women (r=0.23, p<0.001) was significant before adjustment. However, this association was no longer significant after controlling for L-LBM. Even after controlling for age, race, and sex, the association between BMD and KES was better explained by L-LBM (partial R(2)=0.14, p<0.001) than by PASE (partial R(2)=0.00). Allometric scaling of KES to body size attenuated the association of BMD with KES (Std Beta=0.03). The significant association between BMD and L-LBM (Std Beta=0.36) remained stronger than that between BMD and weight (Std Beta=0.21). Therefore, muscle mass accounted for a greater proportion of the variance in hip BMD than KES or activity level and explained a significant proportion of the association between weight and BMD.


Studies on thymocyte subpopulations in guinea pigs. VII. Characterization of cell populations responsive to guinea pig interleukin 1 and interleukin 2.
The properties of thymocytes responding by proliferation to a mitogenic lectin (PHA), interleukin 1 (IL 1), or interleukin 2 (IL 2) were studied and compared to the properties of cells known to respond to a separate thymocyte growth factor (TGP), which has so far only been studied in guinea pigs. Thymocytes from guinea pigs were separated into subpopulations by density gradient centrifugation with Percoll and by rosette formation with rabbit erythrocytes. PHA-responsive cells were recovered exclusively in a non-rosetting, low-density population designated Ia, RFC-, constituting approximately 4 per cent of all thymocytes. Thus, according to the prevailing view of lymphocyte mitogenesis, IL 1-producing, IL 2-producing as well as IL 2-responding cells are all present in this population. The mitogen-responsive cells could be further stimulated by addition of IL 1 or IL 2, indicating that the magnitude of the mitogenic response was regulated by the production of these factors and was not restricted by the number of IL 2-responding cells. IL 1, to some extent, also enhanced the mitogen response in a non-rosetting, intermediate density population designated Ib, RFC-. None of the factors could affect the lack of mitogen responsiveness in the high-density population II, constituting approximately 85% of the total population and probably including most small cortical thymocytes. We conclude that IL 2-responding thymocytes are present above all in the quantitatively small population Ia, RFC- (shown to contain also the mature, mitogen-responding cells) and to a smaller extent in Ib, RFC- (where a deficit in IL 1-producing cells may explain the poor mitogen responsiveness), but not in the major, high-density population II. From our data, it is also evident that the mitogen, IL 1- and IL 2-reactive cells can be separated from a population of intensely proliferating thymic precursor cells which are stimulated to grow by TGP. Therefore, the growth of these immature cells does not seem to be regulated by IL 1 or IL 2 in the guinea pig.


Increased proteinase inhibitor-9 (PI-9) and reduced granzyme B in lung cancer: mechanism for immune evasion?
Cytotoxic CD8(+) T-cells mount immune responses to cancer via cytotoxic pathways including granzyme B. Cancer cells are also known to develop immune evasion mechanisms. We hypothesised that lung cancer cells would over-express the granzyme B-inhibitor, proteinase inhibitor-9 (PI-9) and down-regulate granzyme B expression by neighbouring CD8(+) T-cells. We investigated PI-9 expression in lung cancer cell lines, and primary lung cancer cells obtained at curative lung resection from cancer patients with/without chronic obstructive pulmonary disease (COPD). Granzyme B and PI-9 expression was also determined in CD8(+) T-cells from the cancer and non-cancer areas of resected lung tissue and from bronchoalveolar lavage (BAL). We then evaluated the effects of conditioned media from lung cancer cell lines on granzyme B expression and the cytotoxic activity of CD8(+) T-cells. PI-9 was highly expressed in lung cancer cell lines. Increased PI-9 expression was also observed in primary cancer cells vs. epithelial cells from non-cancer tissue or bronchial brushing-derived normal primary large airway epithelial cells. Expression significantly correlated with cancer stage. Significantly reduced granzyme B was noted in CD8(+) T-cells from cancer vs. non-cancer tissue. Granzyme B production by CD8(+) T-cells was reduced in the presence of conditioned media from lung cancer cell lines. Our data suggest that lung cancer cells utilise their increased PI-9 expression to protect from granzyme B-mediated cytotoxicity as an immune evasion mechanism, a function that increases with lung cancer stage.


Care coordination for rural residents with chronic disease: Predictors of improved outcomes.
The purpose of this study was to assess the effect of an integrated system of coordinated care on chronic disease health outcomes of patients with poorly controlled diabetes, hypertension, and congestive heart failure (CHF) living in a rural area. Longitudinal study of patients aged 18 years or older, living in a rural area, with diabetes glycated hemoglobin (A1C) > 8%, hypertension blood pressure (BP) > 150/90, heart failure, and suffering excessive weight gain and hospital admission in last 6 months. Dependent variables were A1C, cholesterol, microalbumin, body mass index (BMI), BP, emergency department (ED) visits, and hospital admissions. Predictor variables included time in the program, age, sex, race, and Diabetes Self-Management Education (DSME) completion. Descriptive variables included telemedicine and specialty referrals and travel savings. Time had a significant effect on A1C, microalbumin, BP, and ED visits. Race, sex, and DSME also impacted A1C and BP outcomes. Length of time in the program played a crucial role in improved outcomes for patients in the program for a year or more. Long-term, consistent reinforcement in the form of education and coordinated care provided by certified care coordination nurses achieve better health outcomes.


Suppression of ventricular arrhythmias with intravenous disopyramide and lidocaine: efficacy comparison in a randomized trial.
Twenty-six patients with clinically significant ventricular arrhythmias were randomly assigned to treatment with either intravenous disopyramide or lidocaine; crossover to the other agent was permitted in nine cases of primary drug failure. In addition, disopyramide was administered nonrandomly to seven patients with ventricular arrhythmias not controlled by lidocaine in standard doses. Arrhythmia control (greater than 50 percent reduction of premature ventricular complexes) was achieved in all 22 trials with disopyramide and in 9 of 13 trails with lidocaine in the random study, whereas clinical efficacy (arrhythmia control with absence of side effects) occurred respectively in 15 of 22, and 8 of 13 trials. In all 11 patients (7 nonrandom, 4 random) whose arrhythmia was not controlled with lidocaine the arrhythmia was controlled with disopyramide. Thus, the clinical efficacy of intravenous disopyramide ran parallel to that of lidocaine in patients with ventricular arrhythmias. Furthermore, intravenous disopyramide was an effective alternative agent for patients with arrhythmia not controlled by lidocaine.


Fruit lead concentrations of tomato (Solanum lycopersicum L.) grown in lead-contaminated soils are unaffected by phosphate amendments and can vary by season, but are below risk thresholds.
Urban agriculture in post-industrial cities faces concerns on human health risks posed by elevated lead (Pb) concentrations of edible plant tissues grown in Pb-enriched soils. A recommended mitigation strategy to decrease soil Pb bioavailability to humans is the addition of soluble phosphate (PO43--P), but it is unclear if this strategy can also reduce crop Pb uptake and accumulation in edible tissues. Across urban agriculture sites in Chicago, Illinois (6 site-years) with elevated total soil Pb, we tested the hypothesized decrease in tomato fruit Pb following soil-based application of three phosphate-based mitigation amendments: triple superphosphate, composted biosolids, and air dried biosolids. Fruit Pb concentrations (mg Pb kg-1 dry mass) and loads (mg Pb m-2) were unaffected by mitigation amendments. However, fruit Pb concentrations were higher by an order of magnitude in 2020 (≥0.13 mg kg-1) compared to 2019 (0.01 mg kg-1) for two of the three sites. Though highly variable across site-years, the bioconcentration factor (BCF) of Pb from soil to fruit varied was unaffected by mitigation amendments. Relatively low BCF values were consistent with fruit Pb concentrations being below FAO/WHO risk limits. Collectively, our findings support previous propositions that fruits of plants grown in soils with elevated Pb generally pose lower risk to consumers. To mitigate health risks of consuming tomatoes grown in soils with Pb contamination, the seasonality of Pb uptake should be investigated, and greater focus should be placed on where tomatoes are grown rather than phosphate-based immobilization strategies originally designed to mitigate human bioavailability.


Stoichiometric characteristics and resonance Raman spectra of azidosemimethemerythrin.
With extra precautions to remove dissolved oxygen, reduction of aquomethemerythrin with dithionite occurs with a stoichiometry very close to 1.0. The aquosemimethemerythrin so produced combines with N3- ion almost on a 1:1 basis per monomer. Resonance Raman spectra of azidosemimethemerythrin differ from those of azidomethemerythrin in the position of the Fe-N stretching frequency and in the absence of a feature corresponding to a mu-oxo bridge, but in both complexes the internal azide stretch occurs at the same frequency and the substitution of isotopically unsymmetrical 15N14N-2 leads to a splitting of the Fe-N band. These observations provide some insight into the structural features of the binuclear functional site.


In vivo translocation of the cell wall acid phosphatase across the yeast endoplasmic reticulum membrane: are there multiple signals for the targeting process?
The repressible Saccharomyces cerevisiae acid phosphatase (APase) coded by the PHO5 gene is a cell wall protein that follows the yeast secretory pathway. We had previously described the in vivo fate of a multicopy plasmid-encoded modified protein, lacking 15 out of 17 signal peptide amino acids. This modified protein accumulates mainly within the cell as an inactive unglycosylated form. However 30% of this precursor is translocated, glycosylated and dispatched to the cell wall. We establish, in the present report, that this phenomenon did not result from an overproduction of the plasmid encoded protein, since it was also observed in a normal single copy situation. The secretion persisted after a deletion including the single hydrophobic segment present in the N-terminus of the mature protein. The entry of both wild type and mutant APase into the ER was inhibited in sec62 mutants suggesting that the SEC62 gene product would not be implicated in signal peptide recognition.


Associations of emotional social support, depressive symptoms, chronic stress, and anxiety with hard cardiovascular disease events in the United States: the multi-ethnic study of atherosclerosis (MESA).
Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality around the globe and psychosocial factors are not sufficiently understood. In the current study, we aimed to evaluate the role of different psychosocial factors including depressive symptoms, chronic stress, anxiety, and emotional social support (ESS) on the incidence of hard CVD (HCVD). We examined the association of psychosocial factors and HCVD incidence amongst 6,779 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Using physician reviewers' adjudication of CVD events incident, depressive symptoms, chronic stress, anxiety, emotional social support scores were measured by validated scales. We used Cox proportional Hazards (PH) models with psychosocial factors in several of the following approaches: (1) Continuous; (2) categorical; and (3) spline approach. No violation of the PH was found. The model with the lowest AIC value was chosen. Over an 8.46-year median follow-up period, 370 participants experienced HCVD. There was not a statistically significant association between anxiety and HCVD (95%CI) for the highest versus the lowest category [HR = 1.51 (0.80-2.86)]. Each one point higher score for chronic stress (HR, 1.18; 95% CI, 1.08-1.29) and depressive symptoms (HR, 1.02; 95% CI, 1.01-1.03) was associated with a higher risk of HCVD in separate models. In contrary, emotional social support (HR, 0.98; 95% CI, 0.96-0.99) was linked with a lower risk of HCVD. Higher levels of chronic stress is associated with greater risk of incident HCVD whereas ESS has a protective association.


Damage to biological tissues induced by radical initiator 2,2'-azobis(2-amidinopropane) dihydrochloride and its inhibition by chain-breaking antioxidants.
A water-soluble azo compound, 2,2'-azobis(2-amidinopropane) dihydrochloride, a well-known free radical initiator, was administered intraperitoneally to mice to study the toxicological effects on biological tissues in vivo and their inhibition by chain-breaking antioxidants. It caused damage to biological tissues without biotransformation. No specific target organ was observed. The most striking fine structural changes were the degeneration, swelling, and disruption of the endothelium lining cells of the capillaries in various organs. Furthermore, the death of lymphocytes in the lymphoid tissues and the fatty degeneration of the liver and kidneys have also been observed. Water-soluble chain-breaking antioxidants, such as 2-carboxy-2,5,7,8-tetramethyl-6-chromanol (a vitamin E analogue), uric acid, cysteine, and glutathione suppressed the above damage, whereas vitamin C was ineffective.


Adsorption of Nafamostat Mesilate on AN69ST Membranes: A Single-Center Retrospective and In Vitro Study.
We examined whether AN69ST (acrylonitrile and methallyl sulfonate copolymer) membranes adsorb nafamostat mesilate. This study retrospectively analyzed 87 continuous hemodiafiltration sessions in vivo. We divided the continuous hemodiafiltration sessions into AN69ST and non-AN69ST groups using the nafamostat mesilate dose and activated clotting time as indicators of nafamostat mesilate adsorption onto the membrane. Furthermore, we studied the in vitro adsorption of nafamostat mesilate from nafamostat mesilate solutions onto four different hemodialysis membranes. This in vivo study shows that nafamostat mesilate doses were significantly higher, but activated clotting times were shorter (P < 0.001) in the AN69ST group than in the non-AN69ST group. These results suggest that AN69ST adsorbs nafamostat mesilate. Further, the in vitro experiments show that nafamostat mesilate adsorbs AN69ST on membranes significantly more than the other membranes tested. These in vitro and clinical findings provide evidence that AN69ST may adsorb nafamostat mesilate.


Dose-dependent relationship between social drinking and brain aging.
Low-level alcohol consumption is commonly perceived as being inconsequential or even beneficial for overall health, with some reports suggesting that it may protect against dementia or cardiovascular risks. However, these potential benefits do not preclude the concurrent possibility of negative health outcomes related to alcohol consumption. To examine whether casual, non-heavy drinking is associated with premature brain aging, we utilized the Brain-Age Regression Analysis and Computational Utility Software package to predict brain age in a community sample of adults [n = 240, mean age 35.1 (±10.7) years, 48% male, 49% African American]. Accelerated brain aging was operationalized as the difference between predicted and chronological age ("brain age gap"). Multiple regression analysis revealed a significant association between previous 90-day alcohol consumption and brain age gap (β = 0.014, p = 0.023). We replicated these results in an independent cohort [n = 231 adults, mean age 34.3 (±11.1) years, 55% male, 28% African American: β = 0.014, p = 0.002]. Our results suggest that even low-level alcohol consumption is associated with premature brain aging. The clinical significance of these findings remains to be investigated.


Obstructive hydrocephalus-induced parkinsonism. I: Decreased basal ganglia regional blood flow.
A 17-year-old male developed acute parkinsonism after obstruction of a ventriculoperitoneal shunt with subsequent hydrocephalus. Following a previous shunt replacement, he developed florid parkinsonism which was associated with Parinaud syndrome. The initial single-photon emission computed tomography of the brain using 99mTc-hexamethylpropylenamine oxime demonstrated decreased cerebral blood flow in the regions of the left caudate and putamen. The patient underwent shunt revision with minimal improvement and therefore levodopa/carbidopa (Sinemet 100/25) was administered. Subsequently, he experienced almost complete recovery which may have been correlated with probable improvement of the basal ganglia regional cerebral blood flow. Parkinsonism associated with ventriculoperitoneal shunt obstruction is a rare but reversible disorder that is responsive to shunt replacement and antiparkinsonian drug administration. Cerebral perfusion studies may prove to be of value in delineating the pathophysiology of this complication.


Changes in cardiovascular disease risk factors during menopausal transition in Japanese women: the Circulatory Risk in Communities Study (CIRCS).
We aimed to longitudinally clarify the changes in cardiovascular disease risk factors associated with menopause in Japanese women in the 2000s. Of the 4,596 women who underwent health examinations between 2007 and 2012 in three communities of the Circulatory Risk in Communities Study, 263 women who reported going through menopause during that period were included in the study. We randomly selected 1,665 men as control subjects who participated in a health examination at least once between 2001 and 2009 and at least once between 2010 and 2018 by 1:1 pair-matching for age, community, and examination year. The health examination data from 3 to 6 years before (2001-2009) and after menopause age (2010-2018) were compared in terms of body mass index, systolic and diastolic blood pressure levels, serum total cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, triglycerides, uric acid, hemoglobin A 1c , hemoglobin, aspartate aminotransferase, alanine aminotransferase, and current smoker status. Compared with the men, the women showed a greater increase in serum total cholesterol (+16.7 vs -3.1 mg/dL, P < 0.001), non-high-density lipoprotein cholesterol (+15.9 vs -6.3 mg/dL, P < 0.001), fasting triglycerides (+1.2 vs +1.0 mg/dL, P = 0.027), triglycerides regardless of fasting status (+1.2 vs -0.9 mg/dL, P < 0.001), uric acid (+0.5 vs +0.2 mg/dL, P = 0.008), hemoglobin (+0.9 vs -0.3 g/dL, P < 0.001), aspartate aminotransferase (+2.9 vs -2.7 IU/L, P < 0.001), and alanine aminotransferase (+2.9 vs -2.6 IU/L, P < 0.001). No differences were found in the changes in body mass index, systolic and diastolic blood pressures, and hemoglobin A 1c between the women and the matched men. Menopause may be a crucial factor related to changes in serum total cholesterol, non-high-density lipoprotein cholesterol, triglycerides, uric acid, hemoglobin, and liver enzymes.


Human leukemia K-562 cells: induction of erythroid differentiation by 5-azacytidine.
In this article we show that the cytidine analog 5-azacytidine is able to induce differentiation of the human leukemia K-562 cell line. Erythroid induction is associated with (a) an increase of the overall globin synthesis and globin mRNA accumulation, (b) a relative increase of fetal with respect to embryonic globins, and (c) a decrease of the proliferative capacity of hemoglobin-containing cells. In addition, we have analysed the DNA methylation pattern at the cleavage sites of MspI and HpaII restriction enzymes, which are known to cleave differently CCGG DNA sequences when 5-methylcytosine is present. These experiments indicate that in K-562 cells treated with 5-azacytidine, DNA becomes hypomethylated, suggesting that genetic programmes leading to an erythroid phenotype may be activated by a reduction of DNA methylation.


Influence of Cardiopulmonary Resuscitation Coaching on Interruptions in Chest Compressions During Simulated Pediatric Cardiac Arrest.
To determine the impact of a cardiopulmonary resuscitation coach on the frequency and duration of pauses during simulated pediatric cardiac arrest. This is a secondary analysis of video data collected from a prospective multicenter trial. Forty simulated pediatric cardiac arrest scenarios (20 noncoach and 20 coach teams), each lasting 18 minutes in duration, were reviewed by three clinical experts to document events surrounding each pause in chest compressions. Four pediatric academic medical centers from Canada and the United States. Two-hundred healthcare providers in five-member interprofessional resuscitation teams that included either a cardiopulmonary resuscitation coach or a noncoach clinical provider. Teams were randomized to include either a trained cardiopulmonary resuscitation coach or an additional noncoach clinical provider. The frequency, duration, and associated factors with each interruption in chest compressions were recorded and compared between the groups with and without a cardiopulmonary resuscitation coach, using t tests, Wilcoxon rank-sum tests, or chi-squared tests, depending on the distribution and types of outcome variables. Mixed-effect linear models were used to explore the effect of cardiopulmonary resuscitation coaching on pause durations, accounting for multiple measures of pause duration within teams. A total of 655 pauses were identified (noncoach n = 304 and coach n = 351). Cardiopulmonary resuscitation-coached teams had decreased total mean pause duration (98.6 vs 120.85 s, p = 0.04), decreased intubation pause duration (median 4.0 vs 15.5 s, p = 0.002), and similar mean frequency of pauses (17.6 vs 15.2, p = 0.33) when compared with noncoach teams. Teams with cardiopulmonary resuscitation coaches are more likely to verbalize the need for pause (86.5% vs 73.7%, p < 0.001) and coordinate change of the compressors, rhythm check, and pulse check (31.7% vs 23.2%, p = 0.05). Teams with cardiopulmonary resuscitation coach have a shorter pause duration than non-coach teams, adjusting for number and types of tasks performed during the pause. When compared with teams without a cardiopulmonary resuscitation coach, the inclusion of a trained cardiopulmonary resuscitation coach leads to improved verbalization before pauses, decreased pause duration, shorter pauses during intubation, and better coordination of key tasks during chest compression pauses.