[Clinical characteristics and therapy of pan-drug resistant Acinetobacter baumannii infection].
To analyze clinical characteristics and therapy of pan-resistant Acinetobacter baumannii (PDRAB) infection and explore the methods for effective therapy and prevention of this infection. Nine hospitalized patients with PDRAB infection confirmed by pathogen and susceptibility testing were analyzed for the risk factors and the treatment outcomes were assessed by case analysis. PDRAB infections occurred mainly in patients with severe complications, most of whom had complications by diabetes or hypertension or damaged mucosal integrity due to mechanical ventilation, surgery and catheterization. The polymyxin sensitivity were 100% for these infections, but all the bacteria identified showed a antimicrobial resistance rates of 100%. The majority of the infections were acquired during hospitalization occurring mainly in the lungs; all the patients had prolonged hospitalization and received antibiotic treatments with high proportions of broad-spectrum antimicrobial agents especially third-generation cephalosporins and quinolones. Exclusive or sequential use of carbapenems and sulbactam in combination with quinolone or aminoglycoside produced favorable effects. The prevalence of hospital-acquired pan-resistance of PDRAB infections increased significantly in recent years, particularly in patients with high risk factors. The widespread use of broad-spectrum antibiotics may have some relevance to drug resistant occurrence. The application of carbapenems or sulbactam, or their sequential use, in combination with other agents may produce good effects.


Recycling and Separation of Homogeneous Catalyst from Aqueous Multicomponent Mixture by Organic Solvent Nanofiltration.
Organic solvent nanofiltration (OSN) has evolved to an established recycling method for homogeneous catalysts. However, commercial availability has not circumvented the need for classification and the scoping of possible applications for specific solvent mixtures. Therefore, Evonik's DuraMem® 300 was assessed for the recycling of magnesium triflate at two transmembrane pressures from a mixture of ethanol, ethyl acetate and water. Catalyst retention up to 98% and permeability of up to 4.44·10-1∙L∙bar-1∙m-2∙h-1 were possible when less than 25% ethyl acetate was in the mixture. The retention of some of the components in the ternary mixture was observed while others were enriched, making the membrane also suitable for fractioning thereof.


In vitro activity of ceftazidime/avibactam against clinical isolates of Enterobacterales and Pseudomonas aeruginosa from Middle Eastern and African countries: ATLAS global surveillance programme 2015-18.
To assess the in vitro activity of ceftazidime/avibactam against a recent, 2015-18, collection of clinical isolates of Gram-negative bacilli from Middle Eastern and African countries with a focus on isolates from ICUs and with MDR and difficult-to-treat resistance (DTR) phenotypes. Antimicrobial susceptibility testing of 4608 isolates of Enterobacterales (997 isolates from ICU patients) and 1358 isolates of Pseudomonas aeruginosa (374 isolates from ICU patients) was performed by CLSI broth microdilution methodology in a central laboratory. MICs were interpreted using both CLSI (2020) and EUCAST (2020) MIC breakpoints. Most isolates of Enterobacterales (Middle East: ICU, 99.1% susceptible, non-ICU, 99.1%; Africa: ICU, 96.9% susceptible, non-ICU, 98.3%) and P. aeruginosa (Middle East: ICU, 93.4%, non-ICU, 92.1%; Africa: ICU, 89.8%; non-ICU, 94.1%) were susceptible to ceftazidime/avibactam. Applying CLSI and EUCAST breakpoints, MDR rates were similar for Enterobacterales (27.8%-36.0% of isolates) and P. aeruginosa (25.0%-36.4%) while DTR rates were lower for Enterobacterales (1.6%-1.8%) than for P. aeruginosa (5.2%-7.4%). Percentage susceptible rates for ceftazidime/avibactam for MDR Enterobacterales were 96.8%-97.5% (Middle East) and 92.5%-94.3% (Africa) while rates for P. aeruginosa were 70.1%-80.0% (Middle East) and 69.5%-78.2% (Africa). 60.5%-65.8% (Middle East) and 38.9%-52.2% (Africa) of isolates of Enterobacterales with DTR phenotypes were ceftazidime/avibactam susceptible as were 29.2%-31.1% (Middle East) and 28.2%-35.8% (Africa) of DTR P. aeruginosa. Overall, the isolates of Enterobacterales and P. aeruginosa tested from Middle Eastern and African countries were highly susceptible to ceftazidime/avibactam. Most MDR and many DTR isolates of Enterobacterales and P. aeruginosa were susceptible to ceftazidime/avibactam.


The time course of methanethiol in the rat.
The first order rate constant for the conversion of intraperitoneally administered methanethiol to sulfate in the rat was found to be 0.571 hr-1. The first order rate constant for the urinary excretion of sulfate was 0.0818 hr-1. Thus, the half-life for the metabolism of methanethiol to sulfate was 1.21 hr and for the elimination of sulfate in the urine was 8.47 hr.


Granulocyte colony-stimulating factor for hepatitis C therapy-associated neutropenia: systematic review and economic evaluation.
Hepatitis C virus (HCV) treatment requires maximal adherence to pegylated interferon (Peg-IFN) and ribavirin to achieve a sustained virologic response (SVR). Neutropenia is the most common cause for Peg-IFN dose reduction. Our objectives were to evaluate the effectiveness, safety and cost-effectiveness of granulocyte colony-stimulating factor (G-CSF) versus Peg-IFN dose reduction for HCV therapy-associated neutropenia in treatment naïve adults. We conducted a systematic review to identify controlled trials and observational studies. Study selection, quality assessment and data extraction were completed independently by two investigators. Cost-effectiveness and cost-utility analyses compared G-CSF with dose reduction. Nineteen studies were included. In one trial, the SVR for those receiving G-CSF was 54.5% (95% CI: 34.7-73.1) compared with 26.3% (95% CI: 11.8-48.8) for dose reduction. The remaining studies were case series or retrospective cohorts and provided weak evidence for the relationship between SVR and G-CSF. The risk of adverse events, including infection, associated with G-CSF was low (13.1%; 95% CI: 8.0-20.8) and clinically insignificant. G-CSF had an incremental cost-effectiveness ratio of $41,701 per SVR achieved in genotype 1, and $16,115 per SVR achieved in genotype 2 or 3. Estimates were robust under a variety of resource and intervention scenarios. While administration of G-CSF may enable patients to remain on or resume optimal HCV therapy, there was weak evidence that this improves the likelihood of SVR compared with dose reduction. Adverse effects of G-CSF are mild. The economic evaluation was inconclusive.


Maneuver for the recovery of a foreign body causing a complete airway obstruction: illustrative case.
This is a case of a 12-month-old child who had an upper respiratory tract foreign body that was completely obstructing the airway. There was no intubation or cricothyroidotomy equipment available. Traditional methods of removal had failed. The child was kept in a prone position, and it was only by mouth-to-mouth and/or nose aspiration, spitting out the secretions, that complete blockade transformed into a partial one. A few minutes after keeping on using this maneuver to maintain an open airway, a soft, light plastic object was recovered. Foreign body removal can be a life-threatening emergency occurring where no trained medical personal or medical equipment is available. This is a simple method that a practitioner or a parent may be able to use as an option in extreme circumstances when traditional methods have failed.


Feasibility of including APF gel application in a school oral health promotion program as a caries-preventive agent: a community intervention trial.
A community intervention trial was conducted to assess the feasibility of APF gel as a caries-preventive agent in a high-risk group of school children in Bangalore City. The study was conducted in two schools, randomly selected from a list of schools catering to underprivileged children. These schools were randomly allocated into experimental and control groups. Children aged 9-16 years having three or more incipient or cavitated primary or secondary carious lesions were enrolled in the study. In the experimental group, APF gel was applied and oral health education was provided to both groups at baseline and 6 months. Follow-up examination was performed at 6 and 12 months and the caries status was recorded by an investigator who was blinded to the allocation of intervention. There was no statistically significant difference in DMFT and DMFS values, but a significant difference was seen in incipient carious lesions between the experimental and control groups at 6 and 12 months. These results suggest that biannual APF gel application is an effective preventive measure in reversing incipient carious lesions.


Optimization of routine microscopic and molecular detection of parasitic protozoa in SAF-fixed faecal samples in Sweden.
Background: Nucleic acid-based methods are increasingly used for screening of gastrointestinal parasites. Microscopy is still used and Swedish routine protocol consists of formalin ethyl-acetate concentration and do not include screening for trophozoites or Cryptosporidium spp. This study aimed to compare detection with the Swedish routine microscopy method to an extended method that includes screening for trophozoites and Cryptosporidium. Furthermore, we also developed a method for DNA recovery from SAF-fixed faecal samples and compared the real-time PCR detection of Giardia intestinalis, Dientamoeba fragilis, Cryptosporidium spp., Entamoeba histolytica and Entamoeba dispar from SAF-fixed and unpreserved faecal samples. PCR results were then compared with microscopy results.Methods: SAF-fixed and unpreserved faecal samples from 1000 patients at the Clinical microbiology laboratory in Region Jönköping County, Sweden, were included. Samples were analysed with routine formalin ethyl-acetate concentration, wet mounts from both concentrated and unconcentrated samples, Ziehl-Neelsen staining on patients with certain symptoms and real-time PCR.Results: We found a significant higher detection rate of parasites with the extended microscopy method compared to the Swedish routine microscopy method when SAF-fixed samples were used. The detection rate with real-time PCR in SAF-fixed samples was equal to the detection rate in unpreserved samples. There was no significant difference in detection comparing extended microscopy and real-time PCR.Conclusion: In conclusion, this study showed that the extended microscopy method increased detection of intestinal protozoa with detection of both trophozoites and Cryptosporidium spp. We also showed that SAF-fixative can be used for detection of parasite-DNA with real-time PCR.


Network pharmacology analysis of the mechanism of Huisheng oral liquid in the treatment of lung cancer.
To study the active ingredient and possible mechanism of Huisheng oral liquid in the treatment of lung cancer by network pharmacology. The active ingredient and drug targets of Huisheng oral liquid were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID), and lung cancer targets were screened using the Gene Expression Omnibus (GEO) database. The drug targets of the effective components of Huisheng oral liquid were matched with disease targets and the obtained intersecting targets were imported into the Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) database to construct a protein-protein interaction (PPI) network. R software and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database were used for Gene Ontology (GO) and KEGG enrichment analyses, and Cytoscape software was used to construct a Huisheng oral liquid component target-lung cancer target network. The function and pathway of the therapeutic target of Huisheng oral liquid for lung cancer were analyzed. A total of 1,376 differentially expressed genes (DEGs) of lung cancer were obtained, and 185 potential effective components of Huisheng oral liquid in the treatment of lung cancer were obtained, including quercetin, luteolin, kaempferol, and baicalein. There were 36 intersecting targets between Huisheng oral liquid and lung cancer, and the key targets for lung cancer treatment were CDKN1A, CCNB1, MDM2, CDK1, ErbB2, E2F1, EGFR, etc. Huisheng oral liquid mainly regulates the p53 signaling pathway. The mechanism of Huisheng oral liquid in the treatment of lung cancer is mainly reflected in regulating tumor cell apoptosis, inhibiting angiogenesis, and improving immunity.


A functional genetic screen for metabolic proteins unveils GART and the de novo purine biosynthetic pathway as novel targets for the treatment of luminal A ERα expressing primary and metastatic invasive ductal carcinoma.
Targeting tumor cell metabolism is a new frontier in cancer management. Thus, metabolic pathway inhibitors could be used as anti-estrogen receptor α (ERα) breast cancer (BC) drugs. Here, the interplay among metabolic enzyme(s), the ERα levels and cell proliferation was studied. siRNA-based screen directed against different metabolic proteins in MCF10a, MCF-7 and MCF-7 cells genetically resistant to endocrine therapy (ET) drugs and metabolomic analyses in numerous BC cell lines unveil that the inhibition of GART, a key enzyme in the purine de novo biosynthetic pathway, induces ERα degradation and prevent BC cell proliferation. We report here that a reduced GART expression correlates with a longer relapse-free-survival (RFS) in women with ERα-positive BCs. ERα-expressing luminal A invasive ductal carcinomas (IDCs) are sensitive to GART inhibition and GART expression is increased in receptor-positive IDCs of high grade and stage and plays a role in the development of ET resistance. Accordingly, GART inhibition reduces ERα stability and cell proliferation in IDC luminal A cells where it deregulates 17β-estradiol (E2):ERα signaling to cell proliferation. Moreover, the GART inhibitor lometrexol (LMX) and drugs approved for clinical treatment of primary and metastatic BC (4OH-tamoxifen and the CDK4/CDK6 inhibitors) exert synergic antiproliferative effects in BC cells. In conclusion, GART inhibition by LMX or other inhibitors of the de novo purine biosynthetic pathway could be a novel effective strategy for the treatment of primary and metastatic BCs.


Peripheral vision: abdominal pathology missed outside the centre of gaze.
Radiology misses have been the subject of much debate on both sides of the Atlantic in recent years. There is now greater focus in trying to reduce radiology errors by continuous education and changing the working environment to try and protect the radiologist, and ultimately the patient from potential harm. Duty of candour is a relevant and sensitive area. Developing robust validated reporting pathways within the healthcare structure is very important so as to encourage a "learning from discrepancies" culture and to put the patient and their families at the center of reporting and acknowledging errors in radiology. Having reflected in our daily practice and while writing this pictorial review, we have concluded that during reporting MRI scans, routine assessment of the localizer images, focusing outside the area of interest and having a more structured approach to image interrogation are key actions which may help reduce the number of omissions. We present a myriad of cases where pathology was "missed" outside the center of gaze in relation to the abdomen or outside the abdomen on abdominal MRI, and suggest key high yield sequence related review areas to minimize the chance of missing potentially significant pathology.


FKBP38 protects Bcl-2 from caspase-dependent degradation.
The cellular processes that regulate Bcl-2 at the posttranslational levels are as important as those that regulate bcl-2 synthesis. Previously we demonstrated that the suppression of FK506-binding protein 38 (FKBP38) contributes to the instability of Bcl-2 or leaves Bcl-2 unprotected from degradation in an unknown mechanism. Here, we studied the underlying molecular mechanism mediating this process. We first showed that Bcl-2 binding-defective mutants of FKBP38 fail to accumulate Bcl-2 protein. We demonstrated that the FKBP38-mediated Bcl-2 stability is specific as the levels of other anti-apoptotic proteins such as Bcl-X(L) and Mcl-1 remained unaffected. FKBP38 enhanced the Bcl-2 stability under the blockade of de novo protein synthesis, indicating it is posttranslational. We showed that the overexpression of FKBP38 attenuates reduction rate of Bcl-2, thus resulting in an increment of the intracellular Bcl-2 level, contributing to the resistance of apoptotic cell death induced by the treatment of kinetin riboside, an anticancer drug. Caspase inhibitors markedly induced the accumulation of Bcl-2. In caspase-3-activated cells, the knockdown of endogenous FKBP38 by small interfering RNA resulted in Bcl-2 down-regulation as well, which was significantly recovered by the treatment with caspase inhibitors or overexpression of FKBP38. Finally we presented that the Bcl-2 cleavage by caspase-3 is blocked when Bcl-2 binds to FKBP38 through the flexible loop. Taken together, these results suggest that FKBP38 is a key player in regulating the function of Bcl-2 by antagonizing caspase-dependent degradation through the direct interaction with the flexible loop domain of Bcl-2, which contains the caspase cleavage site.


Signalling pathways and mechanisms of protection in pre- and postconditioning: historical perspective and lessons for the future.
Ischaemic pre- and postconditioning are potent cardioprotective interventions that spare ischaemic myocardium and decrease infarct size after periods of myocardial ischaemia/reperfusion. They are dependent on complex signalling pathways involving ligands released from ischaemic myocardium, G-protein-linked receptors, membrane growth factor receptors, phospholipids, signalling kinases, NO, PKC and PKG, mitochondrial ATP-sensitive potassium channels, reactive oxygen species, TNF-α and sphingosine-1-phosphate. The final effector is probably the mitochondrial permeability transition pore and the signalling produces protection by preventing pore formation. Many investigators have worked to produce a roadmap of this signalling with the hope that it would reveal where one could intervene to therapeutically protect patients with acute myocardial infarction whose hearts are being reperfused. However, attempts to date to show efficacy of such an intervention in large clinical trials have been unsuccessful. Reasons for this inability to translate successes in the experimental laboratory to the clinical arena are evaluated in this review. It is suggested that all patients with acute coronary syndromes currently presenting to the hospital and being treated with platelet P2Y12 receptor antagonists, the current standard of care, are indeed already benefiting from protection from the conditioning pathways outlined earlier. If that proves to be the case, then future attempts to further decrease infarction will have to rely on interventions which protect by a different mechanism.


Respiratory Depression as Antibacterial Mechanism of Linalool against Pseudomonas fragi Based on Metabolomics.
Linalool showed a broad-spectrum antibacterial effect, but few studies have elucidated the antibacterial mechanism of linalool on Pseudomonas fragi (P. fragi) to date. The present study aimed to uncover the antimicrobial activity and potential mechanism of linalool against P. fragi by determining key enzyme activities and metabolites combined with a high-throughput method and metabolomic pathway analysis. As a result, linalool had excellent inhibitory activity against P. fragi with MIC of 1.5 mL/L. In addition, the presence of linalool significantly altered the intracellular metabolic profile and a total of 346 differential metabolites were identified, of which 201 were up-regulated and 145 were down-regulated. The highlight pathways included beta-alanine metabolism, pantothenic acid and CoA metabolism, alanine, aspartate and glutamate metabolism, nicotinate and nicotinamide metabolism. Overall, linalool could cause metabolic disorders in cells, and the main metabolic pathways involved energy metabolism, amino acid metabolism and nucleic acid metabolism. In particular, the results of intracellular ATP content and related enzymatic activities (ATPase, SDH, and GOT) also highlighted that energy limitation and amino acid disturbance occurred intracellularly. Together, these findings provided new insights into the mechanism by which linalool inhibited P. fragi and theoretical guidance for its development as a natural preservative.


Assessment of Hospital Emergency Department Response to Potentially Infectious Diseases Using Unannounced Mystery Patient Drills - New York City, 2016.
Recent outbreaks of infectious diseases have revealed significant health care system vulnerabilities and highlighted the importance of rapid recognition and isolation of patients with potentially severe infectious diseases. During December 2015-May 2016, a series of unannounced "mystery patient drills" was carried out to assess New York City Emergency Departments' (EDs) abilities to identify and respond to patients with communicable diseases of public health concern. Drill scenarios presented a patient reporting signs or symptoms and travel history consistent with possible measles or Middle East Respiratory Syndrome (MERS). Evaluators captured key infection control performance measures, including time to patient masking and isolation. Ninety-five drills (53 measles and 42 MERS) were conducted in 49 EDs with patients masked and isolated in 78% of drills. Median time from entry to masking was 1.5 minutes (range = 0-47 minutes) and from entry to isolation was 8.5 minutes (range = 1-57). Hospitals varied in their ability to identify potentially infectious patients and implement recommended infection control measures in a timely manner. Drill findings were used to inform hospital improvement planning to more rapidly and consistently identify and isolate patients with a potentially highly infectious disease.


[A case of early poorly-differentiated neuroendocrine carcinoma of stomach].
A 45-year-old male was admitted to our hospital complaining of anemia. Gastric endoscopy showed a type IIa+IIc tumor at the anterior wall of the gastric angle. Based on the pathology of the biopsy specimen, poorly-differentiated adenocarcinoma was diagnosed. Computed tomography scans showed regional lymph node swelling. Distal gastrectomy with a D2 lymph node dissection was performed. On pathology, the tumor was immunohistochemically positive for chromogranin A and synaptophysin. The Ki67 index was 70%. The tumor was diagnosed as poorly-differentiated neuroendocrine carcinoma of the stomach. He was treated with S-1 and CPT-11. Neuroendocrine cell carcinoma of the stomach is rare and usually has a very poor prognosis. Thus, we are reporting this case of early poorly-differentiated neuroendocrine carcinoma of the stomach that was curatively resected and had 12-month survival without recurrence.


Nestin- and doublecortin-positive cells reside in adult spinal cord meninges and participate in injury-induced parenchymal reaction.
Adult spinal cord has little regenerative potential, thus limiting patient recovery following injury. In this study, we describe a new population of cells resident in the adult rat spinal cord meninges that express the neural stem/precursor markers nestin and doublecortin. Furthermore, from dissociated meningeal tissue a neural stem cell population was cultured in vitro and subsequently shown to differentiate into functional neurons or mature oligodendrocytes. Proliferation rate and number of nestin- and doublecortin-positive cells increased in vivo in meninges following spinal cord injury. By using a lentivirus-labeling approach, we show that meningeal cells, including nestin- and doublecortin-positive cells, migrate in the spinal cord parenchyma and contribute to the glial scar formation. Our data emphasize the multiple roles of meninges in the reaction of the parenchyma to trauma and indicate for the first time that spinal cord meninges are potential niches harboring stem/precursor cells that can be activated by injury. Meninges may be considered as a new source of adult stem/precursor cells to be further tested for use in regenerative medicine applied to neurological disorders, including repair from spinal cord injury.


CD148, a new membrane tyrosine phosphatase involved in leukocyte function.
Protein tyrosine phosphatases play an essential role in the control of leucocyte cell growth an differentiation. Recently a new receptor type membrane tyrosine phosphatase named CD148 has been identified. This molecule is present on the membrane of all the hematopoietic lineages as well as on several other cell types, mainly epithelial cells and its expression increases after cell activation. This molecule is able to act as a transducing molecule. Moreover, CD148 is able to modulate the signal transduction through the TCR/CD3 complex, in a manner similar to CD45. It has also been suggested that CD148 could be involved in mechanisms of differentiation and inhibition of cell growth. In addition, CD148 seems to be associated with a serine/threonine kinase in certain epithelial cell lines and leucocytes. Here, we review recent data on the expression and function of CD148 in both human, mouse and rat.


Examining non-stationary effects of social determinants on cardiovascular mortality after cold surges in Taiwan.
Details about the impact of extreme cold on cardiovascular mortality are little known in the countries with warm winters like Taiwan. This study aimed to examine the ecological associations between various social determinants and cardiovascular mortality after cold surges in Taiwan with a spatial perspective focusing on spatial non-stationarity. The mortality rates at township level in Taiwan were observed from 1997 to 2003. Five social determinants (social disadvantage, lack of economic opportunity, stability, sensitive group, and rurality) were created with the 2000 Taiwan Census data. We analyzed the data using Geographically Weighted Poisson Regression. On average, an immediate increase in cardiovascular mortality was found right after cold surges. All of the five determinants were found to have spatial non-stationary effects on the cardiovascular mortality rates after cold surges. This finding provided an empirical basis for developing public health programs with local emphases on the impacts of extreme cold.


Indeterminate genotypes of hepatitis C virus by the Abbott RealTime HCV Genotype II assay in Morocco. About eight cases resolved by a sequencing method.
The early detection and genotyping of the hepatitis C virus (HCV) are important in the management of this infection. The genotype is the major factor influencing treatment decisions. That's why it is necessary to use fast and accurate methods in its determination. This study reports, over a period of 3 years (from May 2012 to July 2015), the percentage of indeterminate genotypes by the Abbott RealTime HCV Genotype II test and their results using a sequencing technique. Of 309 samples of 309 patients tested, 11 were indeterminate (4.4%). There were three cases of cross-reactivity (1b/4 in one case, 2/5 in two cases) and a possible co-infection 1 + 4. Among those indeterminate genotypes, cross-reactivities and co-infections, ten samples were tested by sequencing. The results were for four of them a 1d subtype, five were a 2i subtype and one was a 2l subtype. These results support the thesis of complementarity between the two methods: genotyping for the detection of mixed reactions and sequencing for resolving indeterminate cases by genotyping.


In vivo administration of interferon gamma does not cause marrow aplasia in mice with a targeted disruption of FANCC.
Hematopoietic cells from patients with Fanconi anemia (FA) and mice carrying a targeted disruption of the gene encoding complementation group C protein (FANCC(-/-)) demonstrate an apoptotic phenotype in response to alkylating agents and cytokines including interferon gamma (IFN-gamma) in vitro. The aim of this study was to explore these apoptosis-inducing effects of IFN-gamma on the bone marrow of FANCC(-/-) mice as a potential strategy to select gene-corrected cells in vivo. Following pharmacokinetic studies to determine if serum concentrations effective in vitro can be achieved in vivo, we injected FANCC(-/-) mice with recombinant murine IFN-gamma. Hematopoietic effects were investigated by serial determinations of blood counts, progenitor colony formation, and marrow cellularity. Serial weekly intraperitoneal administrations of escalating doses of rmIFN-gamma did not affect peripheral blood counts in FANCC(-/-) mice, even after subsequent antibody-mediated fas ligation. Additionally, prolonged exposure after sequential daily administration of recombinant IFN-gamma did not impair progenitor cell clonogenicity in vitro. Pharmacokinetic data confirmed that the failure of IFN-gamma to induce marrow aplasia occurred in spite of peak serum levels greater than 100-fold in excess of those effective in vitro. We conclude that in spite of the well-documented in vitro apoptotic tendency of FA-phenotype hematopoietic cells, the in vivo administration of IFN-gamma with and without subsequent fas ligation does not induce bone marrow failure in FANCC(-/-) (129SvJ strain) mice. Additional selective pressure may be necessary to achieve targeted ablation of uncorrected, FA-phenotype, marrow cells.


Protein Promiscuity in H2O2 Signaling.
Decrypting the cellular response to oxidative stress relies on a comprehensive understanding of the redox signaling pathways stimulated under oxidizing conditions. Redox signaling events can be divided into upstream sensing of oxidants, midstream redox signaling of protein function, and downstream transcriptional redox regulation. Recent Advances: A more and more accepted theory of hydrogen peroxide (H2O2) signaling is that of a thiol peroxidase redox relay, whereby protein thiols with low reactivity toward H2O2 are instead oxidized through an oxidative relay with thiol peroxidases. These ultrareactive thiol peroxidases are the upstream redox sensors, which form the first cellular port of call for H2O2. Not all redox-regulated interactions between thiol peroxidases and cellular proteins involve a transfer of oxidative equivalents, and the nature of redox signaling is further complicated through promiscuous functions of redox-regulated "moonlighting" proteins, of which the precise cellular role under oxidative stress can frequently be obscured by "polygamous" interactions. An ultimate goal of redox signaling is to initiate a rapid response, and in contrast to prokaryotic oxidant-responsive transcription factors, mammalian systems have developed redox signaling pathways, which intersect both with kinase-dependent activation of transcription factors, as well as direct oxidative regulation of transcription factors through peroxiredoxin (Prx) redox relays. We highlight that both transcriptional regulation and cell fate can be modulated either through oxidative regulation of kinase pathways, or through distinct redox-dependent associations involving either Prxs or redox-responsive moonlighting proteins with functional promiscuity. These protein associations form systems of crossregulatory networks with multiple nodes of potential oxidative regulation for H2O2-mediated signaling.


Optical-resolution photoacoustic microscopy with ultrafast dual-wavelength excitation.
Fast functional and molecular photoacoustic microscopy requires pulsed laser excitations at multiple wavelengths with enough pulse energy and short wavelength-switching time. Recent development of stimulated Raman scattering in optical fiber offers a low-cost laser source for multiwavelength photoacoustic imaging. In this approach, long fibers temporally separate different wavelengths via optical delay. The time delay between adjacent wavelengths may eventually limits the highest A-line rate. In addition, a long-time delay in fiber may limit the highest pulse energy, leading to poor image quality. In order to achieve high pulse energy and ultrafast dual-wavelength excitation, we present optical-resolution photoacoustic microscopy with ultrafast dual-wavelength excitation and a signal separation method. The signal separation method is validated in numerical simulation and phantom experiments. We show that when two photoacoustic signals are partially overlapped with a 50-ns delay, they can be recovered with 98% accuracy. We apply this ultrafast dual-wavelength excitation technique to in vivo OR-PAM. Results demonstrate that A-lines at two wavelengths can be successfully separated, and sO2 values can be reliably computed from the separated data. The ultrafast dual-wavelength excitation enables fast functional photoacoustic microscopy with negligible misalignment among different wavelengths and high pulse energy, which is important for in vivo imaging of microvascular dynamics.


Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin.
Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure-activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the l- allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the d-phenylalanine. On the basis of the antibacterial activities that resulted from corresponding modifications of the d-phenylalanine, we propose a hydrophobic interaction between lipid II and the N-terminal of teixobactin analogues, which we map out with our analogue 35. Finally, a representative analogue from our series showed high efficiency in a mouse model of Streptococcus pneumoniae septicemia.


Bilateral total conservative parotidectomy: a tale behind an aesthetic surgery.
Any facial swelling is associated with stress for the patient due to cosmesis. Especially when one has bilateral symmetrical enlarged parotids, having exhausted all available conservative management, surgery becomes the last resort; which in such cases pose specific challenges. A 29-year-old man presented with problems of bilateral symmetrical enlarged parotid lesion for 5 years, which did not have an adequate response to medical line of management. He underwent proposed surgery and was diagnosed to have chronic sclerosing parotitis (CSS). The challenges faced during surgery of this non-neoplastic inflammatory lesion, with significant fibrosis, is being described. He recovered completely without any complications related to surgery. CSS rarely affects bilateral parotid glands. Surgery, results of which are outstanding, must be considered in cases where these lesions do not respond to medical line of management. Bilateral total conservative parotidectomy with sternocleidomastoid flap reconstruction provides excellent aesthesis and improves quality of life.


Neuroprotective properties of levosimendan in an in vitro model of traumatic brain injury.
We investigated the neuroprotective properties of levosimendan, a novel inodilator, in an in vitro model of traumatic brain injury. Organotypic hippocampal brain slices from mouse pups were subjected to a focal mechanical trauma. Slices were treated after the injury with three different concentrations of levosimendan (0.001, 0.01 and 0.1 μM) and compared to vehicle-treated slices. After 72 hrs, the trauma was quantified using propidium iodide to mark the injured cells. A significant dose-dependent reduction of both total and secondary tissue injury was observed in cells treated with either 0.01 or 0.1 μM levosimendan compared to vehicle-treated slices. Levosimendan represents a promising new pharmacological tool for neuroprotection after brain injury and warrants further investigation in an in vivo model.


CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products.
Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cell has changed the treatment landscape of B-cell non-Hodgkin's lymphoma (NHL), especially for aggressive B-cell lymphomas. Single-center and multicenter clinical trials with anti-CD19 CAR T-cell therapy have shown great activity and long-term remissions in poor-risk diffuse large B-cell lymphoma (DLBCL) when no other effective treatment options are available. Two CAR T-cell products [axicabtagene ciloleucel (axi-cel) and tisagenlecleucel] have obtained US Food and Drug Administration approval for the treatment of refractory DLBCL after two lines of therapy. A third product, liso-cel, is currently being evaluated in clinical trials and preliminary results appear very promising. CAR T-cell-related toxicity with cytokine-release syndrome and neurotoxicity remain important potential complications of this therapy. Here, we review the s biology, structure, clinical trial results and toxicity of two commercially approved CAR T-cell products and others currently being studied in multicenter clinical trials in B-cell NHLs.


Modulation of Lower-Limb Muscle Activity in Maintaining Unipedal Balance According to Surface Stability, Sway Direction, and Leg Dominance.
Determining temporal similarity in shape between electromyographic (EMG) and center-of-pressure (COP) signals reflects neuromuscular control in terms of which relevant muscles are involved in maintaining balance. The current study aimed to investigate a cross-correlation between seven lower-limb EMG activities and COP displacements, simultaneously measured in 25 young adults unipedally balancing on stable and multiaxial-unstable surfaces. The effect of surface stability, sway direction, and leg dominance was then tested on two EMG-COP correlation levels: individual muscles and groups (patterns) of multi-muscles involved in postural sway, as determined by principal component analysis (PCA). The results show that two factors demonstrate their effects only at the level of individual muscles: sway direction (p ≤ 0.003) and leg dominance (p = 0.003). Specifically, the semitendinosus, tibialis anterior, peroneus longus, and soleus correlate more with the mediolateral postural sway than with the anteroposterior postural sway, except for the gastrocnemius medialis. Additionally, balancing on the non-dominant leg shows a lower correlation between the semitendinosus and postural sway than on the dominant leg. The current findings suggest that when achieving unipedal equilibrium, the postural control system may be constrained the most in the specific muscles of the least steady conditions, e.g., the frontal plane and non-preferred leg.


PPAR-alpha-null mice are protected from high-fat diet-induced insulin resistance.
Peroxisome proliferator-activated receptor (PPAR)-alpha controls the expression of genes involved in lipid metabolism. PPAR-alpha furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-alpha-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-alpha in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-alpha-null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-alpha-null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-alpha-null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat-fed wild-type mice, whereas it remained unchanged in PPAR-alpha-null mice. In contrast, PPAR-alpha deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-alpha dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-alpha deficiency on glucose homeostasis seem not to occur via the pancreas, because glucose-stimulated insulin secretion of islets was not influenced by the PPAR-alpha genotype. These data suggest that PPAR-alpha plays a role for the development of IR in response to a Western-type high-fat diet.


Gingival melanin depigmentation by 810 nm diode laser.
The color of gingiva is determined by number and size of blood vessels, thickness of epithelium, keratinization degree, and melanin pigments present in epithelium. Melanocytes, located in basal and suprabasal layers of epithelium, are the cells that produce melanin pigments which play a main role for pigmentation of gingiva. In this case series, the use of 810 nm diode laser for depigmentation of gingiva is presented. Two female patients applied with a chief complaint of "darkened gums" due to heavy smoking. In intraoral examination, diffuse melanin pigmentation was observed in both the maxilla and mandible. Under the local anesthesia, 810 nm diode laser was applied for depigmentation at 1.3 W power in continuous mode. Patients were recalled at weeks 1, 4, and 12 to evaluate the healing and recurrence rate. Both the patients had no postoperative pain or edema, and complete healing was observed at week 12. This study revealed that depigmentation with 810 nm diode laser is successful in terms of esthetics and patient comfort.


[Tridimensional theory of personality: applications to substance abuse disorders].
We have assessed the weight that Cloninger' dimensions play in the substance abuse disorder. Also, we have analysed the hypothetical self-independence of these dimensions and if there is some correlation between those and some demographic variables. 20 drug abstinents and 20 controls, all males, fulfilled the Tridimensional Personality Questionnaire. All the values on the Novelty Seeking (NS) subclass and the overall NS scale were higher in the abstinent group. The most meaningful differences were found on the excitable and extravagant subclass and the total NS scale. There was also a significant though smaller difference on the disorderly subclass. Only the Harm Avoidance (HA) subclass fatigability was significantly higher in the abstinent group. The value of persistence substantially low in the abstinent subjects was the most significant difference between groups when the Reward Dependence (RD) scale was considered. The correlation analysis demonstrated that the three dimensions were mutually independent in the controls. However, in the abstinent group NS correlated positively with HA and negatively with persistence. Any correlation was found between the dimensions and the demographic variables in both groups. A high sensation seeking behaviour and a low persistence seems to be the most prominent characteristic of our abstinent subjects. Both tendencies could explain in part their high substance seeking tendency and possibly the high rate of relapse found in similar populations. Finally, the Cloninger's hypothesis about the mutually independence of the dimensions seems to be fulfilled only in the control group.


A rapid procedure for the detection and isolation of enterohaemorrhagic Escherichia coli (EHEC) serogroup O26, O103, O111, O118, O121, O145 and O157 strains and the aggregative EHEC O104:H4 strain from ready-to-eat vegetables.
Human infections with Enterohaemorrhagic Escherichia coli strains (EHEC) as agents of Haemorrhagic Colitis (HC) and Haemolytic Uraemic Syndrome (HUS) are frequently associated with the consumption of EHEC contaminated foodstuffs of different origins. EHEC O26, O103, O111, O118, O121, O145 and O157 strains are responsible for the majority of HC and HUS cases worldwide. In May 2011, the emerging aggregative EHEC O104:H4 strain caused a large outbreak with high HUS incidence in northern Germany. Contaminated sprouted seeds were suspected to be the vehicles of transmission. The examination of vegetables retailed for raw consumption revealed low numbers of E. coli (<100 cfu/g) together with high titres of Enterobacteriaceae and Pseudomonas (approx. 5.6 × 10⁷ cfu/g). Specific methods of EHEC detection adapted to vegetables are not yet published. Therefore, we have developed a rapid and sensitive method for detecting low EHEC contamination in vegetables (1-10 cfu/25 g) with artificially EHEC contaminated ready-to-eat salads. A 6-hour enrichment period in BRILA-broth was sufficient to detect 1-10 EHEC from spiked samples after plating 0.1 ml portions of enrichment culture on selective TBX-agar and CHROMagar STEC plates that were incubated at 44 °C overnight. Unlike EHEC strains, the growth of bacteria of the plant flora was substantially inhibited at 44 °C. DNA for real-time PCR detection of EHEC characteristic genes (stx(1), stx(2), eae, ehxA, and O-antigen associated) was prepared with bacteria grown on TBX-agar plates. The storage of EHEC inoculated salad samples for 72 h at 6 °C resulted in a significant reduction (mean value 14.6%) of detectable EHEC, suggesting interference of EHEC with the resident plant microflora. CHROMagar STEC was evaluated as a selective medium for the detection of EHEC strains. Growth on CHROMagar STEC was closely associated with EHEC O26:[H11], O111:[H8], O118:H16, O121:[H19], O145:[H28], O157:[H7] and aggregative EHEC O104:H4 strains and with the presence of the terB gene (tellurite resistance). TerB sequences were found in 87.2% of 235 EHEC but only in only 12.5% of 567 non-EHEC strains. EHEC strains which did not grow on CHROMagar STEC were negative for terB as frequently observed with EHEC O103:H2 (52.9%) and sorbitol-fermenting O157:NM strains (100%). The enrichment and detection method was applied in the examination of sprouted seeds incriminated as vehicles in the EHEC O104:H4 outbreak in Germany. Aggregative EHEC O104:H4 could be detected and isolated from a sample of sprouted seeds which was suspected as vector of transmission of EHEC O104 to humans.


Rapid evolution of the mitochondrial genome in Chalcidoid wasps (Hymenoptera: Chalcidoidea) driven by parasitic lifestyles.
Among the Chalcidoids, hymenopteran parasitic wasps that have diversified lifestyles, a partial mitochondrial genome has been reported only from Nasonia. This genome had many unusual features, especially a dramatic reorganization and a high rate of evolution. Comparisons based on more mitochondrial genomic data from the same superfamily were required to reveal weather these unusual features are peculiar to Nasonia or not. In the present study, we sequenced the nearly complete mitochondrial genomes from the species Philotrypesis. pilosa and Philotrypesis sp., both of which were associated with Ficus hispida. The acquired data included all of the protein-coding genes, rRNAs, and most of the tRNAs, and in P. pilosa the control region. High levels of nucleotide divergence separated the two species. A comparison of all available hymenopteran mitochondrial genomes (including a submitted partial genome from Ceratosolen solmsi) revealed that the Chalcidoids had dramatic mitochondrial gene rearrangments, involved not only the tRNAs, but also several protein-coding genes. The AT-rich control region was translocated and inverted in Philotrypesis. The mitochondrial genomes also exhibited rapid rates of evolution involving elevated nonsynonymous mutations.


The epidemiology of anal cancer.
Anal cancer comprises malignancies of the anal canal principally of two morphologic variants: squamous cell carcinoma (SCC) and adenocarcinoma. In most settings, SCC compromises more than 70% of cases. In the general population, anal cancer is uncommon, with age-standardised incidence rates mostly between 1 and 2 per 100000 per year. However, incidence of anal SCC is increasing by 1-3% per year in developed country settings. High-risk human papillomavirus (HPV) types can be detected in 80-90% of all anal SCC cases, making it second only to cervical cancer in the closeness of its association with this virus. HPV-16 can be detected in ~90% of HPV-positive cases of anal SCC. Case-control studies have demonstrated that sexual risk factors (homosexuality in men and multiple sexual partners in women) are strongly associated with anal cancer risk. Other risk factors include immune deficiency and tobacco exposure. Anal cancer rates are highest in homosexual men, particularly in those who are HIV-positive, in whom anal cancer is among the most common of all cancers. Vaccination against HPV holds great promise for anal cancer prevention for those not already HPV-infected. For the current generation of adult high-risk populations, screening programs to allow early detection and treatment are under investigation.


Stereoselective and regioselective 5-exo-dig cyclization of 8-alkynylnaphthalen-1-amines for the synthesis of (E)-2-(arylthio)alkylene-1,2-dihydrobenzo[cd]indoles.
A palladium and iodine-cocatalyzed 5-exo-dig aza-thiocyclization of 8-alkynylnaphthalen-1-amines for the synthesis of (E)-2-alkylene-1,2-dihydrobenzo[cd]indole thioethers is reported. As a result of broad reaction scope, simple operation, mild conditions, and high stereoselectivity and regioselectivity, this reaction should have potential utility in organic synthesis.


Scutellarin Inhibits the Growth and EMT of Gastric Cancer Cells through Regulating PTEN/PI3K Pathway.
Gastric cancer is one of the most common malignancies with a high mortality rate world. This study intends to make clear the role and mechanism of the Scutellarin (Scu), a flavonoid isolated from Erigeron breviscapus (Vant.) Hand.-Mazz, in regulating the evolvement of gastric cancer. We selected different doses of Scu to treat gastric cancer cells (MGC-803 and AGS). Then, cell counting kit-8 (CCK8) assay was conducted to verify the proliferation of tumor cells, while flow cytometry was adopted to test the apoptosis rate. Meanwhile, Western blot was conducted to examine epithelial-mesenchymal transition (EMT) markers and the expression of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K) and apoptosis-related proteins (Bax, Bcl2 and Caspase3). Moreover, xenograft tumor experiment in nude mice was established to verify the effect of Scu on tumor growth. Furthermore, the knockdown model of PTEN was constructed, and the influence of PTEN on the anti-tumor effect of Scu was investigated. As a result, Scu inhibited cell proliferation, EMT and promoted the apoptosis in gastric cancer dose-dependently. Additionally, Scu attenuated tumor cell growth in vivo. Besides, Scu enhanced the expression of PTEN while reduced the phosphorylated level of PI3K. Moreover, the mechanistic study proved that Scu inactivated PI3K by up-regulating PTEN, thus dampening tumor progression. In conclusion, Scu dampened the growth and EMT of gastric cancer by regulating the PTEN/PI3K pathway.


Fluoroquinolones. New miracle drugs?
Fluoroquinolones are the newest antibiotics for treatment of some infections caused by highly resistant bacteria (eg, Pseudomonas aeruginosa). Clinically sound indications for these drugs include resistant infections of the urinary, intestinal, and respiratory tracts; otitis externa; osteomyelitis; foot infections in diabetic patients; and late infections complicating burns. Fluoroquinolone therapy is not indicated in children younger than 12 years old and patients with foreign bodies, abscesses, pelvic inflammatory disease, or infections requiring a prophylactic antibiotic. Drug interactions with antacids or theophylline may occur.


Lodopyridones D - G from a marine-derived bacterium Saccharomonospora sp.
The intensive investigation of chemical components from the culture broth of the bacterium Saccharomonospora sp. CNQ-490 has yielded four new natural products, lodopyridones D - G (1 - 4) along with the previously reported compounds, lodopyridones A - C (5 - 7) and cotteslosin A (8). The planar structures of the lodopyridones D - G (1 - 4) were elucidated by interpreting the mass spectrometry, ultraviolet (UV) spectroscopy, and 1D and 2D nuclear magnetic spectroscopy (NMR) data, as well as comparing NMR data with those of the lodopyridones A - C (5 - 7).


[Relationship of 24-hour ambulatory blood pressure and rennin-angiotensin-aldosterone system in children with primary nephrotic syndrome].
To investigate the changes of blood pressure by 24-hour ambulatory blood pressure (ABP) monitoring in children with primary nephrotic syndrome (PNS) and explore the relationship of the changes in blood pressure with rennin-angiotensin-aldosterone system (RAAS) in these children. ABP and casual blood pressure (CBP) monitoring were performed in 114 children with PNS. Plasma levels of rennin activity (PRA), angiotensin II (AngII) and aldosterone (ALD) were measured. The correlation of plasma levels of PRA, AngII and ALD with ABP was evaluated. Of the 114 children with PNS, 101 (88.6%) presented elevated blood pressure. Mild or severe masked hypertension was found in 45 children (39.5%). Eighty (70.2%) children showed non-dipper blood pressure. The index and load of systolic blood pressure were higher than those of diastolic blood pressure. The blood pressure index and blood pressure load during sleep were higher than those during wakefulness. The boy presented higher diastolic blood pressure index and load than girls. Decubitus blood PRA, AngII and ALD levels in children with PNS were significantly higher than normal controls. The group with elevated blood pressure presented significantly higher decubitus blood PRA, AngII and ALD levels than the group with normal blood pressure. AngII level was significantly positively correlated with the index and load of both systolic blood pressure and diastolic blood pressure. The children with PNS present a high incidence of hypertension, with a large percentage of masked hypertension and non-dipper blood pressure. Systolic blood pressure increases more significantly than diastolic blood pressure. Blood pressure during sleep increases more significantly than that during wakefulness. Diastolic blood pressure increases more significantly in boys than in girls. RAAS activity is elevated and the elevated RAAS activity might increase the blood pressure mainly by AngII in children with PNS.


Toxicological insights of Spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?
The Spike protein (S protein) is a critical component in the infection of the new coronavirus (SARS-CoV-2). The objective of this work was to evaluate whether peptides from S protein could cause negative impact in the aquatic animals. The aquatic toxicity of SARS-CoV-2 Spike protein peptides derivatives has been evaluated in tadpoles (n = 50 tadpoles/5 replicates of 10 animals) from species Physalaemus cuvieri (Leptodactylidae). After synthesis, purification, and characterization of peptides (PSDP2001, PSDP2002, PSDP2003) an aquatic contamination has been simulated with these peptides during 24 h of exposure in two concentrations (100 and 500 ng/mL). The control group ("C") was composed of tadpoles kept in polyethylene containers containing de-chlorinated water. Oxidative stress, antioxidant biomarkers and AChE activity were assessed. In both concentrations, PSPD2002 and PSPD2003 increased catalase and superoxide dismutase antioxidants enzymes activities, as well as oxidative stress (nitrite levels, hydrogen peroxide and reactive oxygen species). All three peptides also increased acetylcholinesterase activity in the highest concentration. These peptides showed molecular interactions in silico with acetylcholinesterase and antioxidant enzymes. Aquatic particle contamination of SARS-CoV-2 has cholinesterasic effect in P. cuvieri tadpoles. These findings indicate that the COVID-19 can constitute environmental impact or biological damage potential.


Ontogeny of odor liking during childhood and its relation to language development.
One important aspect of odor hedonics is its plasticity during human development. The present study set out to probe the modulators of such olfactory change during that period by testing the hypothesis that language and semantic representations of objects are strong organizers of odor liking. To this end, 15 three-year-old children were tested in a longitudinal study. Participants were exposed to exactly the same 12 odorants once a year over a 3-year period. At each experimental session, they were asked to answer 2 questions: 1) "Do you like or dislike this odor?" and 2) "Can you tell me what it is?" The level of language production was assessed on a standardized test. The 3-year-old children were found to categorize the same number of odorants as liked and as disliked. The follow-up study, in contrast, showed that at 5 years of age they categorized more of these odors as liked and that the shift was significant only in the children with higher language production skills. Taken as a whole, these findings suggest that the 3- to 5-year age range, when children begin to master language, is a turning point in the construction of olfactory hedonic categories during childhood.


Prevention of malaria-induced foetal abnormalities following immunization of mice with Plasmodium berghei merozoite antigen.
Pre-pregnancy immunization of Swiss albino mice with merozoite antigen of P. berghei entrapped in multilamellar phosphatidyl choline liposomes resulted in (i) increased prepatent period, (ii) either no or low parasitaemic levels, (iii) reduced mortality, and (iv) normal foetal and placental development, upon challenge with P. berghei on 13th gestational day. The unimmunized animals which received either phosphate buffered saline or empty multilamellar phosphatidyl choline liposomes before pregnancy developed high parasitaemic and 30-40 per cent animals died before parturition while 60-70 per cent unimmunized animals revealed foetal abnormalities such as low body weight and larger spleen size. Placentae of unprotected animals had hyperplasia of trophoblastic membrane and plugging of placental sinusoids with parasitized erythrocytes and malarial pigments. The data suggest that prior immunization of animals with merozoite antigen entrapped in multilamellar phosphatidyl choline liposomes could abrogate the ill effects induced by malaria infection under the stress of pregnancy.


[Prevalence and influencing factors of dyslipidemia among the elderly in Changsha: a community-based study].
To study the prevalence and influencing factors of dyslipidemia in the elderly in Changsha. Multi-stage randomized cluster sampling method was used to select 3 500 persons aged 65 and over in Changsha. Levels of serum lipids were detected and questionnaire was used to investigate the related factors (such as smoking, drinking, history of chronic diseases). The prevalence rate of dyslipidemia was 43.72%. The abnormal rate of serum triglyceride, cholesterol and low-density lipoprotein was 26.54%, 25.31% and 16.65%, respectively. Multiple logistic regression analysis showed that smoking, drinking, overweight or obesity were risk factors of dyslipidemia. The incidence of dyslipidemia is high and the influencing factors are common among the elderly. Community health education will help improve the effect of prevention and control.


Effects of Helicobacter pylori on intracellular Ca2+ signaling in normal human gastric mucous epithelial cells.
In stomach, Helicobacter pylori (Hp) adheres to gastric mucous epithelial cells (GMEC) and initiates several different signal transduction events. Alteration of intracellular Ca2+ concentration ([Ca2+]i) is an important signaling mechanism in numerous bacteria-host model systems. Changes in [Ca2+]i induced by Hp in normal human GMEC have not yet been described; therefore, we examined effects of Hp on [Ca2+]i in normal human GMEC and a nontransformed GMEC line (HFE-145). Cultured cells were grown on glass slides, porous filters, or 96-well plates and loaded with fura 2 or fluo 4. Hp wild-type strain 60190 and vacA-, cagA-, and picB-/cagE- isogenic mutants were incubated with cells. Changes in [Ca2+]i were recorded with a fluorimeter or fluorescence plate reader. Wild-type Hp produced dose-dependent biphasic transient [Ca2+]i peak and plateau changes in both cell lines. Hp vacA- isogenic mutant produced changes in [Ca2+]i similar to those produced by wild type. Compared with wild type, cagA- and picB-/cagE- isogenic mutants produced lower peak changes and did not generate a plateau change. Preloading cultures with intracellular Ca2+ chelator BAPTA blocked all Hp-induced [Ca2+]i changes. Thapsigargin pretreatment of cultures to release Ca2+ from internal stores reduced peak change. Extracellular Ca2+ removal reduced plateau response. Hp-induced peak response was sensitive to G proteins and PLC inhibitors. Hp-induced plateau change was sensitive to G protein inhibitors, src kinases, and PLA2. These findings are the first to show that H. pylori alters [Ca2+]i in normal GMEC through a Ca2+ release/influx mechanism that depends on expression of cagA and picB/cagE genes.


Relevance of Sociodemographics and Clinical Tests in Single- and Dual-Task Conditions as Gait Speed Predictors of Parkinson's Disease.
This cross-sectional study aimed to identify the patient characteristics and clinical test results that predict the functional gait speed of people with Parkinson's disease (PD). The impact of dual tasks on gait in Parkinson's disease (PD) reveals a lack of automaticity and increased cognitive demands. We explored which characteristics explained walking speed with and without dual-task interference and if they reflected the cognitive demands of the task. The preferred gait speed, stride length, and cadence were measured in individuals with PD through five conditions: single-task (ST) and visual, verbal, auditory, and motor dual-tasks (DTs). Sociodemographic and disease characteristics and the results from clinical tests such as the Dynamic Parkinson's Disease Gait Scale (DYPAGS), Frontal Assessment Battery (FAB), and Parkinson's Disease Questionnaire-39 (PDQ-39), among others, were also recorded. Two models of multiple regression analysis were used to explore the predictive value of outcomes concerning speed. In Model I, clinical results were included, and in Model II, spatiotemporal variables were added to the significant predictors of Model I. Forty PD patients (aged 66.72 (7.5) years) completed the assessments. All the models generated were significant (p < 0.01). Models I and II accounted for 47% and 93% of the variance, respectively, in the single-task condition. A patient's gender, prescribed medication (drugs), academic level, and Hoehn and Yahr (H&Y) stage, along with the FAB, DYPAGS, and PDQ-39 scores, were significant predictors of gait speed in Model I for the ST and DT conditions. In Model II, the H&Y stage and prescribed medication (drugs), along with the FAB and DYPAGS scores, remained significant predictors. This research found that sociodemographics, the patient's stage disease, and their clinical test results contribute to their walking speed, highlighting the multifactorial nature of gait in demanding environments.


Determination of genome size and a preliminary physical map of an extreme alkaliphile, Micrococcus sp. Y-1, by pulsed-field gel electrophoresis.
Large restriction fragments of genomic DNA from Micrococcus sp. Y-1 were separated by pulsed-field gel electrophoresis (PFGE). Since Micrococcus sp. Y-1 has a G+C content of approximately 70%, restriction fragments were obtained by digesting chromosomal DNA with endonucleases which recognize A+T-rich sequences. Five enzymes, SspI, SpeI, XbaI, HpaI and EcoRI, were used for generation of distinctly separated fragments in the size range 100-500 kb. No site for DraI was detected. In contrast, sites for 8-base-recognizing enzymes, but not for NotI and SfiI, were frequent. The genome size of Micrococcus sp. Y-1 was determined from restriction fragments separated by PFGE, and was estimated to be approximately 4061 kb. Partial digestion experiments revealed the order of the six SspI fragments on the chromosome.


Bilateral posterior shoulder dislocation: the importance of the axillary radiographic view.
Whilst posterior shoulder dislocation is rare, it remains a frequently missed diagnosis. In all patients with a history of seizure, electrocution or similar trauma, where external rotation of the shoulder is limited, we recommend that an axillary or modified axillary view be added to the standard two radiographic shoulder views as routine protocol, to avoid missing a posterior dislocation.


[A case of spinocerebellar ataxia type 2 presenting with a clinical course similar to spastic paraparesis].
We report a 50-year-old woman with an unremarkable birth and developmental history, and with no family history of neurological disorders. The patient had a 6-year history of progressive cervical dystonia, oral dyskinesia, and hyperreflexia. She was initially considered to have spastic paraparesis of unknown cause. Because brain MRI showed mild atrophy of the cerebellar vermis, genetic analysis for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, and 17, and dentatorubral-pallidoluysian atrophy was performed. The results revealed an abnormal expansion of CAG repeats (38 repeats) in one allele of ATXN2, and the patient was diagnosed with spinocerebellar ataxia type 2 (SCA2). She had no major clinical features of SCA2 such as cerebellar ataxia, slow saccade, or hyporeflexia. Recent reports have shown the CAG repeat expansion in ATXN2 to be detected in patients with familial L-dopa-responsive parkinsonism. The present case suggests that CAG repeat expansion in ATXN2 may be detected in some patients with spastic paraparesis, and that wide variations of clinical manifestations exist in SCA2.


Stacking symmetry governed second harmonic generation in graphene trilayers.
Crystal symmetry plays a central role in governing a wide range of fundamental physical phenomena. One example is nonlinear optical second harmonic generation (SHG), which requires inversion symmetry breaking. We report a unique stacking-induced SHG in graphene trilayers, whose individual monolayer sheet is centrosymmetric. Depending on layer stacking sequence, we observe a strong optical SHG in a Bernal ABA-stacked non-centrosymmetric trilayer, while it vanishes in a rhombohedral ABC-stacked one, which preserves inversion symmetry. This highly contrasting SHG due to the distinct stacking symmetry enables us to map out the ABA and ABC crystal domains in an otherwise homogeneous graphene trilayer. The extracted second-order nonlinear susceptibility of the ABA trilayer is surprisingly large, comparable to the best known two-dimensional semiconductors enhanced by excitonic resonance. Our results reveal a novel stacking order-induced nonlinear optical effect, as well as unleash the opportunity for studying intriguing physical phenomena predicted for stacking-dependent ABA and ABC graphene trilayers.


Morphological and kinetic analyses of regime transition for poly[(S)-lactide] crystal growth.
Regime transitions of poly[(S)-lactide] (PLA) crystal growth from the melt were investigated by studying the morphological changes and carrying out kinetic analysis using microscopic techniques. PLA thin films with an average layer thickness of 100 nm were isothermally crystallized at a given crystallization temperature after melting at 220 degrees C. Following isothermal crystallization at a temperature below 145 degrees C, uniform two-dimensional spherulites having stacked flat-on lamellar texture were developed throughout the PLA thin films. On the basis of electron diffraction analysis for two-dimensional spherulites of PLA, it was found that the average growth direction of an individual lamellar crystal was parallel to the crystallographic b axis. At temperatures above 150 degrees C, hexagonal lamellar crystals were formed from the melt. Electron diffractograms of these lamellae showed that the crystal had orthogonal packing of PLA molecules and a truncated-lozenge-shaped growth behavior. The growth surfaces of the hexagonal crystal were parallel to either the crystallographic (110) or the (100) plane. The PLA crystal growth rate along the b axis direction was evaluated at various crystallization temperatures of the thin films. Kinetic analysis of crystal growth in the PLA thin film demonstrated that the regime transitions of PLA crystal growth, from regime III to regime II and from regime II to regime I, occur at around 120 and 147 degrees C, respectively. The transition from regime II to regime I induced morphological changes in the crystalline aggregates whereby spherulitic aggregates transformed into hexagonal lamellar stacking. As for the transition between regimes II and III, no obvious morphological change in the spherulitic crystal aggregates was observed.


Development of statistics as a discipline for clinical research: Past, present and future.
This article traces the history and evolution of statistics in the era of evidence based medicine, and focuses on the Indian perspective of this growth of statistics as a discipline for clinical research. Statistics will assume a more inter disciplinary form. Use of software other than SAS likely to grow further. In India, innovative statistical methods will help propel the development of biosimilars. The future is exciting with statistics being used for real world evidence, development of biosimilars, mining of adverse event data and becoming a core function in medicinal product development and lifecycle maintenance.


Speech outcomes and velopharyngeal function after surgical treatment of velopharyngeal insufficiency in individuals with signs of velocardiofacial syndrome.
The objective of the study was to analyze if individuals with velocardiofacial syndrome (VCFS) present the same characteristics of speech and velopharyngeal function (VPF) compared with patients with nonsyndromic submucous cleft palate, as well as to compare the effectiveness of palate surgery on the speech function and VPF between groups. This was a prospective study performed at the Speech Therapy Sector and Physiology Laboratory, Hospital for Rehabilitation of Craniofacial Anomalies/University of São Paulo.The procedure performed was primary palatoplasty associated or not to superiorly based pharyngeal flap surgery.There were 50 patients with velopharyngeal insufficiency: 25 with signals of VCFS (VCFS group) and 25 without syndrome with submucous cleft palate (SMCP group).The hypernasality was scored by 3 examiners; nasalance was evaluated by nasometry, and VPF was assessed by the size of the velopharyngeal gap on the nasoendoscopy. The evaluations were conducted before and, in average, 18 months after surgery. Before surgery, the VCFS and SMCP groups presented similar speech function and VPF characteristics in all parameters, with no statistically significant differences. After surgery, there was reduction in the hypernasality, nasalance, and VPF in, respectively, 20%, 31%, and 36% of patients in the VCFS group and in 24%, 30%, and 30% in the SMCP group. Elimination/normalization of variables was obtained in 28%, 19%, and 8% of patients in the VCFS group and 20%, 40%, and 25% in the SMCP group, respectively, for hypernasality, nasalance, and VPF. There was no statistically significant difference between groups. Patients with VCFS presented similar speech function and VPF characteristics as patients with nonsyndromic SMCP. The surgery for velopharyngeal insufficiency correction was equally effective for the improvement and resolution of speech symptoms and VPF in patients with VCFS compared with the SMCP group.


Highly enantioselective phenylacetylene additions to both aliphatic and aromatic aldehydes.
The readily available and inexpensive BINOL in combination with Ti(O(i)Pr)(4) is found to catalyze the reaction of an alkynylzinc reagent with various types of aldehydes including aliphatic aldehydes, aromatic aldehydes, and other alpha,beta-unsaturated aldehydes to generate chiral propargyl alcohols with 91-99% ee at room temperature. No previous chiral catalysts have exhibited such a broad scope of enantioselectivity with respect to the type of aldehydes for this reaction. [reaction: see text]


Targeting Heparan Sulfate Proteoglycans as a Novel Therapeutic Strategy for Mucopolysaccharidoses.
Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage.


High-affinity myo-inositol transport in Candida albicans: substrate specificity and pharmacology.
Inositol is considered a growth factor in yeast cells and it plays an important role in Candida as an essential precursor for phospholipomannan, a glycophosphatidylinositol (GPI)-anchored glycolipid on the cell surface of Candida which is involved in the pathogenicity of this opportunistic fungus and which binds to and stimulates human macrophages. In addition, inositol plays an essential role in the phosphatidylinositol signal transduction pathway, which controls many cell cycle events. Here, high-affinity myo-inositol uptake in Candida albicans has been characterized, with an apparent K(m) value of 240 +/- 15 microM, which appears to be active and energy-dependent as revealed by inhibition with azide and protonophores (FCCP, dinitrophenol). Candida myo-inositol transport was sodium-independent but proton-coupled with an apparent K(m) value of 11.0 +/- 1.1 nM for H(+), equal pH 7.96 +/- 0.05, suggesting that the C. albicans myo-inositol-H(+) transporter is fully activated at physiological pH. C. albicans inositol transport was not affected by cytochalasin B, phloretin or phlorizin, an inhibitor of mammalian sodium-dependent inositol transport. Furthermore, myo-inositol transport showed high substrate specificity for inositol and was not significantly affected by hexose or pentose sugars as competitors, despite their structural similarity. Transport kinetics in the presence of eight different inositol isomers as competitors revealed that proton bonds between the C-2, C-3 and C-4 hydroxyl groups of myo-inositol and the transporter protein play a critical role for substrate recognition and binding. It is concluded that C. albicans myo-inositol-H(+) transport differs kinetically and pharmacologically from the human sodium-dependent myo-inositol transport system and constitutes an attractive target for delivery of cytotoxic inositol analogues in this pathogenic fungus.


Comparison of risk scores to estimate perioperative mortality in aortic valve replacement surgery.
Transaortic valve implantation has recently been introduced as an alternative to aortic valve replacement (AVR) for high-risk patients with aortic stenosis. However, accurate assessment of surgical risk is critical for appropriate patient selection. We compared the accuracy of The Society of Thoracic Surgeons (STS) risk score, the European System for Cardiac Risk Evaluation (EuroSCORE), and the Veterans Administration (VA) risk score in predicting perioperative mortality after AVR. We included 537 consecutive patients who underwent AVR for severe aortic stenosis at the Minneapolis VA Medical Center between 1997 and 2008. Observed and predicted perioperative (30-day) mortality rates were compared. Hosmer-Lemeshow goodness-of-fit test and receiver operating characteristic curves were performed to assess the performance of the scores. Perioperative mortality rate was 5.9% (n=32). Predicted mortality rates for the EuroSCORE, STS score, and VA score were 15.6%, 3.6%, and 6.7%, respectively (p=0.001). The EuroSCORE overestimated mortality in all patients, most notably among those with ejection fraction less than 35% (49% predicted versus 9% observed). The EuroSCORE had poor calibration (goodness-of-fit test p<0.008), whereas the STS and the VA scores were well calibrated. However, all three scores displayed good discrimination characteristics per the areas under the receiver operating characteristic curves: STS score 0.73 (95% confidence interval: 0.69 to 0.77); VA score 0.66 (95% confidence interval: 0.62 to 0.70); and EuroSCORE 0.68 (95% confidence interval: 0.64 to 0.72; p>0.05). The EuroSCORE substantially overestimates perioperative mortality risk in AVR, particularly in patients with low ejection fraction. These data have implications when deciding the appropriate intervention (transaortic valve implantation versus AVR) for high-risk aortic stenosis patients.


[Activity of the corpora allata of diapausing females of Tetrix undulata (SWRB) (Orthoptera-Tetrigidae)].
The implantation of one or two pairs of corpora allata of diapausing females in another diapausing females (two weeks old) induces vitellogenesis and laying of one, two or three egg-pods in a great number of females. The denervation of the corpora-allata of a diapausing female also induced vitellogenesis. These results suggeste that corpora-allata of diapausing females are not active. The denervation induces the break of the inhibition "travelling" by the corpora-allata-cardiaca nerves or stimulates the corpora-allata.


Effect of sleep restriction on orthostatic cardiovascular control in humans.
We hypothesized that sleep restriction (4 consecutive nights, 4 h sleep/night) attenuates orthostatic tolerance. The effect of sleep restriction on cardiovascular responses to simulated orthostasis, arterial baroreflex gain, and heart rate variability was evaluated in 10 healthy volunteers. Arterial baroreflex gain was determined from heart rate responses to nitroprusside-phenylephrine injections, and orthostatic tolerance was tested via lower body negative pressure (LBNP). A Finapres device measured finger arterial pressure. No difference in baroreflex function, heart rate variability, or LBNP tolerance was observed with sleep restriction (P > 0.3). Systolic pressure was greater at -60 mmHg LBNP after sleep restriction than before sleep restriction (110 +/- 6 and 124 +/- 3 mmHg before and after sleep restriction, respectively, P = 0.038), whereas heart rate decreased (108 +/- 8 and 99 +/- 8 beats/min before and after sleep restriction, respectively, P = 0.028). These data demonstrate that sleep restriction produces subtle changes in cardiovascular responses to simulated orthostasis, but these changes do not compromise orthostatic tolerance.


The effects of monocrotaline pyrrole on cultured bovine pulmonary artery endothelial and smooth muscle cells.
Monocrotaline pyrrole (MCTP), a reactive electrophile, induces delayed and progressive pulmonary edema, vascular remodeling, and pulmonary hypertension after a single intravenous administration to rats. The effects of a single exposure of cultured bovine pulmonary artery endothelial cells (BEC) and bovine pulmonary artery smooth muscle cells (BSMC) to MCTP were examined. Monocrotaline pyrrole caused a dose-dependent, delayed, and progressive cell detachment and release of lactate dehydrogenase activity from monolayers of BECs but not BSMCs. Monolayers of BECs also released increased concentrations of 6-keto-prostaglandin F1 degrees, the stable metabolite of prostacyclin, as the post-treatment interval increased. Progressive and marked endothelial cell hypertrophy occurred after exposure to a nominal concentration of 5 or 50 micrograms/ml of MCTP but not after 0.5 micrograms/ml. Morphologic changes in monolayers of BSMCs were minimal, even up to 2 weeks after exposure. Ultrastructurally the hypertrophic, MCTP-treated BECs had enlarged cell profiles with enlarged nuclei. The nucleoli were prominent, occasionally multiple, and had separation of granular and fibrillar components. Cytoplasmic microtubules and perinuclear intermediate filaments were prominent in some cells, as were the golgi apparatus and endoplasmic reticulum. Degenerative changes were not prominent in cells that remained in the monolayer. Monocrotaline pyrrole inhibited proliferation of both cell types at concentrations (0.5 micrograms/ml) that were not cytotoxic. These findings indicate that MCTP induces direct, dose-dependent injury to cells in culture that is delayed and progressive, and the expression of this injury depends, in part, on the cell type.


A novel two-step approach for retrieval of an impacted biliary extraction basket.
Biliary extraction baskets are a commonly used instrument for the removal of choledocholithiasis in endoscopic retrograde cholangiopancreatography (ERCP). Impaction of the extraction basket is a recognized complication of ERCP, and is usually the result of discrepancy between the size of bile duct stone and the diameter of the distal bile duct. Whilst mechanical lithotriptors can be used to crush the stone or break the wires of the basket to allow its release, failure of the lithotriptor device can occur. We describe the case of a 59-year-old gentleman who had an ERCP performed for choledocholithiasis. Basket impaction was encountered, and the mechanical lithotriptor failed to dislodge the stone/basket complex. A two-step technique involving balloon dilatation and forceps manipulation of the basket was applied to successfully dislodge the impacted basket. We believe this simple and safe technique should be adopted to rescue impacted biliary extraction baskets to avoid the need for potential surgical removal.


Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[(18)F]fluoropropyl)-1-propylxanthine ([(18)F]CPFPX): a potent and selective A(1)-adenosine receptor antagonist for in vivo imaging.
This report describes the precursor synthesis and the no-carrier-added (nca) radiosynthesis of the new A(1) adenosine receptor (A(1)AR) antagonist [(18)F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX), 3, with fluorine-18 (half-life = 109.6 min). Nucleophilic radiofluorination of the precursor tosylate 8-cyclopentyl-3-(3-tosyloxypropyl)-7-pivaloyloxymethyl-1-propylxanthine, 2, with nca [(18)F]KF under aminopolyether-mediated conditions (Kryptofix 2.2.2/K(2)CO(3)) followed by deprotection was straightforward and, after formulation, gave the radioligand ready for injection with a radiochemical yield of 45 +/- 7%, a radiochemical purity of >98% and a specific radioactivity of >270 GBq/micromol (>7.2 Ci/micromol). Preparation time averaged 55 min. The synthesis proved reliable for high batch yields ( approximately 7.5 GBq) in routine production (n = 120 runs). The radiotracer was pharmacologically evaluated in vitro and in vivo and its pharmacokinetics in rodents determined in detail. After iv injection a high accumulation of radioactivity occurred in several regions of mouse brain including thalamus, striatum, cortex, and cerebellum. Antagonism by the specific A(1)AR antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and N(6)-cyclopentyl-9-methyladenine (N-0840), but not with the A(2)AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), indicated specific and reversible binding of the radioligand to A(1)AR in cortical and subcortical regions of interest. In mouse blood at least two polar metabolites formed rapidly (50% at 5 min after tracer application). However, chromatographic analyses of brain homogenate extracts taken 60 min pi showed that >98% of radioactivity was unchanged radioligand. Chromatographic isolation and reinjection of peripherally formed radioactive metabolites revealed no accumulation of radioactivity in mouse brain, probably due to the polarity of the metabolites. These preliminary results suggest that nca [(18)F]CPFPX is a useful radioligand for the noninvasive imaging of the brain A(1)AR.


Galcanezumab: a humanized monoclonal antibody for the prevention of migraine and cluster headache.
Migraine is a common, painful and highly disabling neurological condition that has plagued mankind for millennia, but its pathophysiology remained largely obscure until recently. The clinical success of triptans for treating migraine and the discovery that calcitonin gene-related peptide (CGRP) plays a prominent role in migraine led to increased research interest into this disease. An important improvement has been the development of monoclonal antibodies, including galcanezumab, that bind to CGRP or to its receptor, preventing its activation. Subsequent clinical trials have reported that galcanezumab is safe and well tolerated, and is effective in reducing the frequency of migraine attacks in patients with episodic or chronic migraine. At the same time, increased study of the pathophysiology of cluster headache, a relatively rare condition with excruciatingly painful headache attacks (i.e., "suicide headaches"), led to the discovery that, as in migraine, CGRP plays an important role in its pathology. Clinical trials suggest that galcanezumab is safe and effective for the prevention of episodic cluster headache, and it is under study for chronic cluster headache. Galcanezumab is approved for the prevention of migraine in the U.S., the European Union, Canada and Mexico, and was also approved for the treatment of episodic cluster headache in the U.S.


Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis.
This article reports the rational medicinal chemistry of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pHIB) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure-activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pHIB to pH 6.0 and similarly improved mycobactericidal activity compared with 1 against both Mycobacterium bovis-BCG and Mtb. Compound 5a possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar pKa value to natural 1. This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pHIB, and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.


Nosocomial and non-nosocomial Clostridium difficile infections in hospitalised patients in Belgium: compulsory surveillance data from 2008 to 2010.
Surveillance of Clostridium difficile infection (CDI) is compulsory in Belgian hospitals. Our objectives were to compare incidence and case characteristics of nosocomial infections (Nc-CDI) with onset of diarrhoea more than two days after hospital admission, with non-nosocomial cases (Nnc-CDI). The database included inpatients from 2008 to 2010. Of 8,351 cases reported by 150 hospitals, 3,102 (37%) were classified as Nnc-CDI and 5,249 (63%) as Nc-CDI. In 2010, the mean incidence per 1,000 admissions was 0.95 for Nc-CDI and 0.56 for Nnc-CDI. Both incidences were relatively stable over the three years, with a slight decrease in 2010 (p<0.01). Onset of symptoms in Nnc- CDI cases took place in the community (57.1%), nursing homes (14.2%) or hospitals (17.5%); data for 11.2%were missing. Nnc-CDI cases were younger than Nc-CDI (median age 75 vs. 79 years, p<0.001), and more likely to be women (62% vs. 57%, p<0.001) and to have pseudomembranous colitis (5.3% vs. 1.6%, p<0.001). In 2009, C. difficile ribotype 027 was found in 32 of 70 reporting hospitals compared with 19 of 69 in 2010 (p<0.03). Although our study population only included hospitalised patients, the results do not support the hypothesis of an increase in the incidence of severe community-associated CDI.


The role of the surgeon in treating patients with lung cancer. An updating article.
Lung cancer is a type of neoplasia with one of the highest incidences worldwide and is the largest cause of mortality due to cancer in the world today. It is classified according to its histological and biological characteristics, which will determine its treatment and prognosis. Non-small cell lung cancer accounts for 85% of the cases, and these are the cases that surgeons mostly deal with. Small cell lung cancer accounts for the remaining 15%. Surgery is the main method for treating early stage lung cancer, and lobectomy is the preferred procedure for treating primary lung cancer, while sublobar resection is an alternative for patients with poor reserve or with very small tumors. Surgeons need to be trained to use the resources and techniques available for lung resection, including less invasive approaches such as video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS), and need to be familiar with new oncological approaches, including curative, adjuvant or palliative treatments for patients with lung cancer.


Pan-cancer analysis of oncogenic TNFAIP2 identifying its prognostic value and immunological function in acute myeloid leukemia.
Tumor necrosis factor alpha-induced protein 2 (TNFAIP2), a TNFα-inducible gene, appears to participate in inflammation, immune response, hematopoiesis, and carcinogenesis. However, the potential role of TNFAIP2 in the development of acute myeloid leukemia (AML) remains unknow yet. Therefore, we aimed to study the biological role of TNFAIP2 in leukemogenesis. TNFAIP2 mRNA level, prognostic value, co-expressed genes, differentially expressed genes, DNA methylation, and functional enrichment analysis in AML patients were explored via multiple public databases, including UALCAN, GTEx portal, Timer 2.0, LinkedOmics, SMART, MethSurv, Metascape, GSEA and String databases. Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Beat AML database were used to determine the associations between TNFAIP2 expression and various clinical or genetic parameters of AML patients. Moreover, the biological functions of TNFAIP2 in AML were investigated through in vitro experiments. By large-scale data mining, our study indicated that TNFAIP2 was differentially expressed across different normal and tumor tissues. TNFAIP2 expression was significantly increased in AML, particularly in French-American-British (FAB) classification M4/M5 patients, compared with corresponding control tissues. Overexpression of TNFAIP2 was an independent poor prognostic factor of overall survival (OS) and was associated with unfavorable cytogenetic risk and gene mutations in AML patients. DNA hypermethylation of TNFAIP2 at gene body linked to upregulation of TNFAIP2 and inferior OS in AML. Functional enrichment analysis indicated immunomodulation function and inflammation response of TNFAIP2 in leukemogenesis. Finally, the suppression of TNFAIP resulted in inhibition of proliferation by altering cell-cycle progression and increase of cell death by promoting early and late apoptosis in THP-1 and U937AML cells. Collectively, the oncogenic TNFAIP2 can function as a novel biomarker and prognostic factor in AML patients. The immunoregulation function of TNFAIP2 warrants further validation in AML.


Kainate-induced inactivation of NMDA currents via an elevation of intracellular Ca2+ in hippocampal neurons.
1. Ionic currents and the cytosolic free calcium concentration ([Ca2+]i) were recorded in rat hippocampal neurons in culture using the whole-cell configuration of the patch-clamp technique and confocal laser scanning microscopy with the fluorescent Ca2+ indicator Fluo-3 or dual-emission microspectrofluorimetry with the fluorescent Ca2+ indicator Indo-1. The excitatory amino acids, kainate and N-methyl-D-aspartate (NMDA), were repeatedly applied to the neurons using either a fast perfusion system or pressure-ejection from micropipettes. 2. Conditioning (1-10 s) applications of NMDA induced desensitization of NMDA currents. Recovery from desensitization, estimated from analysis of the amplitudes of short (20-50 ms) test NMDA currents, was double exponential. The time constant of the first phase was < 2 s and for the second phase it was in the range 10-50 s. 3. Conditioning applications of kainate decreased the amplitude of NMDA currents. Recovery of NMDA currents from kainate-induced inactivation was slow and could be fitted with a single exponential. The time constant of recovery was in the range 10-50 s and increased with prolongation of the conditioning pulse of kainate. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) prevented kainate-induced inactivation of NMDA currents. 4. Depolarizing voltage pulses (1-10 s) also induced an inactivation of NMDA currents with a slow recovery. The time course of the recovery increased with prolongation of depolarizing pulses and with an elevation of external calcium. Cadmium, a blocker of voltage-gated channels, prevented development of the depolarization-induced inactivation of NMDA currents. 5. Simultaneous recording of ionic currents and fluorescence of Ca(2+)-sensitive dyes showed that application of kainate, NMDA, or depolarizing pulses resulted in a rise of [Ca2+]i. Cadmium (100 microM) reversibly blocked [Ca2+]i transients induced by depolarizing pulses without modification of kainate-induced rise in fluorescence intensity. 6. For equal inward currents the elevation of [Ca2+]i was approximately 3.5-fold higher for applications of NMDA than for kainate. 7. Strong buffering of [Ca2+]i prevented the inactivation of NMDA currents induced by kainate or by depolarization. 8. Our results suggest that in the hippocampal neurons kainate produces inactivation of NMDA currents via an elevation of [Ca2+]i.


On the conformation of the COOH-terminal domain of the large mechanosensitive channel MscL.
COOH-terminal (S3) domains are conserved within the MscL family of bacterial mechanosensitive channels, but their function remains unclear. The X-ray structure of MscL from Mycobacterium tuberculosis (TbMscL) revealed cytoplasmic domains forming a pentameric bundle (Chang, G., R.H. Spencer, A.T. Lee, M.T. Barclay, and D.C. Rees. 1998. SCIENCE: 282:2220-2226). The helices, however, have an unusual orientation in which hydrophobic sidechains face outside while charged residues face inside, possibly due to specific crystallization conditions. Based on the structure of pentameric cartilage protein, we modeled the COOH-terminal region of E. coli MscL to better satisfy the hydrophobicity criteria, with sidechains of conserved aliphatic residues all inside the bundle. Molecular dynamic simulations predicted higher stability for this conformation compared with one modeled after the crystal structure of TbMscL, and suggested distances for disulfide trapping experiments. The single cysteine mutants L121C and I125C formed dimers under ambient conditions and more so in the presence of an oxidant. The double-cysteine mutants, L121C/L122C and L128C/L129C, often cross-link into tetrameric and pentameric structures, consistent with the new model. Patch-clamp examination of these double mutants under moderately oxidizing or reducing conditions indicated that the bundle cross-linking neither prevents the channel from opening nor changes thermodynamic parameters of gating. Destabilization of the bundle by replacing conservative leucines with small polar residues, or complete removal of COOH-terminal domain (Delta110-136 mutation), increased the occupancy of subconducting states but did not change gating parameters substantially. The Delta110-136 truncation mutant was functional in in vivo osmotic shock assays; however, the amount of ATP released into the shock medium was considerably larger than in controls. The data strongly suggest that in contrast to previous gating models (Sukharev, S., M. Betanzos, C.S. Chiang, and H.R. Guy. 2001a. NATURE: 409:720-724.), S3 domains are stably associated in both closed and open conformations. The bundle-like assembly of cytoplasmic helices provides stability to the open conformation, and may function as a size-exclusion filter at the cytoplasmic entrance to the MscL pore, preventing loss of essential metabolites.


Resolving Continua of Fractional Excitations by Spinon Echo in THz 2D Coherent Spectroscopy.
We show that the new technique of terahertz 2D coherent spectroscopy is capable of giving qualitatively new information about fractionalized spin systems. For the prototypical example of the transverse field Ising chain, we demonstrate theoretically that, despite the broad continuum of excitations in linear response, the 2D spectrum contains sharp features that are a coherent signature of a "spinon echo," which gives previously inaccessible information such as the lifetime of the two-spinon excited state. The effects of disorder and finite lifetime, which are practically indistinguishable in the linear optical or neutron response, manifest in dramatically different fashion in the 2D spectra. Our results may be directly applicable to model quasi-1D transverse field Ising chain systems such as CoNb_{2}O_{6}, but the concept can be applied to fractionalized spin systems in general.