Are the beneficial effects of 'antioxidant' lipoic acid mediated through metabolism of reactive sulfur species?
The health benefits of lipoic acid (LA) are generally attributed to mitigating the harmful effects of reactive oxygen species (ROS). ROS are chemically similar to reactive sulfur species (RSS) and signal through identical mechanisms. Here we examined the effects of LA on RSS in HEK293 cells using H2S and polysulfide (PS) specific fluorophores, AzMC and SSP4. We show that LA concentration-dependently increased both H2S and PS. Physioxia (5% O2) augmented the effects of LA on H2S production but decreased PS production. Thiosulfate, a known substrate for reduced LA, and an intermediate in the catabolism of H2S enhanced the effects of LA on H2S and PS production. Inhibiting peroxiredoxins with conoidin A and gluraredoxins with tiopronin augmented the effects of LA on PS and H2S, respectively while decreasing glutathione with buthionine-sulfoximine (BSO) or diethyl maleate (DEM) decreased the stimulatory effect of LA on H2S production but augmented LA's effect on PS. Aminooxyacetate (AOA) and propargylglycine (PPG), inhibitors of H2S production from cysteine partially inhibited LA augmentation of H2S production and further decreased the LA effect when applied concurrently with BSO and DEM. The selective and cell-permeable H2S scavenger, SS20, inhibited the effects of LA on cellular H2S. Estimates of single-cell H2S production suggest that 0.1-0.2% of O2 consumption is used to metabolize H2S and these requirements may increase to 1-2% with 1 mM LA. Collectively, these results suggest that LA rescues H2S from irreversible oxidation and that the effects of LA on RSS directly confer antioxidant, anti-inflammatory and cytoprotective responses. They also suggest that TS may be an effective supplement to increase the efficacy of LA in clinical settings.


Nasotransmucosal Delivery of Curcumin-Loaded Mucoadhesive Microemulsions for Treating Inflammation-Related CNS Disorders.
This investigation was aimed at designing an effective mucoadhesive microemulsion system to accomplish higher brain uptake of curcumin through intranasal route. Mucoadhesive microemulsion of curcumin (MMEC) was developed using screened oil, surfactant, and co-surfactant by Box-Behnken design and was evaluated for mucoadhesion, stability, and naso-ciliotoxicity study. Comparative brain uptake of curcumin after nasal administration of MMEC and polycarbophil curcumin gel and intravenous administration of plain curcumin solution was studied by performing bio-distribution study in Swiss albino rats. The results showed that all formulation variables i.e., the amount of capmul MCM (X1), Smix (accenon CC: transcutol P) (X2) and percentage of aqueous. Polycarbophil (X3) had a significant effect (p<0.05) on the responses. The developed MMEC was stable and non-ciliotoxic with 66.74 ± 3.46 nm and 98.58% ± 1.21 as average globule size and drug content, respectively. Polydispersibility index (0.133 ± 0.17) data and transmission electron microscopy study depicted the narrow size distribution of MMEC. Furthermore, following a comparative investigation of the brain uptake of curcumin among MMEC, plain drug gel and intravenous administration at 2.86 mg/kg, more brain uptake of curcumin was demonstrated for MMEC over intravenous application. Moreover, curcumin uptake in olfactory bulb after nasal administration of MMEC (31.11 ± 1.6) was than 9.44 times higher than intravenous injection of curcumin solution (3.25 ± 1.01). Area under curve represents the ratio of 2.86 mg/kg in brain tissue to plasma acquired afterward(s) the intranasal injection of MMEC (and it) was essentially greater than after the intravenous administration of curcumin solution. Findings of the investigation revealed that optimal MMEC and intranasal route may be considered to be promising and an alternative approach for brain targeting of curcumin.


Diagnostic approaches for pancreatic cystic lesions.
Cystic lesions of the pancreas (PCLs) may be inflammatory or proliferative and making an accurate and timely pre-operative diagnosis remains a significant clinical challenge. This is principally due to the heterogeneity of the pathological processes involved. PCLs constitute an entity with diverse histology and although infrequent, the possible potential for malignant transformation of these lesions and the opportunity for curative surgery mandates that our diagnostic approaches are up to date and evidence based. In addition, improved diagnostic accuracy is crucial to prevent unnecessary surgical procedures with the inevitable associated morbidity. This narrative review examines the current diagnostic benchmarks and identifies novel diagnostic techniques that warrant further consideration, a number of which are beginning to be included in routine clinical practice when these PCLs are being investigated. A computerized search was made of MEDLINE, EMBASE and PubMed using the search words 'diagnostic approaches to pancreatic cystic lesions'. All relevant articles in English language or with an English abstract were retrieved and additionally cross referenced. The increasing accuracy of available imaging techniques together with the wider availability of endoluminal ultrasound and the development of additional novel methods to assess PCLs presents an opportunity to significantly improve the pre-operative diagnosis rate. This is essential to classify the type of PCL and hence guide the management particularly with lesions where there is a likelihood of progression to more serious pathology. We have highlighted the need for a comprehensive and standardized algorithm for the diagnosis and management of PCLs.


Overexpression of thioredoxin reductase 1 can reduce DNA damage, mitochondrial autophagy and endoplasmic reticulum stress in Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Several factors, including neuroinflammation, neuronal excitotoxicity, genetic mutations and incorrect protein folding are involved in PD pathophysiology. However, the precise mechanism that contributes to the decreased number of dopaminergic neurons is unknown. A growing body of research suggests that oxidative stress is a major factor in PD. Therefore, antioxidant therapy is an important approach for treating PD. The thioredoxin system is an important antioxidant system, and thioredoxin reductase 1 (TR1) is a major member of the thioredoxin system. The present study demonstrates that oxidative stress is increased and that the expression of TR1 is decreased in the SNc of A53T mice; TR1 has emerged as an important antioxidant agent in dopaminergic neurons. Therefore, we over-expressed TR1 in the MPP+-induced cellular model and in the A53T transgenic mouse model of PD. We confirmed that the overexpression of TR1 in neuronal cells decreased DNA damage and malondialdehyde (MDA) and ROS generation, increased T-SOD and GSH production, and decreased the ER stress, and autophagy in the PD model. In summary, our findings demonstrate that the overexpression of TR1 could be effective as a novel neuroprotective strategy for PD. This research suggests a novel direction in the treatment of PD.


Costs of endometriosis in Austria: a survey of direct and indirect costs.
The literature includes a wealth of medical data on endometriosis, but the economic significance of the condition has so far been neglected. An analysis of hospital costs for endometriosis in Austria was, therefore, carried out for economic purposes. Seventy-three patients with endometriosis were included in the study. A bottom-up approach was used to collect data on the average hospital costs of an endometriosis patient over a time period of 1 year. In addition, a prevalence approach was used that allows subsequent estimation of the total costs of endometriosis for the health-care system in Austria for that period. Retrospective questionnaire survey was conducted. The average annual costs of one case of endometriosis are <euro>7,712, with <euro>5,605.55 attributable to direct costs and <euro>2,106.34 to indirect costs. This indicates an overall economic burden of <euro>328 million. In-patient care (45 %) and loss of productivity (27 %) were identified as the major cost factors. The patients themselves pay for 13 % of the costs (through out-of-pocket payments). This study impressively demonstrates the financial burden on the economy and on each individually affected patient caused by the disease of endometriosis. The massive consumption of resources represents a high level of usage of the medical services provided. The question arises as to whether more timely diagnosis, followed by better-targeted treatment, might have the potential to reduce these costs. The overall economic burden of endometriosis in Austria is currently comparable with that of Parkinson's disease.


Assessment of coronary flow reserve in the coronary sinus by cine 3T-magnetic resonance imaging in young adults after surgery for tetralogy of Fallot.
This study aimed to evaluate CFR by assessing blood flow in the coronary sinus and systemic endothelial function measured by FMD of the brachial artery in an open prospective study of 10 control subjects and 10 patients (ages, 15-25 years) who have undergone surgical TOF repair. Reduced ventricular function, impaired exercise capacity, and ventricular arrhythmia have been proposed as risk factors for sudden cardiac death after surgical repair of TOF. Some of this may be related to impaired myocardial perfusion. A 3.0T GE Signa Excite scanner was used to achieve phase-contrast, velocity-encoding cine magnetic resonance imaging in the coronary sinus before and during infusion with adenosine (0.14 mg/kg/min). FMD was measured in the brachial artery before arterial occlusion and 5 min afterward. The TOF group demonstrated significantly higher volumetric blood flow in the coronary sinus (282 ± 63 ml/min) than the normal control subjects at rest (184 ± 57 ml/min) (P = 0.006). During adenosine infusion, this difference disappeared. The CFR was 2.00 ± 0.43 in the control group and 1.19 ± 0.34 in the TOF group (P = 0.002). No correlation between FMD and CFR was observed in the study group (r (s) = 0.61, n = 8, P = 0.15). This study showed a reduced CFR due to a higher blood flow of the subject at rest in the TOF group. This reduced CFR may disable a normal adaptation to increased oxygen demand during exercise and increase myocardial vulnerability to reduced blood supply postoperatively for TOF patients with coronary heart disease.


Suspect screening strategy for pesticide application history based on characteristics of trace metabolites.
Pesticides are widely used to protect crops but can also threaten public health as they can remain in the environment for a long time. Additionally, some transformation products (TPs) of unknown toxicity, stability, or bioaccumulation properties can further be formed from the hydrolysis, photolysis and biodegradation of pesticides. The identification and quantification of those TPs can be challenging for environmental regulation and risk assessment due to a limited understanding about them. In this study, a suspect screening strategy for pesticide application history was developed and then used to organic products (tea). Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) was used to screen and identify the TPs in crops and their toxicity was subsequently predicted with the open-source software (ECOSAR and admetSAR). Finally, the SIRIUS software was applied and 142 TPs from 20 pesticides were identified in tea plants based on the fragmentation-degradation relationship. Of these, standards (level 1) and 53 were considered as tentatively identified (levels 2a and 2b). Some TPs were also found to be present in tea plants and soil after 65 days, thus indicating higher persistency or stability than parent pesticides. While others from diafenthiuron and neonicotinoids had higher predicted toxicity of daphnid, and demonstrated positive for honeybee toxicity. Suspect screening is a powerful tool to screen pesticide TPs on the complex matrix of crops. Such screening can provide potential evidence of pesticide application, especially in cases of illegal practices in organic farming.


Can in vitro maturation overcome cycles with repeated oocyte maturation arrest? A classification system for maturation arrest and a cohort study.
To investigate the role of gonadotropin-stimulated and human chorionic gonadotropin (hCG) -primed in vitro oocyte maturation (IVM) in cases of repeated in vitro fertilization (IVF) failure due to various forms of oocyte maturation arrest (OMA). Retrospective cohort study. In all, 63 women with IVF failure due to OMA were evaluated in this study. According to the Hatirnaz & Dahan classification, 11 (17.5%) women were OMA type 1, 22 (34.9%) were OMA type 2, 0 were OMA type 3, 11 (17.5%) were OMA type 4, and 19 women were OMA type 5 (30.1%). Fewer oocytes were retrieved in the IVM than in the IVF cycles. No embryos were produced from oocytes collected in the IVM cycles of women with OMA types 1, 2, and 4. In the OMA type 5 group, 9 (47.4%) day 2 embryos and 6 (31.6%) day 3 embryos were obtained. The difference between the groups was statistically significant (P = 0.001, P = 0.002, respectively). Single day 3 embryo transfer was performed for the six patients with OMA type 5 but no clinical pregnancies occurred. Follicle-stimulating hormone-stimulated and hCG-primed IVM does not improve oocyte maturation, developmental potential, or pregnancy rates of women with OMA. Future studies directed to re-establishing normal cytoskeletal architecture and machinery, and resumption of meiosis may be beneficial for obtaining mature oocytes.


Airway oxidative stress causes vascular and hepatic inflammation via upregulation of IL-17A in a murine model of allergic asthma.
Oxidants are generated in asthmatic airways due to infiltration of inflammatory leukocytes and resident cells in the lung. Reactive oxygen species (ROS) such as hydrogen peroxide and superoxide radical may leak into systemic circulation when generated in uncontrolled manner and may impact vasculature. Our previous studies have shown an association between airway inflammation and systemic inflammation; however so far none has investigated the impact of airway oxidative inflammation on hepatic oxidative stress and Th1/Th2/Th17 cytokine markers in liver/vasculature in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of systemic/hepatic Th1/Th2/Th17 cytokines balance and hepatic oxidative stress. Mice were sensitized intraperitoneally with cockroach extract (CE) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with CE. Mice were then assessed for systemic/hepatic inflammation through assessment of Th1/Th2/Th17 cytokines and oxidative stress (iNOS, protein nitrotyrosine, lipid peroxides and myeloperoxidase activity). Challenge with CE led to increased Th2/Th17 cytokines in blood/liver and hepatic oxidative stress. However, only Th17 related pro-inflammatory markers were upregulated by hydrogen peroxide (H2O2) inhalation in vasculature and liver, whereas antioxidant treatment, N-acetyl cysteine (NAC) downregulated them. Hepatic oxidative stress was also upregulated by H2O2 inhalation, whereas NAC attenuated it. Therefore, our study shows that airway oxidative inflammation may contribute to systemic inflammation through upregulation of Th17 immune responses in blood/liver and hepatic oxidative stress. This might predispose these patients to increased risk for the development of cardiovascular disorders.


Prognostic value of phase angle and bioelectrical impedance vector in critically ill patients: A systematic review and meta-analysis of observational studies.
Assessment of the raw parameters derived from bioelectrical impedance analysis (BIA) has gained emphasis in critically ill patients. The phase angle (PhA) reflects the integrity of the cell membrane, and bioelectrical impedance vector analysis (BIVA) is indicative of patients' hydration status. The aim of this study was to investigate whether these parameters are associated with clinical outcomes in the intensive care unit (ICU) setting. We conducted a systematic review with meta-analysis. We searched PubMed, Embase, Scopus and Web of Science for all published observational studies without language restrictions up to April 2022. Two reviewers independently performed study selection and data extraction. We judged the risk of bias by the Newcastle-Ottawa Scale and the certainty of evidence by the GRADE approach. Mortality was the primary outcome. Secondary outcomes included ICU length of stay, hospital length of stay, duration of mechanical ventilation, nutritional risk, and malnutrition. A meta-analysis with a random-effect model was performed to combine data on R version 3.6.2. Twenty-seven studies were included in the systematic review (4872 participants). Pooled analysis revealed that patients with low PhA had a higher risk of death (14 studies; RR = 1.82, 95% CI 1.46 to 2.26; I2 = 42%) and spent more days in ICU (6 studies; MD = 1.79, 95% CI 0.33 to 3.24, I2 = 69%) in comparison to patients with normal PhA. The pooled analysis also showed higher PhA values in survivors compared to non-survivor patients (12 studies; MD = 0.75°, 95% CI 0.60° to 0.91°, I2 = 31%). Overhydration defined by BIVA was not a predictor of mortality (4 studies; RR = 1.01, 95% CI 0.70 to 1.46; I2 = 0%). More than 40% of primary studies were classified with a high risk of bias, and the quality of evidence ranged from low to very low. This meta-analysis revealed, with limited evidence, that low PhA was associated with higher mortality and ICU length of stay, while overhydration identified by BIVA was not a predictor of death in critically ill patients.


Reconciling depressed Ca2+ sparks occurrence with enhanced RyR2 activity in failing mice cardiomyocytes.
Abnormalities in cardiomyocyte Ca2+ handling contribute to impaired contractile function in heart failure (HF). Experiments on single ryanodine receptors (RyRs) incorporated into lipid bilayers have indicated that RyRs from failing hearts are more active than those from healthy hearts. Here, we analyzed spontaneous Ca2+ sparks (brief, localized increased in [Ca2+]i) to evaluate RyR cluster activity in situ in a mouse post-myocardial infarction (PMI) model of HF. The cardiac ejection fraction of PMI mice was reduced to ∼30% of that of sham-operated (sham) mice, and their cardiomyocytes were hypertrophied. The [Ca2+]i transient amplitude and sarcoplasmic reticulum (SR) Ca2+ load were decreased in intact PMI cardiomyocytes compared with those from sham mice, and spontaneous Ca2+ sparks were less frequent, whereas the fractional release and the frequency of Ca2+ waves were both increased, suggesting higher RyR activity. In permeabilized cardiomyocytes, in which the internal solution can be controlled, Ca2+ sparks were more frequent in PMI cells (under conditions of similar SR Ca2+ load), confirming the enhanced RyR activity. However, in intact cells from PMI mice, the Ca2+ sparks frequency normalized by the SR Ca2+ load in that cell were reduced compared with those in sham mice, indicating that the cytosolic environment in intact cells contributes to the decrease in Ca2+ spark frequency. Indeed, using an internal "failing solution" with less ATP (as found in HF), we observed a dramatic decrease in Ca2+ spark frequency in permeabilized PMI and sham myocytes. In conclusion, our data show that, even if isolated RyR channels show more activity in HF, concomitant alterations in intracellular media composition and SR Ca2+ load may mask these effects at the Ca2+ spark level in intact cells. Nonetheless, in this scenario, the probability of arrhythmogenic Ca2+ waves is enhanced, and they play a potential role in the increase in arrhythmia events in HF patients.


Isolation of Ala1-proctolin, the first natural analogue of proctolin, from the brain of the Colorado potato beetle.
Methanolic head and brain extracts of the Colorado potato beetle contain several myotropins, active in the Locusta oviduct motility assay. Reversed phase high performance liquid chromatography (RP HPLC) gave evidence for the presence of three myotropic factors, with retention times close to that of proctolin. Both strongly stimulated the frequency, amplitude and tonus of the myogenic oviduct contractions. Gas phase sequencing and FAB-MS revealed that, besides proctolin (Arg-Tyr-Leu-Pro-Thr), two natural proctolin analogues were present. The first one is Ala-Tyr-Leu-Pro-Thr and is designed as Ala1-proctolin. The threshold concentration for biological activity of Ala1-proctolin was 10(-7) M, compared to 10(-10) M for proctolin itself. Ala1-proctolin is the first identified biological analogue of proctolin. The full nature of the first amino acid of a third proctolin-analogue (x-Tyr-Leu-Pro-Thr) is probably a modified amino acid of which the identity could as yet not be revealed. Our results suggest the existence of a family of proctolin-like peptides.


Mesophilic Acidogenesis of Food Waste-Recycling Wastewater: Effects of Hydraulic Retention Time, pH, and Temperature.
The effects of hydraulic retention time (HRT), pH, and operating temperature (T OP) on the degradation of food waste-recycling wastewater (FRW) were investigated in laboratory-scale hydrolysis/acidogenesis reactors. Response surface analysis was used to approximate the production of volatile organic acids and degradation of volatile suspended solids (VSS), carbohydrate, protein, and lipid with regard to the independent variables (1 ≤ HRT ≤ 3 days, 4 ≤ pH ≤ 6, 25 ≤ T OP ≤ 45 °C). Partial cubic models adequately approximated the corresponding response surfaces at α < 5 %. The physiological conditions for maximum acidification (0.4 g TVFA + EtOH/g VSadded) and the maximal degradation of VSS (47.5 %), carbohydrate (92.0 %), protein (17.7 %), and lipid (73.7 %) were different. Analysis of variance suggested that pH had a great effect on the responses in most cases, while T OP and HRT, and their interaction, were significant in some cases. Denaturing gradient gel electrophoresis analysis revealed that Sporanaerobacter acetigenes, Lactobacillus sp., and Eubacterium pyruvivorans-like microorganisms might be main contributors to the hydrolysis and acidogenesis of FRW. Biochemical methane potential test confirmed higher methane yield (538.2 mL CH4/g VSadded) from an acidogenic effluent than from raw FRW.


Systemic Immune-Inflammation (SII) index predicts poor outcome after spontaneous supratentorial intracerebral hemorrhage.
In experimental models, enhanced inflammation contributes to secondary brain injury in spontaneous intracerebral hemorrhage (ICH). Several inflammatory markers have investigated in humans with inconclusive results. Here, we report the relationship between Systemic Immune-Inflammation (SII) Index and outcome. We reviewed the medical records of 239 supratentorial spontaneous ICH patients. Patients were dichotomized based on modified Rankin Scale (mRS) at discharge in good (mRS 0-3) and poor (mRS 4-6) outcome. Demographic, clinical, laboratory and imaging data at admission were compared for both groups. SII index was calculated as [(Platelet counts x Absolute Neutrophil Counts (ANC)/Absolute Lymphocyte Counts (ALC))/1000]. Logistic regression analyses were performed to determine the association between markers of inflammation (ANC, ALC, Platelets, SII index) and outcome adjusting for baseline differences. Sixty-two percent of patients had poor outcome (median [IQR] age= 60 [52-71] years). Patients with poor outcome had lower Glasgow coma scale, larger hematoma volumes, and higher incidence of diabetes and intraventricular extension (p<0.05 for each variable). In univariate analysis, ANC and SII index were independently associated with poor outcome (p<0.05). In multivariate analysis, only SII index remained significantly associated with poor outcome (OR=1.34, 95% CI=1.04-1.72, p=0.02). ROC analysis showed that adjusted SII index is a good discriminator for poor outcome (AUC=0.89, 95% CI=0.84-0.93; P <0.0001), with the best cut-off value being 0.73 (Sensitivity 95%, Specificity 71%). In patients with supratentorial spontaneous ICH early SII index is an independent predictor of poor outcome at time of hospital discharge.


Clinical applications of auto indirect ophthalmoscopy.
A phakic eye that has undergone vitrectomy and gas-fluid exchange produces a real, inverted aerial image anterior to the cornea similar to that produced by a lens for indirect ophthalmoscopy. This image can be used during surgery to perform a variety of maneuvers that would otherwise require a contact prism, high-minus contact lens, or handheld indirect ophthalmoscope lens. Applications of auto indirect ophthalmoscopy include visualization of the retina and vitreous during endophotocoagulation and while using a vitreous cutter.


The roles of RNA polymerase and RNAase I in stable RNA degradation in Escherichia coli carrying the srnB+ gene.
In Escherichia coli cells carrying the srnB+ gene of the F plasmid, rifampin, added at 42 degrees C, induces the extensive rapid degradation of the usually stable cellular RNA (Ohnishi, Y., (1975) Science 187, 257-258; Ohnishi, Y., Iguma, H., Ono, T., Nagaishi, H. and Clark, A.J. (1977) J. Bacteriol. 132, 784-789). We have studied further the necessity for rifampin and for high temperature in this degradation. Streptolydigin, another inhibitor of RNA polymerase, did not induce the RNA degradation. Moreover, the stable RNA of some strains in which RNA polymerase is temperature-sensitive did not degrade at the restrictive temperature in the absence of rifampin. These data suggest that rifampin has an essential role in the RNA degradation, possibly by the modification of RNA polymerase function. A protein (Mr 12 000) newly synthesized at 42 degrees C in the presence of rifampin appeared to be the product of the srnB+ gene that promoted the RNA degradation. In a mutant deficient in RNAase I, the extent of the RNA degradation induced by rifampin was greatly reduced. RNAase activity of cell-free crude extract from the RNA-degraded cells was temperature-dependent. The RNAase was purified as RNAase I in DEAE-cellulose column chromatography and Sephadex G-100 gel filtration. Both in vivo and with purified RNAase I, a shift of the incubation mixture from 42 to 30 degrees C, or the addition of Mg2+ ions, stopped the RNA degradation. Thus, an effect on RNA polymerase seems to initiate the expression of the srnB+ gene and the activation of RNAase I, which is then responsible for the RNA degradation of E. coli cells carrying the srnB+ gene.


Longus Colli Tendinitis: The Lost Twin of Retropharyngeal Abscess.
Longus colli calcific tendinitis is a rare condition which mimics the alarming condition, retropharyngeal abscess. Clinically, the patient presents which acute cervical pain, dysphagia and fever. Since this condition is little known to otorhinolaryngologists, it is usually misdiagnosed as a retropharyngeal abscess which is more common. This is a case report of a 52 year old female who presented with complaints of neck pain and difficulty in swallowing along with fever which were acute in onset. Clinically, the symptoms overlapped with those of a retropharyngeal abscess. The diagnosis was confirmed as longus colli calcific tendinitis. Longus colli calcific tendinitis is a rare entity which can be diagnosed solely based on radiological investigation. The knowledge of this disease is crucial to otorhinolaryngolists as it avoids over treatment, unwarranted chance surgical exposure.


Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders.
Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in β3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABAARs may directly contribute to the pathophysiology of ASDs.


The effect of folate and VitB12 in the treatment of MCI patients with hyperhomocysteinemia.
This study aims to investigate the effect of folate combined with VitB12 on serum total homocysteine (tHcy) levels and cognitive function in patients with mild cognitive impairment (MCI) complicated by hyperhomocysteinemia (HHcy). (1) A total of 92 MCI patients with HHcy were enrolled in this study and randomly divided into two groups: the intervention group (46 cases) and the control group (46 cases). (2) The patients in both groups received the routine treatment for their condition, but patients in the intervention group were also given 5 mg/day of folate and 500 μg × 3/day of VitB12. (3) The changes in levels of folate, VitB12, and tHcy, the Montreal Cognitive Assessment (MoCA) score and the event-related potential (P300) were observed before and after treatment. (1) There were no statistically significant differences in folate, VitB12, and tHcy levels, the MoCA score and the P300 between the two groups before treatment. (2) At the 4th, 12th and 24th week, folate and VitB12 levels in the intervention group were higher than those in the same group before treatment and those in the control group at the same time points, while tHcy levels were lower than those in the same group before treatment and those in the control group at the same time points. (3) At the 24th week, the MoCA score in the control group was lower than before treatment, and the MoCA score in the intervention group was higher than in the same group before treatment and in the control group at the same time point. The P300 latency was shorter than it was in the same group before treatment and in the control group at the same time point. Folate and VitB12 can effectively reduce levels of tHcy in patients with MCI and improve cognitive function.


Effect of chemokine CC ligand 2 (CCL2) on α‑synuclein‑induced microglia proliferation and neuronal apoptosis.
The present study aimed to investigate the effect of chemokine CC ligand 2 (CCL2) on α‑synuclein‑mediated microglia proliferation and neuronal apoptosis. Primary cultured microglia and primary neurons were isolated and cultured in vitro. Microglia were divided into four groups: The cells in the control group were treated with an identical amount of PBS, whereas the cells in the CCL2 group were cultured in medium containing 0.05 ng/µl CCL2; cells in the α‑synuclein group were treated with medium containing 0.2 ng/µl α‑synuclein; and cells in the CCL2 plus α‑synuclein group were cultured in medium containing 0.05 ng/µl CCL2 and 0.2 ng/µl α‑synuclein. After incubation for 24 h, the proliferation of glial cells, and the level of α‑synuclein in the cells, were measured. The levels of tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β) and nitric oxide (NO) in the culture medium were also measured. Levels of cleaved caspase‑3, Akt and phosphorylated (p)‑Akt in neurons treated with primary microglia culture medium in each group were subsequently monitored. The proliferation activity and secretion of TNF‑α, IL‑1β and NO in the CCL2, α‑synuclein and CCL2 plus α‑synuclein groups were significantly higher compared with that in the control group (P<0.05), as were the levels of α‑synuclein (P<0.01). The levels of neuronal apoptosis and cleaved caspase‑3 protein in the CCL2, α‑synuclein and CCL2 plus α‑synuclein groups were also significantly higher compared with that in the control group (P<0.01). Taken together, these results have demonstrated that CCL2 is able to promote α‑synuclein secretion and the apoptosis of neurons induced by α‑synuclein, thus inducing proliferation of the microglia and secretion of TNF‑α, IL‑1β and NO.


Determination of uric acid in human urine and serum by capillary electrophoresis with chemiluminescence detection.
A simple and sensitive method based on capillary electrophoresis (CE) with chemiluminescence (CL) detection has been developed for the determination of uric acid (UA). The sensitive detection was based on the enhancement effect of UA on the CL reaction between luminol and potassium ferricyanide (K3[Fe(CN)6]) in alkaline solution. A laboratory-built reaction flow cell and a photon counter were deployed for the CL detection. Experimental conditions for CL detection were studied in detail to achieve a maximum assay sensitivity. Optimal conditions were found to be 1.0 x 10(-4) M luminol added to the CE running buffer and 1.0 x 10(-4) M K3[Fe(CN)6] in 0.2 M NaOH solution introduced postcolumn. The proposed CE-CL assay showed good repeatability (relative standard deviation [RSD]=3.5%, n=11) and a detection limit of 3.5 x 10(-7) M UA (signal/noise ratio [S/N]=3). A linear calibration curve ranging from 6.0 x 10(-7) to 3.0 x 10(-5) M UA was obtained. The method was evaluated by quantifying UA in human urine and serum samples with satisfactory assay results.


Structures of (1→6)-β-D-glucans from Bulgaria inquinans (Fries) and their immunological activities.
In previous study, an unbranched (1→6)-β-D-glucan with Mw 2.6kDa was isolated from fruit bodies of Bulgaria inquinans (Fries). In present paper, three branched (1→6)-β-D-glucans were obtained from the water-extracted residues by a sequential KOH-extraction, namely BIK2, BIK10 and BIK30. Their molecular weights were determined to be 37.5kDa (BIK2), 288.9kDa (BIK10) and 175.5kDa (BIK30). Structural analysis indicated that their backbones were substituted by single glucosyls at C-3 positions, the branching ratios were 0.01 (BIK2), 0.17 (BIK10), 0.25 (BIK30). Immunological tests showed that all the four β-D-glucans could significantly increase the ConA or LPS-induced lymphocytes proliferation in vivo. Moreover, branched (1→6)-β-D-glucans have more significantly lymphocytes proliferation activities than unbranched (1→6)-β-D-glucan, and the effect of (1→6)-β-D-glucans on lymphocytes proliferation increases along with molecular weights. The present results well enrich the structure-activity relationships of (1→6)-β-D-glucan, and indicate (1→6)-β-D-glucans from B. inquinans (Fries) are potential immunostimulating agents.


Molecular characterization and genetic diversity of Ornithonyssus sylviarum in chickens (Gallus gallus) from Hainan Island, China.
The northern fowl mite (NFM), Ornithonyssus sylviarum, is an obligatory hematophagous ectoparasite of birds and one of the most important pests in the poultry industry on several continents. Although NFM poses a serious problem, it remains a neglected pest of poultry in China and other Asian countries. Therefore, a molecular analysis was conducted to provide baseline information on the occurrence, genetic diversity and emergence of NFM in poultry farms from China. This study focused on morphological description and identification of adults based on electron microscopy, molecular sequencing of the mitochondrial cox1 gene and phylogenetic analysis. We have also used the DNA sequences of the cox1 gene to study the genetic diversity, population structure and demographic history. The neutrality tests were used to analyze signatures of historical demographic events. The mites collected were identified as the northern fowl mite Ornithonyssus sylviarum based on external morphological characterization using electron microscopy. Molecular analysis using a 756-bp long partial fragment of the cox1 gene revealed 99-100% sequence identity with NFM and phylogenetic inferences showed a bootstrap value of 99% indicating a well-supported monophyletic relationship. Molecular diversity indices showed high levels of haplotype diversity dominated by private haplotypes, but low nucleotide divergence between haplotypes. The Tajima's D test and Fu's Fs test showed negative value, indicating deviations from neutrality and both suggested recent population expansion of mite populations supported by a star-like topology of the isolates in the network analysis. Our genetic data are consistent with a single introduction of NFM infestations and the spread of NFM infestation in Hainan poultry farms and a private haplotype dominance, which suggest that infestations are recycled within the farms and transmission routes are limited between farms. To our knowledge, this is the first time a molecular report of NFM in chicken from China including other Asian countries using DNA barcoding. The findings have potential implications with respect to understanding the transmission patterns, emergence and populations trends of parasitic infestations of poultry farms that will help for setting the parameters for integrated pest management (IPM) tactics against mite infestations.


When "shoe" becomes free from "putting on": The link between early meanings of object words and object-specific actions.
Nouns referring to objects dominate children's early vocabulary over verbs referring to actions. However, some scholars have argued that early object-word meanings cannot be easily classified into specific object categories; rather, they have much undifferentiated meanings in which both objects and their specific actions are intertwined. We experimentally investigated this view using a two-alternative forced-choice task involving toddlers aged 18-23 months (n = 69). Both the cross-sectional and longitudinal results suggested that unlike older toddlers, younger ones could not select the correct referents when objects and object-specific actions were presented separately (e.g., "doing a filler action with shoes" vs. "putting on filler objects as if they were shoes") despite being successful when both were matched (e.g., "putting shoes on" vs. "doing a filler action with filler objects"). Additionally, toddlers failed to judge object-word referents solely by object-specific actions. These results indicated that early object-word meanings constitute the undifferentiated fusion of both objects and actions, and they subsequently differentiate into specific object categories independent of actions. Furthermore, the extent of such semantic differentiation is associated with the vocabulary growth of action words, suggesting that object-word meaning differentiation encouraged toddlers to develop new labels that could distinguish specific actions from objects. These findings revealed the uniqueness of young children's object-word comprehension, which is different from that of adults.


The interaction of melittin with troponin C.
Melittin has been found to interact with troponin C with high affinity in the presence of Ca2+. The association constant approaches in magnitude that for melittin and calmodulin. The interaction results in a shift to lower wavelengths of the emission band of Trp-19 of melittin and in an increased shielding of Trp-19 from quenching. A major increase occurs in the alpha-helical content of combined melittin. Formation of the complex inhibits tryptic hydrolysis of the connecting strand. The properties of fluorescent labels attached to Met-25 and to AEDANS-98 are altered as a result of the interaction. It is concluded that the combined melittin makes extensive contact with the connecting strand and adjacent portions of the N- and C-terminal lobes.


Prototype device for endoventricular beta-emitting radiotracer detection and molecularly-guided intervention.
We have set out to develop a catheter-based theranostic system that: (a) identifies diseased and at-risk myocardium via endocardial detection of systemically delivered β-emitting radiotracers and (b) utilizes molecular signals to guide delivery of therapeutics to appropriate tissue via direct intramyocardial injection. Our prototype device consists of a miniature β-radiation detector contained within the tip of a flexible intravascular catheter. The catheter can be adapted to incorporate an injection port and retractable needle for therapeutic delivery. The performance of the β-detection catheter was assessed in vitro with various β-emitting radionuclides and ex vivo in hearts of pigs following systemic injection of 18F-fluorodeoxyglucose (18F-FDG) at 1-week post-myocardial infarction. Regional catheter-based endocardial measurements of 18F activity were compared to regional tissue activity from PET/CT images and gamma counting. The β-detection catheter demonstrated sensitive in vitro detection of β-radiation from 22Na (β+), 18F (β+), and 204Tl (β-), with minimal sensitivity to γ-radiation. For 18F, the catheter demonstrated a sensitivity of 4067 counts/s/μCi in contact and a spatial resolution of 1.1 mm FWHM. Ex vivo measurements of endocardial 18F activity with the β-detection catheter in the chronic pig infarct model demonstrated good qualitative and quantitative correlation with regional tissue activity from PET/CT images and gamma counting. The prototype β-detection catheter demonstrates sensitive and selective detection of β- and β+ emissions over a wide range of energies and enables high-fidelity ex vivo characterization of endocardial activity from systemically delivered 18F-FDG.


Finding the sweet spot: the role of nature and nurture in medicinal chemistry.
Given its position at the heart of small-molecule drug discovery, medicinal chemistry has an important role in tackling the well-known productivity challenges in pharmaceutical research and development. In recent years, extensive analyses of successful and failed discovery compounds and drug candidates have improved our understanding of the role of physicochemical properties in drug attrition. Based on the clarified challenges in finding the 'sweet spot' in medicinal chemistry programmes, we suggest that this goal can be achieved through a combination of first identifying chemical starting points with appropriate 'nature' and then rigorously 'nurturing' them during lead optimization. Here, we discuss scientific, strategic, organizational and cultural considerations for medicinal chemistry practices, with the aim of promoting more effective use of what is already known, as well as a wider appreciation of the risks of pursuing suboptimal compounds.


The role of writing motives in the interplay between implicit theories, achievement goals, self-efficacy, and writing performance.
It is well established that students' motivation for writing is a key predictor of their writing performance. The aim of the current study is to study and map the relations underlying different motivational constructs (i.e., implicit theories, achievement goals, self-efficacy, and writing motives) and to investigate how these contribute to students' writing performance. For that, 390 Flemish students in stage three of the academic track of secondary education (16-18 years old) completed questionnaires measuring their implicit theories of writing, achievement goals, self-efficacy for writing, and writing motives. Furthermore, they completed an argumentative writing test. Path analysis revealed statistically significant direct paths from (1) entity beliefs of writing to performance avoidance goals (β = 0.23), (2) mastery goals to self-efficacy for writing (β argumentation = 0.14, β regulation = 0.25, β conventions = 0.18), performance-approach goals to self-efficacy for writing (β argumentation = 0.38, β regulation = 0.21, β conventions = 0.25), and performance-avoidance goals to self-efficacy for writing (β argumentation = -0.30, β regulation = -0.24, β conventions = -0.28), (3) self-efficacy for regulation to both autonomous (β = 0.20) and controlled motivation (β = -0.15), (4) mastery goals to autonomous motivation (β = 0.58), (5) performance approach and avoidance goals to controlled motivation (β = 0.18; β = 0.35), and (6) autonomous motivation to writing performance (β = 0.11). This study moves the field of writing motivation research forward by studying the contribution of implicit theories, achievement goals, and self-efficacy to students' writing performance, via writing motives.


A glycine betaine importer limits Salmonella stress resistance and tissue colonization by reducing trehalose production.
Mechanisms by which Salmonella establish chronic infections are not well understood. Microbes respond to stress by importing or producing compatible solutes, small molecules that stabilize proteins and lipids. The Salmonella locus opuABCD (also called OpuC) encodes a predicted importer of the compatible solute glycine betaine. Under stress conditions, if glycine betaine cannot be imported, Salmonella enterica produce the disaccharide trehalose, a highly effective compatible solute. We demonstrate that strains lacking opuABCD accumulate more trehalose under stress conditions than wild-type strains. ΔopuABCD mutant strains are more resistant to high-salt, low-pH and -hydrogen peroxide, conditions that mimic aspects of innate immunity, in a trehalose-dependent manner. In addition, ΔopuABCD mutant strains require the trehalose production genes to out-compete wild-type strains in mice and macrophages. These data suggest that in the absence of opuABCD, trehalose accumulation increases bacterial resistance to stress in broth and mice. Thus, opuABCD reduces bacterial colonization via a mechanism that limits trehalose production. Mechanisms by which microbes limit disease may reveal novel pathways as therapeutic targets.


Transition from narrow to wide QRS complex during sinus rhythm: What is the mechanism?
A Holter tracing showing transition from narrow QRS to wide QRS after a premature ventricular complex (PVC) during sinus rhythm is presented with explanation of the likely underlying mechanism.


TaqMan real-time PCR quantification: conventional and modified methods.
TaqMan real-time polymerase chain reaction (PCR) is a sensitive and reliable method that is widely used around the world. However, its inability to carry out assays using only small amounts of template DNA represents a serious limitation of the method. Recently, measurement of very small quantities of DNA became possible when a slight modification was applied to the conventional TaqMan real-time PCR method. Using the modified real-time PCR method, we were able to measure very small amounts of DNA template, and succeeded in comparing the levels of aldosterone synthase gene expression in samples of cardiac tissue from patients diagnosed with heart failure and control subjects.


Effect of phenylhydrazine on the plasma lipids of albino rat.
The effect of phenylhydrazine hydrochloride on the lipid composition of plasma of albino rats have been investigated. The data revealed significant increase in the percentages of lysophosphatidyl choline and decrease in that of phosphatidyl choline. There was increase in the cholesterol ester content in the plasma. The assay of plasma lecithin-cholesterol acyltransferase (LCAT) activity showed a significant increase in its activity parallel to the above changes.


Photosystem II single crystals studied by transient EPR: the light-induced triplet state.
Transient electron paramagnetic resonance (TR EPR) at 9.8 GHz has been used to study the light-induced triplet state in single crystals of Photosystem II (PS II). The crystals were grown from a solution of PS II core complexes from the thermophilic cyanobacterium Synechococcus elongatus. The core complexes contain at least 17 subunits, including the water-oxidizing complex, and 32 chlorophyll a molecules per PS II complex. The PS II complexes are active in light-induced electron transfer and water oxidation. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), with four dimers of PS II complexes per unit cell. Laser excitation was used to generate the recombination triplet state in PS II which was then studied by EPR at low temperatures (10 K). The crystal spectra show the same magnitude of the zero-field splitting (ZFS) values D, E as spectra obtained earlier for the triplet state of PS II in frozen solution. The orientation of the ZFS tensor D of the triplet state with respect to the crystallographic axes has been deduced from the analysis of angular-dependent EPR spectra. Knowledge of the orientation of the D tensor component perpendicular to the plane of the chlorophyll (D(Z)) allows an assignment on which chlorophyll of the reaction centre the triplet state is localized at low temperatures. Furthermore, the orientation of the D(X) and D(Y) components of the D tensor yielded the in-plane orientation of the respective chlorophyll in the reaction centre providing first experimental evidence for the orientation of this molecule in the PS II.


What Is the Main Feature Distinguishing the Through-Space Interactions in Cyclophanes from Their Aliphatic Analogues?
Classical cyclophanes with two benzene rings have been compared with cyclophanes with one benzene ring replaced with an aliphatic part and aliphatic compounds, which are cyclophane analogues. Analysis of geometry, atomic charges, and aromatic and steric energy and investigation of intramolecular noncovalent interactions and charge mobility show that there is no special feature that distinguishes the classical cyclophanes from aliphatic analogues, so the definition of cyclophanes can be extended to other compounds.


Spatiotemporal change and prediction of land use in Manasi region based on deep learning.
The Manasi region is located in an arid and semi-arid region with fragile ecology and scarce resources. The land use change prediction is important for the management and optimization of land resources. We utilized Sankey diagram, dynamic degree of land use, and landscape indices to explore the temporal and spatial variation of land use and integrated the LSTM and MLP algorithms to predict land use prediction. The MLP-LSTM prediction model retains the spatiotemporal information of land use data to the greatest extent and extracts the spatiotemporal variation characteristics of each grid through a training set. Results showed that (1) from 1990 to 2020, cropland, tree cover, water bodies, and urban areas in the Manasi region increased by 855.3465 km2, 271.7136 km2, 40.0104 km2, and 109.2483 km2, respectively, whereas grassland and bare land decreased by 677.7243 km2 and 598.5945 km2, respectively; (2) Kappa coefficients reflect the accuracy of the mode's predictions in terms of quantity. The Kappa coefficients of the land use data predicted by the MLP-LSTM, MLP-ANN, LR, and CA-Markov models were calculated to be 95.58%, 93.36%, 89.48%, and 85.35%, respectively. It can be found that the MLP-LSTM and MLP-ANN models obtain higher accuracy in most levels, while the CA-Markov model has the lowest accuracy. (3) The landscape indices can reflect the spatial configuration characteristics of landscape (land use types), and evaluating the prediction results of land use models using landscape indices can reflect the prediction accuracy of the models in terms of spatial features. The results indicate that the model predicted by MLP-LSTM model conforms to the development trend of land use from 1990 to 2020 in terms of spatial features. This gives a basis for the study of the Manasi region to formulate relevant land use development and rationally allocate land resources.


Mechanisms of delivery of liposome-encapsulated cytosine arabinoside to CV-1 cells in vitro. Fluorescence-microscopic and cytotoxicity studies.
Fluorescence microscopy and assays of the cytotoxicity of liposome-encapsulated cytosine arabinoside (araC) have been used to examine the interactions of CV-1 cells with pH-sensitive liposomes, combining phosphatidylethanolamine (PE) with oleic acid or with double-chain protonatable amphiphiles, and with pH-insensitive liposomes combining phosphatidylcholine (PC) and phosphatidylglycerol (PG). Fluorescence-microscopic observations indicate that double-chain protonatable amphiphiles remain tightly associated with pH-sensitive liposomes during incubations with CV-1 cell monolayers, and that cellular uptake of liposomes is strongly promoted by transferrin coupled to the liposome surface. Liposome-encapsulated araC showed much greater cytotoxicity toward CV-1 cells than did the free drug at equivalent concentrations under the same conditions. The cytotoxicity of encapsulated araC was strongly enhanced by liposome-conjugated transferrin and was maximal using pH-sensitive liposomes combining PE with the double-chain protonatable amphiphile N-(N'-oleoyl-2-aminopalmitoyl)serine. However, the drug was also markedly more cytotoxic when encapsulated in other types of transferrin-conjugated liposomes, including pH-insensitive PC/PG/cholesterol liposomes, than in the free form. The cytotoxicity of liposome-encapsulated araC is significantly attenuated by the nucleoside transport inhibitor nitrobenzothioinosine, and fluorescence microscopy using calcein-containing liposomes provides no evidence for efficient fusion between cellular membranes and any of the types of liposomes examined here. Based on these observations, we suggest that the major mechanism for cytoplasmic delivery of liposome-encapsulated araC is the carrier-mediated transport of drug that has been released from liposomes into the endosomal and/or the lysosomal compartments.


Rhythmic variations in the isocitrate dehydrogenase activity in the scorpin, Heterometrus fulvipes (C. Koch).
The activity of isocitrate dehydrogenase was assayed in the pedipalpal muscle and hepatopancreas of scorpion, Heterometrus fulvipes. The enzyme activity showed a circadian rhythmicity with a peak value at 20.00 h in both the tissues.


The uncertain advisor: trust, accuracy, and self-correction in an automated decision support system.
The increasing use of automated systems to support human decision-making is a development that has practical implications across multiple domains, and the dynamics of trust formation in an autonomous system is a critical element in the success of the human-automation team. Here, we employ existing models of human-automation trust to narrow our scope to address, specifically, the concept of dynamically learned trust. In the present experiments we explored how trust in an autonomous system is influenced by variations in system speed, system accuracy, and a novel operationalization of system uncertainty, in which the automated system corrects itself mid-response. Participants monitored the performance of an automated 'Captcha'-like decision support system, and were tasked with indicating whether the system was correct or incorrect on each trial. Dependent variables included subjective trust ratings, response times, hit rates, and false alarm rates. In addition to validating our methodology for quantifying the impact of low-level system design features, we further demonstrate that participants are more likely to miss system errors when they have high trust in a system, and that the speed and level of self-correction with which an automated system produces responses has an impact on human trust in that system.


[Prevalence of SARS-CoV-2 in children from a cohort of 2192 patients].
As of 18 June 2020 a total of 187,764 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were reported in Germany and of these 6.9% were under the age of 19 years. There were initial indications that children are often asymptomatic and show a milder clinical course. The aim of this study was to gain information on the prevalence of SARS-CoV‑2 infections in a pediatric cohort. Between 13 March and 18 June 2020 all children from whom a smear for SARS-CoV‑2 was taken either to rule out an infection or as a suspected case were included. Data were collected on standardized patient record sheets. The analysis of data was anonymized and retrospective. During the given period 2192 children were investigated and 37 patients tested positive (1.7%) for SARS-CoV‑2. Of these 36/37 were suspected cases and 28/37 were symptomatic. The leading symptoms were dry cough, runny nose and fever and three children had to be hospitalized. None showed a difficult course of the disease. Among those tested 505 were patients at risk due to an underlying chronic disease, 3 of whom (0.6%) were tested positive with an asymptomatic or mild course. We can confirm the first data showing that children and adolescents often have an asymptomatic or mild clinical course of infection or disease. We found no evidence of a high grey area of SARS-CoV‑2 infections in this regional pediatric cohort.


Vision is biased near handheld, but not remotely operated, tools.
Previous studies have shown that after actively using a handheld tool for a period of time, participants show visual biases toward stimuli presented near the end of the tool. Research suggests this is driven by an incorporation of the tool into the observer's body schema, extending peripersonal space to surround the tool. This study aims to investigate whether the same visual biases might be seen near remotely operated tools. Participants used tools-a handheld rake (Experiment 1), a remote-controlled drone (Experiment 2), a remote-controlled excavator (Experiment 3), or a handheld excavator (Experiment 4)-to rake sand for several minutes, then performed a target-detection task in which they made speeded responses to targets appearing near and far from the tool. In Experiment 1, participants detected targets appearing near the rake significantly faster than targets appearing far from the rake, replicating previous findings. We failed to find strong evidence of improved target detection near remotely operated tools in Experiments 2 and 3, but found clear evidence of near-tool facilitation in Experiment 4 when participants physically picked up the excavator and used it as a handheld tool. These results suggest that observers may not incorporate remotely operated tools into the body schema in the same manner as handheld tools. We discuss potential mechanisms that may drive these differences in embodiment between handheld and remote-controlled tools.


Association Between the Lockdown for SARS-CoV-2 (COVID-19) and Reduced Surgical Site Infections after Vascular Exposure in the Groin at Two Italian Academic Hospitals.
The aim of this study was to evaluate whether the scrupulous hygiene rules and the restriction of contacts during the lockdown owing to the COVID-19 pandemic affected the rate and severity of surgical site infections (SSI) after vascular exposure in the groin at two Italian University Hospitals. Starting from March 2020, strict hygiene measures for protection of health care workers (HCW) and patients from COVID-19 infection were implemented, and partly lifted in July 2020. The main exposure for analysis purposes was the period in which patients were operated. Accordingly, study subjects were divided into two groups for subsequent comparisons (preCOVID-19 era: March-June 2018-2019 versus COVID-19 era: March-June 2020). The primary endpoint was the occurrence of superficial and/or deep SSI within 30 days after surgery. The Centers for Disease Control and Prevention definitions were used to classify superficial and deep SSI. A total of 194 consecutive patients who underwent vascular exposure in the groin were retrospectively analyzed. Of those, 60 underwent surgery from April 1, 2018 to June 30 of the same year; 83 from April 1, 2019 to June 30 of the same year; and 51 from April 1, 2020 to June 30 of the same year. The mean age of the study cohort was 75 years and 140 (72%) were males. Patients who were operated in the COVID-19 era were less likely to develop SSI (10% vs. 28%; P = 0.008), including both deep SSI (4% vs. 13%; P = 0.04) and superficial SSI (6% vs. 15%; P = 0.05). After multivariate adjustments, being operated in the COVID-19 era was found to be a negative predictor for development of an SSI (odds ratio [OR] = 0.31; 95% confidence interval [CI] = 0.09-0.76; P < 0.001) or deep SSI (OR = 0.21; 95% CI = 0.03-0.98; P < 0.001). Operative time was also found as independent predictor for the development of deep SSI (OR = 1.21; 95%CI = 1.21-1.52; P = 0.02). Using binary logistic regression, there were no independent predictors of superficial SSI that could be identified. Vascular exposure in the groin carries a non-negligible risk of SSI. In this study, we provided important insights that are simple and easily viable precautions (such as the universal use of surgical masks both for patients and health care professionals during wound care, the widespread diffusion of hand sanitizers, and the reduction of the number of visitors in the surgical wards) could be promising and safe tools for SSI risk reduction.


Heart rate changes during conditioning-specific reflex modification of the rabbit's (Oryctolagus cuniculus) nictitating membrane response.
Conditioning-specific reflex modification (CRM) of the rabbit's nictitating membrane response (NMR) involves changes in responding to an unconditioned stimulus (US) when the US is tested in the absence of the conditioned stimulus. Previous experiments have shown that CRM is a function of the type and intensity of the aversive US used during classical conditioning. As a result, it has been suggested that CRM may be mediated, at least in part, by the aversiveness of the US. Here, we show that by using a moderately intense electrical pulse to the skin as a US, CRM of the rabbit NMR is accompanied by an increase in heart rate. The largest changes in heart rate occur at US intensities that produce the strongest levels of CRM. The heart rate data show that there may be an increased emotional/arousal component to the US that is correlated with CRM and support the use of CRM as a potential model for posttraumatic stress disorder.


Three-Dimensional Repositioning of the Maxilla in Orthognathic Surgery Using Patient-Specific Titanium Plates: A Case Series.
Successful orthognathic surgery is fundamentally based on accurately carrying out the intended surgical plan intraoperatively. The purpose of this study was to evaluate the accuracy of bone-borne patient-specific maxillary cutting guides and 3-dimensional (3D)-printed plates in repositioning the maxilla during bimaxillary orthognathic surgery. This was a retrospective case series consisting of patients who had undergone Le Fort I osteotomy with a patient-specific cutting guide and 3D-printed plate as well as a bilateral sagittal split osteotomy and had 6-week postoperative cone-beam computed tomography studies. The primary outcome variable was the difference between the position of the postoperative maxilla and the virtually planned maxilla measured at 10 landmarks in 3 dimensions. Other study variables included the preoperative diagnosis and planned surgical movement at each landmark. Descriptive statistics were tabulated, and bivariate analyses were performed. A total of 10 patients were included in this study. The mean age was 25.7 ± 8.1 years, and there were 5 female patients. The median planned surgical movement was 0.350 mm on the x-axis (right-left), 3.750 mm on the y-axis (anterior-posterior), and 1.704 mm on the z-axis (superior-inferior). The median absolute discrepancy between the postoperative position and the planned position on the x-axis, y-axis, and z-axis was 0.638, 0.798, and 0.481 mm, respectively. There was no significant difference in the discrepancies between the x-axis and y-axis (P = .575), x-axis and z-axis (P = .332), and y-axis and z-axis (P = .114). Using a patient-specific cutting guide and 3D-printed plate when performing Le Fort I osteotomy allows for accurate 3-dimensional positioning of the maxilla in accordance with the surgical plan.


d-Mannose binding, aggregation property, and antifungal activity of amide derivatives of pradimicin A.
Pradimicin A (PRM-A) and its derivatives comprise a unique family of antibiotics that show antifungal, antiviral, and antiparasitic activities through binding to d-mannose (Man)-containing glycans of pathogenic species. Despite their great potential as drug leads with an exceptional antipathogenic action, therapeutic application of PRMs has been severely limited by their tendency to form water-insoluble aggregates. Recently, we found that attachment of 2-aminoethanol to the carboxy group of PRM-A via amide linkage significantly suppressed the aggregation. Here, we prepared additional amide derivatives (2-8) of PRM-A to examine the possibility that the amide formation of PRM-A could suppress its aggregation propensity. Sedimentation assay and isothermal titration calorimetry experiment confirmed that all amide derivatives can bind Man without significant aggregation. Among them, hydroxamic acid derivative (4) showed the most potent Man-binding activity, which was suggested to be derived from the anion formation of the hydroxamic acid moiety by molecular modeling. Derivative 4 also exhibited significant antifungal activity comparable to that of PRM-A. These results collectively indicate that amide formation of PRM-A is the promising strategy to develop less aggregative derivatives, and 4 could serve as a lead compound for exploring the therapeutic application of PRM-A.


NORCCAP (Norwegian colorectal cancer prevention): a randomised trial to assess the safety and efficacy of carbon dioxide versus air insufflation in colonoscopy.
To eliminate the risk of combustion during electrosurgical procedures and to reduce patient discomfort, carbon dioxide (CO2) insufflation has been recommended during colonoscopy. However, air insufflation is still the standard method, perhaps due to the lack of suitable equipment and shortage of randomised studies. This randomised controlled trial was conducted to assess patient tolerance and safety when using CO2 insufflation during colonoscopy. Over an eight month period a successive series of patients referred for a baseline colonoscopy due to findings in a flexible sigmoidoscopy screening trial were randomly assigned to the use of either air or CO2 insufflation during colonoscopy. End tidal CO2 (ETCO2), a non-invasive parameter of arterial pCO2, was registered before and repeatedly during and after the examination. The patient's experience of pain during and after the examination was registered using a visual analogue scale (VAS). Sedation was not used routinely. CO2 insufflation was used in 121 patients (51%) and air in 119 patients (49%). The groups were similar in age, sex, and caecal intubation rate. No rise in ETCO2 was registered. There were statistically significant differences in VAS scores between the groups with less pain reported when using CO2. This randomised study of unsedated patients shows that CO2 insufflation is safe during colonoscopy with no rise in ETCO2 level. CO2 was found to be superior to air in terms of pain experienced after the examination.


High-pressure liquid chromatography of glycosphingolipids (with special reference to gangliosides).
The analysis of mixtures of gangliosides from adult human or bovine brain, supplemented with Tay-Sachs ganglioside, and haematoside from dog erythrocytes by high-pressure liquid chromatography using a moving-wire detector system is described. The complete separation of six gangliosides within 40 min has been achieved, using silica as the stationary phase and acidified chloroform-methanol-water mixtures as the eluent on a 25-cm column. Neutral glycosphingolipids, viz., the major components from normal human erythrocytes, can be completely separated on the same column, using non-aqueous and non-acidic eluents. It is shown that the methods described are useful for both analytical and (micro)-preparative purposes.


Disease mechanisms in neuropathic itch.
Itch, also known as pruritus, is an unpleasant cutaneous sensation that provokes the desire to scratch. Itch is a common symptom of inflammatory skin disorders, but it can also occur in neurological diseases associated with injury to nervous tissue, in the absence of any skin disease and without any notable physiological stimuli in the periphery. This 'neuropathic' type of itch occurs either in combination with neuropathic pain or independently and is thought to be underdiagnosed. In this Review, we describe the physiological characteristics of specific neuronal systems in the PNS and CNS that transmit and process pruriceptive information, and we consider pathological changes that occur in these systems after nerve lesions. We then introduce a classification system for itch and highlight the similarities and differences between neuropathic itch and neuropathic pain. A summary of neuropathic syndromes in the PNS and CNS that are associated with itch is presented. Finally, we propose appropriate treatment strategies for neuropathic itch, in view of the fact that this condition has different mechanisms of itch generation to other types of itch and consequently requires different therapies.


Predictors of participation in an HIV risk reduction intervention for socially deprived Latino women: a cross sectional cohort study.
Little is known about predictors of participation and attrition in HIV prevention programs for socially deprived Latino women. The purpose of this study was to examine factors that predict program participation and attrition among Latino women in a community-based, culturally specific HIV risk reduction intervention. This was a cross-sectional comparison of baseline data drawn from a randomized HIV risk reduction trial. Information was drawn from study subjects residing in a predominately Latino low-income community in Chicago. Among 404 study subjects in the intervention group, 214 of Latino women who had attended at least 5 of 6 intervention sessions were considered participants. One hundred and twelve women who never attended and 29 of women who attended fewer than 3 sessions were considered dropouts. The baseline data of program participants were compared to those of dropouts. The influence of the following factors on program participation was examined: sociodemographic characteristics, self-esteem, HIV knowledge, intimate partner violence, depression, and communication with partner. Logistic regression analysis showed that Mexican women were more likely to participate in the intervention program than Puerto Rican women (odds ratio (OR)=1.88, 95% confidence interval (CI)=1.64, 4.23). Other significant predictors of program participation included: being older (OR=1.08, 95% CI=1.03, 1.14), unemployed (OR=0.46, 95% CI=0.25, 0.83), having higher risk reduction behavior intentions score (OR=1.16, 95% CI=1.06, 1.26), and lower level of depressive symptoms (OR=0.97, 95% CI=0.95, 0.99). The recruitment and retention strategies should be developed by considering those important predictors of intervention participation to prevent Latino women from dropping out of the HIV prevention program.


Why in the age of CT scans and MRIs is a brain tumour mistaken for a psychiatric illness?
The first author of this paper operated on two patients with brain tumour, who had been undergoing long-term treatment for depression. In the age of CT scans and MRIs, why are there still cases in which a brain neoplasia is mistaken for a psychiatric condition with consequent serious delays in diagnosis? In this article, we have highlighted what in our experience are three noticeable obstacles in achieving the right diagnosis.


Circulating biomarkers for gliomas.
Currently, gliomas are diagnosed by neuroimaging, and refined diagnosis requires resection or biopsy to obtain tumour tissue for histopathological classification and grading. Blood-derived biomarkers, therefore, would be useful as minimally invasive markers that could support diagnosis and enable monitoring of tumour growth and response to treatment. Such circulating biomarkers could distinguish true progression from therapy-associated changes such as radiation necrosis, and help evaluate the persistence or disappearance of a therapeutic target, such as an oncoprotein or a targetable gene mutation, after targeted therapy. Unlike for other tumours, circulating biomarkers for gliomas are still being defined and are not yet in use in clinical practice. Circulating tumour DNA (ctDNA) isolated from plasma has been shown to reflect the mutational status of glioblastoma, and extracellular vesicles (EVs) containing ctDNA, microRNA and proteins function as rapidly adapting reservoirs for glioma biomarkers such as typical DNA mutations, regulatory microRNAs and oncoproteins. Ideally, circulating tumour cells could enable profiling of the whole-tumour genome, but they are difficult to detect and can reflect only a single cell type of the heterogeneous tumour composition, whereas EVs reflect the complex heterogeneity of the whole tumour, as well as its adaptations to therapy. Although all categories of potential blood-derived biomarkers need to be developed further, findings from other tumour types suggest that EVs are the most promising biomarkers.


1H-nuclear magnetic resonance study of the association of the basic protein of central nervous system myelin with lysophosphatidylcholine.
High-resolution 270 MHZ 1H-nuclear magnetic resonance spectroscopy has been used to follow the interaction of myristoyllysophosphatidylcholine with bovine myelin basic protein. At lipid/protein ratios up to 30:1 it proved possible to follow changes in the spectra of both the protein and the lipid. Lysophosphatidylcholine induced several changes in the protein spectrum. Foremost amongst these changes were downfield shifts of histidine C2 protons, and upfield shifts and broadening of the phenylalanine aromatic proteins. Several other resonances assigned to nonpolar amino acid side chains also broadened. But even at a lipid/protein molar ratio of 30:1 the majority of the protein appeared to remain in a loosely coiled conformation. In the presence of the protein the lipid acyl chain peaks were moved upfield and broadened, whereas the resonances associated with the head-group protons were unaffected. These changes were consistent with partial immobilization of the acyl chain of lysophosphatidylcholine on binding to the basic protein, with hydrophobic interactions providing the predominant attraction between this lipid and the basic protein.


Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability.
The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state.


Interhemispheric and quadrigeminal cysts.
Interhemispheric and quadrigeminal cysts are rare lesions, similar in their propensity to present in young babies and to be associated with other central nervous system malformations, such as corpus callosum agenesia, holoprosencephaly, encephalocele, and neuronal heterotopias. Recently endoscopy has become increasingly popular in the treatment of arachnoid cysts, but experience with cysts located in the interhemispheric fissure and in the quadrigeminal cistern is limited. This study reviews the specific anatomy of interhemispheric and quadrigeminal cysts and their relationship with the ventricular system and subarachnoid cisterns to select the most appropriated treatment. It also reviews the literature on endoscopic treatment of interhemispheric and quadrigeminal cysts. Interhemispheric and quadrigeminal cysts are not homogeneous, they have different extensions toward surrounding regions. In most cases it is presented as an area of contiguity between the cyst and ventricular system and/or subarachnoid cisterns, making endoscopic treatment feasible. The success rate for endoscopic treatment is not different from that reported in large series of arachnoid cysts elsewhere. Endoscopic treatment should be considered the first-line option in the treatment of such lesions, even if some complications, such as subdural collections due to thinness of the cerebral mantle or subcutaneous CSF collections due to multifactorial associated hydrocephalus, must be expected.


A simplified method for detecting macroamylasemia by measuring serum amylase activity at different reaction temperatures.
Amylase activity in serum and urine, and isoamylase, were measured in 300 patients with abdominal pain to detect cases of macroamylasemia. Of these patients, 9 had hyperamylasemia and 2 were diagnosed as cases of macroamylasemia on the basis of their amylase/creatinine clearance ratio, the gel filtration pattern of their amylase on a dextran column, and results of immunological analysis. Amylase activity in macroamylasemia is reported to show an anomalous response to increase in reaction-temperature. In this report, measurements of the temperature-activity relationships of serum amylase confirmed that the ratio of serum amylase activity at 50 degrees C to that at 25 degrees C (AMY-50 degrees C/AMY-25 degrees C ratio) in patients with macroamylasemia was higher than that in normal subjects or patients with pancreatitis. Moreover, when macromolecular amylase in the sera of patients with macroamylasemia was separated from amylase of normal molecular weight by dextran gel chromatography, it showed a significantly higher AMY-50 degrees C/AMY-25 degrees C ratio than the latter. Measurement of this AMY-50 degrees C/AMY-25 degrees C ratio seems to be a convenient and useful method for differential diagnosis of hyperamylasemia.


Analyses of long non-coding RNAs and mRNA profiling through RNA sequencing of MDBK cells at different stages of bovine viral diarrhea virus infection.
Bovine viral diarrhea virus (BVDV) infection is a dynamic and complex process that leads to significant economic losses in the dairy and cattle industries. However, our understanding of the protective and pathological mechanism underlying host infection is limited. To determine whether BVDV regulates specific activities of the host cell, the expression of long non-coding RNA (lncRNA) during BVDV NADL infection was studied by deep sequencing. A total of 1236 lncRNA transcripts and 3261 mRNA transcripts were differentially regulated at 2h, 6h, and 18h post-infection. The lncRNAs shared same characteristics with other mammals in terms of exon length, number, expression level, and conservation. The Gene Ontology (GO) enrichment and KEGG pathway analyses showed that lncRNAs regulate immune reaction during BVDV infection. Thirteen differentially expressed genes in 18 hpi were selected and independently validated by reverse-transcription qPCR. The present study is the first to provide insights into the biological connection of lncRNAs and BVDV, which can be further explored for the development of antiviral prevention strategies and in understanding persistent infection between viral and host components.


Evaluation of the Xpert Flu test and comparison with in-house real-time RT-PCR assays for detection of influenza virus from 2008 to 2011 in Marseille, France.
Rapid documentation of respiratory specimens can have an impact on the management of patients and their relatives in terms of preventive and curative measures. We compared the results of the Xpert(®) Flu assay (Cepheid) with three real-time RT-PCR assays using 127 nasopharyngeal samples, of which 75 were positive for influenza A (with 52 identified as A/H1N1-2009) and 52 were positive for influenza B. The Xpert(®) Flu assay presented a quasi-absence of non-interpretable tests, and showed sensitivity and specificity of 100% and 100% for Flu A, 98.4% and 100% for A/H1N1-2009, and 80.7% and 100% for Flu B.


Oncology End-of-Life Nursing Education Consortium training program: improving palliative care in cancer.
To describe an evaluation of the oncology version of the End-of-Life Nursing Education Consortium (ELNEC-Oncology) training program, which is designed to provide oncology nurses with the knowledge and materials necessary to disseminate palliative care information to their colleagues in local chapters of the Oncology Nursing Society (ONS). Participant reports. 124 nurses representing 74 ONS chapters attended the first two courses. Dyads of ONS members from local chapters applied to attend ELNEC and completed surveys regarding their goals and expectations for implementing end-of-life (EOL) education and training after completion of the program. Participants educated more than 26,000 nurses after attending the program, including 7,593 nurses within their ONS chapters and 18,517 colleagues within their workplaces. Barriers to implementation included a lack of funding and time constraints. Participants sought additional palliative care learning opportunities, including attending other workshops, subscribing to palliative care journals, and becoming involved in committees focused on palliative care. The ELNEC-Oncology program is a national collaboration with ONS that provides oncology nurses with the tools and expertise to effectively disseminate palliative care content to colleagues within their local chapters and work settings. EOL care information remains critical to the science of oncology nursing, and ELNEC-Oncology provides an effective strategy for disseminating the information.


Long-term vitamin status and dietary intake of healthy elderly subjects. 1. Riboflavin.
1. Long-term clinical and biochemical riboflavin status and dietary intake of riboflavin were monitored for 18 months in a group of twenty-three relatively-healthy elderly subjects living at home in the north of England. 2. Both dietary intake and biochemical status, as measured by the activation coefficient (stimulated:basal activity) of NAD(P)H2:glutathione oxidoreductase (EC 22.214.171.124), remained fairly constant for each individual and for most subjects the usual intake and biochemical status were characterized quite accurately by a single week's intake dietary record and a single measurement of the activation coefficient. 3. The expected relationship between biochemical status and dietary intake was present, but not strongly evident. There was a significant within-subject correlation between alpha values and the immediately preceding dietary intake; however the between-subject correlation between alpha values and dietary intake approached zero if the two subjects receiving long-term riboflavin supplements were omitted. Over the limited range of intakes observed in unsupplemented subjects, non-dietary factors evidently obscure the relationship. 4. Although eight subjects had average values above 1.2 for the activation coefficient, no excessively high values were observed, and no subject showed any clear-cut clinical deficiency symptoms.


Efficiency of interleukin-4 expression in patients with tuberculosis and nontubercular pneumonia.
In the early stage of Mycobacterium tuberculosis infection, macrophages, in cooperation with interferon-gamma, a Th1 effector, are the first line of defense. Interleukin (IL)-4, a Th2 effector, is known to downregulate interferon-gamma. It is believed that the expression levels of IL-4 and its splicing variant-IL-4delta2 might be associated with Mycobacterium tuberculosis infection and chest radiographic patterns. The IL-4 and IL-4delta2 expressions in stimulated peripheral blood mononuclear cells of 76 tuberculosis patients, 48 pneumonic patients. and 36 healthy control subjects were evaluated by nested reverse transcriptase-polymerase chain reaction, and the expression of glyceraldehydes-3-phosphate dehydrogenase was used as an internal reference. The results showed that IL-4 mRNA expression was significantly decreased in patients with tuberculosis and nontubercular pneumonia compared with that in controls. The IL-4delta2 mRNA expression was positively correlated with IL-4 mRNA expression in all cases. The ratio of IL-4delta2 to IL-4 mRNA expression in tubercular patients with a cavity on chest radiography was significantly lower than that in patients without a chest cavity. In conclusion, the ratio of IL-4delta2 to IL-4 mRNA expression may play a key role in disease severity for patients with pulmonary tuberculosis. From our observations, the IL-4 mRNA expression efficiency was attenuated in patients with pulmonary infection, either tuberculosis or pneumonia.


Short-Term Health Outcomes of a Structured Pulmonary Rehabilitation Program Implemented Within Rural Canadian Sites Compared With an Established Urban Site: A Pre-Post Intervention Observational Study.
To evaluate congruence in program delivery and short-term health outcomes of a structured pulmonary rehabilitation (S-PR) program implemented at 11 Canadian rural pulmonary rehabilitation (PR) sites compared with an urban reference site. Multi-center, pre- and post-intervention, comparative, observational study. Eleven rural Canadian PR sites and 1 urban reference PR site. Adults with chronic respiratory diseases (CRDs) referred to PR. Clinicians at the reference site worked with local clinicians to implement the S-PR program in rural sites. A PR survey evaluated site congruence with the S-PR components, with congruence defined as delivering program components ≥80% in alignment with the S-PR program. Participants were enrolled in 16 sessions of group education and supervised exercise, offered twice or thrice a week. Health outcomes were tracked using a quality assurance database. Main outcomes were congruence in program delivery and changes in the 6-minute walk (6MW) distance and COPD Assessment Test (CAT). A total of 555 participants (rural n=204 and reference n=351) were included in the analyses. There was congruence in exercise and group education; however, individual education varied. Following the S-PR program, 6MW distance increased, with greater changes observed at rural sites (51±67 m at rural sites vs 30±46 m at the reference site). CAT score was reduced by -2.6±5.4 points with no difference between reference and rural sites. Changes in 6MW distance and CAT scores were similar for participants at sites that were congruent vs noncongruent with the individual education component, and similar for patients with COPD, asthma, bronchiectasis, and interstitial lung disease. The S-PR program components can be implemented with good congruence in Canadian rural settings, resulting in similar short-term health outcomes as in an established urban site and across CRDs.


2.5D MFFAU-Net: a convolutional neural network for kidney segmentation.
Kidney tumors have become increasingly prevalent among adults and are now considered one of the most common types of tumors. Accurate segmentation of kidney tumors can help physicians assess tumor complexity and aggressiveness before surgery. However, segmenting kidney tumors manually can be difficult because of their heterogeneity. This paper proposes a 2.5D MFFAU-Net (multi-level Feature Fusion Attention U-Net) to segment kidneys, tumors and cysts. First, we propose a 2.5D model for learning to combine and represent a given slice in 2D slices, thereby introducing 3D information to balance memory consumption and model complexity. Then, we propose a ResConv architecture in MFFAU-Net and use the high-level and low-level feature in the model. Finally, we use multi-level information to analyze the spatial features between slices to segment kidneys and tumors. The 2.5D MFFAU-Net was evaluated on KiTS19 and KiTS21 kidney datasets and demonstrated an average dice score of 0.924 and 0.875, respectively, and an average Surface dice (SD) score of 0.794 in KiTS21. The 2.5D MFFAU-Net model can effectively segment kidney tumors, and the results are comparable to those obtained with high-performance 3D CNN models, and have the potential to serve as a point of reference in clinical practice.


Inflammatory and oxidative stress responses of healthy elders to solar-assisted large-scale cleaning system (SALSCS) and changes in ambient air pollution: A quasi-interventional study in Xi'an, China.
An outdoor solar assisted large-scale cleaning system (SALSCS) was constructed to mitigate the levels of fine particulate matter (PM2.5) in urban areas of Xi'an China, providing a quasi-experimental opportunity to examine the biologic responses to the changes in pollution level. We conducted this outdoor SALSCS based real-world quasi-interventional study to examine the associations of the SALSCS intervention and changes in air pollution levels with the biomarkers of systemic inflammation and oxidative stress in healthy elders. We measured the levels of 8-hydrox-2-deoxyguanosine (8-OHdG), Interlukin-6 (IL-6), as well as tumor necrosis factor alpha (TNF-α) from urine samples, and IL-6 from saliva samples of 123 healthy retired participants from interventional/control residential areas in two sampling campaigns. We collected daily 24-h PM2.5 samples in two residential areas during the study periods using mini-volume samplers. Data on PM10, gaseous pollutants and weather factors were collected from the nearest national air quality monitoring stations. We used linear mixed-effect models to examine the percent change in each biomarker associated with the SALSCS intervention and air pollution levels, after adjusting for time trend, seasonality, weather factors and personal characteristics. Results showed that the SALSCS intervention was significantly associated with decreases in the geometric mean of biomarkers by 47.6% (95% confidence interval: 16.5-67.2%) for 8-OHdG, 66% (31.0-83.3%) for TNF-α, 41.7% (0.2-65.9%) and 43.4% (13.6-62.9%) for urinary and salivary IL-6, respectively. An inter-quartile range increase of ambient PM2.5 exposure averaged on the day of the collection of bio-samples and the day before (34.1 μg/m3) was associated, albeit non-significantly so, with 22.8%-37.9% increases in the geometric mean of these biomarkers. This study demonstrated that the SALSCS intervention and decreased ambient air pollution exposure results in lower burden of systemic inflammation and oxidative stress in older adults.


[SEN1500: design and implementation of a registry of infants weighing less than 1,500 g at birth in Spain].
To design and implement a registry of infants weighing less than 1,500 g at birth in Spain. Prospective, cohort, multicenter study. All live born infants weighing less than 1,500 g in several voluntarily participating neonatal units in public and private hospitals were included. In the first 4 years of the registry (2002 to 2005), 9,638 very-low-birth-weight infants were born in the 65 neonatal units that have so far joined the program. The goal of very-low-birth-weight infant databases is to try to improve the quality and safety of the medical care given to these newborns and their families. This type of program helps to coordinate and promote several areas, including those of health education, training of medical staff, research and development, surveillance and quality improvement.


Small habitat matrix: How does it work?
We present herein our perspective of a novel Small Habitats Matrix (SHM) concept showing how small habitats on private lands are untapped but can be valuable for mitigating ecological degradation. Grounded by the realities in Sabah, Malaysian Borneo, we model a discontinuous "stepping stones" linkage that includes both terrestrial and aquatic habitats to illustrate exactly how the SHM can be deployed. Taken together, the SHM is expected to optimize the meta-population vitality in monoculture landscapes for aerial, arboreal, terrestrial and aquatic wildlife communities. We also provide the tangible cost estimates and discuss how such a concept is both economically affordable and plausible to complement global conservation initiatives. By proposing a practical approach to conservation in the rapidly developing tropics, we present a perspective from "ground zero" that reaches out to fellow scientists, funders, activists and pro-environmental land owners who often ask, "What more can we do?"


Molecular analysis of the ORFs 3 to 7 of porcine reproductive and respiratory syndrome virus, Québec reference strain.
The cDNA sequence of the 3'-terminal genomic region of the Québec IAF-exp91 strain of porcine reproductive and respiratory syndrome virus (PRRSV) was determined and compared to those of other reference strains from Europe (Lelystad virus) and US (ATCC VR2385, MN-1b). The sequence (2834 nucleotides) which encompassed ORFs 3 to 7 revealed extensive genomic variations between the Québec strain and Lelystad virus (LV), resulting from high number of base substitutions, additions and deletions. The ORFs 5, 3, and 7 seemed to be relatively the most variable; the predicted encoding products of the Québec and LV strains displayed only 52%, 54%, and 59% amino acid identities, respectively. Nevertheless, in vitro translation experiments of the structural genes (ORFs 5, 6, and 7) and radioimmunoprecipitation assays with extracellular virions gave results similar to those previously reported for LV. In contrast, close genomic relationships were demonstrated between Québec and US strains. Taking together, these results indicate that, although structurally similar, North American PRRSV strains belong to a genotype distinct from that of the LV, thus supporting previous findings that allowed to divide PRRSV isolates into two antigenic subgroups (U.S. and European).


Patterns of anomalies of structures of the middle ear and the facial nerve as revealed in newborn temporal bones.
The purpose of this study is to offer new data about facial nerve malformations in the tympanic cavity. Prospective anatomic study of newborns to demonstrate the submacroscopic anatomy of the intratympanic facial nerve and its surrounding structures by malformations. Step-by-step microdissection of 12 newborn temporal bones and histologic evaluation of 4 middle ears showing multiple malformations. Four of 12 temporal bones presented malformation in the middle ear. All 4 temporal bones showed developmental failures of the stapes, and 3 of them had malposition of the tympanic portion of the facial nerve. In 3 cases, there was an oval window atresia, and in 1 case, the rim of the oval window was not ossified and was positioned medial to the stapes. Malformation or displacement of the stapes can be an indirect sign for facial nerve malformation. The most common site for facial nerve malformation is the tympanic portion. The tympanic segment of the nerve is devoid of bony covering in association with these anomalies of the stapes.


Trends in rifampicin resistance among patients with presumptive TB in the pre-COVID and COVID-era.
The COVID 19 pandemic has had its impact on tuberculosis notification, incidence, and management, particularly in the context of rifampicin-resistant TB. We set out to determine the trends in rifampicin resistant tuberculosis between the pre-COVID and COVID era in a resource-constrained setting. This was a retrospective review of single early morning sputum from presumed tuberculosis between January 2016 and May 2022 in a regional TB referral and treatment centre in South-western, Nigeria. We used a molecular beacon to detect Mycobacterium tuberculosis (MTB) and mutations in the rpoB gene using a real-time polymerase chain reaction (PCR). We analyzed 19,892 of 20,589 presumptive TB with complete data. Most subjects were in the age group 18-45 years (10,594; 53.3 %) and were males (11,492; 57.8 %). Of the 19,892 presumptive TB, 4,526 (22.8 %) were in pre-COVID-19 era (Jan 2016-December 2019) and 15,366 (77.2 %) cases were in COVID-19 era (Jan 2020-May 2022). The MTB notification declined during the COVID-19 era compared with the pre-COVID-19 era (10.5 % vs 12.9 %, p < 0.001). The annual prevalence of MTB rose from 5.6 % (2016) to a peak of 23.2 % in 2019 (pre-COVID-19 era), followed by a decline to 12.8 % in 2020 and 8.6 % in 2022 (COVID-19 era), p = <0.001). The overall incidence of RR-TB was 3.8 %. The incidence of RR was higher during pre-COVID-19 than the COVID-19 era, 9.5 % vs 2.5 %, p = <0.001. The incidence of RR-TB declined substantially from 28.0 % in 2016 to 1.6 % in 2021 but rose exponentially to 5.4 % in 2022. After controlling for confounders, only the pre-COVID-19 status was associated with increased odds for RR (adjusted odds ratio 3.3, 95 % confidence interval, 2.049, 5.421). This study found a progressive decline in MTB notification since the COVID-19 pandemic's outbreak. Furthermore, RR-TB notification decreased gradually in the pre-COVID-19 era, with a resurgence in 2022. In the era of COVID-19, there is an urgent need to increase intervention efforts in order to halt the decline in MTB detection rates and the resurgence of RR-TB.