Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer.
Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels. This physiological process is a hallmark event in normal embryonic development as blood vessels generally supply both oxygen and nutrients to the cells of the body. Any disruption in this process can lead to the development of various chronic diseases, including cancer. In cancer, aberrant angiogenesis plays a prominent role in maintaining sustained tumor growth to malignant phenotypes and promoting metastasis. The leakiness in the tumor microvasculature is attributed to the tumor cells migrating to distal site organs and forming colonies. In this article, we briefly review the various mediators involved in the angiogenic process and the anti-angiogenic potential of selected natural compounds against various malignancies. Several growth factors and their receptors such as vascular endothelial growth factor and receptor (VEGF/VEGFR), basic fibroblast growth factor and receptor (bFGF/FGFR), angiopoietins, and hypoxia inducible factors facilitate the development of angiogenesis and are attractive anti-cancer targets. Natural products represent a rich diversity of compounds for drug discovery and are currently being actively exploited to target tumor angiogenesis. Agents such as curcumin, artemisinin, EGCG, resveratrol, emodin, celastrol, thymoquinone and tocotrienols all have shown prominent anti-angiogenic effects in the preclinical models of tumor angiogenesis. Several semi-synthetic derivatives and novel nano-formulations of these natural compounds have also exhibited excellent anti-angiogenic activity by increasing bioavailability and delivering the drugs to the sites of tumor angiogenesis.


Turning the Tap: Conformational Control of Quantum Interference to Modulate Single-Molecule Conductance.
Together with the more intuitive and commonly recognized conductance mechanisms of charge-hopping and tunneling, quantum-interference (QI) phenomena have been identified as important factors affecting charge transport through molecules. Consequently, establishing simple and flexible molecular-design strategies to understand, control, and exploit QI in molecular junctions poses an exciting challenge. Here we demonstrate that destructive quantum interference (DQI) in meta-substituted phenylene ethylene-type oligomers (m-OPE) can be tuned by changing the position and conformation of methoxy (OMe) substituents at the central phenylene ring. These substituents play the role of molecular-scale taps, which can be switched on or off to control the current flow through a molecule. Our experimental results conclusively verify recently postulated magic-ratio and orbital-product rules, and highlight a novel chemical design strategy for tuning and gating DQI features to create single-molecule devices with desirable electronic functions.


Serum Neurofilament to Magnetic Resonance Imaging Lesion Area Ratio Differentiates Spinal Cord Infarction From Acute Myelitis.
The diagnosis of spontaneous spinal cord infarction (SCI) is limited by the lack of diagnostic biomarkers and MRI features that often overlap with those of other myelopathies, especially acute myelitis. We investigated whether the ratio between serum neurofilament light chain levels and MRI T2-lesion area (neurofilament light chain/area ratio-NAR) differentiates SCI from acute myelitis of similar severity. We retrospectively identified Mayo Clinic patients (January 1, 2000-December 31, 2019) with (1) SCI, (2) AQP4 (aquaporin 4)-IgG or MOG (myelin oligodendrocyte glycoprotein)-IgG-associated myelitis at disease clinical presentation, or (3) idiopathic transverse myelitis from a previously identified population-based cohort of patients seronegative for AQP4-IgG and MOG-IgG. Serum neurofilament light chain levels (pg/mL) were assessed at the Verona University (SIMOA, Quanterix) in a blinded fashion on available stored samples obtained ≤3 months from myelopathy presentation. For each patient, the largest spinal cord lesion area (mm2) was manually outlined by 2 independent raters on sagittal T2-weighted MRI images, and the mean value was used to determine NAR (pg/[mL·mm2]). Forty-eight patients were included SCI, 20 (definite, 11; probable, 6; possible, 3); acute myelitis, 28 (AQP4-IgG-associated, 17; MOG-IgG-associated, 5; idiopathic transverse myelitis, 6). The median expanded disability status scale score (range) at myelopathy nadir were 7.75 (2-8.5) and 5.5 (2-8), respectively. Serum neurofilament light chain levels (median [range] pg/mL) in patients with SCI (188 [14.3-2793.4]) were significantly higher compared with patients with AQP4-IgG-associated myelitis (37 [0.8-6942.9]), MOG-IgG-associated myelitis (45.8 [4-283.8]), and idiopathic transverse myelitis (15.6 [0.9-217.8]); P=0.01. NAR showed the highest accuracy for identification of SCI versus acute myelitis with values ≥0.35 pg/(mL·mm2) yielding 86% specificity and 95% sensitivity (area under the curve=0.93). The positive and negative likelihood ratios were 6.67 and 0.06, respectively. NAR remained independently associated with SCI after adjusting for age, gender, immunotherapy before sampling, and days from myelopathy symptoms onset to sampling (P=0.0007). NAR is a novel and promising clinical biomarker for differentiation of SCI from acute myelitis.


Megakaryocytes regulate the quiescence of hematopoietic stem cells through PF4: 2013 ASH meeting highlights.
Hematopoietic stem cells (HSCs) can take one of the three different pathways: quiescence, self-renewal and differentiation. Mechanisms that control the tight balance to maintain lifelong hematopoietic homeostasis have been a major interest of research. Platelet factor-4 (PF4), a weak chemokine, is synthesized exclusively by megakaryocytes and sequestered in platelets. This meeting report highlights a novel study presented at 2013 ASH annual meeting. This study found that megakaryocyte, a progeny of HSC, was involved in maintaining quiescence of HSCs via PF4 in a feedback loop.


[Heart rupture in acute myocardial infarction: multicenter observational study of the coronary unit of Piedmont].
The aim of this study was to prospectively evaluate the incidence of cardiac rupture during myocardial infarction (MI) as well as the predictive value of the main cardiac rupture risk factors. The study was carried out in 17 coronary care units (CCU) between January and December 1999 in the Piedmont region (Italy). The incidence of cardiac rupture was 1.4% of the total number of MI (n = 3041). Data from 13 out of 17 CCU showed the following causes of death during MI: 66% heart failure, 16% cardiac rupture, 7% arrhythmias, 11% others. Twenty-seven percent out of 44 cardiac ruptures had prior angina, 9% prior MI; 24% of patients were diabetic; 38% had anterior wall MI; 62% infero-postero-lateral MI; 86% showed ST-segment elevation, and 79.5% developed Q waves. Thrombolysis was administered in 39% of cases. Forty-three percent cardiac ruptures occurred within 24 hours. Electromechanical dissociation was present in 73% of cases, syncope and hypotension in 43%, bradycardia in 30%. An echocardiogram was performed in 89% of cases in the suspicion of cardiac rupture but only 45% showed severe pericardial effusion. One patient was referred to surgery but he died in the postoperative period. Autoptical diagnosis was made in 32% of cases. All patients died. The analysis of some qualitative variables (gender, thrombolysis, MI localization, ST-segment/non-ST-segment elevation) in 8 out of 17 CCU, between the cardiac rupture group (n = 22) and the MI group (n = 1330) showed a significant result only for the female gender. Cardiac rupture is the second cause of death during MI after heart failure; there is a higher incidence of cardiac rupture in infero-postero-lateral MI, after the first 24 hours particularly in the female gender; there is a low global incidence (1.4%).


A cross-sectional study on the prevalence and intensity of infection with Schistosoma haematobium students of Northern KwaZulu.
The urines of 7,944 students (aged 5--25 years) from 42 different localities in Northern KwaZulu were screened for the presence of Schistosoma haematobium eggs. Fifty-four percent were infected, but prevalence varied from 8--92% depending on conditions existing in the localities. The age-specific prevalence in each of the four topographical areas was unusual in that peaks were not distinct and sharp decreases towards the end of the 2nd decade of life did not occur. Egg output, determined by using a helminth filter and staining of eggs, was expressed in relation to time (2-hour mid-day specimens) rather than urine volume. Unlike the prevalence, egg output decreased considerably after a distinct peak which occurred at 8 years of age in the low prevalence area and at ages 10 and 11 years in the heavily infected areas. Statistical analyses of the results revealed that the observed prevalence of S. haematobium was dependent on area and age but not on sex. The significance of the findings in this area are discussed.


Biobanking.
Biobanks, more formally known as biological resource centers (BRCs), form an "unsung" yet critical component of the infrastructures for scientific research, industry and conservation, without which much of the current scientific activity involving microbial cultures and cell-lines would be effectively impossible. BRCs are de facto depositories of "biological standards" holding taxonomic and other reference strains on which much of the associated published science and industrial standards are built and upon which some significant international commercial and ethical issues rely. The establishment and maintenance of BRCs is a knowledge- and skill-rich activity that in particular requires careful attention to the implementation of reliable preservation technologies and appropriate quality assurance to ensure that recovered cultures and other biological materials perform in the same way as the originally isolated culture or material. There are many types of BRC, which vary both in the kinds of material they hold and in their functional role. All BRCs are expected to provide materials and information of an appropriate quality for their intended use and work to standards relevant to those applications. There are important industrial, biomedical, and conservation issues that can only be addressed through effective and efficient operation of BRCs in the long term. This requires a high degree of expertise in the maintenance and management of collections of biological materials at ultra-low temperatures, or as freeze-dried material, to secure their long-term integrity and relevance for future research, development, and conservation.


Berberine inhibits HIF-1alpha expression via enhanced proteolysis.
We have studied the antiangiogenic property of berberine. We showed that berberine could directly inhibit in vitro human umbilical vein endothelial cell (HUVEC) tube formation and migration. In addition, to determine whether berberine could influence the cross-talk between the gastric adenocarcinoma cell line SC-M1 and vascular endothelial cells, we performed modified confrontation culture experiments and showed that berberine (7.5 microM, 16 h) could inhibit the capacity of hypoxic SC-M1 cells to stimulate HUVEC migration. These results demonstrated berberine's antiangiogenic property and its clinical potential as an inhibitor of tumor angiogenesis. Parallel Western blot analyses revealed that berberine prevented hypoxic SC-M1 cultures from expressing vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1alpha, two key factors in mediating tumor angiogenesis. However, overexpression of HIF-1alpha in SC-M1 cells dramatically reversed the inhibitory effect of berberine on SC-M1-induced in vitro HUVEC migration. These data indicated that HIF-1alpha repression is a critical step in the inhibitory effect of berberine on tumor-induced angiogenesis. Northern blot analyses plus pulse-chase assays revealed that berberine did not down-regulate HIF-1alpha mRNA but destabilized HIF-1alpha protein. We found that berberine-induced HIF-1alpha degradation was blocked by a 26S proteasome inhibitor. Moreover, immunoprecipitation and Western blot analyses showed that berberine increased the lysine-acetylated HIF-1alpha in hypoxic SC-M1 cultures. These data indicated that a proteasomal proteolytic pathway and lysine acetylation were involved in berberine-triggered HIF-1alpha degradation. In conclusion, our data provided molecular evidence to support berberine as a potent antiangiogenic agent in cancer therapy.


The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI).
Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort. Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints. E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed. APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.


Micropatterned aptasensors for continuous monitoring of cytokine release from human leukocytes.
We report the development of a microdevice for detecting local interferon gamma (IFN-γ) release from primary human leukocytes in real time. Our microdevice makes use of miniature aptamer-modified electrodes integrated with microfluidics to monitor cellular production of IFN-γ. The aptamer species consists of a DNA hairpin molecule with thiol groups on the 3'-end for self-assembly onto Au electrodes. A redox reporter is covalently attached at the 5'-end for electrochemical sensing. This aptasensor has excellent sensitivity for IFN-γ (<60 pM detection limit) and responds to the target analyte in real time without additional washing or labeling steps. Aptamer-functionalized electrode arrays are fabricated on glass slides containing poly(ethylene glycol) (PEG) hydrogel patterns designed to expose glass regions adjacent to electrodes while protecting the remainder of the surface from nonspecific adsorption. The micropatterned substrates are integrated with PDMS microfluidic channels and incubated with T-cell-specific antibodies (Ab) (anti-CD4). Upon injection of blood, leukocytes are bound to Ab-modified glass regions in proximity to aptasensors. Cytokine release from captured cells is triggered by mitogenic activation and detected at the aptamer-modified electrodes using square wave voltammetry (SWV). The IFN-γ signal is monitored in real time with signal appearing as early as 15 min poststimulation from as few as 90 T cells. The observed IFN-γ release profiles are used to calculate an initial IFN-γ production rate of 0.0079 pg cell(-1) h(-1) upon activation. The work described here represents an important step toward development of aptasensors for immune cell analysis and blood-based diagnostics.


The beta-1,3-glucanosyltransferase gas4p is essential for ascospore wall maturation and spore viability in Schizosaccharomyces pombe.
Meiosis is the developmental programme by which sexually reproducing diploid organisms generate haploid gametes. In yeast, meiosis is followed by spore morphogenesis. The formation of the Schizosaccharomyces pombe ascospore wall requires the co-ordinated activity of enzymes involved in the biosynthesis and modification of its components, such as glucans. During sporogenesis, the beta-1,3-glucan synthase bgs2p synthesizes linear beta-1,3-glucans, which remain unorganized and alkali-soluble until covalent linkages are set up between beta-1,3-glucans and other cell wall components. Several proteins belonging to the glycoside hydrolase family 72 (GH72) with beta-1,3-glucanosyltransferase activity have been described in other organisms, such as the Saccharomyces cerevisiae Gas1p or the Aspergillus fumigatus Gel1p. Here we describe the characterization of gas4(+), a new gene that encodes a protein of the GH72 family. Deletion of this gene does not lead to any apparent defect during vegetative growth, but homozygous gas4Delta diploids show a sporulation defect. Although meiosis occurs normally, ascospores are unable to mature or to germinate. The expression of gas4(+) is strongly induced during sporulation and a yellow fluorescent protein (YFP)-gas4p fusion protein localizes to the ascospore periphery during sporulation. We conclude that gas4p is required for ascospore maturation in S. pombe.


Ultrastructure of spermiogenesis and the spermatozoon of Macracanthorhynchus hirudinaceus (Pallas, 1781) (Acanthocephala: Archiacanthocephala), a parasite of the wild boar Sus scrofa.
The present paper describes the ultrastructure of spermiogenesis and the spermatozoon of Macracanthorhynchus hirudinaceus, an acanthocephalan parasite of the wild boar Sus scrofa. At the beginning of spermatogenesis, spermatocytes exhibit synaptonemal complexes and 2 centrioles. In the spermatid, only 1 centriole remains, generating a flagellum with a 9+2 pattern. Another ultrastructural feature observed during the spermiogenesis of M. hirudinaceus is the condensation of the chromatin, forming a "honeycomb" structure in the old spermatid and a homogeneous, electron-dense structure in the spermatozoon. The mature spermatozoon of M. hirudinaceus presents a reversed anatomy, as has been described previously in other species of the Acanthocephala. The spermatozoon is divided into 2 parts: an axoneme, and a nucleocytoplasmic derivative. The spermatozoon flagellum exhibits a 9+2 or 9+0 pattern. The process of spermiogenesis and the ultrastructural organization of the spermatozoon of M. hirudinaceus are compared with available data regarding other acanthocephalan species.


Bibliometric analysis of Severe Acute Respiratory Syndrome-related research in the beginning stage.
Severe Acute Respiratory Syndrome (SARS) has become the major of health issues since its outbreak early 2003. No analyses by bibliometric technique that have examined this topic exist in the literature. The objective of this study is to conduct a bibliometric analysis of all SARS-related publications in Science Citation Index (SCI) in the early stage. A systematic search was performed using the SCI for publications since SARS outbreak early 2003. Selected documents included 'severe acute respiratory syndrome' or 'SARS' as a part of its title, abstract, or keyword from the beginning stage of SARS outbreak, March till July 8, 2003. Analysis parameters included authorship, patterns of international collaboration, journals, language, document type, research institutional address, times cited, and reprint address. Citation analysis was mainly based on impact factor as defined by Journal Citation Reports(JCR) issued in 2002 and on the actual citation impact (ACI), which has been used to assess the impact relative to the whole field and has been defined as the ratio between individual citation per publication value and the total citation per publication value. Thirty-two percent of total share was published as news features, 25% as editorial materials, 22% as articles, 13% as letters, and the remaining being biographic items, corrections, meeting abstracts, and reprints. The US dominated the production by 30% of the total share followed closely by Hong Kong with 24%. Sixty-three percent of publication was published by the mainstream countries. The SARS publication pattern in the past few months suggests immediate citation, low collaboration rate, and English and mainstream country domination in production. We observed no associations of research indexes with the number of cases.


Benford's Law and the screening of analytical data: the case of pollutant concentrations in ambient air.
The need to ensure the robustness of very large data sets produced by analytical measurement processes is increasing. This requires data screening techniques that can identify formatting or transcription errors in large data sets, that have undergone multiple data-handling and manipulation procedures. The empirical observation that the digits 1 to 9 are not equally likely to appear as the initial digit in multi-digit numbers is known as Benford's Law, and may provide a solution to this requirement. Several sets of data pertaining to the measured concentrations of pollutants in ambient air in the UK in 2004 have been analysed for their initial digit frequencies in order to assess the potential for the use of Benford's Law as a data screening, and authenticity-checking, tool for these types of analytical data sets. Benford's Law has been shown to be a robust top-level data screening tool provided that the numerical range of the data set being considered is four orders of magnitude or greater. It has been shown that small changes in the deviation of a data set from Benford's Law may indicate the introduction of errors during data processing. In this way, Benford's Law provides a sensitive technique for identifying data mishandling in large data sets.


The evolution of seed dormancy: environmental cues, evolutionary hubs, and diversification of the seed plants.
Seed dormancy, by controlling the timing of germination, can strongly affect plant survival. The kind of seed dormancy, therefore, can influence both population and species-level processes such as colonization, adaptation, speciation, and extinction. We used a dataset comprising over 14,000 taxa in 318 families across the seed plants to test hypotheses on the evolution of different kinds of seed dormancy and their association with lineage diversification. We found morphophysiological dormancy to be the most likely ancestral state of seed plants, suggesting that physiologically regulated dormancy in response to environmental cues was present at the origin of seed plants. Additionally, we found that physiological dormancy (PD), once disassociated from morphological dormancy, acted as an 'evolutionary hub' from which other dormancy classes evolved, and that it was associated with higher rates of lineage diversification via higher speciation rates. The environmental sensitivity provided by dormancy in general, and by PD in particular, appears to be a key trait in the diversification of seed plants.


First Report of Downy Mildew Caused by Plasmopara obducens on Impatiens in California.
During February 2004, diseased double impatiens (Impatiens walleriana) plants were received from a commercial grower in southern California. The upper surfaces of symptomatic leaves were pale yellow with no distinct lesions. Diseased leaves later wilted, and severely affected leaves abscised from the stem. At the nursery, only double impatiens plants in the Fiesta series were infected, and some cultivars were more heavily infected than others. Disease incidence in cv. Sparkler Hot pink was nearly 100%. The interior of infected leaves was colonized by coenocytic mycelium. A conspicuous white growth was observed only on the underside of leaves. Sporangiophores were hyaline, thin walled, emergent from stomata, and had slightly swollen bases. Sporangiophore branching was distinctly monopodial. Smaller sporangiophore branches were arranged at right angles to the supporting branches, and tips of branches measured 8 to 14 μm long. Sporangia were ovoid and hyaline with a single pore on the distal ends. Distal ends of sporangia were predominantly flat but occasionally had a slight papilla. Short pedicels were present on the attached ends. Sporangia measured 19.4 to 22.2 (-25.0) μm × 13.9 to 16.7 (-19.4) μm. Oospores were not observed in leaf tissue. On the basis of symptoms and morphology of the organism, the pathogen was identified as Plasmopara obducens J. Schröt. Pathogenicity tests were done on double type cvs. Fiesta, Tioga Red, and Tioga Cherry Red and on single type cvs. Cajun Watermelon and Accent Lilac. Plants were spray inoculated with sporangiospore suspensions (1 × 104 sporangiospores per milliliter), incubated for 24 h in a dew chamber (18 to 20°C), and then maintained in a greenhouse (22 to 24°C). Symptoms and signs of downy mildew developed after 12 days only on inoculated cv. Fiesta plants, and the pathogen morphology matched that of the originally observed pathogen. Nontreated control plants did not develop downy mildew. To our knowledge, this is the first report of downy mildew on impatiens in California. P. obducens is one of two causal agents of downy mildew of impatiens (2,4). The other pathogen, Bremiella sphaerosperma, has dichotomous sporangiophore branching and causes lesions with well-defined margins (2,4). In the United States, the disease has been recorded in the eastern and northeastern states and in Indiana, Minnesota, Mississippi, Montana, and Wisconsin (3). In Canada, the disease has been recorded in Manitoba and Quebec (1). References: (1) I. L. Conners. An Annotated Index of Plant Diseases in Canada and Fungi Recorded on Plants in Alaska, Canada, and Greenland. Research Branch, Canada Department of Agriculture, Publication 1251, 1967. (2) O. Constantinescu. Mycologia 83:473, 1991. (3) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, 1989. (4) G. W. Wilson. Bull. Torrey Bot. Club 34:387, 1907.


Adaptive NKG2C+CD57+ Natural Killer Cell and Tim-3 Expression During Viral Infections.
Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions-a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer.


The HRDC domain of BLM is required for the dissolution of double Holliday junctions.
Bloom's syndrome is a hereditary cancer-predisposition disorder resulting from mutations in the BLM gene. In humans, BLM encodes one of five members of the RecQ helicase family. One function of BLM is to act in concert with topoisomerase IIIalpha (TOPO IIIalpha) to resolve recombination intermediates containing double Holliday junctions by a process called double Holliday junction dissolution, herein termed dissolution. Here, we show that dissolution is highly specific for BLM among human RecQ helicases and critically depends upon a functional HRDC domain in BLM. We show that the HRDC domain confers DNA structure specificity, and is required for the efficient binding to and unwinding of double Holliday junctions, but not for the unwinding of a simple partial duplex substrate. Furthermore, we show that lysine-1270 of BLM, which resides in the HRDC domain and is predicted to play a role in mediating interactions with DNA, is required for efficient dissolution.


Sloshed and sentenced: A prevalence study of alcohol use disorders among offenders in the North East of England.
The annual cost of alcohol-related harm in the UK is estimated to be between £17.7 and £25.1 billion with healthcare costs alone reaching £2.7 billion and the costs of alcohol-fuelled crime and disorder accounting for £7.3 billion each year. The aim of the study was to examine the prevalence of alcohol use disorders (AUD) in prison and probation settings in the North East of England, and to compare the ability of the Alcohol Use Disorders Identification Test (AUDIT) and Offender Assessment System (OASys) at identifying alcohol-related need in probation clients. A quantitative prevalence study was carried out using anonymous questionnaires with participants from four prisons and three probation offices in the North East who voluntarily completed the AUDIT questionnaire during a 1-month period in 2006. Response outcomes on AUDIT were compared with OASys scores which identify alcohol-related need in probation. At the time of the study OASys scores were not available for offenders in prison. Seven hundred and fifteen questionnaires were completed. Sixty-three per cent of men and 57% of women were identified as having an AUD with over a third of all individuals scoring within the possibly dependant range (20+ on AUDIT). Around 40% of probation cases who were classified as either hazardous, harmful or possibly dependant drinkers on AUDIT were not identified by OASys. The results indicate that the prevalence of AUD in offenders is much higher than in the general population. In addition, current methods of identifying offenders with alcohol-related need in probation are flawed and as many such people go undetected. Alcohol assessment procedures need to be improved in criminal justice setting order to correctly identify people with AUD.


Integrative repair of the meniscus: lessons from in vitro studies.
Current therapies for meniscal injury seek to preserve and repair damaged tissue since loss of meniscal tissue is associated with degenerative changes in the joint, ultimately leading to osteoarthritis (OA). After a meniscal tear, the difficulty of integrating juxtaposed meniscal surfaces continues to be an obstacle. In order to determine the local factors that are necessary for successful tissue repair, previous studies have developed in vitro model systems that allow both biological and quantitative biomechanical measures of meniscus repair. Many studies have shown the importance of individual factors in meniscus metabolism, but there is a complex interplay among a variety of factors that influence meniscal healing, including inflammatory cytokines, growth factors, mechanical loading, and zonal differences in cell and tissue properties. In particular, the upregulation of inflammatory cytokines following joint injury appears to have significant catabolic influences on meniscal cell metabolic activity that must be overcome in order to promote repair. In the presence of inflammatory cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor alpha (TNF-alpha), intrinsic meniscal repair in vitro is significantly inhibited. While anabolic growth factors, such as transforming growth factor-beta1 (TGF-beta1), enhance meniscal repair, they cannot completely overcome the IL-1-mediated inhibition of repair. The mechanisms by which these mediators influence meniscal repair, and their interactions with other factors in the microenvironment, such as mechanical loading, remain to be determined. Future studies must address these complex interactions during meniscal healing to ultimately enhance meniscal repair.


Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer.
The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC). How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC? We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution. A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples. Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.


The influence of spaying and its timing relative to the onset of puberty on urinary and general behaviour in Labrador Retrievers.
Benefits and risks of spaying on the behaviour of female dogs are controversially discussed. Increased aggressiveness and male urinary behaviour were postulated to be the consequence of masculinization after spaying in some female dogs. To investigate if spaying or its timing relative to the onset of puberty may have a masculinization effect, urinary behaviour, that is, frequency of urination, urinary posture and ground scratching after urination were recorded in 58 female Labrador Retrievers during 15 min of a daily walk with their owners. General behaviour of the dogs during the walks was assessed using an owner questionnaire. Data were analysed for age, reproductive status, lifetime of ovary exposure and/or time interval since spaying. Urinary behaviour of intact females (n = 12) and dogs spayed before (n = 17) or after (n = 29) puberty was similar and not influenced by age, lifetime of ovary exposure and/or time interval since spaying. Owners of spayed dogs described more frequent or more intense fear reaction in their animals in response to loud noises, unfamiliar objects approaching on or near the sidewalk, or if they were approached by unknown dogs barking, growling or jumping. In conclusion, we found no evidence of a masculinization effect after spaying on urinary behaviour in female Labrador Retrievers. In contrast to popular belief, gonadectomy did not inevitably result in a behaviourally more stable dog. Extrapolation of our findings from female Labrador Retrievers to other breeds should be performed with caution, as the effect of spaying on behaviour may differ among dog breeds.


Projection of the vestibular nerve to the SI arm field in the cerebral cortex of the cat.
Evoked cortical focal potentials from electrical vestibular nerve stimulation were recorded in the Pcd-area in cats anaesthetized with Chloralose or Nembutal. For comparison, additional cortical projections were located for n. rad. superficialis and group Ia muscle afferents from n. rad. prof., n. fibularis prof., n. femuralis ramus muscularis and the motor nerve to the trapezoid muscle. Surface positive potentials, which reversed to negativity in middle cortical layers, were for vestibular nerve stimulation recorded in the S I forelimb field in a small area close to Pcd in the posterior medial part of the deep radial nerve projection field. The location of this field is compared with the vestibulo-cortical projections described earlier for rodents, squirrel monkey, and rhesus monkey. The histology shows that the field was within the cytoarchitectonic 3a area.


Effects of Bronchopulmonary Dysplasia on Swallow:Breath Interaction and Phase of Respiration with Swallow During Non-nutritive Suck.
The objective of this study is to describe swallow:breath interaction (SwBr) and phase of respiration incident to swallow (POR) during non-nutritive suck in infants with bronchopulmonary dysplasia and determine if speech-language intervention can modify the characteristics of non-nutritive suck in these infants. Logistic regression models were used to describe SwBr and POR in 16 low-risk preterm (LRP) infants and 43 infants with bronchopulmonary dysplasia. Infants with bronchopulmonary dysplasia were randomized to receive individualized intervention from a speech-language pathologist (BPDwithTX) or standard care (BPDnoTX). No significant differences were noted between low-risk infants and either group of BPD infants for the distribution of SwBr types. Infants with bronchopulmonary dysplasia showed minor differences in the progression of POR. Speech-Language intervention did not change the progression of SwBr or POR in infants with bronchopulmonary dysplasia. Infants with bronchopulmonary dysplasia can improve the progression of SwBr through practice as effectively as low-risk preterm infants can. The minor differences in POR in infants with bronchopulmonary dysplasia are consistent with dysmature development as seen with other feeding studies of infants with this disease. Speech-Language intervention did not modify the developmental progression of swallow:breath interaction or phase of respiration incident to swallow.


Role of coronary physiology in the contemporary management of coronary artery disease.
Coronary artery disease (CAD) remains the leading cause of death worldwide with approximately 1 in 30 patients with stable CAD experiencing death or acute myocardial infarction each year. The presence and extent of resultant myocardial ischaemia has been shown to confer an increased risk of adverse outcomes. Whilst, optimal medical therapy (OMT) forms the cornerstone of the management of patients with stable CAD, a significant number of patients present with ischaemia refractory to OMT. Historically coronary angiography alone has been used to determine coronary lesion severity in both stable and acute settings. It is increasingly clear that this approach fails to accurately identify the haemodynamic significance of lesions; especially those that are visually "intermediate" in severity. Revascularisation based upon angiographic appearances alone may not reduce coronary events above OMT. Technological advances have enabled the measurement of physiological indices including the fractional flow reserve, the index of microcirculatory resistance and the coronary flow reserve. The integration of these parameters into the routine management of patients presenting to the cardiac catheterization laboratory with CAD represents a critical adjunctive tool in the optimal management of these patients by identifying patients that would most benefit from revascularisation and importantly also highlighting patients that would not gain benefit and therefore reducing the likelihood of adverse outcomes associated with coronary revascularisation. Furthermore, these techniques are applicable to a broad range of patients including those with left main stem disease, proximal coronary disease, diabetes mellitus, previous percutaneous coronary intervention and with previous coronary artery bypass grafting. This review will discuss current concepts relevant to coronary physiology assessment, its role in the management of both stable and acute patients and future applications.


Effects of abnormal cannabidiol on oxytocin-induced myometrial contractility.
The objective of this study was to investigate the effects of abnormal cannabidiol (abn-cbd) on oxytocin-induced myometrial contractility occurring during pregnancy. Isometric tension recordings were performed in isolated myometrial strips from biopsies obtained at elective cesarean section. The effects of cumulative doses of abn-cbd (10(-9)-10(-5) M) on oxytocin-induced myometrial contractions alone, and on those following pre-incubation with SR 144528, AM 251, methylene blue, and iberiotoxin were measured, and dose-response curves were constructed. The pD(2) (-log EC(50)) values and the maximal inhibitory (MMI) values that were achieved were compared for each tissue type. Abn-cbd exerted a potent relaxant effect on oxytocin-induced myometrial contractions in vitro. Pre-incubation with the guanylate cyclase inhibitor, methylene blue, and the BK(Ca) channel antagonist, iberiotoxin, significantly attenuated this effect (for pD(2), P<0.01; for MMI, P<0.01). Abn-cbd exerts a potent inhibitory effect on human uterine contractility. This effect is partially mediated through modulation of guanylate cyclase and activation of BK(Ca) channel activity. These findings have implications for physiologic regulation of myometrial quiescence.


Stochastic evaluation of mixing-controlled steady-state plume lengths in two-dimensional heterogeneous domains.
We study plumes originating from continuous sources that require a dissolved reaction partner for their degradation. The length of such plumes is typically controlled by transverse mixing. While analytical expressions have been derived for homogeneous flow fields, incomplete characterization of the hydraulic conductivity field causes uncertainty in predicting plume lengths in heterogeneous domains. In this context, we analyze the effects of three sources of uncertainty: (i) The uncertainty of the effective mixing rate along the plume fringes due to spatially varying flow focusing, (ii) the uncertainty of the volumetric discharge through (and thus total mass flux leaving) the source area, and (iii) different parameterizations of the Darcy-scale transverse dispersion coefficient. The first two are directly related to heterogeneity of hydraulic conductivity. In this paper, we derive semi-analytical expressions for the probability distribution of plume lengths at different levels of complexity. The results are compared to numerical Monte Carlo simulations. Uncertainties in mixing and in the source strength result in a statistical distribution of possible plume lengths. For unconditional random hydraulic conductivity fields, plume lengths may vary by more than one order of magnitude even for moderate degrees of heterogeneity. Our results show that the uncertainty of volumetric flux through the source is the most relevant contribution to the variance of the plume length. The choice of different parameterizations for the local dispersion coefficient leads to differences in the mean estimated plume length.


What Paves the Way to Conventional Language? The Predictive Value of Babble, Pointing, and Socioeconomic Status.
A child's first words mark the emergence of a uniquely human ability. Theories of the developmental steps that pave the way for word production have proposed that either vocal or gestural precursors are key. These accounts were tested by assessing the developmental synchrony in the onset of babbling, pointing, and word production for 46 infants observed monthly between the ages of 9 and 18 months. Babbling and pointing did not develop in tight synchrony and babble onset alone predicted first words. Pointing and maternal education emerged as predictors of lexical knowledge only in relation to a measure taken at 18 months. This suggests a far more important role for early phonological development in the creation of the lexicon than previously thought.


Differential Diagnosis of an Unusual Snakebite Presentation in Benin: Dry Bite or Envenomation?
A 20-year-old man presented to a rural hospital in Bembéréké, northern Benin, after a witnessed bite from a small, dark snake to his left foot that occurred 3 hours earlier. The description of the snake was consistent with several neurotoxic elapids known to inhabit the area in addition to various species from at least 10 different genera of non-front-fanged colubroid (NFFC) venomous snakes. The presentation was consistent with the early signs of a neurotoxic snakebite as well as a sympathetic nervous system stress response. Diagnosis was further complicated by the presence of a makeshift tourniquet, which either could have been the cause of local signs and symptoms or a mechanical barrier delaying venom distribution and systemic effects until removal. Systemic envenomation did not develop after the removal of the constricting band, but significant local paresthesias persisted for longer than 24 hours and resolved after the administration of a placebo injection of normal saline in place of antivenom therapy. This was an unusual case of snakebite with persistent neuropathy despite an apparent lack of envenomation and a number of snakebite- specific variables that complicated the initial assessment, diagnosis, and treatment of the patient. This case presentation provides clinicians with an opportunity to familiarize themselves with the differential diagnosis and approach to a patient bitten by an unidentified snake, and it illustrates the importance of symptom progression as a pathognomonic sign during the early stages of a truly serious snake envenomation. Treatment should be based on clinical presentation and evolution of symptoms rather than on snake identification alone.


Exposure to second-hand smoke damages everyday prospective memory.
Prospective memory (PM: remembering future intentions and activities) is critical to everyday remembering. This study compared a group of never-smokers who reported regular exposure to second-hand smoke (the SHS group) with a group of current smokers (the CS group) and a group of never-smokers who reported never having been exposed to SHS (the non-SHS group) on objective PM. An existing groups design was employed to compare the SHS, CS and non-SHS groups. Twenty-four SHS, 27 CS and 28 non-SHS were tested on objective PM. All participants were university undergraduates aged between 18-30 years. All participants were tested individually in a laboratory setting. The Cambridge Prospective Memory Test (CAMPROMPT) was used to assess objective PM. Age, other drug use, mood and IQ were also measured as covariates in the study. The non-SHS group recalled significantly more time-based PM tasks than the SHS group (means = 16.3 versus 13.7, P < 0.001) and significantly more than the CS group (CS mean = 11.6, P < 0.001); and the SHS group recalled significantly more time-based tasks than the CS group (P < 0.002). The non-SHS group recalled significantly more event-based PM tasks than the CS group (means = 15.2 versus 11.3, P < 0.002) with no significant difference between the non-SHS group and SHS group (SHS mean = 14.3, P = 0.234); and the SHS group recalled significantly more event-based tasks than the CS group (P < 0.001). Non-smokers exposed to second-hand smoke may suffer impairment in time-based prospective memory.


Testing main effects and interactions in latent curve analysis.
A key strength of latent curve analysis (LCA) is the ability to model individual variability in rates of change as a function of 1 or more explanatory variables. The measurement of time plays a critical role because the explanatory variables multiplicatively interact with time in the prediction of the repeated measures. However, this interaction is not typically capitalized on in LCA because the measure of time is rather subtly incorporated via the factor loading matrix. The authors' goal is to demonstrate both analytically and empirically that classic techniques for probing interactions in multiple regression can be generalized to LCA. A worked example is presented, and the use of these techniques is recommended whenever estimating conditional LCAs in practice.


Comparative Effectiveness of Antidepressant Medication versus Psychological Intervention on Depression Symptoms in Women with Infertility and Sexual Dysfunction.
Fertility loss is considered as a challenging experience. This study was conducted to compare the effectiveness of antidepressant medication and psychological intervention on depression symptoms in women with infertility and sexual dysfunctions (SD). This randomized, controlled clinical trial study was completed from December 2014 to June 2015 in Babol, Iran. Of the 485 participants, 93 were randomly assigned in a 1:1:1 ratio to psychosexual therapy (PST), bupropion extended-release (BUP ER) at a dose of 150 mg/d, and control (no intervention) groups. The beck depression inventory (BDI) was completed at the beginning and end of the study. Duration of study was eight weeks. Statistical analyses were performed by using paired-test and analysis of covariance. The mean depression score on the BDI was 22.35 ± 8.70 in all participants. Mean BDI score decreased significantly in both treatment groups (PST: P<0.0001, BUP: P<0.002) from baseline to end of the study, whereas intra-individual changes in BDI score were not significant in the control group. The decrease in mean BDI score was greater with PST compared to BUP treatment (P<0.005) and the control group (P<0.0001). The PST group showed greater improvement in depression levels (severe to moderate, moderate to mild) in comparison with the two other groups (P<0.001). Drug treatment was well tolerated by the participants in the BUP group. PST can be a reliable alternative to BUP ER for relieving depression symptoms in an Iranian population of women with infertility and SD (Registration number: IRCT2015042721955N2).


Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms.
The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors. We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM. A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0-21.9 months) and median overall survival was 51 months (95% CI, 42.8-59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed. The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.


Atomic Level Anisotropy in the Electrostatic Modeling of Lone Pairs for a Polarizable Force Field Based on the Classical Drude Oscillator.
Electron pairs in the valence shell of an atom that do not participate in the bonding of a molecule ("lone pairs") give rise to a concentrated electron density away from the atom center. To account for the asymmetry in the electron charge density that arises from lone pairs, an electrostatic model is developed that is parametrically anisotropic at the atomic level. The model uses virtual interaction sites with partial charges that are associated but not coincident with the nuclei. In addition, the model incorporates anisotropic atomic polarizabilities. The protocol previously outlined in Anisimov et al. [J. Chem. Theory Comput. 2005, 1, 153] for parametrizing the electrostatic potential energy of a polarizable force field using classical Drude oscillators is extended to incorporate additional lone pair parameters. To probe the electrostatic environment around the lone pairs, the static (molecule alone) and perturbed (molecule in the presence of a test charge) electrostatic potential (ESP) are evaluated and compared to high level quantum mechanical (QM) electronic structure calculations. The parametrization of the virtual sites relies on data from the QM static ESP. The contribution to the perturbed ESP from the electronic polarization of the molecule is used to resolve the components of the atomic polarizability tensor. The model is tested in the case of four molecules: methanol, acetone, methylamine, and pyridine. Interaction energies with water and sodium are used to assess the accuracy of the model. The results are compared with simpler models placing all the charge on the nuclei as well as using only isotropic atomic polarizabilities. Analysis shows that the addition of virtual sites reduces the average error relative to the QM calculations. In contrast to models with atom centered charges, the virtual site models correctly predict the minimum energy conformation for acetone and methanol, with water, to be closely coordinated with the lone pair direction. Furthermore, addition of anisotropic atomic polarizabilities to the virtual site model allows for precise fitting to the local perturbed QM ESP.


Perspectives of homeless people on their health and health needs priorities.
This paper is a report of a study of the perspectives of homeless individuals on their health and healthcare needs. Many studies show the high incidence and severity of diseases, physical and mental, amongst the homeless populations. However, the views of homeless people themselves are usually omitted. In order to provide appropriate care, healthcare professionals need to be aware of these perspectives. A descriptive, exploratory design, using semi-structured interviews and observational field notes, was chosen for this qualitative study. A convenience sample of 24 participants experiencing homelessness was recruited in one Canadian city in 2005. Participants described their health and healthcare needs in a holistic sense. They reported concerns about physical illnesses, mental health, addictions and stress. Shelter life promoted spread of diseases and lacked privacy. Violence was rampant in shelters and on the streets, leading to constant fear. There was emotional distress over social exclusion and depersonalization. Participants wanted to work and to be housed, yet felt trapped in a dehumanizing system. The recommendations are (a) elimination or mitigation of most health problems of the homeless through safe, affordable housing; (b) reintegration into the community through job counselling, treatment of addictions and employment. Negative societal attitudes towards these clients need to change. Healthcare professionals, particularly community nurses, have opportunities to collaborate respectfully with these clients and work for changes in public policies, such as national housing and addiction treatment policies, and for streamlined, humanized services to smooth the processes of social reintegration.


Dietary fat intake and the risk of depression: the SUN Project.
Emerging evidence relates some nutritional factors to depression risk. However, there is a scarcity of longitudinal assessments on this relationship. To evaluate the association between fatty acid intake or the use of culinary fats and depression incidence in a Mediterranean population. Prospective cohort study (1999-2010) of 12,059 Spanish university graduates (mean age: 37.5 years) initially free of depression with permanently open enrolment. At baseline, a 136-item validated food frequency questionnaire was used to estimate the intake of fatty acids (saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA), trans unsaturated fatty acids (TFA) and monounsaturated fatty acids (MUFA) and culinary fats (olive oil, seed oils, butter and margarine) During follow-up participants were classified as incident cases of depression if they reported a new clinical diagnosis of depression by a physician and/or initiated the use of antidepressant drugs. Cox regression models were used to calculate Hazard Ratios (HR) of incident depression and their 95% confidence intervals (CI) for successive quintiles of fats. During follow-up (median: 6.1 years), 657 new cases of depression were identified. Multivariable-adjusted HR (95% CI) for depression incidence across successive quintiles of TFA intake were: 1 (ref), 1.08 (0.82-1.43), 1.17 (0.88-1.53), 1.28 (0.97-1.68), 1.42 (1.09-1.84) with a significant dose-response relationship (p for trend = 0.003). Results did not substantially change after adjusting for potential lifestyle or dietary confounders, including adherence to a Mediterranean Dietary Pattern. On the other hand, an inverse and significant dose-response relationship was obtained for MUFA (p for trend = 0.05) and PUFA (p for trend = 0.03) intake. A detrimental relationship was found between TFA intake and depression risk, whereas weak inverse associations were found for MUFA, PUFA and olive oil. These findings suggest that cardiovascular disease and depression may share some common nutritional determinants related to subtypes of fat intake.


Background leak K+-currents and oxygen sensing in carotid body type 1 cells.
One model of oxygen sensing by the carotid body is that hypoxia depolarises type 1 cells leading to voltage-gated calcium entry and the secretion of neurotransmitters which then excite afferent nerves. This paper revues the mechanisms responsible for the membrane depolarisation in response to hypoxia. It concludes that depolarisation is caused not through the inhibition of calcium activated or delayed rectifier K+-channels but through the inhibition of an entirely new type of background K+-channel. This channel lacks sensitivity to the classical K+-channel inhibitors TEA and 4-AP. New evidence does however reveal that background K+-channels in the type 1 cell can be inhibited by Ba2+ and that Ba2+ depolarises isolated type 1 cells. Intriguingly, Ba2+ is the only K+-channel inhibitor thus far reported to stimulate the carotid body. These studies therefore support the hypothesis that depolarisation of the type 1 cell is an integral part of the oxygen sensing pathway in the carotid body.


Responses of succinate dehydrogenase and non-specific alkaline phosphatases and mortality of tilapia to ambient pH stress in a sewage-fed aquaculture pond.
The fish, tilapia (Oreochromis mossambicus) of 50-60 g body weight was experimentally exposed to effluent gradients of highly alkaline pH in a sewage-fed aquaculture farm for examining the pH stress-induced responses of mortality and the stress marker enzyme succinate dehydrogenase and the non-specific alkaline phosphatases of fish prior to death at different hours of intoxication. A second trial was performed after two months when water quality changed along the sewage effluent gradient. An in situ experiment was also performed for better understanding of the responses of enzymatic activities attributable to different levels of pH conditions. Time required for 100% mortality of fish tended to increase from 30 min in pH 11.6 to 22 hr in pH 10.2. There was no mortality of fish when water quality improved significantly (with pH ranging between 9.6 to 8.0) after two months. The activities of succinate dehydrogenase and intracellular alkaline phosphatases assayed in gills and liver prior to death of fish tended to reduce with increase in survival hour, following a pattern of decay curve. On the other hand, percent of enzymatic inhibition of the exposed fish over the control increased as the survival hour increased following a pattern of exponential curve. It appears that the highest water pH of 11.6. maximum ratio for ammonium to ammonium hydroxide (1: 21) and reduced level of dissolved oxygen (2.62 mg/l) were perhaps responsible for the 100% mortality of fish within 30 min of their exposure and the enzymatic activities in the gills and liver assayed prior to death of fish tended to reduce as the acclimatization period of fish increased and vice-versa.


Role of multidrug transporters in neurotherapeutics.
Acquired resistance to antibiotics and other chemotherapeutic agents is a major problem in the practice of neurology and other branches of medicine. There are several mechanisms by which drug resistance is acquired. Multidrug transporters are important glycoproteins located in the cell membrane that actively transport small lipophilic molecules from one side of the cell membrane to the other, most often from the inside to the outside of a cell. They have important protective role yet may prove inconvenient in chemotherapy. In epilepsy and other disorders this mechanism augments the elimination of drugs from their target cells and leads to drug resistance. In this review, we have discussed the biochemical characteristics of multidrug transporters and the mechanisms by which these membrane bound proteins transport their target molecules from one side to the other side of the cell membrane. We have also briefly discussed the application of this knowledge in the understanding of drug resistance in various clinical situations with particular reference to neurological disorders. These proteins located in the placenta have important role in preventing the transplacental movement of drugs in to the fetus which may result in congenital malformations or other defects. The molecular genetic mechanisms that govern the expression of these important proteins are discussed briefly. The potential scope to develop targeted chemotherapeutic agents is also discussed.


Mismatch repair-dependent metabolism of O6-methylguanine-containing DNA in Xenopus laevis egg extracts.
The cytotoxicity of SN1-type alkylating agents such as N-methyl-N'-nitrosourea (MNU), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or the cancer chemotherapeutics temozolomide, dacarbazine and streptozotocin has been ascribed to the persistence of O(6)-methylguanine ((me)G) in genomic DNA. One hypothesis posits that (me)G toxicity is caused by futile attempts of the mismatch repair (MMR) system to process (me)G/C or (me)G/T mispairs arising during replication, while an alternative proposal suggests that the latter lesions activate DNA damage signaling, cell cycle arrest and apoptosis directly. Attempts to elucidate the molecular mechanism of (me)G-induced cell killing in vivo have been hampered by the fact that the above reagents induce several types of modifications in genomic DNA, which are processed by different repair pathways. In contrast, defined substrates studied in vitro did not undergo replication. We set out to re-examine this phenomenon in replication-competent Xenopus laevis egg extracts, using either phagemid substrates containing a single (me)G residue, or methylated sperm chromatin. Our findings provide further support for the futile cycling hypothesis.


Bioprofiling for the quality control of Egyptian propolis using an integrated NIR-HPTLC-image analysis strategy.
Quality control of propolis being a complex mixture of compounds that are very difficult to analyze and standardize is certainly challenging. Shown on the example of 35 Egyptian propolis samples, a strategy for an improved quality control was demonstrated in which efficacy-directed fingerprint analysis of high-performance thin-layer chromatography (HPTLC) fingerprints were evaluated in combination with Near Infra-Red spectrometry (NIRS) to realize precise discrimination and high quality assessment of chemical and effective consistency of propolis samples that are collected from various geographical locations in Egypt. The fingerprints obtained after derivatization and fluorescence detection (FLD) at λ 366 nm were analyzed by using multivariate data analysis and data were used to identify nine marker ingredients of the different propolis samples. These markers were then quantified by a new validated HPTLC method and an attempt to classify the samples by using a targeted approach was implemented. All investigated propolis samples were initially divided into two types in the untargeted and targeted HPTLC image multivariate analysis. The antimicrobial activities of propolis samples were then evaluated and the results showed that there was significant variation in the biological activities of the different samples. The quantitative data of marker compounds as well as the samples bioactivity results were then subjected to partial least squares regression (PLS-R) analysis which revealed that chrysin, galangin‑5‑O‑methylether, pinostrobin, and islapinin were the main bioactive markers. Based on the efficacy-associated marker ingredients, pretreated spectral patterns of NIRS were selected as a complementary evaluation technique directed to the comprehensive efficacy-directed discrimination of the different Egyptian propolis samples which could successfully classify the propolis samples tested into three different types. Hierarchical cluster analysis and orthogonal projection to latent structures discriminant analysis (OPLS-DA) were applied to the quantitative results from the efficacy-associated markers only. From this systematic method, the 35 samples were subsequently divided into three types; orange, green and blue, displaying a more intricate division than OPLS-DA which is based only on the untargeted HPTLC analysis or the full NIR spectral data. This study initiated the research on the Egyptian propolis and confirmed the existence of three different types of Egyptian propolis, the blue, green and orange types. The study also emphasizes how it is critical to implement the fingerprint- efficacy relationship analysis in finding out the main health-relevant biomarkers for the quality assessment especially for samples displaying delicate differences in their chemical composition and bioactivity.


Studies on the carbohydrate-binding characteristics of human pulmonary surfactant-associated protein A and comparison with two other collectins: mannan-binding protein and conglutinin.
The surfactant-associated protein A (SP-A) belongs to the collectin family, a group of C-type lectins encompassing also surfactant-associated protein D, mannan-binding protein (MBP) and conglutinin. These proteins all have carbohydrate-recognition domains joined to collagen stalks. It seems likely that SP-A, like MBP and conglutinin, may mediate anti-microbial activity through binding to carbohydrates on the microorganisms and collectin receptors on phagocytic cells. We have studied the influence of carbohydrates on the binding of SP-A, MBP and conglutinin to mannan in an enzyme-linked lectin-binding assay. All sugars were of D-configuration, except fucose of which both L- and D-configurations were tested. The order of inhibiting potency on the binding of SP-A was: N-acetylmannosamine > L-fucose, maltose > glucose > mannose. The following sugars were non-inhibitory: galactose, D-fucose, glucosamine, mannosamine, galactosamine, N-acetylglucosamine, and N-acetylgalactosamine. The best inhibitor of MBP was N-acetylglucosamine. Otherwise MBP showed a selectivity similar to that of SP-A. Conglutinin binding was inhibited by all the sugars examined except N-acetylgalactosamine. For conglutinin, as for MBP, the best inhibitor was N-acetylglucosamine. Normal human SP-A, alveolar-proteinosis SP-A purified by ion-exchange chromatography, and alveolar-proteinosis SP-A purified by n-butanol extraction showed no difference in sugar selectivity. The influence of pH and of the calcium concentration was also examined. Organic solvent-extracted SP-A from patients suffering from alveolar proteinosis and normal SP-A showed different sensitivity profiles.


Hospitalisation associated with the 2009 H1N1 pandemic and seasonal influenza in Hong Kong, 2005 to 2010.
Reliable estimates of the morbidity burden caused by the 2009 pandemic influenza (pH1N1) are important for assessing the severity of the pandemic. Poisson regression models were fitted to weekly numbers of cause-specific hospitalisation in Hong Kong from 2005 to 2010. Excess hospitalisation associated with the 2009 pandemic and seasonal influenza was derived from the model by incorporating the proxy variables of weekly proportions of specimens positive for the pandemic influenza A(H1N1)pdm09, seasonal influenza A (subtypes H3N2 and H1N1) and B viruses. Compared with seasonal influenza, pH1N1 influenza was associated with higher hospitalisation rates for acute respiratory disease (ARD) among children younger than 18 years and adults aged between 18 and 64 years, but among the elderly aged 65 years and older the hospitalisation rates were lower for pH1N1 than for seasonal H3N2 and H1N1 influenza. Hospitalisation rates for chronic diseases associated with pH1N1 influenza were generally higher than those associated with seasonal influenza. The reported hospitalised cases with laboratory-confirmed pandemic infections accounted for only 16% of pH1N1 influenza-associated hospitalisations for ARD in the age group 75 years and older, and 5‒66% of hospitalisations for chronic diseases in those older than 40 years. The 2009 H1N1 influenza pandemic was associated with a dramatically increased risk of hospitalisation among children and young adults. The morbidity burden of pandemic was underreported in old people and in those with chronic conditions.


Mountain mortality: a review of deaths that occur during recreational activities in the mountains.
The growing popularity of activities such as hiking, climbing, skiing and snowboarding has ensured that the number of visitors to mountain environments continues to increase. Since such areas place enormous physical demands on individuals, it is inevitable that deaths will occur. Differences in the activities, conditions and methods of calculation make meaningful mortality rates difficult to obtain. However, it is clear that the mortality rate for some mountain activities is comparable to hang gliding, parachuting, boxing and other pastimes that are traditionally viewed as dangerous. Deaths in the mountains are most commonly due to trauma, high altitude illness, cold injury, avalanche burial and sudden cardiac death. This review describes the mortality rates of those who undertake recreational activities in the mountains and examines the aetiology that lies behind them.


Persistence of transplanted oral mucosal epithelial cells in human cornea.
To determine the expression of differentiation and progenitor cell markers in corneal tissues that previously underwent autologous cultivated oral mucosal epithelial transplantation (COMET). Four eyes from three alkaline-injured patients and one thermally injured patient underwent COMET to promote re-epithelialization or corneal reconstruction. Between 10 and 22 months (mean, 14.2 +/- 5.5 months [SD]) after COMET, the corneal tissues were obtained after penetrating keratoplasty (n = 1) or autologous limbal transplantation (n = 3). Immunoconfocal microscopy for keratin (K)3, -12, -4, -13, and -8; connexin (Cx)43; MUC5AC; laminin-5; pan-p63; ABCG2; and p75 was performed in those specimens as well as in the oral mucosa and cultivated oral mucosal epithelial cells (OMECs). All four specimens were unanimously positive for K3, -4, and -13 but negative for K8 and MUC5AC, suggesting that the keratinocytes were oral mucosa-derived. However, peripheral K12 staining was positive only in patient 2, suggesting a mixed oral and corneal epithelium in that case. Cx43 staining in the basal epithelium was negative in patients 1, 2, and 3, but was positive in patient 4. Small, compact keratinocytes in the basal epithelium preferentially expressed pan-p63, ABCG2, and p75. Although the staining of pan-p63 and ABCG2 tended to be more than one layer, signal for p75 was consistently localized only to the basal layer. The study demonstrated the persistence of transplanted OMECs in human corneas. In addition, small, compact cells in the basal epithelium preferentially expressed the keratinocyte stem/progenitor cell markers, which may be indicative of the engraftment of the progenitor cells after transplantation.


The potential of transcranial photobiomodulation therapy for treatment of major depressive disorder.
Major depressive disorder is a common debilitating mood disorder that affects quality of life. Prefrontal cortex abnormalities, an imbalance in neurotransmitters, neuroinflammation, and mitochondrial dysfunction are the major factors in the etiology of major depressive disorder. Despite the efficacy of pharmacotherapy in the treatment of major depressive disorder, 30%-40% of patients do not respond to antidepressants. Given this, exploring the alternative therapies for treatment or prevention of major depressive disorder has aroused interest among scientists. Transcranial photobiomodulation therapy is the use of low-power lasers and light-emitting diodes in the far-red to near-infrared optical region for stimulation of neuronal activities. This non-invasive modality improves the metabolic capacity of neurons due to more oxygen consumption and ATP production. Beneficial effects of transcranial photobiomodulation therapy in the wide range of neurological and psychological disorders have been already shown. In this review, we focus on some issue relating to the application of photobiomodulation therapy for major depressive disorder. There is some evidence that transcranial photobiomodulation therapy using near-infrared light on 10-Hz pulsed mode appears to be a hopeful technique for treatment of major depressive disorder. However, further studies are necessary to find the safety of this method and to determine its effective treatment protocol.


[Trends in nursing research in Korea: research trends for studies published from the inaugural issue to 2010 in the Journal of Korean Academy of Nursing and the journals published by member societies under Korean Academy of Nursing Science].
The purpose of this study was to identify trends for studies published in the Journal of Korean Academy of Nursing and journals published by member societies from inaugural issues to 2010. A total of 6890 studies were analyzed using descriptive statistics. Quantitative studies accounted for 83.6% while qualitative studies accounted for 14.4%. Most frequently used research designs were quasi-experimental (91.1%) for experimental research and survey (85.2%) for non-experimental research. Most frequent study participants were healthy people (35.8%), most frequent nursing interventions, nursing skills (53.5%), and 39.8% used knowledge, attitude and behavior outcomes for dependent variables. Most frequently used keyword was elderly. Survey studies decreased from 1991 to 2010 by approximately 50%, while qualitative studies increased by about 20%. True experimental research (1.2%) showed no significant changes. Studies focusing on healthy populations increased from 2001-2005 (37.5%) to 2006-2010 (41.0%). From 1970 to 2010, studies using questionnaire accounted for over 50% whereas physiological measurement, approximately 5% only. Experimental studies using nursing skill interventions increased from 1970-1980 (30.4%) to 2006-2010 (64.0%). No significant changes were noted in studies using knowledge, attitude and behavior (39.9%) as dependent variables. The results suggest that further expansion of true experimental, qualitative studies and physiological measurements are needed.


Steroids for improving recovery following tonsillectomy in children.
This is an update of a Cochrane Review first published in The Cochrane Library in Issue 1, 2003.Tonsillectomy continues to be one of the most common surgical procedures performed worldwide. Despite advances in anesthetic and surgical techniques, post-tonsillectomy morbidity remains a significant clinical problem. To assess the clinical efficacy of a single intraoperative dose of dexamethasone in reducing post-tonsillectomy morbidity. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN; and additional sources for published and unpublished trials. The date of the most recent search was 29 October 2010, following a previous search in September 2002. Randomized, double-blind, placebo-controlled trials of a single dose of intravenous, intraoperative corticosteroid for pediatric patients (age < 18 years) who underwent tonsillectomy or adenotonsillectomy. The first author extracted data regarding the primary outcome measures and measurement tools from the published studies. The first author also recorded data regarding study design, patient ages, procedures performed, dose of corticosteroid and method of delivery, as well as methodological quality. When data were missing from the original publications, we contacted the authors for more information. We performed data analysis with a random-effects model, using the RevMan 5.1 software developed by the Cochrane Collaboration. We included 19 studies (1756 participants). We selected only randomized, placebo-controlled, double-blinded studies to minimize inclusion of poor quality studies. However, the risk of bias in the included studies was not formally assessed. Children receiving a single intraoperative dose of dexamethasone (dose range = 0.15 to 1.0 mg/kg) were half as likely to vomit in the first 24 hours compared to children receiving placebo (risk ratio (RR) 0.49; 95% confidence interval (CI) 0.41 to 0.58; P < 0.00001). Routine use in five children would be expected to result in one less patient experiencing post-tonsillectomy emesis (risk difference (RD) -0.24; 95% CI -0.32 to -0.15; P < 0.00001). Children receiving dexamethasone were also more likely to advance to a soft/solid diet on post-tonsillectomy day one (RR 1.45; 95% CI 1.15 to 1.83; P = 0.001) than those receiving placebo. Finally, postoperative pain was improved in children receiving dexamethasone as measured by a visual analog scale (VAS, 0 to 10) (MD -1.07; 95% CI -1.73 to -0.41; P = 0.001), which correlates clinically to a reduction in pain (on a VAS of 0 to 10) from 4.72 to 3.65. No adverse events were noted in the included studies. The evidence suggests that a single intravenous dose of dexamethasone is an effective, safe and inexpensive treatment for reducing morbidity from pediatric tonsillectomy.


Reverse transcriptase in normal rhesus monkey placenta.
Particles with the morphology of type C virus have been identified from primate placentas by electron microscopy. A reverse transcriptase (RNA-dependent DNA polymerase) was isolated and purified from microsomal pellets of two fresh placentas of rhesus monkeys in the early stages of gestation. This enzyme was biochemically similar yet immunologically distinct from the reverse transcriptases of known tumorigenic type C RNA viruses isolated from primates, but was immunologically related to a reverse transcriptase isolated from a type C virus obtained from normal baboon placenta. These particles may represent endogenous viruses and may function in the transfer of genetic information during embryogenesis.


[Computers in biomedical research: I. Analysis of bioelectrical signals].
A personal computer equipped with an analog-to-digital conversion card is able to input, store and display signals of biomedical interest. These signals can additionally be submitted to ad-hoc software for analysis and diagnosis. Data acquisition is based on the sampling of a signal at a given rate and amplitude resolution. The automation of signal processing conveys syntactic aspects (data transduction, conditioning and reduction); and semantic aspects (feature extraction to describe and characterize the signal and diagnostic classification). The analytical approach that is at the basis of computer programming allows for the successful resolution of apparently complex tasks. Two basic principles involved are the definition of simple fundamental functions that are then iterated and the modular subdivision of tasks. These two principles are illustrated, respectively, by presenting the algorithm that detects relevant elements for the analysis of a polysomnogram, and the task flow in systems that automate electrocardiographic reports.


Environmental factors in childhood IDDM. A population-based, case-control study.
To identify environmental factors involved in the etiology of insulin-dependent diabetes mellitus (IDDM). An estimated 90% of all incident cases of IDDM in patients 0-14 years of age in New South Wales, Australia, were ascertained over 18 months. For each IDDM patient, two age- and sex-matched control subjects were randomly selected from the population. Past environmental exposures were determined with a questionnaire completed by the parents. Response rates were 92% for the IDDM patients (217 of 235) and 55% for the control subjects (258 of 470). The relative risk associated with each exposure was estimated with the odds ratio (OR) adjusted for confounding factors using multiple logistic regression. The introduction of cow's milk-based infant formula into the diet before 3 months of age was associated with an increased risk (OR 1.52, 95% confidence interval [CI] 1.04-2.24). Exclusive breast-feeding for > or = 3 months was associated with a protective effect (OR 0.66, 95% CI 0.45-0.97). High dietary intake of cow's milk protein in the 12 months before the onset of diabetic symptoms was also associated with an increased risk (OR 1.84, 95% CI 1.12-3.00). A recent infection (during the 3 months before onset of diabetic symptoms) was more common in the patients than the control subjects (OR 2.92, 95% CI 1.96-4.35), as was day care attendance before the age of 3 (OR 1.73, 95% CI 1.00-3.00). When two age-groups, defined by the median age at onset of diabetes, were compared, the associations with early infant-feeding were stronger among the younger group (< 9.2 years), and associations with recent diet and recent infection were stronger among the older group (> or = 9.2 years). These results indicate an increased risk of IDDM associated with early dietary exposure to cow's milk-containing formula, short duration of exclusive breast-feeding, high intake of cow's milk protein in the recent diet, recent infection, and early attendance at day care.


Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice.
The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.


How number processing survives left occipito-temporal damage.
We investigated the neural systems that support number processing in a patient (JL) who had damage to the left ventral occipito-temporal cortex (LvOT). JL had severely impaired written word recognition but he was remarkably accurate in number tasks, albeit slower than normal. This suggests LvOT activation is necessary for efficient but not for accurate number decisions. Here we investigated how JL made accurate number decisions using fMRI; we compared JL's brain activation to that in healthy controls and in two patients with frontal lobe damage who, like JL, made slow but accurate responses in number tasks. For semantic relative to perceptual decisions on numbers, JL did not activate the left occipito-temporal area that was involved in all other subjects. However, JL had significantly increased activation in a left posterior middle temporal region. In addition, during semantic and perceptual decisions on numbers, JL showed increased activation in: (1) the right occipito-temporal cortex, (2) right caudate, and (3) bilateral frontal regions. These effects were unique to JL and cannot be explained in terms of abnormally long response times because they were not observed in the other patients who made slow but accurate number decisions. Together these results show that although the LvOT usually contributes to efficient number processing, activation in this region is not essential for accurate performance because (i) perceptual processing of numbers can be supported by right occipital, right caudate, and bilateral frontal activation and (ii) semantic processing of numbers can be supported by increased left posterior middle temporal activation associated with hand actions.


Peeling the astronomical onion.
Water ice is the most abundant solid in the Universe. Understanding the formation, structure and multiplicity of physicochemical roles for water ice in the cold, dense interstellar environments in which it is predominantly observed is a crucial quest for astrochemistry as these are regions active in star and planet formation. Intuitively, we would expect the mobility of water molecules deposited or synthesised on dust grain surfaces at temperatures below 50 K to be very limited. This work delves into the thermally-activated mobility of H2O molecules on model interstellar grain surfaces. The energy required to initiate this process is studied by reflection-absorption infrared spectroscopy of small quantities of water on amorphous silica and highly oriented pyrolytic graphite surfaces as the surface is annealed. Strongly non-Arrhenius behaviour is observed with an activation energy of 2 kJ mol-1 on the silica surface below 25 K and 0 kJ mol-1 on both surfaces between 25 and 100 K. The astrophysical implication of these results is that on timescales shorter than that estimated for the formation of a complete monolayer of water ice on a grain, aggregation of water ice will result in a non-uniform coating of water, hence leaving bare grain surface exposed. Other molecules can thus be formed or adsorbed on this bare surface.


Treatment of ankyloglossia and breastfeeding outcomes: a systematic review.
Ankyloglossia is a congenital condition characterized by an abnormally short, thickened, or tight lingual frenulum that restricts tongue mobility. The objective of this study was to systematically review literature on surgical and nonsurgical treatments for infants with ankyloglossia. Medline, PsycINFO, Cumulative Index of Nursing and Allied Health Literature, and Embase were searched up to August 2014. Two reviewers independently assessed studies against predetermined inclusion/exclusion criteria. Two reviewers independently extracted data regarding participant and intervention characteristics and outcomes and assigned quality and strength-of-evidence ratings. Twenty-nine studies reported breastfeeding effectiveness outcomes (5 randomized controlled trials [RCTs], 1 retrospective cohort, and 23 case series). Four RCTs reported improvements in breastfeeding efficacy by using either maternally reported or observer ratings, whereas 2 RCTs found no improvement with observer ratings. Although mothers consistently reported improved effectiveness after frenotomy, outcome measures were heterogeneous and short-term. Based on current literature, the strength of the evidence (confidence in the estimate of effect) for this issue is low. We included comparative studies published in English. The evidence base is limited, consisting of small studies, short-term outcomes, and little information to characterize participants adequately. No studies addressed nonsurgical interventions, longer-term breastfeeding or growth outcomes, or surgical intervention compared with other approaches to improve breastfeeding, such as lactation consultation. A small body of evidence suggests that frenotomy may be associated with mother-reported improvements in breastfeeding, and potentially in nipple pain, but with small, short-term studies with inconsistent methodology, strength of the evidence is low to insufficient.


Prosopagnosia as a deficit in encoding curved surface.
RP is a case of "developmental" prosopagnosia who, according to brain-imaging segmentation data, shows reduction in volume of a limited set of structures of the right hemisphere. RP is as accurate as control subjects in tasks requiring the perception of nonface objects (e.g., matching subordinate labels to exemplars, naming two-tone images), with the exception of one perceptual task: The matching of different perspectives of amoebae-like stimuli (i.e., volumes made of a single smooth surface). In terms of speed ("efficiency") of responses, RP's performance falls clearly outside the normal limits also in other tasks that include "natural" but nonface stimuli (i.e., animals, artia facts). Specifically, RP is slow in perceptual judgments made at very low (subordinate) levels of semantic categorization and for objects and artifacts whose geometry present much curved features and surface information. We conclude from these analyses that prosopagnosia can be the result of a deficit in the representation of basic geometric volumes made of curved surface. In turn, this points to the importance (necessity) for the normal visual system of such curved and volumetric information in the identification of human faces.


Policies designed for self-interested citizens may undermine "the moral sentiments": evidence from economic experiments.
High-performance organizations and economies work on the basis not only of material interests but also of Adam Smith's "moral sentiments." Well-designed laws and public policies can harness self-interest for the common good. However, incentives that appeal to self-interest may fail when they undermine the moral values that lead people to act altruistically or in other public-spirited ways. Behavioral experiments reviewed here suggest that economic incentives may be counterproductive when they signal that selfishness is an appropriate response; constitute a learning environment through which over time people come to adopt more self-interested motivations; compromise the individual's sense of self-determination and thereby degrade intrinsic motivations; or convey a message of distrust, disrespect, and unfair intent. Many of these unintended effects of incentives occur because people act not only to acquire economic goods and services but also to constitute themselves as dignified, autonomous, and moral individuals. Good organizational and institutional design can channel the material interests for the achievement of social goals while also enhancing the contribution of the moral sentiments to the same ends.


Femoral muscle attachment locations in children and adults, and their prediction from clinical measurement.
Accurate representation of children's musculo-skeletal anatomy is becoming increasingly important to biomechanical techniques such as gait analysis. This study used magnetic resonance imaging to examine the locations of the femoral insertions of the psoas, vastus medialis and gastrocnemius muscles in five adults and 17 children (including 7 children with cerebral palsy). The relationship of muscle attachment locations with age and bone geometry was then determined. Scaling techniques and external measurements of parameters such as femoral anteversion/antetorsion were shown to have potential for prediction of the locations of femoral muscle attachment points. It was shown that femoral anteversion can be modelled geometrically as occurring proximal to the lesser trochanter.


Boolean networks with multiexpressions and parameters.
To model biological systems using networks, it is desirable to allow more than two levels of expression for the nodes and to allow the introduction of parameters. Various modeling and simulation methods addressing these needs using Boolean models, both synchronous and asynchronous, have been proposed in the literature. However, analytical study of these more general Boolean networks models is lagging. This paper aims to develop a concise theory for these different Boolean logic-based modeling methods. Boolean models for networks where each node can have more than two levels of expression and Boolean models with parameters are defined algebraically with examples provided. Certain classes of random asynchronous Boolean networks and deterministic moduli asynchronous Boolean networks are investigated in detail using the setting introduced in this paper. The derived theorems provide a clear picture for the attractor structures of these asynchronous Boolean networks.


Immunofluorescence microscopy-based detection of ssDNA foci by BrdU in mammalian cells.
DNA end resection converts broken ends of double-stranded DNA (dsDNA) to 3'-single-stranded DNA (3'-ssDNA). The extent of resection regulates DNA double-strand break (DSB) repair pathway choice and thereby genomic stability. Here, we characterize an optimized immunofluorescence (IF) microscopy-based protocol for measuring ssDNA in mammalian cells by labeling genomic DNA with 5-bromo-2'-deoxyuridine (BrdU). BrdU foci can be detected under non-denaturing conditions by anti-BrdU antibody, providing an accurate and reliable readout of DNA end resection in most mammalian cell lines. For complete details on the use and execution of this protocol, please refer to Kilgas et al. (2021).


The role of "eye platelet rich plasma" (E-PRP) for wound healing in ophthalmology.
Blood derived products have demonstrated their capacity to enhance healing and stimulate the regeneration of different tissues and this enhancing effect is attributed to the growth factors and bioactive proteins that are synthesized and present in blood. Eye platelet rich plasma (E-PRP) provides higher concentration of essential growth factors and cell adhesion molecules by concentrating platelets in a small volume of plasma as compared with autologous serum, the latter being used widely in ophthalmology for epithelial wound healing of the cornea for the last two decades. These growth factors and cell adhesion molecules have a major role in wound healing and enhance the physiological process at the site of the injury/surgery via eye drops or clot. E-PRP has been used more recently, and has achieved successful outcomes in peer-review articles in the treatment of dormant ulcers (epithelial defects of the cornea that fail to heal), moderate to severe dry eye syndrome, ocular surface syndrome post Laser In Situ Keratomileusis (LASIK), and for surface reconstruction after corneal perforation associated with amniotic membrane transplantation. Preparation of E-PRP in the two available formulations, eyedrops and clot, is inexpensive and easy although it requires following strict sterility conditions using sterile and disposable materials and operating inside a laminar flow hood. No serious adverse effects have been described with the use of these products, and it is generally well tolerated. In summary, Platelet enriched plasma in the form obtained in ophthalmology, E-PRP, is a reliable and effective therapeutic tool to enhance epithelial wound healing in ocular surface disease.