Automated quantitative analysis of estrogen receptor expression in breast carcinoma does not differ from expert pathologist scoring: a tissue microarray study of 3,484 cases.
Estrogen receptor (ER) expression is routinely assessed by immunohistochemistry (IHC) in breast carcinoma. Our study compares visual scoring of ER in invasive breast cancer by histopathologists to quantitation of staining using a fully automated system. A tissue microarray was constructed from 4,049 cases (3,484 included in analysis) of invasive breast carcinoma linked to treatment and outcome information. Slides were scored independently by two pathologists and scores were dichotomised, with ER positivity recognized at a cut-off of >1% positive nuclei. The slides were scanned and analyzed with an Ariol automated system. Using data dichotomised as ER positive or negative, both visual and automated scores were highly consistent: there was excellent concordance between two pathologists (kappa = 0.918 (95%CI: 0.903-0.932)) and between two Ariol machines (kappa = 0.913 (95%CI: 0.897-0.928)). The prognostic significance of ER positivity was similar whether determined by pathologist or automated scoring for both the entire patient cohort and subsets of patients treated with tamoxifen alone or receiving no systemic adjuvant therapy. The optimal cut point for the automated scores using breast cancer disease-specific survival as an endpoint was >0.4% positive nuclei. The concordance between dextran-coated charcoal ER biochemical assay data and automated scores (kappa = 0.728 (95%CI: 0.69-0.75); 0.74 (95%CI: 0.71-0.77)) was similar to the concordance between biochemical assay and pathologist scores (kappa = 0.72 (95%CI: 0.70-0.75; 0.70 (95%CI: 0.67-0.72)). Fully automated quantitation of ER immunostaining yields results that do not differ from human scoring against both biochemical assay and patient outcome gold standards.


Long Chain Alkyl Esters of Hydroxycinnamic Acids as Promising Anticancer Agents: Selective Induction of Apoptosis in Cancer Cells.
Cancer is the major cause of morbidity and mortality worldwide. Hydroxycinnamic acids (HCAs) are naturally occurring compounds and their alkyl esters may possess enhanced biological activities. We evaluated C4, C14, C16, and C18 alkyl esters of p-coumaric, ferulic, sinapic, and caffeic acids (19 compounds) for their cytotoxic activity against four human cancer cells and also examined their effect on cell cycle alteration and apoptosis induction. The tetradecyl (1c) and hexadecyl (1d) esters of p-coumaric acid and tetradecyl ester of caffeic acid (4c), but not the parental HCAs, were selectively effective against MOLT-4 (human lymphoblastic leukemia) cells with IC50 values of 0.123 ± 0.012, 0.301 ± 0.069 and 1.0 ± 0.1 μM, respectively. Compounds 1c, 1d, and 4c significantly increased apoptotic cells in sub-G1 phase and activated the caspase-3 enzyme in MOLT-4 cells. Compound 1c was 15.4 and 23.6 times more potent than doxorubicin and cisplatin, respectively, against the drug resistant MES-SA-DX5 uterine sarcoma cells. These p-coumarate esters were several times less effective against NIH/3T3 fibroblast cells. Docking studies showed that 1c may cause cytotoxicity by interaction with carbonic anhydrase IX. In conclusion, long chain alkyl esters of p-coumaric acid are promising scaffolds for selective apoptosis induction in cancer cells.


Oxidation of sulphide in abandoned mine tailings by ferrate.
In this study, Fe(VI) was applied to treat three mine tailings containing different amounts of sulphides and heavy metals. Oxidation of sulphides by Fe(VI) was studied at pH 9.2 with variation of solid to solution ratio, Fe(VI) concentration and injection number of Fe(VI) solution. The major dissolved products from the treatment of mine tailings with Fe(VI) solution were sulphate and arsenic. Oxidation efficiency of sulphides was evaluated by reduction efficiency of Fe(VI) as well as by measurement of dissolved sulphate concentration. Even though inorganic composition of three mine tailings was different, reduction fraction of Fe(VI) was quite similar. This result can suggest that Fe(VI) was involved in several other reactions in addition to oxidation of sulphides. Oxidation of sulphides in mine tailing was greatly dependent on the total amount of sulphides as well as kinds of sulphides complexed with metals. Over the five consecutive injections of Fe(VI) solution, dissolved sulphate concentration was greatly decreased by each injection and no more dissolved sulphate was observed at the fifth injection. While dissolved arsenic was decreased lineally up to the fifth injection. Sulphate generation was slightly increased for all mine tailings as Fe(VI) concentration was increased; however, enhancement of oxidation efficiency of sulphides was not directly proportional to the initial Fe(VI) concentration.


Chemotherapy of psoriasis: ten years of experience.
The hunt for an effective, easier to administer, more acceptable therapeutic modality for extensive chronic psoriasis continues. The chemotherapy of psoriasis is reviewed in 246 patients from 1964 to 1974 treated with methotrexate, 92 patients from 1971 to 1974 with hydroxyurea, and 36 patients from 1972 to 1974 with azaribine. Currently, the available chemotherapy agents are the least palatable and desirable form of treatment. Methotrexate continues to be the most predictable, effective and least expensive. The use of photochemotherapy may prove to be more effective, less toxic, and more practical until a more specific and effective etiologically directed form of therapy becomes available.


Impact of co-carriage of IncA/C plasmids with additional plasmids on the transfer of antimicrobial resistance in Salmonella enterica isolates.
Antimicrobial resistance in Salmonella enterica is often plasmid encoded. A key resistance plasmid group is the incompatibility group (Inc) A/C plasmids that often carry multiple resistance determinants. Previous studies showed that IncA/C plasmids were often co-located with other plasmids. The current study was undertaken to evaluate the impact of plasmid co-carriage on antimicrobial resistance and plasmid transfer. A total of 1267 Salmonella isolates, representing multiple serotypes and sources were previously subjected to susceptibility testing and 251 isolates with resistance to at least 5 antimicrobial agents were identified for further study. Each isolate was subjected to PCR-based replicon typing, and those with IncA/C plasmids were selected for plasmid isolation, PCR-based mapping of IncA/C plasmid backbone genes, and conjugation assays to evaluate resistance plasmid transferability. Of the 87 identified IncA/C positive isolates, approximately 75% carried a plasmid with another identified replicon type, with the most common being I1 (39%), FIA, FIIA, FIB and HI2 (each 15%). PCR-based mapping indicated significant diversity in IncA/C backbone content, especially in regions encoding transfer-associated and hypothetical proteins. Conjugation experiments showed that nearly 68% of the isolates transferred resistance plasmids, with 90% containing additional identified plasmids or larger (>50 kb) non-typeable plasmids. The majority of IncA/C-positive strains were able to conjugally transfer antimicrobial resistance to the recipient, encoded by IncA/C and/or co-carried plasmids. These findings highlight the importance of co-located plasmids for resistance dissemination either by directly transferring resistance genes or by potentially providing the needed conjugation machinery for IncA/C plasmid transfer.


Scaffold-Mediated Static Transduction of T Cells for CAR-T Cell Therapy.
Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive clinical responses in patients with B-cell malignancies. Critical to the success of CAR-T cell therapies is the achievement of robust gene transfer into T cells mediated by viral vectors such as gamma-retroviral vectors. However, current methodologies of retroviral gene transfer rely on spinoculation and the use of retronectin, which may limit the implementation of cost-effective CAR-T cell therapies. Herein, a low-cost, tunable, macroporous, alginate scaffold that transduces T cells with retroviral vectors under static condition is described. CAR-T cells produced by macroporous scaffold-mediated viral transduction exhibit >60% CAR expression, retain effector phenotype, expand to clinically relevant cell numbers, and eradicate CD19+ lymphoma in vivo. Efficient transduction is dependent on scaffold macroporosity. Taken together, the data show that macroporous alginate scaffolds serve as an attractive alternative to current transduction protocols and have high potential for clinical translation to genetically modify T cells for adoptive cellular therapy.


Endoscope-assisted resection of a brainstem cavernoma.
Procedures on cavernous malformations of the brainstem are challenging due to their eloquent location. This accounts especially for recurrent cavernomas as surgical scars, adhesions, and functional shift might have occurred since primary surgery. We report on a 38-year-old female patient with a large recurrent brainstem cavernoma, who underwent previous successful surgery and experienced recurrent bleeding about 2 years later. She harbored a large associated developmental venous anomaly (DVA) traversing the cavernoma through the midline of the brainstem. In order to visualize complete resection and preservation of the DVA at the same time, endoscopic-assisted resection within the brainstem after decompression in the semisitting position was performed. The video can be found here: https://youtu.be/K1p-Sx7jUpA.


A new species of the genus Proutia Tutt (Lepidoptera, Psychidae) from Korea, based on morphology and DNA barcodes.
The genus Proutia Tutt, 1899 (Lepidoptera, Psychidae) comprises 14 species found throughout the world. In East Asia, three species, Proutiachinensis Hättenschwiler & Chao, 1990, P.maculatella Saigusa & Sugimoto, 2014 and P.nigra Saigusa & Sugimoto, 2014, are known from Korea, Japan and China. Proutiacornucervae Roh & Lee, sp. nov. is newly recognised from Korea. In addition, Bruandellaniphonica (Hori) is transferred to genus Proutia. Male and genitalia of the species are described and DNA barcodes are provided.


Hydrogen peroxide is a second messenger in the salicylic acid-triggered adventitious rooting process in mung bean seedlings.
In plants, salicylic acid (SA) is a signaling molecule that regulates disease resistance responses, such as systemic acquired resistance (SAR) and hypertensive response (HR). SA has been implicated as participating in various biotic and abiotic stresses. This study was conducted to investigate the role of SA in adventitious root formation (ARF) in mung bean (Phaseolus radiatus L) hypocotyl cuttings. We observed that hypocotyl treatment with SA could significantly promote the adventitious root formation, and its effects were dose and time dependent. Explants treated with SA displayed a 130% increase in adventitious root number compared with control seedlings. The role of SA in mung bean hypocotyl ARF as well as its interaction with hydrogen peroxide (H2O2) were also elucidated. Pretreatment of mung bean explants with N, N'-dimethylthiourea (DMTU), a scavenger for H2O2, resulted in a significant reduction of SA-induced ARF. Diphenyleneiodonium (DPI), a specific inhibitor of membrane-linked NADPH oxidase, also inhibited the effect of adventitious rooting triggered by SA treatment. The determination of the endogenous H2O2 level indicated that the seedlings treated with SA could induce H2O2 accumulation compared with the control treatment. Our results revealed a distinctive role of SA in the promotion of adventitious rooting via the process of H2O2 accumulation. This conclusion was further supported by antioxidant enzyme activity assays. Based on these results, we conclude that the accumulation of free H2O2 might be a downstream event in response to SA-triggered adventitious root formation in mung bean seedlings.


A Rat Model of Fetal Alcohol Syndrome: A Series of Undergraduate Laboratory Exercises for Biopsychology Courses.
Many undergraduate students are aware that consuming alcohol during pregnancy can result in many serious physical and behavioral deficits. Student interest in this clinical syndrome allows instructors to provide engaging laboratory exercises that relate topics covered in most biopsychology courses to Fetal Alcohol Syndrome (FAS). Through this series of experiments, students will use rodents to study the behavioral deficits that can be caused by developmental alcohol exposure, including impaired ultrasonic vocalizations, hyperactivity, balance, and spatial learning. Other possible exercises include analyzing blood alcohol concentrations (BACs), completing histological studies of anatomical effects, and/or discussing the societal implications of developmental alcohol exposure. The instructor has the flexibility to determine which of the exercises fit into the class schedule and budget since he or she may choose to complete all of the behavioral tests or only one of them. Students will also learn about the benefits and drawbacks of animal models for human disorders, important considerations in research design such as reliability and validity, while also gaining experience in statistical analyses and writing empirical research papers. The application of these important concepts to a human syndrome and the use of small, easy-to-handle rodent pups make these exercises an accessible, stimulating introduction to animal research for most undergraduate students.


[A collection of songs from Charles-Louis Cadet de Gassicourt].
This unpublished manuscript collection of forty songs by C.-L. Cadet de Gassicourt (1769-1821), written for the most part between 1815 and 1827, offers simultaneously severe judgments on Parisian life, society and royal authority, and reflelctions of the disordered sentimental life of the author. Spiritual in form and sprightly in style, these are the deep feelings of the author, which seem strongly imbued with disappointment and bitterness.


Bone morphogenetic protein 13 stimulates cell proliferation and production of collagen in human patellar tendon fibroblasts.
Recombinant human (rh) bone morphogenetic protein 13 (BMP13) has been shown to induce the formation of tendon and ligament tissues in animal experiments. The role of BMP13 in tissue regeneration in human tendons remains unexplored, however. We collected healthy human patellar tendon samples for histological examination and tendon fibroblast culture. The cultured cells were incubated in the presence and absence of rhBMP13 and the effect of the protein on cell proliferation was measured using 5-bromo-2'-deoxyuridine uptake. BMP13 was detectable by immunohistochemical staining in healthy patellar tendon samples, and was located exclusively in active tenoblasts and perivascular mesenchymal cells but not in interstitial tenocytes. The expression of proliferating cell nuclear antigen (PCNA) and pro-collagen type I showed a similar distribution. In vitro studies showed that rhBMP13 can increase proliferation of tendon fibroblasts and increase the gene expression of pro-collagen type I in tendon fibroblast culture. Our findings indicate that BMP13 may be involved in the matrix remodeling process in adult tendon, and that it may play a role in tissue regeneration in tendons.


Visual imagery during real-time fMRI neurofeedback from occipital and superior parietal cortex.
Visual imagery has been suggested to recruit occipital cortex via feedback projections from fronto-parietal regions, suggesting that these feedback projections might be exploited to boost recruitment of occipital cortex by means of real-time neurofeedback. To test this prediction, we instructed a group of healthy participants to perform peripheral visual imagery while they received real-time auditory feedback based on the BOLD signal from either early visual cortex or the medial superior parietal lobe. We examined the amplitude and temporal aspects of the BOLD response in the two regions. Moreover, we compared the impact of self-rated mental focus and vividness of visual imagery on the BOLD responses in these two areas. We found that both early visual cortex and the medial superior parietal cortex are susceptible to auditory neurofeedback within a single feedback session per region. However, the signal in parietal cortex was sustained for a longer time compared to the signal in occipital cortex. Moreover, the BOLD signal in the medial superior parietal lobe was more affected by focus and vividness of the visual imagery than early visual cortex. Our results thus demonstrate that (a) participants can learn to self-regulate the BOLD signal in early visual and parietal cortex within a single session, (b) that different nodes in the visual imagery network respond differently to neurofeedback, and that (c) responses in parietal, but not in occipital cortex are susceptible to self-rated vividness of mental imagery. Together, these results suggest that medial superior parietal cortex might be a suitable candidate to provide real-time feedback to patients suffering from visual field defects.


A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses.
Zika virus (ZIKV), a re-emerging flavivirus associated with neurological disorders, has spread rapidly to more than 70 countries and territories. However, no specific vaccines or antiviral drugs are currently available to prevent or treat ZIKV infection. Here we report that a synthetic peptide derived from the stem region of ZIKV envelope protein, designated Z2, potently inhibits infection of ZIKV and other flaviviruses in vitro. We show that Z2 interacts with ZIKV surface protein and disrupts the integrity of the viral membrane. Z2 can penetrate the placental barrier to enter fetal tissues and is safe for use in pregnant mice. Intraperitoneal administration of Z2 inhibits vertical transmission of ZIKV in pregnant C57BL/6 mice and protects type I or type I/II interferon receptor-deficient mice against lethal ZIKV challenge. Thus, Z2 has potential to be further developed as an antiviral treatment against ZIKV infection in high-risk populations, particularly pregnant women.


Interleukins and their signaling pathways in the Reactome biological pathway database.
There is a wealth of biological pathway information available in the scientific literature, but it is spread across many thousands of publications. Alongside publications that contain definitive experimental discoveries are many others that have been dismissed as spurious, found to be irreproducible, or are contradicted by later results and consequently now considered controversial. Many descriptions and images of pathways are incomplete stylized representations that assume the reader is an expert and familiar with the established details of the process, which are consequently not fully explained. Pathway representations in publications frequently do not represent a complete, detailed, and unambiguous description of the molecules involved; their precise posttranslational state; or a full account of the molecular events they undergo while participating in a process. Although this might be sufficient to be interpreted by an expert reader, the lack of detail makes such pathways less useful and difficult to understand for anyone unfamiliar with the area and of limited use as the basis for computational models. Reactome was established as a freely accessible knowledge base of human biological pathways. It is manually populated with interconnected molecular events that fully detail the molecular participants linked to published experimental data and background material by using a formal and open data structure that facilitates computational reuse. These data are accessible on a Web site in the form of pathway diagrams that have descriptive summaries and annotations and as downloadable data sets in several formats that can be reused with other computational tools. The entire database and all supporting software can be downloaded and reused under a Creative Commons license. Pathways are authored by expert biologists who work with Reactome curators and editorial staff to represent the consensus in the field. Pathways are represented as interactive diagrams that include as much molecular detail as possible and are linked to literature citations that contain supporting experimental details. All newly created events undergo a peer-review process before they are added to the database and made available on the associated Web site. New content is added quarterly. The 63rd release of Reactome in December 2017 contains 10,996 human proteins participating in 11,426 events in 2,179 pathways. In addition, analytic tools allow data set submission for the identification and visualization of pathway enrichment and representation of expression profiles as an overlay on Reactome pathways. Protein-protein and compound-protein interactions from several sources, including custom user data sets, can be added to extend pathways. Pathway diagrams and analytic result displays can be downloaded as editable images, human-readable reports, and files in several standard formats that are suitable for computational reuse. Reactome content is available programmatically through a REpresentational State Transfer (REST)-based content service and as a Neo4J graph database. Signaling pathways for IL-1 to IL-38 are hierarchically classified within the pathway "signaling by interleukins." The classification used is largely derived from Akdis et al. The addition to Reactome of a complete set of the known human interleukins, their receptors, and established signaling pathways linked to annotations of relevant aspects of immune function provides a significant computationally accessible resource of information about this important family. This information can be extended easily as new discoveries become accepted as the consensus in the field. A key aim for the future is to increase coverage of gene expression changes induced by interleukin signaling.


Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone.
Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%-13% of the general population and 20%-30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABAA receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABAA receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.


Implication of Tityus apiacas (Lourenco, 2002) in scorpion envenomations in the Southern Amazon border, Brazil.
Herein, four cases of scorpion stings caused by Tityus apiacas recorded from the municipality of Apuí, in the southern region of the Brazilian Amazon, are described. Patients showed systemic clinical manifestations, described as unusual, involuntary, and generalized tingling and numbness, reported by patients as an electric shock sensation, lasting up to 24 hours after the sting. All patients described local pain and sensation, along with other clinical symptoms including local edema and erythema. Systemic manifestations were not life threatening. Antivenom therapy was administered to all patients, who were discharged without complaints.


Sirtuins and beta-cell function.
Over the past century, there have been major advances in medicine, diet and living conditions that have substantially extended the health span of people in the developed world. Over the past decade or so, the science of ageing has made great strides in providing an understanding of the underlying causes of ageing and how diet and genes play into the ageing process. In this essay, we will review some of the recent advances made in the science of sirtuins and beta-cell biology, and discuss how we will apply this knowledge to further the progress of humankind in healthy ageing.


Abdominal drainage to prevent intra-peritoneal abscess after appendectomy for complicated appendicitis.
This is the second update of a Cochrane Review first published in 2015 and last updated in 2018. Appendectomy, the surgical removal of the appendix, is performed primarily for acute appendicitis. Patients who undergo appendectomy for complicated appendicitis, defined as gangrenous or perforated appendicitis, are more likely to suffer postoperative complications. The routine use of abdominal drainage to reduce postoperative complications after appendectomy for complicated appendicitis is controversial. To assess the safety and efficacy of abdominal drainage to prevent intraperitoneal abscess after appendectomy (irrespective of open or laparoscopic) for complicated appendicitis; to compare the effects of different types of surgical drains; and to evaluate the optimal time for drain removal. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid Embase, Web of Science, the World Health Organization International Trials Registry Platform, ClinicalTrials.gov, Chinese Biomedical Literature Database, and three trials registers on 24 February 2020, together with reference checking, citation searching, and contact with study authors to identify additional studies. We included all randomised controlled trials (RCTs) that compared abdominal drainage versus no drainage in people undergoing emergency open or laparoscopic appendectomy for complicated appendicitis. We also included RCTs that compared different types of drains and different schedules for drain removal in people undergoing appendectomy for complicated appendicitis. We used standard methodological procedures expected by Cochrane. Two review authors independently identified the trials for inclusion, collected the data, and assessed the risk of bias. We used the GRADE approach to assess evidence certainty. We included intraperitoneal abscess as the primary outcome. Secondary outcomes were wound infection, morbidity, mortality, hospital stay, hospital costs, pain, and quality of life. Use of drain versus no drain We included six RCTs (521 participants) comparing abdominal drainage and no drainage in participants undergoing emergency open appendectomy for complicated appendicitis. The studies were conducted in North America, Asia, and Africa. The majority of participants had perforated appendicitis with local or general peritonitis. All participants received antibiotic regimens after open appendectomy. None of the trials was assessed as at low risk of bias. The evidence is very uncertain regarding the effects of abdominal drainage versus no drainage on intraperitoneal abscess at 30 days (risk ratio (RR) 1.23, 95% confidence interval (CI) 0.47 to 3.21; 5 RCTs; 453 participants; very low-certainty evidence) or wound infection at 30 days (RR 2.01, 95% CI 0.88 to 4.56; 5 RCTs; 478 participants; very low-certainty evidence). There were seven deaths in the drainage group (N = 183) compared to one in the no-drainage group (N = 180), equating to an increase in the risk of 30-day mortality from 0.6% to 2.7% (Peto odds ratio 4.88, 95% CI 1.18 to 20.09; 4 RCTs; 363 participants; low-certainty evidence). Abdominal drainage may increase 30-day overall complication rate (morbidity; RR 6.67, 95% CI 2.13 to 20.87; 1 RCT; 90 participants; low-certainty evidence) and hospital stay by 2.17 days (95% CI 1.76 to 2.58; 3 RCTs; 298 participants; low-certainty evidence) compared to no drainage. The outcomes hospital costs, pain, and quality of life were not reported in any of the included studies. There were no RCTs comparing the use of drain versus no drain in participants undergoing emergency laparoscopic appendectomy for complicated appendicitis. Open drain versus closed drain There were no RCTs comparing open drain versus closed drain for complicated appendicitis. Early versus late drain removal There were no RCTs comparing early versus late drain removal for complicated appendicitis. The certainty of the currently available evidence is low to very low. The effect of abdominal drainage on the prevention of intraperitoneal abscess or wound infection after open appendectomy is uncertain for patients with complicated appendicitis. The increased rates for overall complication rate and hospital stay for the drainage group compared to the no-drainage group are based on low-certainty evidence. Consequently, there is no evidence for any clinical improvement with the use of abdominal drainage in patients undergoing open appendectomy for complicated appendicitis. The increased risk of mortality with drainage comes from eight deaths observed in just under 400 recruited participants. Larger studies are needed to more reliably determine the effects of drainage on morbidity and mortality outcomes.


Sex Differences in Functional Connectivity of the Salience, Default Mode, and Central Executive Networks in Youth with ASD.
Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8-17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.


The aging/precancerous gastric mucosa: a pilot nutraceutical trial.
The aim of this study was to test the effect of antioxidant supplementation on enzymatic abnormalities and free radical-modified DNA adducts associated with premalignant changes in the gastric mucosa of elderly patients with HP-negative atrophic gastritis (CAG). Sixty patients with atrophic gastritis and intestinal metaplasia underwent a nutritional interview and a gastroscopy with multiple biopsy samples in the antrum that were processed for histology and for assaying: alpha-tocopherol, MDA, xanthine oxidase (XO), ornithine decarboxylase (ODC), and 8-OHdG. Patients were randomly allocated into three matched groups and supplemented for 6 months with (1) vitamin E, 300 mg/day; (2) multivitamin, two tablets t.i.d.; and (3) Immun-Age 6 g/day nocte (ORI, Gifu, Japan), a certified fermented papaya preparation with basic science-validated antioxidant/immunomodulant properties. Ten dyspeptic patients served as controls. Histology and biochemistry were blindly repeated at 3 and 6 months. CAG patients showed a significantly (P <.05) increased level of mucosal MDA and XO concentration that were reverted to normal by each supplementation (P <.05). All supplements caused a significant decrease of ODC (P <.01), but Immun-Age yielded the most effective (P < 0.05) and was the only one significantly decreasing 8-OhdG (P < 0.05). These data suggest that antioxidant supplementation, and, namely, Immun-Age, might be potential chemopreventive agents in HP-eradicated CAG patients and especially in the elderly population.


Effect of shape and size of silanated fillers on mechanical properties of experimental photo cure composite resins.
The binary system of hybrid fillers selected from four irregular fillers (1.7-21.5 microns), five spherical fillers (0.46-31.2 microns), and a microfiller of 0.04 micron, were applied to photo cure composite resin and mechanical properties were measured. The strength for the hybrid of irregular and spherical fillers tended to increase as the size of component fillers decreased. The strength for the hybrid of the same fillers in shape also increased as the size of fillers decreased. The strength for the hybrid containing 30% microfiller showed the same trend, especially, the largest strength was obtained from hybrids containing small spherical fillers.


Wind dispersal results in a gradient of dispersal limitation and environmental match among discrete aquatic habitats.
Directional dispersal by wind and other dispersal agents may generate spatial patterns in passively dispersing metacommunities which cannot be detected by classical eigenvector methods based on Euclidean distances. We analysed zooplankton communities (Rotifera, Cladocera, Copepoda) in a cluster of soda pans distributed over a short spatial scale of 18 km and tested explicitly for directional signals in their spatial configuration. The study area is exposed to a prevailing northwestern wind direction. By applying asymmetric eigenvector maps (AEM), we were able to identify corresponding directionality in the spatial structure of communities. Furthermore, the match between community composition and environmental conditions exhibited a spatial pattern consistent with the prevailing wind corridor, with best match found downwind the dominant wind direction. We also found that classical eigenvector methods based on Euclidean distances underestimated the role of spatial processes in our data. Our study furthermore shows that dispersal limitation may constrain community assembly in highly mobile organisms even at spatial scales below 5 km.


A sensitive quantitative assay for the determination of propafenone and two metabolites, 5-hydroxypropafenone and N-depropylpropafenone, in human K2EDTA plasma using LC-MS/MS with ESI operated in positive mode.
Propafenone is a potent antiarrhythmic agent; clinically propafenone has been used for a number of cardiac arrhythmias because it possesses multiple modes of action, via beta adrenergic receptor blockade and calcium antagonistic activity. Propafenone (PPF) exhibits extensive saturable presystemic biotransformation (first-pass effect) resulting in two active metabolites: 5-hydroxypropafenone (5-OH PPF) formed by CYP2D6 and N-depropylpropafenone (NDP) formed by both CYP3A4 and CYP1A2 enzymes. A specific and sensitive LC-MS/MS method was developed and validated for quantitation of PPF, 5-OH PPF and NDP using turboion spray in a positive ion mode. A solid-phase extraction was employed for the extraction from human plasma. Chromatographic separation of analytes was achieved using an ACE-5 C8 (50 × 4.6 mm) column with a gradient mobile phase comprising ammonium acetate containing 0.01% TFA in purified water and acetonitrile. The retention times achieved were 1.36, 1.23, 1.24 min and 1.34 min for PPF, 5-OH PPF, NDP and IS (carbamazepine), respectively. Quantitation was performed by monitoring multiple reaction monitoring transition pairs of m/z 342.30 to m/z 116.20, m/z 358.30 to m/z 116.20, m/z 300.30 to m/z 74.20 and m/z 237.20 to m/z 194.10, respectively. The developed method was validated for various parameters. The calibration curves of PPF and 5-OH PPF showed linearity from 1 to 500 ng/mL, with a lower limit of quantitation of 1.0 ng/mL and for NDP linearity from 0.1 to 25 ng/mL with a lower limit of quantitation of 0.1 ng/mL. The bias and precision for intra- and-inter batch assays were <10 and 5%, respectively. The developed assay was used to evaluate pharmacokinetic properties of propafenone and its major metabolites in healthy human subjects.


Cost effectiveness of rabies post exposure prophylaxis in the United States.
There is growing concern in the United States about the excessive use of rabies post exposure prophylaxis (PEP) treatment. In this paper we have estimated the cost effectiveness of rabies PEP treatment under various scenarios of rabies transmission. When the risk of a patient getting rabies is deemed greater than 0.7%, then giving PEP will be cost saving (societal perspective). For lower risks of transmission, cost effectiveness estimates ranged from approximately $500,000 per life saved to $billions. The uncertainty caused by the wide range of cost effectiveness can only be resolved through analysis of data describing rabies transmission risk in a variety of scenarios.


Resuscitation of multiple trauma and head injury: role of crystalloid fluids and inotropes.
To determine the hemodynamic responses to blunt trauma with a closed-head injury and to investigate the effect that volume resuscitation has on intracranial pressure. Prospective study with retrospective analysis of patient data and hemodynamic responses. Surgical intensive care unit at an inner-city, Level I trauma center. Consecutive patients (n = 30) who sustained multiple system injury, including a closed-head injury that was severe enough to require intracranial pressure monitoring but not a craniotomy. All patients underwent invasive hemodynamic monitoring with percutaneous arterial and pulmonary arterial catheters. Serum lactate concentrations and hemodynamic and oxygen transport variables were measured every 4 hrs. Intracranial pressures and vital signs were recorded each hour. Attempts were made to achieve a state of nonflow-dependent oxygen consumption and a normal serum lactate concentration. Despite being normotensive and neither tachycardiac nor oliguric, 80% of patients had evidence of inadequate tissue perfusion. Only 50% of the remaining patients had an adequate response to volume. The other 50% received vasodilating inotropic agents. Despite volume loading and the administration of inotropic agents, intracranial pressure did not increase. This observation was found in patients who showed clinically important intracranial pathology on computed tomography scan, as well as in all other patients. Intracranial pressure did not correlate with the amount of fluid or blood infused or with hemodynamic performance, but intracranial pressures did correlate with serum lactate concentrations. Many patients with diffuse blunt trauma closed-head injuries, even when they are normotensive, have evidence of impaired peripheral perfusion. Volume infusion and vasodilating inotropic support improve oxygen transport without increasing intracranial pressure. The observed relationship between intracranial pressure and the serum lactate concentration requires further study.


Synthesis and beta-lactamase inhibitory activity of 6-[(1-heteroarylthioethyl-1,2,3-triazol-4-yl)-methylene]penam sulfones.
The synthesis of beta-lactamase inhibitory activity of a series of sodium 6-[(1-heteroarylthioethyl-1,2,3-triazol-4-yl)methylene]pe nicillanate, 1,1-dioxides are described. Their activity was compared with tazobactam and sulbactam. The Z-isomers were more active than the E-isomers. The in vitro activity of the Z-isomers of the phenylthiadiazole derivatives (13a and 15a) was better than sulbactam against the tested beta-lactamases and comparable to tazobactam especially against TEM-2 and cephalosporinase. But their synergistic activity with five antibiotics was inferior to tazobactam.


Bronchiolitis in Infants; Five Years' Experience of a Teaching Hospital.
Bronchiolitis is a clinical syndrome affecting the lower respiratory tract of infants and toddlers <2 years old. Variability in clinical profile and response to therapy in children with Bronchiolitis calls for studying the different clinical aspects of local patient population. The goal of our study is to determine the clinical presentation, past medical history, hospitalization course and prognosis in children below two years of age who have been hospitalized in King Fahad University Hospital over the last five years. A retrospective chart review based on electronic health records of all Bronchiolitis-related hospitalization of infants and toddlers below two years of age, covering the period between January 1, 2015, to April 26, 2020. Out of a total of 446 children <2 years of age, 202 were female (45.4%), and 243 were male (54.6%). Although the length of hospital stay was almost equal between the sexes, there was a significant (p-value=0.01) increase in length of intensive care unit stay among females compared to males. Furthermore, there was a significant prolongation in the duration of ventilator usage among females (p value = 0.062). Out of fifty-five patients admitted to the ICU, 83.63% of them were 12 months of age and below. Our results show a significant increase in length of ICU and ventilator use among females compared to males. It also shows that infants younger than 12 months account for most ICU admissions. These findings, among many others, may help pediatricians formulate a better diagnostic and therapeutic pathways.


A Computerized Tutor Prototype for Prostate Cryotherapy: Key Building Blocks and System Evaluation.
This paper focuses on the evaluation of a prototype for a computer-based tutoring system for prostate cryosurgery, while reviewing its key building blocks and their benchmark performance. The tutoring system lists geometrical constraints of cryoprobe placement, displays a rendered shape of the prostate, simulates cryoprobe insertion, enables distance measurements, simulates the corresponding thermal history, and evaluates the mismatch between the target region shape and a pre-selected planning isotherm. The quality of trainee planning is measured in comparison with a computer-generated plan, created for each case study by a previously developed planning algorithm, known as bubble-packing. While the tutoring level in this study aims only at geometrical constraints on cryoprobe placement and the resulting thermal history, it creates a unique opportunity to gain insight into the process outside of the operation room. System validation of the tutor has been performed by collecting training data from surgical residents, having no prior experience or advanced knowledge of cryotherapy. Furthermore, the system has been evaluated by graduate engineering students having no formal education in medicine. In terms of match between a planning isotherm and the target region shape, results demonstrate medical residents' performance improved from 4.4% in a pretest to 37.8% in a posttest over a course of 50 minutes of training (within 10% margins from a computer-optimized plan). Comparing those results with the performance of engineering students indicates similar results, suggesting that planning of the cryoprobe layout essentially revolves around geometric considerations.


[Technology upgrades and exposure to chemical agents: results of the PPTP study in the footwear industry].
In the present work the chemical compositions of the products used in shoes manufacturing are reported. The data were collected over the period 2004-2007 in 156 shoe factories in Vigevano area during a study aiming the evaluation of safety conditions and occupational exposure to hazardous chemicals of the employees. The study was part of a regional project for "Occupational cancer prevention in the footwear industry". In the first phase of the study an information form on production cycle, products used and their composition was filled during preliminary audit. In the second phase of the study an in depth qualitative/quantitative evaluation of professional exposure was conducted in 13 selected shoe factories. Data analysis showed the increase in use of water-based adhesives at expense of solvent-based adhesives, the reduction to less than 3.5 weight %, and up to 1 weight %, of n-hexane concentration in solvent mixtures, the increase in use of products containing less hazardous ketones, esters, cyclohexane and heptane. Only in very few cases, products containing from 4 to 12 weight% of toluene were used. These data attest a positive trend in workers risks prevention in shoes industry.


The functional and structural alterations of the striatum in chronic spontaneous urticaria.
The brain has long been known to be the regulation center of itch, but the neuropathology of chronic itch, such as chronic spontaneous urticaria (CSU), remains unclear. Thus, we aimed to explore the brain areas involved in the pathophysiology of CSU in hopes that our results may provide valuable insights into the treatment of chronic itch conditions. 40 CSU patients and 40 healthy controls (HCs) were recruited. Urticaria activity scores 7 (UAS7) were collected to evaluate patient's clinical symptoms. Amplitude of low frequency fluctuations (ALFF), voxel-based morphometry (VBM), and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess brain activity and related plasticity. Compared with HCs, CSU patients exhibited 1) higher ALFF values in the right ventral striatum / putamen, which were positively associated with clinical symptoms as measured by UAS7; 2) gray matter volume (GMV) increase in the right ventral striatum and putamen; and 3) decreased rs-FC between the right ventral striatum and the right occipital cortex and between the right putamen and the left precentral gyrus. Using multiple-modality brain imaging tools, we demonstrated the dysfunction of the striatum in CSU. Our results may provide valuable insights into the neuropathology and development of chronic itch.


Validation of the Dutch Sensory Gating Inventory (D-SGI): Psychometric properties and a Confirmatory factor analysis.
The Sensory Gating Inventory (SGI) is an established self-report questionnaire that is used to assess the capacity for filtering redundant or irrelevant environmental stimuli. Translation and cross-cultural validation of the SGI are necessary to make this tool available to Dutch speaking populations. This study, therefore, aimed to design and validate a Dutch Sensory Gating Inventory (D-SGI). To this end, a forward-backward translation was performed and 469 native Dutch speakers filled in the questionnaire. A confirmatory factor analysis assessed the psychometric properties of the D-SGI. Additionally, test-retest reliability was measured. Results confirmed satisfactory similarity between the original English SGI and the D-SGI in terms of psychometric properties for the factor structure. Internal consistency and discriminant validity were also satisfactory. Overall test-retest reliability was excellent (ICC = 0.91, p < 0.001, 95% CI [0.87-0.93]). These findings confirm that the D-SGI is a psychometrically sound self-report measure that allows assessing the phenomenological dimensions of sensory gating in Dutch. Moreover, the D-SGI is publicly available. This establishes the D-SGI as a new tool for the assessment of sensory gating dimensions in general- and clinical Dutch speaking populations.


Epidemic keratoconjunctivitis: a community outbreak of mixed adenovirus type 8 and type 19 infection.
During the fall and winter of 1973, 145 cases of epidemic keratoconjunctivitis were diagnosed in Nashville, Tennessee. Of the 74 cases studied virologically and/or serologically, 62% were caused by adenovirus type 8, and 28% were caused by adenovirus 19. Whereas adenovirus type 8 was isolated only from conjunctival scrapings, adenovirus type 19 was isolated from nose and throat swabs as well as from conjunctivae. The two viruses produced clinically indistinguishable eye disease and household secondary attack rates that were not statistically different. Regardless of etiology, the secondary attack rate in households was significantly higher among the contacts of those patients who had severe disease for greater than 28 days than among the contacts of patients who had milder disease of shorter duration.


Enolases from Gram-positive bacterial pathogens and commensal lactobacilli share functional similarity in virulence-associated traits.
Enolase occurs as a cytoplasmic and a surface-associated protein in bacteria. Enolases of the bacterial pathogens Streptococcus pyogenes, Streptococcus pneumoniae and Staphylococcus aureus, as well as of the commensal lactic acid bacteria, Lactobacillus crispatus and Lactobacillus johnsonii, were purified as His(6)-fusion proteins from recombinant Escherichia coli. The fusion proteins were compared for putative virulence-associated functions, i.e., binding of human plasminogen, enhancement of plasminogen activation by human plasminogen activators, as well as binding to immobilized laminin, fibronectin and collagens. The individual enolases showed varying efficiencies in these functions. In particular, highly and equally effective interactions with plasminogen and laminin were seen with lactobacillar and staphylococcal enolases.


Familial cerebral, hepatic, and retinal cavernous angiomas: a new syndrome.
New, non-invasive neuroradiological techniques [computed tomography (CT) and magnetic resonance (MR)] have led to reassessment of the incidence of cavernous angioma of the brain (CCA), which is sometimes multiple and associated with cavernomas in other organs. CCA is known to be familial, with dominant autosomal transmission. This paper concerns a family with multiple CCA, sometimes in association with liver angiomas, in ten members belonging to four different generations. These malformations can vary in clinical expression: no neurological symptoms have been detected in subjects from the first or second generations, but they were found in adult age in subjects from the third generation; two fourth-generation patients came under our observation at 2.5 years of age. Symptoms include partial epileptic fits, which sometimes become generalized later and which are generally controlled adequately by therapy. Patients also present paresthesia and occasional motor deficiencies corresponding to CCA bleeding episodes; these symptoms have always abated with medical treatment alone. None of the patients are mentally retarded or restricted in their daily lives. Neuroradiological investigations (CT, MR, angiography) reveal typical multiple brain lesions in all patients. Given the first-generation patient's clinical history of symptomatic hepatomegaly and the postmortem finding of multiple liver and brain cavernomas, liver ultrasonography was performed on all members of the family. Liver angioma was detected in two subjects from the second and third generations. Retinal angioma was detected in one patient with quadrantanopsia.(ABSTRACT TRUNCATED AT 250 WORDS)


Geometry dependent features of optically induced forces between silver nanoparticles.
A recently devised, discrete-dipole approximation (DDA) based method for computing optical forces is used to explore geometry dependent aspects of the light induced interactions between pairs of silver nanoparticles, including the influence of particle shape, relative positioning of the particles, and incident field orientation. The interactions are observed to have a large degree of generic character, independent of the details of the particle shape. The size of the optical forces is also compared to estimates for the van der Waals forces, and the results are used to assess the potential importance of radiation forces on recent experiments demonstrating photoinduced self-assembly of triangular silver nanoprisms.


Long-term carbon loss in fragmented Neotropical forests.
Tropical forests play an important role in the global carbon cycle, as they store a large amount of carbon (C). Tropical forest deforestation has been identified as a major source of CO2 emissions, though biomass loss due to fragmentation--the creation of additional forest edges--has been largely overlooked as an additional CO2 source. Here, through the combination of remote sensing and knowledge on ecological processes, we present long-term carbon loss estimates due to fragmentation of Neotropical forests: within 10 years the Brazilian Atlantic Forest has lost 69 (±14) Tg C, and the Amazon 599 (±120) Tg C due to fragmentation alone. For all tropical forests, we estimate emissions up to 0.2 Pg C y(-1) or 9 to 24% of the annual global C loss due to deforestation. In conclusion, tropical forest fragmentation increases carbon loss and should be accounted for when attempting to understand the role of vegetation in the global carbon balance.


Assessing risk factors for postoperative nausea and vomiting: a retrospective study in patients undergoing retromastoid craniectomy with microvascular decompression of cranial nerves.
We have observed that patients, after retromastoid craniectomy (RMC) with microvascular decompression (MVD) of cranial nerves, frequently experienced postoperative nausea and vomiting (PONV). The authors conducted this study to track the incidence of PONV and to identify potential factors for PONV after RMC with MVD. Medical records from 185 adults, who underwent elective RMC with MVD, were identified and reviewed from January 2000 to December 2004. Extracted data included patient, anesthesia, and surgery related variables that were considered to have a possible effect on the patients experiencing PONV after RMC with MVD. Despite the use of intraoperative prophylactic ondansetron in 99% of patients, the overall incidence of PONV (nausea or emesis or both) was 60% during the first 24 hours postoperatively. It was higher for the patients after RMC with MVD of cranial nerve V [69%, 82/119, P=0.005, odds ratio (OR)=2.8]. Regression modeling demonstrated that female sex (OR=3.0, P=0.005) and use of desflurane (OR=2.8, P=0.003) were significant independent predictors of PONV. Prophylactic transdermal scopolamine patch administered preoperatively was associated with less PONV (OR=0.3, P=0.001). We concluded that PONV occurs frequently in adults recovering from RMC with MVD. The results of this study suggest that it may be necessary to administer a combination of antiemetics to decrease the incidence of PONV after RMC.


Immunoreactive calcitonin content in foetal thyroid glands and in placentae of rats.
Immunoreactive calcitonin (I-CT) was assayed in rat thyroid glands from foetuses with a gestational age of 15.5-22 days. The mean content of the hormone was 455.0 +/- 35.8 ng/gland. A positive linear correlation was found between the I-CT content in the thyroid glands and the gestational age of the foetuses. I-CT was also present in rat placentae from 10.5-21.5 days old pregnancies. A mean placental concentration of 4.5 +/- 1.2 ng I-CT/mg wet tissue was found. The highest hormone concentrations were observed in placentae from 10.5 day old foetuses, displaying a progressive fall during the further course of pregnancy. It is concluded that the rat foetal thyroid gland produces I-CT beginning from a gestational age of 15.5 days'. The need for further investigations into a possible role of CT in transplacental calcium transport is also indicated.


GH secretion is impaired in patients with primary hyperparathyroidism.
The activity of the GH/IGF-I axis as a function of parathyroid activity and calcium metabolism in humans has never been assessed. To address this issue, we studied 18 patients (5 men, 13 women; age range, 23-76 yr; mean, 61 yr) with primary hyperparathyroidism (PHP) due to solitary parathyroid adenoma. GH secretion was evaluated by serum IGF-I levels, spontaneous mean GH secretion over two morning hours, and GH response to arginine (ARG) alone or combined with GHRH. In five patients, serum GH concentrations were measured every 20 min for 24 h, and deconvolution analysis was performed. A group of 35 age- and sex-matched normal subjects served as controls. Mean serum IGF-I levels in PHP were lower than in normal controls, and in six PHP patients individual serum IGF-I levels were below the age-related normal range. The mean (+/-SE) peak GH response to ARG alone in PHP patients was significantly lower than in normal subjects (4.0 +/- 1.0 vs. 22.0 +/- 1.3 microg/liter; P < 0.001). Likewise, the mean (+/-SE) peak GH response to ARG plus GHRH was reduced in PHP patients (9.9 +/- 0.9 vs. 38.0 +/- 3.5 microg/liter; P < 0.001). The mean GH concentration over two morning hours in PHP was lower (0.20 +/- 0.05 vs. 1.34 +/- 0.31 microg/liter; P < 0.001). The mean GH concentration over 24 h in five PHP patients was lower than in six normal controls (0.3 +/- 0.1 vs. 0.7+/- 0.1 microg/liter; P < 0.05); the deconvolution analysis showed that 24-h GH production rate (3.0 +/- 1.7 vs. 28.2 +/- 4.7 microg/liter.d; P < 0.05) and mean secretory burst mass (1.2 +/- 0.7 vs. 10.5 +/- 2.6 microg/liter; P < 0.05), but not pulse frequency, were lower in PHP patients than in normal controls. GH half-life and approximate entropy values of 24-h GH profiles were similar in PHP patients and normal controls. No correlation was found between serum-ionized calcium or PTH levels and spontaneous or stimulated GH levels in PHP patients. In conclusion, this study demonstrates that PHP patients have a reduction in both spontaneous and stimulated GH secretion. Accordingly, PHP should be mentioned as a further example of a metabolic condition in which GH secretion in adults is reduced.


CVF-induced decomplementation: effect on lung transvascular protein flux after thrombin.
We examined the effects of cobra venom factor (CVF) on the changes in pulmonary hemodynamics and transvascular fluid and protein exchange following thrombin-induced pulmonary microembolism. Studies were made in unanesthetized sheep prepared with lung lymph fistulas. The animals received tranexamic acid (100 mg) to suppress fibrinolysis and were then challenged with an intravenous infusion of alpha-thrombin (80 U/kg). Control-thrombin challenged sheep were compared with the CVF-treated sheep challenged with the same thrombin dosage. CVF treatment (187 U X kg-1 X day-1 for 4 days) decreased the total hemolytic complement activity by 45% of control. Thrombin infusion in control sheep increased the mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), and lymph protein clearance (pulmonary lymph flow X lymph-to-plasma protein concentration ratio, Clym). Thrombin infusion in CVF-treated sheep produced smaller increments in Ppa, PVR, and Clym. Pulmonary lymph obtained from control-thrombin and CVF-thrombin sheep induced migration of granulocytes obtained from normal unchallenged sheep. The granulocytes obtained from CVF-treated sheep responded relatively less to the migratory and O-2-generating stimuli (i.e., zymosan-treated serum, pulmonary lymph from sheep after thrombin challenge, and plasma from sheep after CVF treatment) compared with normal granulocytes. The attenuation of the thrombin-induced increases in Ppa, PVR, and lung transvascular fluid and protein exchange by CVF treatment may be the result of impaired function of granulocytes.


Chemotherapy of L1210 leukemia with 5-azacytidine in combination with vincristine, adriamycin, or beta-cytosine arabinoside.
The cytotoxicity of vincristine (VCR), beta-cytosine arabinoside (Ara-C), or adriamycin (ADRIA) in combination with 5-azacytidine (Aza-CR) to L1210 leukemia in vivo was measured to determine if schedule-dependent synergistic or antagonistic drug interaction occurred. Two dose levels of Aza-CR were studied (0.1 and 0.5 mg/mouse), and cytotoxicity was measured by the spleen colony assay. For the combination of Aza-CR plus VCR, cytotoxicity was essentially additive or antagonistic when VCR preceded Aza-CR and additive or synergistic when VCR followed Aza-CR. When Aza-CR was combined simultaneously with either Ara-C or ADRIA, cytotoxicity was markedly antagonistic but was additive if drugs were given sequentially. When Ara-C was given as a 24-hour infusion before Aza-CR, the resultant cell kill was antagonistic (although slightly greater than that obtained for Ara-C alone). However, antagonism was even more marked when Aza-CR was given before the 24-hour infusion of Ara-C; cell kill was less than that observed with Ara-CR alone. Synergistic cytotoxicity was observed only with VCR administered after a low dose of of Aza-CR. Therefore, scheduling of drugs in combination with Aza-CR may be critical in the determination of the antileukemic cytotoxic effects.


In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project.
Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.


Fetus in Germany: the Fetus Protection Law of 12.13.1990.
The "Fetus Protection Law" (Embryonenschutzgesetz ESchG) regulates the abusive use of reproductive techniques, the use of human embryos and the choice of sex. The Bundestag has singled out certain practices as being abusive, prohibited them and put criminal sanctions on them. Individual exemptions from criminal prosecution are made in favour of the surrogate mother who is to be the target of an assisted procreation and the foster-father. The ESchG represents a snapshot of current views on current practices in reproductive medicine. And therefore the ESchG will be rendered obsolete by newly created reproductive technologies if legislation does not adapt the law to these changes.


High-performance liquid chromatographic assay for alpha-lipoic acid and five of its metabolites in human plasma and urine.
An isocratic reversed-phase HPLC method for the simultaneous quantitation of alpha-lipoic acid and five of its metabolites in human plasma as well as in human urine employing solid-phase extraction and pulsed amperometric detection was developed and validated. The method was found to be sufficiently precise and accurate for the measurement of alpha-lipoic acid and its metabolites 6,8-bis(methylthio)octanoic acid, 4,6-bis(methylthio)hexanoic acid and 2,4-bis(methylthio)butanoic acid in plasma and urine samples, obtained from patients suffering from diabetic neuropathy as well as from healthy volunteers following daily oral administration of 600 mg alpha-lipoic acid. The quantitation of the metabolite bisnorlipoic acid was often impaired by interferences caused by an unidentified metabolite. However, bisnorlipoic acid was detected in few test samples and the concentrations were consistently low. Despite the poor recovery of the metabolite tetranorlipoic acid from plasma, reproducibility and accuracy were found to be from acceptable magnitude to assess concentration time courses. Thus, the obtained analytical results are considered as reliable and well suited for pharmacokinetic studies of alpha-lipoic acid and its metabolites.


Inverse proximity effect in a strongly correlated electron system.
An anomalous superconducting proximity effect between a strongly correlated electron system and a normal metal is demonstrated. The model system is a 2D ultrathin superconducting quench-condensed Pb film. Such a highly disordered film has a reduced transition temperature (T(c) = 1.7 K) due to the strong e(-)-e(-) interaction. Instead of weakening the superconductivity, an overlayer of Ag on Pb induces an increase of both the T(c) and the gap. The restoration of the electron screening brought about by the quasiparticles from the normal metal can explain this striking inverse proximity effect.


The effect of dextran 40 and Dazmegrel on early platelet deposition onto vascular grafts.
Platelet deposition onto double velour Dacron (n = 14) and double velour Dacron with internal collagen (n = 14) interposition grafts were examined experimentally. The accumulation was assessed by reinfusion of 111In labelled platelets and imaging with a scintillation camera. One group received Dextran-40 intravenously (n = 14) and one group received Dazmegrel (n = 14) intravenously. No graft occlusions were noted. Differences in effects of Dextran-40 and Dazmegrel were not observed. The study indicates a beneficial effect of infused Dextran-40 as well as Dazmegrel. The explanation might be reduced interaction graft wall versus blood-platelets.


Irradiance inversion algorithm for absorption and backscattering profiles in natural waters: improvement for clear waters.
Our iterative inversion algorithm for retrieving absorption a(z) and backscattering b(b)(z) from profiles of upwelling and downwelling irradiance, on the basis of assuming a depth-independent phase function for the medium, was found to have unsatisfactory accuracy for b(b)(z) in clear waters. We modified the algorithm here by assuming a depth-independent phase function for the particles and then performing an additional iteration over the fraction of total scattering that is due to the water itself. The modified algorithm's accuracy is considerably improved over the original in clear waters and reduces to the original in waters for which the particle contribution to b(b)(z) is dominant.


Beta-Expansin of Bermuda, Johnson, and Para grass pollens, is a major cross-reactive allergen for Allergic Rhinitis patients in subtropical climate.
Subtropical grass pollens of Bermuda (BGP), Johnson (JGP), and Para or buffalo grass (PGP), are common causes of pollen allergies in warm climate area. Allergic rhinitis (AR) patients had positive skin prick test (SPT) to extract of these 3 grass pollens. However, no allergenic proteins of 3 grass pollens have never been studied. To identify major allergens of BGP, JGP, and PGP in Thai grass pollen-allergic patients and to examine their sIgE cross-reactivity. Serum of nine AR patients with positive SPT to at least 2 of 3 studied pollens were collected. Based on availability, only ImmunoCAP of BGP and JGP were available to determine a level of sIgE. Profiles of sIgE bound proteins from BGP, JGP, and PGP, were obtained by immunoblot. Major IgE bound protein was identified by liquid chromatography-tandem mass spectrophotometry (LC-MS/MS). Cross-reactivity of purified major allergen of the 3 grass pollens was determined by inhibition of sIgE in both ELISA and immunoblot. AR patients who have positive SPT to extract of BGP, JGP, and PGP, were 9, 8, and 6, respectively. Positive sIgE (> 0.35 kUA/L) to BGP and JGP were found in 9 and 8 patients, respectively. Eight profiles of IgE bound proteins of the 3 grass pollens showed 29-30 kDa pollen protein as major allergen and was identified as beta-expansin (ExpB). Moreover, purified ExpB of the 3 grass pollens cross-inhibited serum sIgE. ~30 kDa ExpB of BGP, JGP, and PGP, is major cross-reactive allergen for AR Thai patients.


Acute Retroperitoneal Hemorrhage Due to Multi-Vessel Aneurysmal Bleeding As the Initial Manifestation of Polyarteritis Nodosa in a Previously Healthy Female.
Polyarteritis nodosa (PAN) is a heterogeneous disease characterized by constitutional symptoms, multi-organ dysfunction, and a subacute to chronic mode of onset. We describe a rarely encountered manifestation of PAN in a previously healthy 64-year-old woman who developed acute intra-abdominal bleeding due to multi-vessel, vasculitis-induced retroperitoneal aneurysmal ruptures, followed by the spontaneous cessation of abdominal pain and intra-abdominal bleeding within 24 hours after hospitalization, in the absence of immunosuppressive treatment. Aneurysms regressed and eventually normalized coincident with a moderate-term course of oral corticosteroids and six months of monthly intravenous cyclophosphamide. Our report reveals that patients with life-threatening PAN may present acutely with unexpected historical, physical examination and laboratory features not commensurate with the gravity of the clinical findings. We also highlight that long-term survival lasting greater than 11 years can occur when the correct diagnosis and appropriate treatment are introduced early in the course of the illness.


Sympathetic restraint of muscle blood flow at the onset of dynamic exercise.
Little attention has focused on sympathetic influences on skeletal muscle blood flow at the onset of exercise. We hypothesized that 1) the sympathetic nervous system constrains muscle blood flow and 2) the decline from peak blood flow is mediated by increasing sympathetic vasoconstrictor tone. Mongrel dogs (n = 7) ran on a treadmill after intra-arterial infusion of saline (control) or combined alpha(1)- and alpha(2)-adrenergic blockade (prazosin and rauwolscine). Immediate and rapid increases in hindlimb blood flow occurred at commencement of exercise with peak iliac blood flows averaging 933 +/- 79 and 1,227 +/- 90 ml/min during control and blockade conditions, respectively. At 1 min of exercise, hindlimb blood flow had decreased to 629 +/- 54 and 1,057 +/- 89 ml/min. In the absence of sympathetic vasoconstrictor tone, there was an enhanced peak blood flow at the onset of exercise. In addition, alpha-blockade attenuated the overshoot of hindlimb blood flow compared with the control condition. These data suggest that an immediate and sustained increase in sympathetic outflow restrains hindlimb blood flow at the onset of exercise and is responsible, at least in part, for an overshoot of blood flow to exercising skeletal muscle.


Influence of Immune Status on the Airborne Colonization of Piglets with Methicillin-Resistant Staphylococcus aureus (MRSA) Clonal Complex (CC) 398.
Colonized vertebrates including humans and pigs are to date the main reservoirs of livestock-associated Methicillin-resistant Staphylococcus aureus (LA-MRSA). Currently, the mechanisms underlying colonization of pigs are not fully understood. We investigated the influence of piglet pre-immune status on airborne MRSA colonization. Three groups of MRSA-negative piglets were primed and exposed to airborne LA-MRSA (104 colony forming units (cfu)/m3) in an aerosol chamber for 24 h. One group was treated intramuscularly with dexamethasone (1 mg/kg body weight) to imitate weaning stress. The second group was exposed to bacterial endotoxin containing MRSA aerosol. Both conditions play a role in the development of multifactorial diseases and may promote MRSA colonization success. The third group served as control. The piglets' MRSA status was monitored for 21 days via swab samples. At necropsy, specific tissues and organs were analyzed. Blood was collected to examine specific immunological parameters. The duration of MRSA colonization was not extended in both treated groups compared to the control group, indicating the two immune-status influencing factors do not promote MRSA colonization. Blood sample analysis confirmed a mild dexamethasone-induced immune suppression and typical endotoxin-related changes in peripheral blood. Of note, the low-dose dexamethasone treatment showed a trend of increased MRSA clearance.


Singularity screening in generic optical fields.
We revisit the widely studied subject of screening in optical fields by topological charges and show that screening does not depend on charge ordering. Instead, for an array of N charges, screening requires that the variance of the charge fluctuations be small compared to N. We show by means of explicit examples that, when this requirement is met, screening can be complete, even for a spatially random arrangement of charges. We derive a minimal screening constraint on the charge correlation function and show that it is this constraint that is met in practice, rather than the more stringent constraints previously assumed.


Age and sex differences in microRNAs expression during the process of thymus aging.
The gender-biased thymus involution and the importance of microRNAs (miRNAs, miRs) expression in modulating the thymus development have been reported in many studies. However, how males and females differ in so many ways in thymus involution remains unclear. To address this question, we investigated the miRNA expression profiles in both untreated 3- and 12-month-old female and male mice thymuses. The results showed that 7 and 18 miRNAs were defined as the sex- and age-specific miRNAs, respectively. The expression of miR-181c-5p, miR-20b-5p, miR-98b-5p, miR-329-3p, miR-341-5p, and miR-2137 showed significant age-difference in mice thymus by quantitative polymerase chain reaction. High expression levels of miR-2137 were detected in mice thymic epithelial cells and gradually increased during the process of thymus aging. MiR-27b-3p and miR-378a-3p of the female-biased miRNAs were confirmed as the sex- and estrogen-responsive miRNAs in mice thymus in vivo. Their potential target genes and the pathway were identified by the online software. Possible regulation roles of sex- and age-specific miRNA expression during the process of thymus aging were discussed. Our results suggested that these miRNAs may be potential biomarkers for the study of sex- and age-specific thymus aging and involution.


The cognitive underpinnings of mental model construction in L1 and L2.
This study investigates the ability to create mental models and the role of working memory in mental model ability in the first and second language with English-Spanish bilinguals using L1 and L2 versions of the Spatial Integration Task. Participants showed effects of continuity in accuracy in L1 and L2, but only in L1 did they show effects in the reading times. In L1, working memory capacity predicted identification accuracy for discontinuous descriptions in L1, as well as reading time for the critical discontinuous sentence. In L2, accuracy was predicted by L2 reading ability only and there were no significant predictors of reading times. The findings suggest that the lack of availability of working memory resources in L2 induces participants to rely primarily on verbal abilities to create mental models.


Feeding preference of Holymenia clavigera and Anisoscelis foliacea marginella (Hemiptera: Coreidae: Anisoscelini) in relation to intra- and interspecific features of host plants (Passifloraceae).
The interactions of Holymenia clavigera (Herbst) and Anisoscelis foliacea marginella (Dallas) with their hosts (Passifloraceae) in southern Brazil are poorly understood. Previous studies have indicated that both species use several host species and plant parts and have superior performance on wild hosts. This study evaluated feeding preferences and host plant use under both laboratory and field conditions. Choice tests were performed to determine preference for Passiflora suberosa parts, preference for P. suberosa and Passiflora misera immature and ripe fruits, and preference for P. suberosa, P. misera, and Passiflora edulis shoots. A field survey was carried out to assess H. clavigera and A. foliacea marginella use of P. suberosa parts. In addition, immature and ripe fruits of P. suberosa and P. misera were characterized in relation to pH, phenols, and anthocyanins. First-instar nymphs preferred the terminal buds, shifting to immature fruits in the second instar. Both coreids more frequently fed on immature fruits than on ripe ones. Neither species showed a significant preference among host species. The immature fruits presented higher phenol content as compared with the ripe fruits; the opposite was observed for anthocyanins. In the field, immature fruits and mature leaves were selected for feeding and resting. Thus, this study confirms the food mixing condition of these coreids, as well as the importance of fruits for their nutrition. Phenols, and presumably water, in the fruits may play a role in their feeding choices.


[Insertion of an epidural catheter from the surgical wound for postoperative analgesia--a case report].
A 62-year-old male was scheduled for discectomy for lumbar disc herniation. He had bronchial asthma, and his asthma was induced by nonsteroidal anti-inflammatory drugs. We decided to use continuous epidural block for postoperative analgesia. However, he was frightened of insertion of an epidural catheter. Therefore, we planned to insert the epidural catheter before the end of surgery under general anesthesia. It was easily placed at L 5-S 1 interspace using a Tuohy needle from the surgical wound, and the contrast medium 5 ml was injected through the epidural catheter to confirm the placement. After the surgery, continuous epidural block with local anesthetics was used for two days. He did not complain of severe pain postoperatively.


Nocardioides dongxiaopingii sp. nov., isolated from leaves of Lamiophlomis rotata on the Qinghai-Tibet Plateau.
Two novel Gram-stain-positive, irregular rod-shaped actinomycetes, S-1144T and 4053, were isolated from leaves of Lamiophlomis rotata on the Qinghai-Tibet Plateau, PR China. Cells were aerobic, catalase-positive and oxidase-negative. Colonies on Reasoner's 2A agar were light yellow, circular, shiny, smooth and convex after 2 days of incubation. The isolates grew optimally at 25 °C, pH 7.5 and with 0 % (w/v) NaCl. The results of polyphasic analyses indicated that strain S-1144T belonged to the genus Nocardioides and its close phylogenetic neighbours (16S rRNA gene sequence similarity) were Nocardioides litoris DSM 103718T (98.4 %), Nocardioides rubriscoriae DSM 23986T (98.2%) and Nocardioides plantarum DSM 11054T (97.8 %). The genome of strain S-1144T showed less than 70 % digital DNA-DNA hybridization and < 95-96 % average nucleotide identity values to the above reference strains. The DNA G+C content of strain S-1144T was 73.5 mol%. MK-8(H4) was the predominant respiratory quinone (96.0 %) and llLL-2,6-diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan. The polar lipid profile of strain S-1144T consisted of diphosphatidylglycerol, phosphatidylglycerol, three unidentified phospholipids, one unidentified glycolipid and one unidentified lipid. The major cellular fatty acids were iso-C16 : 0, C17 : 1 ω8c, C17 : 0 and C18 : 1 ω9c. On the basis of obtained data, strain S-1144T represented a novel species of the genus Nocardioides, for which the name Nocardioides dongxiaopingii sp. nov. is proposed. The type strain is S-1144T (=CGMCC 4.7568T=JCM 33469T).


Design, synthesis and cytotoxicity of novel 2-arylvinyl-4-aminoquinoline derivatives.
With an aim to develop promising anti-tumor agents, a novel series of 2-arylvinyl-4-aminoquinoline derivatives were designed, synthesized and evaluated for their cytotoxicity against H-460, HT-29, HepG2 and SGC-7901 cell lines in vitro. The pharmacological results indicated that most compounds were more potent than the positive controls, especially compounds 8, 14 and 16 with IC(50) values ranging from 0.05 to 0.85 µM against all tested cell lines respectively, which were 5.7- to 112-fold better than Iressa. The most active compound 14 (IC(50) values of 0.05, 0.25, 0.16, 0.68 µM), bearing 4-fluorostyryl at C-2 position and 3-(dimethylamino)-1-propylamino at C-4 position, showed great promise as a lead for the development of more effective quinoline analogues.


Angiographic and intravascular ultrasound findings of the late catch-up phenomenon after intracoronary beta-radiation for the treatment of in-stent restenosis.
We report one-year angiographic and intravascular ultrasound (IVUS) outcomes of in-stent restenosis (ISR) patients treated with intravascular brachytherapy (IVBT). The benefit of IVBT for treating ISR is well documented. However, few data exist on significant angiographic and intravascular ultrasonic in-stent lumen deterioration beyond the habitual 6-month analysis after the index radiation procedure or so-called late catch-up process in the treatment of ISR. Twenty-five consecutive patients with ISR were treated with IVBT using the Beta-Cath System (a 40 mm 90 Sr per 90 gamma source). Quantitative angiographic and IVUS analysis was performed in all of them at 6 and 12 months. IVBT was successful in all patients. Four patients (16%) developed recurrent angiographic binary restenosis at 6-month follow-up, all located within the adjacent reference segments, with 2 being associated with geographical miss. An additional 4 patients (16%) presented with recurrent ISR at 12-month follow-up, all within the stented segment. Significant in-stent lumen loss (0.16 +/- 0.42 mm to 0.34 +/- 0.46 mm; p = 0.008) and in-stent intimal hyperplasia growth (+11.2 +/- 0.48 mm3; p = 0.03) was observed between 6 and 12 months. Intracoronary beta-radiation for the treatment of ISR was associated with significant luminal deterioration (late catch-up) within the stents between 6 and 12 months due to an important late progression of in-stent intimal hyperplasia.


Controversies Surrounding Critical Care Nutrition: An Appraisal of Permissive Underfeeding, Protein, and Outcomes.
Over the past few years, numerous studies have called into question the optimal dose, timing, composition, and advancement rate of nutrition during the early acute phase of critical illness. These studies suggest permissive underfeeding with slow advancement may be more beneficial than aggressive full feeding. These counterintuitive results were possibly explained by enhanced autophagy, less hyperglycemia, or prevention of refeeding syndrome. This review underscores the controversies surrounding permissive underfeeding, aims to answer whether permissive underfeeding is appropriate for all critically ill patients, describes the impact of optimal protein delivery on critical care outcomes, discusses nutrition risk, and cogitates on the impact of nutrition on critical care outcomes.


PPARgamma ligands suppress proliferation of human urothelial basal cells in vitro.
Expression of peroxisome proliferator-activated receptor (PPAR) gamma in the human urinary tract through embryonic development suggests its possible roles in the development, proliferation, and differentiation of uroepithelium. Little is known, however, about physiological roles of PPARgamma in the urinary tract. We investigated effects of PPARgamma ligands on the proliferation of normal human urothelial cells and stromal cells cultivated from surgical specimens. Active proliferation in vitro as well as high molecular weight cytokeratin expression indicated that cultured urothelial cells possess basal cell phenotype. PPARgamma protein, expressed predominantly in the epithelial layer of the normal human urinary tract in vivo, was abundantly expressed in urothelial cells but barely detectable in stromal cells in vitro. Natural ligand for PPARgamma, 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), as well as synthetic ones, troglitazone and pioglitazone, suppressed proliferation of the urothelial cells dose-dependently. These effects were PPARgamma specific because clofibrate or PGF(2alpha) did not affect proliferation of urothelial cells. Neither 9-cis retinoic acid or all-trans retinoic acid (ATRA) at 1 microM showed any synergism on the antiproliferative effects of PPARgamma ligands. Urothelial cells treated with PPARgamma ligands showed drastic morphologic changes and cell cycle arrest at G0/G1 phase accompanied with increased mRNA level of a cyclin-dependent kinase inhibitor p21(WAF1/CIP1). Since 15d-PGJ(2) is present in vivo during the resolution phase of inflammation, these results indicated that PPARgamma might be involved in the terminal phase of urothelial re-epithelialization processes.


Design of Dense Brush Conformation Bearing Gold Nanoparticles as Theranostic Agent for Cancer.
Dense brush conformation-bearing theranostic agents are emerging as drug delivery systems due to their higher ability to escape from reticuloendothelial system uptake which prolongs their in vivo circulation time. With the aim of developing dual therapy agent, 13-nm gold nanoparticles' (AuNPs) surfaces were coated with different amounts of polyethylene glycol (PEG) (SH-PEG-NH2) to obtain dense brush conformation-bearing theranostic agents. Among the 14 different theranostic agent candidates prepared, the one hosting 1819 PEG per particle was selected as the most promising theranostic agent candidate based on structural conformation, stability, size, zeta potential, hemocompatibility, cell inhibition, and cell death pathway towards MCF-7 cell line. To test drug delivery efficiency of the developed PEGylated AuNP and to improve efficacy of the treatment, apoptotic peptide (AP) was covalently conjugated to NH2 terminus of the PEG in various ratios to yield AuNP-AP conjugate. Among the prepared conjugates, the one having 1 nmol of peptide per milliliter of AuNP yielded the most promising results based on the same criteria as employed for PEGylated AuNPs. Besides, incorporation of AP to AuNP returned in superior efficacy of AP since it was possible to achieve 50% cell death with 1000 times less amount of AP alone.


[Pineal Parenchymal Tumor with Marked Cytologic Pleomorphism: Is there a Correlation with the Malignancy Grade?].
In benign pineal parenchymal tumors (PPTs), namely, pineocytoma(PC)and PPT of intermediate differentiation (PPTID), cytologic pleomorphism has occasionally been found;however, it is controversial as to whether the presence of pleomorphic cells leads to upgrading of tumors. We experienced a rare case of pleomorphic PPT in an elderly woman and compared it with a retrospective series of 12 PPTs (PC:3, PPTID:6, pineoblastoma[PB]:3)to evaluate the correlation between pleomorphism and the malignancy grade. CASE AND MATERIALS: A 76-year-old woman presented with gradual cognitive deterioration and gait disturbance. Gadolinium-enhanced magnetic resonance imaging(Gd-MRI)revealed a small, enhanced tumor in the pineal gland with marked hydrocephalus. Endoscopic tumor biopsy and third ventriculostomy were performed simultaneously. The tumor was soft, pinkish, and slightly hemorrhagic. After the biopsy, the patient underwent gamma knife radiosurgery. The PPT presented with areas of tumor cells forming pineocytomatous rosettes and areas of giant and multinucleated cells with hyperchromatic nuclei. Neither mitosis nor necrosis was observed. The tumor cells were positive for synaptophysin(SYN)and neurofilament(NF), but negative for glial fibrillary acidic protein(GFAP)and oligodendrocyte lineage transcription factor 2 (Olig2). The MIB-1 labeling index(LI)was 8.1%. There was no difference in the MIB-1 LI between pleomorphic and non-pleomorphic areas. All the 12 PPTs were immunopositive for the neuronal markers SYN and NF. The MIB-1 LI was 0% in PC, 3.5% in PPTID, and 10.5% in PB. The proliferative potential was correlated with the WHO grade. From these findings, the final diagnosis of this pleomorphic case was PPTID grade II, not PC, because the MIB-1 LI was relatively high, even though some tumor cells were forming pineocytomatous rosettes. Although cytologic pleomorphism in PPTs is generally considered not to be correlated with the malignancy grade, the final pathological diagnosis should be determined while considering the proliferative potential.


[Effect of calcium channel blockers on temperature in mice].
In the experiments on SHR mice, verapamil, nifedipine, cinnarizin, fendilin, diltiazem, and nimodipine were tested for their effects on changes in rectal temperatures after intraperitoneal and intracerebroventricular injections. Intraperitoneal nifedipine (2 and 10 mg/kg), fendilin (5 and 20 mg/kg), and cinnarizin (5 and 50 mg/kg) lowered rectal temperatures. The similar effects were shown by nimodipine (2.4 micrograms), diltiazem (100 micrograms), and verapamil (100 micrograms) after their intracerebroventricular injections. It is concluded that the hypothermal effect of calcium antagonists is based on their central and hemodynamic mechanisms.


Silencing of the CKII alpha and CKII alpha' genes during cellular senescence is mediated by DNA methylation.
Previously we reported that down-regulation of CKII activity is tightly associated with cellular senescence and that the mRNA and protein levels of CKII alpha decrease during senescence. The present study demonstrates that the mRNA and protein levels of CKII alpha' also decrease during senescence. Knockdown of CKII alpha' in IMR-90 cells by RNA interference induced the senescent phenotype. Treatment of senescent IMR-90 cells with a demethylating agent 5-aza-2'-deoxycytidine induced CKII alpha and CKII alpha' expression, suggesting that DNA hypermethylation might be involved in the silencing of CKII alpha and CKII alpha' genes in senescent cells. However, bisulfite sequencing analysis revealed that the methylation status of the CpG islands within the reported CKII alpha and CKII alpha' promoters was not associated with senescence. Instead, senescence-dependent hypermethylation was observed in the region ranging from position +1112 to +1128 of the CKII alpha gene and at positions -527 and +829 of the CKII alpha' gene. In addition, this study indicates that DNA methylation-dependent down-regulation of transcription factors Sp1, Ets1 and NF-kappaB might be involved in silencing of the CKII alpha and CKII alpha' genes during cellular senescence.


Thrust joint manipulation utilization by U.S. physical therapists.
Online survey study. To determine physical therapists' utilization of thrust joint manipulation (TJM) and their comfort level in using TJM between the cervical, thoracic, and lumbar regions of the spine. We hypothesized that physical therapists who use TJM would report regular use and comfort providing it to the thoracic and lumbar spines, but not so much for the cervical spine. Recent surveys of first professional physical therapy degree programs have found that TJM to the cervical spine is not taught to the same degree as to the thoracic and lumbar spines. We developed a survey to capture the required information and had a Delphi panel of 15 expert orthopedic physical therapists review it and provide constructive feedback. A revised version of the survey was sent to the same Delphi panel and consensus was obtained on the final survey instrument. The revised survey was made available to any licensed physical therapists in the U.S.A. using an online survey system, from October 2014 through June 2015. Of 1014 responses collected, 1000 completed surveys were included for analysis. There were 478 (48%) males; the mean age of respondents was 39.7 ± 10.81 years (range 24-92); and mean years of clinical experience was 13.6 ± 10.62. A majority of respondents felt that TJM was safe and effective when applied to lumbar (90.5%) and thoracic (91.1%) spines; however, a smaller percentage (68.9%) felt that about the cervical spine. More therapists reported they would perform additional screening prior to providing TJM to the cervical spine than they would for the lumbar and thoracic spines. Therapists agreed they were less likely to provide and feel comfortable with TJM in the cervical spine compared to the thoracic and lumbar spines. Finally, therapists who are male; practice in orthopedic spine setting; are aware of manipulation clinical prediction rules; and have manual therapy certification, are more likely to use TJM and be comfortable with it in all three regions. Results indicate that respondents do not believe TJM for the cervical spine to be as safe and efficacious as that for the lumbar and thoracic spines. Further, they are more likely to perform additional screening, abstain from and do not feel comfortable performing TJM for the cervical spine. Our research reveals there is a discrepancy between utilization of TJM at different spinal levels. This research provides an opportunity to address variability in clinical practice among physical therapists utilizing TJM.


Opportunities for genetic investigation afforded by Acinetobacter baylyi, a nutritionally versatile bacterial species that is highly competent for natural transformation.
The genetic and physiological properties of Acinetobacter baylyi strain ADP1 make it an inviting subject for investigation of the properties underlying its nutritional versatility. The organism possesses a relatively small genome in which genes for most catabolic functions are clustered in several genetic islands that, unlike pathogenicity islands, give little evidence of horizontal transfer. Coupling mutagenic polymerase chain reaction to natural transformation provides insight into how structure influences function in transporters, transcriptional regulators, and enzymes. With appropriate selection, mutants in which such molecules have acquired novel function may be obtained. The extraordinary competence of A. baylyi for natural transformation and the ease with which it expresses heterologous genes make it a promising platform for construction of novel metabolic systems. Steps toward this goal should take into account the complexity of existing pathways in which transmembrane trafficking plays a significant role.


Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats.
To design colon-targeted codrugs of mycophenolic acid (MPA) and aminosugars as a safer option to mycophenolate mofetil (MMF) in the management of inflammatory bowel disease. Codrugs were synthesized by coupling MPA with aminosugars (D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates (in vitro) and rat blood (in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease control. The prodrugs resisted activation in HCl buffer (pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer (pH 7.4) and intestinal homogenates. Incubation with colon homogenates (in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine (MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA. The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid.