Genes and environments, development and time.
A now substantial body of science implicates a dynamic interplay between genetic and environmental variation in the development of individual differences in behavior and health. Such outcomes are affected by molecular, often epigenetic, processes involving gene-environment (G-E) interplay that can influence gene expression. Early environments with exposures to poverty, chronic adversities, and acutely stressful events have been linked to maladaptive development and compromised health and behavior. Genetic differences can impart either enhanced or blunted susceptibility to the effects of such pathogenic environments. However, largely missing from present discourse regarding G-E interplay is the role of time, a "third factor" guiding the emergence of complex developmental endpoints across different scales of time. Trajectories of development increasingly appear best accounted for by a complex, dynamic interchange among the highly linked elements of genes, contexts, and time at multiple scales, including neurobiological (minutes to milliseconds), genomic (hours to minutes), developmental (years and months), and evolutionary (centuries and millennia) time. This special issue of PNAS thus explores time and timing among G-E transactions: The importance of timing and timescales in plasticity and critical periods of brain development; epigenetics and the molecular underpinnings of biologically embedded experience; the encoding of experience across time and biological levels of organization; and gene-regulatory networks in behavior and development and their linkages to neuronal networks. Taken together, the collection of papers offers perspectives on how G-E interplay operates contingently within and against a backdrop of time and timescales.


Therapeutic effects of Crocin in autoimmune diseases: A review.
The immune system when acts against selfmolecules results in an imbalance in immunologic tolerance leading to the development of several autoimmune diseases (ADs) such as rheumatoid arthritis, asthma, ulcerative colitis, type 1 diabetes, and multiple sclerosis. Improved recognition of the mechanisms of ADs has led to the advancement of the management of these diseases. The principal mediators of ADs are inflammatory molecules. The herbal medicines due to their antioxidant and antiinflammatory properties have an important role in the management of ADs. Crocin is the principal chemical component extracted from saffron, which is a medicinal plant. This review focuses on the therapeutic effects of Crocin in various ADs.


Assignment of Streptococcus agalactiae isolates to clonal complexes using a small set of single nucleotide polymorphisms.
Streptococcus agalactiae (Group B Streptococcus (GBS)) is an important human pathogen, particularly of newborns. Emerging evidence for a relationship between genotype and virulence has accentuated the need for efficient and well-defined typing methods. The objective of this study was to develop a single nucleotide polymorphism (SNP) based method for assigning GBS isolates to multilocus sequence typing (MLST)-defined clonal complexes. It was found that a SNP set derived from the MLST database on the basis of maximization of Simpsons Index of Diversity provided poor resolution and did not define groups concordant with the population structure as defined by eBURST analysis of the MLST database. This was interpreted as being a consequence of low diversity and high frequency horizontal gene transfer. Accordingly, a different approach to SNP identification was developed. This entailed use of the "Not-N" bioinformatic algorithm that identifies SNPs diagnostic for groups of known sequence variants, together with an empirical process of SNP testing. This yielded a four member SNP set that divides GBS into 10 groups that are concordant with the population structure. A fifth SNP was identified that increased the sensitivity for the clinically significant clonal complex 17 to 100%. Kinetic PCR methods for the interrogation of these SNPs were developed, and used to genotype 116 well characterized isolates. A five SNP method for dividing GBS into biologically valid groups has been developed. These SNPs are ideal for high throughput surveillance activities, and combining with more rapidly evolving loci when additional resolution is required.


Fetal porcine ventral mesencephalon grafts: dissection procedure and cellular characterization in culture.
The objective of this study was to develop an optimal dissection procedure for fetal porcine ventral mesencephalon (VM) grafts and to characterize the cellular composition of such an explant, in particular with respect to the dopaminergic and GABAergic components. We have used a monolayer cell culture system to study and identify the various VM cell types. The in vitro development of the fetal VM cells and the effect of the addition of brain-derived neurotrophic factor (BDNF) was investigated during a culture period of 5 days. Extracellular dopamine levels were measured by means of high performance liquid chromatography (HPLC) with electrochemical detection (LCEC). Our results indicate that the ratio of dopaminergic to GABAergic neurons changed in favour of the dopaminergic component when a more selective dissection technique was used. Although addition of BDNF to the cultures appeared to exert trophic influences on all the cellular components of pig fetal VM, this effect was most pronounced on the TH-positive cells. Highest extracellular DA levels were found in the VM culture with the addition of BDNF and when a more selective dissection method was used. Our in vitro findings suggest that porcine fetal dopaminergic cells retain their potential for development and outgrowth after proper explantation and dissociation. Anticipating on the results of ongoing transplantation studies in rat, they suggest that pig fetal VM can be a suitable alternative for the use of fetal human VM as a graft for Parkinson's disease.


Nondestructive distributed measurement of supercontinuum generation along highly nonlinear optical fibers.
Supercontinuum generation (SCG) in optical fibers arises from the spectral broadening of an intense light, which results from the interplay of both linear and nonlinear optical effects. In this Letter, a nondestructive optical time domain reflectometry method is proposed for the first time, to the best of our knowledge, to measure the spatial (longitudinal) evolution of the SC induced along an optical fiber. The method was experimentally tested on highly nonlinear fibers. The experimental results are in a good agreement with the optical spectra measured at the fiber outputs.


Risk of colorectal cancer in juvenile polyposis.
Juvenile polyposis (JP) is an autosomal-dominant syndrome characterised by the development of hamartomatous gastrointestinal polyps and is associated with colorectal cancer. However, the relative and absolute risk of colorectal malignancy in these patients is not known. The incidence rates of colorectal cancer in patients with JP were compared with that of the general population through person-year analysis with adjustment for demographics. In patients with JP, the RR (95% CI) of colorectal cancer was 34.0 (14.4 to 65.7). Similar risks were noted in both males (30.0, 9.6 to 68.6) and females (43.7, 8.8 to 125). The cumulative life-time risk for colorectal cancer was 38.7%. The mean (SD) age of diagnosis of colorectal cancer was 43.9 (10.4) years. Other gastrointestinal malignancies were not noted in this cohort. Patients with JP have a markedly increased RR and absolute risk for colorectal cancer and require vigilant colorectal surveillance starting at young age. A low threshold for recommending surgery with consideration for removal of the entire colorectum seems warranted.


Cross-cultural validation of a disease-specific patient-reported outcome measure for systemic lupus erythematosus in Canada.
The LupusPRO, a disease-targeted patient-reported outcome measure, was developed and validated in US patients with systemic lupus erythematosus (SLE). We report the results of the cross-cultural validation study of the English version of the LupusPRO among patients in Canada with SLE. The LupusPRO was administered to English-speaking Canadian patients with SLE. Demographic, clinical, and serological characteristics were obtained, and the Medical Outcomes Study Short Form-36 (SF-36) and LupusPRO were administered. Disease activity was ascertained using the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and the Lupus Foundation of America definition of flare (Yes/No). Damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Physician disease activity and damage assessments were also ascertained using visual analog scales. A mail-back LupusPRO form was completed within 2-3 days of the index visit. Items tested were internal consistency reliability (ICR), test-retest reliability (TRT), convergent and discriminant validity (against corresponding domains of the SF-36), criterion validity (against disease activity or health status), and known-groups validity. Participants were 123 Canadian patients with SLE (94% women); mean age was 47.7 (SD 14.8) years. The median (interquartile range) SELENA-SLEDAI and SDI were 4 (6) and 1 (3), respectively. The ICR of the LupusPRO domains ranged from 0.60 to 0.93, while the TRT range was 0.62-0.95. Measures observed were convergent and discriminant validity with corresponding domains of SF-36, criterion validity, and known-groups validity against disease activity, damage, and health status. Confirmatory factor analysis showed a good fit. The LupusPRO has fair psychometric properties among Canadian patients with SLE, and prospective studies to establish minimally important difference are continuing.


[Repeated intravital morphological studies of the kidneys in patients with glomerulonephritis].
A clinicomorphological study was conducted over time in 62 patients with different morphological types of glomerulonephritis. An increase in vascular, interstitial and sclerotic changes was noted morphologically in most patients, the worst dynamics was observed in membranoproliferative glomerulonephritis. Disease progression was associated with 2 processes; sclerosis of all elements of the renal tissue or active inflammation.


Comparison of 123I-MIBG SPECT-CT and 18F-DOPA PET-CT in the evaluation of patients with known or suspected recurrent paraganglioma.
Detection of recurrent disease is essential for treatment planning in patients with paraganglioma. The aim of this study was to compare 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy [whole-body and single-photon emission computed tomography (SPECT) computed tomography (CT) scanning] and fluorine-18-L-dihydroxyphenylalanine positron emission tomography CT (18F-DOPA PET-CT) in the re-staging of patients with known or suspected recurrent paraganglioma. Twelve patients with known or suspected recurrent paraganglioma after initial surgery were included in the study. 18F-DOPA PET-CT and 123I-MIBG scintigraphy (whole-body and SPECT-CT scanning) were performed in all patients; the results were compared on a per patient and a per lesion basis. Cytohistology (when available) and a combination of laboratory and imaging studies and follow-up were used as reference standard; any modification in treatment planning was recorded. In all cases recurrent disease (local or distant) was confirmed by cytohistology (four cases) or at subsequent follow-up (eight cases). All patients had positive 18F-DOPA studies (100% sensitivity) whereas nine had positive 123I-MIBG studies (75% sensitivity; P=not significant). 18F-DOPA detected 98% of lesions, whereas 38% were detected with 123I-MIBG (P=0.04). 18F-DOPA showed more lesions than 123I-MIBG in eight patients; both techniques showed the same number of lesions in two cases whereas in two patients 123I-MIBG showed a greater number of lesions. A change in treatment planning was suggested by 18F-DOPA in one patient. These data support the superiority of 18F-DOPA PET-CT over 123I-MIBG scintigraphy to assess disease extension in patients with recurrent paraganglioma; however, in cases with inoperable disease, 123I-MIBG maintains a unique role in allowing the selection of patients suitable for 123I-MIBG therapy.


[Fulminant course of amniotic fluid embolism].
Amniotic fluid embolism is an obstetric complication that can present during pregnancy or labor and is associated with high rates of morbidity and mortality. The incidence is low but the mortality rates for both mother and fetus are high. A 34-year-old woman in the 41st week of gestation was admitted for induction of labor. While still in the labor room, she complained of pruritus around the mouth and tongue. Tonic-clonic convulsions, hypotension, and loss of consciousness followed. Cardiopulmonary resuscitation maneuvers were started and an immediate cesarean section under general anesthesia was performed to deliver a live infant boy. The Apgar score at 5 minutes was 8. The mother was transferred for recovery to the intensive care unit (ICU), where rapid cardiocirculatory and pulmonary decline continued. After 2 episodes of electromechanical dissociation, exitus occurred 2 hours after ICU admission. The autopsy confirmed the diagnosis of amniotic fluid embolism. Keratin squames were found in the capillaries of both lungs and polymorphonuclear cells and proteinaceous material were observed in alveoli. Mechanical obstruction is not the only cause of amniotic fluid embolism. Circulating substances that affect myocardial contractility and coagulation are also implicated and the cause may even be an allergic reaction. The usual signs are acute respiratory failure, cardiovascular collapse, and occasionally convulsions and coagulopathy. Cardiac arrest occurs in 80% of the cases. Treatment is symptomatic to provide life-sustaining measures in response to the clinical picture as it develops.


Serological survey of racing pigeons for selected pathogens in Taiwan.
To investigate the pathogens that racing pigeons in Taiwan are exposed to, a total of 3764 pigeons from 90 lofts were analysed by collection of blood samples in the period between October 2000 and September 2001. The haemagglutination inhibition (HI) test was performed to detect antibodies against Newcastle disease virus (NDV), type 2 avian paramyxovirus (APMV-2), and egg drop syndrome '76 virus (EDS-76V). The agar-gel precipitin (AGP) test was used to detect antibodies against fowl adenovirus (FAV), goose parvovirus (GPV), and avian reovirus (REO). The virus neutralisation (VN) test was applied to detect antibodies against the serotypes FAV-1 and FAV-8. A rapid serum agglutination test was applied for the detection of antibodies against Mycoplasma spp. Antibodies to several infectious agents were found, including NDV (43.3%), EDS-76V (19.2%), FAV (0.8%), REO (0.5%), APMV-2 (0.2%), Mycoplasma columbinum (10.3%), M. columborale (7.1%), M. synoviae (1.8%) and M. gallisepticum (1.3%). Antibodies against GPV, FAV-1, and FAV-8 were not detected in any serum sample. NDV seroprevalence was significantly higher in pigeons of more than one year of age than in pigeons younger than one year. ND or EDS-76 seroprevalence of pigeons vaccinated with ND vaccine or EDS-76 vaccine was significantly higher than that of pigeons that did not receive any vaccination.


Capillary whole blood testing by a new portable monitor. Comparison with standard determination of the international normalized ratio.
We evaluated a new portable monitor (AvoSure PT PRO, Menarini Diagnostics, Firenze, Italy) developed to test the prothrombin time in capillary blood and plasma by comparing it with the standard laboratory determination. We studied 62 patients receiving acenocoumarol therapy. The international normalized ratio (INR) in capillary blood was analyzed by 2 methods: AvoSure PT PRO and Thrombotrack Nycomed Analyzer (Axis-Shield, Dundee, Scotland). Parallel studies were performed in plasma samples by a reference method using the Behring Coagulation Timer (Behring Diagnostics, Marburg, Germany). Plasma samples also were tested with the AvoSure PT PRO. Correlation was good for INR values for capillary blood and plasma samples by AvoSure PT PRO and our reference method (R2 = 0.8596) and for capillary blood samples tested by the AvoSure PT PRO and Thrombotrack Nycomed Analyzer (R2 = 0.8875). The correlation for INR in capillary blood and plasma samples by AvoSure PT PRO was 0.6939 (P < .0004). Capillary blood determinations are rapid and effective for monitoring oral anticoagulation therapy and have a high correlation to plasma determinations. AvoSure PT PRO is accurate for controlling INR in plasma and capillary blood samples, may be used in outpatient clinics, and has advantages over previous portable monitors.


Classification of Volumetric Images Using Multi-Instance Learning and Extreme Value Theorem.
Volumetric imaging is an essential diagnostic tool for medical practitioners. The use of popular techniques such as convolutional neural networks (CNN) for analysis of volumetric images is constrained by the availability of detailed (with local annotations) training data and GPU memory. In this paper, the volumetric image classification problem is posed as a multi-instance classification problem and a novel method is proposed to adaptively select positive instances from positive bags during the training phase. This method uses the extreme value theory to model the feature distribution of the images without a pathology and use it to identify positive instances of an imaged pathology. The experimental results, on three separate image classification tasks (i.e. classify retinal OCT images according to the presence or absence of fluid build-ups, emphysema detection in pulmonary 3D-CT images and detection of cancerous regions in 2D histopathology images) show that the proposed method produces classifiers that have similar performance to fully supervised methods and achieves the state of the art performance in all examined test cases.


The association between perceived social and physical environment and mental health among older adults: mediating effects of loneliness.
Objectives: Despite growing interest in the impact of physical and social environment on mental health, data are lacking on the potential mediating effects of loneliness. We examined it in the association of several social and physical environmental characteristics with mental health among older adults in three municipalities in Flanders (Belgium).Methods: A total of 869 people aged 60 and over were interviewed. Loneliness was assessed through the De Jong Gierveld short scales for emotional and social loneliness. Social participation and social cohesion were assessed following the Neighborhood scales whereas physical environment characteristics were selected from the Neighborhood Environment Walkability Scale. Mental health was assessed through subscale psychological frailty of the Comprehensive Frailty Assessment Instrument plus (CFAI-plus). Linear regression models, including mediation analysis, were used to analyze the survey data.Results: After adjusting for individual characteristics, physical and social environment factors were significantly related to mental health with the significant mediation of emotional and social loneliness. Percentages mediated by both dimensions together were 61% for social cohesion, 43% for social participation, 35% for safety and 25% for mobility. Compared with social loneliness, emotional loneliness was a stronger mediating factor, particularly for mobility and safety. No significant associations between traffic density or basic service availability and mental health were found.Discussion: Improving the social and physical environment might result in a reduction in the prevalence of loneliness and in consequent improvement of mental health among older adults. Special attention should be paid to different types of loneliness.


The study of inheritance analysis and evaluation of lip prints in individuals.
Identification of an individual is a pre-requisite for certification of death and for personal, social, and legal reasons. The study of lip prints (cheiloscopy) was thought as a method for identification of a person. It is safe to assume that cheiloscopy, in its present stage of development, has become a means of criminalistic identification dealing with lip prints. The first aim of the study was to evaluate the visible lip patterns in Rajasthan population in relation to the gender and to ascertain the existence of hereditary pattern followed among parents and offsprings. The second aim was to compare visible and latent lip print patterns on non-biological materials like tracing paper, microscopic glass slides and stainless steel tumblers. The lip prints of 300 subjects including 25 families were obtained using lipstick. Out of these 300 individuals, 60 were selected for latent lip prints. In order to prevent any intra- and inter-observer variability single observer carried out all the observations. The lip prints were analyzed using magnifying lens and were classified using the criteria given by Suzuki and Tsuchihashi. The determination of the pattern in each segment of the lip was based on the numerical superiority of properties of the lines on the fragment. After recording all the values for various parameters, data obtained were statistically analyzed with the help of the Statistical Package for Social Sciences software version-13 using independent t-test. For all the tests, a P value of 0.05 or less was considered. In the present study, most predominant pattern in the entire study population among upper and lower lips considering both males and females was type III lip pattern. Hereditary resemblance was observed between parents and offsprings in 37.66%. The latent lip prints were better visualized on microscopic glass slide when compared to stainless steel tumblers. Lip prints have a good potential for use in criminal investigations. They have been used only occasionally despite their frequent occurrence at crime scenes. A place for cheiloscopy is recommended within the scope of forensic odontology, along with other means of forensic identification.


Comprehensive educational plan for patients with epilepsy and comorbidity (EDU-COM): a pragmatic randomised trial.
The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined. The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity. 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes. The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups. A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov).


A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease.
The diagnosis of Alzheimer's disease (AD), the most common form of dementia in the general population, usually relies upon the presence of typical clinical features and structural changes on brain magnetic resonance imaging. Over the last decade, a number of biological abnormalities have been reported in the cerebrospinal fluid (CSF) of AD patients, in particular altered levels of the tau protein and the 1-42 fragment of the amyloid precursor protein. These, however, have not yet proved sensitive and specific enough to be included in the diagnostic criteria for AD, leaving plenty of room for the search of novel biomarkers. The present study describes the analysis of CSF polypeptides by a protein-chip array technology called surface enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS). Using this approach, we detected statistically significant quantitative differences (p < 0.05) regarding four overexpressed and one underexpressed polypeptides in the CSF of AD patients as compared to healthy controls. Four of them were further purified by strong anionic exchange chromatography (SAX) and identified by MS analysis as cystatin C, two beta-2-microglobulin isoforms, an unknown 7.7 kDa polypeptide, and a 4.8 kDa VGF polypeptide. The combination of the five polypeptides for the diagnosis of AD allowed to classified six AD patients out of the nine included in this study and all the ten controls, which means in this small cohort that the specificity and sensitivity are 100% and 66%, respectively. This study, based on the protein-chip array technology, demonstrates the presence in the CSF of novel potential biomarkers for AD, which may be used for the diagnosis and perhaps the assessment of the severity and progression of the disease.


Can CT measures of tumour heterogeneity stratify risk for nodal metastasis in patients with non-small cell lung cancer?
To undertake a preliminary assessment of the potential for computed tomography (CT) measurement of tumour heterogeneity to stratify risk of nodal metastasis in patients with non-small cell lung cancer (NSCLC). Tumour heterogeneity in CT images from combined positron-emission tomography (PET)/CT examinations in 150 consecutive patients with NSCLC was assessed using CT texture analysis (CTTA). The short axis diameter of the largest mediastinal node was also measured. Forty-two patients without distant metastases subsequently had tumour nodal status confirmed at surgery (n=26) or endobronchial ultrasound (EBUS; n=16). CTTA parameters and largest nodal diameter were related to nodal status using the rank correlation and the risk ratio for each nodal stage (>N0, >N1, >N2) was compared between patients categorised as high and low risk by CTTA or nodal size. The most significant predictor of nodal status was related to overall survival using Kaplan-Meier analysis. N-stage was more significantly correlated with CTTA than nodal diameter (Rs = -0.39, p=0.011, Rs = -0.45, p=0.0025, Rs = -0.40, p=0.0091 for normalised standard deviation (SD), normalised entropy and kurtosis respectively; Rs = -0.39, p=0.042 for nodal diameter). The presence of two or more high-risk CTTA values was the greatest risk factor for mediastinal metastasis (risk ratio: 11.0, 95% confidence interval: 1.56-77.8, p=0.0014) and was associated with significantly poorer overall survival (p=0.016). CTTA in NSCLC is related to nodal status in patients without distant metastases and has the potential to inform selection of investigative strategies for the assessment of mediastinal malignancy.


Effects of declines in personal mastery on self-perceived mobility, physical function, cognitive function, and depressive symptoms: a 6-year follow-up study from the Social Environment and Biomarkers of Aging Study.
As the psychosocial competence, personal mastery helps individuals to cope with stressful life events, and this study aims to examine impacts of declines in personal mastery on healthy aging among community-dwelling middle-aged and older adults using a nationally representative cohort. Data from 648 study participants in the Social Environment and Biomarkers of Aging Study (SEBAS) were retrieved for analysis. All participants were divided into four groups based on their baseline and changes of personal mastery (measured by the Pearlin mastery score) during the 6-year follow-up. Multivariate logistic regression models were adopted to examine associations between declines in personal mastery and indicators for healthy aging (declines in self-perceived mobility, physical function (activities of daily living (ADLs) and instrumental activities of daily living (IADLs)), cognitive function and depressive symptoms). After adjustments for demographics and comorbidities, those with declines in personal mastery were associated with greater risks of declines in self-perceived mobility (adjusted odds ratio (aOR) 1.50 [95% confidence interval 1.01-2.22], p < 0.05). Although the point estimate in the unadjusted models indicated similar associations between declines in personal mastery and declines in ADLs, IADLs, cognitive function or depressive symptoms, these outcomes did not reach statistical significance in the adjusted model. Declines in personal mastery were negatively associated with indicators related to healthy aging (particularly locomotion) in a 6-year follow-up. Further investigations are needed to explore the effects of preventing declines in personal mastery in promoting healthy aging over time.


It's easier to relearn gross motor skills than learn them for the first time after injury: Empirical evidence informing the age at injury debate.
The effect of age at injury on outcomes after brain injury has long been debated. Many have argued that the greater plasticity of the immature brain aids in its recovery from trauma, but others (notably Donald Hebb) have argued that early injury can impair the future ability of the brain to acquire new capabilities. This is difficult to assess empirically due to the presence of many age-dependent confounders. We performed Item Response Theory (IRT) analyses of two datasets of Gross Motor Function Measure (GMFM) observations, one in children with cerebral palsy (CP) and one in children with acquired brain injury (ABI) sustained at later ages. We used IRT to derive independent estimates of test item difficulty in the two populations. Additionally, where comparison between GMFM items and items in the Denver II Developmental Screening Test battery was possible we used the latter to obtain the ages at which these abilities are acquired in typically developing children. Item difficulty estimates for the two populations are highly correlated (adjusted r2=0.89, p<0.0005), but demonstrate significant bias with harder items (typically acquired at later ages) being more readily achieved by children with ABI compared to CP. These results support the Hebbian perspective that (when considering gross motor function) it is easier to maintain or recover previously established functions than to learn them for the first time in an injured brain. This argues for a more cautious outcome prognosis in injury at very young ages.


Distribution of secretory component in hepatocytes and its mode of transfer into bile.
Immunoglobin A in bile and other external secretions is mostly bound to a glycoprotein known as secretory component. This glycoprotein is not synthesized by the same cells as immunoglobulin A and is not found in blood. We now report the mechanism by which secretory component reaches the bile and describe its function in immunoglobulin A transport across the hepatocyte. Fractionation of rat liver homogenates by zonal centrifugation was followed by measurement of the amounts of secretory component in the various fractions by rocket immunoelectrophoresis. Secretory component was found in two fractions. One of these was identified as containing Golgi vesicles from its isopycnic density and appearance in the electron microscope; the other contained principally fragments of the plasma membrane of the sinusoidal face of the hepatocyte, as shown by its particle size and content of marker enzymes. Only the latter fraction bound (125)I-labelled immunoglobulin A added in vitro. At 5min after intravenous injection of [(14)C]fucose, the secretory component in the Golgi fraction was labelled, but not that in the plasma membrane. The secretory component in the sinusoidal plasma membrane did, however, become labelled before the first labelled secretory component appeared in bile, about 30min after injection. We suggest that fucose is added to the newly synthesized secretory component in the Golgi apparatus. The secretory component then passes, with the other newly secreted glycoproteins, to the sinusoidal plasma membrane. There it remains bound but exposed to the blood and able to bind any polymeric immunoglobulin A present in serum. The secretory component then moves across the hepatocyte to the bile-canalicular face in association with the endocytic-shuttle vesicles which carry immunoglobulin A. Hence there is a lag before newly synthesized secretory component appears in bile.


The string sign for diagnosis of mucinous pancreatic cysts.
Pancreas cyst fluid analysis does not provide optimal discrimination between mucinous and nonmucinous cysts. The aim of this study was to assess the performance characteristics of the "string sign" - a test performed at the time of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), for the diagnosis of mucinous pancreatic cysts (branch duct intraductal papillary mucinous neoplasms [bIPMN] and mucinous cystic neoplasms). Patients undergoing EUS-FNA of pancreatic cystic lesions at one referral center between 2003 and 2012 were included. The string sign was performed prospectively, and was considered positive if ≥ 1 cm string formed in cyst fluid and lasted for ≥ 1 second. Performance characteristics of the string sign and a sequential cyst fluid test interpretation model were assessed. For 98 histologically proven cases, the sensitivity, specificity, positive predictive value, and negative predictive value of the string sign for diagnosis of mucinous cysts were 58 % (95 % confidence interval [CI] 44 % - 70 %), 95 % (83 % - 99 %), 94 % (81 % - 99 %), and 60 % (46 % - 72 %), respectively. When string sign results and carcinoembryonic antigen (CEA) concentration (≥ 200 ng/mL) were combined, diagnostic accuracy improved from 74 % and 83 %, respectively, to 89 % (P ≤ 0.03). Among bIPMN, a positive string sign was associated with gastric and intestinal epithelial subtypes. The sequential cyst fluid test interpretation model (including cytology, mucin stain, CEA, and string sign) yielded an overall sensitivity for mucinous lesions of 96 %, with a specificity of 90 %. The string sign is highly specific for diagnosis of mucinous pancreatic cysts, and improves overall diagnostic accuracy of pancreatic cyst fluid analysis. Sequential cyst fluid test interpretation yields high diagnostic sensitivity and specificity for mucinous cysts.


Marihuana in man: three years later.
The past 3 years of renewed research on the effects of marihuana in man has added little not previously known about the clinical syndromes produced by the drug. The major advance has been a quantification of dose in relation to clinical phenomena, and a beginning of an understanding of the drug's metabolism. The crucial clinical experiments in regard to the social questions about marihuana, such as the possible deleterious effects from chronic use, cannot be answered by laboratory experiments. These must be settled by close observations made on those who experiment on themselves. It should be possible, within a relatively short time, to determine whether marihuana has any medical utility, but the future would appear to be no more promising than the past in this regard. The mechanisms by which marihuana alters mental functions are not likely to be answered in man, nor even answered soon by animal studies. As marihuana may be unique among drugs in that more experimentation has been accomplished in man than in animals, it may be necessary to look to additional animal studies to provide leads for pertinent future studies in man.


Health status of Pomatoschistus microps populations in relation to pollution and natural stressors: implications for ecological risk assessment.
Effects induced on wild populations by recurrent environmental contamination may difficult the ecological risk assessment of punctual pollution events such as oil spills. Here, the issue was addressed by comparing the health status of Pomatoschistus microps populations from four NW Iberian estuaries, using an integrated chemical-biological monitoring. Despite high seasonal variability, the parameters measured discriminated estuaries with different contamination levels and associated biological effects with chemical and abiotic stress. The decreased health status of fish from polluted sites strengthens the need of considering pollution-induced background effects and seasonal variability when assessing impacts and risks of oil and other chemical spills.


Separate effects of macronutrient concentration and balance on plastic gut responses in locusts.
It is well established that animal guts are phenotypically plastic, adjusting inter-alia to diet quality. However, the relative contributions due to the two principal dimensions of diet "quality"--nutrient concentration and nutrient balance--remain to be teased apart. We report an experiment using synthetic foods in which the balance and overall concentration (in relation to indigestible cellulose) of protein and digestible carbohydrate were varied orthogonally, and the effects on the dry mass of locust guts measured. There were three principal results: (1) larger guts were associated with dilute compared with concentrated diets, suggesting a compensatory response to ameliorate the impact of reduced diet quality; (2) there was, by contrast, an anti-compensatory response to nutrient imbalance, where larger guts were associated with surplus protein intake; (3) the experimental group given the food that contained low protein and low cellulose, the composition that predicted the smallest guts, showed a bimodal response in which half of the insects had guts that were larger than expected for their cellulose intake, suggesting that they were able to respond to a protein-related cue in the absence of significant dietary fibre. We discuss these results in relation to regulatory theory.


A whole recombinant yeast-based therapeutic vaccine elicits HBV X, S and Core specific T cells in mice and activates human T cells recognizing epitopes linked to viral clearance.
Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4+ and CD8+ T cell responses were observed. Human T cells transduced with HBc18-27 and HBs183-91 specific T cell receptors (TCRs) produced interferon gamma (IFNγ following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses.


Evaluation of the immunogenicity and safety of different doses and formulations of a broad spectrum influenza vaccine (FLU-v) developed by SEEK: study protocol for a single-center, randomized, double-blind and placebo-controlled clinical phase IIb trial.
Current influenza vaccines, based on antibodies against surface antigens, are unable to provide protection against newly emerging virus strains which differ from the vaccine strains. Therefore the population has to be re-vaccinated annually. It is thus important to develop vaccines which induce protective immunity to a broad spectrum of influenza viruses. This trial is designed to evaluate the immunogenicity and safety of FLU-v, a vaccine composed of four synthetic peptides with conserved epitopes from influenza A and B strains expected to elicit both cell mediated immunity (CMI) and humoral immunity providing protection against a broad spectrum of influenza viruses. In a single-center, randomized, double-blind and placebo-controlled phase IIb trial, 222 healthy volunteers aged 18-60 years will be randomized (2:2:1:1) to receive two injections of a suspension of 500 μg FLU-v in saline (arm 1), one dose of emulsified 500 μg FLU-v in Montanide ISA-51 and water for injection (WFI) followed by one saline dose (arm 2), two saline doses (arm 3), or one dose of Montanide ISA-51 and WFI emulsion followed by one saline dose (arm 4). All injections will be given subcutaneously. Primary endpoints are safety and FLU-v induced CMI, evaluated by cytokine production by antigen specific T cell populations (flow-cytometry and ELISA). Secondary outcomes are measurements of antibody responses (ELISA and multiplex), whereas exploratory outcomes include clinical efficacy and additional CMI assays (ELISpot) to show cross-reactivity. Broadly protective influenza vaccines able to provide protection against multiple strains of influenza are urgently needed. FLU-v is a promising vaccine which has shown to trigger the cell-mediated immune response. The dosages and formulations tested in this current trial are also estimated to induce antibody response. Therefore, both cellular and humoral immune responses will be evaluated. EudraCT number 2015-001932-38 ; retrospectively registered clinicaltrials.gov NCT02962908 (November 7th 2016).


Current practices for respiratory syncytial virus surveillance across the EU/EEA Member States, 2017.
BackgroundRespiratory syncytial virus (RSV) is a major contributor to lower respiratory tract infections worldwide and several vaccine candidates are currently in development. Following vaccine introduction, reliable RSV surveillance should enable monitoring of vaccination impact. Data on the RSV disease burden in the European Union and European Economic Area (EU/EEA) are sparse.AimThe aim of this study was to gather knowledge on current practices of national RSV surveillance in the EU/EEA.MethodsNational Coordinators and National Focal Points for Influenza (epidemiologists and virologists) from the EU/EEA countries (n = 31) were invited to participate in an online survey in August and September 2017. The questionnaire covered questions on epidemiological and laboratory aspects of RSV surveillance.ResultsAll EU/EEA countries except Liechtenstein replied to the survey. Eighteen countries reported to have a sentinel surveillance system, 26 countries a non-sentinel surveillance system and three countries to have neither. RSV data collection was mostly done within the context of influenza surveillance. A wide range of diagnostic and characterisation assays was used for the detection of RSV.DiscussionThe majority of EU/EEA countries have some surveillance for RSV in place. The prevailing integration of RSV surveillance into the existing influenza sentinel surveillance system may lead to under-reporting of RSV. The documented variations in existing RSV surveillance systems and their outputs indicate that there is scope for developing guidelines on establishing comparable methods and outcomes for RSV surveillance across the EU/EEA, to ensure the availability of a consistent evidence base for assessing future vaccination programmes.


Negative appraisals of insulin therapy are common among adults with Type 2 diabetes using insulin: Results from Diabetes MILES - Australia cross-sectional survey.
To identify insulin therapy appraisals among adults with Type 2 diabetes using insulin and how negative appraisals relate to clinical, self-care and psychosocial outcomes. Diabetes MILES - Australia 2011 was a national survey of adults with diabetes, focused on behavioural and psychosocial issues. Subgroup analyses were conducted on the responses of 273 adults with Type 2 diabetes using insulin (46% women; mean ± sd age: 59 ± 9 years; diabetes duration: 12 ± 7 years; years using insulin: 4 ± 4). They completed validated measures of insulin therapy appraisals (ITAS), depression (PHQ-9), anxiety (GAD-7), diabetes distress (PAID) and diabetes-specific self-efficacy (DES-SF). Insulin was perceived to be very important, and its benefits (e.g. improves health) were endorsed by most (82%). Fifty-one per cent believed that taking insulin means their diabetes has become worse; 51% that insulin causes weight gain; 39% that they have 'failed to manage' their diabetes. Those with the greatest and least 'ITAS negative' scores did not differ by diabetes duration or years using insulin, or by average number of insulin injections or blood glucose checks per day. Those with more negative insulin appraisals were significantly younger (Mean Diff. = 5 years, P < 0.001), less satisfied with recent blood glucose levels (P < 0.001, d = 0.63), had reduced diabetes-specific self-efficacy (P < 0.001, d = 0.7), and were more likely to report depressive symptoms, anxiety or diabetes distress (all P < 0.001, d = 0.65-1.1). Negative insulin therapy appraisals are common among adults with Type 2 diabetes using insulin, and are associated with lower general and diabetes-specific emotional well-being, reduced diabetes-specific self-efficacy and satisfaction with blood glucose.


Regulation of M1‑type and M2‑type macrophage polarization in RAW264.7 cells by Galectin‑9.
Generally considered as a potent pro‑inflammatory signal, β‑galactosidelectin suppresses T cell receptor activation, can both promote and inhibit integrin‑mediated adhesion and is required in nuclear pre‑mRNA splicing. Galectin‑9 (Gal‑9), a member of β‑galactoside lectin, is involved many processes of T cell‑mediated diseases (such as autoimmune diseases and asthma) and immunomodulation of macrophages. Macrophages are involved in the occurrence of inflammation, development and digestion and other stages. At different stages of the inflammatory response, macrophages exhibit different phenotypes, but mainly two subtypes, classically (M1) or alternatively (M2) polarization. The purpose of this work is to investigate the effect of overexpression or knockdown of Gal‑9 on the macrophage polarization. Macrophage polarization was detected by flow cytometric profiling of secreted cytokines and specific surface markers expression, including nitric oxide synthase 2 (NOS2) and mannose receptor 1 (CD206). Protein and mRNA expression levels of TNF‑α, TGF‑β, IL‑6, IL‑10, NF‑κB, signal transducer and activator of transcription (Stat)1 and Stat3 were determined by ELISA, western blot analysis or qRT‑PCR. Our results implied that differentiation of the mouse macrophage line RAW264.7 into M1‑type and M2‑type macrophages is followed by marked variations of Gal‑9 expression. Furthermore, its overexpression and secretion are tightly associated with M2‑type macrophages, whereas its downregulation promotes macrophages to polarize into M1‑type macrophages, which confirmed by elevated CD206 and NOS2, respectively. In response to the changes of Gal‑9 expression, cytokines, transcription factors and regulators, including TNF‑α, IL‑6, NF‑κB, Stat1, TGF‑β, IL‑10, and Stat3, were tightly regulated and significantly associated with classically and alternatively activated macrophages. Consistent with characteristics of M1‑type macrophages, the transcriptional or translational expression levels or activity of TNF‑α, IL‑6, Stat1 and NF‑κB were markedly increased with knockdown of Gal‑9 in macrophages. By contrast, the expression levels or activity of TGF‑β, IL‑10 and Stat3 were clearly elevated in macrophages with Gal‑9 overexpression, which is closely related with M2‑type macrophages. Specific expression and secretion patterns of cytokines, transcription factors and regulators in M1‑type and M2‑type macrophages contribute to better understanding the role of Gal‑9 in regulation in macrophages. This study provides a new insight that Gal‑9 may be a new immunomodulatory target for macrophages.


68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors.
Several authors reported the superiority of (68)Ga-DOTANOC PET/CT to conventional imaging (CI) for the assessment of neuroendocrine tumors (NET). However, the detection of a higher number of lesions is not necessarily followed by a modification of disease stage or therapeutic approach. The aim of this study was to assess the impact of (68)Ga-DOTANOC PET/CT on the clinical management of NET patients. The study included 90 patients with pathologic confirmation of NET, CT performed within a month of (68)Ga-DOTANOC PET/CT, and a follow-up period of at least 1 y. PET/CT results were compared with CI results. As a standard of reference to finally evaluate PET results, clinical and imaging follow-up data were used. To assess the clinical impact of PET findings, all referring physicians were contacted after PET and asked about how patients were managed. Stage or therapy modifications were independently recorded, and the overall impact was evaluated patient by patient if PET results either affected therapy or caused a change in disease stage. Considering PET/CT and CI concordant cases (47/90 [52.2%]), PET findings affected the therapeutic management in 17 of 47 (36.2%) patients. Although PET did not result in modification of disease stage, (68)Ga-DOTANOC detected a higher lesion number in most patients. PET/CT and CI findings were discordant in 42 of 90 (46.7%) patients: PET resulted in a modification of stage in 12 patients (28.6%) and affected the treatment plan in 32 patients (76.2%). PET and CT were both equivocal in 1 patient (1/90). Considering all cases, (68)Ga-DOTANOC PET/CT affected either stage or therapy in 50 of 90 (55.5%) patients. The most frequent impact on management (27 patients) was the initiation or continuance of peptide receptor radionuclide therapy, followed by the initiation or continuance of somatostatin analog medical treatment (7 patients) and referral to surgery (6 patients). PET prevented unnecessary surgery in 6 patients and excluded from treatment with somatostatin analogs 2 patients with NET lesions that did not express somatostatin receptors. Less frequent impacts on management included the initiation of radiotherapy (1 patient), further diagnostic investigation (1 patient), and liver transplantation (1 patient). (68)Ga-DOTANOC PET/CT either affected stage or caused a therapy modification in more than half the patients, thus confirming the clinical role of PET in the management of NET.


Release of platelet activating factor in rabbits with antibody-mediated injury of the lung: the role of leukocytes and of pulmonary endothelial cells.
This paper describes the release of platelet-activating factor (PAF) into the circulation of rabbits with acute pulmonary injury induced by antibody reacting with pulmonary endothelium. Eight rabbits were injected i.v. with 2 mg/kg of body weight of goat anti-rabbit lung angiotensin-converting enzyme gamma-globulin (GtARbACE). All animals developed acute pneumonitis, characterized by severe endothelial damage, accumulation of polymorphonuclear leukocytes (PMN) and platelets (Plt) in the lumina of alveolar capillaries, and deposits of goat IgG and rabbit C3 along alveolar capillary walls. Six of the rabbits died from acute pulmonary edema. PAF was detected in the plasma of all animals within 5 min after injection of GtARbACE. Five other rabbits were depleted of leukocytes by nitrogen mustard and then injected with 2 mg/kg of body weight of GtARbACE. In three of these rabbits release of PAF was demonstrated, though in amounts smaller than in non-leukocyte-depleted rabbits; all three animals died from pulmonary edema. After injection of 0.03 mg/kg of body weight of GtARbACE in six additional rabbits, three of them leukocyte-depleted, small amounts of PAF were detected in the circulation. None of these six rabbits died of pulmonary edema. PAF release was not observed in ten rabbits injected i.v. with 2 or 0.03 mg/kg of body weight of normal goat gamma-globulin. In separate experiments in vitro, incubation of isolated lung or thoracic aorta with GtARbACE resulted in deposits of goat IgG along endothelia and significant release of PAF. PAF was also released from endothelial cells removed from thoracic aorta by cellulose acetate paper and then incubated with GtARbACE. When segments of thoracic aorta were stripped of endothelium and then incubated with GtARbACE, PAF release could not be shown. The data obtained are consistent with the interpretation that PAF released into the circulation after binding of GtARbACE to the endothelia of lung and aorta originates from leukocytes and from lung and thoracic aorta endothelial cells.


Translating pharmacogenetics into clinical practice: interleukin (IL)28B and inosine triphosphatase (ITPA) polymophisms in hepatitis C virus (HCV) infection.
Hepatitis C virus (HCV) infection is frequently characterized by evolution to chronicity and by a variable clinical course of the disease. The clinical heterogeneities of HCV infection and the imperfect predictability of the response to interferon (IFN) have suggested the need to search for a genetic basis of clinical features. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as on treatment response and adverse effects. This review will cover recent reports on the subject, focusing on the potential use of the new genetic markers in the diagnostic algorithm for the stratification of patients for personalized antiviral regimens.


Phosphorylation of the leukemic oncoprotein EVI1 on serine 196 modulates DNA binding, transcriptional repression and transforming ability.
The EVI1 (ecotropic viral integration site 1) gene at 3q26 codes for a transcriptional regulator with an essential role in haematopoiesis. Overexpression of EVI1 in acute myeloid leukaemia (AML) is frequently associated with 3q26 rearrangements and confers extremely poor prognosis. EVI1 mediates transcriptional regulation, signalling, and epigenetic modifications by interacting with DNA, proteins and protein complexes. To explore to what extent protein phosphorylation impacts on EVI1 functions, we analysed endogenous EVI1 protein from a high EVI1 expressing Fanconi anaemia (FA) derived AML cell line. Mass spectrometric analysis of immunoprecipitated EVI1 revealed phosphorylation at serine 196 (S196) in the sixth zinc finger of the N-terminal zinc finger domain. Mutated EVI1 with an aspartate substitution at serine 196 (S196D), which mimics serine phosphorylation of this site, exhibited reduced DNA-binding and transcriptional repression from a gene promotor selectively targeted by the N-terminal zinc finger domain. Forced expression of the S196D mutant significantly reduced EVI1 mediated transformation of Rat1 fibroblasts. While EVI1-mediated serial replating of murine haematopoietic progenitors was maintained by EVI1-S196D, this was associated with significantly higher Evi1-trancript levels compared with WT-EVI1 or EVI1-S196A, mimicking S196 non-phosphorylated EVI1. These data suggest that EVI1 function is modulated by phosphorylation of the first zinc finger domain.


Channel Formation in Cry Toxins: An Alphafold-2 Perspective.
Bacillus thuringiensis (Bt) strains produce pore-forming toxins (PFTs) that attack insect pests. Information for pre-pore and pore structures of some of these Bt toxins is available. However, for the three-domain (I-III) crystal (Cry) toxins, the most used Bt toxins in pest control, this crucial information is still missing. In these Cry toxins, biochemical data have shown that 7-helix domain I is involved in insertion in membranes, oligomerization and formation of a channel lined mainly by helix α4, whereas helices α1 to α3 seem to have a dynamic role during insertion. In the case of Cry1Aa, toxic against Manduca sexta larvae, a tetrameric oligomer seems to precede membrane insertion. Given the experimental difficulty in the elucidation of the membrane insertion steps, we used Alphafold-2 (AF2) to shed light on possible oligomeric structural intermediates in the membrane insertion of this toxin. AF2 very accurately (<1 Å RMSD) predicted the crystal monomeric and trimeric structures of Cry1Aa and Cry4Ba. The prediction of a tetramer of Cry1Aa, but not Cry4Ba, produced an 'extended model' where domain I helices α3 and α2b form a continuous helix and where hydrophobic helices α1 and α2 cluster at the tip of the bundle. We hypothesize that this represents an intermediate that binds the membrane and precedes α4/α5 hairpin insertion, together with helices α6 and α7. Another Cry1Aa tetrameric model was predicted after deleting helices α1 to α3, where domain I produced a central cavity consistent with an ion channel, lined by polar and charged residues in helix α4. We propose that this second model corresponds to the 'membrane-inserted' structure. AF2 also predicted larger α4/α5 hairpin n-mers (14 ≤n ≤ 17) with high confidence, which formed even larger (~5 nm) pores. The plausibility of these models is discussed in the context of available experimental data and current paradigms.


Investigation of diachronic dietary patterns on the islands of Ibiza and Formentera, Spain: evidence from sulfur stable isotope ratio analysis.
We present sulfur isotope ratio measurements of bone collagen from animals (n = 75) and humans (n = 120) from five sites dating to four chronological periods (Chalcolithic, Punic, Late Antiquity-Early Byzantine, and Islamic) from the Balearic Islands of Ibiza and Formentera, Spain. This study is a follow up to previously published δ(13)C and δ(15)N values by [Fuller et al.: Am J Phys Anthropol 143 (2010) 512-522] and focuses on using δ(34)S values to better understand the dietary patterns of these populations through time and to possibly identify immigrants to these islands. The range of δ(34)S values (10.5-17.8‰) observed for the animals was relatively broad, which suggests that a significant sea spray effect has added marine sulfates to the soils of Formentera and Ibiza. The mean δ(34)S values of the different human populations were found to be: Chalcolithic (16.5 ± 1.4‰), Punic rural (13.6 ± 1.7‰), Punic urban (12.9 ± 1.8‰), Late Antiquity-Early Byzantine (12.3 ± 2.1‰), and Islamic (9.1 ± 2.7‰). These human δ(34)S results are similar to the animal data, a finding that supports the notion that there was little marine protein consumption by these societies and that the diet was mainly based on terrestrial resources. During the Punic and Late Antiquity-Early Byzantine periods the δ(34)S values were used to identify individuals in the population who likely were not born or raised on the islands. In addition, 18 of the 20 individuals analyzed from the Islamic period have δ(34)S values that indicate that they were immigrants to Ibiza who died before acquiring the new local sulfur isotopic signature.


Effects of attention on perceptual direction tuning curves in the human visual system.
In sensory neurophysiology, reverse correlation analyses have advanced our understanding of the spatio-temporal structure of receptive fields (RFs) and the tuning properties of individual neurons. Here, we used a psychophysical variant of the motion reverse correlation technique to investigate how visual selective attention influences human perceptual tuning curves for direction of motion. Direction tuning functions were computed by reverse correlating speeded target-present responses of human observers with a random sequence of brief, fully coherent motion impulses. We found that attention enhanced the amplitude of perceptual tuning curves for direction of motion, while tuning width remained unaffected. Furthermore, the full direction tuning profile across time could be well fitted by a separable model of direction and temporal tuning. Attention enhanced both the direction tuning and its temporal profile, without shifts or changes in shape. Thus, attention exerts a multiplicative effect on human perceptual tuning curves for direction of motion. An analysis of second-order correlations revealed a boost in the likelihood of responses to the target direction when it was followed by a motion impulse in the opposite direction. This perceptual effect might be mediated by biphasic neurons that are preferentially activated by a rapid succession of opposite motion directions.


Morphogenetic aspects of murein structure and biosynthesis.
The shape of Escherichia coli is fixed by the form of the sacculus. This sacculus is a macromolecule made up from the polymer murein. In an investigation of the possible factors determining the shape of the sacculus, we attempted to resolve between two fundamental alternatives. (i) Is the shape of the sacculus automatically fixed by its chemical composition? or (ii) does a special morphogenetic system exist which determines the shape of the sacculus? An analysis of sacculi from cells grown in poor and rich media and harvested at different stages of growth was made. Significant variations in the composition of murein were found, whereas the general shape of the cells remained unchanged. This finding stands opposed to the assumption of a strict correlation between chemistry and shape of the sacculus. The second alternative was investigated by attempting to change artificially the shape of the sacculus by modifying the form of the hypothetical morphogenetic system. Rod-shaped cells were converted into spherical spheroplasts which were subsequently allowed to reform a new spherical sacculus. In chemical composition this spherical sacculus was found to be indistinguishable from the rod-shaped sacculus. This finding is taken as evidence for the existence of a distinct morphogenetic apparatus in the cell wall whose form is reflected by the shape of the sacculus.


Cardiopulmonary Exercise Test as a Tool to Choose Therapy in Heart Failure.
Heart failure treatment depends on several drugs, all providing improvement in outcome, but that cannot be realistically used all together in the same patient. It would be useful to have a tool that allows the arrangement of the most appropriate therapy cocktail for each patient. The aim of this article is to show the main differences in the effects of several drugs on cardiopulmonary function in patients with heart failure, both while resting and during exercise, and to discuss how these differences can be taken into account when choosing the most appropriate therapeutic protocol. In summary, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers act synergistically to increase exercise capacity and peak oxygen uptake, but through different mechanisms: the former improving lung diffusion and exercise ventilatory efficiency, an action that is counteracted by concomitant aspirin therapy, and the latter probably by improving muscle perfusion. As for β-blockers, nonselective compounds, such as carvedilol, improve ventilation efficiency on the one hand, but interfere with lung diffusion on the other, and they are probably less tolerated under hypoxic conditions. On the contrary, β1-selective compounds, such as bisoprolol or nebivolol, have a neutral effect on both lung diffusion and ventilation efficiency. These observations could be the basis for the choice of pharmacological therapy in patients with heart failure.


Chemokines and antimicrobial peptides have a cag-dependent early response to Helicobacter pylori infection in primary human gastric epithelial cells.
Helicobacter pylori infection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The cag pathogenicity island (cag PAI) of H. pylori allows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response to H. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells with H. pylori B128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-α). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models with H. pylori B128ΔcagM, a cag PAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells with H. pylori, inflammatory-mediator production was largely due to cag PAI substrate-independent virulence factors. Thus, H. pylori cag PAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation during H. pylori infection.


Fat Oxidation Kinetics Is Related to Muscle Deoxygenation Kinetics During Exercise.
The present study aimed to determine whether whole-body fat oxidation and muscle deoxygenation kinetics parameters during exercise were related in individuals with different aerobic fitness levels. Eleven cyclists [peak oxygen uptake ( V . O 2  p  e  a  k ): 64.9 ± 3.9 mL⋅kg-1⋅min-1] and 11 active individuals ( V . O 2  p  e  a  k : 49.1 ± 7.4 mL⋅kg-1⋅min-1) performed a maximal incremental cycling test to determine V . O 2  p  e  a  k and a submaximal incremental cycling test to assess whole-body fat oxidation using indirect calorimetry and muscle deoxygenation kinetics of the vastus lateralis (VL) using near-infrared spectroscopy (NIRS). A sinusoidal (SIN) model was used to characterize fat oxidation kinetics and to determine the intensity (Fatmax) eliciting maximal fat oxidation (MFO). The muscle deoxygenation response was fitted with a double linear model. The slope of the first parts of the kinetics (a 1) and the breakpoint ([HHb]BP) were determined. MFO (p = 0.01) and absolute fat oxidation rates between 20 and 65% V . O 2  p  e  a  k were higher in cyclists than in active participants (p < 0.05), while Fatmax occurred at a higher absolute exercise intensity (p = 0.01). a 1 was lower in cyclists (p = 0.02) and [HHb]BP occurred at a higher absolute intensity (p < 0.001) than in active individuals. V . O 2  p  e  a  k was strongly correlated with MFO, Fatmax, and [HHb]BP (r = 0.65-0.88, p ≤ 0.001). MFO and Fatmax were both correlated with [HHb]BP (r = 0.66, p = 0.01 and r = 0.68, p < 0.001, respectively) and tended to be negatively correlated with a 1 (r = -0.41, p = 0.06 for both). This study showed that whole-body fat oxidation and muscle deoxygenation kinetics were both related to aerobic fitness and that a relationship between the two kinetics exists. Individuals with greater aerobic fitness may have a delayed reliance on glycolytic metabolism at higher exercise intensities because of a longer maintained balance between O2 delivery and consumption supporting higher fat oxidation rates.


Serine-294 and threonine-295 in the exofacial loop domain between helices 7 and 8 of glucose transporters (GLUT) are involved in the conformational alterations during the transport process.
The role of a conserved polar motif (STS) in the exofacial loop between helices 7 and 8 of GLUT4 for transporter function was investigated by site-directed mutagenesis and expression of the constructs in COS-7 cells. Reconstituted glucose-transport activity, cytochalasin B binding and photolabelling with the exofacial label 2-N4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1, 3-bis-(d-mannosyloxy)-2-propylamine (ATB-BMPA) were assayed in membranes from transfected cells and corrected for immunoreactivity of expressed transporters. Replacement of Ser-294 with Ala or Thr suppressed transport activity and cytochalasin B binding. ATB-BMPA photolabelling was normal in S294A mutants, and even increased in S294T mutants. Replacement of Thr-295 with Ala suppressed transport activity and cytochalasin B binding, whereas ATB-BMPA photolabelling was normal; substitution of Ser failed to alter the investigated parameters. Similarly, exchanging Ser-296 for Ala generated a normally functioning protein. The data suggest that Ser-294 and Thr-295 are involved in the conformational change in GLUT during the transport process, and that their substitution may arrest the transporter in an outward-facing conformation.


Can stroke physicians and neuroradiologists identify signs of early cerebral infarction on CT?
Doctors managing acute stroke are expected to recognise signs of early infarction on CT before choosing thrombolytic treatment, according to recent trials and guidelines. The ability of 13 physicians and two neuroradiologists to recognise early infarct signs and decide whether patients should be randomised in a hypothetical stroke treatment trial was tested. Only 65% of the CT scans from 14 stroke patients were correctly identified as normal or abnormal (95% CI 60-69%). Neither observer experience nor knowledge of symptoms significantly improved recognition of abnormality, although experience did significantly improve the observers' ability to reproduce their results. Parenchymal hypodensity was the least well recognised sign. Only 45% (95% CI 40%-50%) of patients were identified correctly for the hypothetical acute stroke treatment trial. Early infarction on CT is not well recognised even by experienced doctors. Part of the problem may be in understanding the definitions of the extent of infarction. These difficulties should be considered in the design of acute stroke treatment trials and in the introduction of any new acute stroke treatments.


Ligand-based pharmacophore modelling, structure optimisation, and biological evaluation for the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors.
Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity.


[Psychosomatic reactions to the experience of near death. A state of affective dissociation].
The feelings of persons who had encountered life-threatening danger were analysed and compared with the feelings of persons, who are in hypnosis or trained in autogenic training. The symptoms are widely alike. The result of the comparison is, that there exists a state of affective dissociation, which can be caused by conscious or unconscious actions.


A high-throughput SAMDI-mass spectrometry assay for isocitrate dehydrogenase 1.
The enzyme isocitrate dehydrogenase 1 (IDH1) catalyzes the conversion of isocitrate to alpha-ketoglutarate (αKG) and has emerged as an important therapeutic target for glioblastoma multiforme (GBM). Current methods for assaying IDH1 remain poorly suited for high-throughput screening of IDH1 antagonists. This paper describes a high-throughput and quantitative assay for IDH1 that is based on the self-assembled monolayers for matrix-assisted laser desorption/ionization-mass spectrometry (SAMDI-MS) method. The assay uses a self-assembled monolayer presenting a hydrazide group that covalently captures the αKG product of IDH1, where it can then be detected by MALDI-TOF mass spectrometry. Co-capture of an isotopically-labeled αKG internal standard allows the αKG concentration to be quantitated. The assay was used to analyze a series of standard αKG solutions and produced minimal error in measured αKG concentration values. The suitability of the assay for high-throughput analysis was evaluated in a 384-sample biochemical IDH1 screen. Cells expressing IDH1 were lysed and the lysate was applied to the monolayer to capture αKG, which was then quantitated using the SAMDI-MS assay. Cells in which IDH1 expression was reduced by small-interfering RNA exhibited a corresponding decrease in αKG concentration as measured by the assay. Application of the assay toward the high-throughput screening of IDH1 inhibitors or knockdown agents may facilitate the discovery of treatments for GBM.


Versatile strategy for isolating transcription activator-like effector nuclease-mediated knockout mutants in Caenorhabditis elegans.
Targeted genome editing using transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 systems has recently emerged as a potentially powerful method for creating locus-specific mutations in Caenorhabditis elegans. Due to the low mutation frequencies, one of the crucial steps in using these technologies is screening animals that harbor a targeted mutation. In previous studies, identifying targeted mutations in C. elegans usually depended on observations of fluorescent markers such as a green fluorescent protein or visible phenotypes such as dumpy and uncoordinated phenotypes. However, this strategy is limited in practice because the phenotypes caused by targeted mutations such as defects in sensory behaviors are often apparently invisible. Here, we describe a versatile strategy for isolating C. elegans knockout mutants by TALEN-mediated genome editing and a heteroduplex mobility assay. We applied TALENs to engineer the locus of the neural gene glr-1, which is a C. elegans AMPA-type receptor orthologue that is known to have crucial roles in various sensory behaviors. Knockout mutations in the glr-1 locus, which caused defective mechanosensory behaviors, were efficiently identified by the heteroduplex mobility assay. Thus, we demonstrated the utility of a TALEN-based knockout strategy for creating C. elegans with mutations that cause invisible phenotypes.


Campylobacter jejuni translocation across intestinal epithelial cells is facilitated by ganglioside-like lipooligosaccharide structures.
Translocation across intestinal epithelial cells is an established pathogenic feature of the zoonotic bacterial species Campylobacter jejuni. The number of C. jejuni virulence factors known to be involved in translocation is limited. In the present study, we investigated whether sialylation of C. jejuni lipooligosaccharide (LOS) structures, generating human nerve ganglioside mimics, is important for intestinal epithelial translocation. We here show that C. jejuni isolates expressing ganglioside-like LOS bound in larger numbers to the Caco-2 intestinal epithelial cells than C. jejuni isolates lacking such structures. Next, we found that ganglioside-like LOS facilitated endocytosis of bacteria into Caco-2 cells, as visualized by quantitative microscopy using the early and late endosomal markers early endosome-associated protein 1 (EEA1), Rab5, and lysosome-associated membrane protein 1 (LAMP-1). This increased endocytosis was associated with larger numbers of surviving and translocating bacteria. Next, we found that two different intestinal epithelial cell lines (Caco-2 and T84) responded with an elevated secretion of the T-cell attractant CXCL10 to infection by ganglioside-like LOS-expressing C. jejuni isolates. We conclude that C. jejuni translocation across Caco-2 cells is facilitated by ganglioside-like LOS, which is of clinical relevance since C. jejuni ganglioside-like LOS-expressing isolates are linked with severe gastroenteritis and bloody stools in C. jejuni-infected patients.


Invasive vulvar extramammary Paget's disease in the United States.
To assess the incidence, treatment, and outcomes in patients with invasive vulvar extramammary Paget's disease (EMPD) in a national cohort of patients. Patients from the Surveillance, Epidemiology and End Results (SEER) database with diagnoses of vulvar EMPD from 1992 to 2016 were included. Demographic, treatment, and outcome data were analyzed. A total of 1268 cases of invasive EMPD were identified. Of those, 69.6% had localized disease, 12.0% regional disease, 1.3% distant disease, and 17.1% were unstaged. The annual incidence of invasive vulvar EMPD was 0.36 per 100,000 person years: rates have increased >2-fold since 1992 (1992: 0.19 per 100,000 person years to 0.50 per 100,000 person years in 2016). Most patients underwent primary surgery (n = 1034; 81.5%). Five-year cancer specific survival (CSS) was 95.5% and was associated with stage. Compared to patients with localized disease, patients with distant metastases had dramatically worse CSS (HR: 85.8 (31.8-248) p < 0.0001). Synchronous cancers (diagnosed within one calendar year of EMPD diagnosis year) were observed in 35 cases (2.8%), and 195 patients (15.4%) developed a secondary malignancy (diagnosed >one year from year of EMPD diagnosis year). The most common synchronous breast, gastrointestinal tract, melanoma and the most common secondary cancers were breast, gastrointestinal tract and genitourinary tract. The incidence of invasive vulvar EMPD has increased over time. CSS is excellent for localized disease, but those with metastatic disease are in need of novel therapies. Approximately 15% will develop a secondary malignancy, indicating that patients with invasive vulvar EMPD should undergo site specific preventative health screens during recurrence surveillance.


Human exposure to mercury: a critical assessment of the evidence of adverse health effects.
The ubiquitous nature of mercury in the environment, its global atmospheric cycling, and its toxicity to humans at levels that are uncomfortably close to exposures experienced by a proportion of the population are some of the current concerns associated with this pollutant. The purpose of this review is to critically evaluate the scientific quality of published reports involving human exposures to mercury and associated health outcomes as an aid in the risk evaluation of this chemical. A comprehensive review of the scientific literature involving human exposures to mercury was performed and each publication evaluated using a defined set of criteria that are considered standards in epidemiologic and toxicologic research. Severe, sometimes fatal, effects of mercury exposure at high levels were primarily reported as case studies. The disasters in Minamata, Japan, in the 1950s and in Iraq in 1971-1972 clearly demonstrated neurologic effects associated with ingestion of methylmercury both in adults and in infants exposed in utero. The effects were convincingly associated with methylmercury ingestion, despite limitations of the study design. Several well-conducted studies have investigated the effects of methylmercury at levels below those in the Iraq incident but have not provided clear evidence of an effect. The lower end of the dose-response curve constructed from the Iraq data therefore still needs to be confirmed. The studies of mercury exposure in the workplace were mainly of elemental or inorganic mercury, and effects that were observed at relatively low exposure levels were primarily neurologic and renal. Several studies have investigated effects associated with dental amalgam but have been rated as inconclusive because of methodologic deficiencies. In our overall evaluation, 29 of 110 occupational studies and 20 of 54 studies where exposure occurred in the natural environment provided at least suggestive evidence of an exposure-related effect.


Transitioning to Transradial Access for Cerebral Aneurysm Embolization.
Despite several retrospective studies showing the safety and efficacy of transradial access for cerebral angiography, neurointerventionalists are apprehensive about implementing TRA for neurointerventions. This reluctance is mainly due to anatomic factors, technical factors, and a long learning curve (relative to transfemoral access). We present here our experience of TRA transition for cerebral aneurysm embolization. Our aim was to demonstrate the feasibility and safety of radial access for consecutive embolizations of ruptured and unruptured cerebral aneurysms. We performed a retrospective review of a prospective data base on cerebral aneurysm embolizations. Between April and December 2018, radial access was considered for all consecutive patients referred to our institution for cerebral aneurysm embolization. Technical success was defined as radial access with insertion of the sheath and completion of the intervention without a crossover to conventional femoral access. The primary safety end point was the in-hospital plus 30-day incidence of radial artery occlusion. Secondary end points included intraoperative complications and neurologic complications at discharge and in the following 30 days. Seventy-one patients with a cerebral aneurysm underwent 73 embolization procedures at our institution. The first-choice access route was the radial artery in 62 patients (87.3%) and the femoral artery in 9 (12.6%). Thirty-four embolizations were performed using coils, 22 used a balloon-assisted coil technique, 6 used a stent-assisted coil technique, and 2 used a flow diverter. Crossover to femoral access was observed in 2 patients (3.1%). Four patients developed coil-induced thrombi requiring intra-arterial tirofiban injections. In 1 case, an aneurysm ruptured during the operation but did not have a clinical impact. No cases of radial artery occlusion or hand ischemia were observed. A transition to radial access for cerebral aneurysm embolization is feasible and does not increase the level of risk associated with the procedure.


Correction to Hill and Norcross (2023).
Reports an error in "Psychotherapy skills and methods: Introduction to the special issue" by Clara E. Hill and John C. Norcross (Psychotherapy, 2023[Sep], Vol 60[3], 237-245). In the article, the correct affiliation for John C. Norcross is the Department of Psychology, University of Scranton. The online version of this article has been corrected, (The following abstract of the original article appeared in record 2023-99100-001.) This article introduces the special issue of Psychotherapy on evidence-based skills and methods and concomitantly, outlines the purposes and processes of the Interorganizational Task Force that guided the work. We provide the rationale for reviewing psychotherapy skills and methods, define and contrast skills and methods with other components of psychotherapy, describe how to assess skills, methods, and outcomes (immediate in-session, intermediate, and distal), how to link skills and methods with outcomes, and how to summarize the extant research on those skills and methods. Finally, we describe how the research reviews of skills and methods lead to training implications and therapeutic practices. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Picomolar affinity of 125I-SCH 23982 for D1 receptors in brain demonstrated with digital subtraction autoradiography.
Iodinated SCH 23390, 125I-SCH 23982 (DuPont-NEN), was examined using quantitative autoradiography for its potency, selectivity, and anatomical and neuronal localization of binding to the dopamine D1 receptor in rat brain sections. 125I-SCH 23982 bound to D1 sites in the basal ganglia with very high affinity (Kd values of 55-125 pM), specificity (70-85% of binding was displaced by 5 microM cis-flupenthixol), and in a saturable manner (Bmax values of 65-176 fmol/mg protein). Specific 125I-SCH 23982 binding was displaced by the selective D1 antagonists SCH 23390 (IC50 = 90 pM) and cis-flupenthixol (IC50 = 200 pM) and the D1 agonist SKF 38393 (IC50 = 110 nM) but not by D2-selective ligands (I-sulpiride, LY 171555) or the S2 antagonist cinanserin. Compared with 3H-SCH 23390, the 5- to 10-fold greater affinity for the D1 site and 50-fold greater specific radioactivity of 125I-SCH 23982 makes it an excellent radioligand for labeling the D1 receptor. The concentrations of D1 sites were greatest in the medial substantia nigra and exceeded by over 50% the concentration of D1 sites in the lateral substantia nigra, caudoputamen, nucleus accumbens, olfactory tubercle, and entopeduncular nucleus. Lower concentrations of D1 sites were present in the internal capsule, dorsomedial frontal cortex, claustrum, and layer 6 of the neocortex. D1 sites were absent in the ventral tegmental area. Intrastriatal injections of the axon-sparing neurotoxin, quinolinic acid, depleted by 87% and by 46-58% the concentrations of displaceable D1 sites in the ipsilateral caudoputamen and medial and central pars reticulata of the substantia nigra, respectively. No D1 sites were lost in the lateral substantia nigra. Destruction of up to 94% of the mesostriatal dopaminergic projection with 6-hydroxydopamine did not reduce D1 binding nor, with one exception, increase striatal or nigral D1 receptor concentrations. 125I-SCH 23982 selectively labels D1 binding sites on striatonigral neurons with picomolar affinity, and these neurons contain the majority of D1 sites in rat brain.


A Gap Analysis of Mother, New-born, and Child Health in West Africa with Reference to the Sustainable Development Goals 2030.
The Economic Community of West African States (ECOWAS) comprises 15-member states with an estimated population of 350 million. This account relates the present status of maternal, neonatal, and under-five-mortality to the Sustainable Development Goals (SDG) targets set for 2030. For each SDG indicator, progress observed was compared with that needed to meet the target (assuming linear progression). The time gap was calculated as the difference between the time remaining to the target year (2030) and the estimated time needed to achieve the target. The highest maternal mortality ratio is found in Sierra Leone (1360 in 2015), followed by Nigeria (814) and Liberia (725). Whereas Sierra Leone and Nigeria keep high positions also for the neonatal and under-five mortality rate, Liberia ranks clearly better than the ECOWAS average. Globally skilled health professionals' density is 25 per 10,000 population and in Nigeria close to it with 20.1 whereas Guinea takes the last position with 1.4. The gap analysis shows that ECOWAS countries have a realistic chance to likely reach the SDG targets in 2030 with a delay of less than 4 years regarding maternal, neonatal, and under-five-mortality although their skilled health professionals' density is considerably lower than for the entire African region.


Immunotherapy of genital warts with inosine pranobex (Imunovir): preliminary study.
One hundred and sixty five heterosexual men and women with genital warts were treated with inosine pranobex (Imunovir) or conventional treatment, or both. Inosine pranobex was found to be more effective in lesions of longer duration, whereas conventional treatment was more effective in genital warts of a shorter duration. Supplementation of conventional treatment with inosine pranobex increased the success rate from 41% to 94%. Immunological studies in 134 patients with genital warts showed an increased number of B cells in 21% of peripheral blood samples. Absence of major defects among circulating lymphocytes suggested that patients with genital warts may have a local immune reaction.


Definition of Plant-Pathogenic Pseudomonas Genomospecies of the Pseudomonas syringae Complex Through Multiple Comparative Approaches.
A total of 34 phytopathogenic strain genomes belonging to the Pseudomonas syringae species complex and related species, including many pathotype strains, were assessed using average nucleotide identity (ANI) analysis. Their taxonomic relationships were consistently confirmed by the tetranucleotide frequency correlation coefficient (TETRA) values, multilocus sequence typing analysis (MLSA) performed with seven housekeeping genes, using both maximum likelihood and Bayesian methods, and split consensus network analyses. The ANI, MLSA, and split consensus analyses provided consistent and identical results. We confirmed the occurrence of the well-demarcated genomospecies inferred sensu Gardan et al. using DNA-DNA hybridization and ribotyping analyses. However, some P. syringae strains of the pathovars morsprunorum and lachrymans were placed in different genomospecies in our analyses. Genomospecies 1, 2, 4, 6, and 9 resulted well demarcated, whereas strains of genomospecies 3 and 8 had ANI values between 95 and 96% in some cases, confirming that this threshold reveals very closely related species that might represent cases of splitting entities or the convergence of different species to the same ecological niche. This study confirms the robustness of the combination of genomic and phylogenetic approaches in revealing taxonomic relationships among closely related bacterial strains and provides the basis for a further reliable demarcation of the phytopathogenic Pseudomonas species. Within each species, the pathovars might represent distinct ecological units. The possibility of performing extensive and standardized host range and phenotypic tests with many strains of different pathovars can assist phytobacteriologists for better determining the boundaries of these ecological units.


Community Masks - from an Emergency Solution to an Innovation Booster for the Textile Industry.
The COVID-19 pandemic resulted in shortages of personal protective equipment and medical devices in the initial phase. Agile small and medium-sized enterprises from regional textile industries reacted quickly. They delivered alternative products such as textile-based community masks in collaboration with industrial partners and research institutes from various sectors. The current mask materials and designs were further improved by integrating textiles with antiviral and antimicrobial properties and enhanced protection and comfort by novel textile/membrane combinations, key factors to increase the acceptance and compliance of mask wearing. The innocuity and sustainability of masks, as well as taking into account particular needs of vulnerable persons in our society, are new fields for textile-based innovations. These innovations developed for the next generation of facemasks have a high adaptability to other product segments, which make textiles an attractive material for hygienic applications and beyond.


Gastrointestinal bleeding secondary to the new anticoagulants.
To quantify direct oral anticoagulants (DOACs) related gastrointestinal bleeding (GIB), characterize patients at greatest risk and provide a pragmatic approach for the management of these drugs. This review will also summarize risk-management strategies and highlight evolving areas of clinical knowledge. DOACs permit anticoagulation with predictable dosing without the need for routine serum monitoring. Since their availability on the market, they have quickly emerged as a popular alternative for patients requiring short-term and lifelong anticoagulation. However, they are associated with an increased risk of GIB when compared with warfarin; thus, gastroenterologists must be prepared to manage DOAC-related GIB and prevent drug-related complications. This review will focus on acute and elective periendoscopic DOAC management, high-risk clinical groups for DOAC-related GIB, quantification of DOAC levels, use of reversal agents and minimization of thromboembolic risk associated with temporary interruption. This review will highlight pragmatic strategies for the treatment of DOAC-related bleeding and the prevention of postendoscopic DOAC bleeding. It will address new and evolving areas of periendoscopic management and identify knowledge gaps requiring further research to inform clinical practice.


A systematic review of definitions and reporting of bleeding outcome measures in haemophilia.
Bleeding frequency is an important outcome commonly used in haemophilia studies. There is a variation in practice in how bleeding is measured and defined. The primary objective of this study was to determine how investigators define and report bleeding outcome measures. MEDLINE, EMBASE and the CENTRAL were searched from January 1990 to January 2014. We retrieved all published studies that included patients with haemophilia A or B and reported some measures of bleeding. Two reviewers independently performed title and abstract screening, full-text review and data abstraction of the identified studies. A total of 118 studies fulfilled the inclusion criteria. Study designs were randomized controlled trials (RCT; 14%), cohort (68%), cross-sectional (5%) and others design (11%). The median duration of follow-up (Q1, Q3) was 20 (7.9, 50) months. We found 10 different bleeding outcomes reported [absolute number of bleeding 60 (50.8%) studies, annualized bleeding rate 60 (50.8%) studies, bleed per month 10 (8.5%) studies and others 11 (9.3%) studies]. Of these, 32 (27%) studies reported only mean or median without dispersion and 33 (28%) studies did not report any measures of central tendency (dispersion). There is substantial variation in definitions and measures of bleeding outcomes in the haemophilia literature. This creates difficulty and limitations in comparing the outcomes between studies and in performing meta-analysis. The haemophilia research community needs to develop a consensus on a clear definition of bleeding and how to address the limitations associated with variations in measures of bleeding between centres and studies.


Monitoring of brain interstitial total tau and beta amyloid proteins by microdialysis in patients with traumatic brain injury.
Damage to axons contributes to postinjury disabilities and is commonly observed following traumatic brain injury (TBI). Traumatic brain injury is an important environmental risk factor for the development of Alzheimer disease (AD). In the present feasibility study, the aim was to use intracerebral microdialysis catheters with a high molecular cutoff membrane (100 kD) to harvest interstitial total tau (T-tau) and amyloid beta 1-42 (Abeta42) proteins, which are important biomarkers for axonal injury and for AD, following moderate-to-severe TBI. Eight patients (5 men and 3 women) were included in the study; 5 of the patients had a focal/mixed TBI and 3 had a diffuse axonal injury (DAI). Following the bedside analysis of the routinely measured energy metabolic markers (that is, glucose, lactate/pyruvate ratio, glycerol, and glutamate), the remaining dialysate was pooled and two 12-hour samples per day were used to analyze T-tau and Abeta42 by enzyme-linked immunosorbent assay from Day 1 up to 8 days postinjury. The results show high levels of interstitial T-tau and Abeta42 postinjury. Patients with a predominantly focal lesion had higher interstitial T-tau levels than in the DAI group from Days 1 to 3 postinjury (p < 0.05). In contrast, patients with DAI had consistently higher Abeta42 levels when compared with patients with focal injury. These results suggest that monitoring of interstitial T-tau and Abeta42 by using microdialysis may be an important tool when evaluating the presence and role of axonal injury following TBI.


Isolated renal hydatid disease: experience at the queen rania urology center, the king hussein medical center.
In this retrospective study, we present our experience on the diagnosis and management of isolated Hydatid disease of the kidneys. Between January 1999 and January 2003, eight patients were diagnosed to have Hydatid disease of the kidney and constituted the subjects of this study. Their age ranged between 20 and 63 years age (mean 40); there were five males and three females. Loin pain was the commonest mode of presentation in these patients. Investigations performed included urine analysis, serological tests, eosinophil count and relevant radiological studies. Urine analysis showed hydatiduria in one patient, the Casoni's test was positive in two, Ghedini skin test was positive in three and eosinophilia was noted in two other patients. All patients were treated surgically using loin supracostal extra-peritoneal approach. Total nephrectomy was performed in five patients, partial nephrectomy in one while excision of the cyst was performed in two patients. Our report suggests that a combination of various investigative modalities with a high index of suspicion is necessary in establishing the correct diagnosis. Surgery remains the main option of treatment for renal hydatid disease.