Bsx, a novel hypothalamic factor linking feeding with locomotor activity, is regulated by energy availability.
We recently reported that the hypothalamic homeobox domain transcription factor Bsx plays an essential role in the central nervous system control of spontaneous physical activity and the generation of hyperphagic responses. Moreover, we found Bsx to be a master regulator for the hypothalamic expression of key orexigenic neuropeptide Y and agouti gene-related protein. We now hypothesized that Bsx, which is expressed in the dorsomedial and arcuate nucleus (ARC) of the hypothalamus, is regulated by afferent signals in response to peripheral energy balance. Bsx expression was analyzed using in situ hybridization in fed vs. fasted (24 h) and ghrelin vs. leptin-treated rats, as well as in mice deficient for leptin or the ghrelin signaling. Ghrelin administration increased, whereas ghrelin receptor antagonist decreased ARC Bsx expression. Leptin injection attenuated the fasting-induced increase in ARC Bsx levels but had no effect in fed rats. Dorsomedial hypothalamic nucleus Bsx expression was unaffected by pharmacological modifications of leptin or ghrelin signaling. Obese leptin-deficient (ob/ob) mice, but not obese melanocortin 4 receptor-knockout mice, showed higher expression of Bsx, consistent with dependency from afferent leptin rather than increased adiposity per se. Interestingly, exposure to a high-fat diet triggered Bsx expression, consistent with the concept that decreased leptin signaling due to a high-fat diet induced leptin resistance. Our data indicate that ARC Bsx expression is specifically regulated by afferent energy balance signals, including input from leptin and ghrelin. Future studies will be necessary to test if Bsx may be involved in the pathogenesis of leptin resistance.


Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women.
Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione, and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR -/-) participating in a breast cancer case-control study. We also measured the same steroid hormones, as well as estrone sulfate, and sex hormone-binding globulin (SHBG) in serum from these patients and 100 controls matched on ages at blood collection and on menopause. Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER-/PR- breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER-/PR- breast cancer, although differences were only significant for testosterone. These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER-/PR- breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis.


Scattering Amplitudes and Conservative Binary Dynamics at O(G^{4}).
Using scattering amplitudes, we obtain the potential contributions to conservative binary dynamics in general relativity at fourth post-Minkowskian order O(G^{4}). As in previous lower-order calculations, we harness powerful tools from the modern scattering amplitudes program including generalized unitarity, the double copy, and advanced multiloop integration methods, in combination with effective field theory. The classical amplitude involves polylogarithms with up to transcendental weight two and elliptic integrals. We derive the radial action directly from the amplitude, and determine the corresponding Hamiltonian in isotropic gauge. Our results are in agreement with known overlapping terms up to sixth post-Newtonian order, and with the probe limit. We also determine the post-Minkowskian energy loss from radiation emission at O(G^{3}) via its relation to the tail effect.


[Children: improving the prevention and early advancement in children with behavioral- and developmental disorders in the Ennepe-Ruhr District].
Developmental behavioural disorders in early childhood are a serious public health problem, because they signify a higher risk of social, regulatory and emotional impairment in later life. The public health office in Ennepe-Ruhr develops in cooperation with the communities a programme of health promotion for children and their families. An important motive is continually rising costs for supporting children with developmental problems. An element in the programme is a project of counselling mothers with babies and toddlers with excessive crying, serious sleep disorders and anxiety problems. This example of early intervention promises short-term relief, early identification of problem children and the strengthening of parental resources. A key issue is the introduction of a systematic evaluation of all communal funding for measures of support for preschool children. It shows that such measures start relatively late, and the coordination at community level is not always optimal. Some progress has been made, but criteria to measure the efficiency of current health promotion are still lacking. According to public health research early intervention for risk groups (single mothers, migrant families or families depending on public assistance) promises to give children and their families a better social and health perspective in life. It should be a primary health target for communities to develop evidence-based health programmes for children, focussing on mental and social well-being. Studies indicate that such interventions might have positive financial results.


Clinical and self-perceived oral health assessment of elderly residents in urban, rural, and institutionalized communities.
This study aims to evaluate the self-perception of oral health according to the physical, psychosocial and pain/discomfort dimensions related to clinical conditions and orofacial pain of elderly people living in three different environments. This was an observational, cross-sectional, quantitative study with a population-based approach and nonprobabilistic convenience sampling that included 81 elderly people: 27 resided in institutional homes for elderly individuals, 27 resided in an urban area and 27 resided in a rural area in the interior of Paraíba (PB) in northeastern Brazil. The Geriatric Oral Health Assessment Index (GOHAI) was used to assess self-perception of oral health, while the Questionnaire for Screening of Patients with Temporomandibular Disorders (QST/TMD) was used to assess the influences of orofacial pain and the biofilm indexes of teeth and prostheses. There was a statistically significant difference in the GOHAI scores among the places of residence, with the worst values associated with the rural area. According to the QST/TMD, the majority of individuals were affected by TMDs, with statistical differences for both sex and income. The biofilm analysis showed a higher incidence of clinical conditions in the rural population. The place of residence also influenced self-perception and the clinical oral health condition of elderly people; the rural population presented the worst results.


Metamorphosis in the summer flounder Paralichthys dentatus: changes in gill mitochondria-rich cells.
Salinity tolerance changes during larval development and metamorphosis in the summer flounder (Paralichthys dentatus) and other teleosts. The physiological mechanisms responsible for osmoregulation during these early stages of development are not well understood. This study characterized changes in ultrastructure, intracellular membranes and immunoreactive Na(+)/K(+)-ATPase of mitochondria-rich cells (MRCs) in the gills of summer flounder during metamorphosis. Gill ultrastructure at the start of metamorphosis revealed only one type of MRC, which had weak reactivity to osmium and lacked a well-defined apical pit. In juveniles, two types of MRCs were observed: light-staining MRCs (LMRCs) with weak reactivity to osmium, and dark-staining MRCs (DMRCs) with strong reactivity to osmium and positioned adjacent to LMRCs. Compared with MRCs at the start of metamorphosis, the mitochondria of juvenile MRCs appeared smaller, with more transverse cristae and electron-dense matrices. Changes in MRCs during metamorphosis were also accompanied by increased immunoreactive Na(+)/K(+)-ATPase. These findings suggest that gill MRCs develop during the metamorphosis of summer flounder as the gill takes on an increasingly important osmoregulatory role.


Access to percutaneous transluminal coronary angioplasty and 30-day mortality in patients with incident STEMI: Differentials by educational level and gender over 11 years.
Socioeconomic status and gender are associated with access to cardiac procedures and mortality after AMI, also in countries with universal health care systems. Our objective was to evaluate the association and trends of educational level or gender and the following outcomes: 1) access to PTCA; 2) 30-day mortality. We conducted an observational study based on 14,013 subjects aged 35-74 years, residing in Rome in 2001, and hospitalised for incident STEMI within 2012 in the Lazio region. We estimated adjusted ORs of educational level or gender and: 1) PTCA within 2 days after hospitalisation, 2) 30-day mortality. We evaluated time trends of outcomes, and time trends of educational or gender differentials estimating ORs stratified by time period (two time periods between 2001 and 2012). We performed a hierarchical analysis to account for clustering of hospitals. Access to PTCA among patients with incident STEMI increased during the study period, while 30-day mortality was stable. We observed educational differentials in PTCA procedure only in the first time period, and gender differentials in both periods. Patterns for 30-day mortality were less marked, with educational differentials emerging only in the second period, and gender differentials only in the first one, with patients with low educational level and females being disadvantaged. Educational differentials in the access to PTCA disappeared in Lazio region over time, coherently with scientific literature, while gender differentials seem to persist. It may be important to assess the role of female gender in patients with STEMI, both from a social and a clinical point of view.


In vivo imaging of microglial activation using a peripheral benzodiazepine receptor ligand: [11C]PK-11195 and animal PET following ethanol injury in rat striatum.
To investigate whether [(11)C]PK-11195, a specific peripheral benzodiazepine receptors (PBRs) ligand for positron emission tomography (PET), can show activated microglia in a rat brain injury model. On day 1, ethanol was injected into the rat's right striatum (ST) using a stereotaxic operative procedure. On day 3, head magnetic resonance imaging (MRI) scans for surgically treated rats were performed to evaluate ethanol injury morphologically. On day 4, dynamic PET scans (17 injured rats and 7 non-injured controls) were performed for 60 min with an animal PET scanner under chloral hydrate anesthesia following a bolus injection of [(11)C]PK-11195 through tail vein. Because PBRs are present throughout the brain, there is no suitable receptor-free reference region. The reference tissue model may not be applicable because of low target to background ratio for low affinity of [(11)C]PK-11195 to PBRs. We evaluated the PBRs binding with regions of interest (ROIs)-based approach to estimate total distribution volume (V). We used an integral from 0 min to 60 min (V (60)) as an estimate of V. On the coronal PET image, ROIs were placed on bilateral ST. Differences in right/left ST V (60) ratios between lesioned and unlesioned control rats were compared using unpaired t tests. Immunohistochemical staining was performed for confirming the presence of activated microglia following decapitation on the PET experiment day. The right/left ST V (60) ratios in lesioned rats (1.07 +/- 0.08) were significantly higher than those in unlesioned control rats (1.00 +/- 0.06, P < 0.05). On immunohistochemical staining, activated microglia were exclusively observed in the injured right ST but not in the noninjured left ST of the injury rats and the bilateral ST of the non-injured control rats. These results suggest that [(11)C]PK-11195 PET imaging would be a useful tool for evaluating microglial activation in a rat brain injury model.


Plasma zinc and copper levels of infants fed different milk formulas.
The plasma zinc and copper levels of 32 full-term healthy infants, aged 3-4 months, using different infant formulas, were measured. The plasma zinc levels of infants using soy formula (45.1 +/- 19.1 micrograms/dl) and iron-fortified cow's milk formula (61.6 +/- 12.9 micrograms/dl) were significantly lower than those of the infants using cow's milk formula not fortified with iron (77.5 +/- 13.4 micrograms/dl). The plasma copper levels of the infants using the different formulas were not significantly different from each other. Fortification of infant formulas with high levels of iron may reduce the zinc absorption from such formulas.


Selection of Ig mu heavy chains by complementarity-determining region 3 length and amino acid composition.
Although it is generally accepted that Ig heavy chains (HC) are selected at the pre-B cell receptor (pre-BCR) checkpoint, the characteristics of a functional HC and the role of pre-BCR assembly in their selection have remained elusive. We determined the characteristics of HCs that successfully passed the pre-BCR checkpoint by examining transcripts harboring V(H)81X and J(H)4 gene segments from J(H)(+/-) and lambda5(-/-)mice. V(H)81X-J(H)4-HC transcripts isolated from cells before or in the absence of pre-BCR assembly had no distinguishing complementarity-determining region 3 traits. In contrast, transcripts isolated subsequent to passage through the pre-BCR checkpoint had distinctive complementarity-determining regions 3 of nine amino acids in length (49%) and a histidine at position 1 (73%). Hence, our data define specific structural requirements for a functional HC, which is instrumental in shaping the diverse B cell repertoire.


Fibrinogen catabolism within the procoagulant VX-2 tumor of rabbit lung in vivo: Effluxing fibrin(ogen) fragments contain antiangiogenic activity.
Many types of solid tumors are known to be procoagulant environments. This is partly because a hyperpermeable vascular system within the tumor allows plasma hemostatic factors to accumulate in relatively high concentrations in the stroma, and many solid-tumor cells express tissue factor or a procoagulant factor. These circumstances appear to exist in the VX-2 lung tumor of the New Zealand White (NZW) rabbit, and they sustain a measurable turnover of stromal deposits of fibrin(ogen). We have measured the turnover of fibrinogen within tumors of the VX-2 tumor-burdened rabbit and analysed the catabolic products of fibrin(ogen) and the status of fibrinolysis in tumor-derived interpleural effusate. Using intravenously injected (125)I-labeled rabbit fibrinogen as a marker, we found that fibrinogen (approximate blood concentration 1740 microg/mL) passed from blood to VX-2 tumor stroma, saturating the tumor at a concentration of approximately 348 microg fibrinogen/g in approximately 12 hours. We measured fibrin(ogen) fragments, at a concentration of approximately 292 microg/mL, in interpleural effusates that we recovered from 13% of the VX-2-burdened rabbits. Unreduced fibrin(ogen) fragments consisted of 4 major components with a relative molecular mass of approximately 250,000 (assumed to be fragment X; approximately 9% of total fragments from densitometry of immunoblots), 200,000 (d-dimer; 41%), 110,000 (fragment D; 49%), and 50,000 to 55,000 (fragment E; 1%-2%) kD. Total fibrin(ogen) fragments immunopurified from effusates exhibited an antiangiogenic effect when subjected to a chick embryo chorioallantoic membrane procedure. Interpleural effusates were devoid of plasmin activity or active plasminogen activator inhibitor-1 but contained plasmin complexes and active urokinase-like plasminogen activator (uPA), alpha(2)-antiplasmin, and thrombin-activatable fibrinolysis inhibitor. We speculate that VX-2 cells release uPA to activate fibrinolysis within the tumor stroma. Catabolic products of hemostasis (eg, fibrinolytic fragments, angiostatin) flux from the stroma into the interpleural space, thereby providing a net antiangiogenic property to the effusate and ultimately to the lymphatic and circulatory systems.


Medieval trabecular bone architecture: the influence of age, sex, and lifestyle.
Osteoporosis has become a growing health concern in developed countries and an extensive area of research in skeletal biology. Despite numerous paleopathological studies of bone mass, few studies have measured bone quality in past populations. In order to examine age- and sex-related changes in one aspect of bone quality in the past, a study was made of trabecular bone architecture in a British medieval skeletal sample. X-ray images of 5-mm-thick coronal lumbar vertebral bone sections were taken from a total of 54 adult individuals divided into three age categories (18-29, 30-49, and 50+ years), and examined using image analysis to evaluate parameters related to trabecular bone structure and connectivity. Significant age-related changes in trabecular bone structure (trabecular bone volume (BV/TV), trabecular number (Tb.N), trabecular separation (Tb.Sp), and anisotropic ratio (Tb.An)) were observed to occur primarily by middle age with significant differences between the youngest and two older age groups. Neither sex showed continuing change in trabecular structure between the middle and old age groups. Age-related changes in bone connectivity (number of nodes (N.Nd) and node-to-node strut length (Nd.Nd)) similarly indicated a change in bone connectivity only between the youngest and two older age groups. However, females showed no statistical differences among the age groups in bone connectivity. These patterns of trabecular bone loss and fragility contrast with those generally found in modern populations that typically report continuing loss of bone structure and connectivity between middle and old age, and suggest greater loss in females. The patterns of bone loss in the archaeological samples must be interpreted cautiously. We speculate that while nutritional factors may have initiated some bone loss in both sexes, physical activity could have conserved bone architecture in old age in both sexes, and reproductive factors such as high parity and extended periods of lactation could have played a key role in female bone maintenance in this historic population. The study of qualitative elements (such as trabecular architecture) is vital if we are to understand bone maintenance and fragility in the past.


Predicting Visual Acuity Deterioration and Radiation-Induced Toxicities after Brachytherapy for Choroidal Melanomas.
Ruthenium-106 (Ru-106) brachytherapy is an established modality for eye-preserving treatment of choroidal melanoma. To achieve optimal treatment outcomes, there should be a balance between tumour control and the risk of healthy tissue toxicity. In this retrospective study, we examined normal tissue complication probability (NTCP) for visual acuity deterioration and late complications to aid the understanding of dose-dependence after Ru-106 treatments. We considered consecutive patients diagnosed with choroidal melanoma and primarily treated at a single institution from 2005-2014. Treatment plans were retrospectively recreated using dedicated software and image guidance to contour the tumour and determine the actual plaque position. Dose distributions were extracted from each plan for all relevant anatomical structures. We considered visual acuity deterioration and late complications (maculopathy, optic neuropathy, ocular hypertension, vascular obliteration, cataract and retinal detachment). Lasso statistics were used to select the most important variables for each analysis. Outcomes were related to dose and clinical characteristics using multivariate Cox regressions analysis. In total, 227 patients were considered and 226 of those were eligible for analysis. Median potential follow-up time was 5.0 years (95% CI: 4.5-6.0). Visual acuity deterioration was related to optic disc-tumour distance and dose metrics from the retina and the macula, with retina V10Gy showing the strongest correlation. Macula V10Gy was the only dose metric impacting risk of maculopathy, while optic disc-tumour distance also proved important. Optic disc V50Gy had the largest impact on optic neuropathy along with optic disc-tumour distance. Optic disc V20Gy was the only variable associated with vascular obliteration. Lens D2% had the largest impact on the risk of cataract along with older age and the largest base dimension. We found no variables associated with the risk of ocular hypertension and retinal detachment. Visual acuity deterioration and most late complications demonstrated dependence on dose delivered to healthy structures in the eye after Ru-106 brachytherapy for choroidal melanomas.


Insertion of Tn916 in Neisseria meningitidis resulting in loss of group B capsular polysaccharide.
We recently found that the 16.4-kb conjugative transposon Tn916 could be introduced into Neisseria meningitidis by transformation and that it appeared to transpose to many different sites in the chromosome of recipient meningococci. In order to identify transposon-induced alterations of specific meningococcal virulence determinants, a library of meningococcal Tetr transformants containing Tn916 was made and screened for those altered in the production of group B capsular polysaccharide. A capsule-defective mutant, M7, was identified by using monoclonal and polyclonal antisera to group B polysaccharide in immunoblot and agar antiserum procedures. Growth of M7 was similar to that of the parent strain. M7 produced no group B capsular polysaccharide by rocket immunoelectrophoresis, and the mutation was stable during laboratory passage. The capsule-defective phenotype was linked to Tetr, as demonstrated by immunoblot and Southern blot analysis of progeny Tetr transformants (transformants of the parent strain obtained with DNA from M7). A capsule-deficient mutant, O8, was identified by using a similar approach. Analysis of the Tn916 insertions in M7 and O8 indicated that a significant portion of the transposon on either side of the tetM determinant had been lost. The ability of Tn916 to generate defined, stable mutations in meningococcal virulence determinants is demonstrated by our study.


The influence of visual and somatosensory input on the vestibulo-oculomotor reflex of pigmented rats.
Eye movements were recorded in the pigmented rat during vestibular, optokinetic and combined visual-vestibular stimulation. The dominant time constant in pigmented rats, tested during angular vestibular stimulation in darkness, is about two times longer than the cupular time constant. The gain and the duration of nystagmus, achieved by angular vestibular stimulation, can be enhanced by visual impulses. This is most evident during an optokinetic temporonasal stimulation, but is also seen with a nasotemporal stimulation. A mere optokinetic monocular stimulation without a synchronous vestibular excitation causes nystagmus only when the stimuli has a temporonasal direction. The duration of nystagmus, achieved by angular vestibular stimulation, is prolonged by disturbances of the neck proprioceptive system. This is more evident during a simultaneous visual input than in darkness. The ability to cancel nystagmus during conflicting vestibular and optokinetic impulses is well developed in the pigmented rat.


Cystic fibrosis on the Internet: a survey of site adherence to AMA guidelines.
The Internet permits unprecedented and mostly unrestricted access to medical knowledge; however, concerns exist regarding viewer privacy, accountability of authorship, accuracy of information, and patient safety. To address these issues, the American Medical Association (AMA) has developed guidelines concerning web site content and visitor rights. Cystic fibrosis (CF) is the most common genetically inherited lethal disease in North America. Many Internet sites that provide information on CF have been developed, although adherence to validated guidelines for online health information is not required. The purpose of this study was to assess systematically web sites with content pertaining to CF for adherence to the published AMA guidelines. The search term "cystic fibrosis" was entered into a commonly used search engine (Google), and the first 100 eligible sites were reviewed. Each site was examined for adherence to the AMA Guidelines for Medical and Health Information Sites on the Internet using a series of adapted questions. There were 15 questions divided into the following main categories: 1) site structure and viewer privacy, 2) author accountability, 3) scientific citation, and 4) patient safety. The number of positives for each question was tabulated. With respect to site structure, fewer than half (45%) of the reviewed sites indicated a date of last revision. Only 11 (11%) carried an explicit privacy policy. A responsible author or group was listed in only 43 (43%) of 100 sites. Presented data regarding CF was supported by references, sources, or expert review in only 38 (38%) of 100 sites. A medical disclaimer noting that information provided does not substitute for evaluation by a health care team was evident in only 37 (37%) sites. The majority of easily accessible CF informational web sites do not adhere to guidelines published by the AMA. Patients and families who use the Internet as a CF information resource should examine the web sites carefully and be familiar with the guidelines established by the AMA. Personal information is not protected, and few sites provide explicit privacy guarantees. Finally, CF care teams should inquire about Internet use by patients and families and be prepared to discuss findings from the Internet to heighten patient safety and awareness.


Psychosocial bias in the diagnosis of obesity.
This study explores demographic and psychosocial variables associated with the assignment of the diagnosis of obesity in a family medicine residency model practice. Three groups of adult patients seen during 1978 were studied: a random sample of active patients, patients diagnosed as obese during 1978, and those never diagnosed as obese. While the prevalence of true obesity (greater than 20 percent above ideal body weight) was similar for men (58 percent) and women (47 percent), more women were diagnosed (222 women vs 87 men) and were more likely to be diagnosed within a year of entering the practice (42 percent women vs 10 percent men). Diagnosed obese women were older, had more psychological problems, and visited the practice more often than nonobese women. Diagnosed obese men were older, more frequently had psychological problems, visited the practice more often, and were more likely to be married than nonobese men. Undiagnosed obese men, however, had fewer psychological problems than nonobese men. The results suggest that physician education should address problems with diagnostic labeling and that researchers should anticipate subtle selection biases in retrospective studies when sampling methods depend on diagnosis.


Α- and β-subunit composition of voltage-gated sodium channels investigated with μ-conotoxins and the recently discovered μO§-conotoxin GVIIJ.
We investigated the identities of the isoforms of the α (NaV1)- and β (NaVβ)-subunits of voltage-gated sodium channels, including those responsible for action potentials in rodent sciatic nerves. To examine α-subunits, we used seven μ-conotoxins, which target site 1 of the channel. With the use of exogenously expressed channels, we show that two of the μ-conotoxins, μ-BuIIIB and μ-SxIIIA, are 50-fold more potent in blocking NaV1.6 from mouse than that from rat. Furthermore, we observed that μ-BuIIIB and μ-SxIIIA are potent blockers of large, myelinated A-fiber compound action potentials (A-CAPs) [but not small, unmyelinated C-fiber CAPs (C-CAPs)] in the sciatic nerve of the mouse (unlike A-CAPs of the rat, previously shown to be insensitive to these toxins). To investigate β-subunits, we used two synthetic derivatives of the recently discovered μO§-conotoxin GVIIJ that define site 8 of the channel, as previously characterized with cloned rat NaV1- and NaVβ-subunits expressed in Xenopus laevis oocytes, where it was shown that μO§-GVIIJ is a potent inhibitor of several NaV1-isoforms and that coexpression of NaVβ2 or -β4 (but not NaVβ1 or -β3) totally protects against block by μO§-GVIIJ. We report here the effects of μO§-GVIIJ on 1) sodium currents of mouse NaV1.6 coexpressed with various combinations of NaVβ-subunits in oocytes; 2) A- and C-CAPs of mouse and rat sciatic nerves; and 3) sodium currents of small and large neurons dissociated from rat dorsal root ganglia. Our overall results lead us to conclude that action potentials in A-fibers of the rodent sciatic nerve are mediated primarily by NaV1.6 associated with NaVβ2 or NaVβ4.


[Ocular biometry, refractive error and correlation with height, age, gender and years of formal education].
To assess ocular biometric parameters and refractive error in Brazilian adults and their relationship with height, age, gender and years of formal education. Cross-sectional study that assessed 173 subjects by keratometry, echobiometry, refraction and measurement of body height. The statistical analysis was performed using Pearson's coefficient and a regression model was constructed. The correlations found were: each 10 cm - increase in height was related to a 0.32 mm longer axial length, 0.07 mm deeper anterior chamber, 0.26 mm deeper vitreous chamber and 0.50 D flatter keratometry. Each 10-year increase in age, related to a 0.15 mm smaller axial length, 0.25 mm thicker lens, 0.21 mm shallower vitreous chamber and 0.23 D more positive spherical equivalent. Each 10-year increase in education related to a 0.74 D more negative spherical equivalent. Gender did not influence the analyzed biometric parameters. Equations referring to biometric parameters and spherical equivalent were formulated. Positive correlations were found between: axial length and height; anterior chamber and vitreous cavity depth with height; lens thickness with age; keratometry with height; and spherical equivalent with age. Negative correlations were found between: anterior chamber and vitreous cavity depth with age; spherical equivalent and years of formal education.


The Biomechanical Properties of Human Menisci: A Systematic Review.
Biomechanical characterization of meniscal tissue ex vivo remains a critical need, particularly for the development of suitable meniscus replacements or therapeutic strategies that target the native mechanical properties of the meniscus. To date, a huge variety of test configurations and protocols have been reported, making it extremely difficult to compare the respective outcome parameters, thereby leading to misinterpretation. Therefore, the purpose of this systematic review was to identify test-specific parameters that contribute to uncertainties in the determination of mechanical properties of the human meniscus and its attachments, which derived from common quasi-static and dynamic tests in tension, compression, and shear. Strong evidence was found that the determined biomechanical properties vary significantly depending on the specific test parameters, as indicated by up to tenfold differences in both tensile and compressive properties. Test mode (stress relaxation, creep, cyclic) and configuration (unconfined, confined, in-situ), specimen shape and dimensions, preconditioning regimes, loading rates, post-processing of experimental data, and specimen age and degeneration were identified as the most critical parameters influencing the outcome measures. In conclusion, this work highlights an unmet need for standardization and reporting guidelines to facilitate comparability and may prove beneficial for evaluating the mechanical properties of novel meniscus constructs. STATEMENT OF SIGNIFICANCE: : The biomechanical properties of the human meniscus have been studied extensively over the past decades. However, it remains unclear to what extent both test protocol and specimen-related differences are responsible for the enormous variability in material properties. Therefore, this systematic review analyzes the biomechanical properties of the human meniscus in the context of the underlying testing protocol. The most sensitive parameters affecting the determination of mechanical properties were identified and critically discussed. Currently, it is of utmost importance for scientists evaluating potential meniscal scaffolds and biomaterials to have a control group rather than a direct comparison to the literature. Standardization of both test procedures and reporting requirements is needed to improve and accelerate the development of meniscal replacement constructs.


Validation of Thermal Lethality against Salmonella enterica in Poultry Offal during Rendering.
Recent outbreaks of human disease following contact with companion animal foods cross-contaminated with enteric pathogens, such as Salmonella enterica, have resulted in increased concern regarding the microbiological safety of animal foods. Additionally, the U.S. Food and Drug Administration Food Safety Modernization Act and its implementing rules have stipulated the implementation of current good manufacturing practices and food safety preventive controls for livestock and companion animal foods. Animal foods and feeds are sometimes formulated to include thermally rendered animal by-product meals. The objective of this research was to determine the thermal inactivation of S. enterica in poultry offal during rendering at differing temperatures. Raw poultry offal was obtained from a commercial renderer and inoculated with a mixture of Salmonella serovars Senftenberg, Enteritidis, and Gallinarum (an avian pathogen) prior to being subjected to heating at 150, 155, or 160°F (65.5, 68.3, or 71.1°C) for up to 15 min. Following heat application, surviving Salmonella bacteria were enumerated. Mean D-values for the Salmonella cocktail at 150, 155, and 160°F were 0.254 ± 0.045, 0.172 ± 0.012, and 0.086 ± 0.004 min, respectively, indicative of increasing susceptibility to increased application of heat during processing. The mean thermal process constant (z-value) was 21.948 ± 3.87°F. Results indicate that a 7.0-log-cycle inactivation of Salmonella may be obtained from the cumulative lethality encountered during the heating come-up period and subsequent rendering of raw poultry offal at temperatures not less than 150°F. Current poultry rendering procedures are anticipated to be effective for achieving necessary pathogen control when completed under sanitary conditions.


Cardio- and cerebrovascular events in HIV-infected persons.
Recent results from the D:A:D Study indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). The present study was performed to investigate whether this risk was similar when including other cardio- and cerebro-vascular disease events (CCVE). D:A:D is an international collaboration of 11 cohorts, following 23 468 HIV-infected patients prospectively at 188 clinics in 21 countries situated in Europe, USA and Australia. The end-point was the occurrence of a first CCVE during prospective follow-up, defined as the first of: acute MI, invasive cardiovascular procedures, stroke, or death from other cardiovascular disease. Relative rates (RR) for CCVE from Poisson regression models and 95% confidence intervals (CI) are reported. All models are adjusted for other risk factors for CCVE, including age, gender, ethnicity, family history, body mass index, and smoking status as well as cohort and HIV transmission group. Over 36 145 person-years of follow-up, 207 patients experienced at least one CCVE (23.7% fatal). The first event was MI in 126 patients, invasive cardiovascular procedure in 39 patients, stroke in 38 patients, and death from other cardiovascular disease in four patients. The incidence of first CCVE was 5.7 per 1000 person-years [95% confidence interval (CI) 5.0-6.5] and increased with longer exposure to CART (RR per year of exposure, 1.26; 95% CI, 1.14-1.38; P < 0.0001). CART increases the risk of CCVD, and this increase is comparable with how CART affects the risk of MI. This finding is consistent with the hypothesis that atherosclerosis is a side-effect of CART.


Trends and Disparities in Inpatient Costs for Eye Trauma in the United States (2001-2014).
To determine the trends and disparities in inpatient costs for eye trauma in the United States from 2001 through 2014. Retrospective population-based cross-sectional study. National Inpatient Sample, a representative sample of U.S. hospital discharges, was used to determine costs of eye trauma hospitalizations. Linear regression was used to estimate changes in mean inflation-adjusted cost per admission. Multivariable logistic regression was used to evaluate factors associated with a cost in the highest quartile (>$13 000) including age, sex, race, income quartile, primary payer, hospital location, size, and type. The model was adjusted for year of admission, length of stay, type of trauma, comorbidities, and the type and number of procedures performed. The inpatient costs for eye trauma from 2001 through 2014 totaled $1.72 billion. The mean cost (95% confidence interval [CI]) per stay remained relatively constant: $12 000 ($11 000-13 000) in 2001 to $11 000 ($10 000-12 000) in 2014 (P = .643). A cost in the highest quartile was more likely in African Americans compared to whites (adjusted odds ratio, 1.3; 95% CI, 1.2-1.5), patients in the highest income quartile compared to those in the lowest (1.3; 1.2-1.5), uninsured patients compared to publicly insured patients (1.2; 1.1-1.4), teaching hospitals compared to non-teaching ones (1.5; 1.2-1.8), and the West compared to the South (2.4; 2.0-2.8). Inpatient costs of eye trauma have remained steady and can be potentially reduced by addressing associated disparities. Further research including outpatient costs and eye trauma in vulnerable populations will be key to optimizing care and advancing healthcare equity.


Design of composite scaffolds and three-dimensional shape analysis for tissue-engineered ear.
Engineered cartilage is a promising option for auricular reconstruction. We have previously demonstrated that a titanium wire framework within a composite collagen ear-shaped scaffold helped to maintain the gross dimensions of the engineered ear after implantation, resisting the deformation forces encountered during neocartilage maturation and wound healing. The ear geometry was redesigned to achieve a more accurate aesthetic result when implanted subcutaneously in a nude rat model. A non-invasive method was developed to assess size and shape changes of the engineered ear in three dimensions. Computer models of the titanium framework were obtained from CT scans before and after implantation. Several parameters were measured including the overall length, width and depth, the minimum intrahelical distance and overall curvature values for each beam section within the framework. Local curvature values were measured to gain understanding of the bending forces experienced by the framework structure in situ. Length and width changed by less than 2%, whereas the depth decreased by approximately 8% and the minimum intrahelical distance changed by approximately 12%. Overall curvature changes identified regions most susceptible to deformation. Eighty-nine per cent of local curvature measurements experienced a bending moment less than 50 µN-m owing to deformation forces during implantation. These quantitative shape analysis results have identified opportunities to improve shape fidelity of engineered ear constructs.


Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol.
Imatinib is successfully used in the treatment of chronic myelogenous leukemia (CML), and the main mechanisms of resistance in refractory patients are now partially understood. In the present study, we investigated the mechanism of action of resveratrol in imatinib-sensitive (IM-S) and -resistant (IM-R) CML cell lines. Resveratrol induced loss of viability and apoptosis in IM-S and IM-R in a time- and dose-dependent fashion. Inhibition of cell viability was detected for concentrations of resveratrol as low as 5 microM, and the IC(50) values for viability, clonogenic assays, apoptosis, and erythroid differentiation were in the 10-25 microM range. The effect of imatinib and resveratrol was additive in IM-S but not in IM-R clones in which the resveratrol effect was already maximal. The effect of resveratrol on apoptosis was partially rescued by zVAD-fmk, suggesting a caspase-independent contribution. Resveratrol action was independent of BCR-ABL expression and phosphorylation, and in agreement was additive to BCR-ABL silencing. Finally, phytoalexin inhibited the growth of BaF3 cells expressing mutant BCR-ABL proteins found in resistant patients, including the multiresistant T315I mutation. Our findings show that resveratrol induces apoptosis, caspase-independent death, and differentiation that collectively contribute to the specific elimination of CML cells. Resveratrol should provide therapeutic benefits in IM-R patients and in other hematopoietic malignancies.


Understanding treatment guidelines with bismuth and non-bismuth quadruple Helicobacter pylori eradication therapies.
Recent Helicobacter pylori treatment guidelines recommend the 4-drug combinations bismuth quadruple therapy and concomitant therapy. Areas covered: We review antimicrobial therapy for H. pylori in the context of antimicrobial therapy in general and specifically in relation to good antimicrobial stewardship (defined as optimal selection, dose, and duration of an antimicrobial that results in the best clinical outcome for the treatment of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance). Expert commentary: The lack of regional and local H. pylori susceptibility data prevents implementation of susceptibility-based antimicrobial therapy and forces compromises. Bismuth quadruple therapy employing at least 1,500 mg of metronidazole for 14 days is effective despite metronidazole resistance. The main drawback is side effects causing reduced adherence. Versions where amoxicillin replaces metronidazole or tetracycline also appear effective. It is likely that bismuth quadruple therapy can be simplified by giving bismuth and possibly tetracycline b.i.d., possibly with fewer side effects. Concomitant therapy (a proton pump inhibitor, metronidazole, clarithromycin, amoxicillin) is ineffective with dual clarithromycin-metronidazole resistance and all patients receive at least one unnecessary antibiotic thus promoting antimicrobial resistance worldwide. Concomitant therapy should be abandoned when susceptibility testing becomes widespread or an alternate becomes available.


Ultrafast Flame Annealing of TiO2 Paste for Fabricating Dye-Sensitized and Perovskite Solar Cells with Enhanced Efficiency.
Mesoporous TiO2 nanoparticle (NP) films are broadly used as electrodes in photoelectrochemical cells, dye-sensitized solar cells (DSSCs), and perovskite solar cells (PSCs). State-of-the-art mesoporous TiO2 NP films for these solar cells are fabricated by annealing TiO2 paste-coated fluorine-doped tin oxide glass in a box furnace at 500 °C for ≈30 min. Here, the use of a nontraditional reactor, i.e., flame, is reported for the high throughput and ultrafast annealing of TiO2 paste (≈1 min). This flame-annealing method, compared to conventional furnace annealing, exhibits three distinct benefits. First, flame removes polymeric binders in the initial TiO2 paste more completely because of its high temperature (≈1000 °C). Second, flame induces strong interconnections between TiO2 nanoparticles without affecting the underlying transparent conducting oxide substrate. Third, the flame-induced carbothermic reduction on the TiO2 surface facilitates charge injection from the dye/perovskite to TiO2 . Consequently, when the flame-annealed mesoporous TiO2 film is used to fabricate DSSCs and PSCs, both exhibit enhanced charge transport and higher power conversion efficiencies than those fabricated using furnace-annealed TiO2 films. Finally, when the ultrafast flame-annealing method is combined with a fast dye-coating method to fabricate DSSC devices, its total fabrication time is reduced from over 3 h to ≈10 min.


Orofacial granulomatosis--a 10 year review.
The granulomatous disorder, termed oro-facial granulomatosis, includes a localised condition affecting the mouth and face as well as the oral manifestations of Crohn's disease and sarcoidosis. The clinical presentation is variable and the apparent increase in the number of patients presenting in recent years probably reflects a greater diagnostic awareness. The aetiology remains to be established but some patients have been found to be intolerent of certain foods, the elimination of which from their diet leads to a resolution of the facial swelling.


The clinical neurology of scrapie in Irish sheep.
One hundred twenty-nine sheep with scrapie were identified from 20 flocks in which scrapie previously had been confirmed. Physical and neurologic examinations were performed on all animals. Videotape recordings were made and reviewed to assess gait. These procedures were repeated in 46 sheep at 2- to 3-week intervals until recumbency or inappetence necessitated euthanasia. Confirmation of scrapie was made by histopathologic and immunohistochemical examinations of brain tissue. The clinical signs most frequently recorded in the 129 animals on initial presentation were hindlimb ataxia (71%), head tremor (61%), altered mental status (57%), positive nibble reflex (51%), crouching posture (51%), teeth grinding (44%), low head carriage (38%), body condition score (BCS) < 1.5 (38%), and conscious proprioceptive deficits of the hindlimbs (36%). Progression of the disease was characterized by an increase in the frequency and severity of ataxia, weakness and hypermetria of the hindlimbs, a decreasing sway response, a decreasing extensor response to thoracolumbar pressure, and a reduction in the BCS. No effect of farm of origin on the clinical presentation could be shown. The presence of a nibble reflex was strongly associated (P < .0005) with prion protein (PrP) genotypes AA136RR154QH171 and AA136RR154QQ171. Logistic regression modeling of groups with associated clinical signs showed that animals with a crouching posture (odds ratio [OR], 20.036) and an abnormal yield to thoracolumbar pressure (OR, 7.117) were at increased risk of ataxia. Pruritus (OR, 0.168) was negatively associated with ataxia. Pruritus (OR, 4.974) and teeth grinding (OR, 4.279) were associated with a positive nibble reflex.


Development of salience-driven and visually-guided eye movement responses.
Development of visuospatial attention can be quantified from infancy onward using visually-guided eye movement responses. We investigated the interaction between eye movement response times and salience in target areas of visual stimuli over age in a cohort of typically developing children. A preferential looking (PL) paradigm consisting of stimuli with six different visual modalities (cartoons, contrast, form, local motion, color, global motion) was combined with the automated measurement of reflexive eye movements. Effective salience was defined as visual salience of each target area relative to its background. Three classes of PL stimuli were used: with high- (cartoon, contrast), intermediate- (local motion, form), and low-effective salience (global motion, color). Eye movement response times to the target areas of the six PL stimuli were nonverbally assessed in 220 children aged 1-12 years. The development of response times with age was influenced by effective salience: Response times to targets with high salience reached stable values earlier in development (around 4 years of age) than to targets with low salience (around 9 years of age). Intra-individual response time variability was highest for low-salient stimuli, and stabilized later (around 4 years) than for highly salient stimuli (2 years). The improvement of eye movement response times to visual modalities in PL stimuli occurred earlier in development for highly salient than for low-salient targets. The present age-dependent and salience-related results provide a quantitative and theoretical framework to assess the development of visuospatial attention, and of related visual processing capacities, in children from 1 year of age.


[Dendritic antigen-presenting cells of the distal section of the female reproductive tract in normal, experimental and in pathological conditions].
Female lower genital tract (the vulva, vagina and uterine cervix) contains a system of dendritic antigen-presenting cells (APCs) which are the main elements of the afferent limb of its local immune system. These cells are found both in mucosal epithelium and lamina propria and possess specific ultrastructural, cytochemical, immunocytochemical and functional properties. Most numerous and well-studied populations of APCs in female lower genital tract are Langerhans cells which are highly sensitive to hormones and noxious factors. This review summarizes recent data on distribution, morphological and functional characteristics of dendritic APCs in female lower genital tract under normal and experimental conditions and in some pathological states (viral infections, preneoplastic and neoplastic processes).


Hydrolysed proteins in preterm formula: influence on plasma aminoacids, blood fatty acids and insulinaemia.
The data from the present investigation differ from those of the previous study. The new version of hydrolysed protein formula did not induce changes in insulinaemia or in the insulinaemia/glycaemia ratio in pre- and postprandial samples when compared with the intact protein formula. The investigation also confirmed that branch chain aminoacids regulate insulin secretion and that the length of chain is insulinotropic for fatty acids, while the degree of unsaturation is not able to reduce insulin secretion in the newborn baby. This could be caused by stimulation of insulin output activated by the C20:5 n 3; the effects of fatty acids are probably related more to the variable composition of cell membrane than to the fatty acids circulating levels.


Lung cancer and exposure to diesel exhaust among bus garage workers.
Mortality and cancer incidence was investigated among the 695 bus garage workers employed as mechanics, servicemen, or hostlers for at least six months in five bus garages in Stockholm between 1945 and 1970. The exposure to diesel exhaust and asbestos was estimated by industrial hygienists. A small excess of lung cancer mortality was found in the cohort when occupationally active men in Stockholm were used as the reference group. A case-referent study was performed within the cohort, six referents being selected for each of the 20 lung cancer cases. The lung cancer risk increased with increasing cumulative exposure to diesel exhaust, but not with cumulative asbestos exposure. The relative risk for lung cancer among the highly exposed men was 2.4 (95% CI 1.3-4.5) as compared with those with low exposure. The study indicates that exposure to diesel exhaust increases the risk for lung cancer.


Uptake of amino beta-lactam antibiotics into rat intestinal brush border membrane vesicles.
Uptake of amino beta-lactam antibiotics into rat intestinal brush border membrane vesicles has been examined for characterization of the transport of the antibiotics through the gut wall of the rat. The uptake of cephradine, cephalexin and ampicillin into membrane vesicles was similar, and there were no significant changes in the uptake in the presence of a NaCl or a KCl gradient. These results suggested that the carrier-mediated transport systems relating to amino acids and glucose were not concerned with the intestinal absorption mechanism of amino beta-lactam antibiotics.


GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo.
(18)F-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances (18)F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo. In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on (18)F-FDG uptake in normal versus inflamed arteries, using PET. Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor-α or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial (18)F-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo (18)F-FDG uptake and macrophage staining (R = 0.75, P < 0.01). GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor-α) and increases (18)F-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states.


Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.
Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.


Watching a movie or listening to music is effective in managing perioperative anxiety and pain: a randomised controlled trial.
Despite the use of perioperative anxiolytics and pain medication, surgery can be a stressful and painful experience. Providing patients with distractions using video and/or audio tools in addition to medication may be helpful. To date, no studies have compared different distraction modalities in a same-day surgical setting in adults. This study aims to determine whether audio-visual distraction with video glasses (AVD) is more effective in reducing anxiety and pain compared to audio distraction (AD) in conscious patients undergoing orthopaedic surgery. It was hypothesised that AVD, being the more immersive modality, would be more effective than AD on the outcome parameters. Fifty patients undergoing orthopaedic surgery with local and/or regional anaesthesia in a clinical day-care setting were randomly assigned to receive either fixed-scenery AVD or patient-choice AD with music. Primary outcome was anxiety, as measured by the Dutch version of the Spielberger State-Trait Anxiety Inventory-6 (STAI-6) prior to and 15 min after the intervention. Secondary outcomes were pain (Numeric Rating Scale Pain [NRS-P]), systolic and diastolic blood pressure, heart rate and patient satisfaction. Within each group, there was a significant reduction in anxiety (p = 0.028 for AVD, p < 0.001 for AD). In contrast to our hypothesis, listening to music without watching a video (AD group) reduced anxiety significantly more than experiencing full AVD (p = 0.018). The mean pain score did not change significantly within either user group, nor did pain scores differ between user groups. In conscious patients undergoing surgery, watching a movie (using video glasses and a headphone set) and listening to music (using only a headphone set) are able to significantly reduce anxiety. AVD, although believed to provide higher levels of distraction, did not prove to be superior to AD. The clinical relevance of this study highlights the potential benefits of AVD or AD modalities in improving the surgical experience for conscious patients. Further research is required to examine the influence of freedom of choice in content on the aforementioned outcomes. To estimate the true value of higher immersion levels, different distraction modalities (e.g. AVD versus virtual reality) featuring the exact same scenery or content need to be compared. Level I.


Bacterial genotoxin functions as immune-modulator and promotes host survival.
Bacterial genotoxins are effectors that cause DNA damage in target cells. Many aspects of the biology of these toxins have been characterised in vitro, such as structure, cellular internalisation pathways and effects on the target cells. However, little is known about their function in vivo. Salmonella enterica serovar Typhi (S. Typhi) is a Gram-negative, intracellular bacterium that causes typhoid fever, a debilitating disease infecting more than 20 million people every year. S. Typhiproduce a genotoxin named typhoid toxin (TT), but its role in the contest of host infection is poorly characterized. The major obstacle in addressing this issue is that S. Typhi is exclusively a human pathogen. To overcome this limitation, we have used as model bacterium S. Typhimurium, and engineered it to produce endogenous levels of an active and inactive typhoid toxin, hereby named as TT (or genotoxic) and cdtB (or control), respectively. To our surprise, infection with the genotoxin strain strongly suppressed intestinal inflammation, leading to a better survival of the host during the acute phase of infection, suggesting typhoid toxin may exert a protective role. The presence of a functional genotoxin was also associated with an increased frequency of asymptomatic carriers.


Clemastine-induced enhancement of hippocampal myelination alleviates memory impairment in mice with chronic pain.
Patients with chronic pain often experience memory impairment, but the underlying mechanisms remain elusive. The myelin sheath is crucial for rapid and accurate action potential conduction, playing a pivotal role in the development of cognitive abilities in the central nervous system. The study reveals that myelin degradation occurs in the hippocampus of chronic constriction injury (CCI) mice, which display both chronic pain and memory impairment. Using fiber photometry, we observed diminished task-related neuronal activity in the hippocampus of CCI mice. Interestingly, the repeated administration with clemastine, which promotes myelination, counteracts the CCI-induced myelin loss and reduced neuronal activity. Notably, clemastine specifically ameliorates the impaired memory without affecting chronic pain in CCI mice. Overall, our findings highlight the significant role of myelin abnormalities in CCI-induced memory impairment, suggesting a potential therapeutic approach for treating memory impairments associated with neuropathic pain.


Update on management of bronchiolitis.
Bronchiolitis impacts millions of infants worldwide. Although several therapeutic options stem from highly plausible theoretical rationales for success and some may even offer modest short-term symptom relief, none has been conclusively shown to alter the course of the disease or its major outcomes. However, several recent papers shed light on which treatments show promising preliminary evidence and offer insight into future research endeavors on this topic. This review will summarize bronchiolitis therapy in view of this recent evidence. The agents in which theory promises but treatment does not deliver include systemic corticosteroids alone, inhaled bronchodilators alone and antileukotrienes. The most promising combination to date appears to be that of oral dexamethasone and inhaled epinephrine but numerous related issues need to be clarified further. Caretakers need to be counselled about the usual protracted clinical course of bronchiolitis. Because bronchiolitis is a highly heterogeneous entity, future research challenges should include detailed characterization of infants most likely to benefit from given interventions. In the meantime, stick with the good old time-honored supportive route!


Dual-feedback mid-infrared cavity-enhanced absorption spectroscopy for H2CO detection using a radio-frequency electrically-modulated interband cascade laser.
A mid-infrared cavity-enhanced sensor system was demonstrated for the detection of formaldehyde (H2CO) using a continuous-wave (cw) interband cascade laser (ICL) centered at 3599 nm. A compact Fabry-Perot (F-P) cavity with a physical size of 38 × 52 × 76 mm3 was developed consisting of two concave mirrors with a radius of curvature of 80 mm and a reflectivity of 99.8% at 3.6 μm. Different from the widely reported electro-optical (EO) external modulation based Pound-Drever-Hall (PDH) locking technique, a radio-frequency electrical internal modulation based PDH technique was used for locking the laser mode to the cavity mode. A dual-feedback control on the laser current and on the piezo transducer (PZT) displacement was utilized for further stabilizing mode locking. A 20 m effective optical path length was achieved with a cavity length of 2 cm and a finesse of 1572. The effectiveness and sensitivity of the sensor system were demonstrated by targeting an absorption line at 2778.5 cm-1 for H2CO measurements. A linear relation between the cavity transmitted signal amplitude and the H2CO concentration was obtained within the range of 0-5 ppm. A 1σ detection limit of 25 parts-per-billion (ppb) was achieved with an averaging time of 1 s based on Allan-Werle variance analysis. The reported dual-feedback RF modulation based PDH technique led to a method for gas detection using a similar experimental setup and measurement scheme.


A new difficult airway management algorithm based upon the El Ganzouri Risk Index and GlideScope® videolaryngoscope. A new look for intubation?
An El Ganzouri risk index test (EGRI) score of seven and the ability to achieve difficult laryngeal exposure with the GlideScope® may represent a highly predictive decisional threshold. Hence, we hypothesized that a new difficult airways algorithm that is EGRI- and GlideScope®-based may enable tracheal intubation in every patient. Thirteen staff practitioners trained in videolaryngoscopic intubation followed the algorithm from 2008 through 2010. Elective and emergency neurosurgical patients assessed as having an EGRI score of seven and higher underwent flexible fiberoptic bronchoscopy (FFB) intubation while conscious. Those with a score of six and lower were intubated with the GlideScope®, excluding patients with morbid obesity or pharyngo-laryngeal or neck tumors. A decision to perform alternative procedures, difficult laryngeal exposure [Cormack and Lehane (CL) grades III-IV], difficult ventilation and failure to intubate were recorded. The decisional rule was applied in 6,276 patients and resulted in six FFB intubations in conscious patients. The overall incidence of CL grade III-IV views was 0.2%. Difficult videolaryngoscopy was found in 14 patients (0.14%) with a score of 6 and lower. Post-hoc examinations of FFB intubations revealed five difficult laryngeal exposures. The positive predictive value was 85.7%, while the negative predictive value was 99.9%. The incidence of difficult ventilation and difficult laryngeal exposure was 0.03%. Two patients with neck tumors were assigned to alternative procedures. Adherence to the decisional process of the algorithm and to GlideScope® videolaryngoscopy achieved successful tracheal intubation in our cohort of patients.


Effect of age on the association between body mass index and all-cause mortality: the Ohsaki cohort study.
To clarify the effect of age on the association between body mass index (BMI) and all-cause mortality. We followed 43 972 Japanese participants aged 40 to 79 years for 12 years. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs), using the following BMI categories: <18.5 (underweight), 18.5-20.9, 21.0-22.9, 23.0-24.9 (reference), 25.0-27.4, 27.5-29.9, and ≥30.0 kg/m(2) (obese). Analyses were stratified by age group: middle-aged (40-64 years) vs elderly (65-79 years). We observed a significantly increased risk of mortality in underweight elderly men: the multivariate HR was 1.26 (0.92-1.73) in middle-aged men and 1.49 (1.26-1.76) in elderly men. In addition, we observed a significantly increased risk of mortality in obese middle-aged men: the multivariate HR was 1.71 (1.17-2.50) in middle-aged men and 1.25 (0.87-1.80) in elderly men. In women, there was an increased risk of mortality irrespective of age group in the underweight: the multivariate HR was 1.46 (0.96-2.22) in middle-aged women and 1.47 (1.19-1.82) in elderly women. There was no excess risk of mortality with age in obese women: the multivariate HR was 1.47 (0.94-2.27) in middle-aged women and 1.26 (0.95-1.68) in elderly women. As compared with the reference category, obesity was associated with a high mortality risk in middle-aged men, whereas underweight, rather than obesity, was associated with a high mortality risk in elderly men. In women, obesity was associated with a high mortality risk during middle age; underweight was associated with a high mortality risk irrespective of age. The mortality risk due to underweight and obesity may be related to sex and age.


[Workers' knowledge and perception regarding noise in the neonatal unit].
The objective of the study was to assess the knowledge and perception of professionals working in a Neonatal Intensive Care Unit (NICU) regarding the repercussions of noise on the neonates, families and workers, prior to the implementation of an educational program. This qualitative descriptive study was conducted in a NICU of a São Paulo hospital with 101 professionals. A questionnaire was used for data collection, and chi-square and Student's t test were used to determine the association between variables. The workers described the NICU as very noisy (44.9%); they noticed the effects of noise during and after their work shift (67.4%) and used strategies to reduce noise. Despite not being familiar with legislation regarding noise in the hospital, the workers identify its repercussions on themselves, the neonates and families. Results indicate the need to teach the staff about legislation and noise prevention, as well as reorganize healthcare practices and Neonatal Intensive Care Unit facilities.


Living and training in a tropical environment: a challenge for aerobic exercise applied knowledge and perspectives.
The tropical climate is unique in that the seasons are dominated by the movement of the tropical rain belt, resulting in dry and wet seasons rather than the four-seasonal pattern of changes in temperature and day length seen in other parts of the world. Humid tropics are characterized by consistently high monthly temperatures, often exceeding 18 degrees C throughout the year; and rainfall that exceeds evapotranspiration for at least 270 days per year Although considerable information has been gathered on the physiological adaptation to hot/dry climates, data on acclimation to hot/humid climates are still limited. This review focusses on the effects of the tropical environment on human exercise performance through studies performed in the Caribbean, with a special emphasis on prolonged aerobic exercise such as swimming, cycling and running.


The Coronavirus Pandemic and Lessons Learned in Preschools in Norway, Sweden and the United States: OMEP Policy Forum.
The novel coronavirus, also known as COVID-19, has moved rapidly across the world in 2020. This article reports on the recent consequences of the pandemic for early childhood education in Sweden, Norway, and the United States. The authors illustrate the effects of the pandemic on preschools in their countries, against a backdrop of frequent changes in infection and mortality rates, epidemiological understandings, government strategies, and mitigation strategies regarding preschool closures. Teachers report their experiences and actions in specific early childhood education settings, across the three national contexts. These experiential snapshots identify program priorities, parents' and children's reactions, and the commitment and concerns of teachers. The conversations reveal culturally situated similarities of early childhood educational practices but also differences across contexts. Teachers report on the challenges of their experiences but also benefits for their practice and how they engage with children and their families. Ideas about future preparedness for such pandemics are also discussed.


[Possibilities of boron neutron capture therapy in the treatment of malignant brain tumors].
Boron neutron capture therapy (BNCT) that is of the highest attractiveness due to its selective action directly on malignant tumor cells is a promising approach to treating cancers. Clinical interest in BNCT focuses in neuro-oncology on therapy for gliomas, glioblastoma in particular, and BNCT may be used in brain metastatic involvement. This needs an epithermal neutron source that complies with the requirements for BNCT, as well as a 10B-containing agent that will selectively accumulate in tumor tissue. The introduction of BNCT into clinical practice to treat patients with glial tumors will be able to enhance therapeutic efficiency.


Comparative punting kinematics and pelvic fin musculature of benthic batoids.
Although the majority of batoid elasmobranchs, skates and rays, are benthically associated, benthic locomotion has been largely overlooked in this group. Only skates have been previously described to perform a form of benthic locomotion termed "punting." While keeping the rest of the body motionless, the skate's pelvic fins are planted into the substrate and then retracted caudally, which thrusts the body forward. In this study, we demonstrate that this form of locomotion is not confined to the skates, but is found across a range of phylogenetically and morphologically diverse batoid species. However, only the clearnose skate, Raja eglanteria, and the lesser electric ray, Narcine brasiliensis, performed "true punting," in which only the pelvic fins were engaged. The yellow stingray, Urobatis jamaicensis, and the Atlantic stingray, Dasyatis sabina, performed "augmented punting," in which pectoral fin movement was also used to generate thrust. Despite this supplemental use of pectoral fins, the augmented punters failed to exceed the punting capabilities of the true punters. The urobatid and the true punters all punted approximately half their disc length per punt, whereas the dasyatid punted a significantly shorter distance. The skate punted significantly faster than the other species. Examination of the pelvic fin musculature revealed more specialized muscles in the true punters than in the augmented punters. This concordance of musculature with punting ability provides predictive power regarding the punting kinematics of other elasmobranchs based upon gross muscular examinations. In contrast to previous assumptions, our results suggest that benthic locomotion is widespread among batoids.


Evidence for a primary autoimmune type of diabetes mellitus.
Sixty-eight patients with longstanding diabetes and persistent islet-cell antibody and 35 with coexistent diabetes and Graves's disease or primary myxoedema were studied with particular reference to the HLA system and autoantibody patterns. A higher incidence of HLA-B8 than normal was observed in the two groups. An additive relative risk exists when type I diabetes and autoimmune thyroid disease coexist, indicating that different HLA-linked genes may confer susceptibility to the pancreatic and thyroid disorders. Other characteristics, including female predominance, a later onset of diabetes, and a strong family history of autoimmune endocrinopathy, provide further evidence that this form of diabetes is aetiologically distinct from that generally seen in children. These results support the hypothesis of a primary autoimmune type of diabetes mellitus.


p38 MAP kinase inhibitors as anti inflammatory agents.
The p38 Mitogen-Activated Protein (MAP) kinase, a serine/threonine kinase, is one of the best characterized kinases in the inflammatory process. Among the four identified p38 isoforms (p38α, p38β, p38γ, and p38δ), the α-form is the most fully studied and plays a central role in the biosynthesis of the proinflammatory cytokines i.e. IL-1β and TNF-α at the translational and transcriptional levels. Antagonism of these proinflammatory cytokines has been recognized as an effective possibility for the development of new drug candidates. The characterization of the pharmacological profile displayed by the selective p38 inhibitor prototype SB203580, proved its disease-modifying activity in the adjuvantinduced arthritis model. This strongly suggests that adequate modulation of production of these cytokines can bring significant benefits to the therapy of chronic inflammatory diseases. In addition to its important role for the secretion of proinflammatory cytokines, p38 is also involved in the activation of matrix metalloproteinases and the induction of COX- 2 transcription, proteins that are involved in the process of tissue destruction and inflammation. Because of its multiple functions in modulating the inflammatory response, it is expected that p38 inhibiting drugs will treat the underlying cause of chronic inflammatory diseases and stop their progression. The archetypal small molecule p38 inhibitors are the pyridinylimidazoles and these structures formed the basis for much of the early research. More recently a number of nonimidazole based p38 inhibitors such as the ureas, pyrazoles, pyrazoloheteroaryls, pyridazines, indoles, amides, pyridines, triazolopyridines, etc containing a variety of functionality have been reported to inhibit cytokine activity. This article provides a critical account of these different heterocycles reported for p38 MAPK inhibition and covers the recent research in the development of anti inflammatory agents.


Chronic hepatitis E in liver transplant recipients: a significant clinical problem?
Hepatitis E is an inflammatory liver disease caused by infection with the hepatitis E virus (HEV). Five different HEV genotypes have been described. While HEV genotypes 1 and 2 primarily infect man, genotypes 3 and 4 have been detected both in humans and several animal species including pigs. HEV genotype 1 and 2 infections are frequent in Southern Asia and Africa. However, Hepatitis E is more and more considered as an re-emerging zoonotic disease also in industrialized countries as HEV genotype 3 infections seem to increase in Western Europe and North America. Acute hepatitis E usually takes an acute self limited course but may take a fulminant course in particular in pregnant women and patients with pre-existing chronic liver disease. Several cases of persistent HEV-infection have been reported in immunosuppressed patients during the last three years being associated with progressive liver disease in some patients. Thus, screening for HEV RNA should be part of the diagnostic work-up of elevated liver transaminases in organ transplantation recipients or HIV-infected individuals. In this review we summarize the recent data on hepatitis E with a particular focus on the importance of persistent HEV infections in liver transplant recipients.


Human muscular dystrophy: elevation of urinary dimethylarginines.
The amounts of the dimethylarginines NG,NG-dimethylarginine (DMA) and NG,N'G-dimethylarginine (DM'A) excreted in the urine of muscular dystrophic patients were examined and compared with the amounts excreted by normal controls, patients with other types of neuromuscular diseases, and patients with disuse muscle atrophy resulting from traumatic paralysis. The patients with muscular dystrophy excreted high concentrations of DMA and this urine showed high ratios of DMA to DM'A. This finding indicates a relation between protein methylation processes and muscular dystrophy.


A cost-effectiveness analysis of aspirin versus oral anticoagulants after acute myocardial infarction in Italy -- equivalence of costs as a possible case for oral anticoagulants.
The recent publication of two large trials of secondary prevention of coronary artery disease with oral anticoagulants (WARIS and ASPECT) has caused a revival of the interest for this antithrombotic therapy in a clinical setting where the use of aspirin is common medical practice. Despite this, the preferential use of aspirin has been supported by an American cost-effectiveness analysis (JAMA 1995; 273: 965). Using the same parameters used in that analysis and incidence of events from the Antiplatelet Trialists Collaboration and the ASPECT study, we re-evaluated the economic odds in favor of aspirin or oral anticoagulants in the Italian Health System, which differs significantly in cost allocation from the United States system and is, conversely, similar to other European settings. Recalculated costs associated with each therapy were 2,150 ECU/ patient/year for oral anticoagulants and 2,187 ECU/patient/year for aspirin. In our analysis, the higher costs of oral anticoagulants versus aspirin due to a moderate excess of bleeding (about 10 ECU/ patient/year) and the monitoring of therapy (168 ECU/ patient/year) are more than offset by an alleged savings for recurrent ischemic syndromes and interventional procedures (249 ECU/ patient/year). Preference of aspirin vs. oral anticoagulants in a pharmaco-economical perspective is highly dependent on the geographical situation whereupon calculations are based. On a pure cost-effectiveness basis, and in the absence of data of direct comparisons between aspirin alone versus I.N.R.-adjusted oral anticoagulants, the latter are not more expensive than aspirin in Italy and, by cost comparisons, in other European countries in the setting of post-myocardial infarction.


Intravenous fluid therapy and hospital outcomes for vaso-occlusive episodes in children, adolescents, and young adults with sickle cell disease.
While intravenous fluid (IVF) therapy in patients with sickle cell disease (SCD) admitted for a vaso-occlusive episode (VOE) can help reduce red blood cell sickling, clinical practice varies across institutions. We examined the relationship between IVF therapy and hospital length of stay (HLOS), as well as adverse events, such as acute chest syndrome (ACS), pediatric intensive care unit (PICU) transfer, and 28-day re-admission. This is a single-center retrospective analysis of SCD VOE hospitalizations between January 2015 and April 2020. Patients with SCD, age 0-30, with consecutive hospitalizations for VOE were included. For the first 3 days of each admission, an "IVF ratio" was calculated by dividing actual IVF rate administered by weight-based maintenance IVF (mIVF) rate. A total of 617 hospitalizations for 161 patients were included. Mean HLOS was 5.7 days, (SD 3.9), and mean IVF volume over the first 3 days of admission was 139.6 mL/kg/day (SD 57.8). Multivariate analysis showed that for each additional 0.5 times the mIVF rate, HLOS increased by 0.53 day (p < .001; 95% confidence interval [CI]: 0.609-0.989), but there was no significant association between IVF therapy and adverse events. History of chronic pain was associated with increased odds of re-admission (OR 6.4; 95% CI: 3.93-10.52). Despite the theoretical potential for IVF therapy to slow down the sickling process, our findings suggest that increased IVF therapy was associated with prolonged HLOS, which places a burden on patients, families, and the health system.


Ultraviolet radiation exposure and risk of non-Hodgkin's lymphoma.
Sun exposure has been suggested to increase the risk of non-Hodgkin's lymphoma. The authors analyzed data from a population-based, case-control study of Connecticut women between 1996 and 2000 to study the hypothesis. Women who reported having had a suntan experienced an increased risk of non-Hodgkin's lymphoma with increasing duration (p(trend) = 0.0062) compared with women who reported never having had a suntan. An almost threefold increased risk of non-Hodgkin's lymphoma was observed among women who reported having had a suntan for less than 3 months per year and a suntan history of more than 60 years (odds ratio = 2.8, 95% confidence interval: 1.6, 4.9) compared with those who reported never having had a suntan. For women who reported having spent time in strong sunlight between 9 a.m. and 3 p.m. during the summer, a 70% increased risk of non-Hodgkin's lymphoma was observed for the highest tertile of duration compared with the lowest (odds ratio = 1.7, 95% confidence interval: 1.2, 2.4). The risk increased with increasing duration of time spent in strong sunlight in summer (p(trend) = 0.0051). The risk appears to vary by non-Hodgkin's lymphoma subtypes. Further investigations of the role of ultraviolet radiation on the risk of non-Hodgkin's lymphoma are warranted.


Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease.
Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative activity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology.


Update on use of chloroquine/hydroxychloroquine to treat coronavirus disease 2019 (COVID-19).
Drugs that are specifically efficacious against SARS-CoV-2 have yet to be established. Chloroquine and hydroxychloroquine have garnered considerable attention for their potential to treat coronavirus disease 2019 (COVID-19). Increasing evidence obtained from completed clinical studies indicates the prospects for chloroquine/hydroxychloroquine to treat COVID-19. More randomized control clinical studies are warranted to determine the feasibility of these two drugs in treating COVID-19.


[Candida albicans sensitization in patients with atopic bronchial asthma and atopic dermatitis].
Candida albicans, a component of normal human microflora, can induce synthesis of specific IgE-antibodies in patients with atopic bronchial asthma and atopic dermatitis. The study included 25 patients with atopic dermatitis sensitized to C.albicans and 23 patients with atopic dermatitis non-sensitized to C.albicans. The sensitization was determined by the skin test and enzyme immunoassay. The patients had the history of atopic dermatitis exacerbation after taking food containing baking yeasts. Atopic dermatitis with sensitization to C.albicans is characterized by severe course correlating with the following indices: high total IgE (r = 0.6), level of IgE antibodies to C.albicans (r = 0.6), level of serum IgG (r = 0.46) and IgA (r = 0.33). Contrary to adults, children with sensitization to C.albicans had decreased relative number of CD4+, CD8+ and CD72+ of lymphocyte subpopulations. Thus, sensitization to C.albicans manifests in severe atopic dermatitis which in children is often associated with immune deficiency.


Comment on 'Health aspects of cannabis: revisited' (Hollister).
Dr. Leo Hollister's excellent article begins to address the need for better understanding of the effects of cannabis use on health. The last five years in the US have seen an increase in advocacy groups extolling the medicinal utility of cannabis. On 5 November 1996, this culminated in California (proposition 215) joining the list of states permitting the limited use of cannabis for the medicinal treatment of disorders including intractable pain, glaucoma, nausea induced by chemotherapy for cancer or by AZT or Foscavir for the treatment of AIDS, and for spasticity associated with multiple sclerosis (Burstein, 1997; West and Homi, 1996; Grinspoon and Bakalar, 1995; Nahas and Manger, 1995). Of these potential uses for cannabis, the evidence for the treatment of nausea and the stimulation of appetite in cachetic patients appears most promising (for a review see Voth and Schwartz, 1997). Yet not only do doubts remain about the effectiveness of cannabis for the treatment of these conditions, since definitive controlled clinical studies are typically lacking (Voelker, 1997), but there is concern that any therapeutic advantage is more than offset by its harmful effects. Within this context of increased medical sanction for the use of cannabis in specific disease states for which it may have therapeutic potential, evaluating its risks vs. benefits profile is essential to rational prescribing. In addition, evaluating the public health risks associated with reports of increased risks of cannabis use (Robertson et al., Poulton et al., 1997), is of concern to advocates of its widespread legalization, governmental agencies attempting to limit its promulgation, and to planners and providers of health care charged with providing treatment for its consequences.


Chickens with humanized immunoglobulin genes generate antibodies with high affinity and broad epitope coverage to conserved targets.
Transgenic animal platforms for the discovery of human monoclonal antibodies have been developed in mice, rats, rabbits and cows. The immune response to human proteins is limited in these animals by their tolerance to mammalian-conserved epitopes. To expand the range of epitopes that are accessible, we have chosen an animal host that is less phylogenetically related to humans. Specifically, we generated transgenic chickens expressing antibodies from immunoglobulin heavy and light chain loci containing human variable regions and chicken constant regions. From these birds, paired human light and heavy chain variable regions are recovered and cloned as fully human recombinant antibodies. The human antibody-expressing chickens exhibit normal B cell development and raise immune responses to conserved human proteins that are not immunogenic in mice. Fully human monoclonal antibodies can be recovered with sub-nanomolar affinities. Binning data of antibodies to a human protein show epitope coverage similar to wild type chickens, which we previously showed is broader than that produced from rodent immunizations.


Ixodes scapularis salivary gland microRNAs are differentially expressed during Powassan virus transmission.
Successful tick feeding is facilitated by an assortment of pharmacologically-active factors in tick saliva that create an immunologically privileged micro-environment in the host's skin. Through a process known as saliva-assisted transmission, bioactive tick salivary factors modulate the host environment, promoting transmission and establishment of a tick-borne pathogen. This phenomenon was previously demonstrated for Powassan virus (POWV), a North American tick-borne flavivirus that is the causative agent of a severe neuroinvasive disease in humans. Here, we sought to characterize the Ixodes scapularis salivary gland microRNAs (miRNAs) expressed during the earliest period of POWV transmission to a mammalian host. POWV-infected and uninfected I. scapularis females were fed on naïve mice for 1, 3, and 6 hours, and Illumina next generation sequencing was used to characterize the salivary gland miRNA expression profiles of POWV-infected versus uninfected ticks. 379 salivary miRNAs were detected, of which 338 are reported here as putative novel I. scapularis miRNAs. 35 salivary gland miRNAs were significantly up-regulated and 17 miRNAs were significantly down-regulated in response to POWV infection. To investigate the potential role of salivary gland miRNAs in POWV replication in-vitro, we transfected miRNA inhibitors into VeroE6 cells to profile temporal POWV replication in mammalian cells. Together, the small RNA sequencing data and the in vitro miRNA inhibition assay suggest that the differentially expressed tick salivary miRNAs could act in regulating POWV replication in host tissues.


Immunobiology and gene-based immunotherapy of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide. For most patients with advanced or multifocal HCC treatment options are limited resulting in a poor prognosis. Several local ablation methods have been developed as minimally invasive strategies for HCC treatment. It is unclear, until now, whether these therapies will significantly improve the poor prognosis of patients with unresectable HCC. Novel therapeutic strategies and a better understanding of HCC imunobiology are, therefore, urgently required. The scientific literature since 1970 in all languages cited in Medline was systematically reviewed. Until now, a variety of specific and non-specific immunostimulatory strategies against HCC has been applied in preclinical experimental models with some promising results. The molecular characterization of HCC associated tumour antigens such as alpha-fetoprotein (AFP) and the increased understanding of the immunological pathways involved in liver and tumor immunology have paved the way for the design of promising gene-based cancer vaccines. The first phase I and II immunotherapeutic clinical trials based on dendritic cell immunotherapy and peptide vaccines are ongoing in HCC-patients. Clinical trials have, in general, demonstrated the safety of such strategies. Recently, exciting new immunological techniques and tools have been developed which allow to characterize antigen specific T cells at a single-cell level. In future, HCC specific tumor rejection antigens which can be used therapeutically have to be identified using microarray-based analysis. The different therapeutic modalities need to be compared directly resulting in optimised therapeutic approaches and the identification of sub-groups of HCC-patients responding favourably to treatment.


Ternary hybrid systems of P3HT-CdSe-WS₂ nanotubes for photovoltaic applications.
Hybrid heterojunctions of conjugated polymers and inorganic nanomaterials are a promising combination for obtaining high performance solar cells (SC). In this work we have explored new possible uses of the WS2 nanotubes (NTs) both as the only acceptor material blended with a polymer and in ternary systems mixed with a polymer and quantum dots (QDs). In particular we have spectroscopically investigated binary blends of poly(3-hexylthiophene) (P3HT) and WS2 NTs, P3HT and CdSe QDs, and ternary blends of P3HT, CdSe QDs and WS2 NTs. We report fluorescence quenching effects of the QD signal in the P3HT-CdSe-WS2 system with the increase of NT concentration. Static and time-resolved fluorescence studies reveal efficient resonant energy transfer from the QDs to the NTs upon photoexcitation. The evidence of energetic interaction between WS2 NTs and QDs opens new fields of application of WS2 NTs and holds very promising potential for improving charge transfer phenomena in the active layer of hybrid solar cells.


Intravenous Administration of Standard Dose Tirofiban after Mechanical Arterial Recanalization is Safe and Relatively Effective in Acute Ischemic Stroke.
To investigate the safety and efficacy of intravenous administration of a standard dose of glycoprotein-IIb/IIIa inhibitor tirofiban after vessel recanalization by mechanical thrombectomy in acute ischemic stroke. A consecutive series of patients (n=112) undergoing endovascular ischemic stroke intervention therapy were enrolled. 81 patients were eligible for intravenous (IV) tirofiban treatment for 24 hours after mechanical thrombectomy. The incidence of symptomatic intracranial hemorrhage (sICH), death, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) were assessed. In the 81 patients receiving tirofiban, 52 patients (64.2%) were treated with IV rt-PA before mechanical thrombectomy. sICH was found in 2 (2.5%) patients with no fatal ICH. Four patients died during 3 months after stroke onset. Successful recanalization with thrombolysis in cerebral infarction (TICI) score ≥2b was achieved in 75 of 81 patients (92.6%) after mechanical thrombectomy. The average number of passes with Solitaire stent retriever was 1.3. At 3 months, 55 of 81 patients (67.9%) had favorable outcomes (mRS<=2). The intravenous application of a standard dose of tirofiban post-Solitaire stent retriever thrombectomy and intravenous thrombolysis appears to be safe and relatively effective in acute ischemic stroke.


Desmopressin is an effective treatment for mixed nocturia with nocturnal polyuria and decreased nocturnal bladder capacity.
To investigate the efficacy and safety of desmopressin in patients with mixed nocturia, Patients aged ≥ 18 yr with mixed nocturia (≥ 2 voids/night and a nocturnal polyuria index [NPi] >33% and a nocturnal bladder capacity index [NBCi] >1) were recruited. The optimum dose of oral desmopressin was determined during a 3-week dose-titration period and the determined dose was maintained for 4 weeks. The efficacy was assessed by the frequency-volume charts and the sleep questionnaire. The primary endpoint was the proportion of patients with a 50% or greater reduction in the number of nocturnal voids (NV) compared with baseline. Among 103 patients enrolled, 94 (79 men and 15 women) were included in the analysis. The proportion of patients with a 50% or greater reduction in NV was 68 (72%). The mean number of NV decreased significantly (3.20 to 1.34) and the mean nocturnal urine volume, nocturia index, NPi, and NBCi decreased significantly. The mean duration of sleep until the first NV was prolonged from 118.4 ± 44.1 to 220.3 ± 90.7 min (P<0.001). The overall impression of patients about their quality of sleep improved. Adverse events occurred in 6 patients, including one asymptomatic hyponatremia. Desmopressin is an effective and well-tolerated treatment for mixed nocturia.