Enhanced Integrin Activation of PLD2-Deficient Platelets Accelerates Inflammation after Myocardial Infarction.
Phospholipase (PL)D1 is crucial for integrin αIIbβ3 activation of platelets in arterial thrombosis and TNF-α-mediated inflammation and TGF-β-mediated collagen scar formation after myocardial infarction (MI) in mice. Enzymatic activity of PLD is not responsible for PLD-mediated TNF-α signaling and myocardial healing. The impact of PLD2 in ischemia reperfusion injury is unknown. PLD2-deficient mice underwent myocardial ischemia and reperfusion (I/R). Enhanced integrin αIIbβ3 activation of platelets resulted in elevated interleukin (IL)-6 release from endothelial cells in vitro and enhanced IL-6 plasma levels after MI in PLD2-deficient mice. This was accompanied by enhanced migration of inflammatory cells into the infarct border zone and reduced TGF-β plasma levels after 72 h that might account for enhanced inflammation in PLD2-deficient mice. In contrast to PLD1, TNF-α signaling, infarct size and cardiac function 24 h after I/R were not altered when PLD2 was deleted. Furthermore, TGF-β plasma levels, scar formation and heart function were comparable between PLD2-deficient and control mice 21 days post MI. The present study contributes to our understanding about the role of PLD isoforms and altered platelet signaling in the process of myocardial I/R injury.


Effects of T-2 mycotoxin ingestion on phagocytosis of Aspergillus fumigatus conidia by rabbit alveolar macrophages and on hematologic, serum biochemical, and pathologic changes in rabbits.
Rabbits were given T-2 mycotoxin orally at 0, 0.25, 0.5, and 0.75 mg/kg of body weight/day for 21 days. Only rabbits in the 0.75 mg/kg/day group (4 of 5 rabbits) died. Alveolar macrophages were harvested on day 22 and used for in vitro phagocytosis of killed Aspergillus fumigatus conidia. Cultures included sera from untreated rabbits or rabbits treated with T-2. Phagocytosis was significantly (P less than 0.01) reduced in cultures that used serum from rabbits treated with 0.5 mg of T-2/kg/day and alveolar macrophages from untreated rabbits or rabbits treated with T-2. There was little reduction in phagocytosis when alveolar macrophages from rabbits treated with T-2 and normal serum were used. Ingestion of 0.5 mg of T-2 toxin/kg/day significantly (P less than 0.05) reduced weight gain, serum alkaline phosphatase activity, serum sorbitol dehydrogenase activity, and serum bacteriostasis. Similar changes were found in the 0.75 mg/kg/day group, as well as a significant (P less than 0.05) reduction in PCV, total WBC, and differential leukocyte counts. Neutrophil counts decreased, but not significantly (0.05 less than P less than 0.10). Significant changes were not detected in alanine transaminase activity, aspartate transaminase activity, blood urea nitrogen concentration, or complement hemolytic activity. Histopathologic changes consisting of centrilobular hepatocellular swelling, mild portal and periportal fibrosis and lymphocyte necrosis within secondary lymphoid tissues developed in most rabbits treated with T-2. Thymic atrophy, bile duct reduplication, and lymphocyte depletion of secondary lymphoid tissues developed in the group given 0.75 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)


Gentamicin serum concentrations: pharmacokinetic predictions.
Recent studies that emphasize the unpredictability of gentamicin serum concentrations have cast doubt on the accuracy of commonly used dosing nomograms. We therefore developed a digital computer program to evaluate gentamicin pharmacokinetics and have tested its ability to predict correctly gentamicin serum levels under clinical conditions. A significant relation (P less than .001) was found between 130 measured (bioassayed) and computer predicted levels from 40 patients. Serum levels were reliably estimated in patients with unstable renal function and were statistically, but not clinically, affected by changes in hematocrit. The calculation of volume of distribution on the basis of the patient's lean body weight rather than total body weight was an important factor that contributed to the accuracy of the predicted level. A new dosing chart is presented that incorporates the important variables affecting gentamicin pharmacokinetics into an easily used, convenient form.


Trichoadenoma of Nikolowski.
Trichoadenoma of Nikolowski is a rare benign cutaneous tumor, which is usually solitary, nodular and occurs on the face or buttocks any time during adult life. The morphological differentiation of trichoadenoma is situated between a trichofolliculoma and a trichoepithelioma with hair follicle-like direction of differentiation. We report this case of trichoadenoma in a 28-year-old man who presented with a solitary nodular and ulcerated swelling in the gluteal region, gradually increasing in size. Excision biopsy revealed characteristic features consistent with trichoadenoma. We report this case in view of its rarity.


Stresses and challenges for new graduates in hospitals.
As new graduates enter the workplace, they are faced with many stresses associated with beginning practice. The nurse manager, preceptor, and nursing staff need to be aware of the specific stresses and challenges experienced by new graduates during their orientation period and need to plan interventions for coping with them. What stresses and challenges do new graduates face in clinical practice? To answer this question, 46 new graduates completed the Clinical Stress Questionnaire on which they rated their degree of stress and challenge in clinical practice and the extent they experienced 20 different emotions while learning to care for patients on the unit. They also described what was stressful and challenging for them. This article presents the results of this survey and guidelines for mentoring new graduates during the orientation period.


Aptapaper─An Aptamer-Functionalized Glass Fiber Paper Platform for Rapid Upconcentration and Detection of Small Molecules.
We tested a paper-based platform ("Aptapaper") for the upconcentration and analysis of small molecules from complex matrices for two well-characterized aptamers, quinine and serotonin binding aptamers (QBA and SBA, respectively). After incubating the aptapaper under conditions that ensure correct aptamer folding, the aptapaper was used to upconcentrate target analytes from complex matrices. Aptapaper was rinsed, dried, and the target analyte was detected immediately or up to 4 days later by paper spray ionization coupled to high-resolution mass spectrometry (PS-MS). The minimum concentrations detectable were 81 pg/mL and 1.8 ng/mL for quinine and serotonin, respectively, from 100 mM AmAc or water. Complementary characterization of the QBA aptapaper system was performed using an orthogonal fluorescence microscopy method. Random adsorption was analyte-specific and observed for quinine, but not serotonin. This aptapaper approach is a semiquantitative (10-20% RSD) platform for upconcentration of small metabolites by mass spectrometry.


Mechanical Insufflation Exsufflation, Syringomyelia, and Headache.
Mechanical insufflation exsufflation creates cough flows to clear central airways secretions for patients with ineffective cough flows. At times, patients with even potentially effective spontaneous cough flows can have pain that prevents effective coughing. We describe a patient with Arnold-Chiari syndrome, syringomyelia, and hydrocephalus who had nine episodes of pneumonia through the age of 9 yrs, and cough associated headaches, who upon using mechanical insufflation exsufflation had no subsequent pneumonias for at least the next 17 yrs and no headaches when using it for coughing.


How NHS trusts are tackling healthcare-associated infections.
The National Audit Office's third report on the Sreduction of healthcare-associated infection (HAl) rates, published last summer, examines: the extent and impact of HAls; the effectiveness, sustainability and cost of the Department of Health's approach to reducing HAl rates; the effectiveness of action taken in hospitals to prevent and control HAls, and how the barriers to improvement in reducing HAI rates can be overcome. This article reviews its findings and their implications for practice.


Mode of de-esterification of alkaline and acidic pectin methyl esterases at different pH conditions.
Highly esterified citrus pectin was de-esterified at pH 4.5 and 8.0 by a fungal pectin methyl esterase (PME) that was shown to have an acidic isoelectric pH (pI) and an acidic pH optimum and by a plant PME that was characterized by an alkaline pI and an alkaline pH optimum. Interchain and intrachain de-esterification patterns were studied by digestion of the pectin products with endo-polygalacturonase and subsequent analysis using size exclusion and anion-exchange chromatography. No effect of pH was observed on the de-esterification mode of either of the two enzymes. Acidic, fungal PME converted pectin according to a multiple-chain mechanism, with a limited degree of multiple attack at the intrachain level, both at pH 4.5 and at pH 8.0. A multiple-attack mechanism, with a high degree of multiple attack, was more appropriate to describe the action mode of alkaline, plant PME, both at pH 4.5 and at pH 8.0.


[Altered cerebral excitability and spreading depression. Causes for the comorbidity of epilepsy and migraine?].
Increased co-occurrence and common clinical aspects of epilepsy and migraine lead to the question of a common pathophysiological model of the diseases. Shared genetic risk factors as an explanation for comorbidity could not be proven. Clinical studies underline the unspecific association of migraine and epilepsy. Comorbidity is based on spreading depression as an expression of altered brain state with neuronal hyperexcitability. In comorbid conditions, therapy with valproate, gabapentin, or topiramate may be effective.


Adult pancreatoblastoma: A rare malignant tumor of the pancreas.
Pancreatoblastoma (PB) is a rare malignant tumor in adults. It has an overall incidence of 0.004 per 100,000 inhabitants. Its diagnosis with fine-needle aspiration (FNA) is difficult due to multiple differentiation lines present on PB that overlap with other tumors. A 76-year-old male patient presented with jaundice, weight loss of 10 kg in 6 months, and appetite loss. Abdominal computed tomography scan showed a tumor in the pancreas head. Transendoscopic ultrasound with FNA biopsy revealed a malignant epithelial neoplasia compatible with PB with immunohistochemistry CK19 (+), P63(+), synaptophysin (-), and Ki67 50%. The patient underwent surgical resection and adjuvant chemotherapy. Currently, the patient is in follow-up with the latest imaging showing no evidence of disease at 32 months after his initial diagnosis. PB is an uncommon malignant neoplasia with an aggressive behavior. Its diagnostic and therapeutic protocols are unclear. Its preoperative diagnosis may be difficult since its imaging features and serological markers are non-specific. However, FNA may be useful in some situations. Surgical resection is currently the recommended treatment that is associated with the best long-term survival.


Rural women and violence situation: access and accessibility limits to the healthcare network.
To analyze the access and accessibility to the healthcare network of women dwelling in rural contexts undergoing violence situation, as seen from the professionals' speeches. A qualitative, exploratory, descriptive study with professionals from the healthcare network services about coping with violence in four municipalities in the northern region of Rio Grande do Sul. The information derived from interviews, which have been analyzed by thematic modality. (Lack of) information of women, distance, restricted access to transportation, dependence on the partner and (lack of) attention by professionals to welcome women undergoing violence situation and (non)-articulation of the network are factors that limit the access and, as a consequence, they result in the lack of confrontation of this problem. To bring closer the services which integrate the confrontation network of violence against women and to qualify professionals to welcome these situations are factors that can facilitate the access and adhesion of rural women to the services.


Amylose-iodine complex. I. Sedimentation behavior.
Sedimentation measurements are reported on solutions of blue amylose-iodine complexes in the range of 0.001 to 0.007% amylose. Amylose fractions B and F2, of weight average molecular weight average molecular weight 4.0 X 10(5) and 3.4 X 10(4), respectively, were used in this study. Iodine complexes of these fractions formed polydisperse solutions of limited solubility and stability. Sedimentation coefficients increased as a function of potassium iodide concentration. Values for fraction B complexes varied from (16.3 +/- 1.0) X 10(-13) at 1.2 X 10(-3) M KI to (57.2 +/- 7.5) X 10(-13) at 8.3 X 10(-3) M KI; values for fraction F2 complexes varied from (10.0 +/- 1.2) X 10(-13) at 1.2 X 10(-13) M KI to (24.8 +/- 3.9) X 10(-13) at 9.5 X 10(-3) M KI. At constant potassium iodide concentration, sedimentation coefficients, within our experimental error of 10 to 15% standard deviation, are independent of amylose concentration. Time dependence of sedimentation coefficient values was observed for solutions either saturated or unsaturated with respect to the iodine-binding capacity of amylose. For iodine-saturated complex solutions, sedimentation coefficients extrapolated to zero potassium iodide concentration were two to three times greater than for the parent amylose. Measurements are evaluated in terms of possible polyelectrolytic charge effects and aggregation. Under conditions used in these experiments, aggregation of amylose-iodide complexes appears to be the mechanism responsible for the large increase in sedimentation coefficients.


Changes in the function and ultrastructure of vessels in the rat model of multiple low dose streptozotocin-induced diabetes.
In this study we investigated functional changes in the femoral artery and ultrastructural alterations in mesenteric vessels and capillaries in the rat model of multiple low dose streptozotocin (STZ)-induced diabetes. Participation of oxidative stress in this model of diabetes was established by studying the effect of the pyridoindole antioxidant stobadine (STB) on diabetes-induced impairment. Experimental diabetes was induced by i.v. bolus of STZ (20 mg/kg) given for three consecutive days to male rats. At the 12(th) week following STZ administration, the animals revealed typical signs of diabetes, such as polyphagia, polydypsia and polyuria. There was no weight gain in the diabetic groups throughout the experiment. No exitus occurred in any group. Diabetes was characterised with high levels of plasma glucose, no significant changes in lipid metabolism, decreased serum levels of glutathione, increased serum levels of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAGA), injured endothelial relaxant capacity of the femoral artery and alterations in ultrastructure of mesenteric arteries and capillaries. Antioxidant STB in the dose of 25 mg/kg body weight i.p. (5 times per week) did not influence glucose levels, however, it mitigated biochemical, functional and ultrastructural changes induced by diabetes, suggesting a role of reactive oxygen species in diabetes-induced tissue damage.


An Inorganic Click Reaction for the Synthesis of Interlocked Molecules.
We describe the use of the cyaphide-azide 1,3-dipolar cycloaddition reaction for the synthesis of a new class of inorganic rotaxanes containing gold(I) triazaphosphole stoppers. Electron-deficient bis-azides, which thread perethylated pillar[5]arene in aromatic solvents, readily react with two equivalents of Au(IDipp)(CP) (IDipp=1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene) to afford interlocked molecules via an inorganic click reaction. These transformations proceed in good yields (ca. 65 %) and in the absence of a catalyst. The resulting organometallic rotaxanes are air- and moisture-stable and can be purified by column chromatography under aerobic conditions. The targeted rotaxanes were characterized by multi-element nuclear magnetic resonance (NMR) spectroscopy, mass-spectrometry, and single-crystal X-ray diffraction.


Piercing associated perichondritis of the pinna: are we treating it correctly?
This paper reports a series of patients with sporadic pinna perichondritis who presented to a district general hospital over a period of 10 years. The data examined included the causative organism, risk factors and pattern of antibiotic use. A retrospective analysis of diagnosed cases of pinna perichondritis from 2001 to 2012 was performed. A literature review of pinna perichondritis was carried out using Pubmed with the key words 'pinna perichondritis', 'pinna abscess', 'pinna infection' and 'piercing'. Pinna perichondritis was more likely to result from chondral than lobe piercings. The majority of cases were caused by Pseudomonas aeruginosa. Most patients were not prescribed anti-pseudomonal antibiotics on presentation. This may result in persistent infection and long-term cosmetic defects.


Boron-containing MFI-type zeolites with a hierarchical nanosheet assembly for lipase immobilization.
Hierarchical nanosheet assemblies of boron-containing MFI-type zeolites were successfully synthesized using bifunctional surfactant molecules under static conditions. With the optimized Si/B = 50 in the synthesis gel, a material with high specific surface area (483 m2 g-1) and a maximum pore size of 6.5 nm suitable for lipase encapsulation was obtained.


Surgical treatment of cervical lymph nodes in carcinoma of the tongue.
A series of 56 cases of carcinoma of the anterior two-thirds of the tongue treated surgically was reviewed. Lymph node metastasis occurred in 50% of cases. There was 22% false-negative clinical assessments of lymph node status for the ipsilateral side of the neck. Because of these and the difficulty in ensuring early treatment of subsequent node metastasis, concurrent ipsilateral radical neck dissection is recommended. When the ipsilateral side of the neck was involved the contralateral side has 22% false-negative assessments. Elective radical neck dissection for the contralateral side is recommended in this situation. The overall five-year survival was 50.6%, and was greatly affected by the status of the neck lymph nodes.


Integration of information literacy into a revised medical school curriculum.
The Keck School of Medicine of the University of Southern California's newly revised Year I-II curriculum integrates information literacy components based on the AAMC's medical informatics objectives throughout the two-year continuum. Students are required to participate in various components taught by librarians from the Norris Medical Library including (1) an information skills workshop, (2) a yearlong literature search project, and (3) an evidence-based medicine resources workshop. Critical appraisal of literature also is included in the curriculum to ensure that the students are familiar with the various research study designs. Librarians also provide resources to assist students in researching learning issues related to cases presented in the curriculum. To encourage the faculty mentors to serve as good models of information users, librarians offer brief training sessions on information resources to faculty.


Ingested Foreign Body Causing Duodenal and Colonic Perforations in a Child.
Most ingested foreign bodies usually pass uneventfully through the gastrointestinal tract. Few may cause complications and require surgical interventions. We report a 1.5-year-old child who ingested hair clip and presented with vomiting and obstruction. At operation, we found duodenal and colonic perforations. Hair clip was removed with repair of perforations.


A placebo controlled randomized trial of the effects of phenylpropanolamine and nicotine gum on cessation rates and postcessation weight gain in women.
With smoking prevalence rates beginning to decline, studies designed to promote cessation in more challenging populations, like weight-concerned smokers, warrant attention. This study assessed the efficacy of two forms of pharmacotherapy [nicotine and phenylpropanolamine (PPA) gums] in addition to a 13-week cognitive behavioral smoking cessation program targeted for women. Participants were 439 females who met rigorous screening criteria and were randomized to one of the three treatment intervention groups (PPA gum, nicotine gum, or placebo gum). All participants attended a 13-week cognitive behavioral smoking cessation program and were given specific instructions on gum chewing. At posttest (13 weeks), and 6- and 12-month follow-ups, body weight and point prevalence abstinence were assessed. Analyses to determine potential differences between treatment groups on weight change and cessation rates were performed. Results indicated that neither change in body weight nor cessation rates significantly differed between groups. Attendance to sessions did appear to consistently increase the likelihood of quitting smoking at posttest and at each of the follow-ups. These results suggest that although the pharmacological interventions had no effect on cessation rates and postcessation weight gain, the behavioral component of the intervention was effective in increasing the odds of quitting smoking in weight-concerned women. Future efforts should focus on increasing adherence to behavioral program components, particularly session attendance.


Syndromes of epilepsy in childhood and adolescence.
This report concerns the more commonly recognized epileptic syndromes that have their onset or entire clinical course in childhood and/or adolescence. It hopes to demonstrate the close relationship between the classifications of epileptic syndromes. It will also discuss how knowledge of the epileptic syndromes will enhance the management plan for the patient with epilepsy.


Novel proteasome inhibitor delanzomib sensitizes cervical cancer cells to doxorubicin-induced apoptosis via stabilizing tumor suppressor proteins in the p53 pathway.
Cervical cancer, the third most commonly occurring cancer, is the second leading cause of cancer related mortality among women. Aberrant ubiquitination and proteasome activity, both human papillomavirus and tumor derived, have been shown to contribute to tumor angiogenesis, proliferation, and invasion in many cancers, including cervical cancer. Thus, small molecule proteasome inhibitors are a potential and strategic treatment option for cervical cancer. In this study, novel proteasome inhibitor delanzomib (CEP-18770) exhibited potent pro-apoptotic and cytotoxic effects on a panel of cervical cancer cell lines by blocking proteasomal activity. Delanzomib also significantly sensitized cervical cancer cells to treatment of doxorubicin (Dox), a traditional chemotherapeutic agent. Furthermore, proteasome inhibition revealed stabilization of p53 and p53 transcriptional targets and induction of p38/JNK phosphorylation. Additionally, delanzomib worked synergistically with Dox to further upregulate p53 and its downstream targets and enhanced Dox-induced p38 phosphorylation. Our study strongly supports the 26S proteasome as a potential therapeutic target in cervical cancer and proteasome inhibition by delanzomib may be a potential treatment strategy for cervical cancer patients.


Chronic annular pustular psoriasis resembling subcorneal pustular dermatosis: A case report.
Generalized pustular psoriasis and subcorneal pustular dermatosis are generalized pustular dermatoses that are characterized by the subcorneal accumulation of neutrophils. Careful examination is important in distinguishing these diseases for appropriate management. Patients with acute generalized pustular psoriasis are systemically unwell with discrete pustules as opposed to the chronicity and associated hypopyon lesions in subcorneal pustular dermatosis. Generalized pustular psoriasis lesions demonstrate psoriasiform changes on histology and the increased expression of Th17 cytokines. We describe a middle-aged woman presenting with chronic annular generalized pustular psoriasis, initially mistaken for subcorneal pustular dermatosis due to their clinical and histological semblance. The patient had recurrent skin disease for 6 years despite conventional therapy of oral retinoid, immunosuppressant and biologic therapy. Complete and persistent clearance of her skin lesions was achieved with secukinumab, an interleukin 17A inhibitor.


Survey of the use of colonoscopy in inflammatory bowel disease.
In a survey of patients with inflammatory bowel disease (IBD), colonoscopy with multiple biopsies has been shown to be superior to either colonoscopy alone or barium studies in assessing disease extent. Thus, of a total of 149 patients, 23 (15%) were considered to have total colitis on barium enema, 51 (34%) on macroscopic colonoscopy appearance compared to 92 (62%) on biopsy. Furthermore, radiological assessment of "skip lesions" was shown to be unreliable. Although it remains to be seen whether the more accurate delineation of disease extent achieved by endoscopy is advantageous in terms of clinical management, it may have implications for our understanding of the disease.


Electric-field-enhanced neutralization of deep centers in GaAs.
The charge dynamics of hydrogenlike centers in semi-insulating GaAs have been studied by muon spin resonance in the presence of electric field and RF excitation. Electric-field-enhanced neutralization of deep electron and hole traps by track-induced hot carriers results in an increase of the excess electron's or hole's lifetimes. Similar processes may take place in semiconductor devices working at high voltages and/or under irradiation. As a consequence of the deep traps neutralization, the muonium (mu{+} + e{-}) center can capture a hole.


Revisiting "scale-free" networks.
Recent observations of power-law distributions in the connectivity of complex networks came as a big surprise to researchers steeped in the tradition of random networks. Even more surprising was the discovery that power-law distributions also characterize many biological and social networks. Many attributed a deep significance to this fact, inferring a "universal architecture" of complex systems. Closer examination, however, challenges the assumptions that (1) such distributions are special and (2) they signify a common architecture, independent of the system's specifics. The real surprise, if any, is that power-law distributions are easy to generate, and by a variety of mechanisms. The architecture that results is not universal, but particular; it is determined by the actual constraints on the system in question.


Microbial invasion: a covert activity?
In contrast to nonpathogenic microorganisms that exist happily in biofilms on various organic and inorganic surfaces, many pathogenic microbes have the additional ability to invade host tissues by inducing their own endocytosis and transport across normally protective barriers. This phenomenon, designated "parasite-directed endocytosis," has been observed with a variety of surfaces (intestinal, genital, nasopharyngeal, and tracheal epithelium) as well as in endothelial cells. The mechanisms involved in invasion may involve a single factor as described for some species of Yersinia, or may require multiple factors as observed in Shigellae. For the majority of pathogens, the molecular mechanisms of invasion are not well understood (e.g., Neisseria gonorrhoeae). Because parasite-directed endocytosis is reminiscent of receptor-mediated endocytosis, it is quite possible that some pathogens engage in biologic mimicry by producing a molecule that resembles a natural host ligand, for which there is a host cell receptor. Such a masquerade may allow some microbes to enter the host's inner sanctum covertly in a manner analogous to the Trojan horse, rather than overtly by destroying the mucosa and entering host tissues directly. Whereas this hypothesis is speculative at present, bacteria that produce molecules resembling insulin, calmodulin, and chorionic gonadotropin have been described.


Why women see differently from the way men see? A review of sex differences in cognition and sports.
The differences of learning and memory between males and females have been well documented and confirmed by both human and animal studies. The sex differences in cognition started from early stage of neuronal development and last through entire life span. The major biological basis of the gender-dependent cognitive activity includes two major components: sex hormone and sex-related characteristics, such as sex-determining region of the Y chromosome (SRY) protein. However, the knowledge of how much biology of sex contributes to normal cognitive function and elite athletes in various sports are still pretty limited. In this review, we will be focusing on sex differences in spatial learning and memory - especially the role of male- and female-type cognitive behaviors in sports.


Bone marrow mesenchymal stem cell exosomal miR-345-3p ameliorates cerebral ischemia-reperfusion injury by targeting TRAF6.
The purpose of this study was to investigate the effects of bone marrow mesenchymal stem cells (BMSCs) exosomal miR-345-3p and tumor necrosis factor receptor-associated factor 6 (TRAF6) on cerebral ischemia reperfusion (CIR) injury. Exosomes (Exos) derived from BMSCs were isolated and identified. PC12 (rat pheochromocytoma) cells were used to establish an oxygen and glucose deprivation/reoxygenation (OGD/R) model. Cell counting kit-8, TUNEL staining, lactate dehydrogenase staining, RT-qPCR, and western blotting were utilized for analyzing the functions of miR-345-3p about PC12 cells. Dual-luciferase reporter experiment was then to confirm the link between miR-345-3p and TRAF6. Finally, using male SD rats, the middle cerebral artery occlusion (MCAO) model was constructed. Regulation of I/R damage in MCAO rats of miR-345-3p and TRAF6 were further explored in the changes of modified neurological severity score, cerebral infarction pictures, relative infarct volume, and histopathological changes. After OGD/R treatment, neuronal apoptosis was dramatically increased. After treatment with exosomal miR-345-3p, OGD/R-induced neuroapoptosis was dramatically inhibited. Exosomal miR-345-3p inhibited OGD/R-induced neuroapoptosis by down-regulating the expression of TRAF6. However, the miR-345-3p inhibitor aggravated the changes caused by OGD/R. The corresponding regulations of miR-345-3p were reversed with TRAF6 overexpression. The animal experiments in vivo further verified that miR-345-3p ameliorated brain I/R injury in MCAO rats by targeting TRAF6. This study found that BMSCs-exosomal miR-345-3p protected against CIR injury by decreasing TRAF6.


Aging and glucose homeostasis in C57BL/6J male mice.
Age-dependent changes in glucose homeostasis were assessed in specific pathogen-free C57BL/6J male mice. Increased islet size and pancreatic insulin content in old (21-25-month-old) mice were associated with lower nonfasting plasma glucose levels and improved clearance of either an oral or an i.p. administered glucose load in comparison with young, mature (4-5-month-old) males. The almost twofold increase in islet size correlated with a twofold increase of glucose-stimulated insulin secretion from perifused islets from 25-month-old males compared with 5-month-old males. These aging male mice did not become obese, and there were no fibrotic changes associated with the hyperplastic islets observed in the old males. Thus, the findings that glucose tolerance did not deteriorate with age, coupled with the lack of evidence for impaired beta cell responsiveness to glucose in old males, suggest that deterioration in glucose homeostasis is not an inevitable consequence of aging in the mouse.


Clinical and Genetic Analysis of Fibrodysplasia Ossificans Progressiva: A Case Report and Literature Review.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and disabling heterotopic ossification in specific anatomic locations with a world wide prevalence of 1 in 2 million population. Nearly 90% of patients with FOP are misdiagnosed and mismanaged. We present a case of a four-year-old boy brought by his parents with the complaints of stiffness of right shoulder, neck and multiple swellings over the upper back noted over the past 4 months. On examination bilateral symmetrical hallux valgus with microdactyly of great toes and multiple bony hard swellings on both the scapulae were noted. Skeletal survey revealed all the classical features of FOP. Mutation of the ACVR1gene on genetic analysis confirmed the diagnosis of FOP. Invasive surgical procedures including biopsy and manipulations for stiff joints were avoided as they strikingly end up in rapid progression of FOP. Congenital hallux valgus with short great toe in a child should be considered as an early diagnostic tool for FOP even before the onset of mass lesions. Genetic analysis for mutation of ACVR1gene is confirmatory. Prevention of injury, medical management of acute painful flare-ups and rehabilitation are the mainstay of treatment.


Individualizing treatment decisions. The likelihood of being helped or harmed.
Clinical decision making cannot rely on evidence alone. Although significant advances have occurred in the development of high-quality evidence, similar efforts must be made to develop and evaluate tools that can be used at the bedside to individualize treatment decisions and to facilitate the incorporation of our patients' unique values and circumstances into the decision-making process. These tools should express the helpful and harmful effects of treatment, and it must be possible to modify these statements using patients' values. Finally, this process should be accomplished in real time in a busy clinical practice. In this article, the author outlines some of these decision support tools, describes an attempt to meet some of the challenges inherent in the goal of achieving effective shared decision making, and proposes a patient-centered measure of the likelihood of being helped and harmed by an intervention and discusses its derivation and an evaluation of its usefulness.


[Development of a genetic transformation system for Candida tropicalis based on a reusable selection marker of URA3 gene].
Candida tropicalis, a diploid asporogenic yeast, is frequently utilized in industrial applications and research studies. However, the low efficiency of genetic transformation limits the strain improvement by metabolic engineering. A reliable transformation and efficient deletion of target gene are prerequisite for molecular improvement of C. tropicalis. In this study, an efficient approach for genetic transformation of C. tropicalis was developed based on the URA3 gene as a reusable selection marker and both of PDC allele genes encoding pyruvate decarboxylase were successfully deleted by this approach. Firstly, an auxotrophic mutant strain of C. tropicalis XZX which is defective in orotidine-5'-phosphate decarboxylase (URA3) was isolated by chemical mutagenesis combined with nystatin enrichment selection and 5-fluoro-orotic acid (5-FOA) resistance selection using C. tropicalis ATCC 20336 as the parent strain. Then, the first PDC deletion cassette PDC1-hisG-URA3-hisG- PDC1 (PHUHP) which contains a 1.6 kb URA3 marker gene, two copies of 1.1 kb Salmonella hisG fragments and homologous arms of target gene was constructed and transformed into C. tropicalis XZX cells. Transformants with a single copy of PDC deleted were isolated and identified by PCR and DNA sequencing, which was designated as C.tropicalis XZX02. The C.tropicalis XZX02 cells were spread on the minimal medium containing 5-FOA to generate mutant C. tropicalis XZX03 in which URA3 marker gene was excised from PHUHP fragment integrated into the PDC gene site. The second PDC gene deletion cassette PDCm-URA3-PDCm (MUM) was constructed and transformed into C. tropicalis XZX03 to generate C.tropicalis XZX04 in which both of PDC allele genes were deleted. All strains were confirmed by PCR and DNA sequencing. This efficient genetic transformation approach laid a foundation for further metabolic engineering of C. tropicalis.


Hyperbranched rolling circle amplification as a rapid and sensitive method for species identification within the Cryptococcus species complex.
The Cryptococcus species complex contains two closely related basidiomycetous yeasts: Cryptococcus neoformans and C. gattii, which cause cryptococcosis in humans and other animals. The species and varieties are characterized, by different clinical, epidemiological, biochemical and molecular features. The currently used identification methods are either time-consuming or not anymore commercially available. However, a rapid, sensitive and robust assay for the detection of these pathogens is vital for early diagnosis and appropriate treatment decisions. To overcome those limitations, four padlock probes targeting species-specific single nucleotide polymorphisms at the internal transcribed spacers (ITSs) of the RNA gene locus were developed and applied during isothermal hyperbranched rolling circle amplification (HRCA). The probes were tested against 99 samples, including 94 clinical cryptococcal cultures, three closely related Cryptococcus species, and two clinical specimens. The use of the padlock probes and the combination of probe signal amplification by HRCA provided a quick and sensitive assay for the accurate identification of C. neoformans var. grubii, C. neoformans var. neoformans and C. gattii. HRCA was also useful to detect hybrids, when they were heterozygous at the ITS locus. The HRCA results were in agreement with previous genotyping data based on PCR fingerprinting, amplified fragment length polymorphism and ITS sequencing.


In vitro evaluation of proniosomes as a drug carrier for flurbiprofen.
The purpose of the present investigation is to formulate and evaluate proniosomal transdermal carrier systems for flurbiprofen. Proniosomes were prepared using various non-ionic surfactants, namely span 20 (Sp 20), span 40 (Sp 40), span 60 (Sp 60) and span 80 (Sp 80) without and with cholesterol at percentages ranging from 0% to 50%. The effect of surfactant type and cholesterol content on drug release was investigated. Drug release was tested by diffusion through cellophane membrane and rabbit skin. Drug release from the prepared systems was compared to that from flurbiprofen suspensions in distilled water and HPMC (hydroxypropylmethylcellulose) gels. In case of Sp 20 and Sp 80, the added amount of cholesterol affected the preparation type to be either proniosomal alcoholic solutions or liquid crystalline gel systems. On the other hand, both Sp 40 and Sp 60 produced gel systems in presence or absence of cholesterol. Microscopic observations showed that either proniosomal solutions or gel formulations immediately converted to niosomal dispersions upon hydration. Due to the skin permeation barrier, rabbit skin showed lower drug diffusion rates compared to cellophane membrane. The proniosomal composition controlled drug diffusion rates to be either faster or slower than the prepared flurbiprofen suspensions in HPMC gels or distilled water, respectively. In conclusion, this study demonstrated the possibility of using proniosomal formulations for transdermal drug delivery.


[Double contrast studies of the small intestine. How, when, why].
The double contrast radiological technique involving duodenal intubation for the examination of the small intestine is described. The technical difficulties involved are discussed with ample illustration. This forms the basis for suggestions on the main indications for the technique in a correct diagnostic protocol.


[Effects of tizanidine for refractory sleep disturbance in disabled children with spastic quadriplegia].
Tizanidine is a centrally acting alpha-2 adrenoreceptor agonist widely used in the treatment of spasticity in patients with cerebral or spinal injury, and it is causing drawsiness in some of them. Based on these drug actions, we administered tizanidine to 21 spastic quadriplegic children with severe sleep disturbance not improved by conventional therapies. All these patients were showing abnormalities of both the induction and maintenance of sleep. The dosage of tizanidine was 0.1 to 0.2 mg/kg/day, divided into two or three doses. If daytime drowsiness was severe, tizanidine admistration was restricted to just prior to bedtime. In 13 patients (61.9%), we found improvement in sleep induction and/or maintenance. Moreover, patients' families were satisfied with the treatment. There were no detectable side effects except facial pallor in two patients (9.5%) whose treatment was discontinued. Severe muscle hypertonia causes severe pain, which generates strong sympathetic nerve activity and subsequent sleep disturbance. We consider that tizanidine has direct effects on the induction of sleep, and promotes muscular relaxation bringing about good sleep. We conclude that tizanidine is useful for the treatment of refractory sleep disturbance in spastic quadriplegic patients.


Similarity of RNA secondary structures.
In this article, we propose a relatively similar measure to compare RNA secondary structures. We first transform an RNA secondary structure into a special sequence representation. Then, on the basis of symbolic sequence complexity, we obtain the relative distance of RNA secondary structures. The examination of similarities/dissimilarities of a set of RNA secondary structures at the 3'-terminus of different viruses illustrates the utility of the approach.


DNA Barcoding Meets Nanotechnology: Development of a Universal Colorimetric Test for Food Authentication.
Food trade globalization and the growing demand for selected food varieties have led to the intensification of adulteration cases, especially in the form of species substitution and mixing with cheaper taxa. This phenomenon has huge economic impact and sometimes even public health implications. DNA barcoding represents a well-proven molecular approach to assess the authenticity of food items, although its use is hampered by analytical constraints and timeframes that are often prohibitive for the food market. To address such issues, we have introduced a new technology, named NanoTracer, that allows for rapid and naked-eye molecular traceability of any food and requires limited instrumentation and cost-effective reagents. Moreover, unlike sequencing, this method can be used to identify not only the substitution of a fine ingredient, but also its dilution with cheaper ones.


Effects of prazosin on reflex changes in heart rate evoked by vasopressor and vasodepressor stimuli in conscious rabbits.
In conscious rabbits prepared for continuous arterial pressure measurements by means of a catheter placed into the main ear artery, intravenous administration of prazosin (5.0 micrograms/kg, i.v. over 20 min) produced a significant decrease in arterial pressure and cardioacceleration. This dose of prazosin inhibited by approximately 70% the pressor effects of phenylephrine. However, prazosin failed to produce significant functional modifications of either the bradycardia or the tachycardia which accompanied the changes in arterial pressure evoked, respectively, by intravenous bolus injections of angiotensin II or acetylcholine. It is concluded that prazosin in the dose studied does not appear to interfere with reflex heart rate responses to vasodepressor or vasopressor stimuli in conscious rabbits.


Synthesis and evaluation of novel radioligands for positron emission tomography imaging of the orexin-2 receptor.
Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling, and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [(11)C]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX2Rs). In vivo PET study of [(11)C]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.


Sodium channel blockade may contribute to the analgesic efficacy of antidepressants.
Sodium channel blockers such as lidocaine, lamotrigine, and carbamazepine can be effective in the treatment of neuropathic pain. Though not approved for neuropathic pain indications, tricyclic antidepressants are often considered first-line treatment for conditions such as post-herpetic neuralgia and diabetic neuropathy. Several tricyclic antidepressants have been shown to block peripheral nerve sodium channels, which may contribute to their antihyperalgesic efficacy. In this study, we compared the sodium channel-blocking potency of a number of antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. All compounds tested inhibited Na(V)1.7 in a state- and use-dependent manner, with affinities for the inactivated state ranging from 0.24 micromol/L for amitriptyline to 11.6 micromol/L for zimelidine. The tricyclic antidepressants were more potent blockers of Na(V)1.7. Moreover, IC(50)s for block of the inactivated state for amitriptyline, nortriptyline, imipramine, desipramine, and maprotiline were in the range of therapeutic plasma concentrations for both the treatment of depression as well as neuropathic pain. By contrast, fluoxetine, paroxetine, mianserine, and zimelidine had IC(50)s for Na(V)1.7 outside their therapeutic concentration ranges and generally were not efficacious against post-herpetic neuralgia or diabetic neuropathy. These results suggest that block of peripheral nerve sodium channels may contribute to the antihyperalgesic efficacy of certain antidepressants. Tricyclic antidepressants are often considered first-line treatment for neuropathic pain. Some tricyclic antidepressants block sodium channels, which may contribute to their antihyperalgesic efficacy. In the current study, we compared the potency of peripheral sodium channel blockade for several tricyclic antidepressants and selective serotonin reuptake inhibitors with their therapeutic efficacy.


The impact of pay-for-performance on health care quality in Massachusetts, 2001-2003.
Pay-for-performance (P4P) has become one of the dominant approaches to improving quality of care, yet few studies have evaluated its effectiveness. We evaluated the impact on quality of all P4P programs introduced into physician group contracts during 2001-2003 by the five major commercial health plans operating in Massachusetts. Overall, P4P contracts were not associated with greater improvement in quality compared to a rising secular trend. Future research is required to determine whether changes to the magnitude, structure, or alignment of P4P incentives can lead to improved quality.


[Study of some pharmacological properties of a new adenine derivative].
It is established that the new compound, 9-[2-(4-isopropylphenoxy)ethyl]adenine (9-IPE-adenine) in a dose of 10 mg/kg per day produces neuroprotective effect in rats with brain ischemia model. 9-IPE-adenine decreased the neurologic deficiency 1.2 times more effectively (p < 0.05) than the reference drug mexidol in analogous dose, and had equal effect with this drug at 25 mg/kg per day on the neurologic deficiency and survival of animals. Electrophysiological studies in hippocampal slices in rats showed that 9-IPE-adenine depressed orthodromic population spikes in CA1 area by 42 ± 4%. Non-competitive antagonist of NMDA receptor complex MK-801, in contrast to D-AP5 (competitive NMDA receptor antagonist) and CNQX (competitive AMPA receptor antagonist), enhanced the depressive effect of the new drug more than two times. These ese results are indicative of the ability of 9-IPE-adenine to modulate the ion channel of NMDA receptor complex.


Zebrafish Models of Retinal Disease.
Visual defects affect a large proportion of humanity, have a significant negative impact on quality of life, and cause significant economic burden. The wide variety of visual disorders and the large number of gene mutations responsible require a flexible animal model system to carry out research for possible causes and cures for the blinding conditions. With eyes similar to humans in structure and function, zebrafish are an important vertebrate model organism that is being used to study genetic and environmental eye diseases, including myopia, glaucoma, retinitis pigmentosa, ciliopathies, albinism, and diabetes. This review details the use of zebrafish in modeling human ocular diseases.


Use of subcutaneous DDAVP in infants with central diabetes insipidus.
Traditional methods for treating central diabetes insipidus during infancy, such as fluid therapy or the use of intranasal hormone replacement, have significant potential limitations. In a retrospective study of infants with diabetes insipidus, we examined outcome using subcutaneous (sc) DDAVP, and compared this to infants treated with intranasal lysine vasopressin or DDAVP. After in-patient dosage titration, outpatients' serum sodium concentrations were maintained in a narrower range in the sc group compared with the intranasal group, and the percentage of serum sodium concentrations within the normal range was greater in the sc group. There were no significant complications in either group. We conclude that DDAVP administered subcutaneously can be a safe and effective alternative to traditionally recommended treatments of central diabetes insipidus during infancy.


Is There Additive Therapeutic Effect When GCSF Combined with Adipose-Derived Stem Cell in a Rat Model of Acute Spinal Cord Injury?
Functional and neural tissue recovery has been reported in many animal studies conducted with stem cells. However, the combined effect of cytokines and stem cells has not yet been adequately researched. Here, we analyzed the additive effects of granulocyte colony-stimulating factor (GCSF) on adipose-derived stem cells (ADSCs) infusion in the treatment of acute spinal cord injury (SCI) in rats. Four days after intrathecal infusion tubes implantation in Sprague-Dawley rats, SCI was induced with an infinite horizon impactor. In the Sham group (n=5), phosphate-buffered saline was injected 3, 7, and 14 days after SCI. GCSF, ADSCs, and ADSCs with GCSF were injected at the same time in the GCSF (n=8), ADSC (n=8), and ADSC+GCSF groups (n=7), respectively. The ADSC and ADSC+GCSF groups, but not the GCSF group, showed significantly higher Basso-Beattie-Bresnahan scores than the Sham group during 8 weeks (p<0.01), but no significant difference between the ADSC and ADSC+GCSF groups. In the ladder rung test, all four groups were significantly different from each other, with the ADSC+GCSF group showing the best improvement (p<0.01). On immunofluorescent staining (GAP43, MAP2), western blotting (GAP43), and reverse transcription polymerase chain reaction (GAP43, nerve growth factor), the ADSC and ADSC+GCSF groups showed higher levels than the Sham and GCSF groups. Our analyses suggest that the combination of GCSF and ADSCs infusions in acute SCI in the rat does not have a significant additive effect. Hence, when combination agents for SCI stem cell therapy are considered, molecules other than GCSF, or modifications to the methodology, should be investigated.


[Effect of tranilast on myocardial fibrosis in mice with viral myocarditis].
To study the role of tranilast in the pathogenesis of myocardiac fibrosis in viral myocarditis. Seventy-two BALB/C mice were randomly divided into control, model and intervention groups (n=24 each). Mice in the model and intervention groups were infected with Coxsackievirus B3 to induce viral myocarditis. The intervention group was given with tranilast (200 mg/kg) by gavage until sacrifice for sampling, while the other two groups were administered with the same volume of normal saline. Cardiac tissues were obtained from 8 mice on 7, 14 and 28 days after modeling. The mast cell number was observed by toluidine blue staining and thionine staining. The cardiac tissues were stained with hematoxylin and eosin as well as masson trichrome to observe the pathological changes in cardiac tissues. The mRNA and protein expression of osteopontin and transforming growth factor-β1 was measured by RT-PCR and immunohistochemistry respectively. In the model group, the mRNA and protein expression of osteopontin reached the highest level on the 7th day, decreasing from the 14th day, and became to the least on the 28th day; while the expression of TGF-β1 increased from the 7th day, reaching a peak on the 14th day, and decreased slightly on the 28th day. The mRNA and protein expression of TGF-β1 and OPN was lower in the intervention group than the model group (P<0.05), but higher than the control group (P<0.05). The expression of OPN mRNA was positively correlated to the number of mast cells. Tranilast can reduce myocardial fibrosis by decreasing the number of mast cells, inhibiting the expression of TGF-β1 and OPN.


Probabilistic evaluation of surface-enhanced localized surface plasmon resonance biosensing.
In this paper, we investigate detection characteristics of localized surface plasmon resonance biosensing based on a probabilistic Poisson distribution of target molecules. The model uses random nanoislands for localization of near-fields in three detection scenarios of non-specific, non-colocalized, and colocalized detection. Optical signatures were found to increase monotonically with target concentration and size regardless of the detection scenarios. The signatures were largest in colocalized detection of target interactions to localized fields, followed by non-colocalized and non-specific detection. The confidence interval was the narrowest in the colocalized detection due to the increased spatial certainty by localization. Based on the relative confidence interval, it was found that limit of detection can be enhanced by more than four orders of magnitude through colocalization.


Benign mesenchymoma of the round ligament. A report of two cases with immunohistochemistry.
Benign mesenchymomas are tumors composed of an admixture of two or more mature mesenchymal tissue types. Clinically and histologically they are benign lesions. However, they are seldom encapsulated and therefore may recur locally if incompletely excised. The authors report on two benign mesenchymomas composed of mature fat, thin-walled small and medium size vessels, and spindle cells demonstrated to be smooth muscle by immunohistochemical studies. They were diagnosed in women in their 50s. Both were located in the round ligament of the uterus. One was discovered incidentally during hysterectomy, and the other was unusually large, being diagnosed preoperatively as a retroperitoneal liposarcoma. Most round ligament tumors are leiomyomas or fibromas. To the authors' knowledge, this is the first report of benign mesenchymomas occurring in this location.


PERIORAL DERMATITIS: STILL A THERAPEUTIC CHALLENGE.
Perioral dermatitis is a common and often chronic dermatosis. In its classic form, it primarily affects women aged 15 to 45 years, but there are also variants including lupus-like and granulomatous perioral dermatitis, where granulomatous form is more common in childhood and affects mostly prepubescent boys. The etiopathogenesis of the disease remains unclear, but there is a frequent finding of prolonged use of topical products, especially corticosteroids, in the treatment of rosacea and seborrheic dermatitis, preceding the clinical manifestation of perioral dermatitis. Other causes important for the occurrence of the disease include various skin irritants, as well as other physical and hormonal factors, which all share the epidermal barrier dysfunction as an underlying main pathogenic factor. Clinical presentation of papulovesicular eruption in the perioral region with a typical narrow spared zone around the edge of the lips is characteristic. Therapeutic approach should be individually addressed, depending on the severity of clinical presentation and patient's age, with special attention to patient's education and continuous psychological support. In mild forms of perioral dermatitis, 'zero therapy' is the treatment of choice. In the initial treatment period, patients with steroid-induced perioral dermatitis should be closely followed up because the rebound phenomenon usually develops after cessation of previous topical treatment. In moderate disease, treatment includes topical metronidazole, erythromycin, and pimecrolimus, whereas in more severe cases the best validated choice is oral tetracycline in a subantimicrobial dose until complete remission is achieved. Systemic isotretinoin should be considered as a therapeutic option for patients refractory to all standard therapies.


Effects of Nitrogen and Hydrogen Codoping on the Electrical Performance and Reliability of InGaZnO Thin-Film Transistors.
Despite intensive research on improvement in electrical performances of ZnO-based thin-film transistors (TFTs), the instability issues have limited their applications for complementary electronics. Herein, we have investigated the effect of nitrogen and hydrogen (N/H) codoping on the electrical performance and reliability of amorphous InGaZnO (α-IGZO) TFTs. The performance and bias stress stability of α-IGZO device were simultaneously improved by N/H plasma treatment with a high field-effect mobility of 45.3 cm2/(V s) and small shifts of threshold voltage (Vth). On the basis of X-ray photoelectron spectroscopy analysis, the improved electrical performances of α-IGZO TFT should be attributed to the appropriate amount of N/H codoping, which could not only control the Vth and carrier concentration efficiently, but also passivate the defects such as oxygen vacancy due to the formation of stable Zn-N and N-H bonds. Meanwhile, low-frequency noise analysis indicates that the average trap density near the α-IGZO/SiO2 interface is reduced by the nitrogen and hydrogen plasma treatment. This method could provide a step toward the development of α-IGZO TFTs for potential applications in next-generation high-definition optoelectronic displays.


A first or dominant immunization. II. Induced immunoglobulin carries transforming growth factor beta and suppresses cytolytic T cell responses to unrelated alloantigens.
Fresh sera from mice immunized by bearing an immunogenic tumor or by repeated injections of allogeneic spleen cells or xenogeneic erythrocytes powerfully suppress cytolytic T cell responses in one-way mixed lymphocyte cultures. Suppression is not antigen specific, though is mediated by immunoglobulin (Ig)G specific for the immunizing antigen. Suppression caused by IgG mimics that caused by active transforming growth factor beta (TGF-beta). IgG associates with or carries latent TGF-beta; however, suppression caused by the complex of IgG-TGF-beta requires macrophages (M phi), whereas active TGF-beta alone does not. Also, IgG dissociated from TGF-beta does not cause suppression, suggesting that M phi may take up Ig-TGF-beta, process the complex, and deliver active TGF-beta to lymphocytes. Indeed, suppression by immune serum was prevented by antibody to Fc receptors, by saturating Fc receptors with heterologous IgGs, and by antibodies against TGF-beta. The overall findings reveal a previously unrecognized regulatory circuit whereby IgG produced in response to one antigen nonspecifically downregulates cytolytic T lymphocyte responses to unrelated antigens. The findings introduce the intriguing possibility that TGF-beta delivered by IgG and processed by M phi may mediate important biological effects in processes such as wound healing, tumor growth, and some autoimmune diseases.


Collisional relaxation in the inhomogeneous Hamiltonian mean-field model: Diffusion coefficients.
Systems of particles with long-range interactions present two important processes: first, the formation of out-of-equilibrium quasistationary states (QSS) and, second, the collisional relaxation towards Maxwell-Boltzmann equilibrium in a much longer time scale. In this paper, we study the collisional relaxation in the Hamiltonian mean-field model using the appropriate kinetic equations for a system of N particles at order 1/N: the Landau equation when collective effects are neglected and the Lenard-Balescu equation when they are taken into account. We derive explicit expressions for the diffusion coefficients using both equations for any magnetization, and we obtain analytic expressions for highly clustered configurations. An important conclusion is that in this system collective effects are crucial in order to describe the relaxation dynamics. We compare the diffusion calculated with the kinetic equations with simulations set up to simulate the system with or without collective effects, obtaining a very good agreement between theory and simulations.


Multiple ribosome binding to the 5'-terminal leader sequence of tobacco mosaic virus RNA. Assembly of an 80S ribosome X mRNA complex at the AUU codon.
Tobacco mosaic virus (TMV) RNA with a long 5'-terminal leader sequence, as well as its isolated leader fragment (called omega), can form disome initiation complexes with wheat germ ribosomes. The second ribosome of the disome complex is bound to the leader sequence, upstream of an 80S particle occupying the AUG-containing initiation site [ Filipowicz and Haenni (1979) Proc. Natl Acad. Sci. USA 76, 3111-3115; Konarska et al. (1981) Eur. J. Biochem. 114, 221-227]. In order to identify the parts of omega important for interaction with ribosomes, the 5'-terminally-labelled omega was treated with alkali and the resultant fragments of different lengths were used in binding experiments. A 16-nucleotide-long fragment bearing the AUU sequence at the 3' end is the shortest oligonucleotide capable of forming 80S complexes with wheat germ ribosomes. Full-length (73 nucleotides) omega with AUG at the 3' terminus is the only RNA fragment supporting disome complex formation. Synthetic oligoribonucleotides were prepared for a study of 80S complex assembly at codons other than AUG. Hexadecanucleotide (A) 13A -U-U and, to lesser extent, also (A) 13A -U-C, (A) 13A -U-A and (A) 13A -C-G bind 80S ribosomes. Formation of the (A) 13A -U-U X 80S complex is dependent on the presence of initiator Met- tRNAMerf . Assembly of the 80S particle at the AUU sequence is not an artifact resulting from the terminal position of this triplet. (A) 13A -U-U elongated with over 100 A residues still efficiently binds an 80S ribosome positioned, as established by ribosome protection experiments, at the AUU triplet. The present results support the notion that 80S initiation-like complexes can be formed at sequences containing AUU codons. The possible function of these complexes as intermediates in initiation of translation of some viral RNAs is discussed.


Evaluating platelet aggregation dynamics from laser speckle fluctuations.
Platelets are key to maintaining hemostasis and impaired platelet aggregation could lead to hemorrhage or thrombosis. We report a new approach that exploits laser speckle intensity fluctuations, emanated from a drop of platelet-rich-plasma (PRP), to profile aggregation. Speckle fluctuation rate is quantified by the speckle intensity autocorrelation, g2(t), from which the aggregate size is deduced. We first apply this approach to evaluate polystyrene bead aggregation, triggered by salt. Next, we assess dose-dependent platelet aggregation and inhibition in human PRP spiked with adenosine diphosphate and clopidogrel. Additional spatio-temporal speckle analyses yield 2-dimensional maps of particle displacements to visualize platelet aggregate foci within minutes and quantify aggregation dynamics. These findings demonstrate the unique opportunity for assessing platelet health within minutes for diagnosing bleeding disorders and monitoring anti-platelet therapies.


High-sensitivity optical fiber sensing based on a computational and distributed Vernier effect.
This article reports a novel concept of computational microwave photonics and distributed Vernier effect for sensitivity enhancement in a distributed optical fiber sensor based on an optical carrier microwave interferometry (OCMI) system. The sensor system includes a Fabry-Perot interferometer (FPI) array formed by cascaded fiber in-line reflectors. Using OCMI interrogation, information on each of the interferometers (i.e., sensing interferometers) can be obtained, from which an array of reference interferometers can be constructed accordingly. By superimposing the interferograms of each sensing interferometer and its corresponding reference interferometer, distributed Vernier effect can be generated, so that the measurement sensitivity of each of the sensing interferometers can be amplified individually. This technique is achieved entirely in software without any physical modification to the system and negates the need to carefully fabricate the reference interferometer to obtain the desired magnification factor, as is often the case for traditional Vernier effect-based optical fiber sensors. Importantly, the reference interferometers can be flexibly constructed such that the magnification factor for each sensing interferometer can be precisely and easily controlled. The operating principle is illustrated in detail, followed by a proof of concept. The experimental results match well with theoretical predictions.


Granular cell tumor of the lung and tracheobronchial tree: Two case-presentation with a review of the literature.
Pulmonary granular cells tumors (CGT) are rare tumors, that derive from Schwann cells. In the tracheobronchial and pulmonary tree, they remain a diagnostic challenge. There are no well-established criteria to differentiate between benign, atypical, and malignant GCT. Moreover, its real frequency in the respiratory tract is still unknown. Here, we represent 2 cases of bronchial and lung GCTs. We aim to highlight the frequency of all clinicopathological characteristics of this rare tumor in the tracheobronchial and pulmonary tree location based on our cases and the available literature in a large systematic review.


Virtual Human Role Players for Studying Social Factors in Organizational Decision Making.
The cyber domain of military operations presents many challenges. A unique element is the social dynamic between cyber operators and their leadership because of the novel subject matter expertise involved in conducting technical cyber tasks, so there will be situations where senior leaders might have much less domain knowledge or no experience at all relative to the warfighters who report to them. Nonetheless, it will be important for junior cyber operators to convey convincing information relevant to a mission in order to persuade or influence a leader to make informed decisions. The power dynamic will make it difficult for the junior cyber operator to successfully influence a higher ranking leader. Here we present a perspective with a sketch for research paradigm(s) to study how different factors (normative vs. informational social influence, degree of transparency, and perceived appropriateness of making suggestions) might interact with differential social power dynamics of individuals in cyber decision-making contexts. Finally, we contextualize this theoretical perspective for the research paradigms in viable training technologies.


Comparative Genomic Analysis of Staphylococcal Cassette Chromosome mec Type V Staphylococcus aureus Strains and Estimation of the Emergence of SCCmec V Clinical Isolates in Korea.
Staphylococcal cassette chromosome mec type V (SCCmec V) methicillin-resistant Staphylococcus aureus (MRSA) has been recovered from patients and livestock. Using comparative genomic analyses, we evaluated the phylogenetic emergence of SCCmec V after transmission from overseas donor strains to Korean recipient strains. Sixty-three complete MRSA SCCmec V genomes (including six Korean clinical isolates) were used to construct a phylogenetic tree. Single-nucleotide polymorphisms were identified using Snippy, and a maximum-likelihood-based phylogenetic tree was constructed using RAxML. The possible emergence of the most common ancestor was estimated using BactDating. To estimate mecA horizontal gene transfer (HGT) events, Ranger-dtl was applied to 818 SCCmec V strains using publicly available whole-genome data. The phylogenetic tree showed five major clades. German strains formed a major clade; their possible origin was traced to the 1980s. The emergence of Korean SCCmec V clinical isolates was traced to 2000-2010. mecA HGT events in Staphylococcus spp. were identified in seven strains. P7 (Hong Kong outbreak strain) served as the donor strain for two Korean sequence type (ST) 59 strains, whereas the other five recipient strains emerged from different SCCmec V donors. Most Korean SCCmec V strains may have emerged during 2000-2010. A unique MRSA SCCmec V strain, ST72 (a Korean common type of community-associated MRSA), was also identified. The genomic dynamics of this clone with a zoonotic background should be monitored to accurately understand MRSA evolution.


Spiramycin concentrations in the human respiratory tract: a review.
Spiramycin has exceptionally good distribution properties, especially in respiratory tract tissues and fluids. Three hours after a single oral dose of 3 g spiramycin, the serum concentration ranged from 1.6 to 2.8 mg/l and the reported half-life was approximately 8 h. Studies of lung tissue concentrations showed that high pulmonary levels were achieved after a loading dose of 3 g; the levels were higher after multiple doses and reached approximately 30 to 45 mg/kg in lung tissue and 6.5 to 36 mg/kg in bronchial mucosa; in bronchial secretions and in sputum the concentrations of spiramycin ranged from 1.5 to 7.3 mg/l (after 1 g, multiple doses). In upper respiratory tract tissues and fluids, high levels of spiramycin were reached as well: 8 to 13 mg/kg in sinus mucosa; 15 to 29.5 mg/kg in tonsils or adenoids.


Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC).
PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting.


Light Activation of Calcein Inhibits Vesicle Release of Catecholamines.
Calcein, a fluorescent fluid phase marker, has been used to track and visualize cellular processes such as synaptic vesicle fusion. It is also the fluorophore for live cells in the commonly used Live/Dead viability assay. In pilot studies designed to determine fusion pore open size and vesicle movement in secretory cells, imaging analysis revealed that calcein reduced the number of vesicles released from the cells when stimulated with nicotine. Using amperometry to detect individual vesicle release events, we show that when calcein is present in the media, the number of vesicles that fuse with the cellular membrane is reduced when cells are stimulated with either nicotine or high K+. Experimentally, amperometric electrodes are not undergoing fouling in the presence of calcein. We hypothesized that calcein, when activated by light, releases reactive oxygen species that cause a reduction in secreted vesicles. We show that when calcein is protected from light during experimentation, little to no reduction of vesicle secretion occurred. Therefore, photoactivated calcein can cause deleterious results for measurements of cellular processes, likely to be the result of release of reactive oxygen species.


Delayed stimulatory effect of cyclic AMP on bone resorption in vitro.
The effect of dibutyryl cyclic AMP (dbcAMP) and the phosphodiesterase inhibitors 3-isobutyl methylxanthine (IBMX) and theophylline on bone resorption was studied in an organ culture system for 96-114 h using half calvaria from 6-7 day old mice. The magnitude of resorption was assessed by measuring the release from the bones of previously incorporated 45Ca. It was observed that dbcAMP, IBMX and theophylline, following a lag period or a period of reduced bone resorption, all progressively increased mineral mobilization. Although the continuous presence of dbcAMP increased mineral mobilization more than a temporary exposure, a limited treatment of 24 h with the nucleotide was sufficient to bring about the delayed stimulatory response. It is concluded that the observations support our earlier proposal that cAMP is not a mediator of the early stages of parathyroid hormone (PTH)- and prostaglandin E2 (PGE2)-stimulated bone resorption. We suggest that the role played by cAMP may be related to the capacity of PTH and PGE2 to develop new osteoclasts, a phenomenon which takes more than 24 h to be observed.


Nitrofuran reductase activity in nitrofurantoin-resistant strains of Escherichia coli K12: some with chromosomally determined resistance and others carrying R-plasmids.
The nitrofuran reductase activity of Escherichia coli K12 strains was separated into two components by passage through Sepharose 4B-200. The components differed in their sensitivity to 2 M urea and their reactivity with NADH and NADPH. Some nitrofurantoin-resistant mutants had lost one component (alpha) while retaining the other (beta). Other mutants, resistant to higher levels of nitrofurantoin, had lost most of the beta component as well. Transconjugants which had received plasmids conferring nitrofurantoin resistance were found to have only the alpha component and it was markedly less active when NADH rather than NADPH was supplied as co-enzyme.


The adult Tillaux fracture: one not to miss.
This case is a rare adult type Tillaux fracture. This fracture should be diagnosed in the emergency department. The fracture requires careful evaluation with awareness of associated injury. Standard radiological views (antero-posterior and lateral) of the ankle may not clearly show the fracture displacement hence, an oblique view is required. The fracture should be managed by the emergency physician, if the displacement is less than 2 mm, by immobilising with a non-weight bearing cast or ankle braces for 6 weeks. If the fracture fragment is displaced more than 2 mm, it should be treated by closed reduction failing which open reduction and internal fixation is the standard practice.


Enhanced immunogenicity induced by mRNA vaccines with various lipid nanoparticles as carriers for SARS-CoV-2 infection.
mRNA vaccines have emerged as a highly promising approach for preventing cancer and infectious diseases, attributed to their superior immunogenicity, rapid development speed, and quality-controlled scale production. While homologous mRNA vaccine administration is currently the most prevalent method employed in clinical settings, heterologous administration is a promising avenue worth exploring. In this report, two types of mRNA vaccine formulations for SARS-CoV-2 infection were developed based on different lipid nanoparticle (LNP) delivery systems, and heterologous and homologous mRNA vaccinations were administered to explore the levels of immune responses comparatively. First, five novel H-series ionizable lipids were synthesized and confirmed by NMR and MS. Subsequently, six SARS-CoV-2 receptor-binding domain (RBD) mRNA-encapsulated LNP formulations were prepared using a microfluidic mixer based on H-series and MC3 lipids. These formulations exhibited spherical structures with an average diameter ranging from 90-140 nm, as characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The safety of these formulations was confirmed in vitro by the cytotoxicity assay. Moreover, transfection assay, lysosomal escape test, and western blot, and in vivo biodistribution analyses collectively demonstrated that lipids H03 and MC3 exhibited superior in vitro and in vivo delivery efficacy in comparison to other H-series lipids. Notably, H03-Fluc mRNA exhibited an approximately 2.2-fold higher in vivo bioluminescence signal intensity than MC3-Fluc mRNA. Additionally, evaluation of humoral immunity demonstrated that homologous H03-mRNA vaccination elicited an immune response that was approximately 3-fold higher than that of homologous MC3-mRNA vaccination. More significantly, the heterologous H03-mRNA/MC3-mRNA vaccination elicited an immune response that was approximately 2-3-fold higher than that of homologous H03-mRNA vaccination and 6-9-fold higher than that of homologous MC3-mRNA vaccination, without any observable adverse effects. These results suggest that heterologous mRNA vaccination is superior to homologous mRNA vaccination and may be attributed to differences in LNP carriers. Therefore, our research may inspire further exploration of different delivery systems to enhance mRNA-based therapeutics.


Activated sludge systems with biomass particle support structures.
A mathematical model was developed to simulate the operation of an activated sludge system with biomass support particles. Based on the results of this simulation study, it would appear that a system with biomass particle supports offers several advantages not offered by conventional systems. These include the ability to resist failure from large hydraulic surges; stable nitrification under transient inhibitory conditions resulting from temperature changes, hydraulic surges, and/or toxic chemicals; and the ability to establish stable operating conditions with respect to both carbon oxidation and nitrification at short hydraulic retention times and low sludge ages.


Complex network based techniques to identify extreme events and (sudden) transitions in spatio-temporal systems.
We present here two promising techniques for the application of the complex network approach to continuous spatio-temporal systems that have been developed in the last decade and show large potential for future application and development of complex systems analysis. First, we discuss the transforming of a time series from such systems to a complex network. The natural approach is to calculate the recurrence matrix and interpret such as the adjacency matrix of an associated complex network, called recurrence network. Using complex network measures, such as transitivity coefficient, we demonstrate that this approach is very efficient for identifying qualitative transitions in observational data, e.g., when analyzing paleoclimate regime transitions. Second, we demonstrate the use of directed spatial networks constructed from spatio-temporal measurements of such systems that can be derived from the synchronized-in-time occurrence of extreme events in different spatial regions. Although there are many possibilities to investigate such spatial networks, we present here the new measure of network divergence and how it can be used to develop a prediction scheme of extreme rainfall events.


Origin of the liquid-liquid phase transition for trans-1,2-dichloroethylene observed by IR spectroscopy.
IR vibrational spectroscopy has been employed to study liquid-liquid phase transitions of trans-1,2-dichloroethylene (TDCE). The temperature dependence of the vibrational frequency, band absorbance, and band broadening has been analyzed in the temperature range of 293-237 K. All peaks show distinct increases in their absorbancies at the temperature of 246.7 K accompanied by a frequency shift and bandwidth changes. Weak H...Cl hydrogen bonding has been suggested as the explanation for the overall behavior in a wide temperature range, whereas the significant changes in the spectrum at 246.7 K are probably due to molecular ordering originating from electrostatic interactions. The transition is well described by the model of the cooperative formation of locally favored structures.


Novel positioning sensor with real-time feedback for improved postoperative positioning: pilot study in control subjects.
Repair of retinal detachment frequently requires use of intraocular gas. Patients are instructed to position themselves postoperatively to appose the intraocular bubble to the retinal break(s). We developed a novel wearable wireless positioning sensor, which provides real-time audiovisual feedback on the accuracy of positioning. Eight healthy volunteers wore the wireless sensor for 3 hours while instructed to maintain their head tilted toward the 2 o'clock meridian with no audiovisual feedback. Positioning accuracy was recorded. The subjects repeated the experiment for 3 hours with the audiovisual feedback enabled. With no audiovisual feedback, the percentage of time greater than 10° out of position varied from 8.9% to 93.9%. With audiovisual feedback enabled, these percentages ranged from 9.4% to 65%. Three subjects showed significant improvement in their time out of position (P<0.01, Fisher's exact test). Four subjects demonstrated a nonsignificant improvement, and one subject had a significant increase in time out of position with feedback (P<0.01). When pooled, all subjects demonstrated a statistically significant decrease in degrees out of position (P<0.001, Wilcoxon test) and a statistically significant improvement in total time out of position (P<0.001). The novel positioning sensor showed improved positioning compliance in half of the healthy volunteers during our short pilot study. Other subjects derived little benefit from the feedback. The causes for this observation are unclear. However, given the significant improvement as a group, this new technology could be beneficial to patients who struggle with postoperative positioning.


A block in virus-like particle maturation following assembly of murine leukaemia virus in insect cells.
Expression of the murine leukaemia virus (MLV) major Gag antigen p65(Gag) using the baculovirus expression system leads to efficient assembly and release of virus-like particles (VLP) representative of immature MLV. Expression of p180(Gag-Pol), facilitated normally in mammalian cells by readthrough of the p65(Gag) termination codon, also occurs efficiently in insect cells to provide a source of the MLV protease and a pattern of p65(Gag) processing similar to that observed in mammalian cells. VLP release from p180(Gag-Pol)-expressing cells however remains essentially immature with disproportionate levels of the uncleaved p65(Gag) precursor when compared to the intracellular Gag profile. Changing the p65(Gag) termination codon altered the level of p65(Gag) and p180(Gag-Pol) within expressing cells but did not alter the pattern of released VLP, which remained immature. Coexpression of p65(Gag) with a fixed readthrough p180(Gag-Pol) also led to only immature VLP release despite high intracellular protease levels. Our data suggest a mechanism that preferentially selects uncleaved p65(Gag) for the assembly of MLV in this heterologous expression system and implies that, in addition to their relative levels, active sorting of the correct p65(Gag) and p180(Gag-Pol) ratios may occur in producer cells.


Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.
The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy. Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry. The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001). Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells.


Improvement of intact human lipocortin-I production in Saccharomyces cerevisiae by inhibiting proteolysis.
Human lipocortin-I (hLC1), when was expressed as a secretory product in Saccharomyces cerevisiae, was cleaved to a significant extent by endoproteolytic processing, resulting in the accumulation of des1-26-hLC1 in the culture supernatant. This proteolytic cleavage was inhibited significantly by the addition of high concentrations of l-arginine and l-lysine, with a resultant marked improvement in the yield of intact hLC1. When the hLC1 was expressed in S. cerevisiae mutants deficient in one or two of the following endoproteases, Kex2p, Mkc7p and Yps1p (Yap3p), the mutants exhibited no reduction in the extent of hLC1 proteolysis, indicating that these endoproteases are not involved in the proteolytic cleavage of hLC1.


White Matter Hyperintensities and Poststroke Apathy: A Fully Automated MRI Segmentation Study.
Poststroke apathy (PSA) is a common neuropsychiatric disorder that may affect up to 30% of stroke patients. Despite the difficulties of investigating this condition (overlapping with depression, heterogeneity of diagnostic criteria, a small number of studies), some recent diffusion tensor imaging studies have suggested that widespread microstructural white matter (WM) disruption plays a key role in the development of PSA. Therefore, we intended to investigate this hypothesis by evaluating the relationship between WM hyperintensities (WMH) and apathy in patients with cerebrovascular disease. We studied patients with apathy (n = 7), depression (n = 13), comorbid apathy and depression (n = 13), and controls (n = 20), and we investigated the variables associated with the volume of WMH measured by an automated brain MRI segmentation software. The overall prevalence of PSA was 37.7% (pure and comorbid). Patients with apathy presented a higher volume of WMH in comparison to controls. Mini-Mental State Examination (MMSE), NPI-A, and the number of cerebral microbleeds were the only variables associated with WMH. Conversely, NPI-D did not correlate to WMH. This is an exploratory study that supports the view of PSA as a distinct syndrome from PSD mediated mainly by diffuse white matter hyperintensities, which suggests that WM disruption is an important pathway to the development of apathy in stroke patients.


Frailty and sarcopenia do not predict adverse events in an elderly population undergoing non-complex primary elective surgery for degenerative conditions of the lumbar spine.
Sarcopenia measured by normalized total psoas area (NTPA) has been shown to predict mortality and adverse events (AEs) in numerous surgical populations. The relationship between sarcopenia and postoperative outcomes after surgery for degenerative spine disease (DSD) has not been investigated. This study aimed to determine the relationships between sarcopenia, frailty, and postoperative AEs in the elderly DSD population. Secondary objectives were to describe the distribution and predictors of NTPA and to determine the relationship between sarcopenia, frailty, and length of stay, discharge to a facility, and in-hospital mortality. This is an ambispective study from a quaternary care academic center. A total of 102 patients over 65 years old who underwent elective thoracolumbar surgery for DSD between 2009 and 2013 were included in this study. The primary outcome was a composite of perioperative AEs; the secondary outcomes were length of stay, discharge disposition, and in-hospital mortality. Total psoas area (TPA) at mid-L3 level on preoperative computed tomography scan adjusted for height (NTPA) defined sarcopenia. The modified frailty index (mFI) of 11 clinical variables defined frailty. The distribution and predictors of sarcopenia (NTPA) were determined. The association of NTPA with AEs, length of stay, discharge disposition to care facility, and mortality was analyzed, including adjusting for known and suspected confounders using multivariate regression. Median Spine Surgical Invasiveness Index was 8 (interquartile range 2-10), and mean NTPA was 674 mm2/m2 (293.21-1636.25). Using the mFI, 20.6% were pre-frail and 19.6% were frail. Inter- and intraobserver reliability for determining NTPA were near perfect with kappa 0.95-0.97 and 0.94-1.00, respectively. The NTPA was independently associated with patient gender and body mass index (BMI) but not frailty (mFI). Age, BMI, mFI, and American Anesthesiologists' Society score were not associated with incidence of postoperative AEs. The NTPA did not predict the occurrence of AE (odds ratio [OR] 1.06 per 100 mm2/m2, 95% confidence interval [CI] 0.91-1.23, p=.45). Similarly, NTPA was not predictive of length of stay (rho=-0.04, p=.67), discharge home (OR 0.95 (95% CI 0.76-1.20) per 100 mm2/m2, p=.70), or death (OR 1.12 (95% CI 0.83-1.53) per 100 mm2/m2, p=.47). In contrast, increasing mFI was associated with increased risk of mortality (OR 3.12 (95% CI 1.21-8.03) per 0.1 increase in frailty score, p=.006). In contrast to other surgical groups, sarcopenia (NTPA) or frailty (mFI) did not predict acute care complications in a selected population of elderly patients undergoing simple lumbar spine surgery for DSD. Although NTPA can be reliably measured in this population, it may be an inappropriate surrogate for sarcopenia given its anatomical relationship to spinal function.


Two new species of Apteroscelio Kieffer (Hymenoptera: Scelionidae) from India.
Two new species of Apteroscelio Kieffer, a previously monotypic genus, are here described, illustrated and keyed. Affinities between Apteroscelio and other scelionine genera are discussed. The male of this genus is imaged and described for the first time.


Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures.
This multicenter, double-blind, double-dummy, randomized, inpatient trial evaluated the safety, tolerability, and pharmacokinetics of intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. Patients were enrolled from an ongoing open-label extension trial of oral lacosamide and randomized (2:1) to either intravenous lacosamide and oral placebo or intravenous placebo and oral lacosamide. During the 2-day inpatient treatment period, patients received twice-daily doses of lacosamide equivalent to their current daily dose of oral lacosamide. The first 30 patients enrolled received infusions with 60-min durations and the next 30 received infusions with 30-min durations. Of 60 patients randomized, 59 completed the trial. Treatment-emergent adverse events (AEs) were reported by 16 patients and included dizziness, headache, back pain, somnolence, and injection site pain. The tolerability profile of intravenous lacosamide was consistent with that of oral lacosamide. All AEs were considered mild or moderate in intensity, and no serious AEs or AEs leading to withdrawal were reported. Intravenous lacosamide, administered as 60- or 30-min twice-daily infusions, showed a similar safety and tolerability profile to oral lacosamide when used as replacement therapy. Results from this trial support further investigation of intravenous lacosamide at shorter infusion durations.


Correlation between Plasma Adiponectin Levels and the Presence and Severity of Coronary Artery Disease.
The existing evidence suggests that plasma adiponectin concentrations can be indicative of the presence and severity of coronary artery disease (CAD). However, the results of the studies conducted hitherto on this subject are inconsistent. We sought to investigate the possible correlation between plasma adiponectin levels and the presence and severity of CAD in patients undergoing non-urgent coronary angiography. In 399 consecutive patients undergoing non-urgent coronary angiography for CAD survey, plasma adiponectin, triglyceride, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, and fasting blood sugar levels were measured and demographic characteristics such as age, sex, Body Mass Index, diabetes mellitus history, systemic hypertension history, and family history of CAD were collected. According to the angiography results, the patients were divided into two groups of CAD and non-CAD. The severity of coronary atherosclerosis in the CAD group was defined using the Gensini score system. Average age was 61.4 ± 9.94 years in the CAD group and 57.9 ± 10.75 years in the non-CAD group. Also, 73.7% of the CAD group and 55.4% of the non-CAD group were male. Totally, 278 (69.7%) patients were found to have CAD. Patients without CAD did not have higher mean plasma adiponectin concentrations than did those with CAD (13.38 ± 11.96 vs. 14.95 ± 14.11 mcg/ml; p value = 0. 896). After adjustment for CAD conventional risk factors, plasma adiponectin levels still were not associated with CAD. No association was found between plasma adiponectin levels and the Gensini score. Furthermore, in contrast to the fairly strong correlation previously reported, there was no correlation between adiponectin levels and conventional CAD risk factors. We could not observe any relationship between plasma adiponectin concentrations and the presence or severity of CAD in patients undergoing coronary angiography.


[The principle of "balanced anesthesia" in high risk canine patients].
The concept of balanced anaesthesia aims at an anaesthetic method for high risk patients by combination of different anaesthetic drugs. The anaesthetics and muscle-relaxants have to work in a way as to potentiate their effects and to reduce the side effects as well as the applied dosage. With this sensible regime the circulation and the metabolic energy should be less burdened. For the introduction of balanced anaesthesia, a combination of benzodiazepines (relaxing and sedative), morphine (analgetic and sedative) and quickly metabolizing hypnotics of the imidazol group (hypnotic and relaxing) is used. A fentanyl-drip-infusion continues and deepens the analgesia. After endotracheal intubation with the help of the carrier-gas nitrous oxide (weakly analgetic) and oxygen (2:1) a low concentration of volatile inhalation anaesthetics (weakly hypnotic) is added. Under artificial respiration low doses of competitive antidepolarizing neuromuscular blockers help to potentiate and reduce drug amounts of other anaesthetics especially of that for inhalation. At the end of balanced anaesthesia an antagonization of benzodiazepines, morphines and competitive neuromuscular blockers is recommended for emergency situations only because of possibly occurring changes of cardiovascular parameters.