The induction of apoptosis in proliferating human fibroblasts by oxygen radicals is associated with a p53- and p21WAF1CIP1 induction.
The role of reactive oxygen species (ROS) generated by hypoxanthine/xanthine oxidase (HX/XO) in the induction of apoptosis was studied in the human fibroblast cell line WI38. Apoptosis but not necrosis was observed in proliferating fibroblasts after 48 h incubation with 1 mM HX and 0.05 U/ml XO. Induction of apoptosis was hindered by catalase. Cell-cycle analysis revealed a reduction of cells in the S/G2 phase 24 and 48 h after stimulation, suggesting that ROS induce a G1 arrest in proliferating fibroblasts. This was supported by an accumulation of p53 and the cdk inhibitor p21WAF1/CIP1. Since apoptosis was not inducible in senescent fibroblasts our data indicate that ROS mainly induces apoptosis in proliferating cells.


A convexity intracerebral arachnoid cyst: a CT entity to be differentiated from a cystic glioma.
A 65-year-old female with an intracerebral cyst was examined in our clinic. It was suspected to be a cystic glioma by the preoperative neuroradiological studies, even with the use of sophisticated CT techniques. By operative and histopathological examination, it was confirmed as an arachnoid cyst mainly embedded in the parenchyma.


Relationship between Waist Circumference and Cardiovascular Risk Factors in Adolescents: Analysis of the Korea National Health and Nutrition Examination Survey Data.
High waist circumference (WC) is associated with increased cardiovascular risk (CVR) in adulthood. We investigated this association in adolescents. We performed a cross-sectional analysis of data for 10-18-year-olds included in the Korea National Health and Nutrition Examination Survey (KNHANES) (2005-2014). The association between WC and CVR factors was evaluated. We analyzed this relationship according to age. We analyzed 8,153 participants (4,319 boys and 3,834 girls) from the KNHANES. High WC was associated with increased incidence of CVR factors: hypertension (odds ratio [OR], 3.5 in boys, 1.9 in girls), high total cholesterol (OR, 3.9 in boys, 1.9 in girls), high triglycerides (OR, 4.9 in boys, 3.2 in girls), high low-density lipoprotein (LDL) cholesterol (OR, 5.0 in boys, 1.8 in girls), low high-density lipoprotein (HDL) cholesterol (OR, 2.6 in boys, 3.0 in girls), and hyperglycemia (OR, 2.8 in girls). In boys, the association between high WC and hypertension, high triglycerides, and low HDL cholesterol was noted in early adolescence. High WC was associated with high total cholesterol and high LDL cholesterol in middle adolescence. In girls, high WC was correlated with high total cholesterol, high triglycerides, and low HDL cholesterol in early adolescence. High WC was shown to be associated with hyperglycemia in middle adolescence, and with hypertension and high LDL cholesterol in late adolescence. High WC in adolescents is associated with increased CVR. The timing of this association differs according to sex and CVR factors.


Brief separation elevates cortisol in mother and infant squirrel monkeys.
The pituitary-adrenal response of mother and infant squirrel monkeys was assessed under basal conditions and after 5, 10, or 20 min of separation followed by 30 min of reunion. All separation conditions produced equal increments of cortisol (approximately 50%) in both mothers and infants. These increments were lower than would have occurred in the absence of reunion. These results extend previous reports that reunion ameliorates the psychoendocrine effects of separation and indicate that mother-infant attachment can be studied with shorter periods of separation than have been used customarily.


Deciphering and engineering photosynthetic cyanobacteria for heavy metal bioremediation.
Environmental pollution caused by heavy metals has received worldwide attentions due to their ubiquity, poor degradability and easy bioaccumulation in host cells. As one potential solution, photosynthetic cyanobacteria have been considered as promising remediation chassis and widely applied in various bioremediation processes of heavy-metals. Meanwhile, deciphering resistant mechanisms and constructing tolerant chassis towards heavy metals could greatly contribute to the successful application of the cyanobacteria-based bioremediation in the future. In this review, first we summarized recent application of cyanobacteria in heavy metals bioremediation using either live or dead cells. Second, resistant mechanisms and strategies for enhancing cyanobacterial bioremediation of heavy metals were discussed. Finally, potential challenges and perspectives for improving bioremediation of heavy metals by cyanobacteria were presented.


Recombinant human tissue-type plasminogen activator is an effective agent for thrombolysis of peripheral arteries and bypass grafts: preliminary report.
The efficacy, safety, and effects on hemostasis and coagulation of two doses of human tissue-type plasminogen activator in patients with acute and subacute peripheral arterial occlusion were compared. Seven patients with lower extremity ischemia and one patient with upper extremity ischemia had peripheral arterial thromboses (five arteries, three grafts) confirmed by clinical history, physical examination, and angiography. The duration of occlusion ranged from 31 hours to 30 days (mean 11.9 days). Tissue-type plasminogen activator was infused via a catheter directly into the thrombus at a randomly assigned dose of 0.05 mg/kg/hr (n = 4) or 0.025 mg/kg/hr (n = 4). Thrombolysis was complete in seven patients and partial in one. Duration of infusion ranged from 1 hour to 21 hours (mean 7.4 hours). The low dose required a longer infusion than did the high dose, but they were both successful in achieving thrombolysis. The one patient with partial thrombolysis had abrupt discontinuation of infusion when extravasation through a recently endarterectomized femoral artery developed. Otherwise there were no significant complications from tissue-type plasminogen activator therapy. Secondary procedures to correct underlying arterial disease were performed in five of the seven patients (71%) who had complete thrombolysis. Even at low dosages, infusion of tissue-type plasminogen activator into arteries or bypass graft thrombus produced complete thrombolysis, and no major complications occurred. This allowed more systematic effects to diagnose and treat underlying arterial disease.


Intracellular analysis of trigeminal motoneuron activity during sleep in the cat.
Intracellular recordings were made from trigeminal motoneurons of normally respiring, unanesthetized cats during naturally occurring sleep. The transition from quiet to active sleep was accompanied by tonic motoneuron hyperpolarization. Stimulation of the reticular formation induced a depolarizing potential in trigeminal motoneurons during quiet sleep and a hyperpolarizing potential during active sleep. The results provide a synaptic explanation for the phenomenon of reticular response reversal and insights into the basic mechanisms controlling motor activity during the sleep states.


Multiple oral mucoceles treated with evening primrose oil: a report of two cases.
Multiple mucoceles of the minor salivary glands are rare in the mouth. Typically, the minor salivary glands of the soft palate are affected. We report two cases that responded entirely following systemic therapy with evening primrose oil. No recurrence was reported over a two-year follow-up period. Evening primrose oil is postulated to have an effect on the composition and/or viscosity of minor salivary gland secretions.


Screening and identification of Monascus strains with high-yield monacolin K and undetectable citrinin by integration of HPLC analysis and pksCT and ctnA genes amplification.
Red yeast rice (RYR), produced by inoculating Monascus strains to steamed rice, contains many kinds of physiologically bioactive compounds, among which monacolin K can be used as an antihypercholesterolaemic agent. However, RYR can be polluted by the mycotoxin citrinin, which has nephrotoxic and hepatotoxic activities. To avoid the risk of citrinin contamination in Monascus fermented products, it is important to screen for Monascus strains that produce no or low citrinin. Five autochthonous Monascus strains with high-yield monacolin K and undetectable citrinin were obtained using high-performance liquid chromatography (HPLC). All five strains were identified as Monascus ruber based on Genealogical Concordance Phylogenetic Species Recognition criteria. Polymerase chain reaction revealed that citrinin polyketide synthase (pksCT) gene was found in these strains, but transcriptional regulator (ctnA) was not found. Five strains are potential strains for producing high-quality RYR. The distribution of the pksCT gene was not restricted to Monascus purpureus and Monascus sanguineus, and M. ruber strains were diverse in pksCT and ctnA genes. The integration of citrinin HPLC analysis and pksCT and ctnA genes amplification could provide a complementary approach in valuable Monascus strains screening.


Biosynthesis of a proinsulin-like molecule in the pancreas of a lizard.
The biosynthesis of insulin, in particular the occurrence of a proinsulin-like molecule (PILM), in the pancreas of the green anole, Anolis carolinensis, was investigated. The laboratory rat was used for comparison and validation of the procedures. Anolian pancreases were incubated in vitro with radiolabeled leucine or proline. Radioactivity incorporated into the acidic ethanol-soluble (AES) phase increased in an essentially linear manner with time. Selective incorporation of labeled amino acids into AES material was not enhanced by a high concentration of glucose (6 mg/ml), by the addition of glucagon, which increases cyclic AMP levels, or by the addition of cytochalasin B; yet all three conditions result in stimulated insulin secretion. Gel filtration of the AES material on columns of Bio-Gel P-30 revealed a major peak of radioactivity whose apex followed closely the apogee of porcine proinsulin. When this presumptive PILM was treated with trypsin and carboxypeptidase B, the radioactivity was shifted towards later elution volumes, but the peak of the converted anolian material was not coincidental with marker insulin. Immunopurification techniques and additional molecular filtrations resulted in the isolation of fractions with both insulin-like immunoreactivity (IRI) and radioactivity derived from tritium-labeled leucine. One peak of radiolabel was present in the region of the proinsulin standards. The level of radioactivity in the region of the insulin standards was relatively high after two days of organ culture of splenic pancreases. By polyacrylamide gel electrophoresis proteins that incorporated radiolabeled amino acids and had insulin-like immunoreactivity possessed migration patterns similar to those of mammalian proinsulin and insulin. The insulin-like component was less readily demonstrated than the proinsulin-like component and raises the possibility that anolian PILM may be a major storage form in this species. The results are consistent with the synthesis of a proinsulin-like precursor in the beta cells of the green anole. The results also provide evidence for a precursor-product relationship in the anolian beta cell.


Core-shell assembly of ZrO2 nanoparticles with ionic liquid: a novel and highly efficient heterogeneous catalysts for Biginelli and esterification reactions.
Imidazolium sulfonic acid chloride grafted ZrO2 nanoparticles (ZrO2-IL) were synthesized through facile post-treatment of the nanoparticles with the imidazolium-sulfonic acid chloride ionic liquid. The immobilization of the ionic liquid over the ZrO2 nanoparticles was evident from the XRD, SEM, TEM, Raman, BET, and XPS analysis. The results obtained from the XRD analysis clearly show that the catalyst has an orthorhombic structure and from the BET analysis it is evident that the surface is mesoporous with uniform pore sizes and pore distribution. Further evidence of immobilization of ionic liquid over the ZrO2 NPs was obtained from the SEM, TEM, XPS, and Raman analysis. Under mild conditions, the synthesized heterostructure was used in the acid-catalyzed esterification of different acids. The ZrO2-IL catalyst converts 99% of the acid to ester with a 98.9% yield in 1h. The material was also shown to be highly efficient as catalyst for the Biginelli reaction under solvent-free conditions, with the catalyst for dihydropyrimidin-2(1H)-one (DHPMs) in 1h with 99.2% conversion and 99% yield. The synergy between the ionic liquid catalyst and the substrates increased the catalytic efficiency and resulted in high-yield product conversion. The mechanism of both transformation reactions was investigated, as well as the synergy between ionic liquid and ZrO2 nanoparticles for better catalytic efficiency was established.


Two decades have passed ... and still it is her eyes that I remember: reflections of a pediatric nurse.
A pediatric nurse reflects on her practice by recounting her experience while caring for a child with Guillian Barre 20 years ago. Principles and lessons relevant to guide pediatric nursing practice in today's health care environment are identified.


Effect of steroid hormones on the regulation of uterine contractility.
The kinetics of myosin light chain (LC20) phosphorylation has been studied during in vitro contraction and relaxation of rat uteri. Phosphorylation preceded contraction and continued during tetanus induced by KCl; the degree of phosphorylation was proportional to the percentage of contraction. On the other hand, during relaxation induced by isoproterenol, the level of phosphorylation did not change in the seconds following relaxation. A rapid change in cAMP did not appear to trigger a rapid change in LC20 phosphorylation. In cyclic rats, progesterone decreased the extent of LC20 phosphorylation: 50%-60% of the LC20 was phosphorylated in untreated animals or estrogen treated animals. This value fell to 30% after progesterone treatment of cyclic rats. In ovariectomized rats, steroid hormones did not affect the phosphorylation reaction. Under the same conditions, the level of cAMP-dependent protein kinases did not change during the cycle, or after estradiol-treatment, but in cyclic rats it doubled after progesterone treatment. Hence, the decrease in the level of LC20 phosphorylation observed in cyclic rats treated by progesterone could be due to a decrease in myosin light chain kinase (MLCK) activity, resulting from a higher proportion of the phosphorylated form of this enzyme. The concomitant increase in the proportion of activatable cAMP-dependent protein kinases could favor the maintenance of a higher level of phosphorylated MLCK for longer periods of time.


Characterizing the trade-off between range of motion and stability of reverse total shoulder arthroplasty.
The trade-off between range of motion (ROM) and stability of reverse total shoulder arthroplasty (RSA) has long been hypothesized to exist but has not yet been well characterized. The goal of this study was to use design optimization techniques to obtain a Pareto curve, which quantifies the trade-off between 2 competing objectives and is defined by the performance of optimum designs that maximize one surgical outcome without sacrificing the other. Multi-objective design optimization techniques were used; 4 design and surgical parameters including glenoid lateralization (GLat), neck-shaft angle (NSA), inferior offset of the center of rotation (CORinf), and humerus lateralization (HLat) were tuned simultaneously. The ROM and stability, the objectives to be optimized, of any candidate design were characterized computationally using a combination of finite element models, musculoskeletal models, analytical equations, and surrogate models. Optimum designs and Pareto curves were determined separately for a standard cup depth and a shallow cup depth. The performance of the optimum designs, in terms of ROM and stability, was compared with a representative commercially available design. A Pareto curve was obtained for each cup depth, confirming there is a trade-off between ROM and stability of RSA. In comparison to the commercially available design (cup depth, 8.1 mm; GLat, 5 mm; NSA, 155°; CORinf, 0 mm; HLat, 0 mm), the designs optimized for ROM offered 38.8% (cup depth, 6 mm; GLat, 16 mm; NSA, 163.6°; CORinf, 4 mm; HLat, 0.6 mm) and 35.2% (cup depth, 8.1 mm; GLat, 16 mm; NSA, 160.5°; CORinf, 4 mm; HLat, -0.2 mm) improvement in ROM. The designs optimized for stability (cup depth of 6 mm with GLat of 16 mm, NSA of 170°, CORinf of 4 mm, and HLat of 3 mm and cup depth of 8.1 mm with GLat of 16 mm, NSA of 170°, CORinf of 4 mm, and HLat of 3 mm) both offered 12.4% improvement in stability over the commercially available design. Designs in the toe region of the Pareto curve offered between 75% and 90% of the maximum possible improvement over the commercially available design for both objectives. It was confirmed that a trade-off exists between ROM and stability of RSA, in which maximizing one outcome requires a sacrifice in the other. The relative gains and sacrifices in the competing outcomes when traversing the Pareto front could aid in understanding clinically optimum designs based on patient-specific needs.


Association between the APC gene D1822V variant and the genetic susceptibility of colorectal cancer.
Adenomatous polyposis coli (APC) gene polymorphisms are believed to contribute to tumor susceptibility. However, the association between genetic variants (A/T) in the APC gene D1822V polymorphism and colorectal cancer (CRC) susceptibility remains unknown. To determine this association, a case-control study was performed. The genotype of the APC gene D1822V variants was analyzed by DNA sequencing in blood samples collected from 196 patients with CRC and 279 healthy subjects. There were no significant associations between the case and control groups in the distribution of AT [odds ratio (OR), 0.604; 95% confidence interval (CI), 0.355-1.029) and TT genotypes (OR, 0.438; 95% CI, 0.045-4.247) relative to the AA genotype. The ratio of the T allele was significantly lower (P=0.047) in the case group compared with the control group (OR, 0.611; 95% CI, 0.374-0.997), indicating that the T allele conferred a protective effect in CRC. The frequency of the AT genotype among the subjects diagnosed at >45 years of age was lower than those diagnosed at a younger age (P<0.05). The present study demonstrates that the T allele of the D1822V polymorphism may exert a protective effect against CRC, however, these findings require further validation in a larger sample size.


Textured ceramic membranes for desilting and deoiling of produced water in the Permian Basin.
Oil production in the Permian Basin gives rise to large volumes of produced water contaminated by silt, emulsified oil, and additives used for enhanced oil recovery. There is intense interest in the design of membrane modules as sustainable alternatives for produced water treatment to enable the reuse of produced water for agricultural applications, injection into aquifers, and redeployment in oil recovery. Here, we report a hierarchically textured cement-based membrane exhibiting orthogonal wettability, specifically, superhydrophilic and underwater superoleophobic characteristics. The in situ formation of ettringite needles accompanied by embedding of glass spheres imbues multiscale texturation to stainless-steel mesh membranes, enabling the separation of silt and oil from produced water at high flux rates (1600 L h-1۰m-2, at ca. 2.7 bar). Oil concentration is reduced as low as 1 ppb with an overall separation efficiency of 99.7% in single-pass filtration. The membranes show outstanding mechanical resilience and retention of performance across multiple cycles.


Initial psychometric analysis of novel instruments to assess decisional distress and decisional uncertainty in women who have considered using preimplantation genetic testing.
To analyze psychometric properties of two novel instruments assessing decisional distress and uncertainty experienced by individuals considering preimplantation genetic testing (PGT). The new PGT Decisional Distress instrument (22 items) assesses negative/positive emotions. The new PGT Decisional Uncertainty instrument assesses Clarity about test benefits/disadvantages (5 items) and Certainty of having adequate information/support to make a good decision (7 items). Scales ranged from 0 to 4. Psychometrics (central tendencies, internal consistency reliability, and discriminant validity) were evaluated. Stratified analysis by decision stage was conducted. All participants had considered or used PGT in the previous 6 months. N = 106 females (mean age 36.5 ± 4.8 years; 16% non-Caucasian; 9% Hispanic) across 16 US states completed an online anonymous questionnaire. On average, respondents reported minimal distress (mean 0.96), high clarity (mean 3.26), and high certainty (mean 3.06), particularly those who had already decided compared to undecided women (P ≤ .02). Instruments had excellent internal consistency (Cronbach's α's 0.92-0.94) and displayed sufficient inter-individual variability (SD's 0.75-0.89). Correlations confirmed expected patterns of association between instruments (P's < .01), indicating discriminant validity. We document initial reliability and validity of new instruments to measure emotional distress and uncertainty in female patients who have recently considered PGT for single-gene or chromosomal disorders.


Airborne gamma-ray spectrometry data processing using 1.5D inversion.
Standard processing of Airborne Gamma-Ray Spectrometry data generally gives good results when the measurement conditions are almost constant within several footprint area sizes, with the possible exception of flight height variations in a small range. In practice, deviations, such as large or abrupt changes of flight height and/or rugged terrain are not so rare and lead to certain problems. This article proposes a different approach where the solutions of inverse problems are used for data processing. The approach is quite natural in the processing of field data measured along the flight lines: it explicitly takes into account 1.5D survey models and flight parameters - from topography to sources distribution on the surface. Also, it clearly demonstrates that the inverse problem of the Airborne Gamma-Ray Spectrometry does not have a unique solution. This feature can be used in accordance with the underlying geological problem since various formulations of inverse problems can lead to various geological solutions. The use of the approach is illustrated by several examples given for flight lines and survey areas. This approach can be particularly useful in situations where geological, geophysical and/or geographic survey conditions are far from the standard assumptions.


Degenerate recognition of MHC class I molecules with Bw4 and Bw6 motifs by a killer cell Ig-like receptor 3DL expressed by macaque NK cells.
The killer cell Ig-like receptors (KIRs) expressed on the surface of NK cells recognize specific MHC class I (MHC-I) molecules and regulate NK cell activities against pathogen-infected cells and neoplasia. In HIV infection, survival is linked to host KIR and MHC-I genotypes. In the SIV macaque model, however, the role of NK cells is unclear due to the lack of information on KIR-MHC interactions. In this study, we describe, to our knowledge, the first in-depth characterization of KIR-MHC interactions in pigtailed macaques (Macaca nemestrina). Initially, we identified three distinct subsets of macaque NK cells that stained ex vivo with macaque MHC-I tetramers loaded with SIV peptides. We then cloned cDNAs corresponding to 15 distinct KIR3D alleles. One of these, KIR049-4, was an inhibitory KIR3DL that bound MHC-I tetramers and prevented activation, degranulation, and cytokine production by macaque NK cells after engagement with specific MHC-I molecules on the surface of target cells. Furthermore, KIR049-4 recognized a broad range of MHC-I molecules carrying not only the Bw4 motif, but also Bw6 and non-Bw4/Bw6 motifs. This degenerate, yet peptide-dependent, MHC reactivity differs markedly from the fine specificity of human KIRs.


Some characteristics of collagenase activity in gingival crevicular fluid and its relationship to gingival diseases in humans.
Collagenase activity in human gingival fluid was measured using a radioactive collagen fibril assay. The activity was positively correlated with the severity of gingival disease. The fluid collagenase seemed to be controlled by alpha 2-macroglobulin, based on its activation by NaSCN, and to be present solely in the extracellular fraction. Examination of the collagen breakdown products by acrylamide gel electrophoresis indicated that the fluid collagenase was of tissue rather than bacterial origin.


Multiple pregnancies, hepatitis C, and risk for hepatocellular carcinoma in Egyptian women.
The reasons for the worldwide sex disparity in the incidence of hepatocellular carcinoma (HCC) remain elusive. We investigated the role of multiple pregnancies on the associations between viral hepatitis C (HCV) infection and HCC risk among Egyptian women. We used data collected from blood specimens and questionnaires administered to female HCC cases and controls in Cairo, Egypt, from 1999 through 2009. HCV infection was defined as being sero-positive for either anti-HCV antibodies or HCV-RNA. Using logistic regression models we calculated odds ratios (OR) and 95% confidence intervals (CI) to estimate the associations between being HCV positive and HCC risk, and how it is modified by the number of pregnancies, after adjustment for other factors, including hepatitis B status. Among 132 confirmed female cases and 669 controls, the risk of HCV-related HCC increased with the number of pregnancies. Women infected with HCV had higher risk for HCC if they had more than five pregnancies, as compared to those who had five or fewer pregnancies (adjusted OR (95% CI): 2.33 (1.29-4.22)). The association of HCV infection with HCC risk was significantly greater among the former (21.42 (10.43-44.00)) than among the latter (6.57 (3.04-14.25)). Having multiple pregnancies increases the risk of HCV-related HCC among Egyptian women, raising questions about the roles of estrogens and other pregnancy-related hormones in modulating HCV infection and its progression to HCC.


Trajectories of mothers' and fathers' depressive symptoms from pregnancy to 24 months postpartum.
This study investigated trajectories of mothers' and fathers' depressive symptoms from prenatal to 24 months postpartum. Prenatal correlates of the trajectories were also examined. Mothers (N = 1670) and fathers (N = 1604) from the Finnish CHILD-SLEEP birth cohort, reported depressive symptoms at 32nd pregnancy week and 3, 8, and 24 months postpartum using the Center for Epidemiologic Studies Depression Scale (CES-D, 10-item). Profile analysis was used to group participants according to their longitudinal patterns of depressive symptoms. Prenatal predictors (sociodemographic, health, substance use, sleep, and stress related factors, family atmosphere) of depressive symptom trajectories as well as association between parents' trajectories were analyzed using multinomial logistic regression. For both mothers and fathers, a solution with three stable depressive symptom trajectories (low: 63.1% mothers and 74.9% fathers; moderate: 28.1% and 22.6%; high: 8.8% and 2.6%) was considered the best fitting and most informative. Insomnia, earlier depression, anxiousness, stressfulness, and poor family atmosphere predicted the moderate and high (compared to low) depressive symptom trajectories among both mothers and fathers in multivariate analyses. Mother's higher depressive symptom trajectory was significantly associated with father's higher symptom trajectory (p < 0.001). Number of cases in the high depressive symptom trajectory group among fathers was low. Maternal and paternal depressive symptom trajectories from prenatal period up to two years postpartum seem stable, indicating the chronic nature of perinatal depressive symptoms. Mothers' and fathers' trajectories are associated with each other and their strongest predictors are common to both.


Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course.
The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. While conventional cytogenetic analyses only detected chromosome aberrations in 40-50% of cases, new molecular cytogenetic methods, such as fluorescence in situ hybridization (FISH), have greatly enhanced our ability to detect chromosomal abnormalities in CLL. Today, genomic aberrations are detected in over 80% of CLL cases. Genes potentially involved in the pathogenesis were identified with ATM in a subset of cases with 11q deletion and p53 in cases with 17p13 deletion. For the most frequent aberration, the deletion 13q14, candidate genes have been isolated. Genetic subgroups with distinct clinical features have been identified. 11q deletion is associated with marked lymphadenopathy and rapid disease progression. 17p deletion predicts for treatment failure with alkylating agents, as well as fludarabine and short survival times. In multivariate analysis 11q and 17p deletions provided independent prognostic information. Recently, another important issue of genetic risk classification in CLL was identified with the mutation status of the immunoglobulin variable heavy chain genes (V(H)). CLL cases with unmutated V(H) show more rapid disease progression and shorter survival times. Whether CD38 expression can serve as a surrogate marker for V(H) mutation status is currently discussed controversially. V(H) mutation status and genomic abnormalities, such as 17p and 11q deletion, have recently been shown to be related to each other, but were of independent prognostic information in multivariate analysis. Moreover, genomic aberrations and V(H) mutation status appear to give prognostic information irrespective of the clinical stage and may therefore allow a risk assessment for individual patients early in the course of their disease.


Increased Prevalence of Gastroesophageal Reflux Disease Among Patients With Rheumatoid Arthritis: A Systematic Review and Meta-analysis.
This study was conducted to determine the association between gastroesophageal reflux disease (GERD) and rheumatoid arthritis (RA) by pooling the evidence from all available studies. Potentially eligible studies were identified from MEDLINE and EMBASE database from inception to April 2021 employing a search strategy that consisted of terms for "Rheumatoid Arthritis" and "Gastroesophageal Reflux Disease". Eligible studies for the meta-analysis were recruited with conditions of being cohort studies that included rheumatoid arthritis and without rheumatoid arthritis individuals. Together with this, prevalence of GERD in both groups and the odds ratio (OR) comparing the prevalence of GERD between the two cohorts have been reported. The retrieved point estimates with standard errors from each study were pooled into the final result by the random-effect model and generic inverse variance method as described by DerSimonian and Laird. A total of 3,646 articles were identified. After two rounds of independent review by two investigators, five cohort studies were included in the meta-analysis as they met the eligibility criteria. The pooled analysis demonstrated a significant association between RA and GERD with the pooled odds ratio of 1.98 (95% CI, 1.49 - 2.65). High statistical heterogeneity with I2 of 83% was observed. The funnel plot was symmetric and publication bias was not observed. This systematic review and meta-analysis found a significant association between GERD and RA.


[Autochthonous Rickettsia parkeri rickettsiosis in the Paranaense Forest, Misiones, Argentina].
We report an autochthonous case of Rickettsia parkeri rickettsiosis occurred in June 2018 in a forested area of the Urugua-í Provincial Park, Misiones, Argentina. No previous records of this disease in humans have been previously reported in this region. The epidemiological, ecological, clinical, and laboratory features required for a proper diagnosis and adequate treatment are described here. The fact of considering rickettsiosis as a differential diagnosis in a patient with exanthematic acute febrile syndrome is highlighted, being the epidemiological history of exposure to the vector (ticks of the genus Amblyomma) an essential element.


Lower critical concentration temperature as thermodynamic origin of syneresis: Case of kappa-carrageenan solution.
Polysaccharide ubiquity is trimmed for applications of low syneresis impact. This syneresis may be crucial for specific applications that are very sensitive to gel dimension stability, namely, 3D scaffolds for cell culture for disease diagnosis and tissue engineering. We hypothesized that the syneresis origin results from the kappa-carrageenan (kC) polysaccharide thermodynamic instability, and we demonstrated this by measuring the critical (coil-to-coil contact) concentration as a function of temperature. The impact of 5 mM, 10 mM and 15 mM KCl salt on the critical concentration of the solution and the lower critical concentration temperature (LCCT) were particularly investigated. For the kC polysaccharide, the gelation temperature (Tg) falls at temperatures below the LCCT, which explains the shrinking or syneresis reaction of the polysaccharide gels. The gap between Tg and LCCT would be the thermomotive force of the syneresis of many colloidal gels.


Antibiotic prophylaxis in orthopedic prosthetic surgery.
The problem of prophylaxis in orthopedic implant surgery will become increasingly important and complex as the population ages and requires more arthroplasty procedures, and the prevalence of antimicrobial-resistant bacteria meanwhile also continues to rise. Energy spent preventing prosthetic joint infection is more effective than that expended in treating the infection of a prosthetic joint, once established. Preventive measures encompass a wide array of variables related to host response, wound environment, and microorganisms. Prophylaxis should address these areas in the preoperative, intraoperative, and postoperative periods. Antimicrobial prophylaxis remains the single most effective method of reducing the prevalence of infection after total joint arthroplasty. In the postoperative period, prophylaxis aims to protect the prosthetic joint against hematogenous seeding from oral, urologic, skin, or gastrointestinal sources. Currently, dental and urologic advisory statements provide recommendations for antimicrobial prophylaxis for high-risk patients with total joint arthroplasty undergoing high-risk procedures. Close collaboration between the orthopedic surgeon, urologist, or dentist and the infectious disease specialist is crucial for providing recommendations regarding prophylaxis in special circumstances. In these particular circumstances, individual decisions should be made based on clinical judgment.


Chronic lead exposure alters dopaminergic mechanisms in rat pituitary.
The effect of chronic lead treatment on pituitary dopamine (DA) D2 receptors was studied by measuring (-)sulpiride-displaceable [3H]spiroperidol-binding and DA-inhibited adenylate cyclase. Receptor number was reduced in lead-exposed animals and bromocriptine was less able to inhibit cyclase activity in pituitary homogenates. In addition, the capacity of DA to inhibit the VIP-stimulated cAMP formation was decreased.


Pneumomediastinum Mimicking Congenital Pulmonary Airway Malformation.
Pneumomediastinum is the collection of free air in the mediastinum. Its incidence is higher in preterm infants and those on positive airway pressure support or on mechanical ventilation. But it has decreased dramatically after the introduction of surfactant and synchronized, non-invasive mechanical ventilation. Underlying cystic lesions could also increase the risk of pneumomediastinum and other air leak syndromes. Most cases resolve spontaneously but rare hemodynamic compromise may require ultrasound-guided intervention.


Antisense Oligonucleotides Targeting Angiogenic Factors as Potential Cancer Therapeutics.
Cancer is one of the leading causes of death worldwide, and conventional cancer therapies such as surgery, chemotherapy, and radiotherapy do not address the underlying molecular pathologies, leading to inadequate treatment and tumor recurrence. Angiogenic factors, such as EGF, PDGF, bFGF, TGF-β, TGF-α, VEGF, endoglin, and angiopoietins, play important roles in regulating tumor development and metastasis, and they serve as potential targets for developing cancer therapeutics. Nucleic acid-based therapeutic strategies have received significant attention in the last two decades, and antisense oligonucleotide-mediated intervention is a prominent therapeutic approach for targeted manipulation of gene expression. Clinical benefits of antisense oligonucleotides have been recognized by the U.S. Food and Drug Administration, with full or conditional approval of Vitravene, Kynamro, Exondys51, and Spinraza. Herein we review the scope of antisense oligonucleotides that target angiogenic factors toward tackling solid cancers.


HMGA and Cancer: A Review on Patent Literatures.
The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins. Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment. We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions. Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.


Redefining microglia states: Lessons and limits of human and mouse models to study microglia states in neurodegenerative diseases.
Microglia are resident macrophages of the brain parenchyma and play an essential role in various aspects of brain development, plasticity, and homeostasis. With recent advances in single-cell RNA-sequencing, heterogeneous microglia transcriptional states have been identified in both animal models of neurodegenerative disorders and patients. However, the functional roles of these microglia states remain unclear; specifically, the question of whether individual states or combinations of states are protective or detrimental (or both) in the context of disease progression. To attempt to answer this, the field has largely relied on studies employing mouse models, human in vitro and chimeric models, and human post-mortem tissue, all of which have their caveats, but used in combination can enable new biological insight and validation of candidate disease pathways and mechanisms. In this review, we summarize our current understanding of disease-associated microglia states and phenotypes in neurodegenerative disorders, discuss important considerations when comparing mouse and human microglia states and functions, and identify areas of microglia biology where species differences might limit our understanding of microglia state.


Characterizing the Native Microbiome Using Next-Generation Sequencing of Bilateral 'Aseptic' Knees.
Next generation sequencing (NGS) has proven ability to identify organisms beyond those identified through traditional culture-based techniques in cases of suspected prosthetic joint infection. However, there is concern that some microorganisms identified may represent the natural joint microbiome rather than pathogenic agents. This work sought to evaluate the presence of microorganisms identified with NGS in bilateral native, presumed "aseptic" knees with osteoarthritis. There were 40 patients undergoing primary unilateral (30) or bilateral (10) total knee arthroplasty enrolled prospectively. During surgery, samples of fluid and tissue were obtained from operative knees, and joint fluid was obtained from nonoperative knees. Samples were sent for NGS analysis and processed according to manufacturer protocols. Patient age, body mass index, comorbidities, prior history of injections, and grade of arthritis were evaluated for association with positive NGS results. There were 3 of 80 samples (3.8%) that demonstrated positive NGS. There were two of these that had multiple microorganisms identified (1 knee with 4 microorganisms; 1 knee with 2 microorganisms). An additional 2 samples had positive NGS results below the manufacturer's threshold for reporting. The most common organism identified was Cutibacterium acnes, present in 2 of the 3 positive samples. No patient baseline characteristics were associated with positive NGS results. Some native knee joints with osteoarthritis have positive microorganisms identified with NGS. The presence of microorganisms in the native knee has important implications for better understanding the native joint microbiome as well as utilization of NGS in cases of suspected prosthetic joint infection.


Frog glue enhances rotator cuff repair in a laboratory cadaveric model.
Rotator cuff tendons are typically reattached to the proximal humerus using transosseous sutures or suture anchors. Their primary mode of failure is at the tendon-bone interface. We investigated the addition of a novel adhesive secreted from a species of Australian frog (Notaden bennetti) to different methods of rotator cuff repair. We hypothesized that the addition of frog glue would increase the strength of the repaired rotator cuff construct. Three techniques were used to repair 42 fresh frozen sheep infraspinatus tendons with a mattress stitch configuration: transosseous sutures; 2 traditional metallic suture anchors with 1 suture per anchor, and 2 knotless metallic anchors with 1 suture per anchor. In each group, 7 shoulders were repaired with the addition of frog glue to the infraspinatus "footprint," whereas 7 were used as control with no adhesive. Failure occurred in all constructs at the tendon-bone-suture interface. Repair with suture anchors was stronger than with sutures through bone (P < .05). Frog glue significantly increased the load to failure, total energy required for failure, and maximum energy at failure in all repair techniques (P < .01). A 2-fold increase occurred in load to failure of the 2 common anchor types (143 +/- 8 and 165 +/- 20 N). The load to failure for the transosseous repair (86 +/- 8 N) increased 1.7-fold. The addition of an adhesive to the tendon-bone-suture interface significantly enhances ultimate load and total energy required to failure in 3 types of rotator cuff repair. The unique properties of this frog glue (strong, flexible and sets in water) may ultimately lead to its use as an adjunct to rotator cuff repair in humans. Basic science study.


Substrate roughening improves swimming performance in two small-bodied riverine fishes: implications for culvert remediation and design.
Worldwide declines in riverine fish abundance and diversity have been linked to the fragmentation of aquatic habitats through the installation of instream structures (e.g. culverts, dams, weirs and barrages). Restoring riverine connectivity can be achieved by remediating structures impeding fish movements by, for example, replacing smooth substrates of pipe culverts with naturalistic substrates (i.e. river stones; culvert roughening). However, empirical evaluations of the efficacy of such remediation efforts are often lacking despite the high economic cost. We assessed the effectiveness of substrate roughening in improving fish swimming performance and linked this to estimates of upstream passage success. Critical swimming speeds (Ucrit) of two small-bodied fish, purple-spotted gudgeon (Mogurnda adspersa; 7.7-11.6 cm total length, BL) and crimson-spotted rainbowfish (Melanotaenia duboulayi; 4.2-8.7 cm BL) were examined. Swimming trials were conducted in a hydraulic flume fitted with either a smooth acrylic substrate (control) or a rough substrate with fixed river stones. Swimming performance was improved on the rough compared to the smooth substrate, with Mo. adspersa (Ucrit-smooth = 0.28 ± 0.0 m s-1, 2.89 ± 0.1 BL s-1, Ucrit-rough = 0.36 ± 0.02 m s-1, 3.66 ± 0.22 BL s-1, mean ± s.e) and Me. duboulayi (Ucrit-smooth = 0.46 ± 0.01 m s-1, 7.79 ± 0.33 BL s-1; Ucrit-rough = = 0.55 ± 0.03 m s-1, 9.83 ± 0.67 BL s-1, mean ± s.e.) both experiencing a 26% increase in relative Ucrit. Traversable water velocity models predicted maximum water speeds allowing successful upstream passage of both species to substantially increase following roughening remediation. Together these findings suggest culvert roughening may be a solution which allows hydraulic efficiency goals to be met, without compromising fish passage.


Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung.
To investigate mechanisms of chemical-induced congenital heart defects (CHD) we have developed a rat model using dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant, trimethadione (TMD). Dosing pregnant rats with 300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses) produces a mean 74% incidence of CHD with inter litter variability ranging from 40 to 100%. The goal of this study was to determine if the variability in maternal serum concentrations of DMO on GD 14, a surrogate marker for total exposure, was related to the inter-litter differences in teratogenic outcomes. To test this hypothesis, pregnant rats were dosed as described above and serum levels of DMO assessed on GD 14. On GD 21, foetuses were collected by caesarean section, assessed for a number endpoints and the outcomes were correlated with the GD 14 serum concentrations of DMO. DMO exposure was associated with decreased foetal body weight, increased incidence of sternal defects and CHD, but these endpoints were not meaningfully correlated with maternal concentrations of DMO. Novel findings were decreased viability as measured one-hour following caesarean section, and delayed alveolar maturation. The major conclusions from these studies were first, that serum DMO concentrations on GD 14 did not predict teratogenicity, and second, delayed lung development may contribute to the decreased survival of foetuses at the time of caesarean section.


Who, me? Optimism bias about US teenagers' ability to quit vaping.
The vaping rate among US teenagers has doubled in the last 2 years, which may be explained in part by teenagers' optimism that they would have relatively little trouble in quitting. The aim of this study was to estimate the extent to which teenagers exhibited optimism bias, what characteristics are associated with optimism bias and which factors are related to respondents' perceptions of how hard it would be for them to quit. A national, on-line, cross-sectional survey in 2018 using quota sampling. United States. Respondents were 1610 teenagers aged 14-18 years who had ever tried or heard of JUULs or e-cigarettes generally. Optimism bias was defined as respondents' perceptions of their own difficulty quitting vaping compared with that of an average US person of their own age. Linear regression was used to examine associations between respondents' characteristics with both optimism bias and their own perceived difficulty quitting vaping. More than 60% of teenagers were optimistically biased about their ability to quit vaping. Smoking (b = -0.69, P < 0.01) and JUULing (b = -0.62, P < 0.01) were negatively associated with optimism bias but reduced-price school lunch eligibility (0.27, P = 0.02) and school satisfaction were positively associated (b = 0.05, P = 0.02). Smoking (b = 0.85, P < 0.01) was associated with an increased perception of the difficulty of quitting. That association was negative for black respondents (b = -0.81, P = 0.01) and those eligible for reduced-priced lunches (b = -0.48, P = 0.01), and positive for Hispanic respondents (b = 0.47, P = 0.04). On average, US teenagers appear to show optimism bias about their ability to quit vaping, which decreases with smoking and vaping and increases with eligibility for reduced-price school lunches.


Clinical efficacy and safety of different tacrolimus concentrations for the treatment of patients with idiopathic membranous nephropathy.
This retrospective study aimed to explore the relative efficacy and safety of different tacrolimus (TAC) concentrations in the treatment of patients with idiopathic membranous nephropathy (IMN). A total of 260 IMN patients with nephrotic syndrome (NS) were recruited. Among these, 125 patients had TAC concentrations no greater than 5 ng/ml (CTAC ≤ 5 ng/ml), and 135 patients had TAC concentrations greater than 5 ng/ml (CTAC > 5 ng/ml). The primary outcomes included complete remission (CR) rates and overall (OR) response rates. The secondary outcomes included 24-h urinary protein (24-h UP), serum albumin and serum creatinine, and adverse events (AEs). During the 12-month follow-up, the overall response rates were significantly different between the CTAC ≤ 5 ng/ml group and the CTAC > 5 ng/ml group (P < 0.0001). However, there was no significant difference in the CR at 12 months between the two groups (chi-square, 62% vs 63%, P = 0.852). Compared with the CTAC ≤ 5 ng/ml group, the CTAC > 5 ng/ml group had improved levels of 24 h UP (P = 0.017) and serum albumin (P = 0.010). Moreover, the incidences of acute reversible nephrotoxicity (P < 0.001), hepatotoxicity (P = 0.036), new-onset diabetes mellitus (P = 0.036), and glucose intolerance (P = 0.005) were lower in the CTAC ≤ 5 ng/ml group than in the CTAC > 5 ng/ml group. The CTAC > 5 ng/ml group was improved relative to the CTAC ≤ 5 ng/ml group in terms of a PR and CR at 6 months, but there was no difference in the CR between the two groups at 12 months.


T cell subsets and colorectal cancer: discerning the good from the bad.
Tumor-specific T cells must overcome a multitude of suppressive mechanisms to destroy cancerous cells effectively. Furthermore, it appears that the tumor microenvironment facilitates the development of highly immunosuppressive T cells, which may also allow subsequent tumor progression. In colorectal cancer, the relationship between regulatory T cells (e.g. FoxP3(+) Tregs) and tumor prognosis and progression is less clear, despite their well-documented ability to impinge on anti-tumor immune responses. Here we explore our current knowledge of colorectal TIL heterogeneity, deciphering subsets which may be of benefit or detriment.


Incorporation and localisation of ganglioside GM3 in human intimal atherosclerotic lesions.
Immunohistochemical examination showed that sections of intimal atherosclerotic plaques contained cells and cell clusters as well as areas of extracellular matrix specifically stained with antibodies against ganglioside GM3. No immunohistochemical staining was observed in areas bordering the plaques where there was no histological evidence of atherosclerosis. To determine whether the ganglioside GM3 deposits in the intimal plaques derived directly from plasma or were synthesised by intimal cells. intimal plaque and plasma LDL were assayed for ganglioside GM3 fatty acid composition. This assay showed that more than 50% of the fatty acids of GM3 isolated from both atherosclerotic and normal intima are either minor fatty acids or those absent from LDL GM3. We conclude that the GM3 deposits present in intimal plaque arise in intimal cells and do not derive from plasma LDL.


Advances in the management of infected urachal cysts.
Persistent urachal remnants are uncommon congenital anomalies. Unless an umbilical fistula exists, infection may be the first indication of this abnormality. Five children received initial treatment for this problem at the Children's Hospital of Buffalo during a 20-year period, 1964 to 1984, and a sixth was seen secondarily. There were four boys and two girls; their ages ranged from 8 months to 9 years. Lower abdominal mass with fever and local tenderness were the most common presenting signs. Ultrasound was the most accurate study, correctly diagnosing the cyst in both patients so examined. Incision and drainage alone was performed in one patient. The other five were managed with antibiotic therapy and complete excision as the primary procedure. Cultures were obtained in five patients and were positive in four, growing Staphylococcus aureus in three and Escherichia coli in one. Significant genitourinary abnormalities were discovered in four of the five patients evaluated. It is concluded that the previously recommended therapy of incision and drainage followed by delayed resection was developed in the preantibiotic era to minimize the mortality from sepsis and the morbidity from recurrence. Our experience indicates that the use of appropriate antibiotics followed promptly by complete cyst excision as a primary procedure is both possible and safe in most cases. Furthermore, the large number of associated genitourinary abnormalities suggests that a complete work-up for these conditions should be performed.


Impact of differential copayment on patient healthcare choice: evidence from South Korean National Cohort Study.
We evaluate the effectiveness of mild disease differential copayment policy aimed at reducing unnecessary patient visits to secondary/tertiary healthcare institutions in South Korea. Retrospective study using difference-in-difference design. Sample Research database provided by the Korean National Health Insurance Service, between 2010 and 2013. 206 947 patients who visited healthcare institutions to treat mild diseases during the sample period. A linear probability model with difference-in-difference approach was adopted to estimate the changes in patients' healthcare choices associated with the differential copayment policy. The dependent variable was a binary variable denoting whether a patient visited primary healthcare or secondary/tertiary healthcare to treat her/his mild disease. Patients' individual characteristics were controlled with a fixed effect. We observed significant decrease in the proportion of patients choosing secondary/tertiary healthcare over primary healthcare by 2.99 per cent point. The decrease associated with the policy was smaller by 14% in the low-income group compared with richer population, greater by 19% among the residents of Seoul metropolitan area than among people living elsewhere, and greater among frequent healthcare visitors by 33% than among people who less frequently visit healthcare. The mild disease differential copayment policy of South Korea was successful in discouraging unnecessary visits to secondary/tertiary healthcare institutions to treat mild diseases that can be treated well in primary healthcare.


Prostaglandin E(2) suppresses staphylococcal enterotoxin-induced eosinophilia-associated cellular responses dominantly through an E-prostanoid 2-mediated pathway in nasal polyps.
Recent investigations have revealed that staphylococcal enterotoxins (SEs), COX metabolism, or both might participate in the pathogenesis of eosinophilic airway diseases, such as chronic rhinosinusitis with nasal polyposis. We sought to determine whether COX metabolism, especially prostaglandin (PG) E(2), plays a significant role in SE-induced cellular responses in nasal polyps. Dispersed nasal polyp cells (DNPCs) were prepared from nasal polyps by means of enzymatic digestion. DNPCs were cultured with SEB in the presence or absence of COX inhibitors (diclofenac and indomethacin) for 72 hours; then the levels of IL-5, IL-13, RANTES, and eotaxin in the supernatants were measured. The effect of PGE(2) on SEB-induced responses by diclofenac-treated DNPCs was examined, especially in terms of receptor specificity. DNPCs produced significant amounts of IL-5, IL-13, and RANTES in response to SEB. COX inhibitors significantly increased the production of these cytokines. The degree of local eosinophilia was significantly and positively correlated with the changes in IL-5 production induced by diclofenac treatment. PGE(2) significantly and dose-dependently inhibited SEB-induced IL-5, IL-13, and RANTES production by diclofenac-treated DNPCs. E-prostanoid (EP) 2 receptor-selective agonist strongly inhibited the production of all 3 cytokines. EP3 and EP4 receptor-selective agonists partially suppressed these responses, whereas EP1 receptor-selective agonist did not. Interestingly, all of the combined treatments with 2 of the 4 EP receptor-selective agonists significantly inhibited the SEB-induced responses by diclofenac-treated DNPCs. These results suggest that PGE(2) inhibits the pathogenesis of SEB-induced eosinophilic inflammation primarily through the EP2-mediated pathway in patients with chronic rhinosinusitis with nasal polyposis.


Ecologic study of children's use of a computer nutrition education program.
The purpose of this research was to describe the context created by students as they worked in groups on a nutrition computer-assisted instruction (CAI) program. Students worked on the program in groups of three. Observational methods were used to collect data from students in two sixth-grade classrooms that were part of an experimental program designed to restructure the educational process. Thirty-two students, from 12 groups, were observed as they completed the program. The groups were assigned by the teachers according to standard principles of cooperative learning. Students completed "Ship to Shore," a program designed specifically for this research. The program required three to five 50-minute classroom periods to complete. The objectives of the program were to change children's knowledge structure of basic nutrition concepts and to increase children's critical thinking skills related to nutrition concepts. We collected observational data focused on three domains: (1) student-computer interaction, (2) student-student interaction, and (3) students' thinking and learning skills. Grounded theory methods were used to analyze the data. Specifically, the constant-comparative method was used to develop open coding categories, defined by properties and described by dimensions. The open coding categories were in turn used in axial coding to differentiate students' learning styles. Five styles of student interaction were defined. These included (1) dominant directors (n = 6; 19%), (2) passive actors (n = 5; 16%), (3) action-oriented students (n = 7; 22%), (4) content-oriented students (n = 8; 25%), and (5) problem solvers (n = 5; 16%). The "student style" groups were somewhat gender specific. The dominant directors and passive actors were girls and the action-oriented and content-oriented students were boys. The problem solvers group was mixed gender. Children's responses to computer-based nutrition education are highly variable. Based on the results of this research, nutrition educators may recommend that nutrition CAI programs be implemented in mixed gender groups.


Improvement of tumor targeting and antitumor activity by a disulphide bond stabilized diabody expressed in Escherichia coli.
We have generated an anti-Pgp/anti-CD3 diabody which can effectively inhibit the growth of multidrug-resistant human tumors. However, the two chains of the diabody are associated non-covalently and are therefore capable of dissociation. Cysteine residues were introduced into the V-domains to promote disulphide cross-linking of the dimer as secreted by Escherichia coli. Compared with the parent diabody, the ds-Diabody obtained was more stable in human serum at 37 degrees C, without loss of affinity or cytotoxicity activity in vitro. Furthermore, the ds-Diabody showed improved tumor localization and a twofold improved antitumor activity over the parent diabody in nude mice bearing Pgp-overexpressing K562/A02 xenografts. Our data demonstrate that ds-Diabody may be more useful in therapeutic applications than the parent diabody.


High-throughput approaches for plant epigenomic studies.
In plant cells, DNA is packaged into chromatin by wrapping around histone octamers. Pathways that lead to cytosine DNA methylation, posttranslational histone modifications and certain components of the RNA interfering (RNAi) pathway are critically important in modulating chromatin structure, thereby affecting many molecular processes that take place in a cell. Recent advances in microarray and high-throughput sequencing technologies have made it possible to study these pathways on a genome-wide scale. Results from such epigenomic studies are broadening our understanding of plant genomes and are also providing important clues regarding the mechanisms and functions of these pathways that can be further tested using genetic and biochemical approaches. This review focuses on the high-throughput approaches that have been successfully applied in plant epigenomic studies.


Differing Associations between Optic Nerve Head Strains and Visual Field Loss in Patients with Normal- and High-Tension Glaucoma.
To study the associations between optic nerve head (ONH) strains under intraocular pressure (IOP) elevation with retinal sensitivity in patients with glaucoma. Clinic-based cross-sectional study. Two hundred twenty-nine patients with primary open-angle glaucoma (subdivided into 115 patients with high-tension glaucoma [HTG] and 114 patients with normal-tension glaucoma [NTG]). For 1 eye of each patient, we imaged the ONH using spectral-domain OCT under the following conditions: (1) primary gaze and (2) primary gaze with acute IOP elevation (to approximately 35 mmHg) achieved through ophthalmodynamometry. A 3-dimensional strain-mapping algorithm was applied to quantify IOP-induced ONH tissue strain (i.e., deformation) in each ONH. Strains in the prelaminar tissue (PLT), the retina, the choroid, the sclera, and the lamina cribrosa (LC) were associated (using linear regression) with measures of retinal sensitivity from the 24-2 Humphrey visual field test (Carl Zeiss Meditec). This was performed globally, then locally according to a previously published regionalization scheme. Associations between ONH strains and values of retinal sensitivity from visual field testing. For patients with HTG, we found (1) significant negative linear associations between ONH strains and retinal sensitivity (P < 0.001; on average, a 1% increase in ONH strains corresponded to a decrease in retinal sensitivity of 1.1 decibels [dB]), (2) that high-strain regions colocalized with anatomically mapped regions of high visual field loss, and (3) that the strongest negative associations were observed in the superior region and in the PLT. In contrast, for patients with NTG, no significant associations between strains and retinal sensitivity were observed except in the superotemporal region of the LC. We found significant negative associations between IOP-induced ONH strains and retinal sensitivity in a relatively large glaucoma cohort. Specifically, patients with HTG who experienced higher ONH strains were more likely to exhibit lower retinal sensitivities. Interestingly, this trend in general was less pronounced in patients with NTG, which could suggest a distinct pathophysiologic relationship between the two glaucoma subtypes.


Acute intrahepatic portal vein thrombosis complicating cholangitis in biliary atresia.
A 2-year-old boy with Kasai portoenterostomy had systemic features suggestive of cholangitis and acute portal vein obstruction. The rapid rise in portal pressure caused a transient, severe decompensation of hepatic function. A superior mesenteric arterial angiogram confirmed the presence of diffuse intrahepatic portal vein thrombosis. This case provides clinical and radiological evidence supporting an association between ascending cholangitis and acute intrahepatic portal vein thrombosis.


[Delirium, catatonia and substance withdrawal syndrome manifested as psychomotor agitation in COVID-19: a pharmacological management approach for the general hospital setting].
Neuropsychiatric symptoms can be part of the clinical spectrum of COVID-19 infections. To devise an evidence based clinical algorithm as a guide for clinicians, to identify and treat underlying clinical syndromes of psychomotor agitation, such as delirium, catatonia or substance withdrawal in patients who are hospitalized and infected with SARS-CoV-2. A review of the literature about the pharmacological management of neuropsychiatric manifestations of COVID-19 at the general hospital, to develop a clinical protocol based on a consensus from an interdisciplinary expert panel at a Clinical Hospital. A consensual clinical algorithm for the management of delirium, catatonia, and substance withdrawal, manifested as psychomotor agitation in patients hospitalized with COVID-19, was developed as a clinical proposal for physicians at different levels of complexity in health services. Cooperation among different clinical units in the general hospital facilitated the implementation of a clinical algorithm for clinicians for the management of psychomotor agitation in COVID-19 patients.


Lidocaine-prilocaine cream as analgesia for hysterosalpingography: a randomized, double blinded, controlled study.
The efficacy of lidocaine-prilocaine cream (EMLA(®)) analgesia in the practice of hysterosalpingography is controversial. This study provides new drill results and a new method of application in terms of mode, time and place. The aim of the paper is to investigate the efficacy of 5% lidocaine 25 mg-prilocaine 25 mg/g cream applied to the uterine cervix for reducing pain during hysterosalpingography. A randomized, double blinded, controlled study set in the general gynaecology clinic of a university teaching hospital between September 2012 and June 2013. One hundred successive patients programmed to undergo hysterosalpingography were randomized to either 3 ml of EMLA (50) cream or 3 ml of placebo (50), placed endocervically and exocervically, 10 min before hysterosalpingography. Patients' intensity of pain was assessed in four steps: at baseline (speculum application), after application of Pozzi tenaculum and cannula on the uterine cervix, during cervical traction and after contrast medium injection, using a 10-cm Visual Analogue Scale (VAS) immediately after the procedure. The most painful step was also identified. VAS was administered again at one-month follow-up visit. NCT01303614. The contrast medium injection was the most painful step of hysterosalpingography in both groups (EMLA 3.96, placebo 4.54, 95%CI: -0.481 to 1.641). No differences were found between the two groups (P=0.281) during this step. When comparing the VAS scale after the application of Pozzi tenaculum and cannula (EMLA 1.06, placebo 3.34, 95%CI: 1.495-3.065) and after cervical traction (EMLA 2.54, placebo 3.46, 95%CI: 0.034-1.806), significantly less pain was experienced by the EMLA group than the placebo group: P=0.000 and P=0.042, respectively. Endocervical and exocervical topical application of EMLA 10 min before performing hysterosalpingography significantly reduced pain during cervical manipulation with tenaculum and cannula and during cervical traction, but did not reduce pain during injection of contrast that was the most painful step.


Dermatologic manifestations of musicians: a case report and review of skin conditions in musicians.
Chronic practice and performance with a musical instrument predisposes musicians to several unique and characteristic dermatoses, reflecting the hours of dedication to practice to advance their artistic skill. This article briefly discusses a case of a professional musician with a unique allergic contact dermatitis to nickel sulfate and possibly palladium and cobalt chloride in his tuba. We also review several dermatologic causes and manifestations of musical instrument-related dermatitides.


A regimen to minimize pain during blue light photodynamic therapy of actinic keratoses: Bilaterally controlled, randomized trial of simultaneous versus conventional illumination.
Blue light photodynamic therapy (PDT) is effective for actinic keratosis, but many patients experience stinging pain during illumination. To compare a conventional regimen (1 hour of 5-aminolevulinic acid [ALA] preincubation, followed by blue light) versus a new modified regimen in which blue light is started immediately after ALA application. A clinical trial with a bilaterally controlled, intrapatient study design was conducted with 23 patients. Topical 20% ALA was applied to the entire face and/or scalp. On 1 side of the body, blue light was started immediately and continued for either 30, 45, or 60 minutes (simultaneous PDT). On the contralateral side, the blue light began 1 hour after ALA application and lasted 1000 seconds (conventional PDT). Pain was evaluated on a scale from 0 to 10. Actinic keratosis lesion counts were determined by clinical examination and photography. All patients experienced significantly less pain during simultaneous illumination than during the conventional regimen. At 3 months after treatment, lesion clearance was nearly identical on the 2 sides, as determined by statistical testing of noninferiority ± 15% margin. Although bilaterally controlled, the study was relatively small. Additional studies are recommended. The modified PDT regimen is essentially painless, yet it provides treatment efficacy similar to a conventional regimen.


New insights in the treatment of dyslipidemia: a focus on cardiovascular event reduction and the anti-atherosclerotic effects of atorvastatin.
The identification and treatment of dyslipidemia is a critical component of ongoing efforts to reduce the incidence of atherosclerotic disease in both men and women. Several recent large-scale atorvastatin trials provide a plethora of information that expands the current body of literature describing the pathophysiology of cardiovascular disease and the prevention of acute cardiovascular events. These trials demonstrate the benefit of statin therapy in a broad variety of patient populations, explore the clinical efficacy of more intensive statin regimens, and suggest that the pleiotropic effects of statins may contribute to cardiovascular endpoint reduction. In addition, these studies have challenged whether current guidelines for low-density lipoprotein cholesterol levels provide optimal risk reduction for cardiovascular events. Additional studies with atorvastatin are underway to further explore the extent to which statins can provide cardiovascular benefits.


Medication use among children 0-14 years old: population baseline study.
Determine the prevalence of medication use in children and adolescents in 20 municipalities of Vale do Jequitinhonha, Minas Gerais-Brazil, showing the main groups and variables that may have influenced use. Descriptive population-based survey sample of 555 interviews, selected by simple random cluster sampling of 137 census tracts. Inclusion criteria were age ≤ 14 years, mandatory interview with the legal guardians, and regardless of having received medications. Regarding the usage pattern, participants were divided into two groups: consumption and non-consumption of drugs. A descriptive analysis of the variables and tests of association were performed. The prevalence of drug consumption was 56.57%, and 42.43% showed no consumption. The use of medicinal plants was 72.9% for drug users and 74.3% for non-users. The health conditions for consumption were cough, common cold, flu, nasal congestion or bronchospasm (49.7%), fever (5.4%), headache (5.4%), diarrhea, indigestion, and abdominal colic (6.7%). In cases of self-medication, 30.57% of the drugs were given by the mother, and 69.42% were prescription drugs. Self-medication was prevalent using paracetamol (30.2%), dipyrone (20.8%), and cold medicine (18.8%). There was increased use of analgesics/antipyretics, followed by respiratory medications, systemic antibiotics, histamine H1 antagonists, and vitamins/antianemics. The prevalence of drugs use in children was high, indicating the need for formulating educational programs aiming at the awareness of caregivers regarding rational use.


Delivering on the Promise of Biosimilars.
Fifteen years of experience with biosimilar evaluation in Europe and advancement in the science behind biological medicines, provides a timely moment to open up debate as to whether the requirements for biosimilar approval could be further tailored. Further optimizing of data requirements to truly decisional information will allow to continuously deliver on the promise of biosimilars, providing benefits for patients and society.


Determination of methane emission rates on a biogas plant using data from laser absorption spectrometry.
The aim of the work was to establish a method for emission control of biogas plants especially the observation of fugitive methane emissions. The used method is in a developmental stage but the topic is crucial to environmental and economic issues. A remote sensing measurement method was adopted to determine methane emission rates of a biogas plant in Rhineland-Palatinate, Germany. An inverse dispersion model was used to deduce emission rates. This technique required one concentration measurement with an open path tunable diode laser absorption spectrometer (TDLAS) downwind and upwind the source and basic wind information, like wind speed and direction. Different operating conditions of the biogas plant occurring on the measuring day (December 2013) could be represented roughly in the results. During undisturbed operational modes the methane emission rate averaged 2.8 g/s, which corresponds to 4% of the methane gas production rate of the biogas plant.


Parafoveal processing of repeated words during reading.
In an eye-tracking experiment during reading, we examined the repetition effect, whereby words that are repeated in the same paragraph receive shorter fixation durations. Target words that were either high-frequency or low-frequency words and of which the parafoveal preview was either correct or with all letters replaced were embedded three times in the same paragraph. Shorter fixation times and higher skipping rates were observed for high-frequency compared to low-frequency words, words for which the parafoveal preview was correct versus incorrect, and as the word was being repeated more often. An interaction between frequency and repetition indicated that the reduction in fixation times due to repetition was more pronounced for low-frequency words. We also observed influences of word repetition on parafoveal processing, as repeated words were skipped more often. An interaction between parafoveal preview and repetition indicated an absent repetition effect when the preview was incorrect, but this effect was short lived, as it was restricted to the first fixation duration on the target word.


Engineering the surface structure of MoS2 to preferentially expose active edge sites for electrocatalysis.
Controlling surface structure at the atomic scale is paramount to developing effective catalysts. For example, the edge sites of MoS(2) are highly catalytically active and are thus preferred at the catalyst surface over MoS(2) basal planes, which are inert. However, thermodynamics favours the presence of the basal plane, limiting the number of active sites at the surface. Herein, we engineer the surface structure of MoS(2) to preferentially expose edge sites to effect improved catalysis by successfully synthesizing contiguous large-area thin films of a highly ordered double-gyroid MoS(2) bicontinuous network with nanoscaled pores. The high surface curvature of this catalyst mesostructure exposes a large fraction of edge sites, which, along with its high surface area, leads to excellent activity for electrocatalytic hydrogen evolution. This work elucidates how morphological control of materials at the nanoscale can significantly impact the surface structure at the atomic scale, enabling new opportunities for enhancing surface properties for catalysis and other important technological applications.


Hybrid thermionic-photovoltaic converter with graphene-on-semiconductor heterojunction anode for efficient electricity generation.
Thermionic energy converters are solid-state heat engines to produce electricity with significant potential, whereas the output voltage is constrained by the work function difference between cathode and anode. In this work, we originally apply a graphene-on-semiconductor heterojunction anode to a thermionic-photovoltaic (TIPV) converter to output additional voltage. Thermionic electrons are injected into the graphene layer and then recombined with photogenerated holes. Photogenerated electrons are extracted from the conduction band and reinjected into the cathode through an external load. A proof-of-concept demonstration of the TIPV converter is developed with barium surface-engineered cathode and anode. Open-circuit voltage is increased from ∼0.9 to ∼1.9 V by comparing with an identical configuration without graphene layer. The TIPV converter yields a power generation density of 2.7 kW/m2 with an electronic efficiency of ∼27%. This work paves the way for the development of TIPV converter toward high power density.


Use of pharmacological treatment for posttraumatic stress disorder: Analysis of a psychiatric population in Switzerland and comparison with international guidelines.
Several international guidelines for the pharmacological treatment of posttraumatic stress disorder (PTSD) have been published. However, it is unclear whether clinicians use these procedures in their daily practice. We compared the psychopharmacological prescription patterns in a Swiss adult psychiatric center with international clinical guidelines at admission and discharge. Retrospective chart review study between 2005 and 2015 of adult patients with PTSD and no other documented psychiatric comorbidity. Fifty-two outpatients and 21 inpatients were included; 47% had at least one psychopharmacological treatment at admission. Among them, 47% had one or several antidepressants, mainly escitalopram (31%, n=5) or citalopram. At discharge, 68% had at least one psychopharmacological treatment. Among them, 76% had at least one antidepressant, mainly escitalopram (34%, n=13) or mirtazapine (21%, n=8). They were compared to the guidelines of the Department of Veterans Affairs and Department of Defense (VA/DoD), showing 19% of the patients treated with antidepressants at admission were in agreement with the guidelines (sertraline, fluoxetine, paroxetine, venlafaxine), and 26% at discharge. In addition, we found prescriptions of benzodiazepines (62% at admission and 50% at discharge), antipsychotics (12% and 22%), Z-drugs (zolpidem, zopiclone: 15 and 40%) and a few pregabalin prescriptions (n=4). Clinicians in this study frequently prescribed antidepressants to treat PTSD, as recommended. However, most of the antidepressants used were not recommended in the VA/DoD guidelines. Benzodiazepines and Z-drugs remained widely used, although they are not recommended.


Macromolecular protein crystallisation with biotemplate of live cells.
Macromolecular protein crystallisation was one of the potential tools to accelerate the biomanufacturing of biopharmaceuticals. In this work, it was the first time to investigate the roles of biotemplates, Saccharomyces cerevisiae live cells, in the crystallisation processes of lysozyme, with different concentrations from 20 to 2.5 mg/mL lysozyme and different concentrations from 0 to 5.0 × 107 (cfu/mL) Saccharomyces cerevisiae cells, during a period of 96 h. During the crystallisation period, the nucleation possibility in droplets, crystal numbers, and cell growth and cell density were observed and analysed. The results indicated the strong interaction between the lysozyme molecules and the cell wall of the S. cerevisiae, proved by the crystallization of lysozyme with fluorescent labels. The biotemplates demonstrated positive influence or negative influence on the nucleation, i.e. shorter or longer induction time, dependent on the concentrations of the lysozyme and the S. cerevisiae cells, and ratios between them. In the biomanufacturing process, target proteins were various cells were commonly mixed with various cells, and this work provides novel insights of new design and application of live cells as biotemplates for purification of macromolecules.


An initial investigation of a wireless patient radiation dosimeter for use in interventional radiology.
Radiation exposure during interventional radiology (IR) procedures is a critical issue. We have developed a wireless real-time dosimeter for IR patients that use nontoxic phosphor (four sensors). We evaluated the basic performance parameters (such as dose linearity, batch uniformity, reproducibility, and wireless-communication conditions) of the developed system using an IR X-ray system. Further, we investigated the influence of noise from other medical equipment on our wireless real-time dosimeter in the IR X-ray room. Overall, our wireless system exhibited excellent performance in terms of uniformity, reproducibility, and linearity; moreover, the wireless communication performance was better. The developed system enabled real-time visualization of patient radiation dose, without noise contamination from other medical equipment. In addition, the wireless system can be easily installed in a location where the PC screen (display) can be readily viewed by the IR physician. Hence, we developed a wireless system that can display the patient radiation dose data in real time; the system performed satisfactorily upon application in radiation dosimetry. Therefore, our wireless system will facilitate the real-time monitoring/management of patient radiation dose during IR.


Metastatic NSCLC: Clinical, molecular, and therapeutic factors associated with long-term survival.
Patients with metastatic non-small-cell lung cancer (NSCLC) who survive more than 2 years are considered long-term survivors (LTSs). The present study examined factors associated with long-term survival and collected information for future comparison. Clinical, molecular, and therapeutic data were collected from patients followed for primary stage IV (7th TNM classification) NSCLC within 2 years from diagnosis in the respiratory medicine departments of 53 French non-teaching hospitals. LTS and non-LTS records were compared. Factors associated with long-term survival were examined by univariate and multivariate analyses using logistic regression models. Vital status at least 2 years after diagnosis was known for 1977 stage IV NSCLC patients; 220 (11.1%) were LTSs. On multivariate analysis, independent positive factors comprised: TTF-1(+) immunochemistry, EGFR-mutation, surgery, rescue radiotherapy, and targeted therapy. Independent negative factors comprised: prediagnosis weight loss>5kg, ECOG performance status>1, and primary radiotherapy. Molecular biology and targeted therapy were decisive for long-term survival. With their development and their widespread implementation in clinical practice, the percentage of LTSs is expected to grow. Factors determining long-term survival found in this study should be taken into account when considering treatment options for patients with stage IV NSCLC.


In Vitro Analysis of N-Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions.
A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies. To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels. One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method. NDMA detected in simulated gastric fluid 2 hours after adding ranitidine. At a supraphysiologic nitrite concentration (ie, 10 000 μmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L). In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.


On pre-messenger RNA and transcriptions. A review.
From the present review integrating old and new data emerge a few principles of gene expression in eukaryotes, and an infinite variety of possible mechanistic details generating the overal pattern. The few principles, most of which are not fundamentally new, may thus be summarized. 1) The eukaryotic genome is subdivided into transcriptional units: into transcriptons which are subject to individual activation controlled at DNA level. 2) Viral genomes may contain one or a few transcriptons, while cells of multicellular organisms contain from 3 x 10(3) in diptera up to an estimated 2 x 10(5) in birds and mammals. 3) Transcriptons may include one or several coding sequences. 4) Transcriptons vary considerably in size: in mammals and birds their size spectrum falls into the 2,000 to 20,000 bp range. 5) Units of coding information constituting one message (genes) and, possibly, units of regulative information are frequently broken up and stored within the transcripton in sub-genic blocks (of so far unknown significance) in general located at a certain distance from the 5' and 3' transcript terminals which are determined by the promotor and terminator signals. 6) The gene, in its specific definition as the functional unit underlying the phenotype, is in general constituted posttranscriptionally by the processing mechanisms from the mosaic of its genomic subunits in the transcripton; segments of coding, service and regulative sequences are recombined within themselves and with each other, polygenic transcripts separate into their unit messages. 7) Activated transcriptons produce pre-mRNA; these primary transcripts are colinear with the DNA of the transcriptional unit. 8) Primary pre-mRNA is processed into secondary pre-mRNA's by extragenic cleavage and intragenic ("splicing") processing, giving rise stepwise to functional mRNA. During this process chemical modifications as methylation, 5'-terminal capping and 3'-terminal polyadenylation take place. 9) Translation yields either potentially functional polypeptides or polycistronic polyproteins subject to further processing. 10) Processing is a regulated process; it involves many of the possible phases and mechanisms of post-transcriptional regulation (cf. 39, 40).


Luminal Ca(2+) activation of cardiac ryanodine receptors by luminal and cytoplasmic domains.
The ryanodine receptors form the calcium release channel in the membrane of the sarcoplasmic reticulum (SR, the main intracellular Ca(2+) store). The importance of ryanodine receptors (RyRs) to cardiac pacemaking and rhythmicity is highlighted by more than 69 mutations, RyR mutations, which underlie arrhythmias and sudden cardiac death. Although most of these mutations lie in cytoplasmic domains, they all cause increased RyR activation by Ca(2+) in the SR lumen. Presented here is a review of the mechanisms by which cytoplasmic domains of the RyR can determine luminal activation.


If the prophet does not come to the mountain: dynamics of signaling complexes in NF-kappaB activation.
Recruitment of the NF-kappaB-activating IKK signaling complex to the TNF receptor is shown to be driven by induced binding of NEMO, a regulatory component of this complex, to K63-linked polyubiquitin chains attached to RIP1, a receptor-associated adaptor protein (Ea et al., 2006 [in a recent issue of Molecular Cell]; Li et al., 2006; Wu et al., 2006a).


Role of N6-methyladenosine modification in central nervous system diseases and related therapeutic agents.
N6-methyladenosine (m6A) is a ubiquitous mRNA modification in eukaryotes. m6A occurs through the action of methyltransferases, demethylases, and methylation-binding proteins. m6A methylation of RNA is associated with various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), depression, cerebral apoplexy, brain injury, epilepsy, cerebral arteriovenous malformations, and glioma. Furthermore, recent studies report that m6A-related drugs have attracted considerable concerns in the therapeutic areas of neurological disorders. Here, we mainly summarized the role of m6A modification in neurological diseases and the therapeutic potential of m6A-related drugs. The aim of this review is expected to be useful to systematically assess m6A as a new potential biomarker and develop innovative modulators of m6A for the amelioration and treatment of neurological disorders.


The Heart Failure Survival Score outperforms the peak oxygen consumption for heart transplantation selection in the era of device therapy.
The peak oxygen consumption (VO(2)) and the Heart Failure Survival Score (HFSS) risk stratify patients with chronic heart failure (CHF) referred for heart transplantation. However, these tools were developed before widespread use of implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT). The prognostic accuracy of these tools in patients with ICD and/or CRT is unknown. Cardiopulmonary exercise testing with measurement of peak VO(2) and calculation of the HFSS was done in 715 CHF patients (54 ± 12 years; ICD, 244; CRT, 30; CRT-D, 108; none, 333) referred for heart transplantation. During an average follow-up of 962 ± 912 days, 354 patients died or received urgent heart transplant or left ventricular assist device. By Cox hazard analysis, both peak VO(2) and HFSS were powerful independent prognostic markers. By Kaplan-Meier analysis, the HFSS was effective in discriminating patients into low-, medium-, and high-risk groups in all device groups. In contrast, the peak VO(2) did not discriminate between low (>14 ml/min/kg) and medium (10.1 to 14 ml/min/kg) risk in device patients. By area under the receiver operating characteristic curve, the HFSS performed better than the peak VO(2) (1-year in total cohort; 0.72 vs. 0.65; p < 0.001; 1-year in device patients; 0.69 vs. 0.65; p < 0.001). The HFSS outperforms the peak VO(2) in risk stratification for CHF in the presence of an ICD and/or CRT. Furthermore, a peak VO(2) ≤ 10 ml/kg/min rather than the traditional cutoff value ≤ 14 ml/min/kg may be more useful for risk stratification in the device era.


Genetic and Functional Identifying of Novel STAT1 Loss-of-Function Mutations in Patients with Diverse Clinical Phenotypes.
Mutations in signal transducer and activator of transcription 1 (STAT1) cause a broad spectrum of disease phenotypes. Heterozygous STAT1 loss-of-function (LOF) mutations cause Mendelian susceptibility to mycobacterial diseases (MSMD) infection, which is attributable to impaired IFN-γ signaling. The identification of novel mutations may extend the phenotypes associated with autosomal dominant (AD) STAT1 deficiency. Five patients with heterozygous STAT1 variations were recruited and their clinical and immunologic phenotypes were analyzed, with particular reference to JAK-STAT1 signaling pathways. Four, heterozygous STAT1 deficiency mutations were identified, three of which were novel mutations. Two of the mutations were previously unreported mRNA splicing mutations in AD STAT1-deficient patients. Patients with heterozygous STAT1 deficiency suffered not only mycobacterial infection, but also intracellular non-mycobacterial bacterial infection and congenital multiple malformations. AD-LOF mutation impaired IFN-γ-mediated STAT1 phosphorylation, gamma-activated sequence (GAS), and IFN-stimulated response element (ISRE) transcription activity and IFN-induced gene expression to different extents, which might account for the diverse clinical manifestations observed in these patients. The infectious disease susceptibility and phenotypic spectrum of patients with AD STAT1-LOF are broader than simply MSMD. The susceptibility to infections and immunological deficiency phenotypes, observed in AD-LOF patients, confirms the importance of STAT1 in host-pathogen interaction and immunity. However, variability in the nature and extent of these phenotypes suggests that functional analysis is required to identify accurately novel, heterozygous STAT1 mutations, associated with pathogenicity. Aberrant splice of STAT1 RNA could result in AD-LOF for STAT1 signaling which need more cases for confirmation.


Hepatitis B core-based virus-like particles: A platform for vaccine development in plants.
Virus-like particles (VLPs) are a class of structures formed by the self-assembly of viral capsid protein subunits and contain no infective viral genetic material. The Hepatitis B core (HBc) antigen is capable of assembling into VLPs that can elicit strong immune responses and has been licensed as a commercial vaccine against Hepatitis B. The HBc VLPs have also been employed as a platform for the presentation of foreign epitopes to the immune system and have been used to develop vaccines against, for example, influenza A and Foot-and-mouth disease. Plant expression systems are rapid, scalable and safe, and are capable of providing correct post-translational modifications and reducing upstream production costs. The production of HBc-based virus-like particles in plants would thus greatly increase the efficiency of vaccine production. This review investigates the application of plant-based HBc VLP as a platform for vaccine production.


Corrigendum: A single vaccination of nucleoside-modified Rabies mRNA vaccine induces prolonged highly protective immune responses in mice.
[This corrects the article DOI: 10.3389/fimmu.2022.1099991.].


Need for a unified decision-making tool for ultrafiltration therapy in heart failure; call for action.
Although ultrafiltration portends several theoretical advantages over the standard therapy for acute decompensated heart failure, it might not be the optimal treatment for all patients presenting with an episode of decompensation. It is not yet clear how to prospectively identify the subset of patients that would benefit from this therapeutic modality. Based on the pathophysiologic mechanisms underlying acute decompensated heart failure, early ultrafiltration therapy can be an appropriate initial management strategy for those patients with diuretic resistance whose associated renal dysfunction is related to hemodynamic changes rather than a structural abnormality. In the absence of widely accepted consensus guidelines, ultrafiltration use is currently subject to considerable variations among physicians. A clinical tool (eg, a scoring system) that is based on the individual patient's characteristics is therefore needed to prospectively identify the appropriate candidates for this therapy. Using this system is likely to portend better outcomes while helping to avoid unnecessary exposure to potential risks of extracorporeal therapies.


Growth rates of Dekkera/Brettanomyces yeasts hinder their ability to compete with Saccharomyces cerevisiae in batch corn mash fermentations.
Growth rates determined by linear regression analysis revealed that Saccharomyces cerevisiae consistently grew more rapidly than Brettanomyces yeasts under a wide array of batch fermentative conditions, including acetic acid stress, in normal gravity (ca. 20 degrees Plato) mashes made from ground corn. Brettanomyces yeasts only grew more rapidly than S. cerevisiae when acetic acid concentrations were elevated to industrially irrelevant levels (>0.45%, w/v). Furthermore, the three Brettanomyces isolates used in this study failed to produce significant quantities of acetic acid under pure culture fermentative conditions. In fact, the small amounts of acetic acid which accumulated in pure culture fermentations of whole corn mash were below the concentration required to inhibit the growth and metabolism of S. cerevisiae. Acetic acid concentrations in pure culture Brettanomyces fermentations exceeded 0.05% (w/v) only in media containing low levels of glucose (<4%, w/v) or when aeration rates were elevated to at least 0.03 vol. air vol.-1 mash min-1. Consequently, it was concluded that Brettanomyces yeasts would not be capable of competing with S. cerevisiae in industrial batch fermentations of whole corn mash based solely on growth rates, nor would they be capable of producing inhibitory concentrations of acetic acid in such fermentations.