Cleavable cationic antibacterial amphiphiles: synthesis, mechanism of action, and cytotoxicities.
The development of novel antimicrobial agents having high selectivity toward bacterial cells over mammalian cells is urgently required to curb the widespread emergence of infectious diseases caused by pathogenic bacteria. Toward this end, we have developed a set of cationic dimeric amphiphiles (bearing cleavable amide linkages between the headgroup and the hydrocarbon tail with different methylene spacers) that showed high antibacterial activity against human pathogenic bacteria (Escherichia coli and Staphylococcus aureus) and low cytotoxicity. The Minimum Inhibitory Concentrations (MIC) were found to be very low for the dimeric amphiphiles and were lower or comparable to the monomeric counterpart. In the case of dimeric amphiphiles, MIC was found to decrease with the increase in the spacer chain length (n = 2 to 6) and again to increase at higher spacer length (n > 6). It was found that the compound with six methylene spacers was the most active among all of the amphiphiles (MICs = 10-13 μM). By fluorescence spectroscopy, fluorescence microscopy, and field-emission scanning electron microscopy (FESEM), it was revealed that these cationic amphiphiles interact with the negatively charged bacterial cell membrane and disrupt the membrane integrity, thus killing the bacteria. All of the cationic amphiphiles showed low hemolytic activity (HC(50)) and high selectivity against both gram-positive and gram-negative bacteria. The most active amphiphile (n = 6) had a 10-13-fold higher HC(50) than did the MIC. Also, this amphiphile did not show any cytotoxicity against mammalian cells (HeLa cells) even at a concentration above the MIC (20 μM). The critical micellar concentration (CMC) values of gemini surfactants were found to be very low (CMC = 0.30-0.11 mM) and were 10-27 times smaller than the corresponding monomeric analogue (CMC = 2.9 mM). Chemical hydrolysis and thermogravimetric analysis (TGA) proved that these amphiphiles are quite stable under both acidic and thermal conditions. Collectively, these properties make the newly synthesized amphiphiles potentially superior disinfectants and antiseptics for various biomedical and biotechnological applications.


Hyperaggregation effect in idiopathic thrombocytopenia and multiple transfused patients.
A new technique for detecting platelet antibodies was investigated. The serum from patients having platelet antibodies was added to normal group O compatible pooled platelet-rich plasma. Platelet aggregation induced by adrenaline and adenosine diphosphate (ADP) was significantly increased as compared to the identical platelet-rich plasma without serum. The platelet-rich plasma with serum added did not aggregate spontaneously. When an alpha-adrenergic blocking agent (tolazoline) was added, the primary wave of aggregation induced by adrenaline was equally reversed with platelet-rich plasma, with or without serum. Although platelet antibodies by themselves did not agglutinate platelets in our test system, it is probable that platelet antibodies interact with platelets and potentiate their ability to aggregate. It is suggested that the platelet aggregometer is a useful tool for the detection of platelet antibodies in vitro.


The heart and the liver.
Cardiac failure affects the liver and liver dysfunction affects the heart. Chronic and acute heart failure can lead to cardiac cirrhosis and cardiogenic ischemic hepatitis. These conditions may impair liver function and treatment should be directed towards the primary heart disease and seek to secure perfusion of vital organs. In patients with advanced cirrhosis, physical and/or pharmacological stress may reveal a reduced cardiac performance with systolic and diastolic dysfunction and electrophysical abnormalities, termed cirrhotic cardiomyopathy. Pathophysiological mechanisms include reduced beta-adrenergic receptor signal transduction and defective cardiac electromechanical coupling. However, the QT interval is prolonged in approximately half of patients with cirrhosis and it may be improved by beta-blockers. No specific therapy can be recommended but it should be supportive and directed against the heart failure. Transjugular intrahepatic portosystemic shunt insertion and liver transplantation affect cardiac function in portal hypertensive patients and cause stress to the cirrhotic heart, with a risk of perioperative heart failure. The risk and prevalence of coronary artery disease are increasing in cirrhotic patients and since perioperative mortality is high, careful evaluation of such patients with dobutamine stress echocardiography, coronary angiography and myocardial perfusion imaging is required prior to liver transplantation. Future research should focus on beneficial effects of treatment on cardiac function and mortality.


A Motivational Interviewing Intervention to Promote CRC Screening: A Pilot Study.
Appalachian Kentuckians suffer a disproportionate incidence and mortality from colorectal cancer (CRC) and are screened at lower rates (35%) compared with 47% of Kentuckians. The aim of this study was to evaluate the efficacy of a motivational interviewing intervention delivered by trained Lay Health Advisors on CRC screening. Eligible participants recruited from an emergency department (ED) completed a baseline survey and were randomized to either the control or the motivational interviewing intervention provided by Lay Health Advisors. Follow-up surveys were administered 3 and 6 months after baseline. To evaluate potential differences in treatment and control groups, t tests, χ2, and Mann-Whitney U tests were used. At either the 3- or 6-month assessment, there was no difference in the CRC screening by group (χ2 = 0.13, P = .72). There was a significant main effect for the study group in the susceptibility to CRC model; regardless of time, those in the intervention group reported approximately 1-point higher perceived susceptibility to CRC, compared with controls (est. b = 0.68, P = .038). Age and financial adequacy had a significant effect related to CRC screening. Older participants (est. b = 0.09, P = .014) and those who reported financial inadequacy (est. b = 2.34, P = .002) reported more screening barriers. This pilot study elucidated important factors influencing the uptake of CRC for an ED transient population and this may be useful in the design of future interventions using motivational interviewing in EDs. Nurses can provide information about CRC screening guidelines and provide referrals to appropriate screening resources in the community.


Patient-focused care from a materials manager perspective.
In one year, Cedars-Sinai Medical Center (Los Angeles, CA) implemented patient-focused care on 32 nursing units. Through utilizing a continuous quality improvement (CQI) model of which patient-focused care was one operative, successful implementation was completed. The key concept was teamwork, and Materials Management Services proved to be a valuable member at all levels in the process whether at the oversight, design, or specialty task force level. Materials Management Services provided a consistent, efficient, streamlined service while following the guiding principles of patient-focused care: managed demand, redesigned work, and empowered employees.


BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.
Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD). Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2. BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming. In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.


Pan-Cancer Analysis of Immune Complement Signature C3/C5/C3AR1/C5AR1 in Association with Tumor Immune Evasion and Therapy Resistance.
Despite the advances in our understanding of the genetic and immunological basis of cancer, cancer remains a major public health burden with an ever-increasing incidence rate globally. Nevertheless, increasing evidence suggests that the components of the complement system could regulate the tumor microenvironment (TME) to promote cancer progression, recurrence, and metastasis. In the present study, we used an integrative multi-omics analysis of clinical data to explore the relationships between the expression levels of and genetic and epigenetic alterations in C3, C5, C3AR1, and C5AR1 and tumor immune evasion, therapy response, and patient prognosis in various cancer types. We found that the complements C3, C5, C3AR1, and C5AR1 have deregulated expression in human malignancies and are associated with activation of immune-related oncogenic processes and poor prognosis of cancer patients. Furthermore, we found that the increased expression levels of C3, C5, C3AR1, and C5AR1 were primarily predicted by copy number variation and gene methylation and were associated with dysfunctional T-cell phenotypes. Single nucleotide variation in the gene signature co-occurred with multiple oncogenic mutations and is associated with the progression of onco-immune-related diseases. Further correlation analysis revealed that C3, C5, C3AR1, and C5AR1 were associated with tumor immune evasion via dysfunctional T-cell phenotypes with a lesser contribution of T-cell exclusion. Lastly, we also demonstrated that the expression levels of C3, C5, C3AR1, and C5AR1 were associated with context-dependent chemotherapy, lymphocyte-mediated tumor killing, and immunotherapy outcomes in different cancer types. In conclusion, the complement components C3, C5, C3AR1, and C5AR1 serve as attractive targets for strategizing cancer immunotherapy and response follow-up.


Synthesis of biotinylated glycoconjugates and their use in a novel ELISA for direct comparison of HIV-1 Gp120 recognition of GalCer and related carbohydrate analogues.
As part of our program directed toward the design and synthesis of high-affinity ligands for the GalCer-binding site on the HIV cell surface glycoprotein, gp120, we required a reliable method for qualitatively assessing relative binding affinities for related analogues. Due to the hydrophilic nature of these synthetic conjugates, difficulties were encountered with typical ELISA methods, which rely upon hydrophobic interactions to anchor the ligand to a microtiter plate. Other types of assays were also problematic due to nonspecific binding of gp120. Therefore, we developed a general method for plating water-soluble ligands on microtiter plates using biotin/NeutrAvidin recognition for adhesion. A water-soluble GalCer analogue was prepared by conjugating psychosine to biotin using a novel tetraethylene glycol linker. In a similar manner, LacCer and GlcCer analogues were prepared and these conjugates were plated into microtiter wells containing NeutrAvidin. Unoccupied sites were blocked using biotin functionalized as a primary amide. Gp120 binding to galactosyl sphingosine, GalSph (19), GlcSph (22), and LacSph (23) conjugates was assessed through incubation with recombinant HRP-gp120. It was determined that LacSph has the strongest interaction with gp120. The binding affinities of GalSph and GlcSph were similar to each other and less strong than LacSph. These data contradict earlier studies where HPTLC showed that LacCer and GlcCer do not significantly bind gp120. They also contradict liposome-based assays that reported psychosine is not recognized by gp120. The extent of plating for each biotinylated molecule was quantified using HRP-biotin, allowing direct comparison of ligand plating efficiencies for the first time. Several other synthetic biotin conjugates were prepared and tested, demonstrating the feasibility of performing ELISA on water-soluble ligands.


Predictors of physical health: toward an integrated model of genetic and environmental antecedents.
People in higher-income groups tend to experience better physical health, yet this does not appear to be the direct result of access to medical care. This has prompted a search for psychological factors more likely to be present in high-income environments that might help to explain the relationship. Physical health has been associated with a number of such psychological measures including positive affect and well-being, negative affect and neuroticism, positive social relationships, and perceived control. Building from recent findings of moderation of genetic variance in physical health by income and perceived control, we explore the genetic and environmental relationships among all these variables in a nationwide U.S. twin sample. These relationships suggest possible mechanisms by which psychological characteristics, behaviors, physical health, and environmental circumstances could be influenced by common groups of genes with varying degrees of activity in different environments. We discuss the implications of such mechanisms for differential expression of genetic variation in the population and suggest ways in which consideration of such effects can inform gerontology research.


Investigations by Protein Film Electrochemistry of Alternative Reactions of Nickel-Containing Carbon Monoxide Dehydrogenase.
Protein film electrochemistry has been used to investigate reactions of highly active nickel-containing carbon monoxide dehydrogenases (CODHs). When attached to a pyrolytic graphite electrode, these enzymes behave as reversible electrocatalysts, displaying CO2 reduction or CO oxidation at minimal overpotential. The O2 sensitivity of CODH is suppressed by adding cyanide, a reversible inhibitor of CO oxidation, or by raising the electrode potential. Reduction of N2O, isoelectronic with CO2, is catalyzed by CODH, but the reaction is sluggish, despite a large overpotential, and results in inactivation. Production of H2 and formate under highly reducing conditions is consistent with calculations predicting that a nickel-hydrido species might be formed, but the very low rates suggest that such a species is not on the main catalytic pathway.


Odorant receptors from Culex quinquefasciatus and Aedes aegypti sensitive to floral compounds.
Mosquitoes rely heavily on the olfactory system to find a host for a bloodmeal, plants for a source of energy and suitable sites for oviposition. Here, we examined a cluster of eight odorant receptors (ORs), which includes one OR, CquiOR1, previously identified to be sensitive to plant-derived compounds. We cloned 5 ORs from Culex quinquefasciatus and two ORs from Aedes aegypti, ie, CquiOR2, CquiOR4, CquiOR5, CquiOR84, CquiOR85, AaegOR14, and AaegOR15 and then deorphanized these receptors using the Xenopus oocyte recording system and a large panel of odorants. 2-Phenylethanol, phenethyl formate, and phenethyl propionate were the best ligands for CquiOR4 somewhat resembling the profile of AaegOR15, which gave the strongest responses to phenethyl propionate, phenethyl formate, and acetophenone. In contrast, the best ligands for CquiOR5 were linalool, PMD, and linalool oxide. CquiOR4 was predominantly expressed in antennae of nonblood fed female mosquitoes, with transcript levels significantly reduced after a blood meal. 2-Phenylethanol showed repellency activity comparable to that of DEET at 1%. RNAi experiments suggest that at least in part 2-phenylethanol-elicited repellency is mediated by CquiOR4 activation.


Pathology reevaluation of the Kociba et al. (1978) bioassay of 2,3,7,8-TCDD: implications for risk assessment.
The chronic bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) reported in 1978 by Kociba et al. has been considered to be the primary evidence supporting its carcinogenicity, and is the basis for most dioxin regulations in North America and Western Europe. Because the histopathological criteria for proliferative lesions in the rat liver have changed significantly since 1978, a reevaluation of the liver slides was conducted recently by an independent panel of pathologists. Using current National Toxicology Program criteria, their study showed, in contrast to the original findings, that about two-thirds fewer tumors were present in the livers of female Sprague-Dawley rats. The no-observed-adverse-effect level (NOAEL) for hepatocellular carcinomas was 0.01 micrograms/kg/d rather than 0.001 micrograms/kg/d, which had been reported in 1978. In light of these significant findings, a quantitative dose-response assessment of 2,3,7,8-TCDD was undertaken to predict the potential carcinogenic risks to humans. Risk-specific doses (RsDs) and cancer potency factors (CPFs) were calculated by applying the linearized multistage (LMS) model to the combined incidences of hepatocellular carcinomas and adenomas, classified in accordance with the 1990 histopathological criteria. Based on the weight of evidence regarding the mechanism of action of 2,3,7,8-TCDD, body weight rather than surface area was selected as the appropriate means for scaling rodent data to predict the human response. Using the survival-adjusted data, the RsD for a 1 in 1,000,000 (10(-6)) plausible upper bound (95%) lifetime incremental cancer risk was 370 fg/kg/d based only on the incidence of hepatocellular carcinomas, and 100 fg/kg/d when hepatocellular carcinomas and adenomas were combined. The corresponding upper-bound (95%) CPFs were 2700 and 9700 (mg/kg/d)-1, respectively. These results indicate that the carcinogenic risk to humans from exposure to 2,3,7,8-TCDD is at least 16-fold lower than previous estimates derived from the Kociba et al. (1978) bioassay.


Finding meaning in reporting requirements. Provider sampling and survey length.
Meeting compliance requirements to report information such as provider satisfaction typically inspires groans, followed by hasty actions by those who must collect and supply the information. Reports often reflect this lack of interest as findings are rarely defended as representative. Our medical group employed statistical methodology to make this process meaningful while also keeping it fairly simple and without incurring added costs. By establishing our provider satisfaction survey as a scientifically based endeavor, we improved the likelihood the provider would actively and honestly participate, and report findings with confidence.


[Treatment with indomethacin for the control of the metabolic disorder caused by a villous adenoma of the rectum].
A 79 year old patient with a previous history of 10 months of mucous diarrhea is admitted due to pre-renal insufficiency, hyponatremia, hypokalemia and metabolic alkalosis secondary to rectal villous adenoma. The volume of the rectal discharge was 2.500 cc/day. Sodium level of the rectal secretion was 145 mEq/L and potassium 20 mEq/L. E2 prostaglandin: 1500 pg/ml. After hydroelectrolytic treatment, a PG synthetase inhibitor (indomethacin) was added to a dosage of 25 mg q/d PO. Rectal discharge was reduced to 500 cc/day, as well as sodium and prostaglandin levels. It has been proved that the use of PG synthetase inhibitors can facilitate the preparatory metabolic control in patients with villous adenoma.


Lipid asymmetry in plant plasma membranes: phosphate deficiency-induced phospholipid replacement is restricted to the cytosolic leaflet.
As in other eukaryotes, plant plasma membranes contain sphingolipids, phospholipids, and free sterols. In addition, plant plasma membranes also contain sterol derivatives and usually <5 mol% of a galactolipid, digalactosyldiacylglycerol (DGDG). We earlier reported that compared to fully fertilized oats (Avena sativa), oats cultivated without phosphate replaced up to 70 mol% of the root plasma membrane phospholipids with DGDG. Here, we investigated the implications of a high DGDG content on membrane properties. The phospholipid-to-DGDG replacement almost exclusively occurred in the cytosolic leaflet, where DGDG constituted up to one-third of the lipids. In the apoplastic (exoplasmic) leaflet, as well as in rafts, phospholipids were not replaced by DGDG, but by acylated sterol glycosides. Liposome studies revealed that the chain ordering in free sterol/phospholipid mixtures clearly decreased when >5 mol% DGDG was included. As both the apoplastic plasma membrane leaflet (probably the major water permeability barrier) and rafts both contain only trace amounts of DGDG, we conclude that this lipid class is not compatible with membrane functions requiring a high degree of lipid order. By not replacing phospholipids site specifically with DGDG, negative functional effects of this lipid in the plasma membrane are avoided.-Tjellström, H., Hellgren, L. I., Wieslander, A., Sandelius, A. S. Lipid asymmetry in plant plasma membranes: phosphate deficiency-induced phospholipid replacement is restricted to the cytosolic leaflet.


Use of a programmable calculator in processing and interpreting serum cholinesterase phenotypes.
Cholinesterase phenotyping is done at 25 degrees C with use of benzoylcholine as substrate and dibucaine, fluoride, chloride, and succinyldicholine as inhibitors. We wrote a diagnostic program in modified BASIC language for the processing and interpretation of these cholinesterase phenotypes. We used the HP 9830A calculator. The diagnostic aspect of the program uses 646 words, a further 86 words being used to run this program. The traditional and the programmed reporting procedures were duplicated for 296 consecutive patients, with no case of disagreement between the two reporting methods as to the appropriate phenotype. The programmed system requested nine repeat analyses more than did the traditional method. Seven of these were due to the tight limits set in the program for the fluoride inhibitor numbers. These tight limits were set to ensure that there was as limited an overlap as possible between the phenotypes E1uE1u and E1uE1f. The remaining two repeats were due to the restrictions placed on the succinyldicholine inhibitor numbers that would be acceptable before a patient was designated as having the relatively rare phenotype, E1aE1f.


Development and implementation of a method for characterizing clinical pharmacy interventions and medication use in a cancer center.
Develop and implement a method to characterize clinical pharmacy activities and the associated medication use in a comprehensive cancer center. A standard characterization of clinical pharmacy services facilitates benchmarking and informs continuous development. A set of quantifiable parameters to describe clinical pharmacy activities and the associated medication use was proposed and validated by peer review. For implementation, clinical pharmacy interventions for six clinical pharmacy services at the King Hussein Cancer Center in 2008 were prospectively documented and the numbers of patients and medications dispensed for the same period were obtained from the admission office and pharmacy database respectively. The method comprised four main aspects: (1) number of interventions, (2) type of interventions, (3) number of doses dispensed, and (4) the NNI which is the number of doses dispensed for one intervention to occur. A total of 8552 interventions were recorded for 37,784 patient days. Interventions were highest in the pediatric oncology and ICU with 2612 (31%) and 1867 (22%) respectively, followed by medical oncology 1563 (18%), BMT 998 (12%), palliative care 792 (9%), and surgery 720 (8%). Interventions per 1000 patient days were: ICU 555, pediatric oncology 326, BMT 319, palliative care 244, medical oncology 137, and surgery 83. Main intervention categories for all services: therapeutic 3055 (36%), safety 2195 (26%), quality assurance 2376 (28%), and education-information 925 (10%). The number of doses dispensed per 1000 patient days was: BMT 19,404, palliative care 17,272, ICU 12,290, medical oncology 13,182, pediatric oncology 12,093, and surgery 8976. Finally, NNI was as follows: ICU 22, pediatric oncology 39, BMT 60, palliative care 71, medical oncology 96, and surgery 109. A method for characterizing clinical pharmacy interventions and medication use was developed and used to compare different oncology clinical pharmacy services. Further work is warranted to refine and validate the parameters proposed.


Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation.
Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case-cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow-up was used for identification. Validation was provided by a similar case-cohort sample of patients with AF from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase-9, NT-proBNP (N-terminal pro-B-type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor-3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00-1.38), 1.55 (1.28-1.88), 1.28 (1.07-1.53), 1.19 (1.02-1.39), 1.23 (1.05-1.45), and 1.19 (0.97-1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase-9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT-proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor-3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.


Virus-specific glycoproteins associated with the nuclear fraction of herpes simplex virus type 1-infected cells.
Monospecific antisera to herpes simplex virus type 1 (HSV-1) glycoproteins gB, gC, and gD were used to identify the HSV-1-specific glycoproteins associated with the nuclear fraction as compared with those associated with cytoplasmic fraction, whole-cell lysates, and purified virions. The results indicate that a predominance of HSV glycoprotein precursors pgC(105), pgB(110), and pgD(52) is associated with the nuclear fraction. Treatment of the nuclear fraction with the enzyme endo-beta-N-acetylglucosaminidase H indicated that the lower-molecular-weight glycoproteins are sensitive to this endoglycosidase. These results suggest that in the nuclear fraction of HSV-1-infected cells virus-specific glycoproteins gB, gC, and gD are predominately in the high-mannose precursor form; however, detectable amounts of the fully glycosylated forms of gC and gD were also found.


Assessment of serologic markers for Epstein-Barr virus.
Antibody responses to early antigen (EA) and viral capsid antigen (VCA) were analyzed in 48 proven cases of Epstein-Barr Virus infection and in 48 age- and sex-matched healthy controls to establish optimal cutoff values for diagnosing EBV infection. Predictive values were determined for individual EA and VCA antibody titers and for EA to VCA antibody ratios and the optimal dilution cutoff values for positivity of EA (1:20), VCA (1:640), and EA to VCA (0:031) were selected. When evaluated on a subset of 10 VCA IgM positive cases and 35 negative controls, the three selected cutoff values identified as infections nine of 10, four of 10, and 10 of 10 of the cases and one of 35, none of 35, and one of 35 of the controls, respectively. When evaluated individually on 22 cases of suspected EBV infection who were heterophile antibody-negative and presented with symptoms compatible with EBV infection, an equal number of VCA IgM-positive and negative cases were identified as EBV infections. Overall, the cutoffs EA, VCA, and ratio identified 19 of 22 (86.4%), 14 of 22 (63.6%), and 18 of 22 (81.8%), respectively, and all cases could be identified using combinations of these values. Although these serologic values may be used with some accuracy, until more definitive markers are described a combination of heterophile responses, lymphocyte analysis, clinical symptoms, and serologic cutoff values should be used to assess the role of EBV in patient evaluation.


Generation of ultrafast terahertz radiation pulses on metallic nanostructured surfaces.
A resonant "incoherent" rectification process is presented relying on the excitation of surface plasmons on a nanostructured metal surface. Excitation of gold and silver films with 800-nm femtosecond laser pulses results in the emission of terahertz radiation with an angle-dependent efficiency and an approximately third-order power dependence. It is shown that the source of this terahertz pulse generation is the surface-plasmon-assisted multiphoton ionization and ponderomotive acceleration in the evanescent field of the surface plasmon. Simple models are used to understand the forces and dynamics near the surface.


Functional arterial baroreflex attenuates the effects of antihypertensive drugs in conscious rats.
The present work was designed to observe the influences of arterial baroreflex (ABR) function on cardiovascular effects produced by four routinely used antihypertensive drugs in conscious rats. A low ABR model was obtained by the performance of sinoaortic denervation (SAD). The doses of the four drugs were as follows: nifedipine (1.5, 3.0 mg/kg), captopril (50, 100 mg/kg), atenolol (10, 20 mg/kg), and hydrochlorothiazide (20, 40 mg/kg). They were administered via an intra-gastric catheter. Compared with sham-operated rats, SAD significantly increased blood pressure variability about 2 times without modification of blood pressure level. The decrease in blood pressure level induced by the four tested drugs was larger in SAD rats than in sham-operated rats, which decreased to about 10 mmHg. Pulse interval was not changed by the treatment of captopril, but prolonged by atenolol in both sham-operated and SAD rats. In sham-operated groups, treatment of both nifedipine and hydrochlorothiazide decreased pulse interval. Whereas in sinoaortic denervated ones, this tachycardia was prevented. Among the four tested drugs, it was found that only nifedipine and atenolol significantly decreased blood pressure variability in SAD rats. It can be concluded that arterial baroreflex function was able to attenuate the hypotensive effects produced by antihypertensive drugs in conscious rats.


Identifying sublethal endpoints for evaluating neurotoxic compounds utilizing the fish embryo toxicity test.
Fish embryos are increasingly being utilized in aquatic toxicity testing, as evidenced by the Organisation for Economic Co-operation and Development's approval of the fish embryo acute toxicity (FET) test. However, the FET test only allows for the estimation of acute toxicity, whereas other test methods such as the larval growth and survival (LGS) test allow for the estimation of both acute and chronic toxicity. Additionally, it has been demonstrated that the FET test is less sensitive than other test methods for some neurotoxic compounds. To address these limitations, efforts to identify sublethal endpoints that increase FET test sensitivity and allow for the prediction of sublethal adverse effects have begun. As such, the objectives of the current study were 1) to compare estimated LC50 values from the FET and LGS test for three known neurotoxicants: fluoride (F), nickel (Ni), and cadmium (Cd) and 2) to evaluate the responsiveness of potential sublethal endpoints for the FET test related to growth (i.e., wet weight and snout-vent length), neurological development (i.e., spontaneous contraction frequency and eye size), and cardiovascular function (i.e., heart rate and pericardial area). The calculated LC50 values from the F and Cd FET test were significantly higher than those from the LGS test, demonstrating that the FET test is less sensitive than the LGS test for neurotoxic compounds. Only Cd exposure resulted in alterations in any of the sublethal endpoints investigated. Embryos/eleutheroembryos exposed to Cd displayed alterations in length, eye size, and pericardial area at concentrations five-fold less than the estimated LC50 value, suggesting that for Cd the inclusion of these sublethal endpoints would improve the sensitivity of the FET test. Overall, these results provide evidence that for some neurotoxicants, the inclusion of sublehtal endpoints may improve the utility of the FET test; however, further research utilizing a broader range of neurotoxicants with differing mechanisms of action, is needed to fully establish such endpoints in the context of routine FET test.


Monitoring Membrane Lipidome Turnover by Metabolic 15N Labeling and Shotgun Ultra-High-Resolution Orbitrap Fourier Transform Mass Spectrometry.
Lipidomes undergo permanent extensive remodeling, but how the turnover rate differs between lipid classes and molecular species is poorly understood. We employed metabolic 15N labeling and shotgun ultra-high-resolution mass spectrometry (sUHR) to quantify the absolute (molar) abundance and determine the turnover rate of glycerophospholipids and sphingolipids by direct analysis of total lipid extracts. sUHR performed on a commercial Orbitrap Elite instrument at the mass resolution of 1.35 × 106 (m/z 200) baseline resolved peaks of 13C isotopes of unlabeled and monoisotopic peaks of 15N labeled lipids (Δm = 0.0063 Da). Therefore, the rate of metabolic 15N labeling of individual lipid species could be determined without compromising the scope, accuracy, and dynamic range of full-lipidome quantitative shotgun profiling. As a proof of concept, we employed sUHR to determine the lipidome composition and fluxes of 62 nitrogen-containing membrane lipids in human hepatoma HepG2 cells.


Effect of vasopressin on delayed neuronal damage in hippocampus following cerebral ischemia and reperfusion in gerbils.
Mongolian gerbils were used as delayed neuronal damage (DND) animal models. At the end of 15 minute cerebral ischemia and at various reperfusion time ranging from 1 to 96 hours, the content of water and arginine vasopressin (AVP) in the CA1 sector of hippocampus were measured by the specific gravity method and radioimmunoassay. Furthermore, we also examined the effect of intracerebroventricular (ICV) injection of AVP, AVP antiserum on calcium, Na+, K(+)-ATPase activity in the CA1 sector after ischemia and 96 hour reperfusion. The results showed that AVP contents of CA1 sector of hippocampus during 6 to 96 hour recirculation, and the water content of CA1 sector during 24 to 96 hour were significantly and continuously increased. After ICV injection of AVP, the water content and calcium in CA1 sector of hippocampus at cerebral ischemia and 96 hour recirculation further increased, and the Na+, K(+)-ATPase activity in CA1 sector was remarkably decreased as compared with that of control. While ICV injection of AVP antiserum, the water content and calcium in CA1 sector were significantly decreased as compared with that of control. These suggested that AVP was involved in the pathophysiologic process of DND in hippocampus following cerebral ischemia and reperfusion. Its mechanism might be through the change of intracellular action mediated by specific AVP receptor to lead to Ca ions over-load of neuron and inhibit the Na+, K(+)-ATPase activity, thereby to exacerbate the DND in hippocampus.


Initiation of transcription from the minute virus of mice P4 promoter is stimulated in rat cells expressing a c-Ha-ras oncogene.
Transformation of FR3T3 rat fibroblasts by a c-Ha-ras oncogene but not by bovine papillomavirus type 1 is associated with an increase in the abundance of mRNAs from prototype strain MVMp of infecting minute virus of mice, an oncosuppressive parvovirus. This differential parvovirus gene expression correlates with the reported sensitization of ras- but not bovine papillomavirus type 1-transformed cells to the killing effect of MVMp (N. Salomé, B. van Hille, N. Duponchel, G. Meneguzzi, F. Cuzin, J. Rommelaere, and J. Cornelis, Oncogene 5:123-130, 1990). Experiments were performed to determine at which level parvovirus expression is up-regulated in ras transformants. An MVMp "attenuation" sequence responsible for the premature arrest of RNA elongation was either placed or not placed in front of the chloramphenicol acetyltransferase gene and brought under the control of MVMp early promoter P4. Although the MVMp attenuator reduced P4-driven chloramphenicol acetyltransferase expression, the extent of attenuation was similar in normal and ras-transformed cells. Moreover, the analysis of P4-directed viral RNAs in MVMp-infected cultures by RNase protection and nuclear run-on assays also revealed a transcription elongation block of a similar amplitude in both types of cells. In addition, the stabilities of the three major parvoviral mRNAs did not vary significantly between normal and ras-transformed cells. Hence, it is concluded that the ras-induced increase in the accumulation of parvoviral mRNAs is mainly controlled at the level of transcription. Consistently, the TATA motif of the P4 promoter proved to have a differential photoreactivity when tested by in vivo UV footprinting assays in ras-transformed versus normal cells.


An activin/furin regulatory loop modulates the processing and secretion of inhibin alpha- and betaB-subunit dimers in pituitary gonadotrope cells.
Of all ligands of the transforming growth factor beta superfamily, inhibins and activins are a physiologically relevant pair that are functional antagonists of each other. Activin stimulates whereas inhibin blocks follicle-stimulating hormone biosynthesis and secretion from pituitary gonadotrope cells, and together, inhibin and activin control the pituitary gonadal axis essential for normal reproductive function. Sharing a similar beta-subunit, the secretion of inhibin heterodimers (alpha/beta) or activin homodimers (beta/beta) as mature bioactive ligands depends, in part, on the proteolytic processing of precursor proteins. A short loop regulatory pathway controlling precursor processing and dimer secretion was discovered. Activin stimulates endogenous inhibin alpha- and betaB-subunit mRNA, protein, and proteolytic processing. Simultaneously, activin stimulated the proconvertase furin through a Smad2/3-dependent process. The data provide a mechanism where the regulation of furin and inhibin subunits cooperates in an important positive short feedback loop. This regulatory loop augments the secretion of bioactive mature activin B, as well as inhibin B dimers, necessary for local follicle-stimulating hormone beta regulation.


Brain and behaviour of living and extinct echidnas.
The Tachyglossidae (long- and short-beaked echidnas) are a family of monotremes, confined to Australia and New Guinea, that exhibit striking trigeminal, olfactory and cortical specialisations. Several species of long-beaked echidna (Zaglossus robusta, Zaglossus hacketti, Megalibgwilia ramsayi) were part of the large-bodied (10 kg or more) fauna of Pleistocene Australasia, but only the diminutive (2-7 kg) Tachyglossus aculeatus is widespread today on the Australian mainland. We used high-resolution CT scanning and other osteological techniques to determine whether the remarkable neurological specialisations of modern echidnas were also present in Pleistocene forms or have undergone modification as the Australian climate changed in the transition from the Pleistocene to the Holocene. All the living and extinct echidnas studied have a similar pattern of cortical gyrification that suggests comparable functional topography to the modern short-beaked form. Osteological features related to olfactory, trigeminal, auditory and vestibular specialisation (e.g., foramina and cribriform plate area, osseous labyrinth topography) are also similar in living and extinct species. Our findings indicate that despite differences in diet, habitat and body size, the suite of neurological specialisations in the Tachyglossidae has been remarkably constant: encephalisation, sensory anatomy and specialisation (olfactory, trigeminal, auditory and vestibular), hypoglossal nerve size and cortical topography have all been stable neurological features of the group for at least 300,000 years.


Chromium propionate in turkeys: effects on insulin sensitivity.
The objective of this study was to evaluate the effects of dietary chromium (Cr), as Cr propionate (Cr Prop), on measures of insulin sensitivity in turkeys. Plasma glucose and nonesterified fatty acid (NEFA), and liver glycogen concentrations were used as indicators of insulin sensitivity. One-day-old Nicholas Large White female poults (n = 336) were randomly assigned to dietary treatments consisting of 0 (control), 0.2, 0.4, or 0.6 mg supplemental Cr/kg diet. Each treatment consisted of 12 replicate cages with 7 turkeys per cage. Final BW were taken on d 34, and on d 35 two birds from each cage were sampled for plasma glucose and NEFA, and liver glycogen determination at the initiation (fed state) and termination (fasted state) of a 24-h fast. Following a 24-h fast, 2 turkeys per cage were refed (refed state) their treatment diet for 4 h, and then harvested. Feed/gain and ADG did not differ between control and Cr-supplemented turkeys over the 34-d study, but feed intake tended (P = 0.071) to be greater for controls than turkeys receiving 0.4 mg Cr/kg diet. Fed turkeys had greater plasma glucose (P = 0.002) and liver glycogen (P = 0.001) concentrations, and lower (P = 0.001) NEFA concentrations than fasted birds. Turkeys refed after fasting had greater (P = 0.001) plasma glucose and liver glycogen concentrations, and lower (P = 0.001) plasma NEFA levels than fed turkeys. Liver glycogen and plasma NEFA concentrations did not differ among control and Cr-supplemented birds in the fed, fasted, or refed state. Plasma glucose concentrations were not affected by treatment in fed or fasted turkeys. Turkeys supplemented with 0.2 or 0.4 mg Cr/kg and refed after fasting had lower (quadratic, P = 0.038) plasma glucose concentrations than controls. Plasma glucose concentrations in refed birds did not differ among Cr-supplemented turkeys. The lower plasma glucose concentration in Cr-supplemented turkeys following refeeding is consistent with Cr enhancing insulin sensitivity.


NVP-BSK805, an Inhibitor of JAK2 Kinase, Significantly Enhances the Radiosensitivity of Esophageal Squamous Cell Carcinoma in vitro and in vivo.
Radiotherapy is one major curative treatment modality for esophageal squamous cell carcinoma (ESCC) patients. This study aimed to find out small-molecular kinase inhibitors, which can significantly enhance the radiosensitivity of ESCC in vitro and in vivo. Ninety-three kinase inhibitors were tested for their radiosensitizing effect in ESCC cells through high-content screening. The radiosensitizing effect of kinase inhibitors was investigated in vitro by detection of DNA double-strand breaks (DSBs) and clonogenic survival assay. By the establishment of xenograft tumor models in BALB/c nude mice, the radiosensitizing effect of kinase inhibitors was investigated in vivo. Among the 93 kinase inhibitors tested, we found NVP-BSK805, an inhibitor of JAK2 kinase, significantly radiosensitized ESCC cells through enhancing DSBs, inhibiting DNA damage repair and arresting cell cycle in G2/M or G0/G1 phase. After treatment with NVP-BSK805, ESCC cells showed decreased clonogenic survival and delayed tumor growth in vivo. JAK2 kinase was highly expressed in tumor tissues of ESCC patients, while rarely expressed in matched normal esophageal epithelial tissues. Survival analysis revealed JAK2 kinase as a prognostic factor of ESCC patients treated with chemoradiotherapy. Our study discovered JAK2 kinase as an attractive target to enhance the radiosensitivity of ESCC cells in vitro and in vivo.


Association between mesothelioma and non-occupational asbestos exposure: systematic review and meta-analysis.
The risk of mesothelioma has been shown to be associated with exposure to asbestos fibers. Most of the existing literature focuses on occupational exposure; however, non-occupational asbestos exposure has also been identified as an important risk factor. To estimate the association between mesothelioma and non-occupational asbestos exposure, and evaluate control recruitment and exposure measurement methods. A systematic literature review was conducted to identify case-control (CC) and cohort studies that examined the association between mesothelioma and non-occupational exposure to asbestos, including neighborhood, domestic, and household exposure. Meta-analysis was performed to estimate a summary relative risk estimate (SRRE) and 95% confidence interval using random-effects models. Subgroup analyses were also conducted by exposure type, gender, region, and fiber type. Twenty CC and 7 cohort studies were selected. Controls in CC studies were selected from the general population (55%), hospital records (18%), cancer registry (23%) and a combination of population and hospital records (5%). Multiple methods were used to measure neighborhood exposure (e.g., linear distance and direction of residence from an asbestos factory), domestic (e.g., whether living with an asbestos worker) and household exposure (e.g., whether involved in asbestos-containing home improvement projects). Primary meta-analyses suggested a SRRE of mesothelioma of 5.33 (95%CI: 2.53, 11.23) from neighborhood exposure, 4.31 (95%CI, 2.58, 7.20) from domestic exposure, and 2.41 (95%CI, 1.30, 4.48) from household exposure with large I2 statistics ranging from 83-99%. Non-occupational asbestos exposure is significantly associated with an elevated risk of mesothelioma. Funnel plots indicated a potential of publication bias. Some SRREs should be interpreted with cautions because of high between-studies heterogeneity.


Drugging the unfolded protein response in acute leukemias.
The unfolded protein response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, is mediated by three major stress sensors IRE-1α, PERK, and ATF6α. Studies described the UPR as a critical network in selection, adaptation, and survival of cancer cells. While previous reviews focused mainly on solid cancer cells, in this review, we summarize the recent findings focusing on acute leukemias. We take into account the impact of the underlying genetic alterations of acute leukemia cells, the leukemia stem cell pool, and provide an outline on the current genetic, clinical, and therapeutic findings. Furthermore, we shed light on the important oncogene-specific regulation of individual UPR signaling branches and the therapeutic relevance of this information to answer the question if the UPR could be an attractive novel target in acute leukemias.


Atypical dural arteriovenous fistula associated with meningitis.
A 49-year-old male presented with hemisensory disturbance and gait unsteadiness following a previous episode of meningitis. He had no contributory medical or head injury history. Magnetic resonance imaging revealed innumerable medullary vessels in the white matter of the left cerebral hemisphere, which had not been recognized in the previous imaging study. Cerebral angiography showed variant superior sagittal sinus (SSS) arteriovenous fistula (AVF) fed by the bilateral middle meningeal and superficial temporal arteries, and drained directly to the cortical veins with marked venous engorgement in the affected hemisphere. The fistulas were located on the cortical veins, apart from the SSS. Initial percutaneous transarterial embolization failed, so the AVF was completely obliterated with a combination of surgical and endovascular techniques. The symptoms ameliorated postoperatively. Meningitis may be an underlying pathology of dural AVF. Variant SSS AVF can be treated with a combination of surgical and endovascular techniques.


Nitrate content in dandelion (Taraxacum officinale) and lettuce (Lactuca sativa) from organic and conventional origin: intake assessment.
To estimate the actual intake of nitrate by consumption of different lettuce varieties, 52 samples of lettuce of different origins and dandelion from 15 different areas of northeast Slovenia were analysed. For determination of actual nitrate content, a continuous flow method was used. The lowest nitrate content was detected in dandelion, with a mean value of 195 mg kg(-1) (ranging 47-487 mg kg(-1)). Nitrate content in lettuce of different origins ranged 85-3237 mg kg(-1), with a mean value of 1196 mg kg(-1). The mean nitrate content in organically cultivated lettuce was 890 mg kg(-1), which was considerably lower than the nitrate level in conventionally cultivated lettuce (1298 mg kg(-1)). Consumption of 100 g of dandelion would result in a maximal nitrate intake corresponding to 22% of the acceptable daily intake (ADI), with values up to seven times higher for lettuce.


Quantum dot conjugated S. cerevisiae as smart nanotoxicity indicators for screening the toxicity of nanomaterials.
In this study, we have evaluated the toxicity of different forms of carbon nanotubes (CNTs) using S. cerevisiae-QD (SQD) bioconjugates as a novel fluorescent biological nanotoxicity indicator. A CNT mediated effect in SQD bioconjugates was used as an indicator for the changes occurring at the cell-membrane interfaces that induced disruption of membrane bound QDs resulting in the loss of fluorescence. Single, double and multiwalled carbon nanotubes (SWCNTs, DWCNTs and MWCNTs) were tested for their toxicities imposed on SQD bioconjugates. Bioconjugates exposed to varying concentrations of different forms of CNTs exhibited different modes of toxicities on SQD bioconjugates. SQD bioconjugates were highly responsive in the 0.1-10 μg mL-1 CNT concentration range after 1 h of exposure. The toxicity of CNTs was linked to the number of CNT walls. These results were further confirmed by SEM analysis and cell-viability tests that were consistent with the toxicity assays using fluorescent bioconjugates with different types of CNTs. SWCNTs imposed more severe cellular toxicity followed by MWCNTs and DWCNTs and the order of increasing cellular-damage by CNTs followed DWCNTs < MWCNTs < SWCNTs. This study speculates that the cell-injury by CNTs depends on their physical properties, such as layers of walls, non-covalent forces and dispersion states. Our results demonstrated a facile optical strategy that enables rapid and real-time cytotoxicity screening with yeast as model living-cells for engineering nanomaterials.


NG2 glia are required for maintaining microglia homeostatic state.
Microglia play vital roles in the health and diseases of the central nervous system. Loss of microglia homeostatic state is a key feature of brain aging and neurodegeneration. However, the mechanisms underlying the maintenance of distinct microglia cellular states are largely unclear. Here, we show that NG2 glia, also known as oligodendrocyte precursor cells, are essential for maintaining the homeostatic microglia state. We developed a highly efficient and selective NG2 glia depletion method using small-molecule inhibitors of platelet-derived growth factor (PDGF) signaling in cultured brain slices. We found that loss of NG2 glia abolished the homeostatic microglia signature without affecting the disease-associated microglia profiles. Similar findings were also observed in vivo by genetically depleting NG2 glia or conditionally inhibiting NG2 glia PDGF signaling in the adult mouse brain. These data suggest that NG2 glia exert a crucial influence onto microglia cellular states that are relevant to brain aging and neurodegenerative diseases. In addition, our results provide a powerful, convenient, and selective tool for the investigation of NG2 glia function.


Neuroprotection: a therapeutic strategy to prevent deterioration associated with schizophrenia.
Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia. In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.


Role for Biochemical Assays and Kayser-Fleischer Rings in Diagnosis of Wilson's Disease.
Wilson disease is an autosomal recessive disorder that impairs copper homeostasis and is caused by homozygous or compound heterozygous mutations in ATP7B, which encodes a copper-transporting P-type ATPase. Patients have variable clinical manifestations and laboratory test results, resulting in diagnostic dilemmas. We aimed to identify factors associated with symptoms and features of Wilson disease from a large cohort, over 15 years. We collected data from 715 patients (529 with symptoms, 146 without symptoms, and 40 uncategorized) and a genetic confirmation of Wilson's disease (mean age of diagnosis, 18.84 years), recruited from 3 hospitals in China from 2004 through 2019. We analyzed clinical data along with serum levels of ceruloplasmin (available from 636 patients), 24-hr urinary copper excretion (collected from 131 patients), Kayser-Fleisher rings (copper accumulation in eyes, with neurologic data from 355 patients), and magnetic resonance imaging (MRI) abnormalities. Differences among the groups were analyzed using 1-way analysis of variance followed by Tukey multiple comparison test. Of the 529 patients with symptoms, 121 had hepatic features, 355 had neurologic features, 28 had osteomuscular features (premature osteoarthritis, skeletal deformities, and pathological bone fractures), and 25 had psychiatric symptoms. Age of onset was significantly younger in patients with hepatic (16.94 ± 1.03 years; P = .0105) or osteomuscular features (13 ± 1.33 years; P = .0001) than patients with neurological features (19.48 ± 0.46 years). Serum levels of ceruloplasmin differed among asymptomatic patients and patients with osteomuscular or neurologic symptoms of Wilson disease. Serum levels of ceruloplasmin ranged from 18.93 mg/L to approximately 120.00 mg/L (quantiles of 0.025 to approximately 0.975). Fifty-one of 131 patients (39%) had urinary copper excretion levels below 100 μg/24 hr; there was significant variation in levels of urinary copper excretion between patients older than 14 years vs 14 years or younger. Of the 355 patients with neurologic features, 244 patients (69%) had abnormal findings from MRI and Kayser-Fleisher rings; only 1 patient with abnormal findings from brain MRI was negative for Kayser-Fleisher rings. Serum level of ceruloplasmin, 24-hour urinary copper excretion, and Kayser-Fleisher rings can be used to identify patients who might have Wilson disease. Patients with serum levels of ceruloplasmin below 120 mg/L and children with urinary copper excretion above 40 μg should undergo genetic testing for Wilson's disease. Patients with movement disorders and brain MRI abnormalities without Kayser-Fleisher rings are not likely to have Wilson disease.


A Voice Disease Detection Method Based on MFCCs and Shallow CNN.
The incidence rate of voice diseases is increasing year by year. The use of software for remote diagnosis is a technical development trend and has important practical value. Among voice diseases, common diseases that cause hoarseness include spasmodic dysphonia, vocal cord paralysis, vocal nodule, and vocal cord polyp. This paper presents a voice disease detection method that can be applied in a wide range of clinical. We cooperated with Xiangya Hospital of Central South University to collect voice samples from 352 different patients. The Mel Frequency Cepstrum Coefficient (MFCC) parameters are extracted as input features to describe the voice in the form of data. An innovative model combining MFCC parameters and single convolution layer CNN is proposed for fast calculation and classification. The highest accuracy we achieved was 92%, it is fully ahead of the original research results and internationally advanced. And we use advanced voice function assessment databases (AVFAD) to evaluate the generalization ability of the method we proposed, which achieved an accuracy rate of 98%. Experiments on clinical and standard datasets show that for the pathological detection of voice diseases, our method has greatly improved in accuracy and computational efficiency.


Speech illusions and working memory performance in non-clinical psychosis.
Psychotic disorders are characterized by auditory verbal hallucinations (AVHs), and research has shown that AVHs are linked to deficits in working memory. Our understanding of AVHs across the psychosis continuum is limited. To date, little research has tested whether hallucination proneness (HP) is linked with abnormalities on experimental multispeaker babble tasks. Few investigations have been conducted to determine how task performance might be linked to cognitive functioning. The objective of the current study is to better understand this empirical gap. A total of 70 adults (30 healthy controls and 40 HP individuals) were administered an experimental task in which they listened to multispeaker babble and were instructed to report any words or chains of consecutive words (CCWs) perceived. Participants also were administered nonverbal and verbal working memory tasks. Findings revealed that relative to the control group, the HP individuals perceived more words and longer CCWs during the task. While there were no significant differences in working memory tasks between the HP and control groups, longer CCW's were associated with decreased verbal working memory scores in the HP group. AVH proneness may occur across a continuum of psychosis and may be linked with other theoretically relevant cognitive vulnerability factors.


Circulating Th22 and Th9 levels in patients with acute coronary syndrome.
CD4+ T helper (Th) cells play critical roles in the development and progression of atherosclerosis and the onset of acute coronary syndromes (ACS, including acute myocardial infarction (AMI) and unstable angina pectoris (UAP)). In addition to Th1, Th2, and Th17 cells, Th22 and Th9 subsets have been identified in humans. In the present study, we investigated whether Th22 cells and Th9 cells are involved in the onset of ACS. The frequencies of Th22 and Th9 cells were detected using a flow cytometric analysis and their related cytokine and transcription factor were measured in the AMI, UAP, stable angina pectoris (SAP), and control groups. The results revealed a significant increase in the peripheral Th22 number, AHR expression, and IL-22 levels in patients with ACS compared with those in the SAP and control groups. Although there was no difference in the peripheral Th9 number among the four groups, the PU.1 expression and IL-9 levels were significantly increased in patients with ACS compared with the SAP and control groups. Circulating Th22 and Th9 type responses may play a potential role in the onset of ACS symptom.


SifA permits survival and replication of Salmonella typhimurium in murine macrophages.
SifA was originally identified as a virulence factor required for formation of Salmonella-induced filaments (Sifs), elongated tubules rich in lysosomal glycoproteins that extend from the Salmonella-containing vacuole in infected epithelial cells. Here, we demonstrate that deletion mutants of ssaR, a component of the SPI-2 type III secretion system, do not form Sifs in HeLa epithelial cells. This suggests that SifA is a translocated effector of this system, acting within host cells to form Sifs. In support of this hypothesis, transfection of HeLa cells with a vector encoding SifA fused to the green fluorescent protein caused extensive vacuolation of LAMP-1-positive compartments. Filamentous tubules that closely resembled Sifs were also observed in transfected cells, demonstrating that SifA is sufficient to initiate alteration of host cell endosomal structures. deltasifA mutants were impaired in their ability to survive/replicate in RAW 264.7 murine macrophages, a phenotype similar to ssaR mutants. Our findings suggest that SifA is an effector of the SPI-2 type III secretion system and allows colonization of murine macrophages, the host niche exploited during systemic phases of disease in these animals. A family of SifA-related proteins and their importance to Salmonella pathogenesis is also discussed.


Effect of Covid-19 pandemic on mental health among Albanian people residing in the country and abroad - Implications for mental care.
Coronavirus disease caused by the novel coronavirus Covid-19 is a current worldwide outbreak. The use of quarantine and isolation proved effective in containing the spread of infection. The purpose of this cross-sectional study was to assess the mental health of Albanian people residing in the country and abroad during the quarantine period for the Covid-19 pandemic. This study was carried out from 25th March - 20th April 2020 through a web survey shared on social networks. The goal was to reach at least the minimum sample size for cross-sectional studies. The Patient Health Questionnaire (PHQ-9) was used to assess mental health. Chi-square (χ2) and Fisher -Exact test were used to assess the statistical significance among variables. P values ≤0.05 were considered statistically significant. 715 participants were included in the final analyses (78.41% females and 21.53% males). Most were residents in Albania (80.41%) and the others resided mainly in Italy (6.89%), Greece (3.51%), Germany (2.43%), Kosovo (1.62%) and the UK (1.69%). Statistical association was found between gender, country of residency and measures taken. Summary score of PHQ-9 items was 6.4662. The total score of depression classification shows that 31.82% and 12.90% of participants have respectively mild and moderate depression. Female participants showed the highest score for some items of PHQ-9, p≤0.05. Findings suggest that health care professionals should recognize and address mental health problems associated with Covid-19 especially in vulnerable groups. Acting in a timely and proper manner is essential in preventing these problems from becoming chronic.


Colorectal Cancer: An Emphasis on Factors Influencing Racial/Ethnic Disparities.
Current statistics related to cancer incidence and cancer-related death rates clearly show that specific racial/ethnic minorities are more likely to be diagnosed and/or die with cancer. Colorectal cancer (CRC) is one of the leading causes of cancer deaths in the United States and it disproportionately affects the non-Hispanic Black or African American (AA) population. When compared to the non-Hispanic White (nHW) population, incidence and death rates in AAs are 28% and 60% higher, respectively. Hispanics have an overall lower CRC incidence rate than nHWs (Hispanics: 35.5 per 100,000 population; nHWs: 40.2 per 100,000 population), but their incidence continues to rise, unlike nHWs, who are experiencing a decline. This disparity between Hispanics and nHWs is further highlighted in the younger Hispanic population. While the cause of the disparities is associated with CRC-related genetic and environmental factors, the role of specific genes/mutations in each population are still not fully unraveled. However, because CRC is a slowly progressing disease, routine screening and/or early intervention are key to achieving better outcomes in CRC patients and ultimately in closing the disparity gap among different populations. This review discusses the major factors influencing the disparities in CRC and also focuses on factors such as treatment response, family history, and screening that potentially contribute to the racial/ethnic disparities in CRC.


Mechanics of the canine diaphragm in pleural effusion.
Pleural effusion is a complicating feature of many diseases of the lung and pleura, but its effects on the mechanics of the diaphragm have not been assessed. In the present study, radiopaque markers were attached along muscle bundles in the midcostal region of the diaphragm in anesthetized dogs, and the three-dimensional location of the markers during relaxation before and after the stepwise introduction of liquid into the left or right pleural space and during phrenic nerve stimulation in the same conditions was determined using computed tomography. From these data, accurate measurements of diaphragm muscle length and displacement were obtained, and the changes in pleural and abdominal pressure were analyzed as functions of these parameters. The effect of liquid instillation on the axial position of rib 5 was also measured. The data showed that 1) liquid leaked through the dorsal mediastinal sheet behind the pericardium so that effusion was bilateral; 2) effusion caused a caudal displacement of the relaxed diaphragm; 3) this displacement was, compared with passive lung inflation, much larger than the cranial displacement of the ribs; and 4) the capacity of the diaphragm to generate pressure, in particular pleural pressure, decreased markedly as effusion increased, and this decrease was well explained by the decrease in active muscle length. It is concluded that pleural effusion has a major adverse effect on the pressure-generating capacity of the diaphragm and that this is the result of the action of hydrostatic forces on the muscle.


Case Report: Two Cases of Recurring Ovale Malaria in Sarawak, Malaysia, after Successful Treatment of Imported Plasmodium falciparum Infection.
Here are two cases of recurring ovale malaria in Sarawak, Malaysia, that are likely relapses that occurred 1-2 months after successful treatment of the initial imported falciparum malaria with artemisinin-based combined therapy. The patients have no history or recollection of previous malaria episodes. These cases add to the limited evidence on the relapsing nature of Plasmodium ovale, after a febrile episode. In regions where P. ovale is not known to be autochthonous, active follow-up of treated imported malaria patients is highly recommended following their return, particularly to areas nearing or having achieved elimination.


Host performance as a target of manipulation by parasites: a meta-analysis.
The mechanisms underlying parasite-altered host behavior and fitness remain largely unanswered. The purpose of this review is to provide a perspective that has not been fully incorporated into the debate on how parasites manipulate their hosts. We argue that performance capacity is an important target of parasitic manipulation, and we aim to integrate the study of performance with that of parasitic manipulations of host behavior and fitness. We performed a meta-analysis from the published literature of 101 measures of the effect of parasites on host performance capacity to address the following questions. (1) Do parasites exert an important effect on host performance capacity? (2) Is that effect routinely to decrease or enhance performance capacity? And, (3) what factors explain variation in the effect sizes that have been quantified? Although negligible-small effect sizes were detected in 40/101 measures, host performance capacity was overall affected by parasitic infection, with a negative direction and medium-large magnitude in 58/101 measures and an increase in performance capacity in 3/101 measures. Host age, type of host performance, the host tissue infected by the parasite, and whether the study was experimental or based on natural infections each explained a significant amount of the variation in effect size. The significance of each factor is briefly discussed in light of the potential adaptive character of host manipulations by parasites.


Two stable unfolding intermediates of the disease-causing L68Q variant of human cystatin C.
In hereditary cystatin C amyloid angiopathy (HCCAA), presence of the Leu68 --> Gln substitution in cystatin C is coupled to a decreased concentration of this major cysteine proteinase inhibitor in cerebrospinal fluid and leads to its amyloid deposition in the brain. We established a high-yield expression system for L68Q cystatin C in Escherichia coli resulting in inclusion body accumulation at a level of 40% of the total cellular protein. Refolding of protein from purified inclusion bodies yielded a pure, almost completely monomeric and active inhibitor. CD and NMR spectroscopy demonstrated that so produced L68Q cystatin C is folded, conformationally homogeneous, and structurally very similar to wild-type cystatin C. Incubation at pH 7.0-5.5 caused the cystatin C variant to dimerize rapidly. The molecular form present at pH 6.0 displayed a slightly increased amount of hydrophobic parts on the surface as measured by 1-anilinonaphthalene-8-sulfonic acid (ANS) binding. NMR results showed that the dimer has a structure similar to that of the wild-type cystatin C dimer formed as a result of slight denaturation. Under more acidic conditions, at pH 4.5, another stable unfolding intermediate of L68Q cystatin C was identified. This molecular form exists in a monomeric state, is characterized by changes in secondary structure according to far UV CD spectroscopy, and shows an altered ANS binding resembling that of a molten globule state. The acidic pH also caused an almost complete monomerization of preformed dimers. The state of denaturation of L68Q cystatin C in vivo is thus a critical factor for the concentration of active cysteine proteinase inhibitor in cerebrospinal fluid and likely also for the development of amyloidosis, in HCCAA patients.


The efficacy and safety of post-stroke cognitive impairment therapies: an umbrella review.
Background: Stroke survivors are at significantly increased risk of cognitive impairment, which affects patients' independence of activities of daily living (ADLs), social engagement, and neurological function deficit. Many studies have been done to evaluate the efficacy and safety of post-stroke cognitive impairment (PSCI) treatment, and due to the largely inconsistent clinical data, there is a need to summarize and analyze the published clinical research data in this area. Objective: An umbrella review was performed to evaluate the efficacy and safety of PSCI therapies. Methods: Three independent authors searched for meta-analyses and systematic reviews on PubMed, the Cochrane Library, and the Web of Science to address this issue. We examined ADL and Barthel index (BI), Montreal Cognitive Assessment (MoCA), neurological function deficit as efficacy endpoints, and the incidence of adverse events as safety profiles. Results: In all, 312 studies from 19 eligible publications were included in the umbrella review. The results showed that angiotensin-converting enzyme inhibitors (ACEI) and N-methyl-D-aspartate (NMDA) antagonists, cell therapies, acupuncture, and EGB76 can improve the MoCA and ADL, and the adverse effects were mild for the treatment of PSCI. Moreover, Vinpocetine, Oxiracetam, Citicoline, thrombolytic therapy, Actovegin, DL-3-n-Butylphthalide, and Nimodipine showed adverse events or low article quality in patients with PSCI. However, the research evidence is not exact and further research is needed. Conclusion: Our study demonstrated that ACEI inhibitors (Donepezil) and NMDA antagonists (Memantine), EGB761, and acupuncture are the ADL and BI, MoCA, and neurological function deficit medication/therapy, respectively, for patients with PSCI. Clinical Trial Registration: https://inplasy.com/inplasy-2022-11-0139/; Identifier: INPLASY2022110139.


[Functional continuum of the regulatory peptides enhancing anxiety. Search for the optimal complexes as a basis for developing inhibitory therapeutic agents].
Regulatory peptides (RP) take an active part in managing the majority of physiological processes. One of these functional applications is the monitoring of the anxiety level, of panic state. This work represents the presumptive analysis of literature data of 1960-2004 on the effects of regulatory peptides enhancing anxiety (RP-AT). This information database was used for researching the characteristics of organization and functionality of the system of anxiogenic RP. Taking into account the method of vector representation of RP effects, estimation of spectra of physiological effects that can go with each of RP-AT and their combination, was carried out. The most perspective RP complexes of anxiogenic profile for further experimental development of inhibitory therapeutic agents are proposed.


Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations.
Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1-14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.


Rationale and design of the ADAPT-TAVR trial: a randomised comparison of edoxaban and dual antiplatelet therapy for prevention of leaflet thrombosis and cerebral embolisation after transcatheter aortic valve replacement.
Optimal antithrombotic strategy following transcatheter aortic valve replacement (TAVR) is still unknown. We hypothesised that the direct factor Xa inhibitor edoxaban can potentially prevent subclinical leaflet thrombosis and cerebral embolisation compared with conventional dual antiplatelet therapy (DAPT) in patients undergoing TAVR. The ADAPT-TAVR trial is an international, multicentre, randomised, open-label, superiority trial comparing edoxaban-based strategy and DAPT strategy in patients without an indication for oral anticoagulation who underwent successful TAVR. A total of 220 patients are randomised (1:1 ratio), 1-7 days after successful TAVR, to receive either edoxaban (60 mg daily or 30 mg daily if patients had dose-reduction criteria) or DAPT using aspirin (100 mg daily) plus clopidogrel (75 mg daily) for 6 months. The primary endpoint was an incidence of leaflet thrombosis on four-dimensional, volume-rendered cardiac CT imaging at 6 months post-TAVR. The key secondary endpoints were the number of new lesions and new lesion volume on brain diffusion-weighted MRI and the changes in neurological and neurocognitive function assessment between immediate post-TAVR and 6 months of study drug administration. Detailed clinical information on thromboembolic and bleeding events were also assessed. Ethic approval has been obtained from the Ethics Committee/Institutional Review Board of Asan Medical Center (approval number: 2017-1317) and this trial is also approved by National Institute of Food and Drug Safety Evaluation of Republic of Korea (approval number: 31511). Results of this study will be disseminated in scientific publication in reputed journals. NCT03284827.


Spatial analysis of notified dengue fever infections.
This study aimed to investigate the spatial clustering and dynamic dispersion of dengue incidence in Queensland, Australia. We used Moran's I statistic to assess the spatial autocorrelation of reported dengue cases. Spatial empirical Bayes smoothing estimates were used to display the spatial distribution of dengue in postal areas throughout Queensland. Local indicators of spatial association (LISA) maps and logistic regression models were used to identify spatial clusters and examine the spatio-temporal patterns of the spread of dengue. The results indicate that the spatial distribution of dengue was clustered during each of the three periods of 1993-1996, 1997-2000 and 2001-2004. The high-incidence clusters of dengue were primarily concentrated in the north of Queensland and low-incidence clusters occurred in the south-east of Queensland. The study concludes that the geographical range of notified dengue cases has significantly expanded in Queensland over recent years.


A fiber distribution model for predicting drug release rates.
Sustained drug release can be achieved by loading a drug into polymer material. The drug release can then be controlled for potential use in various biomedical applications. A model for drug release from a polymeric fibrous scaffold, which takes into account the distribution of fiber diameters within its structure, is developed here. It is demonstrated that the fiber diameter distribution significantly affects the drug release profile from electrospun scaffolds. The developed model indicates that altering the fiber distribution can be used as an additional tool to achieve an appropriate drug release profile. Using published data, it was demonstrated that an application of the model allows a more precise calculation of the drug diffusion coefficient within the polymer, which is important for predicting drug release rates from fabricated materials.


Multilayer network changes in patients with migraine.
To investigate changes in the multilayer network in patients with migraine compared to healthy controls. This study enrolled 82 patients with newly diagnosed migraine without aura and 53 healthy controls. Brain magnetic resonance imaging (MRI) was conducted using a 3-tesla MRI scanner, including three-dimensional T1-weighted and diffusion tensor imaging (DTI). A gray matter layer matrix was created with a morphometric similarity network using T1-weighted imaging and the FreeSurfer program. A white matter layer matrix was also created with structural connectivity using the DTI studio (DSI) program. A multilayer network analysis was then performed by applying graph theory using the BRAPH program. Significant changes were observed in the multilayer network at the global level in patients with migraines compared to the healthy controls. The multilayer modularity (0.177 vs. 0.160, p = .0005) and average multiplex participation (0.934 vs. 0.924, p = .002) were higher in patients with migraines than in the healthy controls. In contrast, the average multilayer clustering coefficient (0.406 vs. 0.461, p = .0005), average overlapping strength (56.061 vs. 61.676, p = .0005), and average weighted multiplex participation (0.847 vs. 0.878, p = .0005) were lower in patients with migraine than in the healthy controls. In addition, several regions showed significant changes in the multilayer network at the nodal level, including multiplex participation, multilayer clustering coefficients, overlapping strengths, and weighted multiplex participation. This study demonstrated significant changes in the multilayer network in patients with migraines compared to healthy controls. This could aid an understanding of the complex brain network in patients with migraine and may be associated with the pathophysiology of migraines. Patients with migraine show multilayer network changes in widespreading brain regions compared to healthy controls, and specific brain areas seem to play a hub role for pathophysiology of the migraine.


Targeted metabolomics revealed the mechanisms underlying the role of Liansu capsule in ameliorating functional dyspepsia.
Liansu capsule could alleviate dyspeptic symptoms; however, the mechanisms underlying its role in treating functional dyspepsia (FD) remain unclear. To elucidate the mechanism underlying the efficacy of Liansu capsule in alleviating FD symptoms. Thirty-six male mice were randomly divided into the following six groups: control, model, low-strength Liansu, moderate-strength Liansu, high-strength Liansu, and domperidone groups. Small intestine propulsion rate, gastric residual rate and histopathological analysis were performed to evaluate efficacy of Liansu capsule. Levels of interleukin-1β, interleukin-6, tumor necrosis factor α, phosphorylation of p65, ghrelin and gastrin were verified by real-time quantitative polymerase chain reaction and immunofluorescence assays. Targeted metabolomic analyses, western blotting and immunofluorescence assays were used to explore the mechanism of Liansu capsule in ameliorating FD. The Liansu capsule significantly ameliorated the symptoms of FD, and markedly increased the levels of ghrelin and gastrin. Moreover, Liansu capsule significantly downregulated the levels of the proinflammatory cytokine interleukin-1β, interleukin-6, tumor necrosis factor α, and inhibited the phosphorylation of p65. Targeted metabolomic analyses showed that Liansu capsule significantly reduced the levels of deoxycholic acid and hyodeoxycholic acid, which were significantly elevated in the model group. Furthermore, these results showed that deoxycholic acid and hyodeoxycholic acid markedly promoted the levels of Takeda G-protein-coupled receptor 5 (TGR5), phosphorylated signal transducer and activator of transcription 3 (STAT3), and Kruppel-like factor 5 (KLF5) in vitro. whereas, Liansu capsule significantly reduced the levels of TGR5, phosphorylated STAT3, and KLF5. Our findings indicated that Liansu capsule improved FD by regulating the deoxycholic acid/hyodeoxycholic acid-TGR5-STAT3-KLF5 axis. The findings reveal a novel mechanism underlying the role of Liansu capsule, which may be a promising therapeutic strategy for FD.


Clinically relevant information from sentinel lymph node biopsies of melanoma patients.
Careful laboratory evaluation of sentinel nodes (SNs) is critical to determine the presence of tumor. This requires evaluation of multiple full-face sections from the SN, using H&E staining and immunohistochemistry. In the future, molecular and genetic approaches may be adjunctive to microscopy. Number of tumor-positive SNs and the amount and location of tumor in SNs correlate with tumor spread to non-sentinel nodes, subsequent recurrences and melanoma death, permitting patient assignment to a risk category.


Local topographic and edaphic factors largely predict shrub encroachment in Mediterranean drylands.
Shrub encroachment influences several ecosystem services in drylands worldwide. Yet, commonly used strategies to reduce encroachment show a low medium-term success, calling for a better understanding of its causes. Previous works identified multiple drivers responsible for this phenomenon, including anthropogenic and environmental causes. However, the relative effect of climate, topography and edaphic factors on shrub encroachment is not fully understood nor has been properly quantified in Mediterranean Basin drylands. Also, understanding how these drivers lead to changes in plant communities' functional traits associated to shrub encroachment is crucial, considering traits influence ecosystem processes and associated ecosystem services. Here, we studied the understory of a Mediterranean dryland ecosystem composed of savanna-like Holm-oak woodlands, along a regional climatic gradient. We specifically assessed (i) how climatic, topographic and edaphic factors influence understory relative shrub cover (RSC) and (ii) their direct and indirect effects (via RSC) on plant functional traits. We studied the mean and diversity of 12 functional traits related to plant regeneration, establishment, and dispersal, at the community-level. We found that, under similar low-intensity land use, topographic and edaphic factors, namely slope variations and soil C:N ratio, were the most important predictors of shrub encroachment, determining communities' functional characteristics. Climate, namely summer precipitation, had a much lesser influence. Our model explained 52% of the variation in relative shrub cover. Climate had a stronger effect on a set of functional traits weakly involved in shrub encroachment, related to flowering and dispersal strategies. We show that shrub encroachment is largely predicted by topo-edaphic factors in Mediterranean drylands subject to conventional low-intensity land use. Hence, management strategies to reduce encroachment need to take these drivers into account for efficient forecasting and higher cost-effectiveness. Our results suggest that climate change might not greatly impact shrub encroachment in the Mediterranean Basin, but may affect functional structure and reduce functional diversity of plant communities, thus affecting ecosystem functioning.


[The composition of dietary lipids and the blood coagulation time in the rat].
The study of the coagulation in rats fed with a balanced diet, including 12% of different animal or vegetable fats, during 6 months, shows that the time of coagulation in rats receiving one of the following oils: palm, sunflower, Canbra, is significantly higher than the ones fed with butter. On the other hand, the coagulation time observed in the groups is correlated with the oleic acid level in the corresponding diet. The results obtained here may lead to important practical applications.


Is Nerve Monitoring Required in Total Thyroidectomy? Cerrahpasa Experience.
Thyroidectomy is an elective operation performed in an anatomically complex region in which certain structures are responsible for vital functions and special senses. This study aims to compare the effects of two different technical approaches-nerve dissection combined with intraoperative nerve monitoring (IONM) and no nerve identification-on recurrent laryngeal nerve (RLN) damage in total thyroidectomy. One hundred and sixty-one consecutive cases that underwent total thyroidectomy and 322 RLN under risk were evaluated. In group 1 (n = 162), nerve dissection combined with IONM was performed, whereas no RLN identification was performed in group 2 (n = 160). While the duration of operation in group 1 (34.23 ± 12.21 min) was statistically shorter than that in group 2 (36.98 ± 16.79 min, p = 0.017), there was no significant difference between groups related to RLN palsy (group 1 n = 10, group 2 n = 7). Use of IONM was found only to shorten the duration of operation. According to our presented experience, there is no benefit of IONM-combined routine dissection of RLN during total thyroidectomy on the prevention of RLN palsy.


Metal-free propargylation/aza-annulation approach to substituted β-carbolines and evaluation of their photophysical properties.
An efficient acid-catalyzed propargylation/aza-annulation sequence was developed under metal-free reaction conditions, thus leading to a one-pot synthesis of a variety of substituted β-carbolines starting from propargylic alcohols and indole 2-carbonyls. This versatile strategy was further extended to the synthesis of 5-azaindoles and 5-azabenzothiazoles. Optical properties suggested that manipulation of electron donor and acceptor moieties on β-carbolines has an impact on their ground and excited state electronic behavior. This leads to blue or green emission and should facilitate the development of organic light emitting diodes (OLEDs). Electrochemical and stability studies revealed that 4a-6 shows ease of redox activity and photostability during illumination.


Feasibility of common carotid artery point of care ultrasound in cardiac output measurements compared to invasive methods.
Cardiac output (CO) measurement in the intensive care unit (ICU) requires invasive devices such as the pulmonary artery (PA) catheter or arterial waveform pulse contour analysis (PCA). This study tests the accuracy and feasibility of point of care ultrasound (POCUS) of the common carotid artery to estimate the CO non-invasively and compare it to existing invasive CO measurement modalities. Patients admitted to the surgical and cardiothoracic ICU in a tertiary university-affiliated academic center during a 4-month period, with invasive hemodynamic monitoring devices for management, were included in this cohort study. Common carotid artery POCUS was performed to measure the CO and the results were compared to an invasive device. Intensivists and ICU fellows, using ultrasound of the common carotid artery, obtained the CO measurements. Images of the Doppler flow and volume were obtained at the level of the thyroid gland. Concurrent CO measured via invasive devices was recorded. The patient cohort comprised 36 patients; 52 % were females. The average age was 59 ± 13 years, and 66 % were monitored via PCA device and 33 % via PA catheter. Intraclass correlation coefficient (ICC) analysis demonstrated almost perfect correlation (0.8152) between measurements of CO via ultrasound vs. invasive modalities. The ICC between POCUS and the invasive measurement via PCA was 0.84 and via PA catheter 0.74, showing substantial agreement between the ultrasound and both invasive modalities. Common carotid artery POCUS offers a non-invasive method of measuring the CO in the critically ill population.


Head and neck basal cell carcinoma: treatment using a 2-mm clinical excision margin.
Treatment of basal cell carcinoma (BCC) should completely remove the tumour whilst preserving the maximum amount of normal surrounding skin. Therefore, treatment is a compromise between safe excision margins and obtaining a satisfactory cosmetic result. We report the results of a prospective study of 63 patients who underwent excision of well-demarcated BCCs in the head and neck region. The surgical excision margin used was 2 mm. Histological assessment confirmed complete excision in 95% and there was no evidence of recurrence of the BCC over a 24-month follow-up period in all patients. We propose that a clinical excision margin of 2 mm is adequate for treatment of simple, well demarcated BCCs arising in the head and neck.


Variation in the management of pediatric diabetic ketoacidosis by specialty training.
To compare management strategies for pediatric diabetic ketoacidosis (DKA) among physicians with different specialty training. We conducted a mail survey of 1000 randomly selected physicians, including 200 pediatric endocrinologists, 200 general emergency physicians, 200 pediatric emergency physicians, 200 pediatric intensivists, and 200 pediatric chief residents. We posed questions regarding a hypothetical 10-year-old patient with new onset of diabetes mellitus who is approximately 10% dehydrated but alert, with venous pH of 7.1 and serum glucose concentration of 34.7 mmol/L (625 mg/dL). Questions involved the rate of rehydration, content of intravenous fluids, insulin therapy, potassium replacement, use of sodium bicarbonate, and adjustments in therapy for decreasing serum glucose concentration. We compared responses of physicians in each specialty and used multiple regression analysis to adjust for potential confounding variables, including number of years in practice, number of children with DKA seen per month, and practice setting. Five hundred eighty-one physicians (58.1%) completed the survey, with responses demonstrating significant, consistent differences between specialties. Extremes of responses included the following: (1) 59% of endocrinologists vs 11% of general emergency physicians would give an initial fluid bolus of less than 20 mL/kg (odds ratio [OR], 11.7; 95% confidence interval [CI], 5.0-27.7) (P < .001); (2) 83.5% of general emergency physicians vs 42.5% of pediatric intensivists would administer an initial insulin bolus (OR, 4.1; 95% CI, 2.0-8.7) (P < .001); (3) 58.2% of pediatric intensivists vs 9% of general emergency physicians would replace fluids over a period of greater than 24 hours (OR, 14.1; 95% CI, 5.5-37.5) (P < .001); and (4) 54.3% of general emergency physicians vs 7.3% of pediatric intensivists would use potassium chloride alone for potassium replacement (OR, 10.8; 95% CI, 5.0-23.8) (P < .001). All of these differences persisted after adjusting for the potential confounding variables. Substantial differences exist in the management of pediatric DKA among physicians of different specialties, presumably due to differences in specialty training. These differences obscure our ability to evaluate the treatment of DKA and highlight the necessity for further studies comparing the outcomes of different treatment strategies.


Field study examining the mucosal microbiome in equine glandular gastric disease.
Equine glandular gastric disease (EGGD) is a common disease among athletic horses that can negatively impact health and performance. The pathophysiology of this EGGD remains poorly understood. Previous studies using controlled populations of horses identified differences in the gastric glandular mucosal microbiome associated with disease. The objective of this study was to compare the gastric microbiome in horses with EGGD and those without across multiple barns and differing management practices. We hypothesized that alterations in the microbiome of the gastric glandular mucosa are associated with EGGD. A secondary objective was to perform a risk factor analysis for EGGD using the diet and management data collected. Microbial populations of biopsies from normal pyloric mucosa of horses without EGGD (control biopsies), normal pyloric mucosa of horses with EGGD (normal biopsies) and areas of glandular mucosal disruption in horses with EGGD (lesion biopsies) were compared. Lesion biopsies had a different microbial community structure than control biopsies. Control biopsies had a higher read count for the phylum Actinomycetota compared to lesion biopsies. Control biopsies also had an enrichment of the genera Staphylococcus and Lawsonella and the species Streptococcus salivarius. Lesion biopsies had an enrichment of the genera Lactobacillus and Actinobacillus and the species Lactobacillus equigenerosi. These results demonstrate differences in the gastric glandular microbiome between sites of disrupted mucosa in horses with EGGD compared to pyloric mucosa of horses without EGGD. Risk factor analysis indicated that exercise duration per week was a risk factor for EGGD.


Central haemangioma of the mandible.
The literature on central haemangioma of the jaws has been extensively reviewed. The clinical and radiographic features of central haemangiomas of the jaws and the problems in diagnostic and various modalities of treatment of this lesion are discussed. Central haemangioma of the jaws is rare. Up till 1975, only 53 cases have been reported in the literature. A classical case of central haemangioma of the mandible is presented to illustrate the features of this uncommon disease.