Platelet hyperaggregability: impaired responsiveness to nitric oxide ("platelet NO resistance") as a therapeutic target.
Platelet hyperaggregability and associated thrombosis have been documented in a number of cardiovascular disease states. While one of the current mainstays of anti-thrombotic treatment (i.e. aspirin, clopidogrel, glycoprotein IIb/IIIa antagonists) has been directed at reducing platelet activation and aggregation, it is apparent that there are limitations to the effectiveness of these therapies. Nitric oxide (NO) plays an important role in platelet physiology. The ability of NO to regulate cyclic guanosine-3,'5'-monophosphate (cGMP), via activation of soluble guanylate cyclase, is the principal mechanism of negative control over platelet activity. NO is not only of the endothelial source, it is also released from activated platelets, providing a negative feedback. Studies in patients with symptomatic ischemia, chronic heart failure, diabetes and various risk factors for cardiovascular disease have demonstrated that platelets from these subjects exhibit reduced responsiveness to the anti-aggregating efficacy of NO: a phenomenon termed "platelet NO resistance". It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor or EDRF), and as such may contribute to the increased risk of ischemic events. NO resistance also accounts for reduced pharmaco-activity of exogenous NO donors, e.g. organic nitrates. Platelet NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical and inactivation of soluble guanylate cyclase. NO resistance has both diagnostic and prognostic implications. The current review examines the association of platelet NO resistance with pathological hyperaggregability and discusses potential therapeutic strategies targeting this abnormality.


Nitrogen-doped carbon frameworks decorated with palladium nanoparticles for simultaneous electrochemical voltammetric determination of uric acid and dopamine in the presence of ascorbic acid.
A glassy carbon electrode (GCE) was modified with nitrogen-enriched carbon frameworks decorated with palladium nanoparticles (Pd@NCF/GCEs). The modified GCE is shown to be a viable tool for determination of uric acid (UA) and dopamine (DA) in the presence of ascorbic acid (AA). The Pd@NCF was fabricated though one-step pyrolysis and characterized by X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy and nitrogen-adsorption/desorption analysis. The Pd@NCF/GCE was characterized by differential pulse voltammetry (DPV). Both UA and DA have pronounced oxidation peaks (at 360 mV for UA and 180 mV for DA, all vs. Ag/AgCl) in the presence of AA. Response is linear in the 0.5-100 μM UA concentration range and in the 0.5-230 μM DA concentration range. The detection limits are 76 and 107 nM, respectively (at S/N = 3). This electrode is stable, reproducible and highly selective. It was used for UA and DA determination in spiked serum samples. Graphical abstractSchematic representation of nitrogen-enriched carbon frameworks decorated with palladium nanoparticles co-modified glassy carbon electrode for simultaneous determination of dopamine and uric acid in the presence of ascorbic acid.


Characterization of the spray droplets and spray pattern by means of innovative optical microscopy measurement method with the high-speed camera.
Liquid atomization plays an important role in the manufacturing of the pharmaceutical products. It is used in all production steps where liquid is applied. In some productions steps precise control over spraying parameters is essential. These steps include fluid bed granulation, film coating of tablets and pellet coating. Precise atomization of liquids enables control over the granule formation in granulation steps and film formation in coating steps. Atomization process includes breakup of liquid and formation of droplets, which is a complex and important phenomenon that should be carefully evaluated for each particular use. This study focuses on characterization of atomization process by the means of combining high-speed imaging, optical microscopy and continuous backlight illumination together with robust image processing algorithm. With pure water and three different hypromellose (HPMC) polymer dispersions that are frequently used for film coating of solid dosage forms, we successfully measured mean droplet size (Sauter mean diameter between 49 and 413 μm), droplet size distribution and droplet speed (in average 10-46 m/s). It was shown that the shape of cumulative volumetric droplet size distribution can be used to evaluate the successfulness of ligament breakup (i.e., formation of droplets) and by that the spray quality. Moreover, the obtained trends and empirical correlations between droplet size and other process parameters are useful in practice in order to select appropriate settings for optimal coating process parameters. Due to the simplicity of proposed method and data processing, the entire system is potentially suitable for near real-time coating monitoring and for rapid optimization of the atomization process.


Dual- versus single-coil implantable defibrillator leads: review of the literature.
The preferred use of dual-coil implantable defibrillator lead systems in current implantable defibrillator therapy is likely based on data showing statistically lower defibrillation thresholds with dual-coil defibrillator lead systems. The following review will summarize the clinical data for dual- versus single-coil defibrillator leads in the left and right pectoral implant locations, and will then discuss the clinical implications of single- versus dual-coil usage for atrial defibrillation, venous complications, and the risks associated with lead extraction. It will be noted that there are no comparative clinical studies on the use and outcomes of single- versus dual-coil lead systems in implantable defibrillator therapy over a long-term follow-up. The limited long-term reliability of defibrillator leads is a major concern in implantable defibrillator and cardiac resynchronization therapy. A simpler single-coil defibrillator lead system may improve the long-term performance of implanted leads. Furthermore, the superior vena cava coil is suspected to increase interventional risk in transvenous lead extraction. Therefore, the need for objective data on extractions and complications will be emphasized.


Physical and occupational therapy in the treatment of patients with multiple sclerosis.
The interdisciplinary approach to the management of MS patients includes the services of both physical and occupational therapy. These professions complement one another in their concerted effort to mobilize the patient, thereby minimizing the symptoms of progressive weakness, fatigue, and spasticity. The ambulant patient is far less likely to develop complications of inactivity such as contractures, decubitus ulcers, venous thrombosis, or osteoporosis (with its associated fatigue fractures), as well as bowel or bladder complications.


General improvements versus interruptive or non-interruptive alerts in the blood order set: study protocol for a randomized control trial to improve packed red blood cell utilization.
Blood transfusions can serve as a life-saving treatment, but inappropriate blood product transfusions can result in patient harm and excess costs for health systems. Despite published evidence supporting restricted packed red blood cell (pRBC) usage, many providers transfuse outside of guidelines. Here, we report a novel prospective, randomized control trial to increase guideline-concordant pRBC transfusions comparing three variations of clinical decision support (CDS) in the electronic health record (EHR). All inpatient providers at University of Colorado Hospital (UCH) who order blood transfusions were randomized in a 1:1:1 fashion to the three arms of the study: (1) general order set improvements, (2) general order set improvements plus non-interruptive in-line help text alert, and (3) general order set improvements plus interruptive alert. Transfusing providers received the same randomized order set changes for 18 months. The primary outcome of this study is the guideline-concordant rate of pRBC transfusions. The primary objective of this study is to compare the group using the new interface (arm 1) versus the two groups using the new interface with interruptive or non-interruptive alerts (arms 2 and 3, combined). The secondary objectives compare guideline-concordant transfusion rates between arm 2 and arm 3 as well as comparing all of arms of the study in aggregate to historical controls. This trial concluded after 12 months on April 5, 2022. CDS tools can increase guideline-concordant behavior. This trial will examine three different CDS tools to determine which type is most effective at increasing guideline-concordant blood transfusions. Registered on ClinicalTrials.gov 3/20/21, NCT04823273 . Approved by University of Colorado Institutional Review Board (19-0918), protocol version 1 4/19/2019, approved 4/30/2019.


Electroencephalography and computerized transaxial tomography in epilepsy diagnosis.
Over a 6-month period 89 patients with epileptic seizures were systematically examined by EEGs and CT. Forty-two percent of all cases showed pathological findings in CT compared to 89% with abnormal EEGs. CT is very useful in identifying organic lesions in the epileptic patient. CT identified 11 cases of supratentorial tumour which were correctly localized by EEG. In patients with seizures after trauma or encephalitis the EEG abnormalities were more than could be detected by CT. The EEG and CT findings in cerebrovascular disorders, alcoholism and other diseases are discussed. A remarkable result is the relatively high percentage of hydrocephalus (23%) in the group of cryptogenic epilepsy. Positive EEG findings as to epilepsy could be seen in 62% of the cases.


In vitro activities of several antimicrobial agents against recently isolated and genotyped Chlamydia trachomatis urogenital serovars D through K.
A systematic evaluation of the susceptibility of all Chlamydia trachomatis urogenital serovars (D through K) to levofloxacin, erythromycin, doxycycline, clarithromycin, and azithromycin was performed. All C. trachomatis serovars had comparable susceptibilities with respect to the various antimicrobials tested, thus confirming the homogeneous data so far obtained regarding the susceptibility of C. trachomatis to antimicrobial agents.


Simple binding of protein kinase A prior to phosphorylation allows CFTR anion channels to be opened by nucleotides.
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel is essential for epithelial salt-water balance. CFTR mutations cause cystic fibrosis, a lethal incurable disease. In cells CFTR is activated through the cAMP signaling pathway, overstimulation of which during cholera leads to CFTR-mediated intestinal salt-water loss. Channel activation is achieved by phosphorylation of its regulatory (R) domain by cAMP-dependent protein kinase catalytic subunit (PKA). Here we show using two independent approaches--an ATP analog that can drive CFTR channel gating but is unsuitable for phosphotransfer by PKA, and CFTR mutants lacking phosphorylatable serines--that PKA efficiently opens CFTR channels through simple binding, under conditions that preclude phosphorylation. Unlike when phosphorylation happens, CFTR activation by PKA binding is completely reversible. Thus, PKA binding promotes release of the unphosphorylated R domain from its inhibitory position, causing full channel activation, whereas phosphorylation serves only to maintain channel activity beyond termination of the PKA signal. The results suggest two levels of CFTR regulation in cells: irreversible through phosphorylation, and reversible through R-domain binding to PKA--and possibly also to other members of a large network of proteins known to interact with the channel.


Cerebral embolic protection during transcatheter aortic valve replacement: a systematic review and meta-analysis of propensity score matched and randomized controlled trials using the Sentinel cerebral embolic protection device.
The Sentinel cerebral embolic protection device (CEP) aims to reduce the risk of stroke during transcatheter aortic valve replacement (TAVR). We performed a systematic review and meta-analysis of propensity score matched (PSM) and randomized controlled trials (RCT) investigating the effect of the Sentinel CEP to prevent strokes during TAVR. Eligible trials were searched through PubMed, ISI Web of science databases, Cochrane database, and proceedings of major congresses. Primary outcome was stroke. Secondary outcomes included all-cause mortality, major or life-threatening bleeding, major vascular complications and acute kidney injury at discharge. Fixed and random effect models were used to calculate the pooled risk ratio (RR) with 95% confidence intervals (CI) and absolute risk difference (ARD). A total of 4066 patients from 4 RCTs (3'506 patients) and 1 PSM study (560 patients) were included. Use of Sentinel CEP was successful in 92% of patients and was associated with a significantly lower risk of stroke (RR: 0.67, 95% CI: 0.48-0.95, p = 0.02. ARD: -1.3%, 95% CI: -2.3 - -0.2, p = 0.02, number needed to treat (NNT) = 77), and a reduced risk of disabling stroke (RR: 0.33, 95% CI: 0.17-0.65. ARD: -0.9%, 95% CI: -1.5 - -0.3, p = 0.004, NNT = 111). Use of Sentinel CEP was associated with a lower risk of major or life-threatening bleeding (RR: 0.37, 95% CI: 0.16-0.87, p = 0.02). Risk for nondisabling stroke (RR: 0.93, 95% CI: 0.62-1.40, p = 0.73), all-cause mortality (RR: 0.70, 95% CI: 0.35-1.40, p = 0.31), major vascular complications (RR: 0.74, 95% CI: 0.33-1.67, p = 0.47) and acute kidney injury (RR: 0.74, 95% CI: 0.37-1.50, p = 0.40) were similar. The use of CEP during TAVR was associated with lower risks of any stroke and disabling stroke with an NNT of 77 and 111, respectively.


Linalool odor stimulation improves heat stress tolerance and decreases fat accumulation in nematodes.
Aromatherapy uses plant essential oils and fragrant ingredients for relaxation, sleep assistance, and improvement of restlessness related to dementia. Certain aromatic substances increase the life span and stress tolerance of nematodes. We investigated effects of exposure to linalool, a linear chain monoterpenic alcohol that is present in the essential oils of many plants, and its optical isomer, l-linalool, in Caenorhabditis elegans. Nematodes were repelled by the odor of both linalool and l-linalool; however, linalool odor stimulation decreased fat accumulation and increased motility after thermal stress. Analysis of a gene-deficient mutant revealed that the DAF-16 insulin-signaling pathway, which is involved in heat stress tolerance, was enhanced by linalool treatment. Linalool stimulation increased the expression of downstream genes such as sod-3 and hsp-12.6 via DAF-16. We conclude that linalool odor induces a repelling behavior in nematodes, improves heat stress tolerance through the DAF-16 signaling pathway, and affects fat accumulation.


[Emergency ambulance management of acute pain in children: a national survey].
To assess the knowledge and skills of physicians staffing mobile intensive care units (emergency ambulances) in the management of severe acute pain in children. Questionnaire-based telephone interviews with emergency physicians of all urban emergency ambulance services (n=360). This questionnaire covered knowledge of procedures for assessment of pain, definition of severe acute pain and its, treatment, availability of morphine and similar drugs, local guidelines and the physicians' opinion of the national guidelines. Physicians from all but one ambulance service responded. Forty-nine percent were unaware of the French Society of Anesthesiology and Intensive Care guidelines, and 63% had no local guidelines. Eight percent defined severe acute pain correctly and 10% defined the therapeutic objective correctly. Forty-seven percent used morphine (which was available for 93%), and 7% and 13% respectively followed guidelines about doses and waiting periods between administrations. This survey showed inadequate knowledge about the management (assessment and treatment) of severe acute pain in children in prehospital emergency settings. Training in this area is essential.


Anlotinib combined with the PD-L1 blockade exerts the potent anti-tumor immunity in renal cancer treatment.
Anlotinib have shown certain therapeutic effects of renal cell carcinoma (RCC), but drug resistance during treatment leads to the fact that the therapeutic effect is unsatisfactory. Herein, we investigated the tumor immune microenvironment about resistance mechanisms when application of Anlotinib and further improved its therapeutic effect. Our results showed that Anlotinib suppressed cell proliferation and promoted cell apoptosis in RCC cells. Meanwhile, the significantly up-regulated expression of PD-L1 was observed in Anlotinib-treated RCC cells by the concentration and time-dependent manner. Further study showed that Anlotinib-induced PD-L1 expression was regulated by autocrine IL-6 mediated JAK2/STAT3 signaling pathways. Interestingly, Anlotinib combined with PD-L1 blockade increased the infiltration of IFN-γ+CD8+ T cells and natural killer (NK) cells, also decreased the quantity of Treg cells and MDSCs in vivo. Likewise, the therapy above showed significantly synergistic therapeutic effect as demonstrated by reduced tumor volume and weight. These results indicated that the drug resistance might be attributed to the Anlotinib induced-PD-L1 mediated immunosuppression in renal cancer treatment. Anlotinib combined anti-PDL-1 treatment exerts the potential anti-tumor effect by promoting the induction and activation of immune killer cells. The therapeutic strategy of Anlotinib combined anti-PDL-1 could be a potential and promising approach for the therapy of renal cancer or other malignant tumors.


Management of Primary Necrotizing Fasciitis of the Breast: A Systematic Review.
Necrotizing fasciitis (NF) is a life-threatening infection that involves spreading necrosis of the subcutaneous tissue and fascia that affects the extremities, abdominal wall, and perineum. Primary infection of the breast is a rare occurrence. Shah et al described the first case of primary breast NF and recommended radical "pseudotumor" excision and delayed skin closure months after resolution. Numerous other cases reported were successfully managed with different strategies. We aimed to summarize management options for primary breast NF through a systematic review of the literature. A systematic review of English literature was performed using PubMed. A total of 58 abstracts were reviewed. Data were abstracted from 25 cases that met inclusion criteria. A total of 25 cases of primary NF of the breast without an inciting event were found within the literature. Common initial operations included total mastectomy (36.0%), excisional debridement (32.0%), and partial mastectomy (12.0%). A total or radical mastectomy was completed for definitive source control in 13 (52.0%) cases. A total of 18 cases underwent reconstruction. Split-thickness skin grafts (44.4%) and delayed primary closures (33.3%) were the most common methods of reconstruction. Majority of cases with primary breast NF are managed with a total mastectomy to gain source control. Reconstruction using split-thickness skin grafts was most common. Other options included delayed primary closure, full thickness skin grafts, local tissue rearrangement, and pedicle flap reconstruction. Reconstruction should be patient dependent, but the whole arsenal of the reconstructive ladder may be used.


Enterohemolysin, a new type of hemolysin produced by some strains of enteropathogenic E. coli (EPEC).
42 Escherichia coli O26 strains which had been isolated at geographically different places and over a long time period were examined for hemolysin synthesis. 17 of these were found to be hemolysin-negative, nine strains were found to produce plasmid encoded alpha-hemolysin and 16 strains were shown to produce a phenotypically different hemolysin. This new type of hemolysin was called enterohemolysin and found to be genetically and immunologically non-related with the already described E. coli alpha-hemolysin. Enterohemolytic E. coli were not found in feces of 200 healthy infants under the age of two years. However, four E. coli O111 strains, one O121:H- and one O25:K5:H- strain, all from infants with diarrhoea were also enterohemolysin producers.


[Flouroquinolone activity in clinical isolates of Streptococcus pneumoniae with different susceptibility to penicilline: an epidemiological study in five cities of Mexico].
Determine the susceptibility to five fluoroquinolones and cross-resistance of pneumococcusclinical isolates with different penicillin susceptibilities gathered in a community-based study. Cross-sectional survey. Two hundred and thirty one (231) isolates were obtained from respiratory secretions or blood specimens from 231 patients with acquired acute respiratory infection or bacteremia. In vitro susceptibility to penicillin (PEN), ciprofloxacin (CIP), levofloxacin (LEV), gatifioxacin (GAT), moxifloxacin (MOX) and gemifioxacin (GEM) was determined with minimal inhibitory concentration (MIC) using the E test. 42% of the isolates showed decreased susceptibility to PEN. The lowest antibiotic concentration that inhibited 90% of the isolates was 3 microg/ml (for CIP), 1 microg/ml (for LEV), 0.25 microg/ml (for GAT), 0.125 microg/ml (for MOX) and 0.032 microg/ml (for GEM). Median MIC for LEV, GAT, MOX and GEM increased with decreasing susceptibility to CIP. Susceptibility to CIP was similar between penicillin-susceptible and penicillin-resistant pneumococci. Third and fourth generation fluoroquinolones showed very high inhibitory activity, higher than that for CIP, for both penicillin-susceptible and penicillin-resistant pneumococci. We noted cross-resistance among fluoroquinolones.


Mitochondrial Matrix Processes.
Mitochondria possess their own genome that, despite its small size, is critically important for their functioning, as it encodes several dozens of RNAs and proteins. All biochemical processes typical for bacterial and nuclear DNA are described in mitochondrial matrix: replication, repair, recombination, and transcription. Commonly, their mechanisms are similar to those found in bacteria, but they are characterized by several unique features. In this review, we provide an overall description of mitochondrial matrix processes paying special attention to the typical features of such mechanisms.


Tooth discoloration induced by dental materials.
Tooth discoloration after endodontic treatment is frequently attributed to drugs and filling materials. In this in vitro study the staining potential of various dental materials was investigated by means of a visual method to determine tooth color. Extracted human premolars were prepared, and the following materials were introduced into the pulp cavities: Cavit, Durelon, Dycal, Fletcher's cement, IRM, AH26-silver free, gutta-percha, Duo Percha, Fuji ionomer, and zinc phosphate cement. Before the materials were applied, the original tooth color was assessed on the external buccal tooth surfaces. Further color determinations were undertaken at regular intervals for 6 months after the materials were introduced. Durelon, Fuji ionomer, Fletcher's cement, and zinc phosphate cement did not induce measurable tooth discoloration. Cavit, Dycal, gutta-percha, and IRM caused a mild stain. For the teeth filled with AH26-silver free and Duo Percha, a moderate discoloration was recorded.


Vaginal progesterone to prevent preterm birth in pregnant women with a sonographic short cervix: clinical and public health implications.
Vaginal progesterone administration to women with a sonographic short cervix is an efficacious and safe intervention used to prevent preterm birth and neonatal morbidity and mortality. The clinical and public health implications of this approach in the United States have been critically appraised and compared to other therapeutic interventions in obstetrics. Vaginal progesterone administration to women with a transvaginal sonographic cervical length (CL) ≤25 mm before 25 weeks of gestation is associated with a significant and substantial reduction of the risk for preterm birth from <28 to <35 weeks of gestation, respiratory distress syndrome, composite neonatal morbidity and mortality, admission to the neonatal intensive care unit, and mechanical ventilation. These beneficial effects have been achieved in women with a singleton gestation, with or without a history of spontaneous preterm birth, and did not differ significantly as a function of CL (<10 mm, 10-20 mm, or 21-25 mm). The number of patients required for treatment to prevent 1 case of preterm birth or adverse neonatal outcomes ranges from 10-19 women. The number needed to screen for the prevention of 1 case of preterm birth before 34 weeks of gestation is 125 women, and 225 for the prevention of 1 case of major neonatal morbidity or neonatal mortality. Several cost-effectiveness and decision analyses have shown that the combination of universal transvaginal CL screening and vaginal progesterone administration to women with a short cervix is a cost-effective intervention that prevents preterm birth and associated perinatal morbidity and mortality. Universal assessment of CL and treatment with vaginal progesterone for singleton gestations in the United States would result in an annual reduction of approximately 30,000 preterm births before 34 weeks of gestation and of 17,500 cases of major neonatal morbidity or neonatal mortality. In summary, there is compelling evidence to recommend universal transvaginal CL screening at 18-24 weeks of gestation in women with a singleton gestation and to offer vaginal progesterone to those with a CL ≤25 mm, regardless of the history of spontaneous preterm birth, with the goal of preventing preterm birth and neonatal morbidity and mortality.


[Changes in mitochondria energy function under the effect of eserine and picrotoxin].
Intoxication caused by intramuscular injection of picrotoxin and eserine (5 and 10 mg/kg) to albino rats is found to increase the degree of coupling of oxidation to phosphorylation and the rate of succinate oxidation. The conclusion may be drawn that the reaction of the oxidative phosphorylation system to the injection of the above pharmacological agents is not specific but reflects the compensatory shift in the microchondria functioning in response to hypoxia and seizures accompanying the intoxication.


Liver stiffness measured by virtual touch quantification predicts the occurrence of posthepatectomy refractory ascites in patients with hepatocellular carcinoma.
This study assessed the significance of measuring liver stiffness using virtual touch quantification before hepatectomy to predict posthepatectomy refractory ascites. A total of 267 patients with hepatocellular carcinoma who underwent hepatectomy were prospectively analyzed. Liver stiffness was defined as the median value of the virtual touch quantification (Vs; m/s) by acoustic radio-force-impulse-based virtual touch. A multivariate analysis showed that Vs and the aspartate aminotransferase-to-platelet ratio index were independent risk factors for postoperative refractory ascites (odds ratio = 3.27 and 3.08, respectively). The cutoff value for Vs was 1.52 m/s (sensitivity: 59.5%, specificity: 88.6%) as determined by the analysis of the receiver-operating characteristic curve, and the area under the receiver-operating characteristic curve was 0.79. The cutoff value for the aspartate aminotransferase-to-platelet ratio was 0.952 (sensitivity: 65.5%, specificity: 82.9%), and the area under the receiver-operating characteristic curve was 0.75. Vs is an independent risk factor for refractory ascites after hepatectomy. The measurement of liver stiffness by virtual touch quantification before hepatectomy can help estimate the risk of postoperative refractory ascites. Nonsurgical treatments should be considered for the management of patients who are at high risk for refractory ascites.


Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance.
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), play a paramount role in the central regulation of energy balance. Despite the substantial body of genetic evidence implicating BDNF- or TrkB-deficiency in human obesity, the critical brain region(s) contributing to the endogenous role of BDNF/TrkB signaling in metabolic control remain unknown. We assessed the importance of intact hypothalamic or hindbrain TrkB signaling in central regulation of energy balance by generating Nkx2.1-Ntrk2-/- and Phox2b-Ntrk2+/- mice, respectively, and comparing metabolic parameters (body weight, adiposity, food intake, energy expenditure and glucose homeostasis) under high-fat diet or chow fed conditions. Our data show that when fed a high-fat diet, male and female Nkx2.1-Ntrk2-/- mice have significantly increased body weight and adiposity that is likely driven by reduced locomotor activity and core body temperature. When maintained on a chow diet, female Nkx2.1-Ntrk2-/- mice exhibit an increased body weight and adiposity phenotype more robust than in males, which is accompanied by hyperphagia that precedes the onset of a body weight difference. In addition, under both diet conditions, Nkx2.1-Ntrk2-/- mice show increased blood glucose, serum insulin and leptin levels. Mice with complete hindbrain TrkB-deficiency (Phox2b-Ntrk2-/-) are perinatal lethal, potentially indicating a vital role for TrkB in visceral motor neurons that control cardiovascular, respiratory, and digestive functions during development. Phox2b-Ntrk2+/- heterozygous mice are similar in body weight, adiposity and glucose homeostasis parameters compared to wild type littermate controls when maintained on a high-fat or chow diet. Interestingly, despite the absence of a body weight difference, Phox2b-Ntrk2+/- heterozygous mice exhibit pronounced hyperphagia. Taken together, our findings suggest that the hypothalamus is a key brain region involved in endogenous BDNF/TrkB signaling and central metabolic control and that endogenous hindbrain TrkB likely plays a role in modulating food intake and survival of mice. Our findings also show that female mice lacking TrkB in the hypothalamus have a more robust metabolic phenotype.


Metal organic framework derived Zn/N co-doped hydrophilic porous carbon for efficient solid phase microextraction of polar phenols.
MOF-derived zink and nitrogen co-doped porous carbon (ZNPC) was synthesized through the pyrolysis of MOF-5-NH2 and used as a solid-phase microextraction (SPME) coating material. Coupled with gas chromatography-mass spectrometry (GC-MS), headspace SPME (HS-SPME) based on ZNPC was adopted for the determination of phenols in food samples. The co-existence of N and Zn in ZNPC endows the derived carbon superior hydrophilicity, which is highly beneficial for phenols capture. After optimizing the conditions of extraction and desorption, a sensitive analytical method was established with low limits of detections (LODs, 0.73-2.3 ng g-1) and wide linear ranges (5-5000 ng g-1). Both the intra-fiber repeatability (RSDs from 2.8-7.3%) and inter-fiber reproducibility (RSDs from 9.7-11.7%) were satisfactory. The established method was applied to phenol determination in beef jerky and duck neck with satisfactory recoveries of 81.2-120.4% and RSDs of 2.8-9.9%, which met well with the requirement of practical application.


Nuclear hormone receptors promote gut and glia detoxifying enzyme induction and protect C. elegans from the mold P. brevicompactum.
Animals encounter microorganisms in their habitats, adapting physiology and behavior accordingly. The nematode Caenorhabditis elegans is found in microbe-rich environments; however, its responses to fungi are not extensively studied. Here, we describe interactions of C. elegans and Penicillium brevicompactum, an ecologically relevant mold. Transcriptome studies reveal that co-culture upregulates stress response genes, including xenobiotic-metabolizing enzymes (XMEs), in C. elegans intestine and AMsh glial cells. The nuclear hormone receptors (NHRs) NHR-45 and NHR-156 are induction regulators, and mutants that cannot induce XMEs in the intestine when exposed to P. brevicompactum experience mitochondrial stress and exhibit developmental defects. Different C. elegans wild isolates harbor sequence polymorphisms in nhr-156, resulting in phenotypic diversity in AMsh glia responses to microbe exposure. We propose that P. brevicompactum mitochondria-targeting mycotoxins are deactivated by intestinal detoxification, allowing tolerance to moldy environments. Our studies support the idea that C. elegans NHRs may be regulated by environmental cues.


A genome-wide association study of survival in patients with sepsis.
Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis. This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10-8. Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants. We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37-6.78], p = 4.92 × 10-8). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury. We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings.


Contribution of a multicomponent intervention on functional capacity and independence on activities of daily living in individuals with neurocognitive disorder.
To examine the effects of a 6-month multicomponent (MT) exercise intervention in the functional capacity and ability to independently perform activities of daily living (ADL) of individuals diagnosed with neurocognitive disorder (NCD). A quasi-experimental controlled trial with a parallel design study was conducted in multicentered community-based settings. Forty-three individuals (N Female: 30) were allocated to an exercise group (EG; N: 23; mean 75.09, SD = 5.54 years) or a control group (CG; N:20; mean 81.90, SD = 1.33 years). The EG engaged in a 6-month MT program (60-min sessions, twice a week). Exercise sessions were divided into a warm-up, specific training (e.g., coordination and balance, lower and upper body strength, and aerobics), and cool down. Lower body function, mobility, and gait speed were evaluated through Short Physical Performance Battery (SPPB), Timed-Up and Go test (TUG) and 6-Meter Walk test, respectively. The Barthel Index (BI) was administered to assess individuals' ADL independence. Evaluations were performed before and after the 6-month intervention. Linear Mixed Models revealed a statistically significant interaction (time X group) effect factor on SPPB (B = 2.33, 95% CI: 1.39-3.28, p < 0.001), TUG (B = - 11.15, 95% CI: - 17.23 - - 5.06, p = 0.001), and 6-Meter Walk test (B = 0.17, 95% CI: 0.08-0.25, p < 0.001). No differences between groups or assessment moments were found in the ability of individuals to independently perform ADL. The 6-month MT exercise intervention improves the functional capacity of older adults living with NCD. ClinicalTrials.gov - identifier number NCT04095962 ; retrospectively registered on 19 September 2019.


Expression of a recombinant vector of a mutant human telomerase reverse transcriptase gene in human bladder cancer cell line T24, and its clinical significance.
To construct a mutant enhanced green fluorescence protein (pEGFP) human telomerase reverse transcriptase (hTERT) gene expression vector (pEGFP-hTERT), to observe its expression in transfected human bladder cancer cell line T24 and its role in the molecular regulatory mechanisms of telomerase, and to provide a new target gene for bladder cancer therapy. Polymerase chain reaction (PCR) amplification was performed using primers based on the gene sequence of hTERT. The PCR product was cloned into plasmid pGEMT-T Easy and the sequence of mutant hTERT gene analysed. A recombinant mutant hTERT vector (pEGFP-hTERT) was constructed at the EcoR I and Sal I sites of the pEGFP-C1 vector. After transfecting the fusion gene into T24 cells by the method of calcium phosphate-DNA co-precipitation, we detected steady expression of the GFP-hTERT fusion protein by fluorescent-light microscopy. Changes in the proliferation of T24 cells were detected by light microscopy, and beta-galactosidase staining correlated with senescence. Identification of pEGFP-hTERT by enzyme digestion showed that the mutant hTERT fragment had been cloned into EcoR I and Sal I sites of the pEGFP-C1 vector. Steady expression of GFP-hTERT fusion protein was located in the nucleus of transfected cells. Positive expression senescence-associated beta-galactosidase staining in transfected cells increased gradually with extended cultured time, and their growth was suppressed. The recombinant mutant vector (pEGFP-hTERT) was successfully constructed and expressed steadily in T24 cells. The mutant-type hTERT gene suppresses the proliferation of T24 cells by a competitive effect on telomerase activity. This suggests that the hTERT gene might be a suitable gene target for bladder cancer therapy.


Achiral phosphonium induced remarkable circular polarized luminescence in a chiral cadmium(II) halide perovskite material.
Circular polarized luminescence (CPL) sensitive two-dimensional organic inorganic halide perovskites have versatile applications in optical displays, encrypted transmission and quantum communications. Here, a new chiral hybrid [MePh3P]2CdCl4 (PCC) single crystal (SC) is synthesized using an achiral phosphonium cation by a solvent evaporation process at room temperature (rt). SC x-ray study reveals a non-centrosymmetric point group 23, with 21-screw optical axes providing a chiral Sohncke space group. Hirshfeld surface analysis suggests long-range H-bonding and ionic interactions (~ 3-9 kJ mol-1) and short-range Van der Waals and dispersion interactions (∼0.4-4 kJ mol-1). Both the PCC thin films and SCs exhibit prominent circular dichroism (CD) and remarkably superior CPL activity at rt (|gCD| ≈ 5 × 10-3 and |glum| ≈ 4.3 × 10-2).


The CpG ODNs enriched diets enhance the immuno-protection efficiency and growth rate of Chinese mitten crab, Eriocheir sinensis.
CpG oligodeoxynucleotides (ODNs), the well-known vaccine adjuvant in mammals, have been proved to mount innate immune responses in crustaceans. In the present study, CpG ODNs was employed as supplements in diets to fed crab Eriocheir sinensis, and the changes of immune parameters as well as weight gain were investigated to evaluate its possible application in crab farming. After the crabs were fed with 40 mg/kg and 100 mg/kg CpG ODNs containing diets (designated as C40 and C100 group) for four weeks, the lysozyme activities were significantly enhanced (p < 0.01) in both groups, while the catalase activity was only increased (p < 0.01) in the C40 group. When those crabs were subsequently challenged with Aeromonas hydrophila, the cumulative mortalities in C40 and C100 groups were declined by 10.4% and 10.8% (p < 0.05) compared with that of control group, respectively. Interestingly, the final weights of crabs were increased after four weeks' feeding of CpG ODNs, and the percentage of weight gain in C40 group reached 124.5 ± 14.2%, which was significantly higher (p < 0.05) than that of control group (78.1 ± 19.2%) and C100 group (107.3 ± 28.2%). The uptake of CpG ODNs by haemocytes and the possible mechanism of CpG ODNs to active the immune response were investigated by using the laser scanning confocal microscope. CpG ODNs (labeled with 5'-end-FAM) could be internalized by the haemocytes after incubation of 20 min, with strong signals detected at the cell membrane and in the cytoplasm. In the cytoplasm, most of the CpG ODNs were localized in lysosome, and some of them escaped from the lysosomal compartments and aggregated around the nuclear. The results clearly demonstrated that CpG ODNs could be internalized directly by crab haemocytes and mostly located in the late endosome. The enhancements of immuno-protection efficiency and growth rate from CpG ODNs as supplements in diets might depend on the uptaking and locating processes, and they could be used as a potential immunostimulant for the crab aquaculture.


Mechanisms of autophagosome biogenesis.
Autophagy is a unique membrane trafficking process whereby newly formed membranes, termed phagophores, engulf parts of the cytoplasm leading to the production of double-membraned autophagosomes that get delivered to lysosomes for degradation. This catabolic pathway has been linked to numerous physiological and pathological conditions, such as development, programmed cell death, cancer, pathogen infection, neurodegenerative disorders, and myopathies. In this review, we will focus on recent studies in yeast and mammalian systems that have provided insights into two critical areas of autophagosome biogenesis - the source of the autophagosomal membranes, and the mechanisms regulating the fusion of the edges of the double-membraned phagophores to form autophagosomes.


Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension.
Autophagy has a fundamental role in maintaining cell homeostasis. Although autophagy has been implicated in glaucomatous pathology, how it regulates retinal ganglion cell (RGC) injury is largely unknown. In the present work, we found that biphasic autophagy in RGCs occurred in a mouse model of chronic ocular hypertension (COH), accompanied by activation of Rac1, a member of the Rho family. Rac1 conditional knockout (Rac1 cKO) in RGCs attenuated RGC apoptosis, in addition to blocking the increase in the number of autophagosomes and the expression of autophagy-related proteins (Beclin1, LC3-II/I, and p62) in COH retinas. Electron micrograph and double immunostaining of LAMP1 and LC3B showed that Rac1 cKO accelerated autolysosome fusion in RGC axons of COH mice. Inhibiting the first autophagic peak with 3-methyladenine or Atg13 siRNA reduced RGC apoptosis, whereas inhibiting the second autophagic peak with 3-MA or blocking autophagic flux by chloroquine increased RGC apoptosis. Furthermore, Rac1 cKO reduced the number of autophagosomes and apoptotic RGCs induced by rapamycin injected intravitreally, which suggests that Rac1 negatively regulates mTOR activity. Moreover, Rac1 deletion decreased Bak expression and did not interfere with the interaction of Beclin1 and Bcl-2 or Bak in COH retinas. In conclusion, autophagy promotes RGC apoptosis in the early stages of glaucoma and results in autophagic cell death in later stages. Rac1 deletion alleviates RGC damage by regulating the cross talk between autophagy and apoptosis through mTOR/Beclin1-Bak. Interfering with the Rac1/mTOR signaling pathway may provide a new strategy for treating glaucoma.


Quantitation of globin chains using cellulose acetate electrophoresis: analysis of fetal globin chain production.
A technique involving the quantitative estimation of globin chains using cellulose acetate electrophoresis is described, and applied to the analysis of fetal globin chain production. When cord blood was analyzed, there was poor correlation between the globin chain ratios namely beta/alpha, gamma/alpha and beta/gamma ratios with either age or weight of newborn babies between 36-40 weeks gestation: best correlations were obtained for the beta/gamma ratio against weight (P less than 0.05). However, there was highly significant correlation between the various globin chain ratios and either age or weight of the newborn infant up to 12 weeks of age (P less than 0.001). This technique allows visual demonstration and quantitation of abnormal haemoglobins in a single procedure.


Effects of culling intensity on diel and seasonal activity patterns of sika deer (Cervus nippon).
Adaptive hunting management is commonly used for controlling the populations of overabundant large herbivores; however, induced behavioural changes can make the effective control of target populations difficult. However, few studies have compared the impact of different levels of hunting intensities on the activity patterns of ungulates before, during, and after a culling program. We investigated how different culling intensities affect the activity patterns of sika deer on Nakanoshima Island in Lake Toya, Hokkaido, Japan using camera-trap surveys comparing the period of treatment before, during, and after a culling program. We used the number of deer photographed per hour per camera as an index of activity. Sika deer showed consistent crepuscular activity patterns (i.e., dawn and dusk) during spring-summer and trimodal activity patterns (i.e., dawn, dusk, and midnight) in autumn throughout the study period. In response to increased culling intensity, the activity peaks shifted slightly towards the night. The shift towards nocturnal activity persisted during post-culling period. Understanding the changes in activity patterns in response to culling intensity could be used to facilitate population control and assist in establishing a night shooting program. Thus, wildlife managers should consider night shooting once hunting during day time has shifted the normal diurnal activity of deer to nocturnal activity.


A hint for the obesity paradox and the link between obesity, perirenal adipose tissue and Renal Cell Carcinoma progression.
Increasing evidence supports a role for local fat depots in cancer outcomes. Despite the robust positive association of obesity with renal cell carcinoma (RCCa) diagnosis, increased adiposity is inversely related to RCCa oncological outcomes. Here, we sought to ascertain whether imagiologically assessed local fat depots associate with RCCa progression and survival and account for this apparent paradox. A retrospective cohort of renal carcinoma patients elective for nephrectomy (n = 137) were included. Beyond baseline clinicopathological characteristics, computed tomography (CT)-scans at the level of renal hilum evaluated areas and densities of different adipose tissue depots (perirenal, subcutaneous, visceral) and skeletal muscle (erector spinae, psoas and quadratus lumborum muscles) were analyzed. Univariate and multivariable Cox proportional hazards models were estimated following empirical analysis using stepwise Cox regression. Age, visceral adipose tissue (VAT) area and body mass index (BMI) predicted tumour-sided perirenal fat area (R2 = 0.584), which presented upregulated UCP1 expression by 27-fold (P = 0.026) and smaller adipocyte areas, compared with subcutaneous depot. Multivariate analyses revealed that increased area of perirenal adipose tissue (PRAT) on the contralateral and tumour side associate with improved progression-free survival (HR = 0.3, 95CI = 0.1-0.8, P = 0.019) and overall survival (HR = 0.3, 95CI = 0.1-0.7, P = 0.009). PRAT measurements using CT, might become a possible tool, well correlated with other measures of obesity such as VAT and BMI, that will improve determination of obesity and contribute to assess the risk for disease progression and mortality in renal cancer patients. Present data supports the obesity paradox in RCCa, assumed that larger PRAT areas seem to protect from disease progression and death.


Evaluation of the complications in transperitoneal laparoscopic renal and adrenal surgery with Clavien-Dindo classification.
To evaluate our complications in renal and adrenal transperitoneal laparoscopic surgeries with Clavien-Dindo classification. Two hundred and eight patients to whom renal and adrenal laparoscopic surgeries were performed between January 2008 and June 2015 were included the study. One hundred and twenty one (58.2%) patients were female and 87 (41.8%) of them were male. Laparoscopic procedures were performed as radical nephrectomy (n=49; 23.6%), simple nephrectomy (n=56; 26.9%), and partial nephrectomy (n=7; 3.4%), renal cyst decortication (n=27; 13%), pyelopasty (n=14; 6.7%) and adrenalectomy (n=55; 26.4%). Complications were classified according to Clavien-Dindo classification. The mean age of the patients was 48.01±14.9 years. The mean duration of hospital stay was 3.5±1.9 days. According to European Scoring System for Laparoscopic Operations the procedures were graded based on procedural difficulty as simple (n=27; 12.9%), difficult (n=172; 82.8%), and highly difficult (n=9; 4.3%). Complications were observed in 13 (6.3%) interventions. One of these occurred during very hard and 14 during difficult procedures. According to Clavien-Dindo Classification; Grades 1, 2, and 3 A complications developed in 3 (1.4%), 9 (4.3%), and 1(0.5%) patient, respectively. Laparoscopic surgery is an efficient procedure in well-chosen patients for renal and adrenal diseases with low complication rates.


Continuously moving table MRI with SENSE: application in peripheral contrast enhanced MR angiography.
An integration of SENSitivity Encoding (SENSE) with continuously moving table (CMT) MRI for extended field-of-view (FOV) acquisitions is described. In this work, the approach in which receiver coils are attached to the object and move in synchrony with the scanner table is considered. Technical issues dealing with the implementation of SENSE-CMT are addressed, including coil calibration, correction for non-uniform magnetic gradients, and specific reconstruction steps. An explanation of combining SENSE with gradient non-linearity correction is given, as the latter becomes necessary in CMT acquisitions where a large sampling FOV is used. It is hypothesized that SENSE can provide at least a 2-fold improvement in lateral spatial resolution compared to non-accelerated CMT acquisitions. The hypothesis is tested in phantoms, where the effectiveness of both SENSE and gradient non-linearity correction to improve spatial resolution is shown. The SENSE-CMT technique is further demonstrated in vivo with contrast-enhanced MR angiography of the peripheral vasculature.


Application of the cell growth and DNA-inhibition tests for characterizing sulfate pulp mill waste waters.
The evaluation of cytotoxic and genotoxic effects of selected technological samples from sulfate pulp mill waste waters by using the growing activity method for pseudodiploid fibroblasts V79 from lungs of the Chinese hamster and from human heteroploid fibroblasts EUE has been described along with the DNA-inhibition test for studying the synthesis of DNA after it has been influenced by the above-mentioned samples. Both the waste solution produced during the preparation of bleaching agents and the liquor generated after using hypochlorite (1st stage) as a fourth filter (after the production of paper pulp) are cytotoxic waste waters. Black liquor generated during the production of viscose pulp may have mutagenic effects and black liquor obtained from the production of paper pulp is characterized by mutagenic as well as carcinogenic effects.


Analysis of the incidence and risk factors for wound infections in open bariatric surgery.
Our clinical impression derived from >95% follow-up of patients was that our wound infection rate was higher than the 1-10% reported in the literature. The purpose of this study was to determine the incidence and risk factors for wound infection in open bariatric surgery. We queried our prospectively acquired bariatric surgery outcomes database, and retrospectively audited the charts of patients operated from April 1 to March 31, 2003. Risk categories were obtained using the National Nosocomial Infection Surveillance (NNIS) definitions and stratification. Expected site-specific rates were adjusted for duration of operation, degree of wound contamination, and underlying disease condition. 269 patients undergoing a standardized open Roux-en-Y gastric bypass were studied. The mean age (SD) was 39.5 (10.5) years and the mean BMI was 54.3 (9.9). Operating time averaged 63 (17) minutes, and length of stay was 4.1 (1.3) days. Based on NNIS categories 10.9 wound infections were expected, but 54 were observed, for a rate of 20%. Bacterial isolates included S. aureus (39%), alpha-hemolytic strep (26%), Enterococcus (16%), P.mirabilis (9%), and multiple other bacteria at 10%. Epidural analgesia and delayed antibiotic prophylaxis administration (after the incision was made) increased the odds of developing a wound infection, whereas gender, age, BMI, duration of surgery, and incidence of diabetes had no effect. There was a high correlation between wound infection and subsequent incisional hernia formation. The incidence of wound infections following open bariatric surgery is high, and the current recommendations for antibiotic prophylaxis are ineffective. As these infections carry significant morbidity, effective methods to prevent them are needed.


Association between angiogenic factors and signs of arterial aging in women with pre-eclampsia.
Pre-eclampsia (PE) is associated with an increased risk of cardiovascular disease later in life. In cases with PE there is a substantial increase in levels of the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased levels of the proangiogenic factor placental growth factor (PlGF). Elevated levels of sFlt-1 are also found in individuals with cardiovascular disease. The aims of this study were to assess levels of sFlt-1, PlGF and the sFlt-1/PlGF ratio and their correlation with signs of arterial aging by measuring the common carotid artery (CCA) intima and media thicknesses and their ratio (I/M ratio) in women with and without PE. Serum sFlt-1 and PlGF levels were measured using commercially available enzyme-linked immunosorbent assay kits, and CCA intima and media thicknesses were estimated using high-frequency (22-MHz) ultrasonography in 55 women at PE diagnosis and in 64 women with normal pregnancy at a similar gestational age, with reassessment at 1 year postpartum. During pregnancy, higher levels of sFlt-1, lower levels of PlGF, a thicker intima, a thinner media and a higher I/M ratio of the CCA were found in women with PE vs controls (all P < 0.0001). Further, sFlt-1 and the sFlt-1/PlGF ratio were positively correlated with intima thickness and I/M ratio (all P < 0.0001). At 1 year postpartum, levels of sFlt-1 and the sFlt-1/PlGF ratio had decreased in both groups; however, their levels in the PE group were still higher than in the controls (P = 0.001 and < 0.0001, respectively). Levels of sFlt-1 and the sFlt-1/PlGF ratio remained positively correlated with intima thickness and I/M ratio at 1 year postpartum. Higher sFlt-1 levels and sFlt-1/PlGF ratio in women with PE were positively associated with signs of arterial aging during pregnancy. At 1 year postpartum, sFlt-1 levels and the sFlt-1/PlGF ratio were still higher in the PE group and were associated with the degree of arterial aging. © 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.


Double opposing rectangular advancement flap is an alternative technique in the treatment of wide linear postburn scar contractures.
Double opposing rectangular advancement is a new and alternative technique in the treatment of postburn scar contractures. The technique consists of opposing two adjacent subcutaneously pedicled rectangular flaps by advancement and lengthening a contracture band. Experimental studies demonstrated that the technique is efficient to elongate a tension line as much as Z-plasty in the rat inguinal skin. In this clinical study we investigated the efficiency and versatility of the technique in the treatment of wide linear postburn scar contractures in various parts of the body. We applied 16 double opposing rectangular advancement in 7 patients (aged 4-56). Flaps were applied in the upper extremity (11 flaps), lower extremity (4 flaps) and trunk (1 flap). Average follow-up was 1-year. All flaps achieved adequate relaxation postoperatively and healed uneventfully. Postoperative measurements indicated that the lengthening provided with the technique ranged from 72 to 100%. The subcutaneous pedicle of the rectangular flaps provided a distinct advantage in terms of vascularity. Recontracture was seen in one patient to whom two double opposing rectangular flaps in series were applied in the axilla. Clinical results indicated that double opposing rectangular advancement is effective in the treatment of wide linear postburn scar contractures. Preoperative planning and application of flaps are simple. One knows preoperatively the exact elongation along the contracture line and narrowing perpendicular to this line which will be provided with the technique. Since the flaps are subcutaneously pedicled, the vascularity of the flaps are reliable. However the technique may not avoid recontracture in the axilla.


Exercise-induced changes in blood, red cell, and plasma volumes in man.
Changes in blood (BV), red cell (RCV), and plasma (PV) volumes were computed from hemoglobin and hematocrit values during submaximal treadmill exercise at 5 work intensities (30, 45, 60, 75, and 90% VO2 max) in 5 male subjects. RCV remained constant under all conditions. Changes in BV (hemoconcentration) could, therefore, be accounted for entirely by decreases in PV at all work levels. PV was a linear function of work intensity from rest through 60% VO2 max. However, a "break" occurred at that point in the data. Modeling of this break was accomplished by the use of one model (the "Fold" catastrophe) taken from the generalized catastrophe therory. However, several limitations to the acceptance of the model are presented, including the need to demonstrate a hysteresis in PV occurring at about 65% VO2 max.


Capsular infarcts: location, size and etiology of pure motor hemiparesis, sensorimotor stroke and ataxic hemiparesis.
We investigated the types of syndrome, location, size and presumed causes of 72 patients with acute capsular lacunar infarction. Clinical syndromes were classified into pure motor hemiparesis (PM), sensorimotor stroke (SM) and ataxic hemiparesis (AH). Lesion sizes of AH were significantly smaller than those of PM (p < 0.01) or SM (p < 0.01). When the lesion volume was classified into two groups, > or = 1 ml and < 1 ml, the large volume group had more frequent cardioembolic sources than the small volume group (41% and 18% respectively, p < 0.05). In AH patients no cardioembolic sources could be detected. Significant carotid stenosis was found in only 4% of patients. Patients with anterior choroidal artery territory infarction had infrequent cardioembolic sources (7%). The results suggest that the lesion size varies with clinical syndrome and some etiological trends are seen in the volume and the location of lesions.


Plasmonic field confinement for separate absorption-multiplication in InGaAs nanopillar avalanche photodiodes.
Avalanche photodiodes (APDs) are essential components in quantum key distribution systems and active imaging systems requiring both ultrafast response time to measure photon time of flight and high gain to detect low photon flux. The internal gain of an APD can improve system signal-to-noise ratio (SNR). Excess noise is typically kept low through the selection of material with intrinsically low excess noise, using separate-absorption-multiplication (SAM) heterostructures, or taking advantage of the dead-space effect using thin multiplication regions. In this work we demonstrate the first measurement of excess noise and gain-bandwidth product in III-V nanopillars exhibiting substantially lower excess noise factors compared to bulk and gain-bandwidth products greater than 200 GHz. The nanopillar optical antenna avalanche detector (NOAAD) architecture is utilized for spatially separating the absorption region from the avalanche region via the NOA resulting in single carrier injection without the use of a traditional SAM heterostructure.


Predictors of sustained ventricular tachycardia inducibility in patients with nonsustained ventricular tachycardia and chronic coronary artery disease.
To assess the likelihood of inducing sustained ventricular tachycardia, we analyzed a cohort of 58 retrospective and 18 prospective patients with chronic coronary artery disease who underwent electrophysiologic study because of spontaneous nonsustained ventricular tachycardia (three or more beats, lasting less than 30 seconds, at a rate greater than 100/min). In 24 of the 58 retrospective patients (41%) sustained ventricular tachycardia was inducible. Stepwise logistic regression identified two "major" variables--left ventricular aneurysm/dyskinesis/akinesis (p = 0.0001; relative risk = 11.88) and ejection fraction less than 40% (p = 0.0002; relative risk = 9.69)--and one "minor" variable--nonsustained ventricular tachycardia longer than 10 beats (p = 0.0151; relative risk = 4.21)--as significant predictors of inducibility. Nineteen patients with both major variables had a high probability of inducibility (greater than 90%). Nineteen patients with neither major variable had a low probability of inducibility (less than 5%). The remaining 20 patients with only one of the major variables had an intermediate probability of inducibility (14% to 75%). The significance of the third minor factor, nonsustained ventricular tachycardia longer than 10 beats, was confined to this intermediate group, in which it could be used to segregate relatively high (65% to 75%) and relatively low (14% to 20%) probability of inducibility. Prospective application of the predictor function stratified 18 additional patients into three groups with high (six patients), intermediate (seven patients), and low (five patients) probability of inducibility. The observed rate of inducibility in each group was 5 of 6 (83%), 2 of 7 (29%), and 0 of 5 (0%), respectively. These data suggest that patients with nonsustained ventricular tachycardia and chronic coronary artery disease can be stratified into subgroups with high, intermediate, and low probability of inducibility of sustained ventricular tachycardia on the basis of ejection fraction and regional ventricular wall motion defects alone.


Visual and haptic representations of scenes are updated with observer movement.
Scene recognition has been found to be sensitive to the orientation of the scene with respect to the stationary observer. Recent studies have shown, however, that observer movement can compensate for changes in visual scene orientation, through a process of spatial updating. Here we investigated whether spatial updating in scene recognition is affected by the encoding or learning modality by examining whether observer movement can also compensate for orientation changes in haptic scene recognition. In experiment 1, we replicated previously reported effects of observer movement on visual scene recognition. In experiment 2, we used the same apparatus as in experiment 1 but here participants were required to learn and recognize the scenes using touch alone. We found a cost in recognition performance with changes in scene orientation relative to the stationary observer. However, when participants could move around the scene to recognize the new orientation, then this cost in recognition performance disappeared. Thus, we found that spatial updating applies to recognition in both the visual and haptic modalities, both of which intrinsically encode the spatial properties of a scene.


Focal pancreatic ductal change induced by 10-Fr S-type plastic stent in chronic pancreatitis.
Stent-induced ductal change (SIDC) is a complication of endoscopic pancreatic stenting (EPS) in patients with chronic pancreatitis (CP). However, the evaluation of SIDC associated with S-type pancreatic plastic stent (PS) and large-caliber PS, such as 10 Fr, is limited. This study aimed to analyze the SIDC of the main pancreatic duct (MPD) associated with 10-Fr S-type PS in patients with CP. Between January 2008 and December 2021, 132 patients with CP in whom a 10-Fr S-type PS had been installed by EPS were retrospectively reviewed. The SIDC incidence rate was examined, and the clinical features of patients with and without SIDC were investigated, including the outcomes for detected SIDC. Stent-induced ductal change during EPS was confirmed in 41 patients (31.1%) of 132 patients at a site coincident with the PS tip or distal flap in the MPD. All patients were asymptomatic during the development of SIDC. Morphological changes in the MPD were detected as elevated (75.6%) or bearing stricture changes (24.4%). A total of 90.2% of SIDC developed after the first 10-Fr PS installation. No significant differences were noted between the patients with and without SIDC. The outcomes of continued PS installment for SIDC showed persistence and secondary change. Stent-induced ductal change-associated 10-Fr PS installation was performed in just under one-third of the patients, indicating a substantial incidence rate and a possible development of SIDC from early stages onwards. More emphasis should be placed on SIDC as the complication.


Insulin mediator stimulation of pyruvate dehydrogenase phosphatases.
A two stage assay for detecting insulin mediator based upon its stimulation of soluble pyruvate dehydrogenase (PDH) phosphatase to activate soluble pyruvate dehydrogenase complex (PDC) has been developed. This coupled assay determines the activation of PDC by monitoring production of [14C]CO2 from [1-14C]pyruvic acid. In addition to being more sensitive than the rat liver mitoplast assay previously used, it allows for the separation and investigation of the effects of mediator on the PDH phosphatases individually. It has been previously shown that the insulin mediator stimulates the most abundant PDH phosphatase, the divalent cation dependent PDH phosphatase, by decreasing the phosphatase's metal requirement (1). A metal independent PDH phosphatase has been found in bovine heart mitochondria. This phosphatase is not immunoprecipitated by antiphosphatase 2A antibody, it is not inhibited by okadaic acid, and it is not stimulated by spermine. However, it is stimulated (more than threefold) by insulin mediator prepared from isolated rat liver membranes. It is inhibited by Mg-ATP, with half-maximal inhibition at 0.3 mM; however, this inhibition is overcome by the insulin mediator.


Gly(6) of kalata B1 is critical for the selective binding to phosphatidylethanolamine membranes.
The membrane interaction of the cyclotide kalata B1, an all-d-analogue and a single alanine substituted analogue (G6A), was studied by surface plasmon resonance (SPR) and atomic force microscopy (AFM). Kalata B1 showed a strong binding selectivity for dimyristoyl-phosphatidylethanolamine (DMPE) compared to dimyristoyl-phoshatidylcholine (DMPC)-containing lipids. However, when the interaction was visualized by AFM the peptide interacted with DMPC and DMPE in a similar manner. There was no apparent change in membrane morphology with either lipid, suggesting that kalata B1 does not act via a carpet-like disruption mechanism. The d-analogue showed similar binding by SPR and the same strong selectivity for DMPE, indicating that the membrane-interaction and lipid selectivity are not stereo-specific. SPR studies of the G6A analogue revealed that it interacted in a similar way to kalata B1 on the DMPC containing lipids, but showed no increased response on the DMPE containing lipids observed for kalata B1 and d-kalata B1. These results indicate that the Gly6 residue directly influences membrane binding as it is located near a putative membrane interacting hydrophobic patch. Overall, the data suggest that very small changes in amino acid composition (with no change in conformation) can influence specific self-association in combination with membrane binding and mediate the activity of kalata B1.


Long-term oral administration of Epimedii Folium induced cholestasis in mice by interfering with bile acid transport.
Epimedii Folium (EF) is a common traditional Chinese medicine that functions as a tonifying kidney yang to strengthen bones and muscles and dispel wind dampness (limb pain, lethargy, nausea, anorexia, and loose stools). Several studies have reported the potential risk of cholestatic liver damage from EF use; however, there have been few investigations of EF-induced cholestasis, particularly the underlying mechanisms. The purpose of this study was to evaluate the risk of EF-induced cholestasis in vivo and to explore the mechanisms of action. ICR mice were orally administered a water extract of EF (WEF) in doses of 6.5 and 19.5 g/kg/day for 14 weeks. Liver-to-body weight ratios, body weight, histopathological examination, and biochemical analyses were performed to assess WEF-induced cholestasis in the mice. Genes associated with bile acid (BA) metabolism and transport, including sodium taurocholate cotransporting polypeptide (NTCP), cytochrome P450 8B1 (CYP8B1), bile-salt export pump (BSEP), multidrug resistance P-glycoproteins 1 (MDR1), and farnesoid X receptor (FXR), were measured at the transcript and protein levels to investigate the potential mechanisms through which cholestasis is aroused by EF. After administration of WEF for 14 weeks, mice in the high-dose WEF group showed poor health with an increased liver-to-body weight ratio as well as higher serum aminotransferase, alkaline phosphatase, direct bilirubin, and total BA levels. Compared with the control group, mRNA expression of NTCP and cholesterol 7a-hydroxylase (CYP7A1) increased, and levels of BSEP, MDR1, multidrug resistance-associated protein 2, and multidrug resistance-associated protein 3 decreased in the WEF-treated group. NTCP, BSEP, MDR1, and CYP8B1 showed similar mRNA and protein expression trends. We demonstrated that the long-term oral administration of WEF causes cholestatic liver injury in mice, which is consistent with reported clinical cases. Furthermore, we found that the destruction of BA metabolism and transport is involved in WEF-induced cholestasis. The fine-scale molecular mechanisms of WEF-induced cholestasis and the active compounds of EF need further study.


Perilesional and contralesional brain activations related to associative encoding of unfamiliar face-names pairs in adults with left chronic stroke with or without ischemic infarct on left inferior frontal gyrus.
The study of an Ischemic stroke infarction allows verifying how the lesion produces alterations in the neuronal networks resulting in cognitive deficits. It also allows the verification of adaptive and maladaptive cerebral reorganization related to the injury. In our previous fMRI study, we found that patients without ischemic vascular lesions in left inferior frontal gyrus showed an efficient compensation mechanism during the associative encoding of face name pairs, by the increased activation of ventrolateral and dorsolateral areas of contralesional hemisphere associated with better memory performance. While patients with ischemic vascular lesions on left inferior frontal gyrus (IFG) demonstrated worse memory performance and no signs of compensation mechanism. The present study explores more of these findings by analyzing perilesional and contralesional activations related to unfamiliar face name associative encoding in adults with chronic ischemic stroke, with or without left IFG lesion, compared to healthy controls. The main results showed that stroke survivors without lesions in IFG demonstrated increased activation in perilesional and contralesional prefrontal regions associated with better associative memory recognition, which are indicative of adaptive compensatory mechanisms. However, they also showed a negative correlation between the activation of right anterior prefrontal and inferior parietal regions and the associative memory performance, which may indicate the presence of maladaptive interhemispheric disinhibition. On the other hand, stroke survivors with IFG lesions demonstrated negative correlations in activations of the ipsilesional inferior parietal cortex and positive correlations in activations of the left middle frontal gyrus and left precentral cortex, which demonstrate the simultaneous occurrence of adaptive and maladaptive brain reorganization mechanisms in this group. However, the increase in perilesional prefrontal regions, associated with bilateral activation of the hippocampus and amygdala, was not enough to compensate for the inefficiency of associative memory performance. Finally, the differences in activation observed in stroke survivors reflect their clinical heterogeneity and demonstrate that adaptive or maladaptive compensatory mechanisms can coexist in the same group of patients. Furthermore, they reinforce the importance of the left IFG in the associative encoding of unfamiliar face name pairs and may suggest a deficit in associative memory related to injury in this region.


Soybean leaf estimation based on RGB images and machine learning methods.
RGB photographs are a powerful tool for dynamically estimating crop growth. Leaves are related to crop photosynthesis, transpiration, and nutrient uptake. Traditional blade parameter measurements were labor-intensive and time-consuming. Therefore, based on the phenotypic features extracted from RGB images, it is essential to choose the best model for soybean leaf parameter estimation. This research was carried out to speed up the breeding procedure and provide a novel technique for precisely estimating soybean leaf parameters. The findings demonstrate that using an Unet neural network, the IOU, PA, and Recall values for soybean image segmentation can achieve 0.98, 0.99, and 0.98, respectively. Overall, the average testing prediction accuracy (ATPA) of the three regression models is Random forest > Cat Boost > Simple nonlinear regression. The Random forest ATPAs for leaf number (LN), leaf fresh weight (LFW), and leaf area index (LAI) reached 73.45%, 74.96%, and 85.09%, respectively, which were 6.93%, 3.98%, and 8.01%, respectively, higher than those of the optimal Cat Boost model and 18.78%, 19.08%, and 10.88%, respectively, higher than those of the optimal SNR model. The results show that the Unet neural network can separate soybeans accurately from an RGB image. The Random forest model has a strong ability for generalization and high accuracy for the estimation of leaf parameters. Combining cutting-edge machine learning methods with digital images improves the estimation of soybean leaf characteristics.


Preclinical and clinical models of lung cancer chemoprevention.
In smokers, beta-carotene, retinol, and vitamins E and C appear to have little or a negative effect against human lung cancer development. Similarly, these chemicals have generally failed to inhibit lung tumorigenesis in rodents. The agents that have been shown to inhibit lung tumorigenesis in rodents, such as glucocorticoids, green tea, NSAIDs, and isothiocyanates, have not been tested yet in humans. These agents may be more effective in preventing human lung cancer in smokers than are the chemicals tested so far, especially if they are delivered by inhalation route.


Varicocele and a vascular tumor in the testis.
A 50-year-old man presented a rare morphological constellation: a left-sided varicocele (stage 3) and a vascular rich Sertoli cell tumor.


A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies.
We present the results of a prospective, randomised study comparing PBPC and BM focusing on engraftment, acute and chronic GVHD and survival. Forty patients with haematological malignancies received HLA-identical sibling BM (group A) or PBPC (group B). Evaluable patients were 19 (A) and 18 (B). Median age was 35 (17-56) in A and 29.5 (9-51) in B. Conditioning was mainly Bu-Cy2; GVHD prophylaxis was CSA-MTX. PBPC were harvested after 5 days of G-CSF 10 microg/kg/day. Median days for an ANC >0.5 x 10(9)/l was 18 (13-30) in A and 16 (11-25) in B (P = 0.10). Platelets >20 x 10(9)/l occurred at +17 (10-40) in A and +12 (9-36) in B (P = 0.01). The probability of > or =2 grade a-GVHD was 19% (A) and 27% (B) (P = 0.53). The probability of all grade c-GVHD was 70% with BM. In spite of the small number of patients in group B (PBPC), our data suggest the great majority of them will have c-GVHD (P = 0.08); extensive disease was present in 50 and 100%, respectively (P = 0.05). The estimates of overall survival for A and B at 1000 days are 51 and 47%, respectively (P = 0.67); DFS at 1000 days are 52 and 58%, respectively (P = 0.50). PBPC resulted in faster platelet engraftment. The incidence of acute and chronic GVHD was similar in both groups, but the severity of c-GVHD was higher with PBPC. No differences in survival and DFS have been observed to date.


Ultrasensitive near-infrared aptasensor for enrofloxacin detection based on wavelength tunable AgBr nanocrystals electrochemiluminescence emission triggered by O-terminated Ti3C2 MXene.
Toxic-free and easily accessible electrochemiluminescence (ECL) emitter/luminophore with near-infrared (NIR) emission is highly anticipated for ECL biosensor evolution. In this study, well-dispersed AgBr nanocrystals (NCs) decorated Ti3C2 MXene nanocomposites (Ti3C2-AgBrNCs) were prepared using a simple wet chemical technique and demonstrated highly efficient NIR ECL emission. For the first time, Ti3C2-AgBrNCs displayed wavelength-tunable ECL emission with varied Ti3C2 contents. Interestingly, further experimental data revealed that the ECL emission wavelength of Ti3C2-AgBrNCs red-shifted from 550 to 665 nm as Ti3C2 content increased, which can be attributed to the surface-defect effect generated by the oxygen-containing functional groups in Ti3C2 MXene. In particular, the ECL emission at 665 nm of Ti3C2-AgBrNCs nanocomposites not only revealed a 3.5 times increased ECL intensity but also a more stable ECL signal compared to pure AgBr NCs. As a proof of concept, a direct-type NIR ECL aptasensor with signal-on strategy was constructed with the Ti3C2-AgBrNCs nanocomposites as an ECL platform and enrofloxacin (ENR) as a model analyte. The NIR ECL aptasensor exhibited high sensitivity, a wide linear range from 1.0 × 10-12 mol/L to 1.0 × 10-6 mol/L and a low detection limit (5.97 × 10-13 mol/L). This research offered a viable alternative way for producing toxic-free and efficient near-infrared ECL luminophores in bioanalysis and wavelength-tuning light-emitting devices.


Burden in caregivers of spinal cord injury patients: a systematic review and meta-analysis.
Caregivers of individuals with spinal cord injury encounter high levels of physical, psychosocial, and financial burden by providing lifelong assistance. In the present study, we aimed to assess the overall burden score of caregivers in spinal cord injury by pooling different standard scores together as a review. Search on databases of PubMed/Medline, Web of Science and Scopus was conducted using PRISMA guidelines. Studies that assessed the burden of care using the caregiver burden inventories of CBI (caregiver burden inventory), CBS (caregiver burden scale), CG (caregiver), CSI (Caregiver Strain Index), and short- and long-form Zarit questionnaires were included in our study. The results were analyzed using the meta-analysis method and a random effect pooled estimator. All analyses were performed using STATA SE software version 14. A total of 23 articles out of 399 retrieved studies were added to this review study. The overall score of caregiver burden in individuals with SCI was calculated 48.68 (95% CI 42.574-54.788). The I2 heterogeneity was 11.7%, suggesting a low level of heterogeneity among the included studies. There was no systematic difference between various questionnaires added to meta-analysis (P = 0.526). In addition, the caregiver burden did not differ in less and highly developed countries (P = 0.405). Since SCI places a considerable burden on caregivers, scoring the burden of care can help policymakers plan for essential interventions and allocate more facilities for these patients and their caregivers.


Reports of self-rated health by citizenship and homeownership, United States 2000-2010.
Citizenship facilitates home ownership, which promotes access to additional resources and structures social context, factors that improve the health of individuals and communities. The objective of this study was to examine whether citizenship moderated the association between homeownership and self-rated health. We used multivariate logistic regression models and propensity score matching techniques to examine this association using pooled years 2000-2010 of the Medical Expenditure Panel Survey data linked with the National Health Interview Survey to examine U.S. adults aged 18 and older (N=170,429). Rates of fair/poor health among homeowners vs. non-homeowners were comparable for foreign-born non-citizens. However, native- and foreign-born citizen non-homeowners showed significantly higher rates of reporting fair/poor health, with native-born citizens having the highest rates of poor health. While homeownership is protective for self-rated health, not meeting the "American Dream" of home ownership may be embodied more in the health of native-born citizens as "failure" and translate into poorer self-rated health. However, the economic privileges of homeownership and its association with better self-rated health are limited to citizens. Non-citizens may be disadvantaged despite socioeconomic position, particularly wealth as considered by homeownership, placing citizenship at the forefront as the most proximate and important burden besides socioeconomic status that needs further investigation as a fundamental health determinant.


An evaluation of the International Diabetes Federation definition of metabolic syndrome in Chinese patients older than 30 years and diagnosed with type 2 diabetes mellitus.
The objective of the study was to determine the most accurate metabolic syndrome (MS) definition among the definitions proposed by the International Diabetes Federation (IDF), the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATPIII]), and the World Health Organization (WHO) and to evaluate the cutoff point of waist circumference using the IDF definition for optimally defining MS in the Chinese population. One thousand thirty-nine Chinese patients older than 30 years and diagnosed with type 2 diabetes mellitus were investigated by randomized cluster sampling in the Shanghai downtown, and 1008 patients were analyzed in this study. Body mass measurements, resting blood pressure, fasting blood measures, and carotid atherosclerotic measurements including common carotid artery intima-media thickness (IMT) and carotid plaque were investigated. The IDF definition was compared with the other 2 definitions, and the carotid atherosclerosis was evaluated among the patients according to these definitions. (1) The MS prevalence was 50.0%, 55.7%, and 70.0% under the IDF, ATPIII, and WHO definitions, respectively. (2) The percentage of all the participants categorized as either having or not having the MS was 69.9% (under the IDF and ATPIII definitions) and 70.2% (under the IDF and WHO definitions). (3) Common carotid artery IMT of patients with MS determined by the IDF definition was thicker than those determined by the WHO and ATPIII definitions, and the percentage of carotid plaque of patients with MS determined by the IDF definition was greater than those determined by the WHO and ATPIII definitions. (4) When the cutoff point of waist circumference in men determined by the IDF definition was modified from 90 to 85 cm, common carotid artery IMT of the emerging male patients with MS was thicker than that of the male patients with MS determined by the original IDF definition. In conclusion, the prevalence of MS was 50.0%, 55.7%, and 70.0% under the IDF, ATPIII, and WHO definitions, respectively. The preferable IDF definition served as a better predictor of cardiovascular disease risk in the Chinese patients diagnosed with type 2 diabetes mellitus compared with the ATPIII and WHO definitions. The modified cutoff point of waist circumference in men under the IDF definition specific for the Chinese population (from 90 to 85 cm) might be more suitable for predicting atherosclerosis.


Scleroderma lung disease: evolving understanding in light of newer studies.
To review therapeutic goals in pulmonary fibrosis in systemic sclerosis in the light of pathogenetic thinking and therapeutic data, with particular attention to recent data questioning the importance of the identification of alveolitis. Immunological/inflammatory activation remains the primary therapeutic target, based on recent data. Other effective therapies have not been developed, despite investigation of many pathogenetic pathways. In most cases, lung disease is predominantly fibrotic and prevention of progression is the only practicable therapeutic goal. Indications for introducing treatment remain uncertain. A granulocytosis on bronchoalveolar lavage and ground-glass attenuation on computed tomography, previously thought to denote an inflammatory histological picture ('alveolitis'), are usually indicative of fibrotic disease. By contrast, a recent staging system, integrating computed tomography and pulmonary function data, might, with refinement, identify patients likely to benefit from treatment. Treatment benefits consist of the prevention of progression and are largely confined to patients with extensive pulmonary fibrosis. Historical algorithms for the identification of alveolitis, using computed tomography and bronchoalveolar lavage, are inaccurate and do not identify patients most likely to benefit from treatment. Accurate prognostic evaluation by staging the severity of lung disease remains central to management and will be a major focus of future studies.


Key media microsupplements for boosting de novo lipogenesis in an oleaginic yeast isolate.
Present work reports a simple approach of microsupplementing nitrogen starved production media with potential activators of lipogenic enzymes for boosting de novo lipogenesis and demonstrated a 70-117 % rise in lipid content (LC) of yeast isolate Geotrichum candidum NBT-1. A hypothesis was proposed to increase the LC in the isolate at fixed minimum C/N ratio and small molecular activators for 3 key enzymes of lipogenic pathways. ATP citrate lyase, malic enzyme and acetyl CoA-carboxylase were screened in silico. Screened molecules were microsupplemented in nitrogen-starved media for examining the actual influence of their individual and synergistic combination on boosting LC of the isolate, which revealed sodium acetate as a major effector. Acetate in 4 mM concentration, independently and in combination with citric acid and sucrose resulted in a 2-2.2-fold increase in G. candidum LC from 24.8% in control to 49.27% and 53.96%, respectively. A volumetric lipid productivity of 0.0288 g/L/h with appreciable lipid coefficient of 9.77 was achieved in acetate supplemented media. Extracted lipids were 70-90% concentrated in a medium chain fatty acid (MCFA)-caprylic acid (C8:0), which has upsurging nutritional and nutraceutical importance.


Family composition, socioeconomic status, and adolescent substance use.
The hypothesis that deprivation in the form of parental absence and economic hardship causes youth substance use was tested in a study population consisting of two hundred sixty-two adolescents, ages 13 through 17, and one parent of each. No correlation between family composition and youth substance use was found. Two measures of socioeconomic status, family income and parents' subject rating, also revealed no correlation with youths' substance use behavior. However, when father's occupation was used to evaluate this relationship, significantly more abstainers were shown to have fathers who are professionals, and significantly more users had fathers occupying managerial or foreman-level positions; a possible explanation for this result is that occupation may somehow be related to parental style. The common sense assumption that parental absence and economic hardship are directly responsible for youth substance use is unsupported by our data.


The gap between available knowledge and its use in clinical psychiatry.
The time span between knowledge becoming available and its integration into daily clinical routine is lengthy. This phenomenon is explored in this study. We used the outcomes of our activities for investigating and strengthening the research-based activities to improve physical health in the routines of clinical psychiatric wards as examples for our analyses. The time span between new knowledge becoming available and its implementation into general clinical treatment is very long. However, a shortening of this time span is seen through active leadership backup and clinical research experience among psychiatrists and staff in the wards. In particular, the involvement of medical students interested in clinical research activities seems to have a positive impact. Academia needs to be re-implemented into clinical psychiatry. Staff with research experience is needed in all professions to increase evidence-based practice. Leaders must take responsibility for implementing new knowledge into the routines of the department and must support staff in these activities on a daily basis.


Incidence and outcomes following pulmonary barotrauma in COVID-19 ventilated and non-ventilated patients with acute respiratory failure: A retrospective study.
: Alveolar rupture following increased transalveolar pressure on positive pressure ventilation is associated with pulmonary barotrauma (PB). The spectrum varies from pneumothorax, pneumomediastinum, pneumopericardium, pneumoperitoneum, retro-pneumoperitoneum and subcutaneous emphysema. We studied the incidence of PB and their clinical characteristics in patients with coronavirus disease 19 (COVID-19)-associated acute respiratory failure. Patients aged >18 years with COVID-19-associated acute respiratory distress syndrome were included in the study. We recorded demographics (age, gender, comorbidities), severity scores (APACHE II on admission, SOFA on the day of barotrauma), type of PB and outcomes at discharge from the hospital. Patient characteristics are descriptively reported. Survival analysis was done using Kaplan-Meier survival tests after classifying by various factors. Survival was compared using the log-rank test. Thirty-five patients experienced PB. Eighty per cent of patients in this cohort were males with mean age of 55.89 years. The commonest comorbidities were diabetes mellitus and hypertension. Twelve spontaneously breathing patients developed barotrauma. Eight patients experienced sequential events. In all, 18 patients required insertion of pigtail catheters. The median survival time in patients was 37 days (95% CI: 25-49 days). The overall survival rate was 34.3%. Mean serum ferritin levels were six times upper limit of normal in deceased, reflecting the severity of lung involvement. A high incidence of PB was noted following severe acute respiratory syndrome coronavirus (SARS CoV-2) infection even in the non-ventilated patients, a consequence of SARS CoV-2 effects on the pulmonary parenchyma causing widespread lung injury.


Evaluation of Gliomas with Magnetic Resonance Fingerprinting with PET Correlation-A Comparative Study.
Advanced MR imaging of brain tumors is still mainly based on qualitative imaging. PET imaging offers additive metabolic information, and MR fingerprinting (MRF) offers a novel approach to quantitative data acquisition. The purpose of this study was to evaluate the ability of MRF to predict tumor regions and grading in combination with PET. Seventeen patients with histologically verified infiltrating gliomas and available amino-acid PET data were enrolled. ROIs for solid tumor parts (SPo), perifocal edema (ED1), and normal-appearing white matter (NAWM) were selected on conventional MRI sequences and aligned to the MRF and PET images. The predictability of gliomas by region and grading as well as intermodal correlations were assessed. For MRF, we calculated an overall predictability by region (SPo, ED1, and NAWM) for all of the MRF parameters of 76.5%, 47.1%, and 94.1%, respectively. The overall ability to distinguish low- from high-grade gliomas using MRF was 88.9% for LGG and 75% for HGG, with an accuracy of 82.4%, a ppV of 85.71%, and an npV of 80%. PET positivity was found in 13/17 patients for solid tumor parts, and in 3/17 patients for the edema region. However, there was no significant difference in region-specific MRF values between PET positive and PET negative patients. MRF and PET provide quantitative measurements of the tumor tissue characteristics of gliomas, with good predictability. Nonetheless, the results are dissimilar, reflecting the different underlying mechanisms of each method.


Recent advances in understanding depressive disorder: Possible relevance to brain stimulation therapies.
Recent research has provided novel insights into the major depressive disorder (MDD) and identified certain biomarkers of this disease. There are four main mechanisms playing a key role in the related pathophysiology, namely (1) monoamine systems dysfunction, (2) stress response, (3) neuroinflammation, and (4) neurotrophic factors alteration. Robust evidence on the decreased homovanillic acid in the cerebrospinal fluid (CSF) of patients with MDD supports a rationale for therapeutic stimulation of the medial forebrain bundle activating the dopamine reward system. Both activation and suppression of the hypothalamic-pituitary-adrenal (HPA) axis in MDD and related conditions indicate usefulness of its evaluation for the disease subtyping. Elevated proinflammatory cytokines (specifically, interleukin-6) in CSF imply the role of neuroinflammation resulting in activation of the tryptophan-kynurenine pathway. Finally, neuroplasticity and trophic effects of the brain-derived neurotrophic factor (BDNF) may be related to both structural abnormalities of the brain in MDD and the underlying mechanisms of various therapies. In addition, the gut-brain interaction is pivotal, since lack of beneficial microbes confer the risk of MDD through negative effects on the dopamine system, HPA axis, and vagal nerve. All these factors may be highly relevant to treatment of MDD with contemporary brain stimulation therapies.


Hesperetin induces apoptosis of esophageal cancer cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species.
Esophageal cancer is of high prevalence and poor prognosis. Hesperetin has been reported to exert antitumor ability by inducing apoptosis in many cancers in vitro and in vivo without obvious toxicity. However, there is no study concerning about the effect of hesperetin on esophageal cancer. In this study, we aimed to investigate whether hesperetin could induce apoptosis in esophageal cancer cells and explore its potential mechanism. We found that hesperetin induced esophageal cancer cells apoptosis in a concentration-dependent and time-dependent manner compared with the untreated cells. Hoechst 33258 staining and flow cytometry analysis showed more apoptotic cells in the hesperetin-treated group (p < 0.05, respectively). The intracellular reactive oxygen species (ROS) increased significantly, and glutathione (GSH) was depleted. The loss of △Ψ m was more tremendous in the hesperetin-treated cells. N-acetylcysteine (NAC) reduced the proapoptotic ability of hesperetin, while DL-buthionine-S, R-sulfoximine (BSO) enhanced the anticancer effect. Western blotting showed that the expression levels of cytochrome C (Cyt C) and apoptosis-inducing factor (AIF) decreased in mitochondria and increased in cytoplasm (p < 0.05). The levels of intracellular cleaved caspase-9, cleaved caspase-3, Apaf-1, Bcl-2-associated X protein (Bax), and suppressor of fused (SuFu) increased, while B cell lymphoma 2 (Bcl-2) and Survivin decreased. What is more, in xenograft tumor model, hesperetin inhibited the tumor growth significantly via induction of cell apoptosis which was detected by TUNEL assay (p < 0.05). Taken together, our study demonstrated that hesperetin could induce cell apoptosis in esophageal cancer cells via mitochondrial-mediated intrinsic pathway by accumulation of ROS.


The chemical basis of ferroptosis.
Lipid peroxidation underlies the mechanism of oxidative cell death now known as ferroptosis. This modality, distinct from other forms of cell death, has been intensely researched in recent years owing to its relevance in both degenerative disease and cancer. The demonstration that it can be modulated by small molecules in multiple pathophysiological contexts offers exciting opportunities for novel pharmacological interventions. Herein, we introduce the salient features of lipid peroxidation, how it can be modulated by small molecules and what principal aspects require urgent investigation by researchers in the field. The central role of non-enzymatic reactions in the execution of ferroptosis will be emphasized, as these processes have hitherto not been generally considered 'druggable'. Moreover, we provide a critical perspective on the biochemical mechanisms that contribute to cell vulnerability to ferroptosis and discuss how they can be exploited in the design of novel therapeutics.