Pretreatment neutrophil-to-lymphocyte ratio predicts worse survival outcomes and advanced tumor staging in patients undergoing radical cystectomy for bladder cancer.
To determine the role of neutrophil-to-lymphocyte ratio (NLR) in prognosticating survival outcomes in patients with advanced/metastatic urothelial bladder cancer. We retrospectively reviewed 84 patients undergoing radical cystectomy (RC) for UCB from January 2002 to June 2012. NLR was computed (median: 5 days) prior to surgery. No patients received neoadjuvant chemotherapy. NLR was analyzed as a continuous variable and a cut-off point of 2.7 was obtained, with a statistical receiver operating characteristics of 0.74. Kaplan-Meier curves, multivariate Cox proportional hazard and logistics regression models were used to predict NLR association with survival outcomes. The median follow-up period was 30.1 months (range: 3.2-161.7) owing to high recurrence rate and subsequent mortalities, compared to the median 64.7 months in patients alive at the end of study period. NLR ≥2.7 was associated with worse survival outcomes (5-year disease-specific survival: 22% vs 58%, p = 0.017, 95%CI: 1.193-6.009; 5-year overall survival: 23% vs 60%, p = 0.008, 95%CI: 1.322-6.147). Furthermore, on multivariate analyses, higher NLR was independently associated with higher recurrence rate (p = 0.007, HR =6.999, 95%CI: 1.712-28.606), higher T staging (p = 0.021, HR = 3.479, 95%CI: 1.212-9.990) and lymph node involvement (p = 0.009, HR = 4.534, 95%CI: 1.465-14.034). This study suggests that NLR can be an inexpensive novel factor for patients risk stratification pre-operatively. This improves patient counseling and identifies patients who may benefit from multimodal treatment.


Endovascular Thrombectomy Outcomes with and without Intravenous Thrombolysis for Large Ischemic Cores Identified with CT or MRI.
Background Whether intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) provides additional benefits in patients with acute ischemic stroke (AIS) and a large infarct core (LIC) remains unclear. Purpose To examine whether treatment with IVT before EVT is beneficial in patients with LIC identified with CT or MRI (Alberta Stroke Program Early CT score 0-5). Materials and Methods This retrospective study included consecutive adult patients diagnosed with AIS due to large vessel occlusion (LVO) and LIC treated with EVT who were enrolled in the ETIS (Endovascular Treatment in Ischemic Stroke) Registry in France between January 2015 and January 2022. The primary outcome measure was a favorable outcome (modified Rankin Scale [mRS] score 0-3) at 90 days. Secondary outcomes included functional independence (mRS score 0-2) at 90 days, improvement in degree of disability (ordinal shift in mRS score toward a better outcome) at 90 days, early neurologic improvement at 24 hours, and successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b or higher). Safety outcomes included symptomatic intracerebral hemorrhage within 24 hours and mortality at 90 days. Inverse probability of treatment weighting (IPTW)-adjusted analysis was used to assess the treatment effect of IVT adjusted for baseline variables. Results Of 1408 patients (mean age, 68.3 years ± 15.4 [SD]; 789 men), 654 (46.4%) were treated with IVT prior to EVT. In the IPTW-adjusted data set, IVT plus EVT was associated with a higher rate of favorable outcome at 90 days (odds ratio [OR], 1.24 [95% CI: 1.05, 1.46]; P = .01), functional independence at 90 days (OR, 1.47 [95% CI: 1.22, 1.77]; P < .001), improvement in degree of disability at 90 days (common OR, 1.30 [95% CI: 1.13, 1.49]; P < .001), early neurologic improvement (OR, 1.26 [95% CI: 1.07, 1.49]; P = .005), and successful reperfusion (OR, 1.43 [95% CI: 1.14, 1.79]; P = .002) than EVT alone. Rates of brain hemorrhage within 24 hours and mortality at 90 days were similar between groups. Conclusion In patients with AIS due to LVO with LIC identified with CT or MRI, treatment with IVT before EVT appeared to provide a clinical benefit over EVT alone. Clinical trial registration no. NCT03776877 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kallmes and Rabinstein in this issue.


[Role of the abnormal tracheobroncheal tree in the efficiency of treatment of patients with pulmonary tuberculosis].
The efficiency of treatment has been studied in 100 patients with pulmonary tuberculosis caused by drug-resistant (DR) Mycobacterium tuberculosis (MBT) strains and complicated by bronchial diseases, treated at the units of the Clinic of Phthisiopulmonology, I. M. Sechenov Moscow Medical Academy, in 2004 to 2006. Several forms of specific and/or nonspecific bronchial diseases are shown to be detected in patients with drug resistance in MBT. Pulmonary tuberculosis caused by DR MBT strains and complicated by bronchial diseases is characterized by the lower interferon-producing capacity of bronchoalveolar lavage (BAL) cells and by more significant impairments in the mechanisms of local lung protection. Inclusion of the immunomodulator leukinferon into the combined therapy of patients with pulmonary tuberculosis complicated by bronchial diseases contributes to the elevation of BAL cell production of alpha and gamma-interferons, reduces the generation of active oxygen forms in the BAL phagocytes and brush biopsy specimens, and increases the levels of immunoglobulins in BAL. The local administration of leukinferon reduces the time of cure of specific and nonspecific bronchial diseases in patients with pulmonary tuberculosis who isolate DR MBT strains, thus promoting the enhanced efficiency of treatment in reducing the times of bacterial isolation and decay cavity closure and the length of hospital stay.


Perioperative Hypertension Management during Facelift under Local Anesthesia with Intravenous Hypnotics.
Perioperative hypertension is a phenomenon in which a surgical patient's blood pressure temporarily increases throughout the preoperative and postoperative periods and remains high until the patient's condition stabilizes. This phenomenon requires immediate treatment not only because it is observed in a majority of patients who are not diagnosed with high blood pressure, but also because occurs in patients with underlying essential hypertension who show a sharp increase in their blood pressure. The most common complication following facelift surgery is hematoma, and the most critical risk factor that causes hematoma is elevated systolic blood pressure. In general, a systolic blood pressure goal of <150 mm Hg and a diastolic blood pressure goal of >65 mm Hg are recommended. This article discusses the causes of increased blood pressure and the treatment methods for perioperative hypertension during the preoperative, intraoperative, and postoperative periods, in order to find ways to maintain normal blood pressure in patients during surgery. Further, in this paper, we review the causes of perioperative hypertension, such as anxiety, epinephrine, pain, and postoperative nausea and vomiting. The treatment methods for perioperative hypertension are analyzed according to the following 3 operative periods, with a review of the characteristics and interactions of each drug: preoperative antihypertensive medicine (atenolol, clonidine, and nifedipine), intraoperative intravenous (IV) hypnotics (propofol, midazolam, ketamine, and dexmedetomidine), and postoperative antiemetic medicine (metoclopramide and ondansetron). This article focuses on the knowledge necessary to safely apply local anesthesia with IV hypnotics during facelift surgery without the assistance of an anesthesiologist.


Vertical eruption patterns of impacted mandibular third molars after the mesialization of second molars using miniscrews.
To investigate (1) whether vertical eruption of impacted third molars improves after mesialization of second molars and (2) what factors affect the vertical eruption of impacted third molars when space caused by missing molars is successfully closed by mesialization of the second molar using miniscrews. The treatment group (Group 1) included 52 patients who had (1) missing mandibular first molars (ML-6) or missing deciduous mandibular second molars (ML-E), (2) initially impacted mandibular third molars, and (3) successful space closure of the edentulous area with orthodontics. Panoramic radiographs at start of treatment (T1) and at time of space closure (T2) were collected. The control group (Group 2) included 46 nonedentulous patients with impacted mandibular third molars without molar protraction treatment. Panoramic radiographs with similar T1/T2 treatment times were selected. Nine measurements were obtained regarding horizontal available space, vertical eruption, and third molar angulation. Third molars erupted vertically an average of 2.54 mm in Group 1 compared with 0.41 mm in Group 2. Age, gender, Nolla stage, and angle of the third molars did not show significant correlations with the vertical change of the impacted third molars, whereas the depth of third molar impaction and available space showed significant correlations. Impacted mandibular third molars vertically erupt as a result of uprighting with mesialization of the second molar, and vertical eruption is affected by the initial vertical location of impacted third molars and available space.


Economic Burden of Hepatitis C Virus Infection in Different Stages of Disease: A Report From Southern Iran.
Hepatitis C virus (HCV) infection is a major blood-borne infection which imposes high economic cost on the patients. The current study aimed to evaluate the total annual cost due to chronic HCV related diseases imposed on each patient and their family in Southern Iran. Economic burden of chronic hepatitis C-related liver diseases (chronic hepatitis C, cirrhosis and hepatocellular carcinoma) were examined. The current retrospective study evaluated 200 Iranian patients for their socioeconomic status, utilization (direct and indirect costs) and treatment costs and work days lost due to illness by a structured questionnaire in 2015. Costs of hospital admissions were extracted from databases of Nemazee hospital, Shiraz, Iran. The outpatient expenditure per patient was measured through the rate of outpatient visits and average cost per visit reported by the patients; while the inpatient costs were calculated through annual rate of hospital admissions and average expenditure. Self-medication and direct non-medical costs were also reported. The human capital approach was used to measure the work loss cost. The total annual cost per patient for chronic hepatitis C, cirrhosis and hepatocellular carcinoma (HCC) based on purchasing power parity (PPP) were USD 1625.50, USD 6117.2, and USD 11047.2 in 2015, respectively. Chronic hepatitis C-related liver diseases impose a substantial economic burden on patients, families and the society. The current study provides useful information on cost of treatment and work loss for different disease states, which can be further used in cost-effectiveness evaluations.


Human eye development is characterized by coordinated expression of fibrillin isoforms.
Mutations in human fibrillin-1 and -2, which are major constituents of tissue microfibrils, can affect multiple ocular components, including the ciliary zonule, lens, drainage apparatus, cornea, and retina. However, the expression pattern of the three human fibrillins and an integral microfibrillar component, MAGP1, during human eye development is not known. We analyzed sections from human eyes at gestational weeks (GWs) 6, 8, and 11 and at 1 and 3 years of age with antibodies specific for each human fibrillin isoform or MAGP1, using immunofluorescence microscopy. During embryonic development, each fibrillin isoform was detected in vascular structures bridging the ciliary body and the developing lens, hyaloid vasculature, and retina. In addition, they were present in the developing corneal basement membranes and lens capsule. MAGP1 codistributed with the fibrillin isoforms. In contrast, the juvenile zonule was composed of fibrillin-1 microfibrils containing MAGP1, but fibrillin-2 was absent and fibrillin-3 was only sparsely detected. Fibrillin-1, -2, and, unique to humans, fibrillin-3 are found in various ocular structures during human embryonic eye development, whereas fibrillin-1 dominates the postnatal zonule. We speculate that vasculature spanning the ciliary body and lens, which elaborates fibrillin-2 and -3, may provide an initial scaffold for fibrillin assembly and zonule formation.


OPRM1 c.118A>G Polymorphism and Duration of Morphine Treatment Associated with Morphine Doses and Quality-of-Life in Palliative Cancer Pain Settings.
Despite increased attention on assessment and management, pain remains the most persistent symptom in patients with cancer, in particular in end-of-life settings, with detrimental impact on their quality-of-life (QOL). We conducted this study to evaluate the added value of determining some genetic and non-genetic factors to optimize cancer pain treatment. Eighty-nine patients were included in the study for the evaluation of palliative cancer pain management. The regression analysis showed that age, OPRM1 single nucleotide polymorphism (SNP), as well as the duration of morphine treatment were significantly associated with morphine doses at 24 h (given by infusion pump; p = 0.043, 0.029, and <0.001, respectively). The mean doses of morphine decreased with age but increased with the duration of morphine treatment. In addition, patients with AG genotype c.118A>G OPRM1 needed a higher dose of morphine than AA patients. Moreover, metastases, OPRM1 SNP, age, and gender were significantly associated with the QOL in our population. In particular, AA patients for OPRM1 SNP had significantly lower cognitive function than AG patients, a result not previously reported in the literature. These findings could help increase the effectiveness of morphine treatment and enhance the QOL of patients in regards to personalized medicine.


Plasma concentrations of insulin-like growth factor-I and insulin in the infant calf: ontogeny and influence of altered nutrition.
The developmental pattern of plasma insulin-like growth factor-I (IGF-I) and insulin in calves subject to different patterns of weaning was investigated from birth until the age of 6 months. Fifteen male Friesian calves were fed on whole milk (10% of body weight per day) for the first 8 weeks after birth, then allocated into three balanced groups. Group 1 was weaned at 8 weeks; group 2 was weaned at 8 weeks, returned to milk-feeding at 13 weeks to be weaned again at the age of 16 weeks; group 3 was weaned at 12 weeks. After weaning the calves were fed on concentrates and lucerne hay. At birth, circulating concentrations of IGF-I correlated with birth weight (r = 0.78, P less than 0.001). There was a significant (P less than 0.001) fall in plasma IGF-I from birth (40.3 +/- 2.5 micrograms/l) until 5 weeks (23.8 +/- 1.3 micrograms/l), and then a gradual (P less than 0.01) rise until week 8 (35.0 +/- 2.2 micrograms/l). Weaning (groups 1 and 2 after week 8) caused a significant (P less than 0.01) decrease in plasma IGF-I (20.5 +/- 1.9 micrograms/l); thereafter plasma levels of IGF-I rose gradually (P less than 0.01) in animals fed on concentrates. The milk-fed calves (group 3) showed a progressive increase in plasma IGF-I with age until they were weaned at 12 weeks (51.0 +/- 3.4 micrograms/l); IGF-I levels then decreased to be similar to group 1 (32.5 +/- 2.1 micrograms/l).(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition of CDC25B phosphatase through disruption of protein-protein interaction.
CDC25 phosphatases are key cell cycle regulators and represent very attractive but challenging targets for anticancer drug discovery. Here, we explored whether fragment-based screening represents a valid approach to identify inhibitors of CDC25B. This resulted in identification of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic domain of CDC25B. Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein-protein interaction interface with CDK2/Cyclin A substrate. Furthermore, we developed a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin A and inhibits dephosphorylation of CDK2. Based on these studies, we provide a proof of concept that targeting CDC25 phosphatases by inhibiting their protein-protein interactions with CDK2/Cyclin A substrate represents a novel, viable opportunity to target this important class of enzymes.


Polymyositis-like syndrome in hypothyroidism: review of cases reported over the past twenty-five years.
Polymyositis-like syndrome, with proximal muscle weakness and elevation of muscle enzymes, may be a clinical manifestation of hypothyroidism. To define the clinical, biochemical, electromyographic, and pathologic characteristics of patients with this syndrome, we identified and reviewed by MEDLINE all cases reported in the English literature from January 1, 1975 through December 31, 2000. Thirty-two cases were considered. Fifty-nine percent of the patients were male with a mean age of 54.7 +/- 22.6 years, (+/- 1 standard deviation [SD]). Weakness was described in 100% of patients. Other common clinical manifestations were: delayed tendon reflexes with slow relaxation phase (41%), muscle tenderness (25%), and muscle induration (9%). The mean creatine kinase (CK) was 2164 +/- 1954 U/L (+/- 1 SD) and the mean thyroid-stimulating hormone (TSH) was 114.8 +/- 85.6 mIU/L (+/- 1 SD). Fifty percent of patients had electromyography; half of the studies were normal while the other half showed nonspecific myopathic changes. Biopsies were performed in 80% of the patients. The most common findings were type II fiber atrophy, type I fiber hypertrophy, central nuclei disposition, necrosis, increased percentage of type I fibers, and decreased percentage of type II fibers, inflammatory infiltrate and the presence of core-like structures. The characteristics of polymyositis-like syndrome in hypothyroidism did not differ from those of nonspecific hypothyroid myopathy. Clinical judgment alone may not be sufficient to suspect and detect these patients. Serum TSH levels should be routinely determined in all patients with muscle weakness or elevation of creatine kinase.


Aeroacoustic catastrophes: upstream cusp beaming in Lilley's equation.
The downstream propagation of high-frequency acoustic waves from a point source in a subsonic jet obeying Lilley's equation is well known to be organized around the so-called 'cone of silence', a fold catastrophe across which the amplitude may be modelled uniformly using Airy functions. Here we show that acoustic waves not only unexpectedly propagate upstream, but also are organized at constant distance from the point source around a cusp catastrophe with amplitude modelled locally by the Pearcey function. Furthermore, the cone of silence is revealed to be a cross-section of a swallowtail catastrophe. One consequence of these discoveries is that the peak acoustic field upstream is not only structurally stable but also at a similar level to the known downstream field. The fine structure of the upstream cusp is blurred out by distributions of symmetric acoustic sources, but peak upstream acoustic beaming persists when asymmetries are introduced, from either arrays of discrete point sources or perturbed continuum ring source distributions. These results may pose interesting questions for future novel jet-aircraft engine designs where asymmetric source distributions arise.


Atypical findings on computed tomography in tuberous sclerosis. Case reports.
In 3 patients with tuberous sclerosis computed tomography showed numerous low-density areas suggestive of brain demyelination. In addition, solitary small subependymal calcifications were noted. These features in an infant or child with unexplained seizures should alert one to the diagnosis of tuberous sclerosis.


The amyloid precursor protein shows a pH-dependent conformational switch in its E1 domain.
The amyloid precursor protein (APP) and its proteolytic cleavage product Aβ are widely believed to be central to the etiology of Alzheimer's disease (AD). APP and its family members are also essential for proper neuronal development and homeostasis. APP is located at the cell surface and within intracellular compartments, cellular regions that exhibit different pH values. The AD-associated amyloidogenic processing of APP is initiated predominantly in intracellular acidic compartments, whereas its non-amyloidogenic cleavage is initiated at the cell surface at slightly basic pH. We analyzed the influence of pH on the APP-E1 domain and found that its two constituting subdomains, GFLD and CuBD, interact with each other in a pH-dependent manner. Dynamic light scattering showed that APP-E1 represents a more open conformation at neutral pH and a more closed conformation at acidic pH. Analyzing a 1.4 Å, high-resolution X-ray structure of E1 derived from merohedrally twinned crystals resulted in the identification of individual residues that are responsible for these pH-dependent interactions. Mutational studies and dynamic light scattering measurements further proved that specific hydrogen bonds between the two carboxylates of D177 and E87, as well as between N89 and H147, are major determinants of this pH-driven conformational switch in APP-E1. These findings show how APP can adopt different conformations depending on pH and suggest that the protein fulfils different functions at distinct localizations within the cell. Additionally, our data suggest a novel strategy for treating AD based on regulating the amyloidogenic processing of APP by the specific interruption of the interaction between the APP-E1 subdomains.


4-Chlorocatechol 1,2-dioxygenase from the chlorophenol-utilizing Gram-positive Rhodococcus opacus 1CP: crystallization and preliminary crystallographic analysis.
4-Chlorocatechol 1,2-dioxygenase (4-ClC1,2DO) from the Gram-positive bacterium Rhodococcus opacus (erythropolis) 1CP, an enzyme involved in the aerobic biodegradation of chloroaromatic compounds, has been crystallized. 4-ClC1,2DO, which specifically catalyzes the intradiol cleavage of 4-substituted catechols, which are intermediates in the degradation of a variety of aromatic pollutants, to the corresponding maleylacetates, has recently been purified to homogeneity. The enzyme is an homodimer composed of two identical subunits in an alpha(2)-type quaternary structure; it has a molecular weight of about 29 kDa per monomer and contains one Fe(III) and one Mn(II) ion per homodimer. Hexagonal crystals grown in 1.6 M ammonium sulfate, 0.1 M sodium chloride, 100 mM Tris-HCl pH 9.0, 5-15% glycerol were successfully frozen under liquid nitrogen, adding 30% glycerol to the mother-liquor solution as a cryoprotectant. A complete data set was collected at 2.8 A resolution using the EMBL beamline BW7A at the DORIS storage ring, DESY, Hamburg, Germany with a MAR CCD detector and a wavelength of 1.01 A. The crystals belong to the primitive hexagonal space group P6(3)22, with unit-cell parameters a = 90.4, c = 307.5 A. This is the first intradiol dioxygenase which specifically catalyzes the cleavage of chlorocatechols in Gram-positive bacteria to give diffraction-quality crystals.


Potential interactions with anticancer agents: a cross-sectional study.
Patients with cancer are particularly susceptible to drug interactions (DIs), but the extent of the problem has received limited attention. We aimed to evaluate the frequency of interactions with anticancer agents in a group of cancer patients. The study was performed in a Belgian teaching hospital. One hundred and twenty-two patients with solid malignancies were included. A comprehensive drug history was performed by a clinical pharmacist. Three renowned DI compendia were used to identify DIs. Forty-one potential interactions involving an anticancer agent and considered to be clinically significant were identified among 25% of patients. The anticancer drugs mostly involved were cisplatin and methotrexate, and the most frequent co-medications involved were vitamin K antagonists, proton pump inhibitors and diuretics. In the majority of cases, the potential adverse consequence was increased toxicity of the anticancer agent and/or of the co-medication. Less than 10% of DIs were identified by the three compendia. Preventive measures should be taken to avoid increased toxicity or decreased efficacy of the drugs. Most of the time, this simply involves surveillance of biological or clinical parameters. Collaboration with a clinical pharmacist may be useful for the prescribing physician.


Caution with Use of the EPIC-50 Urinary Bother Scale: How Voiding Dysfunction Modifies its Performance.
We evaluated agreement between patient reported urinary function and bother, and sexual function and bother in patients treated with radical prostatectomy to help inform possible nonfunctional, modifiable mechanisms for patient bother. Patients were recruited from 2011 to 2014 at Washington University, and Brigham and Women's Hospital. Urinary and sexual outcomes were assessed by EPIC-50 (Expanded Prostate Cancer Index Composite-50) before, 5 weeks and 12 months after radical prostatectomy. Spearman rank correlation coefficients and agreement/disagreement categories were used to describe the relation between function and bother. Despite moderate to good agreement between function and bother (urinary r = 0.51-0.69 and sexual r = 0.65-0.80) discordant groups were observed. In the urinary domain these groups were men disproportionately bothered by function at baseline (16.9%) and 12 months after radical prostatectomy (6.1%) and men less bothered by function 5 weeks (26.8%) and 12 months (9.9%) after radical prostatectomy. Discordant groups in the sexual domain were men less bothered by function at baseline (20.8%), and 5 weeks (21.1%) and 12 months (15.7%) after radical prostatectomy. Splitting the urinary bother scale into 2 subscales, including one for incontinence related bother to complement the urinary function scale which measures only incontinence, and one for voiding dysfunction related bother yielded considerably better agreement (urinary function and incontinence related bother r = 0.78-0.83). Factors contributing to the group less bothered by sexual function were unclear. When using EPIC-50, investigators should consider splitting the urinary bother scale by the relation to incontinence to prevent distortions of function-bother and comparisons before vs after radical prostatectomy by coexisting voiding dysfunction.


Efficacy and safety of indomethacin 0.1% versus flurbiprofen 0.03% eyedrops in inflammation after argon laser trabeculoplasty. The Belgian Study Group on Glaucoma.
After Argon Laser Trabeculoplasty (ALT), non steroidal anti-inflammatory drugs (Indomethacin 1% suspension and Flurbiprofen 0.03% solution) were shown to be efficient in the management of post laser inflammation. To evaluate the efficacy and safety of Indomethacin 0.1% solution versus Flurbiprofen 0.03% eyedrops in that purpose. 64 patients suffering from glaucoma were recruited in a multicenter randomized double masked study. The results demonstrate that Indomethacin 0.1% eyedrops is as efficient as Flurbiprofen 0.03% in terms of control of post ALT inflammation, with a good tolerance.


Draft genome sequence of the plant growth-promoting bacterium Bacillus siamensis KCTC 13613T.
Bacillus siamensis KCTC 13613(T), a novel halophilic Bacillus species isolated from a salted Thai food, produced antimicrobial compounds against plant pathogens and promoted plant growth by volatile emission. We determined the 3.8-Mb genome sequence of B. siamensis KCTC 13613(T) to reveal the plant-beneficial effect at the genomic level.


[Chromatographic fingerprint and quality control of traditional Chinese medicines].
The development of modern chromatographic technologies and related chemometric methods in the research of chromatographic fingerprint, and their applications in quality control of traditional Chinese medicines (TCMs) are comprehensively reviewed. Furthermore, we preliminarily discuss the quality control methods and their feasibility to guarantee that the TCMs can be used stably and effectively. A new strategy is proposed to establish the comprehensive relationships between chromatographic fingerprints and their pharmacodynamic (toxicity) information with the help of the techniques of modern chromatography, chemometrics and system biology to reveal the working mechanism of TCMs and then to comprehensively control the quality of TCMs.


Workflow methodology for rat brain metabolome exploration using NMR, LC-MS and GC-MS analytical platforms.
We developed a multi-platform approach for the metabolome exploration of rat brain tissue, using liquid chromatography coupled with mass spectrometry (LC-MS), nuclear magnetic resonance spectroscopy (NMR) and gas-chromatography coupled with mass spectrometry (GC-MS). The critical steps for metabolite exploration of cerebral tissues are tissue lysis and metabolites extraction. We first evaluated the impact of freeze-drying compared to wet tissue metabolites extraction using NMR and LC-MS with a reversed phase liquid chromatography. Then, we compared four metabolite extraction methods Based on the number of metabolites extracted, their intensity and their coefficient of variation (%CV), the most reproducible protocol (one-step extraction with acetonitrile on lyophilized material) was chosen to further evaluate the impact of sample mass on method performance (3, 6, and 9mg were essayed). GC-MS analysis was also investigated by analyzing four different methoximation/silylation derivatization combinations. The optimal analytical protocols were proposed to establish the reliability required to realize untargeted brain tissue metabolomics exploration. The most reliable workflow was then exemplified by analyzing three rat brain regions (cerebellum, frontal and parietal cortices, n=12) by 1H NMR, LC-MS and GC-MS, allowing their clustering based on their metabolic profiles. We present here an example of development of methodology that should be done before running analysis campaigns.


Reduction of cystic cavity, promotion of axonal regeneration and sparing, and functional recovery with transplanted bone marrow stromal cell-derived Schwann cells after contusion injury to the adult rat spinal cord.
The authors previously reported that Schwann cells (SCs) could be derived from bone marrow stromal cells (BMSCs) in vitro and that they promoted axonal regeneration of completely transected rat spinal cords in vivo. The aim of the present study is to evaluate the efficacy of transplanted BMSC-derived SCs (BMSC-SCs) in a rat model of spinal cord contusion, which is relevant to clinical spinal cord injury. Bone marrow stromal cells were cultured as plastic-adherent cells from the bone marrow of GFPtransgenic rats. The BMSC-SCs were derived from BMSCs in vitro with sequential treatment using beta-mercaptoethanol, all-trans-retinoic acid, forskolin, basic fibroblast growth factor, platelet derived-growth factor, and heregulin. Schwann cells were cultured from the sciatic nerve of neonatal, GFP-transgenic rats. Immunocytochemical analysis and the reverse transcriptase-polymerase chain reaction were performed to characterize the BMSC-SCs. For transplantation, contusions with the New York University impactor were delivered at T-9 in 10- to 11-week-old male Wistar rats. Four groups of rats received injections at the injury site 7 days postinjury: the first received BMSCSCs and matrigel, a second received peripheral SCs and matrigel, a third group received BMSCs and matrigel, and a fourth group received matrigel alone. Histological and immunohistochemical studies, electron microscopy, and functional assessments were performed to evaluate the therapeutic effects of BMSC-SC transplantation. Immunohistochemical analysis and reverse transcriptase-polymerase chain reaction revealed that BMSC-SCs have characteristics similar to SCs not only in their morphological characteristics but also in their immunocytochemical phenotype and genotype. Histological examination revealed that the area of the cystic cavity was significantly reduced in the BMSC-SC and SC groups compared with the control rats. Immunohistochemical analysis showed that transplanted BMSCs, BMSC-SCs, and SCs all maintained their original phenotypes. The BMSC-SC and SC groups had a larger number of tyrosine hydroxilase-positive fibers than the control group, and the BMSC-SC group had more serotonin-positive fibers than the BMSC or control group. The BMSC-SC group showed significantly better hindlimb functional recovery than in the BMSC and control group. Electron microscopy revealed that transplanted BMSC-SCs existed in association with the host axons. Based on their findings, the authors concluded that BMSC-SC transplantation reduces the size of the cystic cavity, promotes axonal regeneration and sparing, results in hindlimb functional recovery, and can be a useful tool for spinal cord injury as a substitute for SCs.


INTRASEXUAL SELECTION CONSTRAINS THE EVOLUTION OF THE DORSAL COLOR PATTERN OF MALE BLACK SWALLOWTAIL BUTTERFLIES, PAPILIO POLYXENES.
Males of the eastern black swallowtail (Papilio polyxenes asterius Stoll) with typical coloration were more successful in intrasexual competition for mating territories than were males altered to have female-like mimetic coloration. Sibling males were matched for wingspan and emergence date and released as pairs, one with its pattern altered and one a control that was marked but with unaltered appearance. Significantly fewer altered males were resighted one or more days after release compared with control males (33% vs. 76%, 1990; 46% vs. 83%, 1993). Altered males were less able to establish and maintain themselves in preferred territories. The inability of released, altered males to establish a territory appears related to significantly longer male-male encounters. Encounters involving at least one participant with altered appearance averaged 66 s compared with 24 s if neither male was altered. However, altering the coloration of P. polyxenes males that already had established themselves in a territory had little effect. After courtships of similar duration (≈ 40 s), released virgin females were equally likely to mate with either altered or control males. This suggests that male-male intrasexual selection is of greater importance than female mate choice in maintaining a non-mimetic dorsal coloration in male P. polyxenes.


Crystal structure of the C-terminal domain of Ebola virus VP30 reveals a role in transcription and nucleocapsid association.
Transcription of the highly pathogenic Ebola virus depends on VP30, a nucleocapsid-associated Ebola virus-specific transcription factor. The transcription activator VP30 was shown to play an essential role in Ebola virus replication, most likely by stabilizing nascent mRNA. Here we present the crystal structure of the C-terminal domain (CTD) of VP30 (VP30(CTD)) at 2.0-A resolution. VP30(CTD) folds independently into a dimeric helical assembly. The VP30(CTD) dimers assemble into hexamers that are present in virions, by an oligomerization domain located in the N terminus of VP30. Mutagenesis of conserved charged amino acids on VP30(CTD) revealed that two regions, namely a basic cluster around Lys-180 and Glu-197, are required for nucleocapsid interaction. However, only mutagenesis of the basic cluster was shown to impair transcription activation, suggesting that both processes are regulated independently. The structure and the mutagenesis results reveal a potential pocket for small-molecule inhibitors that might prevent VP30 activity and thus virus propagation as it has been shown previously by peptides, which interfere with VP30 homooligomerization.


Isolation Rate and Clinical Significance of Uropathogens in Positive Urine Cultures of Hemodialysis Patients.
Hemodialysis (HD) patients are known to be vulnerable to infections. However, there are limited data on the urine microbiology spectrum among patients with end-stage renal disease and on the development of antimicrobial resistance of uropathogens in these patients. A single-center, retrospective study was conducted to assess the spectrum and antimicrobial resistance profile of microorganisms isolated in urine cultures of HD patients who were hospitalized between September 2008 and August 2015 with an admitting diagnosis of fever, sepsis, or urinary tract infection. Characteristics of patients were recorded, and associations between the aforementioned parameters were assessed with Fisher's exact test. We included 75 HD patients (33 males, mean age 73.6 ± 16.6 years) with positive urine cultures. Despite urine culture positivity, the urinary tract was the confirmed source of infection in only 31 (41.3%) patients. Among the different pathogens, Escherichia coli was the predominant microorganism. Identification of E. coli as the involved uropathogen was associated neither with a growth of ≥105 CFU/ml, presence of fever, sepsis, urinary catheter use nor with higher antimicrobial resistance. E. coli growth, however, was significantly associated with polycystic kidney disease (P = 0.027). Extended antimicrobial resistance was noted in 29 (38.7%) patients but was associated neither with higher incidence of fever or sepsis nor with urinary catheter use. In our series of HD patients with positive urine cultures, the isolation rates of different uropathogens do not seem to differ from the most commonly encountered ones in nondialysis patients although resistance to antimicrobials may be more frequently observed.


[The effects of intrathecally administered baclofen on somato-sympathetic reflex potentials].
We investigated the antinociceptive effect of intrathecally administered S(-)-baclofen and R (+)-baclofen in cats using somato-sympathetic reflex potentials derived from lumbar sympathetic ganglion by stimulation of the femoral nerve. S(-)-baclofen 10 mg maximally reduced both A reflex potential and C reflex potential to 65.3% and 83.7% of control values, respectively, 1 minute after the administration, but these changes were not significant. The inhibition of A reflex potential at this dosage was greater than that of blood pressure and heart rate induced by the same dosage of S(-)-baclofen. While, R(+)-baclofen 1 mg maximally inhibited A reflex potential to 48.6% of control value 20 minutes after the administration, and this change was significant (P < 0.05). The inhibition of A reflex potential was greater than that of blood pressure and heart rate induced by the same dosage of R(+)-baclofen. This dosage of baclofen reduced C reflex potential to 66.4% of control value 10 minutes after the administration. The degree of reduction of A and C reflex potentials induced by 1 mg of R(+)-baclofen was higher in comparison with that induced by 10 mg of S(-)-baclofen. These reduction of A and C reflex potentials were reversed by 1 to 1.5 mg of intrathecally administered saclofen. These results indicate that R(+)-baclofen has higher potency than S(-)-baclofen and suggest that S(-)-baclofen and R(+)-baclofen show antinociceptive effect by intrathecal administration. On the other hand, it is possible that these two drugs exert antinociceptive effect via A delta fiber.


Aqueous Oxidations Started by TiO2 Photoinduced Holes Can Be a Rate-Determining Step.
In aqueous TiO2 photocatalytic hydroxylation of weakly polar aromatics, a series of inverse H/D KIEs of 0.7-0.8 were observed, which is different than the normal H/D kinetic isotope effects (KIEs) usually observed for polar aromatics. This result indicated that the oxidation started by photo-induced hvb+ can be the rate-determining step.


IL-17 and IL-22 in immunity: Driving protection and pathology.
IL-17 and IL-22 are tissue-signaling cytokines that favor protection and regeneration of barrier organs such as the skin, lung, and gastrointestinal system. Both cytokines share cellular sources, signaling pathways, and functional aspects; however, taking a closer look they differ, e.g. in their pro-inflammatory or regenerative potential. An imbalance of the carefully orchestrated tissue-signaling system might result in autoimmune diseases, promote cancer growth, or predispose to infectious diseases. This review highlights recent understandings in cellular sources, signaling mechanisms, physiologic as well as pathogenic role of the double-faceted cytokines IL-17 and IL-22.


A prospective randomized comparative placebo-controlled double-blind study in two groups to assess the effect of the use of biologically active additives with Siberian fir terpenes for the biological age of a person.
A prospective randomized comparative placebo-controlled double-blind study was carried out based on Arterial Indices model of biological age. The study involved 60 men and women aged 40-65 years that were randomly divided into two equal groups of 30 people: the main group and the control one. The study participants from the main group received a dietary supplement containing Siberian fir terpenes, limonene, alpha-linolenic acid, and vitamin E-1 capsule 3 times a day for 90 days. Patients in the comparison group received a placebo according to a similar scheme. Anthropometric and biochemical characteristics of patients from both groups have not undergone any significant changes. According to ultrasound examination of the carotid arteries, we observed a statistically significant decrease in the minimum thickness of the intima-media complex (by 45%). The maximum carotid artery stenosis on the right or left and the expansion index in patients of both groups did not change significantly during treatment. According to the results of applanation tonometry, it was revealed that when taking the studied dietary supplement, the pulse wave velocity significantly decreased compared to the initial one (by 10%). Accordingly, the Arterial Indices biological age decreased by 2.5 years compared to the baseline level in patients of the main group and did not change in patients from the comparison group. Supplementation of fir terpenes in middle-aged patients of both sexes reduces the biological age reflecting the condition of the arteries.


Isolation and characterization of renin-like aspartic-proteases from Echis ocellatus venom.
Three aspartic proteases (SVAPs) have been isolated from venom of the saw-scaled viper, Echis ocellatus. In confirmation of prior transcriptomic predictions, all three forms match to sequences of either of the two SVAP transcripts (EOC00051 and EOC00123), have a molecular weight of 42 kDa and possess a single N-glycan. The SVAPs act in a renin-like manner, specifically cleaving human and porcine angiotensinogen into angiotensin-1 and possess no general protease activity. Their activity is completely inhibited by the aspartyl protease inhibitor Pepstatin A.


Synthesis of Structurally Precise Polysiloxanes via the Piers⁻Rubinsztajn Reaction.
Silicone materials are widely used, from daily life to the military industry. With the advancement of science and technology and the increasing demands of industry, the requirement for high-performance precise structural silicone materials has increased. Therefore, the most important aspect in this field is finding a breakthrough in the synthetic methods. In this review, the latest research developments in controllable morphological structure and composite structure optimized synthesis of silicone materials using the Piers⁻Rubinsztajn (PR) reaction are summarized. The advantages of the PR reaction compared with traditional synthetic routes to silicone materials are presented. The highly controllable spatial structure of silicone materials and the structural combination of biomass or inorganic materials with silicone materials results in an improvement in performance or function. The morphological control of more complex silicone materials and the synthesis of non-traditional silicone materials with composite structures through the PR reaction will be the main research directions for the development of silicone materials in the future.


Military Service Member and Veteran Reintegration: A Conceptual Analysis, Unified Definition, and Key Domains.
Returning military service members and veterans (MSMVs) may experience a variety of stress-related disorders and challenges when reintegrating from the military to the community. Facilitating the reintegration, transition, readjustment and coping, and community integration, of MSMVs is a societal priority. To date, research addressing MSMV reintegration has not identified a comprehensive definition of the term or defined the broader context within which the process of reintegration occurs although both are needed to promote valid and reliable measurement of reintegration and clarify related challenges, processes, and their impact on outcomes. Therefore, this principle-based concept analysis sought to review existing empirical reintegration measurement instruments and identify the problems and needs of MSMV reintegration to provide a unified definition of reintegration to guide future research, clinical practice, and related services. We identified 1,459 articles in the health and social sciences literature, published between 1990 and 2015, by searching multiple electronic databases. Screening of abstracts and full text review based on our inclusion/exclusion criteria, yielded 117 articles for review. Two investigators used constant conceptual comparison to evaluate relevant articles independently. We examined the term reintegration and related terms (i.e., transition, readjustment, community integration) identifying trends in their use over time, analyzed the eight reintegration survey instruments, and synthesized service member and veteran self-reported challenges and needs for reintegration. More reintegration research was published during the last 5 years (n = 373) than in the previous 10 years combined (n = 130). The research suggests coping with life stresses plays an integral role in military service member and veteran post-deployment reintegration. Key domains of reintegration include individual, interpersonal, community organizations, and societal factors that may facilitate or challenge successful reintegration, and results suggest that successful coping with life stressors plays an integral role in post-deployment reintegration. Overall, the literature does not provide a comprehensive representation of reintegration among MSMVs. Although, previous research describes military service member and veteran reintegration challenges, this concept analysis provides a unified definition of the phenomenon and identifies key domains of reintegration that may broaden our understanding and guide reintegration research and practice.


Relationship of Apgar scores and Bayley mental and motor scores.
Infants with 0-3 Apgar scores at 1 minute had significantly lower 8-month mental and motor scores than infants with 7-10 scores and significantly lower mental but not motor scores than infants with 4-6 Apgar scores. Correlations indicated significant relationships (independent of birth weight) between Apgar scores and Bayley mental and motor scores for random, Colored Portuguese, and total samples but not for Negroes and whites. Results demonstrated a significant difference in Apgar scores by 8-month classifications with significantly lower scores for children classified as abnormal, and by longevity with significantly lower scores for neonates who died within 2 days.


The effects of neurologic assessment E-learning in nurses.
A firm understanding of the preliminary assessment of a patient with neurological disorders is needed for ensuring optimal patient outcomes. The purpose of this study is to evaluate the effects of using e-learning on neurologic assessment knowledge, ability, and self-confidence among nurses. This study used a non-equivalent control group pretest-posttest design. Nurses working in the neurology and neurosurgery wards, Republic of Korea PARTICIPANTS: A convenience sample of 50 nurses was assigned to either the experimental group (n=24) or the control group (n=26). The experimental group participated in the self-directed e-learning program related to neurologic assessment, and control group underwent self-directed learning with handout. Knowledge, ability, and self-confidence were measured at pretest and posttest. There were no significant differences in knowledge (U=270, p=0.399) and self-confidence (U=241.5, p=0.171) between the two groups. Nurses in the experimental group showed higher neurologic assessment ability compared with those in the control group (U=199, p=0.028). Self-directed neurologic assessment e-learning induced improvement in the neurologic assessment ability among nurses. Self-directed e-learning can be applied for improving competencies in neurologic assessment.


Alternative Splicing in the Human PMP22 Gene: Implications in CMT1A Neuropathy.
CMT1A patients commonly share PMP22 genetic overloading but they show phenotypic heterogeneity and variability in PMP22 mRNA and protein expression. Moreover, PMP22 mRNA levels do not correlate with clinical outcome measures in these patients, suggesting their uselessness as a disease biomarker. Thus, in-depth analysis of PMP22 transcription and translation might help to define its pathogenic role in CMT1A. We focused on the alternative splicing of PMP22 gene to verify whether mRNA processing is altered in CMT1A. We identified three new PMP22 transcripts enriched in human sural nerve biopsies. One of them was an untranslated variant, whereas the other two originated from a PMP22 undescribed exon and encoded for a new putative protein localized in the endoplasmic reticulum. As splicing events in the PMP22 gene are differently regulated in tissues and during development, we analyzed the levels of PMP22 transcripts and their splicing pattern in human and experimental CMT1A. We found an altered PMP22 splicing ratio in the CMT1A rat. In addition, we showed a remarkable derangement in rat QKI expression, which is a critical regulator of splicing during myelination. Overall, our data suggest that an alteration of mRNA processing could be a pathogenic mechanism in CMT1A.


Dundee's Longitudinal Integrated Clerkship: drivers, implementation and early evaluation.
Dundee University School of Medicine established a pilot for a 40 week long comprehensive Longitudinal Integrated Clerkship (LIC) in 2016. Ten places for year 4 students are available which are shared between two regions of Scotland which are largely rural areas by UK definitions. This paper describes the drivers for the pilot, its implementation and early evaluation. For the evaluation, data were collected using focus groups and semi-structured interviews from the first cohort of seven students, four health service employed staff (two with leadership roles and two with regional student facing roles), 21 General Practitioner tutors, and from reflective audio-diaries kept by all students. Analysis was thematic, the themes being identified from the data. Summative assessment data were collated. Students reported positive learning experiences though access to secondary care learning linked to their patients was sometimes problematic. GP tutors were positive and enthusiastic about the programme and could see the potential benefits on recruitment to GP careers. Pre-existing workload pressures were a challenge. Summative assessment results were encouraging. The Dundee LIC is successful in delivering Dundee's year 4 curriculum. Ongoing development has been focused on improving awareness of the programme in secondary care services.


[Seroprevalence of Anaplasma phagocytophilum in patients with suspected Lyme borreliosis].
Human granulocytic anaplasmosis (HGA) is an emerging tick-borne zoonotic disease caused by an obligate intracellular bacterium, Anaplasma phagocytophilum. In Europe, A. phagocytophilum is transmitted by Ixodes ricinus ticks. After Lyme borreliosis and European tick-borne encephalitis, HGA is the third most common tick-borne infection in the USA and Europe. The clinical symptoms of anaplasmosis are non-specific and include malaise, fever, headache, myalgia, and arthralgia. In more severe cases, the gastrointestinal or respiratory tract may be affected. However, most infections are asymptomatic. The aim of our study was to determine the seroprevalence of A. phagocytophilum in patients with suspected Lyme borreliosis. A total of 314 sera from patients with suspected Lyme borreliosis were screened for IgG and IgM antibodies against A. phagocytophilum. The immunoblot assay was used to detect the antibodies. Anti-A. phagocytophilum antibodies were detected in 34 patients, i.e. in 10.82%. IgM antibodies were positive in 19 cases and IgG antibodies in 10 cases. Positivity to both IgM and IgG antibodies was revealed in five patients. Antibodies against Borrelia burgdorferi sensu lato were detected in 181 patients (57.64%). Co-seroprevalence of Borrelia burgdorferi s. l. and A. phagocytophilum was found in 26 patients (8.3%). Positivity for anti-A. phagocytophilum antibodies was most often seen in samples from the age group 60-69 years. Our results show that A. phagocytophilum infection is not uncommon in the Czech Republic and should be considered in patients with a history of a tick bite.


4-oxo-aldehydes from the dorsal abdominal glands of the bed bug (Hemiptera: Cimicidae).
Analyses of the dorsal abdominal glands of fourth- and fifth-instar nymphs of the bed bud, Cimex lectularius L. (Hemiptera: Cimicidae), indicated the predominant constituents were (E)-2-hexenal and (E)-2-octenal, with lesser amounts of 4-oxo-(E)-2-hexenal and 4-oxo-(E)-2-octenal. The latter two compounds have not been reported previously as occurring in bed bugs. There were no differences in the chemical composition of the dorsal abdominal glands excised from exuviae left behind by either male or female adults, nor from glands excised from fourth-instar exuviae. Because the two oxo-aldehydes made up at least 16% of the gland contents, further study of the functional role of these chemicals seem advisable.


Electroacupuncture Mediates Fat Metabolism and Autophagy via a Sirt3-Dependent Mechanism in Mice Fed High-Fat Diet.
This study investigates the therapeutic potential of electroacupuncture (EA) on obesity, focusing on its influence on autophagy and energy metabolism, utilizing a high-fat diet (HFD)-induced mouse model. Treatment with EA significantly reduces body weight, fat deposition, and lipid accumulation in HFD-fed mice. Additionally, EA effectively ameliorates metabolic imbalances, reducing blood glucose levels and plasma markers of liver function. At the molecular level, EA enhances the expression of thermogenesis-associated genes in brown adipose tissue and decreases p53 expression, suggesting a decrease in apoptosis. Autophagy in white adipose tissue is inhibited by EA, as demonstrated by the suppression of key autophagy-related proteins. Further experiments highlight the critical role of Sirtuin 3 (Sirt3) in EA's anti-obesity effects. Sirt3 supplementation combined with EA results in reduced body weight, fat deposition, and lipid accumulation, along with modulations in key metabolic indicators. Moreover, EA's modulatory effect on uncoupling protein 1 (Ucp1), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α), and p53 is found to be Sirt3 dependent. In conclusion, EA exerts beneficial effects against obesity through Sirt3-dependent modulation of autophagy and energy metabolism, indicating a potential therapeutic approach for obesity and related metabolic disorders.


Cataracts and hypertension in salt-sensitive rats. A possible ion transport defect.
In previous unrelated studies, we observed a 35 to 50% incidence of cataract formation in several groups of Dahl salt-sensitive hypertensive rats (DS) over a 4-year period. In the present study we evaluated longitudinal changes in blood pressure in DS in which cataracts eventually developed and those in which cataracts did not develop when all animals were maintained on a high sodium diet. Lenses were evaluated by slit-lamp microscopy to determine if cataractous lesions were similar among rats, to classify lesion types, and to define the age at which cataracts were detectable in DS. The possible participation of several cataractogenic risk factors as major influences on cataract formation also was evaluated. Finally, aqueous humor concentrations and lenticular content of sodium and potassium were determined to evaluate the possibility that a defect in ion transport at the lens epithelium and ciliary body might play a role in cataractogenesis in DS, since ion transport defects have been shown to lead to lens opacification in other models of genetic and experimental cataracts. Parallel studies were performed in Dahl salt-resistant control rats (DR). A high incidence of cataract formation was found in DS. Although systolic blood pressure was not consistently greater in adult DS with cataracts compared with values in age-matched DS without cataracts, the initial pressor response to a high salt diet was greatest in weanling DS in which cataractous lesions later developed. Slit-lamp analysis revealed that cataracts in this genetic model were cortical, with one mixed cortical, nuclear lesion. Posterior subcapsular lesions were not observed, suggesting that lesions were not steroid-induced.(ABSTRACT TRUNCATED AT 250 WORDS)


[Successful treatment of neuroendocrine ductal carcinoma in situ with loco-regional therapy].
Herein, we report the use of microdochectomy for neuroendocrine ductal carcinoma in situ( NE-DCIS). The patient was 44-year-old woman who experienced spontaneous nipple discharge for 5 years. We were unable to detect the origin of the nipple discharge by computed tomography (CT), magnetic resonance imaging (MRI), mammography, ductal endoscopy, or ultrasonography. Subsequently, endoscopy-assisted microdochectomy was performed under local anesthesia. Pathological examination of the resected specimen led to a diagnosis of NE-DCIS positive for estrogen and progesterone receptors and negative for HER2/neu protein expression. The Ki-67 positive cell index was 80%. The surgical margins were negative. After surgery, tamoxifen was administered. One year after the operation, the patient is well and metastases have not been noted. This case suggests that endoscopy-assisted microdochectomy under local anesthesia is useful for evaluating spontaneous nipple discharge.


Effect of silver nanoparticles on mitogen-activated protein kinases activation: role of reactive oxygen species and implication in DNA damage.
Large quantities of engineered nanoparticles (NP), such as nanosilver (AgNP), have been widely applied, leading to an increased exposure and potential health concerns. Herein, we have examined the ability of AgNP to induce reactive oxygen species (ROS), their role in genotoxic effects and the involvement of mitogen-activated protein kinases (MAPK). AgNP exposure induced ROS production in human epithelial embryonic cells which could be decreased by diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation, induced by AgNP, was an early response but not sustained in time. Furthermore, JNK and ERK activation could be inhibited by both DPI and a free radicals scavenger N-acetyl cysteine. We also investigated the role of MAPK in the DNA damage. Using a modified comet assay for the specific detection of hOGG1 sensitive sites, we showed that AgNP induced DNA oxidation after 30-min treatment, whereas no response was observed after 2h. In conclusion, AgNP seem to induce DNA damage via a mechanism involving ROS formation. The oxidative DNA damage observed was transient, likely due to DNA repair; furthermore, higher damage was achieved upon inhibition of ERK activation by pre-treatment with U0126, suggesting a role for ERK in DNA damage repair. Activation of different MAPK might play an important role in the NP toxicity outcomes; understanding this process may be helpful for the identification of NP toxicity.


EL5, a rice N-acetylchitooligosaccharide elicitor-responsive RING-H2 finger protein, is a ubiquitin ligase which functions in vitro in co-operation with an elicitor-responsive ubiquitin-conjugating enzyme, OsUBC5b.
EL5, a rice gene responsive to N-acetylchitooligosaccharide elicitor, encodes a RING-H2 finger protein with structural features common to the plant-specific ATL family. We show that the fusion protein of EL5 with maltose binding protein (MBP) was polyubiquitinated by incubation with ubiquitin, ubiquitin-activating enzyme (E1), and the Ubc4/5 subfamily of the ubiquitin-conjugating enzyme (E2). EL5 possesses the activity to catalyse the transfer of ubiquitin to the MBP moiety, and the RING-H2 finger motif of EL5 is necessary for this activity. Thus, we concluded that EL5 represents a ubiquitin ligase (E3). We also show that two rice E2s (OsUBC5a, OsUBC5b) of the Ubc4/5 subfamily function as E2 which catalyses EL5-mediated ubiquitination, and OsUBC5b was induced by elicitor, as well as EL5. These results strongly suggest that EL5 and OsUBC5b have roles in plant defense response through the turnover of protein(s) via the ubiquitin/proteasome system.


Proximal femoral replacement for non-neoplastic conditions: a systematic review on current outcomes.
Proximal femoral replacement (PFR) is a well-established treatment for neoplasia of the proximal femur. The use of this surgical technique for non-neoplastic conditions has increased over the years. We carried out a systematic review of the literature to study the indications, complications, and functional results when PFR is used for non-neoplastic conditions. Twenty-seven studies were included in the review with a total of 828 PFRs with a mean follow-up of 50 months (range 1-225 months). The main indications were infection (28%), periprosthetic fracture (27%), aseptic loosening (22%), and fracture (16%). The rate of reoperation was 20.3% overall. The overall revision rate was 15.4%. The main complications were dislocation (10.2%) and infection (7.3%). After 2010, the rates of reoperation (25.5% versus 18.2%), loosening (9.4% versus 3.2%), and dislocation (15.7% versus 7.9%) were lower than before 2010. The 30-day mortality ranged from 0% to 9%. The hip function scores improved post-surgery. In conclusion, the use of PFR in non-neoplastic conditions remains a marginal tool, associated with low direct mortality and high complication rates, but we expect its use to increase in the near future.


Colloidal Polyelectrolyte Complexes from Hyaluronic Acid: Preparation and Biomedical Applications.
Hyaluronic acid (HA) is a naturally occurring polysaccharide which has been extensively exploited in biomedical fields owing to its outstanding biocompatibility. Self-assembly of HA and polycations through electrostatic interactions can generate colloidal polyelectrolyte complexes (PECs), which can offer a wide range of applications while being relatively simple to prepare with rapid and "green" processes. The advantages of colloidal HA-based PECs stem from the combined benefits of nanomedicine, green chemistry, and the inherent properties of HA, namely high biocompatibility, biodegradability, and biological targeting capability. Accordingly, colloidal PECs from HA have received increasing attention in the recent years as high-performance materials for biomedical applications. Considering their potential, this review is aimed to provide a comprehensive understanding of colloidal PECs from HA in complex with polycations, from the most fundamental aspects of the preparation process to their various biomedical applications, notably as nanocarriers for delivering small molecule drugs, nucleic acids, peptides, proteins, and bioimaging agents or the construction of multifunctional platforms.


High mobility group-box 3 overexpression is associated with poor prognosis of resected gastric adenocarcinoma.
To elucidate high mobility group-box 3 (HMGB3) protein expression in gastric adenocarcinoma, its potential prognostic relevance, and possible mechanism of action. Ninety-two patients with gastric adenocarcinomas surgically removed entered the study. HMGB3 expression was determined by immunohistochemistry through a tissue microarray procedure. The clinicopathologic characteristics of all patients were recorded, and regular follow-up was made for all patients. The inter-relationship of HMGB3 expression with histological and clinical factors was analyzed using nonparametric tests. Survival analysis was carried out by Kaplan-Meier (log-rank) and multivariate Cox (Forward LR) analyses between the group with overexpression of HMGB3 and the group with low or no HMGB3 expression to determine the prognosis value of HMGB3 expression on overall survival. Further, HMGB3 expression was knocked down by small hairpin RNAs (shRNAs) in the human gastric cancer cell line BGC823 to observe its influence on cell biological characteristics. The MTT method was utilized to detect gastric cancer cell proliferation changes, and cell cycle distribution was analyzed by flow cytometry. Among 92 patients with gastric adenocarcinomas surgically removed in this study, high HMGB3 protein expression was detected in the gastric adenocarcinoma tissues vs peritumoral tissues (P < 0.001). Further correlation analysis with patients' clinical and histology variables revealed that HMGB3 overexpression was obviously associated with extensive wall penetration (P = 0.005), a positive nodal status (P = 0.004), and advanced tumor-node-metastasis (TNM) stage (P = 0.001). But there was no correlation between HMGB3 overexpression and the age and gender of the patient, tumor localization or histologic grade. Statistical Kaplan-Meier survival analysis disclosed significant differences in overall survival between the HMGB3 overexpression group and the HMGB3 no or low expression group (P = 0.006). The expected overall survival time was 31.00 ± 3.773 mo (95%CI = 23.605-38.395) for patients with HMGB3 overexpression and 49.074 ± 3.648 mo (95%CI = 41.925-57.311) for patients with HMGB3 no and low-level expression. Additionally, older age (P = 0.040), extensive wall penetration (P = 0.008), positive lymph node metastasis (P = 0.005), and advanced TNM tumor stage (P = 0.007) showed negative correlation with overall survival. Multivariate Cox regression analysis indicated that HMGB3 overexpression was an independent variable with respect to age, gender, histologic grade, extent of wall penetration, lymph nodal metastasis, and TNM stage for patients with resectable gastric adenocarcinomas with poor prognosis (hazard ratio = 2.791, 95%CI = 1.233-6.319, P = 0.019). In the gene function study, after HMGB3 was knocked down in the gastric cell line BGC823 by shRNA, the cell proliferation rate was reduced at 24 h, 48 h and 72 h. Compared to BGC823 shRNA-negative control (NC) cells, the cell proliferation rate in cells that had HMGB3 shRNA transfected was significantly decreased (P < 0.01). Finally, cell cycle analysis by FACS showed that BGC823 cells that had HMGB3 knocked down were blocked in G1/G0 phase. The percentage of cells in G1/G0 phase in BGC823 cells with shRNA-NC and with shRNA-HMGB3 was 46.84% ± 1.7%, and 73.03% ± 3.51% respectively (P = 0.001), whereas G2/M cells percentage decreased from 26.51% ± 0.83% to 17.8% ± 2.26%. HMGB3 is likely to be a useful prognostic marker involved in gastric cancer disease onset and progression by regulating the cell cycle.


Original Network of Zigzag Chains in the β Polymorph of Fe2WO6: Crystal Structure and Magnetic Ordering.
The structural and physical properties of the β polymorph of iron tungstate Fe2WO6 have been investigated by synchrotron and neutron diffraction vs temperature, combined with magnetization and dielectric properties measurements. The monoclinic P21/a crystal structure of β-Fe2WO6 has been determined and consists of an original network of zigzag chains of FeO6 and WO6 octahedra sharing trans and skew edges, connected through corners into a 3D structure. Magnetization measurements indicate an antiferromagnetic transition at TN = 264 K, which corresponds to a ↑↑↓↓ nearly collinear ordering of iron moments inside sequences of four edge-sharing FeO6 octahedra, as determined by neutron diffraction. A canting of the moments out of the ac plane is observed below 150 K, leading to a noncollinear antiferromagnetic structure, the P21/a' magnetic space group remaining unchanged. These results are discussed in comparison with the crystal and magnetic structures of γ-Fe2WO6 and with the magnetic couplings in other iron tungstates and trirutile Fe2TeO6.


Psychological resources of adults with developmental dyslexia.
The aim of our study was to describe specific psychological resources of adults with developmental dyslexia and compare them with psychological resources of adults without developmental dyslexia. Potential differences were analyzed in visual-spatial, creative, and motivational abilities. No evidence was found for either creative, or visuospatial superiority in adults with developmental dyslexia. The results suggest, however, that visual-spatial processing of nonverbal material by adults with developmental dyslexia allows them to efficiently execute tasks that are based on sequential material. Moreover, the participants with specific difficulties in reading and writing exhibited a significantly higher level of aspirations than their peers without such difficulties with a comparable level of educational achievement. These results suggest that succeeding in different fields by highly functioning adult dyslexics may depend on personality and motivational factors, rather than cognitive factors.


[Electroconvulsive therapy as a "last resort" in the treatment of depression?].
The use of electroconvulsive therapy (ECT) in treatment-resistant depressed patients is supported by numerous international guidelines. This study aims to describe what type of patients are actually referred to treatment with ECT. We included all patients referred to two main ECT-treatment centers in Switzerland during the period of August 2008 to February 2011. We collected data on the diagnosis, severity of illness, and the history of treatment. Most of the patients (n = 104) were referred after an average of 124 weeks of an index episode of unipolar depression. The patients were severely and chronically ill and had been treated on average for more than a decade. Eighty-three percent of the patients were referred for ECT treatment for the first time. The surveyed practice of referral does not concur with evidence-based guidelines for the use of ECT in the treatment of depression.


Adverse-drug-event rates for high-cost and high-use drugs in the intensive care unit.
The rates of adverse drug events (ADEs) associated with high-cost and high-use drugs in the intensive care unit (ICU) were studied. This retrospective analysis was conducted from October 1997 through June 2001 in a 647-bed academic medical center with over 120 ICU beds. Adult patients with a documented ADE occurring in the ICU were included in the analysis. ADE information, including suspected medication, causality, preventability, and severity, was extracted from the institutional ADE database. Published definitions of ADEs and published scales for causality and severity assessments were used. High-cost medications were those in the top 50% of cumulative ICU medication costs, and high-use medications accounted for the upper 50% of all medications used in the ICU. Between-group comparisons of ADE rates, preventability, and severity associated with high-cost and high-use medications were conducted. Of the 17 medications that were considered high cost, 9 (53%) were associated with ADEs. Of the 15 medications that met the criteria for high-use drugs, 12 (80%) were associated with ADEs. The rates of ADEs associated with high-cost and high-use drugs did not significantly differ (43% versus 75%, respectively; p = 0.098). ADEs associated with high-cost and high-use medications were categorized as mild (15% versus 10%, respectively), moderate (52% versus 50%, respectively), and severe (33% versus 40%, respectively) (p > 0.05). The frequency, severity, and preventability of ADEs in the ICU were not associated with a drug's cost or frequency of use. Monitoring priorities of the critical care pharmacist should not be dictated by cost alone but should include frequency of use and the potential for causing an ADE.


Changes in health services usage associated with insulin initiation in primary care.
Insulin initiation is often delayed in primary care partly because of clinician concerns about the additional clinical work. This study describes health services usage (HSU) pre- and post-insulin initiation in people with type 2 diabetes and out-of-target glycaemic levels. Secondary analysis of participant data from the Stepping Up randomised controlled trial of a model of care for insulin initiation in general practice was undertaken. For 142 people who commenced insulin, HSU in the 6 months prior was compared to that in the 12 months following insulin initiation. Overall, HSU events increased in the 6 months following insulin initiation from a median (IQR) of 18 (15, 29) to 23 (16, 36); (P=0.05), mostly because of an increase in general practitioner (GP) consultations (6 (4, 10) to 8 (5, 11); (P=0.01)). HSU and GP consultations subsequently returned to baseline at 12 months. There was no effect on hospitalisations or specialist consultations. Insulin initiation is associated with a small increase in GP consultations that reverts to baseline after 12 months without affecting other health services. This study can inform health services planning and resource allocation at practice and health policy levels to support insulin initiation in general practice.


The use of acupuncture and attitudes to regulation among doctors in the UK--a survey.
To assess the usage of acupuncture by members of British Medical Acupuncture Society (BMAS) in their daily work, in the course of a survey of attitudes to regulation of the acupuncture profession. A brief questionnaire survey of all members was conducted in December 2002. After a single mailing, 1112 members responded (a response rate of 48%). Seventy-five percent of these were general practitioners. The majority were in support of a regulatory process. Ninety percent of respondents indicated that they use acupuncture in their practice, giving an average of about eight treatments per week. Sixty-one percent of these treatments are given within the National Health Service (NHS) at no cost to the patient. It is estimated that BMAS members provide a total of about one million acupuncture treatments each year, of which well over half a million are given within the NHS.


Exploring the Effectiveness of Natural Food Flavors in Protecting Carbon Steel against CO2-Induced Corrosion.
Two food flavors, furfuryl mercaptan (2-FFT) and difurfuryl disulfide (DFDS), were investigated as green corrosion inhibitors for the N80 steel in a CO2-saturated solution containing 3.5% NaCl. Experimental methods, quantum chemical calculations, and molecular dynamics simulation were employed to evaluate the effectiveness of 2-FFT and DFDS. The results of the study indicate that both 2-FFT and DFDS act as mixed corrosion inhibitors, with a dominant inhibition effect on the cathodic reaction. 2-FFT is physiochemically adsorbed on the steel surface in a tiled form through the furan ring and the - SH groups as adsorption sites. On the other hand, DFDS is chemisorbed on the steel surface through the - S-S- groups in a parallel manner. DFDS exhibits a higher tendency for electron transfer and stronger adsorption to steel compared to 2-FFT. Overall, this study highlights the potential of natural food flavors as effective and environmentally friendly corrosion inhibitors for carbon steel in CO2-saturated environments. The findings of this research can contribute to the development of sustainable and nontoxic corrosion inhibitors for the oil and gas industry.


100 years after Griffith: From brittle bulk fracture to failure in 2D materials.
Brittle fracture and ductile failure are critical events for any structural or functional component, as it marks the end of lifetime and potential hazard to human life. As such, materials scientists continuously strive to better understand and subsequently avoid these events in modern materials. A century after the seminal initial contribution by Griffith, fracture mechanics has come a long way and is still experiencing vivid progress. Building on classical fracture testing standards, advanced in situ fracture experiments allow local quantitative probing of fracture processes on different length scales, while microscopic analysis grants access to chemical and structural information along fracture paths in previously unseen detail. This article will provide an overview of how these modern developments enhance our understanding of local fracture processes and highlight future trends toward designing strong yet ductile and damage-tolerant materials.


A system for fluorescence metaphase finding and scoring of chromosomal translocations visualized by in situ hybridization.
Full automation on the scoring of radiation-induced chromosomal aberrations in conventionally stained metaphase spreads cannot be achieved reliably due to the complex image analysis problems involved. More success may be obtained by using in situ hybridization staining of the chromosomes. We describe the development of a system to detect metaphases on the basis of a fluorescent counterstain and subsequently analyze the number of translocations with the aid of whole chromosome paints fluorescing in a different colour. The system consists of a Macintosh IIfx computer, an automated Ergolux microscope equipped for fluorescence, and a Sony CCD camera. The performance of the metaphase finder was measured on a small set of slides counterstained with DAPI, whereas the suitability of the system for scoring aberrations was tested in a small feasibility study for the detection or radiation-induced translocations involving chromosome 4. The potentialities of the system for the use of multiple colours are discussed.


Release of free fatty acids and loss of hill activity by aging spinach chloroplasts.
The free fatty acid content of spinach chloroplasts, isolated at pH 5.8 to 8.0, has been found to vary between 3.1 and 5.5% of the total chloroplast fatty acids. When chloroplasts were incubated at room temperature for 2 hours, the free fatty acids increased by 42% and the Hill activity decreased by 70%. After 2 hours of incubation at 37 degrees , the free fatty acids increased about 3-fold and the Hill activity decreased to almost 0. The addition of crystalline bovine serum albumin largely prevented the loss of Hill activity at room temperature and at 5 degrees , but had little effect during incubation at 37 degrees . Both the release of free fatty acids and the loss of Hill activity were pH dependent. The losses were the least during incubation at pH 5.8 and the greatest during incubation at pH 8.0. The major free fatty acids released at pH 5.8 were saturated, while those released at pH 7.0 or 8.0 were mainly the unsaturated acids, alpha-linolenic acid and hexadecatrienoic acid.


Techniques for studying adipocytes.
Various fixatives as well as tissue and slide handling procedures have been evaluated in attempts to demonstrate adipocytes histochemically while maintaining cell and tissue integrity. The optimal procedure for analysis of immature adipose depots consists of the following steps: 1) fresh, unfixed tissues are rapidly in isopentane quenched in a liquid nitrogen bath; 2) cryostat sections are cut, removed from the knife with a room temperature slide, and then air dried for 5-10 minutes; 3) slides can be stained directly with picro-Ponceau or toluidine blue procedures or with oil red O following fixation for 30 minutes in cold (4 C) 10% formalin-CaCl2 (1.25%). For analysis of mature rat adipose depots steps 2 and 3 are modified as follows: 2) cryostat sections are removed from the knife with a cold slide (-20 C) and dried for 30 minutes at 4 C; 3) the mounted sections are stained with oil red O following fixation for 30 minutes in cold (4 C) 10% formalin-HgCl2 (2.5%). When procedures described above for immature adipose depots are combined with esterase staining, adipocyte cytoplasm is clearly demonstrated. These procedures allow the routine use of fresh frozen, unfixed cryostat sections in studies of adipose cellularity.


Physicochemical properties of alginate/polycaprolactone-based films containing essential oils.
Oregano, savory, and cinnamon essential oils (EOs) 1% (w/v) were separately incorporated as natural antioxidant agents in alginate/polycaprolactone-based films. Films were then treated in 2 or 20% (w/v) CaCl2 solutions in order to generate insoluble films. The mechanical properties and the insoluble matter of films were determined. Intermolecular interactions between film components and alginate cross-linkage were characterized by Fourier transform infrared (FTIR) spectroscopy. Surface morphology of the polymer membrane was determined by scanning electron microscopy (SEM) analysis. Antiradical properties of films were also evaluated following a modified colorimetric method using the N,N-diethyl-p-phenylenediamine (DPPD) discoloration test. Results showed that films treatment with CaCl2 (20%) solution increased the percentage of insoluble matter in films but did not enhance their mechanical properties. FTIR analysis showed higher interactions in films treated in CaCl2 solutions despite the concentration used (2 vs 20%). The SEM observations of films showed a smoother surface with a higher density when films were treated in CaCl2 (20%) solution. The DPPD test showed that the oregano-based films had the highest antiradical properties.


Examining the synergistic effects of a cognitive control video game and a home-based, self-administered non-invasive brain stimulation on alleviating depression: the DiSCoVeR trial protocol.
Enhanced behavioral interventions are gaining increasing interest as innovative treatment strategies for major depressive disorder (MDD). In this study protocol, we propose to examine the synergistic effects of a self-administered home-treatment, encompassing transcranial direct current stimulation (tDCS) along with a video game based training of attentional control. The study is designed as a two-arm, double-blind, randomized and placebo-controlled multi-center trial (ClinicalTrials.gov: NCT04953208). At three study sites (Israel, Latvia, and Germany), 114 patients with a primary diagnosis of MDD undergo 6 weeks of intervention (30 × 30 min sessions). Patients assigned to the intervention group receive active tDCS (anode F3 and cathode F4; 2 mA intensity) and an action-like video game, while those assigned to the control group receive sham tDCS along with a control video game. An electrode-positioning algorithm is used to standardize tDCS electrode positioning. Participants perform their designated treatment at the clinical center (sessions 1-5) and continue treatment at home under remote supervision (sessions 6-30). The endpoints are feasibility (primary) and safety, treatment efficacy (secondary, i.e., change of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week six from baseline, clinical response and remission, measures of social, occupational, and psychological functioning, quality of life, and cognitive control (tertiary). Demonstrating the feasibility, safety, and efficacy of this novel combined intervention could expand the range of available treatments for MDD to neuromodulation enhanced interventions providing cost-effective, easily accessible, and low-risk treatment options.ClinicalTrials.gov: NCT04953208.


Comparison of two preparation methods for endocervical evaluation.
To assess the validity of SurePath liquid-based preparation method for examination of endocervical brush specimens as a substitute for conventionally prepared cytology methods for evaluating the endocervical canal during colposcopic examination and biopsy. Paired SurePath liquid-based test slides and conventional smears were obtained using an endocervical brush in a split sample protocol before biopsy at the time of colposcopy. The level of agreement between cytologic results obtained was assessed. Accuracy and operating characteristics were evaluated compared to histologic follow-up. Agreement between cytology results for the methods was excellent. The overall kappa was 0.924 (p = 0.0000). There was exact agreement on interpretation between the methods in 283 of 299 cases (94.6%). Cytohistologic follow-up results correlation were: SurePath liquid-based Pap test results and conventional smear results agreed with histology results in 47.8% and 49.2% of cases, respectively. Allowing for a discrepancy within 1 level of severity of cytologic grade, agreements were 76.6% and 77.2%, respectively. This study demonstrates that the SurePath method is equivalent to conventional endocervical brush cytology preparation and performs well for detection of cervical intraepithelial lesions and cancer. SurePath is acceptable for endocervical evaluation as a substitute for endocervical curettage at colposcopic biopsy.


Novel movement disorder of the lower lip: is it epilepsia partialis continua? Clues from a secondary case.
A 28-year-old woman developed an acute-onset novel movement disorder of the lower lip mimicking focal dystonia. Investigations showed it to be a presentation of epilepsia partialis continua occurring in association with agenesis of the corpus callosum. It responded favorably to anti-epileptic drug therapy. Recently, Kleopa and Kyriakides reported on 4 patients who developed sudden-onset movement disorder characterized by a tonic sustained, lateral and outward protrusion of half of the lower lip. They failed to find any causative factors, despite extensive investigation. Treatment with anticholinergics, clonazepam, and botulinum toxin injection failed to improve the movement disorder. I present an additional case of similar focal movement disorder occurring in the presence of agenesis of the corpus callosum. A scalp electroencephalogram revealed focal epileptic activity, and the movement disorder responded favorably to treatment with antiepileptic drugs.


2,5-Bis{2,2-bis-[4-(dimethyl-amino)-phen-yl]ethen-yl}-N,N'-diphenyl-N,N'-dipropyl-benzene-1,4-diamine.
The title compound, C(60)H(68)N(6), was prepared by Horner olefination of a terephthaldialdehyde and a diaryl-methyl phospho-nate. There is one half-mol-ecule, located on an inversion centre, in the asymmetric unit. The dihedral angle between the plane of the vinyl-ene unit and the central ring is 36.79 (15)°, while those between the vinyl-ene unit and the lateral phenyl rings are 53.04 (10) and 53.74 (9)°.


A suggested color scheme for reducing perception-related accidents on construction work sites.
Changes in workforce demographics have led to the need for more sophisticated approaches to addressing the safety requirements of the construction industry. Despite extensive research in other industry domains, the construction industry has been passive in exploring the impact of a color scheme; perception-related accidents have been effectively diminished by its implementation. The research demonstrated that the use of appropriate color schemes could improve the actions and psychology of workers on site, thereby increasing their perceptions of potentially dangerous situations. As a preliminary study, the objects selected by rigorous analysis on accident reports were workwear, safety net, gondola, scaffolding, and safety passage. The colors modified on site for temporary facilities were adopted from existing theoretical and empirical research that suggests the use of certain colors and their combinations to improve visibility and conspicuity while minimizing work fatigue. The color schemes were also tested and confirmed through two workshops with workers and managers currently involved in actual projects. The impacts of color schemes suggested in this paper are summarized as follows. First, the color schemes improve the conspicuity of facilities with other on site components, enabling workers to quickly discern and orient themselves in their work environment. Secondly, the color schemes have been selected to minimize the visual work fatigue and monotony that can potentially increase accidents.


Interaction of the P-glycoprotein multidrug efflux pump with cholesterol: effects on ATPase activity, drug binding and transport.
Resistance to a broad spectrum of structurally diverse chemotherapeutic drugs (multidrug resistance; MDR) is a major impediment to the treatment of cancer. One cause of MDR is the expression at the tumor cell surface of P-glycoprotein (Pgp), which functions as an ATP-powered multidrug efflux pump. Since Pgp interacts with its substrates after they partition into the lipid bilayer, changes in membrane physicochemical properties may have substantial effects on its functional activity. Various interactions between cholesterol and Pgp have been suggested, including a role for the protein in transbilayer movement of cholesterol. We have characterized several aspects of Pgp-cholesterol interactions, and found that some of the previously reported effects of cholesterol result from inhibition of Pgp ATPase activity by the cholesterol-extracting reagent, methyl-beta-cyclodextrin. The presence of cholesterol in the bilayer modulated the basal and drug-stimulated ATPase activity of reconstituted Pgp in a modest fashion. Both the ability of drugs to bind to the protein and the drug transport and phospholipid flippase functions of Pgp were also affected by cholesterol. The effects of cholesterol on drug binding affinity were unrelated to the size of the compound. Increasing cholesterol content greatly altered the partitioning of hydrophobic drug substrates into the membrane, which may account for some of the observed effects of cholesterol on Pgp-mediated drug transport. Pgp does not appear to mediate the flip-flop of a fluorescent cholesterol analogue across the bilayer. Cholesterol likely modulates Pgp function via effects on drug-membrane partitioning and changes in the local lipid environment of the protein.


Optimal Approach and Strategies to Strengthen Pharmacovigilance in Sub-Saharan Africa: A Cohort Study of Patients Treated with First-Line Artemisinin-Based Combination Therapies in the Nanoro Health and Demographic Surveillance System, Burkina Faso.
Resource-limited countries face challenges in setting up effective pharmacovigilance systems. This study aimed to monitor the occurrence of adverse events (AEs) after the use of artemisinin-based combination therapies (ACTs), identify potential drivers of reporting suspected adverse drug reactions (ADRs) and monitor AEs among women who were inadvertently exposed to ACTs in the first trimester of pregnancy. We conducted a prospective observational study from May 2010 to July 2012 in Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso. The HDSS area was divided into active and passive surveillance areas to monitor AEs among patients (regardless of age or sex) who received a first-line ACT (artemether-lumefantrine or artesunate-amodiaquine). In the active surveillance area, patients were followed up for 28 days, while in the passive surveillance area, patients were encouraged to return voluntarily to the health facility to report any occurrence of AEs until day 28 after drug intake. We assessed the crude incidence rates of AEs in both cohorts and performed Cox regression with mixed random effects to identify potential drivers of ADR occurrence. In total, 3170 participants were included in the study. Of these, 40.3% had reported at least one AE, with 39.6% and 44.4% from active and passive surveillance groups, respectively. The types of ADRs were similar in both groups. The most frequent reported ADRs were anorexia, weakness, cough, dizziness and pruritus. One case of abortion and eight cases of death were reported, but none of them was related to the ACT. The variance in random factors showed a high variability of ADR occurrence between patients in both groups, whereas variability between health facilities was low in the active surveillance group and high in passive surveillance group. Taking more than two concomitant medications was associated with high hazard in ADR occurrence, whereas the rainy season was associated with low hazard. This study showed that both passive and active surveillance approaches were useful tools. The HDSS allowed us to capture a few cases of exposure during the first trimester of pregnancy. The passive surveillance approach, which is more likely to be implemented by malaria control programs, seems to be more relevant in the Sub-Saharan African context.


Functional topology of the mossy fibre-granule cell--Purkinje cell system revealed by imaging of intrinsic fluorescence in mouse cerebellum.
We report an activity-induced green fluorescence signal observed when mouse cerebellar slices were illuminated with blue light and parallel fibre-Purkinje cell synapses were activated. The optical signal consisted of an initial increase in fluorescence that peaked within 1-2 s after the onset of stimulation, followed by a long lasting (40 s) transient decrease in fluorescence. Single or tetanic electrical stimuli applied to the molecular layer elicited 'beam-shaped' fluorescence changes along the trajectory of parallel fibres. These signals reported activation of Purkinje cells as they were depressed by antagonists of ionotropic and metabotropic glutamate receptors at Purkinje cells and correlated with Purkinje cell spiking activity. Optical responses induced by direct pharmacological activation of glutamate receptors were reduced by a calcium-free extracellular medium, consistent with the hypothesis that they reflect metabolic activity due to an increased intracellular calcium load associated with neuronal activation. We used these intrinsic fluorescence signals to address the question of whether granule cells excite Purkinje cells only locally via the ascending branches of their axons, or more widespread along the parallel fibre trajectory. White matter stimulation of the mossy fibres also elicited a beam-like fluorescence change along the trajectory of parallel fibres. Simultaneous imaging and extracellular recording demonstrated the association between the beam-like fluorescence signal and Purkinje cell spiking. This non-invasive imaging technique supports the notion that parallel fibre activity, evoked either locally or through the mossy fibre-granule cell pathway, can activate postsynaptic Purkinje cells along more than 3 mm of the parallel fibre trajectory.


Mouse protection assay for group B streptococcus type III.
The mucin model for group B Streptococcus (GBS) type III was used to assay the protective effect of sera against a type III challenge in mice. Hyperimmune rabbit sera, prepared by the Lancefield method against the laboratory reference strain (SS620) and a clinical isolate (M732), protected against a lethal challenge with either strain of GBS type III. Absorption of the sera with either of these type III strains removed the protective effect. Neither normal rabbit sera nor heterologous antisera (anti-Ia, SS615) provided protection; however, protection was obtained with pooled human gamma globulin. Sera from adult volunteers were tested to assay protective levels in the mouse model. Human sera enhanced the mouse lethality of the clinical isolate, M732, but not the laboratory reference strain, SS620. Sera from adults vaccinated with type III polysaccharide of GBS were also tested. The murine-mucin-GBS model may be developed as a screening test to measure protective antibody levels in the pre- and postvaccine treatment period. The model may also be used to measure protective antibody in pooled human gamma globulin for use in the passive immunization of high-risk individuals.


Acquired Parkinson's Disease in Alcoholic Cirrhosis: The Rarest Association.
Hepatic encephalopathy is the most common neurologic complication of liver cirrhosis, whereas acquired hepatocerebral degeneration (AHD) is an underappreciated neurologic manifestation. Parkinsonism, ataxia, and neuropsychiatric symptoms are its defining characteristics. In individuals with chronic parenchymal liver disease with portosystemic shunting, it is an underrecognized etiology of psychomotor retardation. It has been hypothesized that the etiology of AHD is due to manganese buildup in the basal ganglia. This case report details a hepatocerebral degeneration (AHD) case in a patient with chronic parenchymal liver disease who improved after taking a dopamine agonist.


Lipoprotein (a): its role in childhood thromboembolism.
Elevated lipoprotein (a) [LP (a)] concentrations are independent risk factors of coronary heart disease or stroke in young adults. To clarify its role in childhood thromboembolism, Lp (a) was measured in 72 children with thromboembolism. In addition to Lp (a), defects of the protein C anticoagulant system, antithrombin, and antiphospholipid antibodies were investigated in children with arterial (n = 36) or venous (n = 36) thrombosis. Enhanced Lp (a) >50 mg/dL was diagnosed in 8 out of 36 children with arterial and 5 out of 36 patients with venous thrombosis. Of the 72 children, 25 showed the factor V Leiden mutation, 10 showed protein C deficiency, 2 showed antithrombin deficiency, and 4 showed primary antiphospholipid syndrome. Three children with increased Lp (a) were heterozygous for the factor V Leiden mutation, and 1 girl showed additional protein C deficiency. Data of this study indicate that increased concentrations of Lp (a) play an important role in childhood thrombosis.