Resveratrol prevents Ang II-induced cardiac hypertrophy by inhibition of NF-κB signaling.
Pathological cardiac hypertrophy is a hallmark of various cardiovascular diseases (CVD) including chronic heart failure (HF) and an important target for the treatment of these diseases. Aberrant activation of Angiotensin II (Ang II)/AT1R signaling pathway is one of the main triggers of cardiac hypertrophy, which further gives rise to excessive inflammation that is mediated by the key transcription factor NF-κB. Resveratrol (REV) is a natural polyphenol with multiple anti-inflammatory and anti-oxidative effects, however the ability of REV in preventing Ang II-induced cardiac hypertrophy in combination with NF-κB signaling activation remains unclear. Murine models of cardiac hypertrophy was conducted via implantation of Ang II osmotic pumps. Primary neonatal rat cardiomyocyte and heart tissues were examined to determine the effect and underlying mechanism of REV in preventing Ang II-induced cardiac hypertrophy. Administrations of REV significantly prevented Ang II-induced cardiac hypertrophy, as well as robustly attenuated Ang II-induced cardiac fibrosis, and cardiac dysfunction. Furthermore, REV not only directly prevented Ang II/AT1R signal transductions, but also prevented Ang II-induced expressions of pro-inflammatory cytokines and activation of NF-κB signaling pathway. Our study provides important new mechanistic insight into the cardioprotective effects of REV in preventing Ang II-induced cardiac hypertrophy via inhibiting adverse NF-κB signaling activation. Our findings further suggest the therapeutic potential of REV as a promising drug for the treatment of cardiac hypertrophy and heart failure.


Haemostatic therapy in coronary artery bypass graft patients with decreased platelet function: comparison of fibrinogen concentrate with allogeneic blood products.
Patients undergoing coronary artery bypass grafting (CABG) are at risk of postoperative bleeding because of decreased platelet function and cardiopulmonary bypass (CPB)-induced haemostatic impairment. Fibrinogen concentration decreases by 34-42% of the preoperative level by the end of CPB. An inverse relationship between perioperative plasma fibrinogen levels and postoperative bleeding has been reported in CABG patients. Administration of fibrinogen concentrate after weaning from CPB in patients with diffuse microvascular bleeding may help promote haemostasis. We compared patient outcomes following fibrinogen concentrate administration or transfusion of allogeneics in CABG patients with decreased platelet function. Thirty-eight patients with decreased preoperative platelet function in Multiplate aggregometry were included. Patients with bleeding after CPB received either fibrinogen concentrate (guided by the measurement of fibrin clot quality using the FIBTEM thromboelastometric test) or allogeneics. Twenty-nine of 38 patients received haemostatic therapy (bleeding + fibrinogen group, n = 10; bleeding + allogeneics group, n = 19). Total transfusion (median (interquartile range)) was significantly lower in the bleeding + fibrinogen group (0 (0, 3.8) units), compared with the bleeding + allogeneics group (6 (5, 8) units, p = 0.0073). Bolus administration of fibrinogen concentrate increased FIBTEM maximum clot firmness from 10.5 (9.3, 11) mm after CPB to 20.5 (20, 21.8) mm at the end of surgery. Postoperative outcomes were similar in both groups. No treatment-related complications were observed after fibrinogen concentrate. In CABG patients with bleeding after CPB, FIBTEM-guided administration of fibrinogen concentrate resulted in overall decreased transfusion, compared with haemostatic therapy with allogeneics. Fibrinogen concentrate administration increased the fibrin clot quality and helped achieve haemostasis.


Fluorescence reflectance imaging of macrophage-rich atherosclerotic plaques using an alphavbeta3 integrin-targeted fluorochrome.
Macrophages play an important role during the development and progression of atherosclerotic plaques. alphavbeta3 integrins are highly expressed by macrophages; thus, targeting alphavbeta3 may allow targeting of culprit macrophage-loaded atherosclerotic lesions in vivo. An alphavbeta3-targeted Arg-Gly-Asp (RGD) peptide was labeled with the cyanine 5.5 (Cy 5.5) dye and applied to image atherosclerotic plaques in apolipoprotein E-deficient mice. The peptide-dye conjugate binds to alphavbeta3 integrin-positive RAW264.7 macrophages with high affinity. Competition experiments confirmed binding specificity of the probe. A significant fluorochrome accumulation in atherosclerotic plaques was demonstrated 24 h after injection by fluorescence reflectance imaging, which was blocked with high efficiency by competition with the unlabeled peptide. Conversely, the nonconjugated dye revealed only a minor fluorescence signal in the plaques. Fluorescence microscopy revealed colocalization of the probe with macrophages in the plaque of a mouse model for accelerated atherosclerosis, which was corroborated in human carotid artery specimens. In addition to macrophage-associated signals, binding of the probe to the neointima or elastica of the arteries was observed. RGD-Cy 5.5, combined with near-infrared optical imaging methods, allows the specific imaging of alphavbeta3-integrin expression on macrophages recruited to vascular lesions and may serve to estimate macrophage-bound inflammatory activity of atherosclerotic lesions.


The redox state of the plastoquinone (PQ) pool is connected to thylakoid lipid saturation in a marine diatom.
The redox state of the plastoquinone (PQ) pool is a known sensor for retrograde signaling. In this paper, we asked, "does the redox state of the PQ pool modulate the saturation state of thylakoid lipids?" Data from fatty acid composition and mRNA transcript abundance analyses suggest a strong connection between these two aspects in a model marine diatom. Fatty acid profiles of Phaeodactylum tricornutum exhibited specific changes when the redox state of the PQ pool was modulated by light and two chemical inhibitors [3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) or 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (DBMIB)]. Data from liquid chromatography with tandem mass spectrometry (LC-MS/MS) indicated a ca. 7-20% decrease in the saturation state of all four conserved thylakoid lipids in response to an oxidized PQ pool. The redox signals generated from an oxidized PQ pool in plastids also increased the mRNA transcript abundance of nuclear-encoded C16 fatty acid desaturases (FADs), with peak upregulation on a timescale of 6 to 12 h. The connection between the redox state of the PQ pool and thylakoid lipid saturation suggests a heretofore unrecognized retrograde signaling pathway that couples photosynthetic electron transport and the physical state of thylakoid membrane lipids.


Rapid and sensitive determination of dehydroascorbic acid in addition to ascorbic acid by reversed-phase high-performance liquid chromatography using a post-column reduction system.
An improved procedure for the direct determination of l-dehydroascorbic acid (DHAA), in addition to l-ascorbic acid (AA), has been developed. The two biologically active forms of vitamin C were separated using reversed-phase high-performance liquid chromatography. DHAA was reduced to AA with dithiothreitol (DTT) in a post-column reaction system. Complete conversion was achieved at 50 degrees C using a 1-ml reaction coil. Recoveries were in the range of 95-99% and both forms could be detected spectrophotometrically at 267 nm with high sensitivity. Reproducible results [relative standard deviations 2.4% (DHAA) and 1.0% (AA), n = 5] were obtained when the method was applied to the analysis of rose hip samples.


Graft loss due to percutaneous sclerotherapy of a lymphocele using acetic acid after renal transplantation.
Development of lymphoceles after renal transplantation is a well-described complication that occurs in up to 40% of recipients. The gold standard approach for the treatment of symptomatic cases is not well defined yet. Management options include simple aspiration, marsupialization by a laparotomy or laparoscopy, and percutaneous sclerotherapy using different chemical agents. Those approaches can be associated, and they depend on type, dimension, and localization of the lymphocele. Percutaneous sclerotherapy is considered to be less invasive than the surgical approach; it can be used safely and effectively, with low morbidity, in huge, rapidly accumulating lymphoceles. Moreover, this approach is highly successful, and the complication rate is acceptable; the major drawback is a recurrence rate close to 20%. We herewith report a renal transplant case in which the patient developed a symptomatic lymphocele that was initially treated by ultrasound-guided percutaneous sclerotherapy with ethanol and thereafter using acetic acid for early recurrence. A few hours after injection of acetic acid in the lymphatic cavity, the patient started to complain of acute pain localized to the renal graft and fever. An ultrasound of the abdomen revealed thrombosis of the renal vein and artery. The patient was immediately taken to the operating room, where the diagnosis of vascular thrombosis was confirmed and the graft was urgently explanted. In conclusion, we strongly suggest avoiding the use of acetic acid as a slerosating agent for the percutaneous treatment of post-renal transplant lymphocele because, based on our experience, it could be complicated by vascular thrombosis of the kidney, ending in graft loss.


Microbiological risk assessment: a new approach to food safety control.
The food industry is continually looking to be innovative in the development and production of food. New techniques are also being employed to distribute the food, and even the way the consumer treats the food before consumption has changed dramatically over recent years, for example, with the development of microwavable meals. These changes can lead to differences in the pathogens encountered and the general level of immunity in the population. This in turn puts increased emphasis on food producers to know and understand more about the pathogens likely to occur in the products they are making and their origin. To help food manufacturers tackle this consistently, Microbiological Risk Assessment (MRA) is being applied as a systematic tool to allow effective decisions to be made to reduce the impact of pathogens on health.


Intracisternal inclusions in Schwann cells of the sural nerve.
Biopsy of the sural nerve in a 74-year-old man with chronic neuropathy demonstrated Schwann cells that possessed multiple cisterns of rough endoplasmic reticulum filled with 7- to 8-nm filaments and perinuclear cisterns that were markedly distended with fine granular substances and electron-dense globules. To our knowledge, this is the third case exhibiting filamentous inclusions in Schwann cells. Unlike the previous cases, however, this case showed inclusions in the distended perinuclear cisterns and axonal degeneration. The significance of these alterations remains to be elucidated.


Essential cysteine residues in Bacillus subtilis spore photoproduct lyase identified by alanine scanning mutagenesis.
Endospore-forming bacteria (Bacillus and Clostridium spp.) are highly ultraviolet (UV) resistant and repair UV-induced DNA damage in part using the spore-specific DNA repair enzyme spore photoproduct (SP) lyase. SP lyase in all known sporeformers contains four conserved cysteine residues; three absolutely conserved residues are located at the "Radical SAM" consensus (C91xxxC95xxC98), which presumably participates in [4Fe-4S] cluster formation. A fourth conserved cysteine, the function of which is unknown, is located at C141 in SP lyase from all Bacillus spp. sequenced to date. To probe the function of the fourth cysteine, each conserved cysteine in the B. subtilis SP lyase was systematically altered to alanine by site-directed mutagenesis. UV-visible spectroscopy of wild-type and mutant SP lyases indicated that C141 does not participate in [4Fe-4S] formation and redox chemistry; however, in vivo SP lyase activity was abolished in all mutants, indicating an essential role for C141 in SP lyase activity.


Efficacy of a 3-day oral regimen of a quinine-quinidine-cinchonine association (Quinimax) for treatment of falciparum malaria in Madagascar.
In the search for an effective, safe and field-adapted alternative to chloroquine for therapy of chloroquine-resistant Plasmodium falciparum infections in Africa, a 3-d oral regimen of Quinimax (an association of quinine, quinidine and cinchonine) was evaluated in 35 individuals with P. falciparum in Madagascar, an area with chloroquine resistance. 63% of the parasite strains isolated were resistant in vitro to chloroquine, and 59% of the infections were present despite previous chloroquine intake. Three daily oral doses of 10 mg/kg Quinimax for 3 d cleared parasitaemia and improved clinical status in all subjects. Mean parasite and fever clearance times were 51.7 and 37.4 h, respectively. All patients were aparasitaemic at the end of the 7-d follow-up. When formulating therapy guidelines, the 3-d Quinimax regimen should be considered as a valuable alternative to chloroquine for treating falciparum malaria in African areas with clinical resistance to chloroquine.


LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair.
Leukemia/lymphoma-related factor (LRF) is a POZ/BTB and Krüppel (POK) transcriptional repressor characterized by context-dependent key roles in cell fate decision and tumorigenesis. Here we demonstrate an unexpected transcription-independent function for LRF in the classical non-homologous end joining (cNHEJ) pathway of double-strand break (DSB) repair. We find that LRF loss in cell lines and mouse tissues results in defective cNHEJ, genomic instability and hypersensitivity to ionizing radiation. Mechanistically, we show that LRF binds and stabilizes DNA-PKcs on DSBs, in turn favouring DNA-PK activity. Importantly, LRF loss restores ionizing radiation sensitivity to p53 null cells, making LRF an attractive biomarker to direct p53-null LRF-deficient tumours towards therapeutic treatments based on genotoxic agents or PARP inhibitors following a synthetic lethal strategy.


Structure of partially-activated E. coli heat-labile enterotoxin (LT) at 2.6 A resolution.
Biological toxicity of E. coli heat-labile enterotoxin and the closely related cholera toxin requires that the assembled toxin be activated by proteolytic cleavage of the A subunit and reduction of a disulfide bond internal to the A subunit. The structural role served by this reduction and cleavage is not known, however. We have crystallographically determined the structure of the E. coli heat-labile enterotoxin AB5 hexamer in which the A subunit has been cleaved by trypsin between residues 192 and 195. The toxin is thus partially activated, in that it has been cleaved but the disulfide bond has not been reduced. The structure of the A subunit in the cleaved toxin is substantially the same as that previously observed for the uncleaved AB5 structure, suggesting that although such cleavage is required for biological activity of the toxin it does not by itself cause a conformational change.


The unusual osteochondroma: A case of snapping scapula syndrome and review of the literature.
Snapping scapula syndrome is a rare condition characterized by crepitus of the scapula on motion of the ipsilateral upper extremity. It may be quite painful and disabling. The majority of cases are due to bursal and muscular disorders. Snapping scapula syndrome secondary to an underlying osteochondroma is an even more infrequent phenomenon. The case presented highlights the unusual post pubertal growth of an osteochondroma of the scapula that progressed to develop a snapping scapular syndrome. Review of the literature revealed less than fifty reported cases of this phenomenon secondary to an underlying osteochondroma.


[Analysis of a Chinese pedigree affected with dyschromatosis symmetrica hereditaria due to a novel variant of ADAR gene].
To explore the genetic basis for a Chinese pedigree affected with dyschromatosis symmetrica hereditaria (DSH). PCR and Sanger sequencing were carried out for the proband, and suspected variant was validated by Sanger sequencing in the pedigree. The proband was found to harbor a novel variant of c.1352delA (p.N451Mfs*13) of the ADAR (NM_001111) gene. The same variant was found in her affected mother and sister, but not in her unaffected father, uncle, and 100 healthy individual. The novel variant of the ADAR gene probably underlay the pathogenesis of DSH in this pedigree.


[Modern concepts of the metabolism and genetic polymorphism of collagen (a review)].
The data on structure, biosynthesis, post-synthetic modifications, extracellular development and degradation of collagen are briefly reviewed. Role of main enzymes, participating in collagen turnover, is discussed. Isoforms of the protein are considered in details. The importance of studies on collagen proteins is noted in connection with investigations on morphogenesis, cell differentiation, regeneration.


Application of immunohistochemistry to liver and gastrointestinal neoplasms: liver, stomach, colon, and pancreas.
Immunohistochemistry has become an integral component of the practice of pathology. Newer antibodies allow for increasingly precise diagnoses for tumors that previously could not be easily identified. Recently, immunohistochemical evaluations have begun to allow pathologists to actively assist in determining prognosis and even in selecting therapies. To summarize the usefulness of currently available immunostains for the study of liver and gastrointestinal system neoplasms and to make recommendations for panels of immunostains that can be particularly helpful. Information has been collected from recent literature as well as from personal experience and practice. Many immunostains are now available for the practicing pathologist that allow for increasing accuracy in diagnosis of liver and gastrointestinal tract neoplasms. Panels of immunostains can be used to differentiate between various tumors and also to identify site of origin in the case of a metastatic neoplasm. Immunostains that allow for prognostic determinations and for guidance in the selection of chemotherapeutic agents can also be used by pathologists to assist in the management of patients with malignant tumors affecting the liver and gastrointestinal tract.


An update on human and mouse glandular kallikreins.
Human glandular kallikreins are secreted serine proteases, involved in many biological processes. Recently, the complete organization of the human and mouse genomic loci has been elucidated. These loci harbor the largest clusters of serine proteases within the human and mouse genomes. Mouse orthologs to all human kallikrein genes, except for KLK2 and KLK3 genes, have now been identified. Here, we describe an update of the genomic organization of these families in human and mouse, and provide some thoughts for future research directions.


What Is the Role of the Gut in Wound Infections?
Emerging evidence suggest a major role for the gut microbiome in wound infections. A Trojan Horse mechanism of surgical site infections has been hypothesized to occur when pathogens in the gut, gums, and periodontal areas enter an immune cell and silently travel to the wound site where they release their infectious payload. Genetic tracking of microbes at the strain level is now possible with genetic sequencing techniques and can clarify the origin of microbes that cause wound infections. An emerging field of dietary prehabilitation to modulate the microbiome before surgery is being described to improve infection-related outcomes from surgery.


Efficient extraction of xylan from delignified corn stover using dimethyl sulfoxide.
Xylan can be extracted from biomass using either alkali (KOH or NaOH) or dimethyl sulfoxide (DMSO); however, DMSO extraction is the only method that produces a water-soluble xylan. In this study, DMSO extraction of corn stover was studied at different temperatures with the objective of finding a faster, more efficient extraction method. The temperature and time of extraction were compared followed by a basic structural analysis to ensure that no significant structural changes occurred under different temperatures. The resulting data showed that heating to 70 °C during extraction can give a yield comparable to room temperature extraction while reducing the extraction time by ~90 %. This method of heating was shown to be the most efficient method currently available and was shown to retain the important structural characteristics of xylan extracted with DMSO at room temperature.


Small Molecule Radiopharmaceuticals - A Review of Current Approaches.
Radiopharmaceuticals are an integral component of nuclear medicine and are widely applied in diagnostics and therapy. Though widely applied, the development of an "ideal" radiopharmaceutical can be challenging. Issues such as specificity, selectivity, sensitivity, and feasible chemistry challenge the design and synthesis of radiopharmaceuticals. Over time, strategies to address the issues have evolved by making use of new technological advances in the fields of biology and chemistry. This review presents the application of few advances in design and synthesis of radiopharmaceuticals. The topics covered are bivalent ligand approach and lipidization as part of design modifications for enhanced selectivity and sensitivity and novel synthetic strategies for optimized chemistry and radiolabeling of radiopharmaceuticals.


A randomized controlled trial of chair interventions on back and hip pain among sewing machine operators: the los angeles garment study.
Determine whether an adjustable chair with a curved or a flat seat pan improved monthly back and hip pain scores in sewing machine operators. This 4-month intervention study randomized 293 sewing machine operators with back and hip pain. The participants in the control group received a placebo intervention, and participants in the intervention groups received the placebo intervention and one of the two intervention chairs. Compared with the control group, mean pain improvement for the flat chair intervention was 0.43 points (95% CI = 0.34, 0.51) per month, and mean pain improvement for the curved chair intervention was 0.25 points (95% CI = 0.16, 0.34) per month. A height-adjustable task chair with a swivel function can reduce back and hip pain in sewing machine operators. The findings may be relevant to workers who perform visual- and hand-intensive manufacturing jobs.


Curcumin nanoparticles incorporated collagen-chitosan scaffold promotes cutaneous wound healing through regulation of TGF-β1/Smad7 gene expression.
Wound healing is a tissue regeneration process which is regulated by a complex interaction of multiple growth factors, primarily transforming growth factor-β1 (TGF-β1). The natural antagonist of transforming growth factor-β (TGF-β) signaling is Smad7. It has been shown that curcumin (an antioxidant) and some biocompatible polymers like collagen and chitosan enhance cutaneous wound healing. In this study, three scaffolds made with curcumin-nanoparticles (CNs) and using collagen and chitosan with various ratios of collagen and chitosan were used for evaluation of wound healing activity on full thickness punch wound model using male Wistar rats. The wound healing in terms of histology and morphology was assessed at different time points post-wounding and the expression pattern of TGF-β1 and Smad7 was studied. CNs incorporated collagen-chitosan scaffolds significantly accelerated the healing of the wounds, as revealed by a significant change in the wound area, the epidermal thickness, the density of granulation tissue, the number of new vessels and a higher collagen content compared to the control group. However, blank collagen-chitosan scaffolds did not cause any significant change in the above parameters, except for epidermal thickness compared to the control group. Incorporation of CNs into collagen-chitosan scaffold changed expression of TGF-β1 and Smad7 mRNAs in the healing wounds compared to the control group. Indeed, blank collagen-chitosan scaffold did not cause any significant up-regulation either in TGF-β1 mRNA expression or in Smad7 mRNA expression (except for day 3 post-wounding), compared to the control group. This study indicates that topical application of CNs-incorporated collagen-chitosan scaffold promotes wound healing via a regulatory effect on the expression of TGF-β1 and Smad7 mRNA in the cutaneous wound-healing model.


The influence of personality and dysfunctional sleep-related cognitions on the severity of insomnia.
Previous findings suggest that personality traits and dysfunctional sleep-related cognitions may perpetuate insomnia, but findings concerning this have been scarce. Thus, we hypothesized that personality and sleep-related cognitions influence the severity of insomnia, and investigated the association personality and sleep-related cognitions had with various sleep-related parameters, including severity of insomnia. Forty-four patients with psychophysiological insomnia were assessed using The Temperament and Character Inventory, the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, the Dysfunctional Belief and Attitudes toward Sleep Scale, the Pre-Sleep Arousal Scale and the Hospital Anxiety and Depression Scale. Insomnia severity was significantly and positively correlated with harm avoidance, self-transcendence and sleep-related cognitions, and negatively correlated with novelty seeking, reward dependence, and cooperativeness. Dysfunctional sleep-related cognitions were positively correlated with insomnia severity and sleep quality. Stepwise multiple regression analysis showed that sleep-related cognitions, depression and reward dependence scores were significant determinants of insomnia severity, and that sleep-related cognitions and self-transcendence were significant positive determinants of sleep quality. Reward dependence, depression and sleep-related cognitions were associated with insomnia severity, and comparison with previous findings implied that 'internalizing behavior' and depression may be more plausible candidates for the link between personality and insomnia than anxiety. Considering the major role of cognitive-behavioral treatment (CBT) in the treatment of insomnia, assessment of these factors and management of sleep-related cognitions may help alleviate symptoms in patients with insomnia.


In vivo microdialysis to characterize drug transport in brain tumors: analysis of methotrexate uptake in rat glioma-2 (RG-2)-bearing rats.
Brain microdialysis was applied to sample free methotrexate (MTX) concentrations in brain extracellular fluid of normal and RG-2 glioma-bearing rats. All animals received 50 mg/kg of MTX intra-arterially following which serial blood and interstitial fluid samples were collected for 3 h and measured for MTX by an HPLC assay. Retrodialysis was used to estimate the in vivo recovery of MTX from brain. A linear two-compartment model was fitted to the plasma MTX concentration-time data in both the normal and RG-2 groups. The mean total body clearance and volume of distribution at steady state of MTX varied from 0.90 +/- 0.3 to 0.24 +/- 0.02 l h-1 kg-1 (P < 0.05) and from 0.58 +/- 0.24 to 0.21 +/- 0.16 l kg-1 (P < 0.05) in control and tumor rats, respectively. The significant reductions in clearance and volume of distribution at steady-state were attributed in part to a cachectic state in the RG-2 animals in which total body water was reduced. The mean MTX area under the interstitial fluid concentration-time curve (AUC) was 171.6 +/- 69.14 micrograms min ml-1(control) and 583.5 +/- 296.7 micrograms min ml-1 (brain tumor-bearing rats). The significantly higher AUC values obtained with RG-2 rats compared with control rats may have resulted from high plasma MTX concentrations and a more permeable blood-tumor barrier (BTB). A hybrid physiologically based pharmacokinetic model was used to characterize the mechanisms responsible for the high MTX brain tumor concentrations. In conclusion, a microdialysis technique was successfully utilized to examine the extracellular uptake of MTX in brain. This technique can be a powerful tool to evaluate intracerebral drug kinetics and the delivery of drugs to brain tumors.


Importance of communication in counselling the spinal cord injury patient.
The purpose of this paper is to emphasise the value of counselling in the medical and vocational rehabilitation of the spinal cord injury patient in a world passing through a stage of deep and rapid evolution, and the importance that effective communication may have in it so that a better social integration or reintegration of the patient may be achieved.


Evaluation of coronary artery calcification by multi-detector row computed tomography for the detection of coronary artery stenosis in Japanese patients.
The development of an efficient noninvasive examination to detect coronary atherosclerosis is needed as a strategy to prevent coronary heart disease. To evaluate the usefulness of calcium score measured by multi-detector row computed tomography (MDCT), we compared calcium score derived from MDCT with findings of coronary artery stenosis assessed by coronary angiography (CAG). In 108 patients (94 men, 14 women; average age, 65.7 years), we performed unenhanced CT scans and calculated coronary artery calcium score in 259 vessels without previous intervention and severe motion artifact to determine the correlation with the degree of coronary stenosis by CAG. The sensitivity and the specificity of calcification (calcium score 0.1+) for severe stenosis (75+%) were 89% and 43%, respectively. All four vessels with calcium score 1000+ had a severe stenosis. The areas under the receiver operating characteristics curve of calcium score for severe stenosis were 0.80 +/- 0.04, indicating the efficacy of this technique. Coronary artery calcification and calcium score determined by MDCT were associated with coronary arteries with severe stenosis. This technique appears to be useful for the evaluation of coronary atherosclerosis.


The Effect of Granulocyte Colony-Stimulating Factor Use on Hospital Length of Stay after Allogeneic Hematopoietic Cell Transplantation: A Retrospective Multicenter Cohort Study.
Granulocyte colony-stimulating factor (G-CSF) is administered after allogeneic hematopoietic cell transplantation (HCT) to aid neutrophil recovery. We compared the effect of empiric G-CSF administration on the duration of index inpatient hospitalization stay after HCT for patients aged ≥18 years with a hematologic malignancy. G-CSF was considered empiric if administered between day -3 and day +6 in relation to graft infusion. We studied 3562 HCTs (1487 HLA-matched sibling donor HCTs and 2075 HLA-matched unrelated donor HCTs) between 2007 and 2016. Three hundred and thirteen (21%) recipients of HLA-matched sibling donor HCT and 417 (20%) recipients of HLA-matched unrelated donor HCT received empiric G-CSF therapy. The effect of G-CSF therapy on the index hospitalization stay was examined in generalized linear models (GLMs) with adjustment for other patient, disease, and transplantation characteristics and acute graft-versus-host disease and infection post-transplantation. The duration of index hospitalization by treatment group did not differ for HLA-matched sibling donor HCT but was shorter with G-CSF for HLA-matched unrelated donor HCT (15 days versus 19 days; P < .001). Our GLMs confirmed shorter hospitalization with the use of G-CSF therapy for HLA-matched unrelated donor HCT (P = .01). G-CSF therapy was not associated with early survival for either donor type, and there was no benefit or disadvantage of giving G-CSF to promote neutrophil recovery.


[Tachykinins and conformational aspects of their interactions with receptors].
Several peptides of the tachykinin family are reviewed. Special attention is spared to mammalian tachykinins as peptide neurotransmitters. Conformational possibilities of the tachykinins are considered in connection with their ability to interact with specific receptors. The results of theoretical and experimental studies suggest a significant identity of spatial structures of the tachykinins and explain the absence of the strict specificity in tachykinin-receptor interactions.


Firing properties of frog tectal neurons in vitro.
Whole-cell recordings from frog tectal slices revealed different types of neuronal firing patterns in response to prolonged current injection. The patterns included regular spiking without adaptation, accelerating firing, adapting spiking, repetitive bursting and phasic response with only one spike. The observed firing patterns are similar to those found in the mammalian superior colliculus. The frog tectum could be a useful preparation in elucidating the relationship between neuronal function and membrane properties.


A highly reproducible model of cerebral ischemia/reperfusion with extended survival in CB-17 mice.
To simulate the clinical and pathologic situation in patients with stroke, as well as to evaluate future potential therapeutic approaches, it is essential to have a highly reproducible model that displays long-term survival. Though a range of rodent models has been employed in the literature, there are questions regarding reproducibility, especially in terms of ischemic zone (i.e., degree of ischemia) and long-term survival. We have developed a highly reproducible stroke model that produces a consistent ischemic zone as a result of direct transient occlusion of the middle cerebral artery (MCA) in CB-17 (CB-17/Icr-+/+Jcl) mice. The model employs a thin monofilament to twist the artery resulting in complete interruption of blood flow. Transient ischemia can be induced for up to 240min and the survival rate at 7 days post-ischemia was more than 60%, even in mice subjected to 240min of transient ischemia resulting in hemorrhagic infarction in most animals. Our method can be used to model several pathologic conditions, such as reversible reperfusion injury, delayed neuronal death, necrotic brain injury and hemorrhagic infarction. We believe this preclinical model provides a step forward for testing future therapeutic approaches applicable to patients with ischemic brain injury.


Combined biocidal action of silver nanoparticles and ions against Chlorococcales (Scenedesmus quadricauda, Chlorella vulgaris) and filamentous algae (Klebsormidium sp.).
Despite the extensive research, the mechanism of the antimicrobial and biocidal performance of silver nanoparticles has not been unequivocally elucidated yet. Our study was aimed at the investigation of the ability of silver nanoparticles to suppress the growth of three types of algae colonizing the wetted surfaces or submerged objects and the mechanism of their action. Silver nanoparticles exhibited a substantial toxicity towards Chlorococcales Scenedesmus quadricauda, Chlorella vulgaris, and filamentous algae Klebsormidium sp., which correlated with their particle size. The particles had very good stability against agglomeration even in the presence of multivalent cations. The concentration of silver ions in equilibrium with nanoparticles markedly depended on the particle size, achieving about 6 % and as low as about 0.1 % or even less for the particles 5 nm in size and for larger ones (40-70 nm), respectively. Even very limited proportion of small particles together with larger ones could substantially increase concentration of Ag ions in solution. The highest toxicity was found for the 5-nm-sized particles, being the smallest ones in this study. Their toxicity was even higher than that of silver ions at the same silver concentration. When compared as a function of the Ag(+) concentration in equilibrium with 5-nm particles, the toxicity of ions was at least 17 times higher than that obtained by dissolving silver nitrite (if not taking into account the effect of nanoparticles themselves). The mechanism of the toxicity of silver nanoparticles was found complex with an important role played by the adsorption of silver nanoparticles and the ions released from the particles on the cell surface. This mechanism could be described as some sort of synergy between nanoparticles and ions. While our study clearly showed the presence of this synergy, its detailed explanation is experimentally highly demanding, requiring a close cooperation between materials scientists, physical chemists, and biologists.


[Association of left diaphragmatic hernia, lung agenesia and esophageal atresia (author's transl)].
A literature study has been written about each failure concerning a very particular mishaping linking an agenesy of the left lung and of the left diaphragm to an esophagal atresia (type III). None similar case has been discovered in the literature. Concerning the diaphragmatic agenesies, the authors report several familial cases and outline the possibility of a genetic pathogeny.


Effects of soil amendment with PCB-contaminated sediment on the growth of two cucurbit species.
The aim of the study was to evaluate the influence of the application of increasing proportions (0%, 10%, 25%, 50%, 75%, and 100%) of an admixture of PCB-contaminated Hudson River sediment collected from the Upper Hudson River, near Waterford, Saratoga county (New York, USA) on soil properties, phytotoxicity, and biometric and physiological responses of cucumber (Cucumis sativus L. cv 'Wisconsin SMR 58') and zucchini (Cucurbita pepo L. cv 'Black Beauty') grown as potential phyto- and rhizoremediators. The experiment was performed for 4 weeks in a growth chamber under controlled conditions. Amendment of Hudson River sediment to soil led to a gradual increase in PCB content of the substratum from 13.7 μg/kg (with 10% sediment) to 255 μg/kg (with 100% sediment). Sediment amendment showed no phytotoxic effects during the initial stages, even Lepidium sativum root growth was stimulated; however, this positive response diminished following a 4-week growth period, with the greatest inhibition observed in unplanted soil and zucchini-planted soil. The stimulatory effect remained high for cucumber treatments. The sediment admixture also increased cucurbit fresh biomass as compared to control samples, especially at lower doses of sediment admixture, even though PCB content of the soil amended with sediment increased. Cucurbits' leaf surface area, in turn, demonstrated an increase for zucchini, however only for 50% and 75% sediment admixture, while cucumber showed no changes when lower doses were applied and decrease for 75% and 100% sediment admixture. Chlorophyll a + b decreased significantly in sediment-amended soils, with greater inhibition observed for cucumber than zucchini. Our results suggest that admixture of riverine sediment from relatively less-contaminated locations may be used as soil amendments under controlled conditions; however, further detailed investigation on the fate of pollutants is required, especially in terms of the bioaccumulation and biomagnification properties of PCBs, before contaminated sediment can be applied in an open environment.


Significance of IL-34 and SDC-1 in the pathogenesis of RA cells and preclinical models.
IL-34 shares a common receptor with M-CSF, while it can bind to other distinct receptors including protein-tyrosine phosphatase zeta (PTPζ), and syndecan1 (SDC-1). In physiological conditions, IL-34 has a critical role in the maintenance and development of Langerhans and microglial cells in part through PTPζ ligation. Conversely, in autoimmune diseases such as rheumatoid arthritis (RA), SDC-1-induced phosphorylation of M-CSFR was responsible for the pathological effect of IL-34 in patient cells and/or preclinical models. Intriguingly, enrichment of IL-34 is strongly linked to rheumatoid factor (RF), disease activity score (DAS)28, erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), and radiographic progression. In parallel, IL-34-induced naïve cell reprogramming into glycolytic RA CD14+CD86+GLUT1+ macrophage was dysregulated via M-CSFR or SDC-1 antibody therapy. Moreover, the inflammatory and erosive imprints of IL-34 arthritic mice were mitigated by glucose uptake inhibition and SDC-1, or RAG deficiency through nullifying macrophage metabolic rewiring and their ability to advance Th1/Th17 cell polarization. Consistently, IL-34-/- and SDC-1-/- mice could effectively impair CIA joint inflammation, osteoclast formation, and neovascularization by restraining monocyte infiltration as well as suppressing the inflammatory macrophage and T effector cell reconfiguration via metabolic deactivation. In conclusion, targeting IL-34/SDC-1 signaling, or its interconnected metabolites can uniquely intercept the crosstalk between glycolytic RA myeloid and lymphoid cells and their ability to trigger arthritis.


Static stability of partially crystalline emulsions: Impacts of carrageenan and its blends with xanthan gum and/or guar gum.
In the present study, four different combinations of gums, including carrageenan (CG), its binary blends with xanthan gum (XG) or guar gum (GG) in equal ratios, and its ternary blends with XG and GG in three equal ratios, were involved into making partially crystalline emulsions (PCEs), respectively. The freshly prepared emulsions were systematically characterized by rheological property, particle size distribution, microscopic morphology, interfacial property, and intermolecular interactions, and their emulsion stabilities were further evaluated using multiple light scattering technique and storage test. All PCEs stabilized by gum blends (CG + XG, CG + GG, and CG + XG + GG) obtained decreased apparent viscosities at 0.01 s-1 (10.12-25.32 Pa·s), particle sizes (3.12-4.06 μm), as well as interfacial protein concentrations (22.60-27.01 mg/m2), which were much lower than those with single CG (35.98 Pa·s, 6.72 μm, and 47.74 mg/m2, respectively). The microscopic morphology showed that blending CG with XG and/or GG contributed to formation of firmer three-dimensional matrix, thereby preventing the aggregation of fat droplets. Inclusion of XG and/or GG also significantly reduced contribution of hydrophobic interactions from 0.72 to 0.24-0.44 mg/mL. Both multiple light scattering and storage test revealed that emulsion instabilities were mainly manifested as a clarification at the bottom and an agglomeration at the top. PCE-CG + XG + GG exhibited superior stability with low creaming index (6.20 %) and viscosity (1180.0 mPa·s) after three months of storage. The research aims to evaluate the effects of CG and its blends with XG and GG on stability of PCEs, and the results potentially provide valuable information for manufacture of stable PCE foods.


ESCRTs Cooperate with a Selective Autophagy Receptor to Mediate Vacuolar Targeting of Soluble Cargos.
Autophagy transports cytosolic materials into lysosomes/vacuoles either in bulk or selectively. Selective autophagy requires cargo receptor proteins, which usually link cargos to the macroautophagy machinery composed of core autophagy-related (Atg) proteins. Here, we show that fission yeast Nbr1, a homolog of mammalian autophagy receptor NBR1, interacts with and facilitates the transport of two cytosolic hydrolases into vacuoles, in a way reminiscent of the budding yeast cytoplasm-to-vacuole targeting (Cvt) pathway, a prototype of selective autophagy. We term this pathway Nbr1-mediated vacuolar targeting (NVT). Surprisingly, unlike the Cvt pathway, the NVT pathway does not require core Atg proteins. Instead, it depends on the endosomal sorting complexes required for transport (ESCRTs). NVT components colocalize with ESCRTs at multivesicular bodies (MVBs) and rely on ubiquitination for their transport. Our findings demonstrate the ability of ESCRTs to mediate highly selective autophagy of soluble cargos, and suggest an unexpected mechanistic versatility of autophagy receptors.


Cathepsin K-Activated Probe for Fluoro-Photoacoustic Imaging of Early Osteolytic Metastasis.
Precise detection of early osteolytic metastases is crucial for their treatment but remains challenging in the clinic because of the limited sensitivity and specificity of traditional imaging techniques. Although fluorescence imaging offers attractive features for the diagnosis of osteolytic metastases, it is hampered by limited penetration depth. To address this issue, a fluoro-photoacoustic dual-modality imaging probe comprising a near-infrared dye caged by a cathepsin K (CTSK)-cleavable peptide sequence on one side and functionalized with osteophilic alendronate through a polyethylene glycol linker on the other side is reported. Through systematic in vitro and in vivo experiments, it is demonstrated that in response to CTSK, the probe generated both near-infrared fluorescent and photoacoustic signals from bone metastatic regions, thus offering a potential strategy for detecting deep-seated early osteolytic metastases.


Evaluation of a Pediatric Early Warning Score as a Predictor of Occult Invasive Bacterial Infection in the Pediatric Emergency Department.
The aims of the study were to evaluate the diagnostic performance of Pediatric Early Warning Score (PEWS) to predict occult invasive bacterial infection (IBI) in well-appearing pediatric emergency department (PED) patients without known risk factors for bacterial infection and to compare PEWS to heart rate (HR) and Emergency Severity Index (ESI). We performed a retrospective case-control analysis of febrile PED patients aged 60 days to 18 years over a 2-year period. Subjects were excluded if they were ill appearing, admitted to an intensive care unit, or had a known high-risk condition. Cases of occult IBI were included if they had a noncontaminant positive culture other than an isolated positive urine culture. Two febrile control subjects were identified for each case. Odds ratios and receiver operating characteristic curves were evaluated to determine performance characteristics of PEWS at triage and disposition, age-adjusted HR at triage and disposition, and ESI at triage. Compared with 178 controls, 89 cases had higher disposition PEWS, higher disposition HR, lower ESI, and higher rate of hospital admission. Disposition PEWS ≥3 (odds ratio, 2.57; 95% confidence interval, 1.08-6.18), disposition HR > 99th percentile, and ESI demonstrated increased odds of occult IBI. Area under the receiver operating characteristic curve for disposition PEWS (0.56) was similar to triage PEWS (0.54), triage HR (0.54), disposition HR (0.58), and ESI (0.65). Subjects with PEWS ≥3 at PED disposition have increased odds of occult IBI; however, PEWS has poor discriminative ability at all cutoffs. We cannot recommend PEWS used in isolation to predict occult IBI.


Evaluation of serology to measure exposure of piglets to Ascaris suum during the nursery phase.
The aim of this study was to evaluate whether serology can be used to measure exposure of piglets to Ascaris suum during the nursery phase. Experimental infection studies were performed in which 7 groups of 10 piglets of 4 weeks of age were orally infected with either 10, 20, 40, 60, 80, 100 and 500 A. suum eggs/day during 7 consecutive weeks, mimicking a nursery phase in an A. suum contaminated environment. Serum was collected on a weekly basis to monitor seroconversion on 2 ELISA tests based on the antibody recognition of either a haemoglobin protein purified from the pseudocoelomic fluid of adult A. suum or a water-soluble complete homogenate of the 3rd stage larvae isolated from the lungs (L3-lung). A dose-dependent seroconversion was measurable with the L3-lung ELISA starting from 4 weeks post-infection onwards, whereas this was not measurable with the haemoglobin-based test. After 7 weeks, equivalent to the end of the nursery phase, the L3-lung ELISA showed a 99% specificity and a 90% sensitivity to detect exposure of piglets to A. suum, with a minimum infection level of 20 A. suum eggs per day. To further evaluate the test under field conditions, a seroprevalence study was performed by sampling 10 piglets on 68 different nursery farms in Belgium. The results showed that for 38% of the farms analysed all piglets tested seronegative, whereas for the remaining 62% of the farms the percentage seropositive piglets ranged from 10 to 100%. This indicates contamination of the nursery facilities with A. suum eggs. In conclusion, the outcome of this study shows that serology can be used to measure exposure of nursery piglets to A. suum, thereby providing an additional tool in the control of this widespread parasite.


Safflower seed extract inhibits osteoclast differentiation by suppression of the p38 mitogen-activated protein kinase and IκB kinase activity.
Safflower seed has been reported to have a protective effect against bone loss diseases. However, the precise molecular mechanisms underlying the inhibitory effect of safflower seed in osteoclast differentiation remain unclear. In this study, we investigated the inhibitory action of safflower seed extract (SSE) on the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in cultured mouse-derived bone marrow macrophages (BMMs). We found that SSE significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells in BMMs without cytotoxicity. The gene expressions of nuclear factor of activated T-cells (NFATc1) and TRAP, which are genetic markers of osteoclast differentiation, were substantially decreased by SSE in a dose-dependent manner. Also, SSE diminished RANKL-mediated intracellular reactive oxygen species (ROS) generation on osteoclastogenesis in a dose-dependent manner. The SSE thereafter suppressed RANKL-induced p38 mitogen-activated protein kinase and IκBα kinase signalling activities which were activated by ROS generation for osteoclastogenesis. Additionally, SSE was found to decrease RANKL-induced actin ring formation, which is required for bone resorption activity. Taken together, our results suggest that SSE acts as a RANKL-induced osteoclastogenesis inhibitor by suppression of ROS generation. This induces a remarkable suppression of the p38 and IκBα kinase pathways, thereby suppressing the gene expression of NFATc1 in osteoclast precursors.


Identification of Salmonella typhi promoters activated by invasion of eukaryotic cells.
The interaction of pathogenic microorganisms with host tissues, and the underlying genetic events which regulate these interactions, are difficult to analyse where no suitable animal model exists. The approach described here, for obtaining information on the genes involved in these interactions, employs an infection system based on the invasion of Henle cells by Salmonella typhi to select promoter-containing DNA sequences able to activate gene expression inside eukaryotic cells. Several DNA fragments exhibiting different promoter strengths and extent of selective activation within eukaryotic cells were identified. Three were selected and characterized according to the expression level of the reporter gene, the polynucleotide sequence, the transcription start, and the dependence upon regulatory proteins. All fragments gave much stronger expression of the reporter gene when the recombinant S. typhi carrier strains invaded cells compared with the expression measured in growth medium. One promoter-containing region exhibited sequence homology to sigma 54-dependent promoters, whereas another appears to be dependent on the stationary-phase RNA polymerase subunit sigma s. S. typhi containing the S1 subunit gene of pertussis toxin cloned under the control of these promoters, selectively expressed the S1 subunit following infection of different phagocytic and non-phagocytic cell lines of human or murine origin. Deletion and point mutant derivatives of two promoters enabled the identification of the main motif required for promoter activity. This method may be helpful for the analysis of pathogenesis in organisms previously difficult to study because of the lack of a convenient animal model, and could provide insights into the chronology and topology of gene expression during infection, including a possible genetic basis for tissue tropism.


Triage skill and associated factors among emergency nurses in Addis Ababa, Ethiopia 2017: a cross-sectional study.
The aim of this study was to assess levels of triage skill and associated factors among emergency nurses in Addis Ababa, Ethiopia, 2017. Above half of the participants (52.9%) had a moderate level of triage skill. A strong positive relationship was found between nurses' level of triage knowledge and skill (r = .68, p .01). Knowledge about triage, educational level and training experience had a significant relationship with triage skill with (B = 1.09, CI (1.41, 1.77), p = .002), (B = - 19.96, CI (- 30.208, - 9.715), p = .001), (B = .55, CI .16, .94), p = .006) respectively. This study revealed that most triage nurses had a moderate level of skills. Therefore, the ministry of health and hospitals should provide training and education to improve triage skill.


Novel in-situ gel for intravesical administration of ketorolac.
The urinary bladder stores urine until the time of urination. Systemic administration of drugs to treat bladder diseases faces several limitations. Therefore, intravesical drug delivery is a promising alternative route of administration. An in-situ gel is used to form a gel inside the bladder cavity and ensure continuous release of the drug even after urination. The objective of the present study was to optimize an in-situ gel formulation of poloxamer and chitosan for intravesical delivery of ketorolac tromethamine. The gelling temperature of the prepared combinations ranged from 20.67 to 25.8 °C. In-vitro release of KT was sustained for up to 7 h using a poloxamer concentration ranging from 17% to 19% and a chitosan concentration ranging from 1% to 2%. Design-Expert® 10 was used to select the optimized formulation (poloxamer/chitosan 17/1.589% w/w) which significantly (p < 0.05) extended the drug release more than each polymer alone. An ex-vivo study showed the ability of the optimized formulation to sustain drug release after emptying two times to mimic urination. Furthermore, the formed gel adhered to the bladder tissue throughout the time period of the experiment. Intravesical administration of the optimized formulation to rabbits via catheter showed no obstruction of urine flow and continuous release of the drug for 12 h.


High-pressure liquid chromatographic assay of chloramphenicol in biological fluids.
Chloramphenicol can be assayed by a sensitive and selective high-pressure liquid chromatographic assay technique. The method described is easily adapted to analysis of many other drugs.


Multiphoton microscopy for label-free multicolor imaging of peripheral nerve.
Means for quantitation of myelinated fibers in peripheral nerve may guide diagnosis and clinical decision making in management of peripheral nerve disorders. Multiphoton microscopy techniques such as the third-harmonic generation enable label-free in vivo imaging of peripheral nerves. Develop a multiphoton microscope based on a custom high-power infrared fiber laser for label-free imaging of peripheral nerve. A cost-effective multiphoton microscope employing a single fiber laser source at 1300 nm was designed and used for stain-free multicolor imaging of murine and human peripheral nerve. Second-harmonic generation signal from collagen centered about 650-nm delineated neural connective tissue, whereas third-harmonic general signal centered about 433-nm delineated myelin and other lipids. In sciatic nerve from transgenic reporter mice expressing yellow fluorescent protein within peripheral neurons, three-photon-excitation with emission peak at 527-nm delineated axoplasm. The signal obtained from unlabeled axially sectioned samples was adequate for segmentation of myelinated fibers using commercial image processing software. In unlabeled whole mount specimens, imaging depths over 100-μm were achieved. A multiphoton microscope powered by a fiber laser enables stain-free histomorphometry of mammalian peripheral nerve. The simplicity of the microscope design carries potential for clinical translation to inform decision making in peripheral nerve disorders.


Associations between serum insulin and homocysteine in a Swedish population-a potential link between the metabolic syndrome and hyperhomocysteinemia: the Skaraborg project.
The objective of this study is to examine the association between serum levels of insulin and homocysteine (Hcy) in a population-based sample of Swedish men and women. Men and women (537 and 571, respectively) 40 years or older, who were randomly selected from the population in Skara, southwestern Sweden, with valid information on serum levels of Hcy and insulin, were subject to a physical examination, including anthropometric measurement. Lifestyle factors were assessed by a questionnaire, and venous blood samples were drawn after an overnight fast. Insulin resistance was estimated by the homeostasis model assessment index. Homocysteine was higher in men (11.0 micromol/L) than in women (9.7 micromol/L) (P < .001) and was positively associated with age (P < .001 in both sexes) and serum creatinine (P = .009 in men, P < .001 in women), but inversely associated with leisure time physical activity (P = .012 in men, P = .001 in women). There was a positive association between serum insulin and serum Hcy independent of age and sex (P = .004). Upon exclusion of patients with diabetes and individuals with serum creatinine level greater than 130 microcat/L, this association was significant in the remaining 999 individuals also after adjustment for age, sex, serum creatinine, leisure time physical activity, body mass index, and smoking status (P = .003). A 1 SD difference in serum insulin corresponded to a difference of 0.5 micromol/L in serum Hcy. A similar association was found between insulin resistance and serum Hcy. In conclusion, there is an association between serum insulin and Hcy that may constitute a link between the metabolic syndrome and Hcy, either unilaterally or as part of a vicious circle.


Rescue of Helicobacter pylori-induced cytotoxicity by red ginseng.
Helicobacter pylori has been known to provoke gastric inflammation, ulceration, and DNA damage, based on which WHO defined H. pylori as a class I carcinogen. Although ginseng, the root of Panax ginseng C.A. Meyer, has been reported to possess antiadhesion or antimicrobial activity against H. pylori, in this study, we examined the protective effect of red ginseng extracts (RGE) against H. pylori-induced cytotoxicity and DNA damage. RGE significantly attenuated both H. pylori-induced DNA damage assessed by comet assay and apoptosis measured by DNA fragmentation. Inactivation of ERK1/2 signaling and attenuation of caspase-3 activation and PARP cleavage were revealed with RGE against H. pylori infection. RGE decreased H. pylori-stimulated IL-8 gene expression, which resulted from the transcriptional regression of NF-kappaB. In conclusion, RGE showed significant gastroprotective effects against H. pylori-associated gastric mucosal cell damage, suggesting that red ginseng could be used as a medicinal phytonutrient against H. pylori infection.


Load size and energy delivery in birds feeding nestlings: Constraints on and alternative strategies to energy-maximization.
The Orians-Pearson model of central place foraging for multiple-prey loaders assumes, as does most of current foraging theory, (i) that the quantity to be maximized is rate of energy delivery, and (ii) that the capacity of the foraging animal is the only relevant constraint on this rate. When applied to the case of birds feeding nestlings the model predicts, therefore, that the parents should select whichever load size maximizes the rate of energy delivery to the young.We assume here (i) that the parents could alternatively maximize the rate of energy delivery to the nest (m-strategy), maximize the time available for activities other than foraging (e.g. brooding) (b-strategy), or minimize the frequency of visits to the nest (v-strategy). We further assume (ii) that the nestlings impose constraints on the foraging behaviour of their parents in that there is a maximum load size that a brood can receive, as well as a maximum and a minimum rate of energy delivery that is acceptable. These three quantities are increasing functions of the age of the nestlings.Load size as a function of the age of the nestlings is predicted to increase initially and then to approach either the load size corresponding to maximum parental efficiency (m- and b-strategies) or a larger load size (v-strategy). For the b- and v-strategies rate of energy delivery is predicted to correspond to the minimum requirement of the nestlings throughout the nestling period. For the m-strategy energy delivery is predicted to be the maximum energy requirements of the nestlings initially, and then to level off to the energy delivery rate that corresponds to the maximum parental efficiency. As these strategies are not always compatible, foraging behaviour in a particular case may be an adaptive compromise between them.


Identification of synthetic dyes in early colour photographs using capillary electrophoresis and electrospray ionisation-mass spectrometry.
Capillary electrophoresis with photodiode array detection (CE-PDA) and with electrospray ionisation-mass spectrometry (CE-ESI-MS) was used for the separation and the identification of 23 synthetic organic dyes, among those used in early 20th century colour photographs such as autochromes. Both cationic and anionic dyes could be separated within 15min using a single CE-PDA method. The method was used as the basis to develop a CE-ESI-MS methodology through the optimisation of the relevant ESI and MS parameters. Sheath liquid composition, nebulising gas pressure, drying gas flow rate and drying gas temperature were found to influence the sensitivity of the detection. These parameters were optimised in positive and negative ion modes for cationic dyes and anionic dyes, respectively. The two analyses could be carried out successively on a single sample. In view of the application to cultural heritage objects, the CE-ESI-MS analytical procedure was applied to identify the dyes in a Filmcolor artefact, late version of the autochrome. The results complemented and enhanced current knowledge as four cationic dyes and three anionic dyes were identified. Four additional dyes are proposed as possibly present as traces.


Plasma von Willebrand factor proteolysis in patients with chronic myeloproliferative disorders: no possibility of ex vivo degradation by calcium-dependent proteases.
Patients with chronic myeloproliferative disorders (CMPD) frequently have abnormalities of plasma von Willebrand factor (vWf) multimers. The pathogenesis of this phenomenon is still unknown. In order to evaluate the possibility of ex vivo degradation of vWf during blood processing, we compared vWf antigen, ristocetin cofactor and the multimeric composition of vWf in plasmas obtained in the presence of trisodium citrate with or without calcium-dependent protease inhibitors (leupeptin, N-ethylmaleimide and Na2EDTA). The subjects included 20 patients with CMPD, 11 with other diseases and 8 normal subjects. In patients with CMPD and normal subjects, the values of vWf antigen, ristocetin cofactor, ristocetin cofactor/vWf antigen ratio and the relative amount of large multimers of vWf did not significantly differ from each other in plasma samples with and without protease inhibitors. In other diseases, especially in a patient with disseminated intravascular coagulation, a somewhat higher amount of large multimers were found in plasma with protease inhibitors than without inhibitors. These findings indicate that the ex vivo proteolysis during blood processing is negligible in patients with CMPD, and that the observed abnormalities in vWf is an in vivo phenomenon.


Myeloid-related protein-8/14 in acute coronary syndrome.
The alarmin family member myeloid-related protein (MRP)-14 (S100A9), which has been identified by platelet transcriptional profiling as an acute myocardial infarction gene, regulates vascular inflammation and thrombosis. Elevated plasma levels of MRP-8/14 (S100A8/A9) heterodimer predict first and recurrent cardiovascular events. The aim of this study was to elucidate pathophysiological roles of MRP-8/14 in acute coronary syndrome (ACS). In 38 consecutive ACS patients, the MRP-8/14 level in coronary artery blood obtained at thrombus aspiration was higher in 23 patients, in whom aspirated thrombus was confirmed, compared to the 15 patients, in whom it was absent [4.86 (1.95, 8.29) vs 2.94 (1.31, 4.44), P=0.017]. The MRP-8/14 level was correlated with myeloperoxidase (MPO) level (R2=0.52), but not with soluble P-selectin level (R2=0.0002) in the coronary artery blood. Immunohistochemistry of the aspirated thrombus exhibited that expression of MRP8/14 was co-localized with leukocytes positive for activated Mac-1. Finally, in cultured human umbilical vein endothelial cells, MRP-8/14 increased tissue factor expression. Our findings indicate that MRP-8/14 concentration increases in coronary artery blood in association with thrombus formation in ACS, co-localizes with leukocytes, and is associated with leukocyte activation. MRP-8/14 is positioned as a unique biomarker at the interface of inflammation and thrombosis in ACS.


[Path dependency, bifurcation points and the role of sociology. A sociological attempt at interpreting the corona crisisDépendance au sentier, points de bifurcation et le rôle de la sociologie. Une tentative d'interprétation sociologique de la crise du coronavirus].
The contribution begins by attempting to specify the corona crisis' essence and form by means of acceleration theory. In so doing, the diagnosis of a politically induced, objectively measurable deceleration is pivotal. In a second step, the social theoretical conclusions from this diagnosis are drawn in contrast to system theory on the one hand, and neomarxist approaches on the other. The focus is on the argument that the political reaction to SARS-CoV‑2 can neither be explained by reference to the principles of functional differentiation nor through the logic of securing political power or through capital accumulation. Following this line of thought, the article maps out the possibilities created by the crisis for societal path and system change, and outlines the role that sociology as a scientific discipline can and should play in this historical situation.


Surgical options in deep-bite mandibular deficiency with prominent chin - aesthetic considerations.
A deep-bite hypoplastic mandible associated with a strong chin poses an aesthetic challenge. Functional correction of the distal occlusion can bring the chin point beyond the ideal or normal profile line. The aim of the study was to outline the indications and drawbacks of four approaches that are currently used to deal with this problem. A retrospective study was done using lateral cephalograms and pre- and postoperative pictures of 40 randomly selected patients, judged by a panel of four surgeons. The following parameters were studied apart from occlusion: A-P chin position, chin height, mentolabial and submental folds, cervicomental and gonial angles, antegonial notch, lower lip position, and anterior mandibular bowing. Procedures that involve a setback of the chin are potentially prone to create or increase submental fullness, especially the mandibular advancement/chin setback osteotomy. Procedures involving advancement of the anterior dentoalveolar segment relative to the symphyseal prominence (e.g. mandibular advancement/chin setback osteotomy, dentoalveolar mandibular advancement osteotomy) are prone to flatten the mentolabial fold excessively. The position of the chin point after mandibular advancement-posterior rotation osteotomy is difficult to predict. Maxillomandibular posterior rotation has potentially the best aesthetic outcome, provided that the chin point is not set back.


Relative activities of substance P-related peptides in the guinea-pig ileum and rat parotid gland, in vitro.
The relative potencies of a series of substance P analogues have been determined for spasmogenic activity in the guinea-pig ileum in vitro and for the release of 86Rb and alpha-amylase activity from rat parotid gland slices in vitro. Equipotent molar ratios (EMR), relative to substance P, were determined for all the compounds. In the rat parotid gland, EC50 values for amylase release were, on average, 35.5 times greater than those for 86Rb release. Analysis of Hill plots suggests that spare receptors exist for 86Rb release but not for amylase release and it is suggested that the stimulus-response coupling for amylase release may be less efficient than that for 86Rb release. In the parotid gland, the octapeptide and [less than Glu6]-hexapeptide C-terminal fragments of substance P were less active than substance P itself, whereas in the ileum, the octapeptide was as active as substance P. Substitutions at the Phe7 or Phe8 positions in general reduced activity relative to substance P. This effect was particularly apparent in C-terminal hexapeptide analogues. Substitutions at the Phe7 and Phe8 positions in C-terminal hexapeptide analogues produced a greater reduction in activity in the parotid gland than in the ileum. The most marked difference was observed with eledoisin-related peptide for which the ratio of EMRs for ileum and 86Rb release was 18.1. The unsubstituted C-terminal octapeptide fragment similarly showed a discrepancy between the two assay systems (EMR ratio, ileum: 86Rb release = 7.75). It is suggested that the results may indicate the presence of sub-populations of 'substance P receptors' which are represented at least in different proportions in the two tissues studied, although alternative explanations such as differences in metabolism of agonists are possible.


Mobilization of hematopoietic progenitor cells by yeast-derived beta-glucan requires activation of matrix metalloproteinase-9.
Poly-(1,6)-beta-d-glucopyranosyl-(1,3)-beta-d-glucopyranose (PGG) beta-glucan is a soluble yeast-derived polysaccharide that has previously been shown to induce hematopoietic progenitor cell (HPC) mobilization. However, the mobilizing mechanism of action remains unknown. Here, we confirmed that PGG beta-glucan alone or in combination with granulocyte colony-stimulating factor (G-CSF) mobilizes HPC into the periphery. Optimal mobilizing effects were seen 24-48 hours after PGG beta-glucan doses of 4.8-9.6 mg/kg. Animals treated with G-CSF and PGG beta-glucan showed a collaborative effect in HPC mobilization compared with G-CSF treatment alone. Additional studies demonstrated that neither complement 3 nor complement receptor 3 played a role in this effect and that PGG beta-glucan treatment did not induce proinflammatory cytokine secretion. However, bone marrow cells from PGG beta-glucan-treated mice secreted abundant matrix metalloproteinase-9 (MMP-9), and PGG beta-glucan-induced HPC mobilization was abrogated in MMP-9 knockout mice. Moreover, we demonstrated that both hematopoietic and nonhematopoietic cells contributed to MMP-9 secretion upon PGG beta-glucan treatment. In addition, HPCs mobilized by PGG beta-glucan had similar levels of engraftment in host and lineage differentiation capability compared with those mobilized by G-CSF. Thus, PGG beta-glucan is an agent that enhances HPC mobilization and may improve the outcome of clinical stem cell transplantation.


Parasite infection is associated with Kaposi's sarcoma associated herpesvirus (KSHV) in Ugandan women.
Immune modulation by parasites may influence susceptibility to bacteria and viruses. We examined the association between current parasite infections, HIV and syphilis (measured in blood or stool samples using standard methods) and antibodies against Kaposi's sarcoma herpesvirus (KSHV), measured by ELISA, in 1915 stored plasma samples from pregnant women in Entebbe, Uganda. Seroprevalence of KSHV was higher in women with malaria parasitaemia (73% vs 60% p = 0.01), hookworm (67% vs 56% p = 0.001) and Mansonella perstans (69% vs 59% p = 0.05); seroprevalence increased with increasing intensity of hookworm infection (p < 0.001[trend]). No associations were found for HIV, five other parasites or active syphilis. These effects were not explained by socioeconomic status or education. Specific parasite infections are associated with presence of antibodies against KSHV, perhaps mediated via their effect on immune function.


Comparative in vitro activity of ceftobiprole against staphylococci displaying normal and small-colony variant phenotypes.
The antistaphylococcal activity of ceftobiprole was compared with those of cefuroxime, linezolid, and moxifloxacin by using the agar dilution method. Apart from three strains with small-colony variant phenotypes, all Staphylococcus aureus isolates tested were inhibited by < or =2 microg/ml of ceftobiprole. This compound exhibited an excellent antistaphylococcal activity, comparable to that of linezolid.


The concentration of intracellular nickel in Haemophilus influenzae is linked to its surface properties and cell-cell aggregation and biofilm formation.
Of the known proteins which use nickel as a co-factor, Haemophilus influenzae contains only urease and glyoxalase I (gloA). We have recently reported that this pathogen harbours a unique nickel uptake system (nikKLMQO-nimR). Unusually, the disruption of the nickel uptake system (nikQ or nimR mutants) resulted in cells that aggregated and formed an increased biofilm compared to the wild type cells. Using a gloA mutant strain and urease-specific inhibitor we showed that this phenotype is not due to the loss-of-function of these enzymes. By generating H. influenzae "resting cells" which are enzymatically inactive but maintain their structural integrity we have shown that the cell aggregation in the nikQ/nimR mutants is not due to the loss of enzymatic function. The nikQ mutant was unable to accumulate nickel but the addition of excess nickel did restore intracellular nickel levels and this resulted in the nikQ mutant returning to the wild type "free-living" phenotype; cells with no aggregation and no biofilm formation. We used a range of techniques which showed that the nikQ mutant possesses changes to its cell surface properties. The mutant was more negatively charged than wild type cells as well as being more hydrophobic. Analysis of the outer membrane constituents showed that there were molecular differences. Although the nikQ mutant appears to grow the same as its wild type cell we have shown that there is a change in the "lifestyle" of these nickel limited cells and this induces changes to the surface of the cell to promote cell-cell aggregation and biofilm formation.


Osteoporosis and Colles' fractures in the elderly.
There is no documentation of the incidence of osteoporosis in patients with Colles' fractures. We have prospectively studied 127 patients over the age of fifty with unilateral Colles' fractures to determine the incidence of osteoporosis and to investigate its influence on the bony deformity. The cortical width of the second metacarpal was used as the indicator of osteoporosis. 74.8% of patients in this group were osteoporotic. The final deformity was significantly greater in patients with osteoporosis.


Integrating COVID-19 health risks into crowding costs for transit schedule planning.
The public transport sector worldwide experienced the worst impact in recent history, in terms of ridership loss, due to the COVID-19 pandemic. The pandemic negatively affected passengers' perceptions of public transport and is likely to make a lasting impact on ridership, trip patterns, and modal share. Without any supportive changes to transit operations, ridership is likely to decline. This study explores the setting of frequencies in transit lines and proposes a two-part methodology that addresses the changing perceptions of users, especially in a health-related context. The first part develops a mathematical model that expresses the pre-COVID-19 cost of passenger crowding as an integral part of user costs to determine the optimal headway that considers the trade-offs between user and operator costs. A continuum approximation for the demand of the bus line has been used in the derivation. The second part extends the developed model to include both the costs of the health risks associated with the COVID-19 pandemic and crowding. The developed models will help transit planners and operators to plan and adapt operations to changing health risks during the pandemic and post-pandemic. Several numerical examples are provided to describe the uses and applications of the analytical models using information obtained from the literature.


Genetic engineering of peppermint for improved essential oil composition and yield.
The biochemistry, organization, and regulation of essential oil metabolism in the epidermal oil glands of peppermint have been defined, and most of the genes encoding enzymes of the eight-step pathway to the principal monoterpene component (-)-menthol have been isolated. Using these tools for pathway engineering, two genes and two expression strategies have been employed to create transgenic peppermint plants with improved oil composition and yield. These experiments, along with related studies on other pathway genes, have led to a systematic, stepwise approach for the creation of a 'super' peppermint.


NMP4, an Arbiter of Bone Cell Secretory Capacity and Regulator of Skeletal Response to PTH Therapy.
The skeleton is a secretory organ, and the goal of some osteoporosis therapies is to maximize bone matrix output. Nmp4 encodes a novel transcription factor that regulates bone cell secretion as part of its functional repertoire. Loss of Nmp4 enhances bone response to osteoanabolic therapy, in part, by increasing the production and delivery of bone matrix. Nmp4 shares traits with scaling factors, which are transcription factors that influence the expression of hundreds of genes to govern proteome allocation for establishing secretory cell infrastructure and capacity. Nmp4 is expressed in all tissues and while global loss of this gene leads to no overt baseline phenotype, deletion of Nmp4 has broad tissue effects in mice challenged with certain stressors. In addition to an enhanced response to osteoporosis therapies, Nmp4-deficient mice are less sensitive to high fat diet-induced weight gain and insulin resistance, exhibit a reduced disease severity in response to influenza A virus (IAV) infection, and resist the development of some forms of rheumatoid arthritis. In this review, we present the current understanding of the mechanisms underlying Nmp4 regulation of the skeletal response to osteoanabolics, and we discuss how this unique gene contributes to the diverse phenotypes among different tissues and stresses. An emerging theme is that Nmp4 is important for the infrastructure and capacity of secretory cells that are critical for health and disease.


Publishing in black and white: the relevance of listing of scientific journals.
Scientific publishing, including in the field of Rheumatology, is evolving rapidly. Predatory journals are one of the major threats to contemporary publishing, especially to eager and naïve authors. In this narrative review, we discuss mechanisms that authors can employ to white list genuine scientific journals and blacklist "predatory" ones. Inclusion of a journal in reputed indices such as Medline (but not just Pubmed), Web of Science, Scopus or Embase raises the likelihood that the journal is genuine, more so if it is included in the current Journal Citation Reports. Other commercially available whitelists also exist, so also whitelists published by regulatory authorities in some countries. A commercially available blacklist has emerged since the very useful Beall's blacklist became defunct. In the absence of access to a whitelist or blacklist, certain characteristics such as repeated email solicitations for articles with an extremely narrow deadline from unknown sources, lack of inclusion in reputed indices, journals not published or endorsed by national or international society and scarcity of currently published articles should render authors suspicious of the genuine nature of a journal. National societies should work together to generate subject-specific (including Rheumatology specific) whitelists that can be available free of cost to authors from all over the world.


[Binding of antacids to bile acids (author's transl)].
The bile acid binding capacity of various liquid antacids and of colestyramin were compared. Aluminium hydroxide containing antacids showed the highest binding capacity. This seems to be of importance also in therapeutic doses for treatment of chologenic diarrhoea, vagotomy diarrhoea and gastric ulcer.


Oral step-down for Staphylococcus aureus bacteraemia: an opportunity for antimicrobial stewardship?
Long courses of intravenous antimicrobial therapy are traditionally recommended for the treatment of methicillin sensitive Staphylococcus aureus bacteraemia (MS-SAB), but are not always completed in clinical practice. Early intravenous to oral antibiotic switch is a key component of antimicrobial stewardship. This study aimed to identify whether intravenous antibiotic duration may be safely reduced in MS-SAB. We performed a single-centre retrospective study of MS-SAB management. Successful outcome was defined as 90-day recurrence-free survival. Effect of intravenous antibiotic duration on 90-day recurrence risk was examined. 281 adult cases of MS-SAB were evaluated, of which 208 (74%) had a successful outcome. 176 cases (63%) received less than 14 days of intravenous antimicrobial therapy. Very short durations of intravenous therapy were associated with increased risk of recurrence (<7 days iv, 9.8% recurrence; 7-13 days, 1.4%; ≥14 days, 2.9%; p 0.005). This effect was robust to sensitivity analysis for total antimicrobial therapy duration of 14 days. CRP reduction of at least 37% from peak value at intravenous to oral antibiotic switch was associated with decreased risk of recurrence (<37% CRP reduction, 12% recurrence; >37%, 2.0%; p 0.001). Oral antimicrobial switch may allow safe reductions in duration of intravenous therapy in MS-SAB.


Acute acalculous cholecystitis in the critically ill patient.
Nine cases of acute acalculous cholecystitis were diagnosed in the surgical intensive care unit at Hartford Hospital during a 2 year period after abdominal, cardiovascular, and traumatic surgery. A tender mass in the right upper quadrant was suggestive but not diagnostic of the condition. Hyperamylasemia was seen in all patients. Ultrasonography is the most useful diagnostic tool; serial studies reveal progressive gallbladder dilatation and edema. Tube cholecystostomy was used in five patients and cholecystectomy in four. Cholecystostomy led to resolution of the inflammatory process in all five patients. Cholecystectomy should be reserved for those patients with extensive gallbladder necrosis. Six of the nine patients in the series died, all from multiple systems failure with concomitant sepsis. Hypotension is probably central to the development of acute acalculous cholecystitis. In the face of elevated intraluminal gallbladder pressure caused by ampullary edema and increased bile viscosity, hypotension may result in mucosal ischemia and necrosis with subsequent bacterial colonization. Acute acalculous cholecystitis represents another organ failure in critically ill patients who are experiencing progressive failure of multiple organ systems. An aggressive approach to the manifestations of organ failure, including acalculous cholecystitis, must be employed.


Exploring the synergic effect of fly ash and garbage enzymes on biotransformation of organic wastes in in-vessel composting system.
The aim of the present work was to study the synergic effect of fly ash (FA) and garbage enzymes (GE) on biotransformation of organic wastes in in-vessel composting system. In-vessel composting of organic waste (household + brown in vessel 1) was performed with fly ash (mixed 5% in vessel 2; 10% in vessel 3; 15% in vessel 4; and 20% in vessel 5) by addition of extra carbon source (5%) and garbage enzyme in a fixed-dose (5%) for 15 days and changes in chemical properties (C: N ratio, nitrates, sulphates, phosphates and macro-elements) were analyzed at maturity. Vessel 5 showed better results in terms of organic matter degradability and C: N ratio (13.68) of mature compost. Principal Component Analysis (PCS) also confirmed vessel 5 as the best performing among other vessels. FTIR analysis indicated a major shift in chemical structure of organic waste due to the composting action.


Mapping oscillating magnetic fields around rechargeable batteries.
Power storage devices such as batteries are a crucial part of modern technology. The development and use of batteries has accelerated in the past decades, yet there are only a few techniques that allow gathering vital information from battery cells in a nonivasive fashion. A widely used technique to investigate batteries is electrical impedance spectroscopy (EIS), which provides information on how the impedance of a cell changes as a function of the frequency of applied alternating currents. Building on recent developments of inside-out MRI (ioMRI), a technique is presented here which produces spatially-resolved maps of the oscillating magnetic fields originating from the alternating electrical currents distributed within a cell. The technique works by using an MRI pulse sequence synchronized with a gated alternating current applied to the cell terminals. The approach is benchmarked with a current-carrying wire coil, and demonstrated with commercial and prototype lithium-ion cells. Marked changes in the fields are observed for different cell types.


Association between DRD2 and ANKK1 polymorphisms with the deficit syndrome in schizophrenia.
The clinical course of schizophrenia varies among patients and is difficult to predict. Some patient populations present persistent negative symptoms, referred to as the deficit syndrome. Compared to relatives of non-deficit schizophrenia patients, family members of this patient population are at an increased risk of developing schizophrenia. Therefore, the aim of this study was to search for genetic underpinnings of the deficit syndrome in schizophrenia. Three SNPs, i.e., rs1799732 and rs6276 located within DRD2, and rs1800497 within ANKK1, were identified in the DNA samples of 198 schizophrenia probands, including 103 patients with deficit (DS) and 95 patients with non-deficit schizophrenia (NDS). Results: No significant differences concerning any of the analyzed polymorphisms were found between DS and NDS patients. However, significant links were observed between family history of schizophrenia and the deficit syndrome, G/G genotype and rs6276 G allele. In a separate analysis, we identified significant differences in frequencies of rs6276 G allele between DS and NDS patients with family history of schizophrenia. No significant associations were found between DRD2 and ANKK1 SNPs and the age of onset or schizophrenia symptom severity. The results of our preliminary study fail to provide evidence of associations between DRD2 and ANKK1 polymorphisms with the deficit syndrome or schizophrenia symptom severity, but suggest potential links between rs6276 in DRD2 and the deficit syndrome in patients with hereditary susceptibility to schizophrenia. However, further studies are necessary to confirm this observation.


The benefits of intensive lipid lowering in patients with stable coronary heart disease with normal or high systolic blood pressure: an analysis of the Treating to New Targets (TNT) study.
This post-hoc analysis of the Treating to New Targets (TNT) study evaluated the joint effects of managing low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on cardiovascular outcomes. Patients (N=9739) with clinically evident, stable coronary heart disease (CHD) were randomized to atorvastatin 10 or 80 mg/d. The primary end point was occurrence of a first major cardiovascular event. At 3 months' follow-up, patients were stratified according to SBP (< 140 mm Hg vs > or = 140 mm Hg) and tertiles of LDL-C. At 4.9 years' median follow-up, the rate of major cardiovascular events was reduced most in patients with lower LDL-C (P < .001) and in patients with SBP < 140 mm Hg (P = .014). A 42% relative risk reduction was observed for patients in the lowest LDL-C tertile with an SBP < 140 mm Hg, compared with patients in the highest LDL-C tertile with an SBP > or = 140 mm Hg. The effect of lower SBP on stroke was most pronounced in the lowest LDL-C tertile.


Simvastatin induces the expression of hemeoxygenase-1 against ischemia-reperfusion injury on the testes in rats.
We evaluate the protective role of simvastatin-induced HO-1 in remote preconditioning against testis ischemia-reperfusion (IR) injury in vivo. Simvastatin was intraperitoneally (i.p.) injected 24 h before IR injury. Testis was occluded in the right testis for 40 min and followed by 30 min of reperfusion to induce IR injury. Tin protoporphyrin (Snpp), a competitive inhibitor of hemeoxygenase, was i.p. injected 1 h before the IR injury in separate groups of rats. The rat testes were harvested 24 h later. Induction of HO-1 expression by simvastatin was significantly increased at 24 and 48 h. Rats pre-treated with simvastatin showed higher expression of HO-1 protein by Western blotting and immunohistochemistry (IHC), and presented lower caspases-3 activity by caspase-3 activity assay. TUNEL staining analysis revealed simvastatin pretreatment significantly reduced IR induced cellular apoptosis. Contrarily, the simvastatin-induced cytoprotective effect was entirely abolished by administrations of Snpp. Further, lower caspase-3 activities were also noted in simvastatin plus Snpp (SS) group than the control plus Snpp (CS) group. After IR injury, eNOS immunoreactivity was markedly increased in the germ cell and Leydig cell of testicular tissues. Pretreatment of simvastatin significantly decreased eNOS immunoreactivity in the germ cell of the tubules in the rat testes. In conclusion, we suggest HO-1 plays a protective role in IR-induced injury in the testes of rats.


Nocturnal regulation of free fatty acids in healthy young and elderly men.
To determine the effects of age on nocturnal fuel regulation, we measured spontaneous plasma glucose and free fatty acid (FFA) levels as well as counterregulatory hormones in healthy young (n = 9, mean age 26 +/- 3 years) and old (n = 10, mean age 69 +/- 3 years) men from midnight to 8 AM. FFA levels rose from midnight (660 +/- 80 mEq/L for young subjects, 545 +/- 55 mEq/L for old) to a peak mean level of 866 +/- 110 mEq/L at 3 AM in young and 713 +/- 120 mEq/L at 1:30 AM in old (P less than .05). FFA levels declined thereafter for both groups. FFA levels were lower in older subjects (P less than .05) but integrated glucose (P less than .05) and insulin (P less than .05) levels were higher. FFA levels were inversely related to integrated insulin (r = -0.46, P less than .05) and glucose concentrations (r = -0.66, P less than .05). Integrated insulin levels were significantly higher in older subjects, which may explain the lower FFA levels as may lower growth hormone levels in the older subjects. While fasting glucose responsivity to endogenous insulin is impaired in healthy older men, the FFA response appears to be preserved.


Crystal structure of catena-poly[silver(I)-μ-l-valinato-κ2N:O].
The reaction of Ag2O with l-valine (l-Hval, C5H11NO2) in a 1:2 molar ratio in water, followed by vapour diffusion, afforded a coordination polymer of the title compound, [Ag(C5H10NO2)] n , with N-Ag-O repeat units, which is classified as a type III silver(I) complex with amino acid ligands. The asymmetric unit consists of two independent units of [Ag(l-val)]. In the crystal, the polymeric chains run along [101], and neighbouring chains are linked via a weak Ag⋯Ag inter-action and N-H⋯O hydrogen bonds. The title complex exhibited anti-microbial activity against selected bacteria (Escherichia coli, Bacillus subtilis, Staphylococcous aureus and Psedomonas aeruginosa).


Exacerbated mechanical hyperalgesia in rats with genetically predisposed depressive behavior: role of melatonin and NMDA receptors.
A connection between pain and depression has long been recognized in the clinical setting; however, its mechanism remains unclear. This study showed that mechanical hyperalgesia induced by unilateral temporomandibular joint (TMJ) inflammation was exacerbated in Wistar-Kyoto (WKY) rats with genetically predisposed depressive behavior. Reciprocally, TMJ inflammation enhanced depressive behavior such that a lower nociceptive threshold correlated with a higher score of depressive behavior in the same WKY rats. As compared with Wistar rats, WKY rats showed a lower plasma melatonin level, downregulation of the melatonin MT1 receptor, but upregulation of the NR1 subunit of the NMDA receptor in the ipsilateral trigeminal subnucleus caudalis (Sp5C). Intracisternal administration of 6-chloromelatonin (250 μg, twice daily for 7 days) concurrently attenuated mechanical hyperalgesia and depressive behavior in WKY rats as well as downregulated the NR1 expression in the ipsilateral Sp5C. In patch-clamp recordings, melatonin dose-dependently decreased NMDA-induced currents in spinal cord dorsal horn substantia gelatinosa neurons. These results demonstrate a reciprocal relationship between TMJ inflammation-induced mechanical hyperalgesia and depressive behavior and suggest that the central melatoninergic system, through modulation of the NMDA receptor expression and activity, may play a role in the mechanisms of the comorbidity between pain and depression.


Serum uric acid levels in patients with infections of central nervous system.
The lower levels of serum uric acid (UA) correlated with meningitis have been reported. However, comparison of UA levels among different kinds of infections of central nervous system (CNS) and changes of UA levels before and after treatment are unknown. Our study aimed to investigate the antioxidant status of serum UA in five common types of CNS infections. We retrospectively evaluated serum UA levels of 399 patients with different types of CNS infections including viral meningitis or meningoencephalitis (VM), brain cysticercosis (BC), tuberculous meningitis or meningoencephalitis (TM), cryptococcus meningitis or meningoencephalitis (CM) and bacterial meningitis or meningoencephalitis (BM), and 119 healthy controls. The changes of serum UA were examined and analyzed. The serum levels of UA in patients with CNS infections were significantly lower than those in normal subjects and among in TM, CM and BM groups were apparently lower when compared with VM and BC groups; otherwise, after effective therapy, serum UA levels were obviously higher than before. Our findings showed that patients with CNS infections had lower serum UA levels, which was independent of the classification and the serum UA levels increased obviously after valid treatment, the variation of UA levels might be considered as an indicator of clinical curative effect in patients with CNS infections.


Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.
The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.


Reassessment of miRNA variant (isomiRs) composition by small RNA sequencing.
IsomiRs, sequence variants of mature microRNAs, are usually detected and quantified using high-throughput sequencing. Many examples of their biological relevance have been reported, but sequencing artifacts identified as artificial variants might bias biological inference and therefore need to be ideally avoided. We conducted a comprehensive evaluation of 10 different small RNA sequencing protocols, exploring both a theoretically isomiR-free pool of synthetic miRNAs and HEK293T cells. We calculated that, with the exception of two protocols, less than 5% of miRNA reads can be attributed to library preparation artifacts. Randomized-end adapter protocols showed superior accuracy, with 40% of true biological isomiRs. Nevertheless, we demonstrate concordance across protocols for selected miRNAs in non-templated uridyl additions. Notably, NTA-U calling and isomiR target prediction can be inaccurate when using protocols with poor single-nucleotide resolution. Our results highlight the relevance of protocol choice for biological isomiRs detection and annotation, which has key potential implications for biomedical applications.