Conservative long-term treatment of children with eosinophilic esophagitis.
Current treatments of eosinophilic esophagitis (EoE), including restrictive diets or glucocorticoids, provide only transient improvement. Proton pump inhibitor (PPI) use in EoE does not lead to histologic improvement; however, the long-term use of PPI on symptoms and prevention of complications has not been evaluated. To evaluate the use of PPI as maintenance therapy in children with EoE. Eosinophilic esophagitis was diagnosed based on initial endoscopic biopsies and persistent eosinophilic inflammation despite PPI therapy. Inclusion criteria included diagnosis of EoE and PPI use as primary maintenance treatment. Patients were excluded if they were treated with dietary or glucocorticoid therapy. Histologic evidence of inflammation as well as degree of subepithelial fibrosis at presentation was compared with most recent biopsies while receiving PPI therapy. Thirty-eight patients (30 males and 8 females; average age 6.7 ± 5.4 years) fulfilled inclusion criteria. Duration of follow-up was 3.0 ± 2.4 years. At presentation, vomiting was significantly more frequent in the younger patients, whereas dysphagia occurred more frequently in the older patients. At follow-up, 26 patients were asymptomatic, and the remaining 12 patients' symptoms were significantly improved. No complications of stricture or food impaction were seen. Significant eosinophilic inflammation persisted in 28 patients. No difference in degree of subepithelial fibrosis at diagnosis compared with most recent biopsies. The z-scores of the treated EoE patients significantly improved. Patients with EoE treated with PPIs show an improvement in symptoms and z-scores despite persistent eosinophilic inflammation. PPI treatment may be useful maintenance therapy in children with EoE.


Correction of heat-induced susceptibility changes in respiratory-triggered 2D-PRF-based thermometry for monitoring of magnetic resonance-guided hepatic microwave ablation in a human-like in vivo porcine model.
To develop and evaluate susceptibility corrected 2D proton resonance frequency (PRF)-based magnetic resonance (MR)-thermometry for the accurate assessment of the ablation zone of hepatic microwave ablation (MWA). Twelve hepatic MWA were performed in five LEWE minipigs with human-like fissure-free liver. Temperature maps during ablation of PRF-based MR-thermometry were corrected by modeling heat induced susceptibility changes. Ablation zones were determined using cumulative equivalent minutes at 43 °C (CEM43) as tissue damage model. T1 weighted (w) post-ablation contrast-enhanced (CE) MR-imaging and manually segmented postmortem histology were used for validation. The agreement of uncorrected (raw) and susceptibility corrected (corr) MR-thermometry with T1w post-ablation CE MR-imaging and histology was evaluated. The Wilcoxon-signed rank test and Bland-Altman analysis were applied. With the susceptibility corrected MR-thermometry a significantly increased dice coefficient (raw: 77% vs. corr: 83%, p < 0.01) and sensitivity (raw: 72% vs. corr: 82%, p < 0.01) was found for the comparison to T1w-CE imaging as well as histopathology (dice coefficients: raw: 76% vs. corr: 79%, p < 0.001; sensitivity: raw: 72% vs. corr: 74%, p < 0.001). While major axis length was significantly increased (7.1 mm, p < 0.001) and minor axis length significantly decreased (2.2 mm, p < 0.001) in uncorrected MR-thermometry compared to T1w-CE MR-imaging, no significant bias was found after susceptibility correction. Using susceptibility corrected 2D PRF-based MR-thermometry to predict the ablation zones of hepatic MWA provided a good agreement in comparison to T1w post-ablation CE MR-imaging and histopathology.


Acute post-cardiopulmonary bypass left atrial thrombosis after mitral valvuloplasty and left atrial thrombectomy.
A patient with mitral stenosis and multiple left atrial thrombi underwent valvuloplasty and thrombectomy. While closing the sternum after completing the cardiopulmonary bypass, a new left atrial thrombus was detected by transesophageal echocardiography. We used heparin for the prevention of new thrombus formation and closed the wound after meticulous bleeding control. Three months later, there was no residual thrombus in the left atrium according to the echocardiographic study.


Genetic and biochemical findings in Chinese children with Leigh syndrome.
This study investigated the genetic and enzymological features of Leigh syndrome due to respiratory chain complex deficiency in Chinese patients. The clinical features of 75 patients were recorded. Mitochondrial respiratory chain enzyme activities were determined via spectrophotometry. Mitochondrial gene sequence analysis was performed in 23 patients. Five core pedigrees were investigated via restriction fragment length polymorphism and gene sequencing. Psychomotor retardation (55%), motor regression (20%), weakness (29%), and epilepsy (25%) were the most frequent manifestations. Sixty-four patients (85.3%) had isolated respiratory complex deficiencies: complex I was seen in 28 patients (37.3%); complex II, seven (9.3%); complex III, six (8%); complex IV, ten (13.3%); and complex V, 13 patients (17.3%). Eleven patients (14.7%) had combined complex deficiencies. Mitochondrial DNA mutations were detected in 10 patients. Eight point mutations were found in mitochondrial structural genes: m.4833A>G in ND2, m.10191T>C in ND3, m.12338T>C and m.13513G>A in ND5, m.14502T>C and m.14487T>C in ND6, m.8108A>G in COXII, and m.8993T>G in ATPase6. Three mutations were found in tRNA genes: m.4395A>G in tRNA-Gln, m.10454T>C in tRNA-Arg, and m.5587T>C in tRNA-Ala. One patient and their mother both had the m.12338T>C and m.8993T>C mutations. In conclusion, mitochondrial respiratory chain complex I deficiency and structural gene mutations frequently occur in Chinese Leigh syndrome patients.


Influence of agitation methods of irrigants after methylene blue-mediated PDT on the bonding interface of a fiber post cementation system.
This study evaluated the effects of final agitation methods of irrigants to remove methylene blue and sodium hypochlorite residues after PDT-assisted endodontic treatment on the bond strength of fiber posts cemented with etch-and-rinse adhesive and conventional resin cement. Ninety bovine teeth were endodontically treated. In sequence, post space preparation followed by methylene blue-mediated PDT and sodium hypochlorite (NaOCl) irrigation were performed. Six final irrigations protocols for dye and NaOCl removal were performed prior to cementation with etch-and-rinse adhesive (Adper Scocthbond Multipurpose) and conventional dual resin cement (RelyX ARC): Conventional endodontic irrigation (CEI), passive ultrasonic irrigation (PUI), mechanical agitation with XP Endo Finisher (XPF), XP Clean (XPC) or Easy Clean (ECL) and distilled water (NCO - control). After fiber post cementation, push-out bond strength test was performed at different thirds of the post space. Failure mode was also analyzed. ANOVA and Tukey's post-hoc test was used for data analysis (α=5%). PUI, XPF e XPC protocols showed the highest bond strength values with no difference among them (p > 0.05), although they were similar to NCO, regardless of the post space third. CEI e ECL showed similar bond strength values, regardless of the third (p > 0.05). Adhesive failure was the most incident for CEI and ECL, while mixed and cohesive failures were predominant in PUI, XPF, XPC and NCO groups. Mechanical agitation of distilled water with XPF, XPC and PUI after methylene blue-mediated PDT and irrigation with 2.5% sodium hypochlorite promoted bond strength of the resin cementation system in post space dentin comparable to control group.


Cytotoxicity of HBD3 for dendritic cells, normal human epidermal keratinocytes, hTERT keratinocytes, and primary oral gingival epithelial keratinocytes in cell culture conditions.
Human β-defensin 3 (HBD3) is a prominent host defense peptide. In our recent work, we observed that HBD3 modulates pro-inflammatory agonist-induced chemokine and cytokine responses in human myeloid dendritic cells (DCs), often at 20.0 μM concentrations. Since HBD3 can be cytotoxic in some circumstances, it is necessary to assess its cytotoxicity for DCs, normal human epidermal keratinocytes (NHEKs), human telomerase reverse transcriptase (hTERT) keratinocytes, and primary oral gingival epithelial (GE) keratinocytes in different cell culture conditions. Cells, in serum free media with resazurin and in complete media with 10% fetal bovine serum and resazurin, were incubated with 5, 10, 20, and 40 μM HBD3. Cytotoxicity was determined by measuring metabolic conversion of resazurin to resorufin. The lethal dose 50 (LD50, mean μM±Std Err) values were determined from the median fluorescent intensities of test concentrations compared to live and killed cell controls. The LD50 value range of HBD3 was 18.2-35.9 μM in serum-free media for DCs, NHEKs, hTERT keratinocytes, and GE keratinocytes, and >40.0 μM in complete media. Thus, HBD3 was cytotoxic at higher concentrations, which must be considered in future studies of HBD3-modulated chemokine and cytokine responses in vitro.


Electronic cigarette use and its association with asthma, chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap syndrome among never cigarette smokers.
Although smoking is a strong risk factor for lung diseases including asthma, COPD, and asthma-COPD overlap syndrome (ACOS), studies are needed to examine the association between e-cigarettes and asthma, COPD, and ACOS. This study evaluated the association between e-cigarette use and self-reported diagnosis of asthma, COPD, and ACOS using a large nationally representative sample of adults aged ≥18 years in the United States. Cross-sectional data from the Behavioral Risk Factor Surveillance System (BRFSS) from 2016 to 2018 were used to examine self-reported information on current e-cigarette use, demographic variables, and asthma and COPD status among never cigarette smokers (n=8736). Asthma and COPD were measured by self-reported diagnosis, and respondents who reported having both diagnoses were then classified as having ACOS. Of the 469077 never cigarette smokers, 4368 non-e-cigarette users were 1:1 propensity score-matched to e-cigarette users on age, sex, race/ethnicity and education level. We used multinomial logistic regression to examine association between current e-cigarette use and self-report asthma, COPD, and ACOS while controlling for marital status and employment in addition to matching variables. Compared with never e-cigarette users, e-cigarette users had increased odds of self-reported ACOS (OR=2.27; 95% CI: 2.23-2.31), asthma (OR=1.26; 95% CI: 1.25-1.27) and COPD (OR=1.44; 95% CI: 1.42-1.46). Our findings suggest that e-cigarette use is associated with an increased odds of self-reported asthma, COPD, and ACOS among never combustible cigarette smokers. BRFSS provides cross-sectional survey data, therefore a causal relationship between e-cigarette use and the three lung diseases cannot be evaluated. Future longitudinal studies are needed to validate these findings.


Ultrasound-guided microwave ablation versus surgery for solitary T1bN0M0 papillary thyroid carcinoma: a prospective multicenter study.
Microwave ablation (MWA) has emerged as a minimally invasive technology for papillary thyroid microcarcinoma (PTMC), but it has not been widely applied to treat T1bN0M0 PTC with high-level evidence. This study was designed to compare the real-world efficacy and safety of MWA or surgery for treating T1bN0M0 PTC. From December 2019 to April 2021, 123 continuous unifocal T1bN0M0 PTC patients without lymph node metastasis (LNM) or distant metastasis (DM) were included from 10 hospitals. Patients were allocated into the MWA or surgery group based on their willingness. The main outcomes were local tumour progression (LTP), new thyroid cancer, LNM, and DM. The secondary outcomes included changes in tumour size and volume, complications, and cosmetic results. Subgroup analyses were conducted to identify influencing factors. Fifty-two patients chose MWA, and 71 patients chose surgery. Patients had similar demographic information and tumour characteristics in the two groups. The follow-up durations after MWA and surgery were 10.6 ± 4.2 and 10.4 ± 3.4 months, respectively. The LNM rate was 5.8% in the MWA group and 1.4% in the surgery group (p = 0.177). No LTP, new thyroid cancer, or distant metastasis (DM) occurred in either group. Five (9.6%) of the 52 patients in the MWA group and 8 (11.3%) of the 71 patients in the surgery group had complications (p = 0.27). Better cosmetic results were found in the MWA group (p < 0.01). MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. MWA achieved comparable short-time treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC. • MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. • The complication rate in the surgery group was higher than that in the MWA group without a significant difference. • There was no statistically significant difference in the LNM rate between the MWA and surgery groups.


Two new species of Cyrtodactylus (Squamata: Gekkonidae) from the Southern Bukit Barisan Range of Sumatra and an estimation of their phylogeny.
We describe Cyrtodactylus psarops sp. nov. and C. semicinctus sp. nov., two new species of bent-toed geckos from montane forests in the southern Bukit Barisan Range of Sumatra, Indonesia. The new species are closely related to one another and to C. semenanjungensis, a lowland species currently known only from Peninsular Malaysia. Three characters of the new species immediately distinguish them from most congeners in the Sunda Region: they lack transversely enlarged subcaudals, have a precloacal depression, and have a greatly enlarged scale positioned at the apex of a continuous series of femoral and precloacal pore-bearing scales. They differ from one another in cephalic pattern, tuberculation of the brachium, and in numbers of cloacal tubercles, dorsal bands, and ventrals in a transverse row. The greatly enlarged scale at the apex of the precloacal pores appears to be a rare apomorphy of these two species and C. agamensis.


Polymorphisms in the interleukin genes and chronic periodontitis: A field synopsis and revaluation by Bayesian approaches.
Periodontitis is a high prevalent disease into the clinical dentistry. Genetic variations in interleukins (IL) genes were associated with chronic periodontitis (CP) and were focus of several meta-analyses. This study aimed to assess the noteworthiness in the meta-analyses by means of a Bayesian approach to determinate possible false report associations. A systematic search was performed for meta-analyses with associations between gene polymorphisms in interleukins and CP. The calculations for the False-Positive Rate Probability (FPRP) and the Bayesian False Discovery Probability (BFDP) were performed to assess the noteworthiness with a statistical power of 1.2 and 1.5 of Odds Ratio at a prior probability of 10-3 and 10-6. As results, eight meta-analyses approaching the IL1A/rs1800587, IL1B/rs1143634, IL1RN/rs2234663, IL4/rs2243250, IL6/rs1800795/rs1800796, IL17A/rs2275913 and IL18/rs1946518/rs187238 polymorphisms have been identified. Twenty-two from 270 calculations (8.15%) were noteworthy. Herein, we have identified the IL1A and IL1B polymorphisms as noteworthy biomarkers for CP susceptibility.


Mesenchymal Stem Cell Homing Into Intervertebral Discs Enhances the Tie2-positive Progenitor Cell Population, Prevents Cell Death, and Induces a Proliferative Response.
Experimental study with human mesenchymal stem cells (MSCs) and intervertebral disc (IVD) tissue samples. This study aimed to characterize the effect of MSC homing on the Tie2-positive IVD progenitor cell population, IVD cell survival, and proliferation. Homing of human MSCs has been described as potential alternative to MSC injection, aiming to enhance the regenerative capacity of the IVD. IVD cells expressing Tie2 (also known as CD202b or Angiopoietin-1 receptor TEK tyrosine kinase) represent a progenitor cell population with discogenic differentiation potential. However, the fraction of Tie2-positive progenitor cells decreases with aging and degree of IVD degeneration, resulting in a potential loss of the IVD's regenerative capacity. Human MSCs, isolated from vertebral bone marrow aspirates, were labeled and seeded onto the endplate of bovine IVDs and human IVD tissue. Following MSC migration for 5 days, IVD cells were isolated by tissue digestion. The fractions of Tie2-positive, dead, apoptotic, and proliferative IVD cells were evaluated by flow cytometry and compared to untreated IVDs. For human IVDs, 3 groups were investigated: nondegenerated (organ donors), IVDs of patients suffering from spinal trauma, and degenerative IVD tissue samples. MSC homing enhanced the fraction of Tie2-positive IVD cells in bovine and human IVD samples. Furthermore, a proliferative response and lower fraction of dead cells were observed after MSC homing in both bovine and human IVD tissues. Our findings indicate that MSC homing enhances the survival and regenerative capability of IVD cells, which may be mediated by intercellular communication. MSC homing could represent a potential treatment strategy to prevent the onset of the degenerative cascade in IVDs at risk such as IVDs adjacent to a fused segment or IVDs after herniation. N/A.


Overview of contraception.
The United States has the highest rates of adolescent pregnancy of any Western industrialized country. Addressing these high rates and preventing adolescent pregnancy are complicated tasks. This article addresses some of the issues involved with preventing adolescent pregnancy, focusing on contraception.


Fetal MRI of the heart and brain in congenital heart disease.
Antenatal assessment of congenital heart disease and associated anomalies by ultrasound has improved perinatal care. Fetal cardiovascular MRI and fetal brain MRI are rapidly evolving for fetal diagnostic testing of congenital heart disease. We give an overview on the use of fetal cardiovascular MRI and fetal brain MRI in congenital heart disease, focusing on the current applications and diagnostic yield of structural and functional imaging during pregnancy. Fetal cardiovascular MRI in congenital heart disease is a promising supplementary imaging method to echocardiography for the diagnosis of antenatal congenital heart disease in weeks 30-40 of pregnancy. Concomitant fetal brain MRI is superior to brain ultrasound to show the complex relationship between fetal haemodynamics in congenital heart disease and brain development.


Optimized multi-stage designs controlling the false discovery or the family-wise error rate.
When a large number of hypotheses are investigated, we propose multi-stage designs where in each interim analysis promising hypotheses are screened, which are investigated in further stages. Given a fixed overall number of observations, this allows one to spend more observations for promising hypotheses than with single-stage designs, where the observations are equally distributed among all considered hypotheses. We propose multi-stage procedures controlling either the family-wise error rate (FWER) or the false discovery rate (FDR) and derive asymptotically optimal stopping boundaries and sample size allocations (across stages) to maximize the power of the procedure. Optimized two-stage designs lead to a considerable increase in power compared with the classical single-stage design. Going from two to three stages additionally leads to a distinctive increase in power. Adding a fourth stage leads to a further improvement, which is, however, less pronounced. Surprisingly, we found only small differences in power between optimized integrated designs, where the data of all stages are used in the final test statistics, and optimized pilot designs where only the data from the final stage are used for testing. However, the integrated design controlling the FDR appeared to be more robust against misspecifications in the planning phase. Additionally, we found that with increasing number of stages the drop in power when controlling the FWER instead of the FDR becomes negligible. Our investigations show that the crucial point is not the choice of the error rate or the type of design, but the sequential nature of the trial where non-promising hypotheses are dropped in the early phases of the experiment.


Cadence (steps/min) as an indicator of the walk-to-run transition.
Humans naturally transition from walking to running at a point known as the walk-to-run transition (WRT). The WRT commonly occurs at a speed of ∼2.1 m/s (m/s) or a Froude number (dimensionless value considering leg length) of 0.5. Emerging evidence suggests the WRT can also be classified using a cadence of 140 steps/min. An accurate cadence-based WRT metric would aid in classifying wearable technology minute-level step metrics as walking vs. running. To evaluate performance of 1) WRT predictors directly identified from a treadmill-based dataset of sequentially faster bouts, and 2) accepted WRT predictors compiled from previous literature. Twenty-eight adults (71.4% men; age = 36.6 ± 12.8 years, BMI = 26.2 ± 4.7 kg/m2) completed a series of five-minute treadmill walking bouts increasing in 0.2 m/s increments until they freely chose to run. Optimal WRT values for speed, Froude number, and cadence were identified using receiver operating characteristic (ROC) curve analyses. WRT value performance was evaluated via classification accuracy metrics. Overall accuracies (metric, percent) according to WRT predictors from previous literature were: speed (2.1 m/s, 55.0%), Froude number (0.5, 76.8%), and cadence (140 steps/min, 91.1%), and those from the dataset herein were: speed (1.9 and 2.0 m/s, 78.6%), Froude number (0.68, 77.3%), and cadence (134, 139, and 141 steps/min, 92.9%). The three equally accurate cadence values support a heuristic range of cadence-based WRT values in young and middle-aged adults: 135-140 steps/min. A tight range of cadence values performed better as WRT predictors compared to either previously reported or directly identified speed or Froude number values. These findings have important implications for gait classification, especially considering cadence is a simple metric which can be readily assessed across settings using direct observation or wearable technologies.


Subcellular distribution and biosynthesis of rat liver gangliosides.
Gangliosides have generally been assumed to be localized primarily in the plasma membrane. Analysis of gangliosides from isolated subcellular membrane fractions of rat liver indicated that 76% of the total ganglioside sialic acid was present in the plasma membrane. Mitochondria and endoplasmic reticulum fractions, while containing only low levels of gangliosides on a protein basis, each contained approx. 10% of total ganglioside sialic acid. Gangliosides also were present in the Golgi apparatus and nuclear membrane fractions, and soluble gangliosides were in the supernatant. Individual gangliosides were non-homogeneously distributed and each membrane fraction was characterized by a unique ganglioside composition. Plasma membrane contained only 14 and 28% of the total GD1a and GD3, respectively, but 80-90% of the GM1, GD1b, GT1b and GQ1b. Endoplasmic reticulum, when corrected for plasma membrane contamination, contained only trace amounts of GM1, GD1b, GT1b and GQ1b, but 11 and 5% of the total GD1a and GD3, respectively. The ganglioside composition of highly purified endoplasmic reticulum was similar. Ganglioside biosynthetic enzymes were concentrated in the Golgi apparatus. However, low levels of these enzymes were present in the highly purified endoplasmic reticulum fractions. Pulse-chase experiments with [3H]galactose revealed that total gangliosides were labeled first in the Golgi apparatus, mitochondria and supernatant within 10 min. Labeled gangliosides were next observed at 30 min in the endoplasmic reticulum, plasma membrane and nuclear membrane fractions. Analysis of the individual gangliosides also revealed that GM3, GM1, GD1a and GD1b were labeled first in the Golgi apparatus at 10 min. These studies indicate that gangliosides synthesized in the Golgi apparatus may be transported not only to the plasma membrane, but to the endoplasmic reticulum and to other internal endomembranes as well.


WRKY transcription factors in plant defense.
Environmental stressors caused by climate change are fundamental barriers to agricultural sustainability. Enhancing the stress resilience of crops is a key strategy in achieving global food security. Plants perceive adverse environmental conditions and initiate signaling pathways to activate precise responses that contribute to their survival. WRKY transcription factors (TFs) are essential players in several signaling cascades and regulatory networks that have crucial implications for defense responses in plants. This review summarizes advances in research concerning how WRKY TFs mediate various signaling cascades and metabolic adjustments as well as how epigenetic modifications involved in environmental stress responses in plants can modulate WRKYs and/or their downstream genes. Emerging research shows that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-mediated genome editing of WRKYs could be used to improve crop resilience.


Role of dendritic cells in MYD88-mediated immune recognition and osteoinduction initiated by the implantation of biomaterials.
Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects. Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials. Previous studies have mainly focused on innate immune cells such as macrophages. In our previous work, we found that T lymphocytes, as adaptive immune cells, are also essential in the osteoinduction procedure. As the most important antigen-presenting cell, whether dendritic cells (DCs) can recognize non-antigen biomaterials and participate in osteoinduction was still unclear. In this study, we found that surgical trauma associated with materials implantation induces necrocytosis, and this causes the release of high mobility group protein-1 (HMGB1), which is adsorbed on the surface of bone substitute materials. Subsequently, HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells, and the inflammatory response was activated. Finally, activated DCs release regeneration-related chemokines, recruit mesenchymal stem cells, and initiate the osteoinduction process. This study sheds light on the immune-regeneration process after bone substitute materials implantation, points out a potential direction for the development of bone substitute materials, and provides guidance for the development of clinical surgical methods.


Allocating leaf nitrogen for the maximization of carbon gain: Leaf age as a control on the allocation program.
Simulations using a biochemically-based model of leaf photosynthesis make it possible to predict the distribution of leaf nitrogen contents that maximizes photosynthetic carbon gain over the canopy of an entire plant. In general, the optimal nitrogen content increased with increasing daily photosynthetically active photon irradiance.Leaf aging in natural environments tended to produce leaf nitrogen contents that were similar to the optimal values but somewhat more clustered. Nitrogen redistribution over the duration of a leaf involves costs that are smaller than the benefits in increased photosynthesis. The costs could become larger than the benefits if nitrogen were redistributed on a shorter time scale.


Message passing on networks with loops.
Message passing is a fundamental technique for performing calculations on networks and graphs with applications in physics, computer science, statistics, and machine learning, including Bayesian inference, spin models, satisfiability, graph partitioning, network epidemiology, and the calculation of matrix eigenvalues. Despite its wide use, however, it has long been recognized that the method has a fundamental flaw: It works poorly on networks that contain short loops. Loops introduce correlations that can cause the method to give inaccurate answers or to fail completely in the worst cases. Unfortunately, most real-world networks contain many short loops, which limits the usefulness of the message-passing approach. In this paper we demonstrate how to rectify this shortcoming and create message-passing methods that work on any network. We give 2 example applications, one to the percolation properties of networks and the other to the calculation of the spectra of sparse matrices.


Increased risk of preterm delivery among people living near the three oil refineries in Taiwan.
The petrochemical and petroleum industries are two of the main sources of industrial air pollution in Taiwan. Data used in this study concern outdoor air pollution and the health of individuals living in communities in close proximity to oil refinery plants. The prevalence of delivery of preterm birth infants was significantly higher in mothers living near the oil refinery plants than in control mothers in Taiwan. After controlling for several possible confounders (including maternal age, season, marital status, maternal education, and infant sex), the adjusted odds ratio was 1.14 (95% CI=1.01-1.28) for delivery of preterm infants for mothers living near oil refinery plants. These data provide further support for the hypothesis that air pollution can affect the outcome of pregnancies.


Survival and complications after insertion of self-expandable metal stents for malignant oesophageal stenosis.
To report on survival and complications after insertion of self-expandable stents in patients with malignant oesophageal stenosis. Data were gathered retrospectively from the medical records of 92 consecutive patients in the period 1994-2003. The study comprised 68 men and 24 women (median age 72 years, range 46-93 years) with stenosis from cancer of the oesophagus (n=61), the gastric cardia (n=26) and the lung (n=5), located mainly above (n=4) or below (n=62) the carina, or at the gastro-oesophageal junction (n=26). One uncovered stent and six different covered stents were used. Median and mean survival times after stenting (n=92) were 83 (range 4-1102) and 125 days, respectively. Thirty-day mortality was 19% (n=17), and 7% (n=6) survived more than one year. Survival was neither significantly influenced by division of the patients into diagnostic subgroups nor by comparison of the three most frequently used stents. One, two, three and four stents were received by 76, 11, 4 and 1 patient(s), respectively. There was no stent-related mortality, and complications were bleeding 1 (1%), stent migration 7 (8%), recurrent stenosis 8 (9%) from both tumour overgrowth (n=8) and tumour ingrowth (n=2) when using uncovered stents. Thirteen (14%) patients were re-stented because of recurrent stenosis (n=8) including fistula formation to the left main bronchus (n=2) and stent migration (n=5). Use of self-expandable stents in patients with inoperable malignant oesophageal stenosis carried few complications and resulted in relatively long survival in comparison with similar studies.


Antifungal and Insecticidal Activities of Selected Plant Species from Cloud Forest of Veracruz, Mexico: A Contribution to the Search of Novel Control Agents against Ambrosia Pest Complexes.
The antifungal and insecticidal activities of 34 extracts from 27 plant species were evaluated against fungal phytopathogens of the genus Fusarium and Xyleborus Scolytine ambrosia beetles involved in Fusarium dieback (FD) and laurel wilt (LW) diseases. Sixteen extracts caused mycelial growth inhibition (MGI) above 23 % at 2 mg mL-1 against F. solani, those from S. nudum and M. argyrophylla exhibited the highest MGI (57 % and 49 %, respectively). Thirteen extracts displayed significant antifungal activity against F. kuroshium, those from C. nocturnum and M. argyrophylla exhibited the highest MGI (100 % and 54.9 %, respectively). Additionally, ten plants extracts caused mortality in at least one of the beetle species tested, mainly from Solanaceae species. In the most active species, 39 phenolics were identified that may have contributed to their biological effects. This study is one of the first to report the potential of plant-derived natural products against the causative agents of FD and LW.


How chloroform anesthesia reached Lowell, Massachusetts: From Simpson's pamphlet to Gladwin's advertisement.
J.Y. Simpson of Edinburgh, Scotland discovered chloroform anesthesia in November 1847. During this time, W.T.G. Morton's agents had been collecting royalties for the use of ether across much of the United States. After reading about the advantages of chloroform as cited in C.T. Jackson's writings in the Boston Daily Atlas, S.F. Gladwin, a dentist in Lowell, Massachusetts, who had been reluctant to pay any ether royalties, demonstrated his independence and opportunism in swiftly adopting chloroform in his practice and publicizing its use through local advertisements.


Two Novel Biosurfactants Produced by Aureobasidium pullulans A11211-4-57 from a Fleabane, Erigeron annus (L.) pers.
Biosurfactants have been widely used in various industrial fields including medicine, food, cosmetics, detergent, pulp and paper, and oil and fat degradation. The culture broth of Aureobasidium pullulans A11211-4-57 using glucose as carbon source exhibited potent surfactant activity. The culture broth was separated by column chromatographies using ODS, silica gel, and Sephadex LH-20 resins, consecutively, to provide two biosurfactants. Based on mass and NMR measurements, their structures were determined as myo-inositol lipids and named pullusurfactans F and G. These compounds showed a high degree of activity, with 27.25 mN/m and 24.07 mN/m, respectively, at 1.0 mg l-1, which is useful for washing and cleaning agents.


Spatial analysis of soil erosion and sediment fluxes: a paired watershed study of two Rappahannock River tributaries, Stafford County, Virginia.
Soil erosion is a serious problem in areas with expanding construction, agricultural production, and improper storm water management. It is important to understand the major processes affecting sediment delivery to surficial water bodies in order to tailor effective mitigation and outreach activities. This study analyzes how naturally occurring and anthropogenic influences, such as urbanization and soil disturbance on steep slopes, are reflected in the amount of soil erosion and sediment delivery within sub-watershed-sized areas. In this study, two sub-watersheds of the Rappahannock River, Horsepen Run and Little Falls Run, were analyzed using the Revised Universal Soil Loss Equation (RUSLE) and a sediment delivery ratio (SDR) to estimate annual sediment flux rates. The RUSLE/SDR analyses for Horsepen Run and Little Falls Run predicted 298 Mg/y and 234 Mg/y, respectively, but nearly identical per-unit-area sediment flux rates of 0.15 Mg/ha/y and 0.18 Mg/ha/y. Suspended sediment sampling indicated greater amounts of sediment in Little Falls Run, which is most likely due to anthropogenic influences. Field analyses also suggest that all-terrain vehicle crossings represent the majority of sediment flux derived from forested areas of Horsepen Run. The combined RUSLE/SDR and field sampling data indicate that small-scale anthropogenic disturbances (ATV trails and construction sites) play a major role in overall sediment flux rates for both basins and that these sites must be properly accounted for when evaluating sediment flux rates at a sub-watershed scale.


End of life experiences of patients with advanced cancer in Myanmar: Results from the APPROACH study.
Access to palliative care services is essential for attaining universal health coverage for patients with a terminal cancer. Despite this, many patients with advanced cancer in low-income countries, such as Myanmar, suffer at the end of life (EOL) due to little or no access to palliative care. However, actual evidence on EOL experiences of cancer patients in Myanmar is lacking. This paper aims to describe various dimensions of EOL experiences among patients with an advanced cancer from the largest public hospital in Myanmar. We surveyed 195 patients with stage IV cancer seeking care from outpatient oncology clinics to assess their quality of life, pain severity, pain medications taken, quality of communication with doctors, nursing care and health care coordination, and desire to end life sooner. We assessed socioeconomic status (SES) differences in each patient outcome using separate multivariate linear/logistic regressions. Forty-one percent of the patients in our sample reported that they wish their life would end sooner. Low SES cancer patients had significantly worse quality of life, reported poor health care coordination and were more likely to report severe pain compared to high SES cancer patients visiting the same hospital. To improve quality of life and pain management and to reduce EOL distress among patients with advanced cancer, there is a pressing need to develop and invest in hospital and community-level palliative care services in Myanmar.


Hydrometallurgical extraction of zinc from CaO treated EAF dust in ammonium chloride solution.
Zinc in Electric Arc Furnace dust or EAF dust mainly exists as ZnFe2O4 and ZnO. While ZnO can be simply dissolved into either an acidic or alkaline solution, it is difficult to dissolve ZnFe2O4. In our previous work, we introduced a process called "CaO treatment", a preliminary pyrometallurgical process designed to transform the ZnFe2O4 in the EAF dust into ZnO and Ca2Fe2O5. The halogens and others heavy metals were favorably vaporized during CaO treatment with no essential evaporation loss of zinc and iron, leaving CaO treated dust which consisted mainly of ZnO and Ca2Fe2O5 and no problematic ZnFe2O4 compound. In this work, the selective leaching of zinc over iron and calcium in the CaO treated dust was investigated using an NH4Cl solution. The effects of temperature, reaction time and NH4Cl concentration on dissolution behavior were examined. While most of the zinc in the CaO treated dust was extracted after 2 h at 70 °C with 2 M NH4Cl, only about 20% of calcium was leached in NH4Cl solution. However, the iron did not dissolve and remained as Ca2Fe2O5 in residue. It was confirmed that zinc can be effectively recovered using NH4Cl solution.


Oxygen-enriched fermentation of sodium gluconate by Aspergillus niger and its impact on intracellular metabolic flux distributions.
Different concentrations of oxygen-enriched air were utilized for sodium gluconate (SG) fermentation by Aspergillus niger. The fermentation time shortened from 20 to 15.5 h due to the increase of volumetric oxygen transfer coefficient (KLa) and the formation of more dispersed mycelia when inlet oxygen concentration ascended from 21 to 32%. According to metabolic flux analysis, during the growth phase, extracellular glucose for SG synthesis accounted for 79.0 and 85.3% with air and oxygen-enriched air (25%), respectively, whereas the proportions were 89.4 and 93.0% in the stationary phase. Intracellular glucose consumption decreased in oxygen-enriched fermentation, as cell respiration was more high-efficiently performed. Metabolic profiling indicated that most intermediates in TCA cycle and EMP pathway had smaller pool sizes in oxygen-enriched fermentations. Moreover, the main by-product of citric acid dramatically decreased from 1.36 to 0.34 g L-1 in oxygen-enriched fermentation. And the sodium gluconate yield increased from 0.856 to 0.903 mol mol-1.


Ethical considerations on kidney transplantation from living donors.
Kidney transplantation from living donors is widely performed all over the world. Living nephrectomy for transplantation has no direct advantage for the donor other than increased self-esteem, but at least remains an extremely safe procedure, with a worldwide overall mortality rate of 0.03%. This theoretical risk to the donor seems to be justified by the socioeconomic advantages and increased quality of life of the recipient, especially in selected cases, such as pediatric patients, when living donor kidney transplantation can be performed in a preuremic phase, avoiding the psychological and physical stress of dialysis, which in children is not well tolerated and cannot prevent retarded growth. According to the Ethical Council of the Transplantation Society, commercialism must be prevented, not only for ethical but also medical reasons. The risks are too high not only for the donors, but also for the recipients, as a consequence of poor donor screening and evaluation with consequent transmission of human immunodeficiency virus or other infectious agents, as well as inappropriate medical and surgical management of donors and also of recipients, who are often discharged too early. Most public or private insurance companies are considering kidney donation a safe procedure without long-term impairment and, therefore, do not increase the premium, whereas recipient insurance of course should cover hospital fees for the donors. "Rewarded gifting" or other financial incentives to compensate for the inconvenience and loss of income related to the donation are not advisable, at least in our opinion. Our center does not perform anonymous living organ donation or "cross-over" transplantation.


Anti-fibrotic potential of human umbilical cord mononuclear cells and mouse bone marrow cells in CCl4- induced liver fibrosis in mice.
Liver fibrosis is the consequence of hepatocyte injury that leads to the activation of hepatic stellate cells (HSC). The treatment of choice is Liver transplantation; however, it has many problems such as surgery-related complications, immunological rejection and high costs associated with the procedure. Stem cell-based therapy would be a potential alternative, so the aim of this study is to investigate the therapeutic potential of human umbilical cord mononuclear cells (MNC) and mouse bone marrow cells (BMC) against carbon tetrachloride (CCl4) induced liver fibrosis in mice and compare it with that of silymarin. In the present study, male albino mice (N=60) were divided into six groups (10 mice each), the first group served as the normal control group while the remaining five groups were rendered fibrotic by intraperitoneal injections of CCl4 and being left for 6 weeks to develop hepatic fibrosis. Thereafter, the mice were divided into CCl4 group, CCl4 group receiving MNC or BMC or silymarin or MNC and silymarin combination. After the specified treatment period, animals were then euthanized, blood and tissue samples were collected for measurement of alanine aminotransferase(ALT), aspartate aminotransferase(AST), malondialdehyde(MDA), reduced glutathione(GSH), collagen, Laminin, transforming growth factor β1(TGFβ1), tumor necrosis factor alpha(TNFα). MNC, BMC, and the combination therapy showed a significant decrease in ALT, AST, MDA, collagen, Laminin, TGFβ1, and TNFα and a significant increase in GSH. The data displayed a similar regression of fibrosis with the histological and immunohistological parameters. In conclusion, MNC, BMC and the combination therapy showed a potential therapeutic effect against liver fibrosis via reducing oxidative stress, inflammatory mediators, and fibrogenic markers.


On the mechanism of the pharmacological activity of the new nonsteroidal antiinflammatory agent 4'-acetamidophenyl-2-(5'-p-toluyl-1'-methylpyrrole)acetate.
4-Acetamidophenyl-2-(5'-p-toluyl-1'-methylpyrrole)acetate (AU 8001), a tolmetin derivative, prepared by esterification with paracetamol, showed antiinflammatory-antirheumatic activity in animal models. This activity is believed to be largely due to the ability of the drug to inhibit the synthesis of prostaglandins. Furthermore, there is evidence that AU 8001 may also reduce the leucocyte immigration into inflamed tissues. Moreover, AU 8001 had no effects, after oral administration, on histamine- and 5-hydroxytryptamine-induced increase of vascular permeability or lysosome membrane stabilization.


Cancer mortality in Common Mental Disorders: A 10-year retrospective cohort study.
Individuals with Common Mental Disorders (CMDs) may have a higher cancer mortality. The purpose of this study was to examine cancer-related mortality among patients with CMDs and verify which cancer types are predominantly involved. We used the Regional Mental Health Registry of the Emilia-Romagna region, in Northern Italy to identify patients aged ≥ 18 years who received an ICD 9-CM diagnosis of CMDs (i.e., depressive and neurotic disorders) over a 10 year period (2008-2017). Information on cause of death was retrieved from the Regional Cause of Death Registry. Comparisons were made with data from the regional population without CMDs. Among 101,487 patients suffering from CMDs (55.7% depression; 44.3% neurotic disorders), 3,087 (37.8%) died from neoplasms. The total standardized mortality ratio (SMR) was 1.82 (95% CI 1.78-1.86) while the SMR for all neoplasms was 2.08 (95% CI 2.01-2.16). Individuals of both genders, with both depressive and neurotic disorders had a higher risk of death from almost all cancers compared with the regional population. Patients with CMDs have considerably higher cancer mortality risk than the general population. Higher mortality was observed for a broad range of cancers associated with different aetiologies. It is imperative to promote cancer awareness, prevention and treatment for people with CMDs.


LDL reduction: how low should we go and is it safe?
High-dose statin therapy or combination statin treatment is necessary for most patients to achieve aggressive low-density lipoprotein cholesterol goals. Adding ezetimibe or bile acid sequestrants appears unlikely to increase the risk of myopathy. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be reasonably safe, the safety of combination with high-dose statins has yet to be determined. To enhance patient outcomes, attention must be paid to characteristics that predict muscle and hepatic statin toxicity when considering using high-dose statin or combination statin therapy.


450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: a randomized controlled trial.
To compare the outcomes of controlled ovarian stimulation/in vitro fertilization cycles using 450 IU and 600 IU gonadotropin per day in women at risk of poor ovarian response. Prospective randomized controlled nonblinded study. University-affiliated private IVF center. Women considered to be at risk of poor ovarian response: aged <41 years with basal FSH >10 IU/L, antimüllerian hormone <1 ng/mL, antral follicle count ≤ 8, or a previous IVF cycle with ≥ 300 IU/d gonadotropin that resulted in a cancellation, <8 follicles, or <5 oocytes. A total of 356 patients underwent a microdose GnRH agonist flare-up IVF/intracytoplasmic sperm injection protocol with a fixed daily dose of either 450 IU FSH (n = 176) or 600 IU FSH (n = 180) equally divided between Menopur and Bravelle. Number of mature oocytes retrieved. The two groups were similar in terms of age, ovarian reserve, cause of infertility, duration of stimulation, and cycle cancellation rate. There were no significant differences in the number of metaphase II oocytes retrieved (4 [range 0-6] vs. 4 [range 2-7]), fertilization rate (62.4% vs. 57.0%), biochemical pregnancy rate (20.5% vs. 22.9%), clinical pregnancy rate (16.4% vs. 18.3%), and implantation rate (29.8% vs. 30.4%) between the 450 IU and 600 IU groups, respectively. Gonadotropin of 600 IU/d does not improve outcome of IVF cycles compared with 450 IU/d in women at risk of poor ovarian response. NCT00971152.


Biodegradation of plastics by white-rot fungi: A review.
Plastic pollution is one of the most environmental problems in the last two centuries, because of their excessive usage and their rapidly increasing production, which overcome the ability of natural degradation. Moreover, this problem become an escalating environmental issue caused by inadequate disposal, ineffective or nonexistent waste collection methods, and a lack of appropriate measures to deal with the problem, such as incineration and landfilling. Consequently, plastic wastes have become so ubiquitous and have accumulated in the environment impacting ecosystems and wildlife. The above, enhances the urgent need to explore alternative approaches that can effectively reduce waste without causing harsh environmental consequences. For example, white-rot fungi are a promising alternative to deal with the problem. These fungi produce ligninolytic enzymes able to break down the molecular structures of plastics, making them more bioavailable and allowing their degradation process, thereby mitigating waste accumulation. Over the years, several research studies have focused on the utilization of white-rot fungi to degrade plastics. This review presents a summary of plastic degradation biochemistry by white-rot fungi and the function of their ligninolytic enzymes. It also includes a collection of different research studies involving white-rot fungi to degrade plastic, their enzymes, the techniques used and the obtained results. Also, this highlights the significance of pre-treatments and the study of plastic blends with natural fibers or metallic ions, which have shown higher levels of degradation. Finally, it raises the limitations of the biotechnological processes and the prospects for future studies.


Effects of ethanol on plasma catecholamines and norepinephrine clearance.
Plasma catecholamines were measured in nine men after they had drunk either 0.5 or 1 ml/kg ethanol. Ethanol was found to induce a dose-dependent rise in plasma norepinephrine concentrations. Epinephrine concentrations were also raised in the initial intoxication phase. To determine whether ethanol raises plasma norepinephrine through increased release or decreased clearance (Cl), we infused norepinephrine into eight male subjects with and without prior ethanol, each subject acting as his own control. During infusions after ethanol, norepinephrine concentrations rose higher, and the mean circulatory Cl of norepinephrine was reduced from 76 to 47 ml/kg/min. This was associated with a prolongation of norepinephrine t 1/2 from 1.7 to 2.05 min. No significant difference in circulatory input of norepinephrine was found between infusions with and without ethanol. These results indicate that ethanol consumption increases plasma norepinephrine by reducing its circulatory Cl.


Steatohepatitis and liver cirrhosis in Chanarin-Dorfman syndrome with a new ABDH5 mutation.
Chanarin-Dorfman syndrome (CDS) is an autosomal recessive neutral lipid storage disease. It is very rare and characterized by ichtiosis, intracellular fat droplets in leucocytes (Jordan anomaly) and involvement of multiple tissues (skeletal muscle, central nervous system, bone marrow, eye and ear) mainly the liver. Our patients were diagnosed as CDS because they had ichtiosis, Jordon anomaly of leucocytes in peripheral blood smear, liver involvement and presence of homozygous 88 insertion C frame shift mutation on exon 4 of ABHD5/CGI-58 gene in genetic analysis. Our cases were two sisters. One of them developed severe steatohepatitis on age 19 and the other one was diagnosed as decompensated cirrhosis when she was 26 years old. We report here a new mutation in comparative gene identification-58 (CGI-58) gene causing syndactyly and steatohepatitis induced early cirrhosis.


The Well-being of children in lock-down: Physical, emotional, social and academic impact.
The Covid-19 pandemic is having an unprecedented impact on societies. In the interest of maintaining social distancing, schools in many countries have closed their doors and children have been confined to their homes. Thus, the objective of the present study was to holistically analyze the well-being of children during a period of full lockdown in Spain, by considering physical, emotional, social, and academic indicators. The scale "Well-being of Children in Lockdown" (WCL) was used to measure the well-being of 1225 children from 2 to 12 years old from Northern Spain. The survey was completed by the parents and was designed to analyze children's well-being in terms of physical, emotional, social and academic aspects. The results suggest that the general well-being of children during lockdown was at an intermediate level. Analysis of the various measures of well-being revealed that the lowest levels were obtained for physical activity, along with creative and playful activities. Girls, younger children, and those who have access to an outdoor space showed the greatest levels of well-being. Finally, we discuss the implications of these findings for the well-being of children and, in particular, how this can be improved amid the current Covid-19 crisis.


Assessing the effectiveness of mandatory outdoor mask policy: The natural experiment of Campania.
Face masks are possibly the main symbol of the COVID-19 pandemic. Once rarely used in Western countries, in the last two years they have become an object it is impossible to leave one's home without. Italy made their use a legal requirement, even outdoors, from late 2020 to early 2022. The effectiveness of this policy in reducing COVID-19 cases has been widely debated. The recent cancellation of their mandatory use in Italy offers an interesting setting in which to test its impact, since one Italian region (Campania) extended the restriction for a further three weeks. We aim to shed some light on the real-world impact of mandatory use of face masks outdoors, identifying the effect of this policy on the spread of COVID-19. By means of a quantitative analysis, employing a synthetic control method approach, we find that Campania had statistically the same number of cases as its synthetic counterfactual, built from a donor pool formed from the other Italian provinces. Hence, results suggest that while it imposes a burden on the public, the use of face masks outdoors is not correlated with a decrease in the number of COVID-19 cases.


Definitive localization of isolated tracheoesophageal fistula using bronchoscopy and esophagoscopy for guide wire placement.
To aid in identification of isolated tracheoesophageal fistulas (TEF), many surgeons have recommended the bronchoscopic placement of a ureteric or Fogarty catheter. This method can fail because of intraoperative dislodgment of the catheter. The authors present a new technique that enables us to definitively isolate and treat all H-type fistulas. Six cases of isolated TEF are presented consisting of 4 H-type fistulas, a proximal pouch fistula, and a recurrent TEF. Three of the patients had undergone a total of four prior failed operations at outside institutions using attempted bronchoscopic catheter placement. On all six patients, bronchoscopy was first performed where the fistula tract was noted in the trachea and a guide wire was passed through the fistula. After orotracheal intubation, the authors performed rigid esophagoscopy; the guide wire was identified and brought out through the mouth. This created a wire loop through the fistula. With the use of x-ray we were then able to visualize the level of the fistula and determine whether a cervical or thoracic approach should be used. Identification of the fistula intraoperatively was then facilitated by traction on the loop by the anesthesiologist. Five of the six TEFs were repaired with neck exploration; one required right thoracotomy. In all patients, the fistula was identified and divided. There were no recurrences or other complications. This new technique is a simple and definitive method in identification and treatment of isolated TEF.


Organochlorine pesticides in the ambient air of Chiapas, Mexico.
Organochlorine (OC) pesticides were measured in the ambient air of Chiapas, Mexico during 2000-2001. Concentrations of some OC pesticides (DDTs, chlordanes, toxaphene) were elevated compared with levels in the Great Lakes region, while those of other pesticides were not (hexachlorocyclohexanes, dieldrin). While this suggests southern Mexico as a source region for the former group of chemicals, comparably high levels have also been reported in parts of the southern United States, where their suspected sources are soil emissions (DDTs, toxaphene) and termiticide usage (chlordane). Ratios of p,p'-DDT/p,p'-DDE and trans-chlordane/cis-chlordane/trans-nonachlor (TC/CC/TN) in Chiapas suggest a mixture of fresh and weathered sources, while congener profiles of toxaphene suggest emission of old residues from soils. This is supported by air parcel back trajectory analysis, which indicated that air masses over Chiapas at the time of sampling had previously passed over areas of continuing or recent use of some OC pesticides as well as areas of past use.


Signaling cross-talk in plant disease resistance.
Hormone signaling crosstalk plays a major role in plant defense against a wide range of both biotic and abiotic stresses. While many reviews on plant-microbe interactions have well described the general trends of signaling pathways in shaping host responses to pathogens, few discussions have considered a synthesis of positive versus negative interactions among such pathways, or variations in the signaling molecules themselves. This review deals with the interaction trends between salicylic, jasmonic, and abscisic acids in the signaling pathways, as well as exceptions to such trends. Here we focused on antagonistic versus cooperative interactions between salicylic and jasmonic acids, two major disease resistance signaling molecules, and some interactions with abscisic acid, a known abiotic stress hormone, and another player in plant defense mechanisms. We provide a set of examples materializing either antagonism or cooperation for each interaction between two pathways, thereby showing the trends and pinpointing the exceptions. Such analyses are practical for researchers working on the subject and essential for a better exploitation of the data already available in plant disease resistance signaling, both in Arabidopsis and crop species, toward the development of better disease management strategies for economically important crops.


Increased fructose consumption has sex-specific effects on fibroblast growth factor 21 levels in humans.
Fibroblast growth factor 21 (FGF21), a primarily hepatic hormone with pleotropic metabolic effects, is regulated by fructose in humans. Recent work has established that 75 g of oral fructose robustly stimulates FGF21 levels in humans with peak levels occurring 2 h following ingestion; this has been termed an oral fructose tolerance test (OFTT). It is unknown whether prolonged high-fructose consumption influences the FGF21 response to acute fructose or whether biological sex influences FGF21-fructose dynamics. Thirty-nine healthy adults underwent baseline OFTT following an overnight fast. For the high-fructose exposure protocol, 20 subjects ingested 75 g of fructose daily for 14 ± 3 d, followed by repeat OFTT. For the control group, an OFTT was repeated following 14 ± 3 d of ad lib diet. For all subjects, FGF21 levels, glucose, insulin, non-esterified fatty acids and triglyceride levels were measured at baseline and 2 h following OFTT. All subjects maintained 3-d food logs prior to OFTT testing. Women demonstrated significantly higher baseline and peak stimulated total and intact FGF21 levels compared with men both before and after high-fructose exposure. Baseline total and intact FGF21 levels decreased following ongoing fructose exposure, maintaining a stable ratio. This decrease was sex specific, with only women demonstrating decreased baseline FGF21 levels. There were no changes in metabolic or anthropometric parameters following the high-fructose exposure. Daily ingestion of 75 g of fructose for 2 weeks results in a sex-specific decrease in baseline FGF21 levels without change in body weight or biochemical evidence of metabolic injury. There were also sex-specific differences in peak fructose-stimulated FGF21 levels, which do not change with high-fructose consumption. The role of FGF21 in the development of metabolic disease caused by fructose consumption may differ based on biological sex. Future long-term studies should consider sex differences in FGF21-fructose dynamics.


Multiple and recurrent systemic thrombotic events associated with congenital anomaly of inferior vena cava.
We describe a case of a 67-year-old woman with a history of cerebral infarction and pulmonary embolism that presented with chest pain. Subsequent evaluation resulted in a diagnosis of acute myocardial infarction and occult DVT, and imaging revealed a rare congenital absence of the infra-renal portion of the inferior vena cava, with lower extremity venous drainage diverted via an ascending lumbar vein. Associations between congenital absence of the inferior vena cava and thrombosis are discussed.


Multiple meningiomas in a child.
We report the case of a 4-year, 5-month-old boy, who had unusual multiple meningiomas occurring simultaneously in the intracranial, intraorbital, and spinal spaces. All lesions were surgically excised and histologically proved. This is the youngest patient with multiple meningiomas without history of neurofibromatosis reported in the literature.


Myocardial Scar and Mortality in Chronic Aortic Regurgitation.
Background Chronic aortic regurgitation (AR) can be associated with myocardial scarring. It is unknown if scarring in AR is linked to poor outcomes and whether aortic valve replacement impacts this association. We investigated the relationship of myocardial scarring to mortality in chronic AR using cardiac magnetic resonance. Methods and Results We enrolled patients with moderate or greater AR between 2009 and 2019 and performed a blinded assessment of left ventricle remodeling, AR severity, and presence and extent of myocardial scarring by late gadolinium enhancement. The primary outcome was all-cause mortality. We followed 392 patients (median age 62 [interquartile range, 51-71] years), and 78.1% were men, and 25.8% had bicuspid valves. Median aortic valve regurgitant volume was 39 mL (interquartile range, 30-60). Myocardial scar was present in 131 (33.4%) patients. Aortic valve replacement was performed in 165 (49.1%) patients. During follow-up, up to 10.8 years (median 32.3 months [interquartile range, 9.8-69.5]), 51 patients (13%) died. Presence of myocardial scar (hazard ratio [HR], 3.62; 95% CI, 2.06-6.36; P<0.001), infarction scar (HR, 4.94; 95% CI, 2.58-9.48; P<0.001), and noninfarction scar (HR, 2.75; 95% CI, 1.39-5.44; P<0.004) were associated with mortality. In multivariable analysis, the presence of scar remained independently associated with death (HR, 2.53; 95% CI, 1.15-5.57; P=0.02). Among patients with myocardial scar, aortic valve replacement was independently associated with a lower risk of mortality (HR, 0.34; 95% CI, 0.12-0.97; P=0.03), even after adjustment for confounders. Conclusions In aortic regurgitation, myocardial scar is independently associated with a 2.5-fold increase risk in mortality. Aortic valve replacement was associated with a reduction in risk of mortality in patients with scarring.


Contextual influences on physical activity and eating habits -options for action on the community level.
This conceptual paper aims to illustrate the ways in which communities are able to advance health improvements on a population level. Outcome measures may include increased physical activity and healthier eating habits in particular, as well as an improved health-related quality of life and social cohesion as more generic outcomes. The paper begins by asking initial questions: Why did previous health-specific interventions only show moderate effects on an individual level and mixed effects on a population level? What is the added value of a community-based public health perspective compared to the traditional biomedical perspective when it comes to prevention? Why are we living the way we are living? Why do we eat what we eat? Why do we move the way we move? Subsequently, we illustrate the broad spectrum of contextual interventions available to communities. These can have geographical and technological as well as economic, political, normative and attitude-specific dimensions. It is shown that communities have a strong influence on health-related contexts and decision-making of adults, adolescents and children. In addition contextual characteristics, effects, mediators, moderators and consequences relevant for health can differ greatly between age groups. Both small-scale settings and overarching sectors possess physical, economic, political and sociocultural characteristics that can be proactively influenced by community decision-makers in the sense of a "health in all policies"-strategy. After presenting various interdisciplinary approaches to community-based health interventions, the manuscript closes with the following core message: Successful community-based health promotion strategies consist of multilevel - multicomponent interventions on the micro, meso and macro-level-environments.


Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence, and glutamine addiction.
Many malignant human tumors, including melanomas, are auxotrophic for arginine due to reduced expression of argininosuccinate synthetase-1 (ASS1), the rate-limiting enzyme for arginine biosynthesis. Pegylated arginine deiminase (ADI-PEG20), which degrades extracellular arginine, resulting in arginine deprivation, has shown favorable results in clinical trials for treating arginine-auxotrophic tumors. Drug resistance is the major obstacle for effective ADI-PEG20 usage. To elucidate mechanisms of resistance, we established several ADI-PEG20-resistant (ADI(R)) variants from A2058 and SK-Mel-2 melanoma cells. Compared with the parental lines, these ADI(R) variants showed the following characteristics: (i) all ADI(R) cell lines showed elevated ASS1 expression, resulting from the constitutive binding of the transcription factor c-Myc on the ASS1 promoter, suggesting that elevated ASS1 is the major mechanism of resistance; (ii) the ADI(R) cell lines exhibited enhanced AKT signaling and were preferentially sensitive to PI3K/AKT inhibitors, but reduced mTOR signaling, and were preferentially resistant to mTOR inhibitor; (iii) these variants showed enhanced expression of glucose transporter-1 and lactate dehydrogenase-A, reduced expression of pyruvate dehydrogenase, and elevated sensitivity to the glycolytic inhibitors 2-deoxy-glucose and 3-bromopyruvate, consistent with the enhanced glycolytic pathway (the Warburg effect); (iv) the resistant cells showed higher glutamine dehydrogenase and glutaminase expression and were preferentially vulnerable to glutamine inhibitors. We showed that c-Myc, not elevated ASS1 expression, is involved in upregulation of many of these enzymes because knockdown of c-Myc reduced their expression, whereas overexpressed ASS1 by transfection reduced their expression. This study identified multiple targets for overcoming ADI-PEG resistance in cancer chemotherapy using recombinant arginine-degrading enzymes.


[Structural and functional changes in human erythrocytes and leukocytes during a 7-day immersion hypokinesia].
Changes in blood parameters (red and white blood cell counts) were examined in 6 healthy male volunteers during an acute stage of adaptation to the exposure simulating physiological effects of weightlessness. The parameters varied, remaining, however, within the physiological limits.


Carcinoma oesophagus--an unusual presentation.
We report a 32 years old female who had carcinoma of the oesophagus and who presented with unusual features.


Update on Pediatric Cough.
Despite the high prevalence of cough in children, the topic has been poorly researched. Although pediatricians recognize that chronic cough in children is different from that in adults, this difference seems less recognizable to other health professionals. During childhood, the respiratory tract and nervous system undergo a series of anatomical and physiological maturation processes that influence the cough reflex. Additionally, immunological responses undergo developmental and memorial processes that make infection and congenital abnormalities the overwhelming cause of cough in children. The lack of comprehensive clinical data regarding chronic cough in children has initially required pediatricians to adopt an adult approach to the problem. In the last 10 years, however, research has led to the reconsideration of the etiology of chronic cough in children. Currently, attention has focused on protracted bacterial bronchitis as a major cause of chronic cough in preschool-aged children and as a possible precursor of bronchiectasis. New research horizons are emerging for both the treatment and prevention of particular causes of chronic cough in children.


Origin of acetylcholine antagonism in ELIC, a bacterial pentameric ligand-gated ion channel.
ELIC is a prokaryotic homopentameric ligand-gated ion channel that is homologous to vertebrate nicotinic acetylcholine receptors. Acetylcholine binds to ELIC but fails to activate it, despite bringing about conformational changes indicative of activation. Instead, acetylcholine competitively inhibits agonist-activated ELIC currents. What makes acetylcholine an agonist in an acetylcholine receptor context, and an antagonist in an ELIC context, is not known. Here we use available structures and statistical coupling analysis to identify residues in the ELIC agonist-binding site that contribute to agonism. Substitution of these ELIC residues for their acetylcholine receptor counterparts does not convert acetylcholine into an ELIC agonist, but in some cases reduces the sensitivity of ELIC to acetylcholine antagonism. Acetylcholine antagonism can be abolished by combining two substitutions that together appear to knock out acetylcholine binding. Thus, making the ELIC agonist-binding site more acetylcholine receptor-like, paradoxically reduces the apparent affinity for acetylcholine, demonstrating that residues important for agonist binding in one context can be deleterious in another. These findings reinforce the notion that although agonism originates from local interactions within the agonist-binding site, it is a global property with cryptic contributions from distant residues. Finally, our results highlight an underappreciated mechanism of antagonism, where agonists with appreciable affinity, but negligible efficacy, present as competitive antagonists.


Comparison of Staged Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy in Patients with Brain Metastases > 2 cm without Prior Whole Brain Radiotherapy: A Systematic Review and Meta-Analysis.
To compare fractionated stereotactic radiotherapy (FSRT) with staged stereotactic radiosurgery (SSRS) in patients with brain metastases >2 cm without prior whole brain radiotherapy. In this systematic review and meta-analysis, PubMed, Scopus, Web of Science, Embase, and Cochrane were searched to include studies that evaluated FSRT and/or SSRS for brain metastases >2 cm or 4 cm3 in adult patients with a known primary malignancy and no prior history of whole brain radiotherapy. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and an indirect random-effect meta-analyses was conducted to compare treatment outcomes between the two modalities. A total of 10 studies were included, comprising 612 (778 metastases) and 250 patients (265 metastases) in the SSRS and FSRT groups, respectively. The SSRS group had significantly older patients (66.6 ± 17.51 years vs. 62.37 ± 37.89 years; P = 0.029) with lower rate of control of primary disease (11.59% vs. 78.7%, P < 0.00001), and more patients with Karnofsky performance status ≥70 at baseline (92.81% vs. 88.56%; P = 0.045). FSRT was associated with a statistically nonsignificant but clinically important lower 12-month overall survival (44.75% [95% confidence interval [CI]: 30.48%-59.95%] vs. 53.25% [95%CI: 45.15%-61.19%], P = 0.1615) and higher rate of salvage radiotherapy (18.18% [95%CI: 8.75%-34%] vs. 12.27% [95%CI: 5.98%-23.53%], P = 0.0841). Both groups had comparable rates of local tumor control, mortality, tumor progression, recurrence, neurological death, and 6-month overall survival. SSRS and FSRT were found to be comparable for treating brain metastases >2 cm not previously irradiated. Given the paucity of such studies, trials directly comparing the two treatment strategies are warranted to support these findings.


Addition of neutral protamine lispro insulin or insulin glargine to oral type 2 diabetes regimens for patients with suboptimal glycemic control: a randomized trial.
Injection of long-acting insulin at bedtime is a common therapeutic approach for patients with type 2 diabetes that is poorly controlled with oral regimens. Neutral protamine lispro (NPL) insulin has demonstrated better glycemic control and similar incidence of hypoglycemic events than that of neutral protamine Hagedorn insulin. To compare the clinical efficacy and safety of bedtime NPL insulin or insulin glargine in patients with type 2 diabetes who had suboptimal glycemic control while receiving stable doses of metformin and sulfonylurea. Open-label, randomized trial. Teaching hospital (Azienda Ospedaliera Universitaria, Second University of Naples), Naples, Italy. 116 adults receiving stable doses of metformin plus sulfonylurea for longer than 90 days with hemoglobin A(1c) (HbA(1c)) levels of 7.5% to 10% and fasting plasma glucose levels of 6.7 mmol/L or greater (> or =120 mg/dL). 10 IU of NPL insulin or insulin glargine injected subcutaneously at bedtime with weekly dose titrations to target fasting glucose levels less than 5.6 mmol/L (<100 mg/dL) in addition to stable oral regimens. Patients receiving nighttime sulfonylurea before the study were switched to metformin. The primary outcome was change in HbA(1c) levels from baseline to week 36. Secondary outcomes were HbA(1c) levels less than 7%, self-reported hypoglycemic episodes, insulin dose, self-monitored glucose level, and body weight. Twenty patients in each group had continuous glucose monitoring for 3 consecutive days before adding insulin and at week 36. Improvement in HbA(1c) levels was similar in both groups (1.83% and 1.89% for NPL and glargine, respectively). The difference between the groups was 0.06 percentage point (95% CI, -0.1 to 0.15 percentage points). Secondary outcomes did not differ between groups. Hemoglobin A(1c) levels less than 7% occurred in 62% of patients receiving NPL and 64% of patients receiving glargine (difference, 2.0 percentage points [CI, -1.1 to 5.0 percentage points]). Fasting plasma glucose levels less than 5.6 mmol/L (<100 mg/dL) occurred in 40% of patients receiving NPL and 41% of patients receiving glargine (difference, 1.0 percentage point [CI, -0.9 to 3.0 percentage points]). Any hypoglycemic event occurred in 74% of patients receiving NPL and 67% of patients receiving glargine (difference, 7 percentage points [CI, -5 to 13 percentage points]). Continuous glucose level monitoring in the patients who had this measurement did not differ statistically. The study was not blinded, had limited power to detect differences in hypoglycemic events, and did not obtain continuous glucose level monitoring for all patients. Similar glycemic control occurred with the addition of NPL or glargine insulin to oral regimens in patients with poorly controlled type 2 diabetes. Hypoglycemia was similar in the 2 groups, but sample size limited the ability to make a definite safety assessment.


Follicular fluid proteins stimulate nitric oxide (NO) synthesis in human sperm: a possible role for NO in acrosomal reaction.
Nitric oxide (NO) is a free radical involved in the regulation of several functions of the male genitourinary system. It is produced by neurons and the endothelium and epithelia of reproductive system; it mediates penile erection and regulates sperm motility, viability, and metabolism. Here we show that human spermatozoa exhibit a detectable NO synthase (NOS) activity, measured both as ability of the intact sperm and cell lysate to convert L-[3H]arginine into L-[3H]citrulline and as 24 h accumulation of extracellular nitrite in intact sperm suspensions. NOS activity (identified as an endothelial isoform) was inhibited by L-canavanine and N(G)-monomethyl-L-arginine, and nitrite accumulation was inhibited by the NO scavenger hemoglobin; both enzyme activity and nitrite production were increased by a 24 h incubation of spermatozoa with protein-enriched extracts of human follicular fluid (PFF); a significant increase of citrulline synthesis was observed only after a 4 h incubation with 40% PFF, a time period during which acrosomal reactivity was significantly increased. PFF-induced acrosomal reaction was inhibited by L-canavanine and hemoglobin, and the NO donors sodium nitroprusside (SNP), S-nitroso-N-acetyl-penicillamine (SNAP), and DETA NONOate were able to increase the percentage of reacted spermatozoa. Our results suggest that NO synthesized by human sperm may play a role in follicular fluid-induced acrosomal reaction.


Diurnal variation in ornithine decarboxylase activity of different brain regions of the rat.
The activity of ornithine decarboxylase (ODC) was studied in the brain of Sprague-Dawley male rats weighing 200-250 g. In this study, animals were maintained at a temperature of 21 +/- 1 degree C and a 12:12 h light--dark cycle for a minimum of 3 weeks prior to any experimentation. Animals were sacrificed at 06.00 h and 18.00 h and the brain cerebral cortex, hypothalamus, amygdala, hippocampus, midbrain, pons, medulla oblongata and cerebellum were isolated and assayed for ODC activity. The data show significant diurnal variations (P less than 0.05) in hypothalamus, midbrain, medulla oblongata and cerebellum, with peak values during the active phase of the animal. Other brain parts studied did not show any significant diurnal variations.


Coordinate transformation methodology for simulating quasistatic elastoplastic solids.
Molecular dynamics simulations frequently employ periodic boundary conditions where the positions of the periodic images are manipulated in order to apply deformation to the material sample. For example, Lees-Edwards conditions use moving periodic images to apply simple shear. Here, we examine the problem of precisely comparing this type of simulation to continuum solid mechanics. We employ a hypoelastoplastic mechanical model, and develop a projection method to enforce quasistatic equilibrium. We introduce a simulation framework that uses a fixed Cartesian computational grid on a reference domain, and which imposes deformation via a time-dependent coordinate transformation to the physical domain. As a test case for our method, we consider the evolution of shear bands in a bulk metallic glass using the shear transformation zone theory of amorphous plasticity. We examine the growth of shear bands in simple shear and pure shear conditions as a function of the initial preparation of the bulk metallic glass.


Oxidative stress induces imbalance of adipogenic/osteoblastic lineage commitment in mesenchymal stem cells through decreasing SIRT1 functions.
With rapidly ageing populations worldwide, the incidence of osteoporosis has reached epidemic proportions. Reactive oxygen species (ROS), a by-product of oxidative stress and ageing, has been thought to induce osteoporosis by inhibiting osteogenic differentiation of mesenchymal stem cells (MSCs). However, specific mechanisms of how ROS results in alterations on MSC differentiation capacity have been inconsistently reported. We found that H2 O2 , an ROS, simultaneously induced MSC lineage commitment towards adipogenesis and away from osteogenesis at the functional as well as transcriptional level. In addition, H2 O2 decreased the activities of SIRT1, a histone deacetylase and longevity gene. By silencing and reconstituting SIRT1 in MSCs, we demonstrated that H2 O2 exerted its disparate effects on adipogenic/osteoblastic lineage commitment mainly through modulating SIRT1 expression levels. Treatment with resveratrol, a SIRT1 agonist, can also reverse this ROS-induced adipogenesis/osteogenesis lineage imbalance. Moreover, SIRT1 regulation of RUNX2 transcriptional activity was mediated through deacetylation of the ROS-sensitive transcription factor FOXO3a. Taken together, our data implicate SIRT1 as playing a vital role in ROS-directed lineage commitment of MSCs by modulating two lineages simultaneously. Our findings on the critical role of SIRT1 in ROS/age-related perturbations of MSC differentiation capacity highlight this molecule as a target for maintenance of MSC stemness as well as a potential anabolic target in osteoporosis.


Unresolved Chronic Diarrhea: A Case of Angiotensin-Converting Enzyme Inhibitor-Induced Mesenteric Angioedema.
Angiotensin-converting enzyme inhibitors (ACEI) are frequently prescribed for cardiovascular and renal diseases. However, ACEI-induced visceral angioedema is a rare occurrence that often goes unnoticed and poses a diagnostic challenge due to its non-specific and diverse symptoms. Key diagnostic indicators on a CT scan include the 'target' sign, elongation of bowel loops, enlarged mesenteric vessels, mesenteric edema with or without ascites, thickened omentum, and the absence of vascular compromise or adenopathy. Discontinuation of ACEI usually results in symptom resolution within 48 hours. While this phenomenon is more commonly observed in females and African Americans, we present a case of a Caucasian male who underwent an extensive diagnostic evaluation, including exploratory surgery, before ACEI-induced angioedema was considered. The occurrence of angiotensin-converting enzyme inhibitors (ACEI)-induced visceral angioedema is infrequent, frequently overlooked, and presents a diagnostic challenge due to its wide range of non-specific symptoms.While ACEI-induced visceral angioedema is more frequently observed in females and African Americans, it is crucial not to overlook the possibility of this phenomenon in other demographic groups as well.Its rarity emphasizes the importance of including it in the list of potential conditions to be considered, thus preventing unnecessary tests and procedures.


Structural and functional studies of S-adenosyl-L-methionine binding proteins: a ligand-centric approach.
The post-genomic era poses several challenges. The biggest is the identification of biochemical function for protein sequences and structures resulting from genomic initiatives. Most sequences lack a characterized function and are annotated as hypothetical or uncharacterized. While homology-based methods are useful, and work well for sequences with sequence identities above 50%, they fail for sequences in the twilight zone (<30%) of sequence identity. For cases where sequence methods fail, structural approaches are often used, based on the premise that structure preserves function for longer evolutionary time-frames than sequence alone. It is now clear that no single method can be used successfully for functional inference. Given the growing need for functional assignments, we describe here a systematic new approach, designated ligand-centric, which is primarily based on analysis of ligand-bound/unbound structures in the PDB. Results of applying our approach to S-adenosyl-L-methionine (SAM) binding proteins are presented. Our analysis included 1,224 structures that belong to 172 unique families of the Protein Information Resource Superfamily system. Our ligand-centric approach was divided into four levels: residue, protein/domain, ligand, and family levels. The residue level included the identification of conserved binding site residues based on structure-guided sequence alignments of representative members of a family, and the identification of conserved structural motifs. The protein/domain level included structural classification of proteins, Pfam domains, domain architectures, and protein topologies. The ligand level included ligand conformations, ribose sugar puckering, and the identification of conserved ligand-atom interactions. The family level included phylogenetic analysis. We found that SAM bound to a total of 18 different fold types (I-XVIII). We identified 4 new fold types and 11 additional topological arrangements of strands within the well-studied Rossmann fold Methyltransferases (MTases). This extends the existing structural classification of SAM binding proteins. A striking correlation between fold type and the conformation of the bound SAM (classified as types) was found across the 18 fold types. Several site-specific rules were created for the assignment of functional residues to families and proteins that do not have a bound SAM or a solved structure.


Sources and behavior of technetium in the environment.
Technetium is a man-made element produced in increasing amounts during the last decades. The chemical and physical properties of some technetium compounds are considered, and a discussion of possible source terms is included. Literature on the environmental behavior of technetium is reviewed to evaluate its transfer and equilibrium distribution in aquatic and terrestrial ecosystems. Considerable effort has been expended in the last years in order to understand the biogeochemical processes responsible for the long-term behavior of technetium in the environment and its transfer through food chains as well as to identify critical pathways of the long-lived radioisotope Tc-99 from the environment to man.


Paradoxical suboptimal vitamin D levels in a Mediterranean area: a population-based study.
Policies in sunny countries, such as those in the Mediterranean area, do not promote vitamin D supplementation despite some studies might suggest the high prevalence of sub-optimal levels. The objective was to determine the vitamin D levels by 25-hydroxyvitamin D (25(OH)D) of a Mediterranean population and their characteristics. This population-based study included a database of public health system from all individuals living in Catalonia > 18 years who had some measure of 25(OH)D between January 2018 and April 2021. More than half million people were classified based on 25(OH)D measurements to study their characteristics. Three vitamin D categories were created: < 20 ng/ml deficiency, 20-30 ng/ml insufficiency and > 30 ng/ml optimal. Less than 10% of the population residing in Catalonia had recent 25(OH)D determinations and the majority of determinations were in ≥ 45 years and in women. Around 80% of young people with determination had sub-optimal levels but the prevalence of vitamin D supplementation prescription increased with age which was associated with better values of 25(OH)D. In a Mediterranean area 25(OH)D determinations were low despite the high prevalence of suboptimal levels in the population with recent determination. In addition, the measurements were especially concentrated in people ≥ 45 years of age and in women who were, in addition, the groups to whom the most vitamin D supplementation was prescribed. On the contrary, young people presented few determinations of 25(OH)D and, although majority of them showed sub-optimal levels, vitamin D supplementation was not prescribed in most cases.


Selective use of PET scan in the preoperative staging of NSCLC.
Positron emission tomography (PET) is a imaging technique which identifies abnormalities by utilising their metabolic properties rather than their anatomical density. In this study, we evaluated the place of PET scanning for the characterisation of additional abnormalities discovered on routine, preoperative CT evaluation of patients with proven NSCLC. A total of 21 patients underwent PET scanning using fluorodeoxyglucose (FDG). In these patients, routine CT scans had found 26 concomitant lesions which were in lung, adrenal gland, liver, kidney, spleen and pleura. FDG uptake was positive at the primary site in all patients. FDG uptake in 13 of the concomitant lesions suggested malignancy. Malignancy was confirmed at all of these foci by histology in eight (six at thoracotomy, fine needle aspiration biopsy (FNAB) and open biopsy) and by clinical and radiological follow-up for 1-15 months in five. In 13 lesions, PET suggested benign disease. Histology reported no evidence of malignancy in five and the six foci followed on clinical and radiographic follow-up for 2-16 months had no evidence of malignancy. PET was falsely negative in only one site where malignancy was proven by thoracotomy. PET failed to detect the remaining lesion which was an unassociated primary kidney tumour in a patient with Li-Fraumeni syndrome. The accuracy of PET scanning in the assessment of those additional lesions found on CT evaluation of otherwise operable NSCLC was found to be 96% with a sensitivity of 93% and specificity of 100%. These results indicate that PET is useful to characterise additional lesions found on CT scan of patients with NSCLC.


Differential modulation of lipopolysaccharide- and zymosan-induced hypophagia by dexamethasone treatment.
The treatment of experimental animals with lipopolysaccharide (LPS) induces behavioral depression, in which the central and peripheral inductions of proinflammatory cytokines are proposed to play an important role. We have shown that the intraperitoneal injection of zymosan, composed of insoluble particles prepared from yeast cell walls, can induce behavioral depression assessed as hypophagia in mice, although the role of proinflammatory cytokines in this response has not yet been investigated. We have also shown that the subcutaneous injection of the corticoid, dexamethasone (Dex), a potent inhibitor of cytokine production, is effective in attenuating hypophagia in LPS-treated mice. The attenuated response was associated with the suppression of the gene induction of proinflammatory cytokines (i.e., IL-1beta, IL-6 and TNFalpha) in the brain and liver. In contrast, no significant induction of proinflammatory cytokine genes was observed in the brain or liver during zymosan-induced hypophagia; the subcutaneous injection of Dex did not attenuate zymosan-induced hypophagia but its intraperitoneal injection did. Thus, zymosan-induced hypophagia was less responsive to a subcutaneous injection of dexamethasone than LPS-induced hypophagia, which may be due to the limited role of systemic inflammation in this response. An important role of localized, rather than systemic, inflammation in zymosan-induced hypophagia was suggested, although the role of local proinflammatory cytokines remains to be clarified.


Energy and protein intakes as determinants of nitrogen balance.
Changes in caloric intake below or above energy needs affect nitrogen balance, so that any change in caloric intake results in a corresponding alteration in nitrogen balance. The improvement in nitrogen balance caused by an increase in energy intake, however, can be frustrated if intake of protein is inadequate; conversely, the beneficial effects of an increase in protein intake can be inhibited by an inadequate energy intake. These observations mean that, in experimental studies, nitrogen balance is the result of levels of both energy and protein; in consequence, protein requirements can be interpreted only from such studies, where energy intake is also defined under the experimental conditions. In addition to the effect of dietary energy supply, dietary carbohydrate has a short-term specific effect on protein metabolism not shared by fat, in which plasma amino acids are diverted into muscle protein through the action of insulin released by the dietary carbohydrate. This metabolic interaction also occurs between carbohydrate and amino acids absorbed from the same meal.


Positive end-expiratory pressure individualization guided by continuous end-expiratory lung volume monitoring during laparoscopic surgery.
To determine whether end-expiratory lung volume measured with volumetric capnography (EELVCO2) can individualize positive end-expiratory pressure (PEEP) setting during laparoscopic surgery. We studied patients undergoing laparoscopic surgery subjected to Fowler (F-group; n = 20) or Trendelenburg (T-group; n = 20) positions. EELVCO2 was measured at 0° supine (baseline), during capnoperitoneum (CP) at 0° supine, during CP with Fowler (head up + 20°) or Trendelenburg (head down - 30°) positions and after CP back to 0° supine. PEEP was adjusted to preserve baseline EELVCO2 during and after CP. Baseline EELVCO2 was statistically similar to predicted FRC in both groups. At supine and CP, EELVCO2 decreased from baseline values in F-group [median and IQR 2079 (768) to 1545 (725) mL; p = 0.0001] and in T-group [2164 (789) to 1870 (940) mL; p = 0.0001]. Change in body position maintained EELVCO2 unchanged in both groups. PEEP adjustments from 5.6 (1.1) to 10.0 (2.5) cmH2O in the F-group (p = 0.0001) and from 5.6 (0.9) to 10.0 (2.6) cmH2O in T-group (p = 0.0001) were necessary to reach baseline EELVCO2 values. EELVCO2 increased close to baseline with PEEP in the F-group [1984 (600) mL; p = 0.073] and in the T-group [2175 (703) mL; p = 0.167]. After capnoperitoneum and back to 0° supine, PEEP needed to maintain EELVCO2 was similar to baseline PEEP in F-group [5.9 (1.8) cmH2O; p = 0.179] but slightly higher in the T-group [6.5 (2.2) cmH2O; p = 0.006]. Those new PEEP values gave EELVCO2 similar to baseline in the F-group [2039 (980) mL; p = 0.370] and in the T-group [2150 (715) mL; p = 0.881]. Breath-by-breath noninvasive EELVCO2 detected changes in lung volume induced by capnoperitoneum and body position and was useful to individualize the level of PEEP during laparoscopy.Trial registry: Clinicaltrials.gov NCT03693352. Protocol started 1st October 2018.


Automated measurements of cerebral atrophy in multiple sclerosis.
An automated method of measuring cerebral atrophy is introduced. Using this method we studied patients with multiple sclerosis and a control group showing premature cerebral atrophy in multiple sclerosis (P = 1,32 x 10(-8) for male and P = 3,6 x 10(-14) for female). There was only a weak correlation between cerebral atrophy and psychological deficits. Multivariate analysis did not show any significant correlation between cerebral atrophy, duration of disease, clinical manifestations and progression of disease. We conclude that our method to measure cerebral atrophy is more accurate and less time-consuming than the use of linear indices. It might be appropriate for further investigations in evaluating atrophic processes in cerebro-vascular, degenerative and exogen-toxic disease of brain.


[Connectivity and care, innovative tools for the benefit of patients].
The first department within Clermont-Ferrand university hospital to have undergone the introduction of electronic patient records, the pulmonology department again served as the pilot for studying connectivity solutions. Time savings, increased use of the electronic patient records and improved quality of care are the outcomes highlighted by a survey of the nurses in this unit.


Evaluation of chromane derivatives: Promising privileged scaffolds for lead discovery within Alzheimer's disease.
The chromane ring system is widely distributed in nature and has proven to be a highly potent pharmacophore in medicinal chemistry, which includes the area of Alzheimer's and Parkinson's diseases. We report on the development of a gem-dimethylchroman-4-ol family that was shown to give good inhibition of equine serum butyrylcholinesterase (eqBuChE) (in the range 2.9 - 7.3 μM) and in the same range of currently used drugs. We also synthesized a small library of gem-dimethylchroman-4-amine compounds, via a simple reductive amination of the corresponding chromanone precursor, that were also selective for eqBuChE presenting inhibitions in the range 7.6 - 67 μM. Kinetic studies revealed that they were mixed inhibitors. Insights into their mechanism of action were obtained through molecular docking and STD-NMR experiments, and the most active examples showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME. We also prepared a set of propargyl gem-dimethylchromanamines, for monoamine oxidase (MAO) inhibition but they were only moderately active (the best being 28% inhibition at 1 µM on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE.


In situ monitoring of photocatalyzed isomerization reactions on a microchip flow reactor by IR-MALDI ion mobility spectrometry.
The visible-light photocatalytic E/Z isomerization of olefins can be mediated by a wide spectrum of triplet sensitizers (photocatalysts). However, the search for the most efficient photocatalysts through screenings in photo batch reactors is material and time consuming. Capillary and microchip flow reactors can accelerate this screening process. Combined with a fast analytical technique for isomer differentiation, these reactors can enable high-throughput analyses. Ion mobility (IM) spectrometry is a cost-effective technique that allows simple isomer separation and detection on the millisecond timescale. This work introduces a hyphenation method consisting of a microchip reactor and an infrared matrix-assisted laser desorption ionization (IR-MALDI) ion mobility spectrometer that has the potential for high-throughput analysis. The photocatalyzed E/Z isomerization of ethyl-3-(pyridine-3-yl)but-2-enoate (E-1) as a model substrate was chosen to demonstrate the capability of this device. Classic organic triplet sensitizers as well as Ru-, Ir-, and Cu-based complexes were tested as catalysts. The ionization efficiency of the Z-isomer is much higher at atmospheric pressure which is due to a higher proton affinity. In order to suppress proton transfer reactions by limiting the number of collisions, an IM spectrometer working at reduced pressure (max. 100 mbar) was employed. This design reduced charge transfer reactions and allowed the quantitative determination of the reaction yield in real time. Among 14 catalysts tested, four catalysts could be determined as efficient sensitizers for the E/Z isomerization of ethyl cinnamate derivative E-1. Conversion rates of up to 80% were achieved in irradiation time sequences of 10 up to 180 s. With respect to current studies found in the literature, this reduces the acquisition times from several hours to only a few minutes per scan.