Bone mineral acquisition during adolescence and early adulthood: a study in 574 healthy females 10-24 years of age.
Low bone mass is known to be associated with an increased risk of fractures. Osteoporosis prevention by maximizing bone mass will be crucial and requires a better knowledge of bone mass acquisition during adolescence. Bone mass was assessed in 574 healthy volunteer females aged 10-24 years. Spine bone mineral density (BMD) in anteroposterior (AP L2-4) and lateral (LAT L3) views was measured using dual-energy X-ray absorptiometry (DXA) and AP bone mineral content (BMC) was calculated. At the same time, spine AP-BMD (L2-4) was evaluated in 333 normal menstruating women, aged 27-47 years. Bone values, osteocalcin and IGF-1 serum concentrations were correlated with chronological age, skeletal age, pubertal stages and time after menarche. In this cross-sectional study, AP- and LAT-BMD and BMC increased dramatically between skeletal ages 10 and 14 or until the first year after menarche. Between 14 and 17 skeletal years of age, AP-BMD and BMC increased moderately, whereas LAT-BMD remained unchanged. After skeletal age 17, or the fourth year after menarche, there was no significant increase in BMD or BMC, and their values did not differ from those of menstruating women. A serum osteocalcin peak was observed at skeletal ages 11-12 or at stage P3, whereas IGF-1 peaked at 13-14 skeletal years of age or at P4 and the first year after menarche. Eighty-six per cent of the adult bone mass of the spine is acquired before skeletal age 14 or the second year after menarche; therefore osteoporosis prevention programs will be particularly effective before that age.


Gender differences in in-hospital clinical outcomes after percutaneous coronary interventions: an insight from a Japanese multicenter registry.
Gender differences in clinical outcomes after percutaneous coronary intervention (PCI) among different age groups are controversial in the era of drug-eluting stents, especially among the Asian population who are at higher risk for bleeding complications. We analyzed data from 10,220 patients who underwent PCI procedures performed at 14 Japanese hospitals from September 2008 to April 2013. A total of 2,106 (20.6%) patients were women. Women were older (72.7±9.7 vs 66.6±10.8 years, p<0.001), and had a lower body mass index (23.4±4.0 vs 24.3±3.5, p<0.001), with a higher prevalence of hypertension (p<0.001), hyperlipidemia (p<0.001), insulin-dependent diabetes (p<0.001), renal failure (p<0.001), and heart failure (p<0.001) compared with men. Men tended to have more bifurcation lesions (p = 0.003) and chronic totally occluded lesions (p<0.001) than women. Crude overall complications (14.8% vs 9.5%, p<0.001) and the rate of bleeding complications (5.3% vs 2.8%, p<0.001) were significantly higher in women than in men. On multivariate analysis in the total cohort, female sex was an independent predictor of overall complications (OR, 1.47; 95% CI, 1.26-1.71; p<0.001) and bleeding complications (OR, 1.74; 95% CI, 1.36-2.24; p<0.001) after adjustment for confounding variables. A similar trend was observed across the middle-aged group (≥55 and <75 years) and old age group (≥75 years). Women are at higher risk than men for post-procedural complications after PCI, regardless of age.


Clinical evaluation of sodium fluoride chewable tablets in dental caries.
Chewable tablets containing low dosage fluoride content were prepared using two varieties of celluloses and their in vitro parameters were evaluated. An eighteen month clinical trial revealed that both these formulations were effective in controlling the caries. However, ethyl cellulose is proved to be superior to methylcellulose as a controlled release matrix material in controlling caries. Thus this study recommends ethylcellulose matrix tablets containing low fluoride content is an efficacious and cost effective drug device in controlling dental caries.


Changes in Resident Well-Being at One Institution Across a Decade of Progressive Work Hours Limitations.
To measure changes in markers of resident well-being over time as progressive work hours limitations (WHLs) were enforced, and to investigate resident perceptions of the 2011 WHLs. A survey study of internal medicine residents was conducted at the University of Washington's multihospital residency program in 2012. The survey included validated well-being questions: the Maslach Burnout Inventory, the two-question PRIME-MD depression screen, and career satisfaction questions. Chi-square tests were used to compare 2012 well-being questionnaire responses against nearly identical surveys conducted in 2001 and 2004 at the same institution. In addition, residents were asked to rate the impact of WHLs on resident well-being and education as well as patient care, and to state preferences for future WHLs. Significantly different proportions of residents met burnout criteria across time, with fewer meeting criteria in 2012 than in 2001 (2001: 76% [87/115]; 2004: 64% [75/118]; 2012: 61% [68/112]; P = .039). Depression screening results also differed across time, with fewer screening positive in 2012 than in 2004 (2001: 45% [52/115]; 2004: 55% [65/118]; 2012 [35/112]: 31%; P = .001). Residents, especially seniors, reported perceived negative impacts of WHLs on their well-being, education, and patient care. Most senior residents favored reverting to the pre-July 2011 system of WHLs. Interns were more divided. Validated measures of resident well-being changed across the three time points measured. Residents had the lowest rates of burnout and depression in 2012. Resident perceptions of the 2011 WHLs, however, were generally negative.


[The use of esophageal anastomoses with "shape memory"].
Two ways of gastrointestinal reconstruction after gastrectomy are presented. The "shape memory" implant (SMI) and compression circular anastomotic device (CCAD) with interchangeable heads are used. The compression effect in CCAD is determined by the use of titanium nickelide, possessing the "shape memory" effect. The leak of esophagointestinal anastomosis, formed with the use of SMI, occurred in 4 (5,4%) of 73 patients. There were no complications in 32 esophagointestinal anastomoses, formed with the CCAD use. No leakage was registered in 105 intestinal anastomoses formed with the use of SMI. Thus, implant and anastomotic device, based on titanium nickelide are simple, handy and reliable in use.


Topical application of royal jelly has a healing effect for 5-fluorouracil-induced experimental oral mucositis in hamsters.
The aim of this study was to evaluate the effects of bee products such as honey, royal jelly and propolis on 5-fluorouracil-induced experimental oral mucositis in hamsters. Oral mucositis was induced in hamsters through a combination of 5-fluorouracil and mild abrasions that were made on the cheek pouch. Honey, royal jelly and propolis were thereafter topically administered to the oral mucosa, and then the healing process was examined by measuring the size of the mucositis. Honey (1%, 10% and 100%) and propolis (0.3%, 1% and 3%) ointments did not reduce the size of the mucositis in comparison to the vaseline-treated control group. However, the royal jelly (3%, 10% and 30%) ointments significantly improved the recovery from 5-fluorouracil-induced damage in a dose-dependent manner. These results suggest the possibility that the topical application of royal jelly has a healing effect on severe oral mucositis induced by chemotherapy.


Vulnerability and hydraulic segmentations at the stem-leaf transition: coordination across Neotropical trees.
Hydraulic segmentation at the stem-leaf transition predicts higher hydraulic resistance in leaves than in stems. Vulnerability segmentation, however, predicts lower embolism resistance in leaves. Both mechanisms should theoretically favour runaway embolism in leaves to preserve expensive organs such as stems, and should be tested for any potential coordination. We investigated the theoretical leaf-specific conductivity based on an anatomical approach to quantify the degree of hydraulic segmentation across 21 tropical rainforest tree species. Xylem resistance to embolism in stems (flow-centrifugation technique) and leaves (optical visualization method) was quantified to assess vulnerability segmentation. We found a pervasive hydraulic segmentation across species, but with a strong variability in the degree of segmentation. Despite a clear continuum in the degree of vulnerability segmentation, eight species showed a positive vulnerability segmentation (leaves less resistant to embolism than stems), whereas the remaining species studied exhibited a negative or no vulnerability segmentation. The degree of vulnerability segmentation was positively related to the degree of hydraulic segmentation, such that segmented species promote both mechanisms to hydraulically decouple leaf xylem from stem xylem. To what extent hydraulic and vulnerability segmentation determine drought resistance requires further integration of the leaf-stem transition at the whole-plant level, including both xylem and outer xylem tissue.


Soluble (pro)renin receptor in elderly chronic heart failure patients.
Overactivation of renin-angiotensin system (RAS) is one of the main pathophysiological features in the evolution of chronic heart failure (CHF). The (pro)renin receptor ((P)RR) represents an important player in a tissue renin-angiotensin system (tissue RAS), which mediates tissue injury through fibrosis and hypertrophy of the affected organs in CHF patients. In our study we used plasma samples from 556 elderly subjects with CHF and 198 healthy participants in order to evaluate prognostic and diagnostic potential of s(P)RR in setting of CHF. The patients with CHF showed significantly higher plasma levels of s(P)RR than the healthy volunteers (p=0.0005). We observed association between higher s(P)RR plasma concentrations and lower left ventricular ejection fraction and higher degree of left ventricular dilatation on baseline echocardiography examination of the CHF patients. Elderly CHF patients with higher baseline s(P)RR plasma concentration were at same risk for death, stroke and hospitalization due to heart failure worsening at mean follow-up from forty-eight months in comparison to low s(P)RR counterparts.


Anticipatory Grief: A Mere Concept?
Anticipatory grief (AG) has been studied, debated, and written about for several decades. This type of grief is also recognized in hospice and palliative care (HPC). The question, however, is whether the reality of AG is sufficiently upheld by professionals at the point of concrete service delivery. In other words, is AG a mere concept or is everyday practice of HPC duly informed of AG as evidenced by the resulting care delivery?


Fuels and pathways as designed systems for support of muscle work.
Muscle in all animals relies upon four potential sources of energy: ATP hydrolysis, phosphagen hydrolysis, fermentations or oxidative metabolism. Although the relative contributions of different fuels varies greatly in different organisms, in none is there a simple reliance on stored ATP. Muscle work therefore requires a balance between rates of utilization and formation of ATP, a provision supplied by one of the three remaining fuels and metabolic pathways. Useful endogenous fuels must be storable at high level, and rapidly mobilizable with minimal perturbation of [ATP] and with minimal end-product effects on pH, charge or osmotic balance. In addition to displaying these properties, good exogenous fuels must be transferable at high rates between depot sites and muscle; actual flux rates of exogenous fuels depend upon respective ATP yields and are lowest for fuels which most amplify the yield of ATP per mol substrate oxidized. Substrate flux rates must be matched with O2 flux rates and with rates of endogenous substrate mobilization in order that the right energy-yielding pathways are activated at the right times. Of various control possibilities, an effective competition for ADP (and possibly Pi) seems at this time to be the dominant strategy for assuring integration of aerobic and anaerobic ATP-yielding pathways.


Circulating microRNAs as clinical biomarkers in the predictions of pregnancy complications.
Predicting pregnancy complications is a major topic for clinicians and biologists for maternal and fetal monitoring. Noninvasive biomarkers in maternal blood such as circulating microRNAs (miRNAs) are promising molecules to predict pregnancy disorders. miRNAs are noncoding short RNAs that regulate mRNA expression by repressing the translation or cleaving the transcript. miRNAs are released to the extracellular systemic circulation via exosomes. The discovery of plasma- or serum-derived miRNAs and of free-circulating exosomes that contain miRNAs provides useful information about the physiological or pathophysiological roles of the miRNAs. Specific placental miRNAs are present in maternal plasma in different ways depending on whether the pregnancy is normal or pathological or if there is no pregnancy. This paper focuses on placental miRNAs and extracellular miRNAs to the placenta whose misregulation could lead to pregnancy complications.


First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline.
Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.


Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms.
Therapeutic hypothermia improves neurologic outcomes in patients resuscitated from cardiac arrest due to ventricular fibrillation. However, its role in patients with cardiac arrest due to non-shockable rhythms (pulseless electrical activity (PEA) and asystole) is unclear. We hypothesized that therapeutic hypothermia favorably impacts neurologic outcome and survival in patients resuscitated from cardiac arrest due to non-shockable rhythms. Retrospectively collected data on consecutive adult patients admitted to Hartford Hospital from 1/1/2004 to 11/1/2010 who survived a cardiac arrest due to PEA or asystole were analyzed. Patients who underwent therapeutic hypothermia (1/1/2007-11/1/2010) formed the hypothermia group while patients admitted prior to the institution of therapeutic hypothermia (1/1/2004-1/1/2007) at Hartford Hospital formed the control group. The primary end-point was measured using the Pittsburgh cerebral performance category (CPC) scale and patients were assessed for a good (CPC 1 and 2) or poor (CPC 3-5) neurological outcome prior to discharge from hospital. A secondary end-point was measured as survival at discharge from hospital. Of 100 post-cardiac arrest patients included in the study, 15/52 (29%) patients in the hypothermia group had a good neurologic outcome as compared to 5/43 (10%) patients in the control group (P=0.021). On multivariate analysis, the odds ratio for good neurologic outcome and survival at discharge from the hospital with therapeutic hypothermia as compared to control were 4.35 (95% CI 1.10-17.24, P=0.04) and 5.65 (CI 1.66-19.23, P=0.006) respectively. Therapeutic hypothermia is associated with favorable neurologic outcome and survival in patients resuscitated after cardiac arrest due to non-shockable rhythms.


Association between Life's simple 7 and rheumatoid arthritis in adult Americans: data from the National Health and nutrition examination survey.
The study aimed to investigate the relationship between Life's Simple 7 (LS7) and the risk of rheumatoid arthritis (RA) in adult Americans. A total of 17,532 participants were included in this study. The association between LS7 and the risk of RA was assessed using a weighted logistic regression model, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated. Moreover, the nonlinear relationship was further characterized through smooth curve fitting (SCF) and weighted generalized additive model (GAM) analysis. After adjusting for all covariates, the weighted logistic regression model demonstrated that the LS7 was negatively correlated with the risk of RA. Compared to quintile 1 of LS7, the OR between the risk of RA and quartile 4 of LS7 (LS7.Q4) was 0.261 (95% CI, 0.203, 0.337) in males under 50 years old, while in females of the same age group, the OR was 0.183 (95% CI, 0.142, 0.234). For females aged between 50 and 70 years old, the OR between the risk of RA and LS7.Q4 was 0.313 (95% CI, 0.264, 0.371). In females aged 70 years or older, the OR between the risk of RA and LS7.Q4 was 0.632 (95% CI, 0.486, 0.822). This finding suggested the healthy lifestyle behaviors represented by LS7 have a negative association with RA. However, further prospective studies are needed to verify the causal relationship in the results.


Estimating initial epidemic growth rates.
The initial exponential growth rate of an epidemic is an important measure of disease spread, and is commonly used to infer the basic reproduction number [Formula: see text]. While modern techniques (e.g., MCMC and particle filtering) for parameter estimation of mechanistic models have gained popularity, maximum likelihood fitting of phenomenological models remains important due to its simplicity, to the difficulty of using modern methods in the context of limited data, and to the fact that there is not always enough information available to choose an appropriate mechanistic model. However, it is often not clear which phenomenological model is appropriate for a given dataset. We compare the performance of four commonly used phenomenological models (exponential, Richards, logistic, and delayed logistic) in estimating initial epidemic growth rates by maximum likelihood, by fitting them to simulated epidemics with known parameters. For incidence data, both the logistic model and the Richards model yield accurate point estimates for fitting windows up to the epidemic peak. When observation errors are small, the Richards model yields confidence intervals with better coverage. For mortality data, the Richards model and the delayed logistic model yield the best growth rate estimates. We also investigate the width and coverage of the confidence intervals corresponding to these fits.


Usefulness of high-frequency ultrasound in the monitoring of laser treatment of acne scars.
Acne scarring is considered one of the complications of acne vulgaris. Scarring is an important aesthetic problem for patients; therefore, effective methods for scar removal are sought. In recent years, laser methods for the treatment of acne scarring have become popular as a result of technological development. Monitoring and objective assessment of treatment outcomes are important elements of laser treatment. High-frequency ultrasonography is a diagnostic modality likely to become a common tool used for this purpose. The aim of this study was to assess the usefulness of high-frequency ultrasonography for the monitoring of laser treatment of acne scarring. The study group included 7 patients (6 women and 1 man) aged 29-43 years with evident facial acne scarring. Each patient underwent laser treatment with Alma Harmony Er:Yag laser. Ultrasound examinations were performed with high-frequency DermaMed scanner. The following parameters were assessed on ultrasound images: the thickness of epidermis and dermis, the depth and width of scars. We additionally collected photographic documentation and assessed patient satisfaction with treatment outcomes. The analysis of our findings showed statistically significant changes in the thickness of the epidermis and the depth of scars. No statistically significant results were obtained for the thickness of the dermis and the extent (width) of scars. The patients rated treatment outcomes as good. High-frequency ultrasonography is a useful method for the monitoring of laser treatment of acne scarring.


Transcriptional regulation of cyclooxygenase 2 by bradykinin and interleukin-1beta in human airway smooth muscle cells: involvement of different promoter elements, transcription factors, and histone h4 acetylation.
Bradykinin and interleukin-1beta (IL-1beta) induce cyclooxygenase 2 (COX-2) in human airway smooth muscle cells. Here we extended our study to explore the gene transcriptional regulation. By transfection with various COX-2 promoter reporter constructs, we found that the bp -327-to-+59 promoter region was essential for COX-2 gene transcription by bradykinin and IL-1beta and that the cyclic AMP response element (CRE) was critical in bradykinin-induced transcription, whereas nuclear factor IL-6 and CRE and, to a lesser extent, nuclear factor-kappaB (NF-kappaB) were involved in IL-1beta-induced transcription. An electrophoretic mobility shift assay revealed that both bradykinin and IL-1beta elicited CRE-binding protein-1 (CREB-1) binding, and IL-1beta also elicited CCAAT/enhancer-binding protein beta and NF-kappaB binding to their respective elements in the COX-2 promoter. These transcription factors were associated with the COX-2 promoter, which was dynamically linked to different patterns of histone H4 acetylation by bradykinin and IL-1beta, as demonstrated by chromatin immunoprecipitation. We also revealed that endogenous prostaglandin E(2) was critical in bradykinin-induced COX-2 transcription initiation and involved in IL-1beta-induced COX-2 transcription at a latter stage. Our result provide the first evidence that COX-2 transcriptional regulation by different stimuli involves different promoter elements and transcription factors and is associated with chromatin remodeling after selective histone H4 acetylation in a stimulus-specific manner.


Visual sustained attention in a child psychiatric population.
To increase knowledge of the diversity and specificity of sustained attention deficits in children with attention-deficit hyperactivity disorder (ADHD), with special reference to the issue of distinguishing between children with ADHD and children with other psychiatric diagnoses. A visual sustained attention task was used to compare 52 boys with ADHD with 55 normal controls, 29 boys with oppositional defiant disorder or conduct disorder (ODD/CD), 29 boys with anxiety or dysthymia (ANX/DYS), 43 boys with pervasive developmental disorder, 24 boys with ADHD plus ODD/CD, and 14 boys with ADHD plus ANX/DYS. Compared with normal controls, children with ADHD were slower, were more inaccurate, were more impulsive, were less responsive to feedback, and showed less perceptual sensitivity and stability of performance, resulting in a marked decrease in vigilance over time. Unresponsiveness to feedback and the extent of the decrease in vigilance during time on task were found to be the only factors that distinguished children with ADHD from children with other diagnoses. Although only children with ADHD are characterized primarily by "attention deficit," sustained attention deficit is common to a certain extent to all children with psychiatric disorders.


Iron and aluminium based adsorption strategies for removing arsenic from water.
Arsenic is a commonly occurring toxic metal in natural systems and is the root cause of many diseases and disorders. Occurrence of arsenic contaminated water is reported from several countries all over the world. A great deal of research over recent decades has been motivated by the requirement to lower the concentration of arsenic in drinking water and the need to develop low cost techniques which can be widely applied for arsenic removal from contaminated water. This review briefly presents iron and aluminium based adsorbents for arsenic removal. Studies carried out on oxidation of arsenic(III) to arsenic(V) employing various oxidising agents to facilitate arsenic removal are briefly mentioned. Effects of competing ions, As:Fe ratios, arsenic(V) vs. arsenic(III) removal using ferrihydrite as the adsorbent have been discussed. Recent efforts made for investigating arsenic adsorption on iron hydroxides/oxyhydroxides/oxides such as granular ferric hydroxide, goethite, akaganeite, magnetite and haematite have been reviewed. The adsorption behaviours of activated alumina, gibbsite, bauxite, activated bauxite, layered double hydroxides are discussed. Point-of-use adsorptive remediation methods indicate that Sono Arsenic filter and Kanchan™ Arsenic filter are in operation at various locations of Bangladesh and Nepal. The relative merits and demerits of such filters have been discussed. Evaluation of kits used for at-site arsenic estimation by various researchers also forms a part of this review.


Clinical and radiographic delineation of odontochondrodysplasia.
The association of dentinogenesis imperfecta (DI) with a distinct form of chondrodysplasia in a boy was reported by Goldblatt et al. [1991; Am J Med Genet 39:170-172] and has been given the name of Goldblatt syndrome or odontochondrodysplasia (ODCD; OMIM#184260). Since the original description, only four further individuals have been reported (one sib pair and two unrelated cases). We report on an additional six individuals, including a second sib pair (brother and sister), with clinical and radiographic features that cluster and thus confirm the nosologic status of this entity. The main radiographic features are congenital platyspondyly with coronal clefts, severe metaphyseal changes particularly of the hands, wrists, and knees, mesomelic limb shortening, and coxa valga. The main physical signs are short stature, joint laxity, narrow chest, scoliosis, and DI. This combination of clinical and radiographic findings allows clear recognition of this syndrome in early childhood. Of note, the signs that are present in the newborn period are not entirely specific and the differential diagnosis includes spondylometaphyseal dysplasia (SMD) Sedaghatian type or platyspondylic lethal dysplasia (PSLD) Torrance type. The occurrence of two sib pairs in a group of only 11 patients suggests an autosomal recessive inheritance pattern. Overmodification of cartilage-extracted collagen 2 has been reported in two sibs, but mutation analysis of COL2A1 as well as of COMP, FGFR3, RMRP, and SBDS in one or more patients have given negative results, and the molecular etiology is as yet unknown.


Polyurethane stent obstruction as a cause of recurrent epiphora. Case report.
A Song's nasolacrimal duct stent was placed in a patient with epiphora due to primary nasolacrimal duct obstruction and the stent was kept for 32 months. Mitomycin C 0.02% eye drops four times a day were prescribed for four weeks following polyurethane stent placement procedure. No epiphora-related complaints occurred for thirty months after then the epiphora started. Nasolacrimal stent was removed from nasal cavity endoscopially and the tissues within the extruded stent were examined histopathologically. The patient's complaints were relieved following stent removal. Dacryocystogram revealed normal passage and a filling defect within the lacrimal sac. Macroscopic evaluation of the stent revealed a firm mass in the stent mushroom, causing complete obstruction. Pathological examination of the mass revealed chronic inflammation, increased connective tissue and vascular proliferation. Nasolacrimal polyurethane stents can be removed easily by nasal approach. Nasolacrimal passage may be left open temporarily after stent removal. The use of Mitomycin C drop is a novel approach in nasolacrimal stent placement cases. However, when the long-term results of endoscopic and external dacryocystorhinostomy are considered, further research is needed on the biocompatibility of stent material.


Three-dimensional resonating metamaterials for low-frequency vibration attenuation.
Recent advances in additive manufacturing have enabled fabrication of phononic crystals and metamaterials which exhibit spectral gaps, or stopbands, in which the propagation of elastic waves is prohibited by Bragg scattering or local resonance effects. Due to the high level of design freedom available to additive manufacturing, the propagation properties of the elastic waves in metamaterials are tunable through design of the periodic cell. In this paper, we outline a new design approach for metamaterials incorporating internal resonators, and provide numerical and experimental evidence that the stopband exists over the irreducible Brillouin zone of the unit cell of the metamaterial (i.e. is a three-dimensional stopband). The targeted stopband covers a much lower frequency range than what can be realised through Bragg scattering alone. Metamaterials have the ability to provide (a) lower frequency stopbands than Bragg-type phononic crystals within the same design volume, and/or (b) comparable stopband frequencies with reduced unit cell dimensions. We also demonstrate that the stopband frequency range of the metamaterial can be tuned through modification of the metamaterial design. Applications for such metamaterials include aerospace and transport components, as well as precision engineering components such as vibration-suppressing platforms, supports for rotary components, machine tool mounts and metrology frames.


Recognition of small interfering RNA by a viral suppressor of RNA silencing.
RNA silencing (also known as RNA interference) is a conserved biological response to double-stranded RNA that regulates gene expression, and has evolved in plants as a defence against viruses. The response is mediated by small interfering RNAs (siRNAs), which guide the sequence-specific degradation of cognate messenger RNAs. As a counter-defence, many viruses encode proteins that specifically inhibit the silencing machinery. The p19 protein from the tombusvirus is such a viral suppressor of RNA silencing and has been shown to bind specifically to siRNA. Here, we report the 1.85-A crystal structure of p19 bound to a 21-nucleotide siRNA, where the 19-base-pair RNA duplex is cradled within the concave face of a continuous eight-stranded beta-sheet, formed across the p19 homodimer interface. Direct and water-mediated intermolecular contacts are restricted to the backbone phosphates and sugar 2'-OH groups, consistent with sequence-independent p19-siRNA recognition. Two alpha-helical 'reading heads' project from opposite ends of the p19 homodimer and position pairs of tryptophans for stacking over the terminal base pairs, thereby measuring and bracketing both ends of the siRNA duplex. Our structure provides an illustration of siRNA sequestering by a viral protein.


Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin.
We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.


Noninvasive study of brain tumours metabolism using phosphorus-31 magnetic resonance spectroscopy.
Phosphorus-31 magnetic resonance spectroscopy (31P MRS) is currently not accepted as a diagnostic tool in the neuro-oncological practice, although it provides useful non-invasive information about biochemical processes ongoing in the intracranial tumours. This pilot study was aimed to present the diagnostic capability of the 31P MRS in brain tumour examination, even its application on clinical 1.5T MR scanner.Seven patients with brain tumorous lesions (four glioblastomas, one ependymoma, and two lung metastasis) underwent multivoxel in vivo 31P MRS performed on clinical 1.5 T MR scanner within measurement time of 20 minutes. Comparing two selected voxels, one in the tumour and the other one in the normal-appearing brain tissue, enabled to investigate their metabolic differences. Enhanced markers of membrane phospholipids synthesis (significantly increased phosphomonoesters ratios) than markers of their degradation (significantly decreased phosphodiesters ratios) manifested a higher cell proliferation ongoing in tumours. High energetic tumorous tissue demands leading to anaerobic metabolic turnover were present as a significant decline in phosphocreatine ratios and adenosine triphosphates. Intracellular pH evaluation showed a tumorous tendency to alkalize. 31P MRS enables the non-invasive metabolic characterization of intracranial tumours and thus appears to be a clinically useful method for the determination of ongoing tumour pathomechanisms (Fig. 2, Ref. 26). Keywords: brain tumour, 31P MRS, 1.5 Tesla; energetic metabolism.


In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1.
Fanconi anemia (FA) is an inherited recessive DNA repair disorder mainly characterized by bone marrow failure and cancer predisposition. Studies in mosaic FA patients have shown that reversion of one inherited germ-line mutation resulting in a functional allele in one or a few hematopoietic stem cells (HSCs) can lead to the proliferation advantage of corrected cells, thus over time normalizing the hematologic status of the patient. In contrast to these observations, it is still unclear whether ex vivo genetic correction of FA HSCs also provides a similar proliferation advantage to FA HSCs. Using an FA mouse model with a marked hematopoietic phenotype, the FA-D1 (Brca2(Delta27/Delta27)) mice, we demonstrate that the lentivirus-mediated gene therapy of FA HSCs results in the progressive expansion of genetically corrected clones in mild-conditioned FA-D1 recipients. Consistent with these data, hematopoietic progenitors from FA recipients progressively became mitomycin C resistant and their chromosomal instability was reverted. No evidence of myelodysplasia, leukemias, or abnormal clonal repopulation was observed at multiple time points in primary or secondary recipients. Our results demonstrate that ectopic expression of BRCA2 confers a beneficial in vivo proliferation advantage to FA-D1 HSCs that enables the full hematopoietic repopulation of FA recipients with genetically corrected cells.


Timing of Cleft Palate Repair in Patients With and Without Robin Sequence.
This cohort study aimed to assess how age at repair affects outcomes in nonsyndromic patients with and without Robin Sequence using a national database of commercial healthcare claims. Children under 4 years of age undergoing palatoplasty were identified in the IBM MarketScan Commercial Database based on ICD-9-CM and CPT procedure codes. They were divided into Robin and non-Robin cleft palate groups, and further divided by time of initial cleft palate repair: Robin Sequence into 2 groups: age ≤10 months or >10 months; non-Robin cleft palate into 3 groups: age ≤10 months, >10-14 months, or >14 months age. Time to cleft palate revision within each group was assessed using Cox proportional-hazard models. A total of 261 patients with Robin Sequence and 3046 with non-Robin cleft palate were identified. In patients with Robin, later repair was associated with decreased risk of secondary procedures compared with early repair (Hazard Ratio (HR) 0.19, 95%CI 0.09-0.39, P < 0.001). In patients with non-Robin cleft palate, decreased risk of revision compared to early repair was associated both with repair at >10-14 months (adjusted HR 0.40, 95%CI 0.31-0.52, P < 0.001) and > 14 months (adjusted HR 0.71, 95%CI 0.57-0.88, P = 0.002). Adjusting for timing of repair, patients with non-Robin cleft palate were at significantly increased risk of secondary procedure if diagnosed with failure to thrive or anemia in the 30 days prior to palatoplasty. In patients with and without Robin sequence, cleft palate repair at or before 10 months of age was associated with higher risk for secondary procedures.


Is there room for 'development' in developmental models of information processing biases to threat in children and adolescents?
Clinical and experimental theories assume that processing biases in attention and interpretation are a causal mechanism through which anxiety develops. Despite growing evidence that these processing biases are present in children and, therefore, develop long before adulthood, these theories ignore the potential role of child development. This review attempts to place information processing biases within a theoretical developmental framework. We consider whether child development has no impact on information processing biases to threat (integral bias model), or whether child development influences information processing biases and if so whether it does so by moderating the expression of an existing bias (moderation model) or by affecting the acquisition of a bias (acquisition model). We examine the extent to which these models fit with existing theory and research evidence and outline some methodological issues that need to be considered when drawing conclusions about the potential role of child development in the information processing of threat stimuli. Finally, we speculate about the developmental processes that might be important to consider in future research.


mRNA nanomedicine: Design and recent applications.
The rational design and application of mRNA-based medicine have recently yielded some key successes in the clinical management of human diseases. mRNA technology allows for the facile and direct production of proteins in vivo, thus circumventing the need for lengthy drug development cycles and complex production workflows. As such, mRNA formulations can significantly improve upon the biological therapies that have become commonplace in modern medicine. Despite its many advantages, mRNA is inherently fragile and has specific delivery requirements. Leveraging the engineering flexibility of nanobiotechnology, mRNA payloads can be incorporated into nanoformulations such that they do not invoke unwanted immune responses, are targeted to tissues of interest, and can be delivered to the cytosol, resulting in improved safety while enhancing bioactivity. With the rapidly evolving landscape of nanomedicine, novel technologies that are under development have the potential to further improve the clinical utility of mRNA medicine. This review covers the design principles relevant to engineering mRNA-based nanomedicine platforms. It also details the current research on mRNA nanoformulations for addressing viral infections, cancers, and genetic diseases. Given the trends in the field, future mRNA-based nanomedicines have the potential to change how many types of diseases are managed in the clinic.


Comparative impact of artificial selection for fungicide resistance on Beauveria bassiana and Metarhizium brunneum.
Hypocreales fungi such as Beauveria bassiana (Balsamo) Vuillemin and Metarhizium brunneum Petch can be negatively affected by fungicides thereby reducing their biocontrol potential. In a previous study, we demonstrated enhanced fungicide resistance in B. bassiana through artificial selection. However, it is not clear if the enhanced resistance was because of improved germination, vegetative growth, or both. Additionally, the enhanced fungicide resistance has only been demonstrated in B. bassiana, and therefore it is of interest to investigate the potential to enhance resistance in other fungi. Thus, the objectives in this study were to determine the potential to enhance fungicide resistance in M. brunneum through artificial selection, and investigate if selection is based on germination, vegetative growth, or both in B. bassiana and M. brunneum. Selection for resistance to fenbuconazole, and triphenyltin hydroxide was assessed through inhibition evaluations on solid media, and germination and mycelial growth in liquid media. Increased resistance after selection was observed for all fungicide-fungus combinations on solid and or liquid media. Selection resulted in increased resistance to fenbuconazole in both fungi in solid and liquid media; in liquid culture fungicide resistance in B. bassiana was manifested by increased germination and mycelial growth, whereas in M. brunneum fungicide resistance concerned only mycelial growth. Selection for resistance to triphenyltin hydroxide varied in the different media. For B. bassiana, triphenyltin hydroxide resistance was enhanced on solid media but not in liquid, whereas enhanced resistance of M. brunneum was detected in both media. Fungicide sensitivity and selection potential differs based on the medium and fungal species. Selection for fungicide resistance, had negative effects on other beneficial traits when fungicide pressure was removed, for example, some selected populations showed decreased germination or growth, relative to their nonselected control populations. Additionally, reduced virulence to the greater wax moth, Galleria mellonella (L.), was observed in all fungal populations that were exposed to fungicide resistance regimes. We conclude that it is possible to use genetic selection to enhance fungicide resistance in B. bassiana and M. brunneum, but before use the resulting populations should be screened for inadvertent negative impacts on beneficial traits.


Gel point and fractal microstructure of incipient blood clots are significant new markers of hemostasis for healthy and anticoagulated blood.
Here we report the first application of a fractal analysis of the viscoelastic properties of incipient blood clots. We sought to ascertain whether the incipient clot's fractal dimension, D(f,) could be used as a functional biomarker of hemostasis. The incipient clot is formed at the gel point (GP) of coagulating blood, the GP demarcating a functional change from viscoelastic liquid to a viscoelastic solid. Incipient clots formed in whole healthy blood show a clearly defined value of D(f) within a narrow range that represents an index of clotting in health, where D(f) = 1.74 (± 0.07). A significant relationship is found between the incipient clot formation time, T(GP), and the activated partial thromboplastin time, whereas the association of D(f) with the microstructural characteristics of the incipient clot is supported by its significant correlation with fibrinogen. Our study reveals that unfractionated heparin not only prolongs the onset of clot formation but has a significant effect on its fractal microstructure. A progressive increase in unfractionated heparin concentration results in a linear decrease in D(f) and a corresponding prolongation in T(GP). The results represent a new, quantitative measure of clot quality derived from measurements on whole blood samples.


Photo-activated platelet-rich plasma (PRP)-based patient-specific bio-ink for cartilage tissue engineering.
Nowadays, scientists focus on the development of tissue-specific and personalized bio-ink that can be used in 3D bioprinting technologies. Platelet-rich plasma (PRP) is a person-specific source that is used as a therapeutic adjunct for the treatment of cartilage damage because it offers a cocktail of growth factors that are necessary for wound healing and tissue regeneration. However, PRP treatments in the clinic are not satisfactory and require upgrading, especially the point of maintaining bioactivity. In this study, we presented PRP as a photo-activated and photo-crosslinkable bio-ink in terms of tissue-specific structures for the first time. We achieved long-term and constant rate growth factor release and bioactivity protection of PRP with satisfactory mechanical characteristics. Photo-crosslinked PRP hydrogel was enabled by the addition of microwave-induced methacrylated gelatin (Gel-MA), which is connected to platelets in PRP via integrin receptors in its structure and chemically cross-linked upon UV irradiation (300-500 nm). Photo-activation of PRP was realized by a polychromatic light source in the near-infrared region (PAC, 600-1200 nm). Our results showed that Gel-MA/PRP hydrogels with the desired mechanical properties (low degradation rate and high mechanical strength) released growth factors at a constant rate for the long-term by the periodic PAC application. In vitro cell culture studies (viability, proliferation, morphology, histology, immunochemistry, biochemistry, gene expression analyses) proved that proliferation and differentiation of the ATDC5 cells increased in the periodically light-applied Gel-MA/PRP hydrogel without any external chemical agents.


Accelerated uptake of 5-hydroxytryptamine by human blood platelets enriched in a sialic acid.
The enzymically catalysed incorporation of N-acetylneuraminic acid into human platelets, whether suspended in their own citrated plasma or in buffered saline containing 0.17 mM-sucrose, accelerated the uptake of 5-hydroxytryptamine. This acceleration decreased with time. The observations may be explained by assuming that N-acetylneuraminic acid is a component of a transport receptor for 5-hydroxytryptamine.


Hypoxemia in Young Children Undergoing One-lung Ventilation: A Retrospective Cohort Study.
One-lung ventilation in children remains a specialized practice with low case numbers even at tertiary centers, preventing an assessment of best practices. The authors hypothesized that certain case factors may be associated with a higher risk of intraprocedural hypoxemia in children undergoing thoracic surgery and one-lung ventilation. The Multicenter Perioperative Outcomes database and a local quality improvement database were queried for documentation of one-lung ventilation in children 2 months to 3 yr of age inclusive between 2010 and 2020. Patients undergoing vascular or other cardiac procedures were excluded. All records were reviewed electronically for the presence of hypoxemia, oxygen saturation measured by pulse oximetry (Spo2) less than 90% for 3 min or more continuously, and severe hypoxemia, Spo2 less than 90% for 5 min or more continuously during one-lung ventilation. Records were also assessed for hypercarbia, end-tidal CO2 greater than 60 mmHg for 5 min or more or a Paco2 greater than 60 on arterial blood gas. Covariates assessed for association with these outcomes included age, weight, American Society of Anesthesiologists (Schaumburg, Illinois) Physical Status 3 or greater, duration of one-lung ventilation, preoperative Spo2 less than 98%, bronchial blocker versus endobronchial intubation, left operative side, video-assisted thoracoscopic surgery, lower tidal volume ventilation (tidal volume less than or equal to 6 ml/kg plus positive end expiratory pressure greater than or equal to 4 cm H2O for more than 80% of the duration of one-lung ventilation), and type of procedure. Three hundred six cases from 15 institutions were included for analysis. Hypoxemia and severe hypoxemia occurred in 81 of 306 (26%) patients and 56 of 306 (18%), respectively. Hypercarbia occurred in 153 of 306 (50%). Factors associated with lower risk of hypoxemia in multivariable analysis included left operative side (odds ratio, 0.45 [95% CI, 0.251 to 0.78]) and bronchial blocker use (odds ratio, 0.351 [95% CI, 0.177 to 0.67]). Additionally, use of a bronchial blocker was associated with a reduced risk of severe hypoxemia (odds ratio, 0.290 [95% CI, 0.125 to 0.62]). Use of a bronchial blocker was associated with a lower risk of hypoxemia in young children undergoing one-lung ventilation.


Three-dimensional structural analysis of the proximal femur in an age-stratified sample of women.
Aging is associated with worsening bone structure and increasing risk of hip fracture. However, the commonly used clinical tool, dual-energy x-ray absorptiometry, does not provide information on changes with age or disease separately in trabecular versus cortical bone or in bone geometry. Here we used 3D quantitative computed tomography (QCT) to analyze age-related changes in femoral volumetric bone mineral density (vBMD) and structure in a well characterized, population-based cohort of Rochester, Minnesota women. MIAF-Femur (MIAF: medical image analysis framework) was used for the analysis of CT datasets from 358 women age 20 to 97 years. Integral, "apparent" cortical (rather than true cortical vBMD, due to volume averaging effects) and trabecular vBMD, volume, and bone mineral content (BMC) as well as cortical thickness of the femur head, neck, trochanter, inter-trochanteric, and proximal shaft volumes of interest (VOIs) were measured. In addition, changes in vBMD in the superior, inferior, posterior and anterior quadrants of the femur neck were assessed. Cross-sectional percent decreases in vBMD across life were 2- to 5-fold higher in trabecular versus cortical bone at all sites in the femur, although absolute changes in the trabecular and cortical bone were fairly similar. In addition, the slopes of the relationships of trabecular vBMD with age were generally similar in pre- and postmenopausal women, whereas apparent cortical vBMD in the femur neck, trochanter, inter-trochanteric region, and proximal shaft remained relatively stable in premenopausal women but decreased significantly with age following the menopause. Bone volume increased at all sites, more so in pre- compared to postmenopausal women. Age-related BMC changes were not significant in premenopausal women, but BMC losses were highly significant in postmenopausal women. Detailed analyses of femur neck cortical bone showed that percent apparent vBMD decreases in the superior quadrants were 2- to 3-fold greater than in the inferior quadrants; changes in absolute values were most different (~2-fold) between the superior-posterior and inferior-posterior quadrants. These data demonstrate that patterns of changes with age within the femur differ in the trabecular versus cortical bone. In the cortical compartment which, due to limitations in spatial resolution, contains some subcortical bone and should be regarded as an "apparent" cortical VOI, the superior quadrants in the femur neck undergo the greatest decreases. These findings may have important implications for understanding the structural basis for increased hip fracture risk with aging.


O-Linked N-acetylglucosamine transferase 1 regulates global histone H4 acetylation via stabilization of the nonspecific lethal protein NSL3.
The human males absent on the first (MOF)-containing histone acetyltransferase nonspecific lethal (NSL) complex comprises nine subunits including the O-linked N-acetylglucosamine (O-GlcNAc) transferase, isoform 1 (OGT1). However, whether the O-GlcNAc transferase activity of OGT1 controls histone acetyltransferase activity of the NSL complex and whether OGT1 physically interacts with the other NSL complex subunits remain unclear. Here, we demonstrate that OGT1 regulates the activity of the NSL complex by mainly acetylating histone H4 Lys-16, Lys-5, and Lys-8 via O-GlcNAcylation and stabilization of the NSL complex subunit NSL3. Knocking down or overexpressing OGT1 in human cells remarkably affected the global acetylation of histone H4 residues Lys-16, Lys-5, and Lys-8. Because OGT1 is a subunit of the NSL complex, we also investigated the function of OGT1 in this complex. Co-transfection/co-immunoprecipitation experiments combined with in vitro O-GlcNAc transferase assays confirmed that OGT1 specifically binds to and O-GlcNAcylates NSL3. In addition, wheat germ agglutinin affinity purification verified the occurrence of O-GlcNAc modification on NSL3 in cells. Moreover, O-GlcNAcylation of NSL3 by wild-type OGT1 (OGT1-WT) stabilized NSL3. This stabilization was lost after co-transfection of NSL3 with an OGT1 mutant, OGT1C964A, that lacks O-GlcNAc transferase activity. Furthermore, stabilization of NSL3 by OGT1-WT significantly increased the global acetylation levels of H4 Lys-5, Lys-8, and Lys-16 in cells. These results suggest that OGT1 regulates the activity of the NSL complex by stabilizing NSL3.


Some generalized sufficient convergence criteria for nonlinear continuous neural networks.
A reason for applying the direct method of Lyapunov to artificial neural networks (ANNs) is to design dynamical neural networks so that they exhibit global asymptotic stability. Lyapunov functions that frequently appear in the ANN literature include the quadratic function, the Persidskii function, and the Luré-Postnikov function. This contribution revisits the quadratic function and shows that via Krasovskii-like stability criteria, it is possible to have a very simple and systematic procedure to obtain not only new and generalized results but also well-known sufficient conditions for convergence established recently by non-Lyapunov methods, such as the matrix measure and nonlinear measure.


cid: a rapid and efficient bioinformatic tool for the detection of SSRs from genomic libraries.
cid is a computational tool developed in the Web environment to process cloned DNA fragments with the objective of masking the vector and adaptor regions, detecting the presence of microsatellites and designing the most appropriate primer pairs for the amplification of the identified repetitive sequences. This entire process is executed by the user in a simple and automated manner with the data input as a Zip file of chromatograms or a multiFASTA file. Thus, it is possible to analyse dozens of sequences at the same time, optimizing data processing and the search for the information of interest. cid is freely available on http://www.shrimp.ufscar.br/cid/index.php.


Intracellular endosymbiotic bacteria of Camponotus species (carpenter ants): systematics, evolution and ultrastructural characterization.
Intracellular endosymbiotic bacteria inherent to ants of the genus Camponotus were characterized. The bacteria were localized in bacteriocytes, which are specialized cells of both workers and queen ants; these cells are intercalated between epithelial cells of the midgut. The bacteriocytes show a different morphology from the normal epithelial cells and carry a large number of the rod-shaped Gram-negative bacteria free in the cytoplasm. The bacteria were never observed in the neighbouring epithelial cells, but they were found intracellularly in oocytes, strongly indicating a maternal transmission of the bacteria. The 16S DNA encoding rrs loci of the endosymbionts of four species of the genus Camponotus derived either from Germany (C. herculeanus and C. ligniperdus), North America (C. floridanus) or South America (C. rufipes) were cloned after polymerase chain reaction (PCR) amplification using oligonucleotides complementary to all so far known eubacterial rrs sequences. The DNA sequences of the rrs loci of the four endosymbionts were determined, and, using various genus- and species-specific oligonucleotides derived from variable regions in the rrs sequences, the identity of the bacteria present in the bacteriocytes and the ovarian cells was confirmed by PCR and in situ hybridization techniques. Comparison of the 16S DNA sequences with the available database showed the endosymbiotic bacteria to be members of the gamma-subclass of Proteobacteria. They formed a distinct taxonomic group, a sister taxon of the taxons defined by the tsetse fly and aphid endosymbionts. Within the gamma-subclass, the cluster of the ant, tsetse fly and aphid endosymbionts are placed adjacent to the family of Enterobacteriaceae. The evolutionary tree of the ant endosymbionts reflects the systematic classification and geographical distribution of their host insects, indicating an early co-evolution of the symbiotic partners and a vertical transmission of the bacteria.


In vitro human antibody production to the Haemophilus influenzae type b capsular polysaccharide.
In vitro production of human antibody to the Haemophilus influenzae type b capsular polysaccharide (PRP) and to tetanus toxoid (TT) and diphtheria toxoid was measured in culture supernatants of peripheral blood mononuclear cells and by enumeration of antibody secreting cells (AbSC) in an enzyme-linked immunosorbent-plaquing assay. Normal adult peripheral blood mononuclear cells stimulated with Epstein-Barr virus secreted anti-PRP antibody with a frequency of 1/552 to 1/1190 relative to total Ig secreting cells; the frequency of AbSC to tetanus toxoid (TT) was 7.5 times higher (p less than 0.05). These frequencies did not change significantly after in vivo immunization, although the isotype distribution shifted toward increased IgG for TT and increased IgG and IgA for PRP. At 8 days postimmunization, spontaneous AbSC to PRP and TT were detected; frequencies for total anti-TT AbSC again being higher than anti-PRP, but there were significantly more IgA plaques among anti-PRP AbSC. Spontaneous AbSC were suppressed in culture by pokeweed mitogen and enhanced by cyclosporine. Three wk after in vivo immunization with PRP and TT, in vitro stimulation with pokeweed mitogen, Staphylococcus aureus Cowan 1 bacteria, or antigen induced anti-TT but not anti-PRP in vitro antibody secretion, although Epstein-Barr virus induced both. These data suggest that PRP, a polysaccharide, and TT, a protein, differ in their requirements for in vitro activation with antigen and mitogens.


Fast track to stroke unit for patients not eligible for acute intervention, a case-control register study on 1066 patients.
Stroke patients not eligible for acute intervention often have low priority and may spend long time at the emergency department (ED) waiting for admission. The aim of this retrospective case-control register study was to evaluate outcomes for such "low priority" stroke patients who were transported via Fast Track directly to the stroke unit, according to pre-specified criteria by emergency medical service (EMS). The outcomes of Fast Track patients, transported directly to stroke unit (cases) were compared with the outcomes of patients who fulfilled these critera for Fast Track, but instead were transported to the ED (controls). In all, 557 cases and 509 controls were identified. The latter spent a mean time of 237 min in the ED before admission. The 90-day mortality rate was 12.9% for cases and 14.7% for controls (n.s.). None of the secondary outcome events differed significantly between the groups: 28-day mortality rate; death rate during hospitalisation; proportion of pneumonias, falls or pressure ulcers; or health-related outcomes according to the EQ-5D-5L questionnaire. These findings indicates that the Fast Track to the stroke unit by an EMS is safe for selected stroke patients and could avoid non-valuable time in the ED.


A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma.
Many driver pathways for cancer cell proliferation have been reported. Driver pathway activation is often evaluated based on a single hotspot mutation such as EGFR L858R. However, because of complex intratumoral networks, the impact of a driver pathway cannot be predicted based on only a single gene mutation. Here, we developed a novel diagnostic system named the "EGFR impact score" which is based on multiplex mRNA expression profiles, which can predict the impact of the EGFR pathway in lung cancer cells and the effect of EGFR-tyrosine kinase inhibitors on malignancy. The EGFR impact score indicated robust predictive power for the prognosis of early-stage lung cancer because this score can evaluate the impact of the EGFR pathway on the tumor and genomic instability. Additionally, the molecular features of the poor prognostic group resembled those of biomarkers associated with immune checkpoint inhibitors. The EGFR impact score is a novel prognostic and therapeutic indicator for lung adenocarcinoma.


Phase-shift between arterial flow and ICP pulse during infusion test.
The dynamic relationship between pulse waveform of intracranial pressure (ICP) and transcranial Doppler (TCD) cerebral blood flow velocity (CBFV) may contain information about cerebrospinal compliance. This study investigated the possibility by focusing on the phase shift between fundamental harmonics of CBFV and ICP. Thirty-seven normal pressure hydrocephalus patients (20 men, mean age 58) underwent the cerebrospinal fluid (CSF) infusion tests. The infusion was performed via pre-implanted Ommaya reservoir. The TCD FV was recorded in the middle cerebral artery. Resulting continuous ICP and pressure-volume (PV) signals were analyzed by ICM+ software. In initial stage of the CSF infusion, the phase shift was negative (median value = -11°, range = +60 to -117). There was significant inverse association of phase shift with brain elasticity (R = -0.51; p = 0.0009). In all tests, phase shift consistently decreased during gradual elevation of ICP (p = 0.00001). Magnitude of decrease in phase shift was inversely related to the peak-to-peak amplitude of ICP pulse waveform at a baseline (R = -0.51; p = 0.001). Phase shift between fundamental harmonics of ICP and TCD waveforms decreases during elevation of ICP. This is caused by an increase of time delay between systolic peak of flow velocity wave and ICP pulse.


TGFBI functions similar to periostin but is uniquely dispensable during cardiac injury.
Extracellular matrix production and accumulation stabilize the heart under normal conditions as well as form a protective scar after myocardial infarction injury, although excessive extracellular matrix accumulation with long-standing heart disease is pathological. In the current study we investigate the role of the matricellular protein, transforming growth factor beta-induced (TGFBI), which is induced in various forms of heart disease. Additionally, we sought to understand whether TGFBI is functionally redundant to its closely related family member periostin, which is also induced in the diseased heart. Surgical models of myocardial infarction and cardiac pressure overload were used in mice with genetic loss of Postn and/or Tgfbi to examine the roles of these genes during the fibrotic response. Additionally, cardiac-specific TGFBI transgenic mice were generated and analyzed. We observed that deletion of Tgfbi did not alter cardiac disease after myocardial infarction in contrast to greater ventricular wall rupture in Postn gene-deleted mice. Moreover, Tgfbi and Postn double gene-deleted mice showed a similar post-myocardial infarction disease phenotype as Postn-deleted mice. Over-expression of TGFBI in the hearts of mice had a similar effect as previously shown in mice with periostin over-expression. Thus, TGFBI and periostin act similarly in the heart in affecting fibrosis and disease responsiveness, although TGFBI is not seemingly necessary in the heart after myocardial infarction injury and is fully compensated by the more prominently expressed effector periostin.


Colonization by aerobic bacteria in karst: laboratory and in situ experiments.
Experiments were carried out to investigate the potential for bacterial colonization of different substrates in karst aquifers and the nature of the colonizing bacteria. Laboratory batch experiments were performed using limestone and PVC as substrates, a natural bacterial isolate and a known laboratory strain (Escherichia coli [E. coli]) as inocula, and karst ground water and a synthetic formula as growth media. In parallel, fragments of limestone and granite were submerged in boreholes penetrating two karst aquifers for more than one year; the boreholes are periodically contaminated by enteric bacteria from waste water. Once a month, rock samples were removed and the colonizing bacteria quantified and identified. The batch experiments demonstrated that the natural isolate and E. coli both readily colonized limestone surfaces using karst ground water as the growth medium. In contrast, bacterial colonization of both the limestone and granite substrates, when submerged in the karst, was less intense. More than 300 bacterial strains were isolated over the period sampled, but no temporal pattern in colonization was seen as far as strain, and colonization by E. coli was notably absent, although strains of Salmonella and Citrobacter were each observed once. Samples suspended in boreholes penetrating highly fractured zones were less densely colonized than those in the borehole penetrating a less fractured zone. The results suggest that contamination of karst aquifers by enteric bacteria is unlikely to be persistent. We hypothesize that this may be a result of the high flow velocities found in karst conduits, and of predation of colonizing bacteria by autochthonous zooplankton.


The oral surgery/orthodontic interface: 1. Ectopically positioned teeth.
The number of patients seeking orthodontic treatment has increased over the last decade. A proportion of these patients present with minor irregularities due to the so-called 'local causes' of malocclusion, many of which require surgical treatment. Some general dental practitioners have taken up the challenge of correcting these causes and the resulting malocclusion themselves; however, all practitioners must be aware of the treatment options available and the surgical and orthodontic considerations to be taken into account. This will allow informed discussion with patients. In this, the first of two papers, the management of ectopically positioned teeth is discussed.


Impact of decompressive craniectomy on functional outcome after severe traumatic brain injury.
The beneficial effect of decompressive craniectomy (DC) in the treatment of traumatic brain injury (TBI) remains controversial. In many centers, it is used as a salvage procedure for uncontrollable intracranial pressure (ICP). It is our contention that DC represents a viable early option for head trauma patients. The purpose of this study was to evaluate the efficacy of DC on functional outcome after severe TBI in the largest single institutional series reported in the literature. Patients with severe TBI (Abbreviated Injury Score 4-5) treated with DC for the management of increased ICP during 6-year period were identified from the trauma registry. Functional outcome was measured 1 year to 6 years postinjury using the Glasgow Outcome Score Extended (GOSE) via telephone interview and classified as good (GOSE 5-8) or poor (GOSE 1-4, including death). Outcomes were compared using Wilcoxon rank-sum and chi2 tests where appropriate. One hundred and seventy-one patients were identified: 137 (80%) men and 34 (20%) women. Overall mortality (all in-hospital) was 32% (head-related = 22%). Of the 117 survivors, follow-up was obtained in all but 6 (95%). Good outcome was achieved in 96 patients (56% overall, 82% of survivors). Those with good outcome were younger (26 years vs. 43 years, p = 0.0028) and experienced a greater change in predecompression to postdecompression ICP (ICP reduced by 23 mm Hg vs. 10 mm Hg, p < 0.0001). Not surprisingly, unchanged ICP (predecompression to postdecompression) was associated with poor outcome (p = 0.0031). There was no difference in immediate predecompression ICP between survivors versus nonsurvivors. However, immediate predecompression Glasgow Coma Score was significantly higher in survivors compared with nonsurvivors (7 vs. 5, p < 0.0001). DC resulted in good functional outcome in >50% of patients with severe TBI. The greatest benefit was observed in younger patients with a demonstrable reduction in ICP after decompression. The prospect of improved functional outcome offered by this procedure in the treatment of severe TBI warrants prospective investigation.


Sodium storage in human tissues is mediated by glycosaminoglycan expression.
The current paradigm regarding sodium handling in animals and humans postulates that total body sodium is regulated predominately via regulation of extracellular volume. Active sodium storage independent of volume retention is thought to be negligible. However, studies in animals, hypertensive patients, and healthy humans suggest water-free storage of sodium in skin. We hypothesized that tissue sodium concentrations ([Na]T) found in humans vary and reflect regulation due to variable glycosaminoglycan content due to variable expression of XYLT-1. Twenty seven patients on dialysis and 21 living kidney transplant donors free of clinically detectable edema were studied. During surgery, abdominal skin, muscle, and arteries were biopsied. [Na]T was determined by inductively coupled plasma-optical emission spectrometry, semiquantitative glycosaminoglycan content with Alcian stain, and XYLT-1 expression by real-time PCR. [Na]T of arteries were ranging between 0.86 and 9.83 g/kg wet wt and were significantly higher in arteries (4.52 ± 1.82 g/kg) than in muscle (2.03 ± 1.41 g/kg; P < 0.001) or skin (3.24 ± 2.26 g/kg wet wt; P = 0.038). For individual patients [Na]T correlated for skin and arterial tissue (r = 0.440, P = 0.012). [Na]T also correlated significantly with blinded semiquantitative analysis of glycosaminoglycans staining (r = 0.588, P = 0.004). In arteries XYLT-1 expression was also correlated with [Na]T (r = 0.392, P = 0.003). Our data confirm highly variable [Na]T in human skin and muscle and extend this observation to [Na]T in human arteries. These data support the hypothesis of water-independent sodium storage via regulated glycosaminoglycan synthesis in human tissues, including arteries.


Changes in Work Habits of Lifeguards in Relation to Florida Red Tide.
The marine dinoflagellate, Karenia brevis, is responsible for Florida red tides. Brevetoxins, the neurotoxins produced by K. brevis blooms, can cause fish kills, contaminate shellfish, and lead to respiratory illness in humans. Although several studies have assessed different economic impacts from Florida red tide blooms, no studies to date have considered the impact on beach lifeguard work performance. Sarasota County experiences frequent Florida red tides and staffs lifeguards at its beaches 365 days a year. This study examined lifeguard attendance records during the time periods of March 1 to September 30 in 2004 (no bloom) and March 1 to September 30 in 2005 (bloom). The lifeguard attendance data demonstrated statistically significant absenteeism during a Florida red tide bloom. The potential economic costs resulting from red tide blooms were comprised of both lifeguard absenteeism and presenteeism. Our estimate of the costs of absenteeism due to the 2005 red tide in Sarasota County is about $3,000. On average, the capitalized costs of lifeguard absenteeism in Sarasota County may be on the order of $100,000 at Sarasota County beaches alone. When surveyed, lifeguards reported not only that they experienced adverse health effects of exposure to Florida red tide but also that their attentiveness and abilities to take preventative actions decrease when they worked during a bloom, implying presenteeism effects. The costs of presenteeism, which imply increased risks to beachgoers, arguably could exceed those of absenteeism by an order of magnitude. Due to the lack of data, however, we are unable to provide credible estimates of the costs of presenteeism or the potential increased risks to bathers.


The Information Loss of a Stochastic Map.
We provide a stochastic extension of the Baez-Fritz-Leinster characterization of the Shannon information loss associated with a measure-preserving function. This recovers the conditional entropy and a closely related information-theoretic measure that we call conditional information loss. Although not functorial, these information measures are semi-functorial, a concept we introduce that is definable in any Markov category. We also introduce the notion of an entropic Bayes' rule for information measures, and we provide a characterization of conditional entropy in terms of this rule.


The rs13347 Polymorphism of the CD44 Gene Is Associated with the Risk of Kidney Stones Disease in the Chinese Han Population of Northeast Sichuan, China.
To investigate the association between the rs13347 polymorphism of the CD44 gene and the risk of kidney stone disease (KSD) in the Han population of northeast Sichuan, China, so as to provide a theoretical basis for the treatment of KSD. We used PCR-restriction fragment length polymorphism (RFLP) technique to perform genotyping at rs13347 locus of the CD44 gene in the KSD group and the gontrol group. SNP Hardy-Weinberg equilibrium (HWE) testing was used to confirm the balance of genetic inheritance. Multivariate logistic regression analysis was used for the assessment of rs13347 polymorphism and the risk of developing KSD and to compare the relationship between the polymorphism of rs13347 and clinical characteristics of patients with KSD. Genotypic results of rs13347 locus of the CD44 gene in the two groups were consistent with the SNP-HWE test, indicating the genetic balance. At the same time, multivariate logistic regression analysis indicated that subjects with CT and TT genotypes at rs13347 in the CD44 gene were more likely to have KSD, and there was a higher prevalence rate in males. Furthermore, carrying allele T at rs13347 was also a risk factor for KSD. In addition, people carrying CT and TT genotypes at rs13347 also have a significantly increased risk of relapsing KSD. The rs13347 polymorphism of the CD44 gene may be associated with the risk of KSD in the Han population of northeast Sichuan in China, and the recurrence rate of KSD in the carriers of CT and TT genotypes is higher.


Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons.
The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations.


Estrogen actions in the male reproductive system involve estrogen response element-independent pathways.
The estrogen receptor-alpha (ERalpha) acts through multiple pathways, including estrogen response element (ERE)-dependent (classical) and ERE-independent (nonclassical) mechanisms. We previously created a mouse model harboring a two-amino-acid mutation of the DNA-binding domain (E207A, G208A) that precludes direct binding of ERalpha to an ERE. After crossing heterozygous mutant mice with an ERalpha knockout (ERKO) line, it was possible to assess the degree of physiological rescue by the isolated ERalpha nonclassical allele (-/AA; AA) when compared with ERKO mice (-/-) and to wild type (+/+; WT). In male ERKO mice up to 8 months of age, testosterone levels were high, although LH levels were similar to WT. Testosterone was normal in the AA mice, indicating that the AA allele rescues the enhanced testosterone biosynthesis in ERKO mice. Male ERKO mice exhibited distention of the seminiferous tubules as early as 2-3 months of age as a consequence of decreased water resorption in the efferent ducts. By 3-4 months of age, ERKO mice had impaired spermatogenesis in approximately 40% of their tubules, and sperm counts and motility declined in association with the histological changes. In the AA mice, histological defects were greatly reduced or absent, and sperm counts and motility were rescued. Levels of aquaporins 1 and 9, which contribute to water uptake in the efferent ducts, were reduced in ERKO mice and partially or fully rescued in AA mice, whereas another water transporter, sodium-hydrogen exchanger-3, was decreased in both ERKO and AA mice. We conclude that non-ERE-dependent estrogen pathways are sufficient to rescue the defective spermatogenesis observed in ERKO mice and play a prominent role in ERalpha action in the testis, including pathways that regulate water resorption and androgen biosynthesis.


Ca(2+)-activated anion channels and membrane depolarizations induced by blue light and cold in Arabidopsis seedlings.
The activation of an anion channel in the plasma membrane of Arabidopsis thaliana hypocotyls by blue light (BL) is believed to be a signal-transducing event leading to growth inhibition. Here we report that the open probability of this particular anion channel depends on cytoplasmic Ca2+ ([Ca2+]cyt) within the concentration range of 1 to 10 microM, raising the possibility that BL activates the anion channel by increasing [Ca2+]cyt. Arabidopsis seedlings cytoplasmically expressing aequorin were generated to test this possibility. Aequorin luminescence did not increase during or after BL, providing evidence that Ca2+ does not play a second-messenger role in the activation of anion channels. However, cold shock simultaneously triggered a large increase in [Ca2+]cyt and a 110-mV transient depolarization of the plasma membrane. A blocker of the anion channel, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, blocked 61% of the cold-induced depolarization without affecting the increase in [Ca2+]cyt. These data led us to propose that cold shock opens Ca2+ channels at the plasma membrane, allowing an inward, depolarizing Ca2+ current. The resulting large increase in [Ca2+]cyt activates the anion channel, which further depolarizes the membrane. Although an increase in [Ca2+]cyt may activate anion channels in response to cold, it appears that BL does so via a Ca(2+)-independent pathway.


Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial.
There is growing evidence that better outcomes are achieved when anticoagulation is managed by anticoagulation clinics rather than by family physicians. We carried out a randomized controlled trial to evaluate these 2 models of anticoagulant care. We randomly allocated patients who were expected to require warfarin sodium for 3 months either to anticoagulation clinics located in 3 Canadian tertiary hospitals or to their family physician practices. We evaluated the quality of oral anticoagulant management by comparing the proportion of time that the international normalized ratio (INR) of patients receiving warfarin sodium was within the target therapeutic range +/- 0.2 INR units (expanded therapeutic range) while they were managed in anticoagulation clinics as opposed to family physicians' care over 3 months. We measured the rates of thromboembolic and major hemorrhagic events and patient satisfaction in the 2 groups. Of the 221 patients enrolled, 112 were randomly assigned to anticoagulation clinics and 109 to family physicians. The INR values of patients who were managed by anticoagulation clinics were within the expanded therapeutic range 82% of the time versus 76% of the time for those managed by family physicians (p = 0.034). High-risk INR values (defined as being < 1.5 or > 5.0) were more commonly observed in patients managed by family physicians (40%) than in patients managed by anticoagulation clinics (30%, p = 0.005). More INR measurements were performed by family physicians than by anticoagulation clinics (13 v. 11, p = 0.001). Major bleeding events (2 [2%] v. 1 [1%]), thromboembolic events (1 [1%] v. 2 [2%]) and deaths (5 [4%] v. 6 [6%]) occurred at a similar frequency in the anticoagulation clinic and family physician groups respectively. Of the 170 (77%) patients who completed the patient satisfaction questionnaire, more were satisfied when their anticoagulant management was managed through anticoagulation clinics than by their family physicians (p = 0.001). Anticoagulation clinics provided better oral anticoagulant management than family physicians, but the differences were relatively modest.


Association of Risk of Viremia, Immunosuppression, Serious Clinical Events, and Mortality With Increasing Age in Perinatally Human Immunodeficiency Virus-Infected Youth.
As perinatally human immunodeficiency virus-infected youth (PHIVY) in the United States grow older and more treatment experienced, clinicians need updated information about the association of age, CD4 cell count, viral load (VL), and antiretroviral (ARV) drug use with risk of opportunistic infections, key clinical events, and mortality to understand patient risks and improve care. To examine the incidence or first occurrence during follow-up of key clinical events (including Centers for Disease Control and Prevention stage B [CDC-B] and stage C [CDC-C] events) and mortality among PHIVY stratified by age, CD4 cell count, and VL and ARV status. Combining data from the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 multicenter cohort studies (March 2007 through April 2015), we estimated event rates during person-time spent in key strata of age (7-12, 13-17, and 18-30 years), CD4 cell count (<200, 200-499, and ≥500/μL), and a combined measure of VL and ARV status (VL <400 or ≥400 copies/mL; ARV therapy or no ARV therapy). A total of 1562 participants in the PHACS Adolescent Master Protocol and IMPAACT P1074 were eligible, and 1446 PHIVY from 41 ambulatory sites in the 12 US states, including Puerto Rico were enrolled. The dates of analysis were March 2015 through January 2017. Clinical event rates stratified by person-time in age, CD4 cell count, and VL and ARV categories. A total of 1446 PHIVY participated in the study (mean [SD] age, 14.6 [4.6] years; 759 female [52.5%]; 953 black [65.9%]). During a mean (SD) follow-up of 4.9 (1.3) years, higher incidences of CDC-B events, CDC-C events, and mortality were observed as participants aged. Older PHIVY (aged 13-17 and 18-30 years) spent more time with a VL of 400 copies/mL or more and with a CD4 cell count of less than 200/µL compared with 7- to 12-year-old participants (30% and 44% vs 22% of person-time with a VL≥400 copies/mL; 5% and 18% vs 2% of person-time with CD4 cell count <200/µL; P < .001 for each comparison). We observed higher rates of CDC-B events, CDC-C events, bacterial infections, and mortality at lower CD4 cell counts, as expected. The mortality rate among older PHIVY was 6 to 12 times that among the general US population. Higher rates of sexually transmitted infections were also observed at lower CD4 cell counts after adjusting for age. Older PHIVY were at increased risk of viremia, immunosuppression, CDC-B events, CDC-C events, and mortality. Interventions to improve ARV therapy adherence and optimize models of care for PHIVY as they age are urgently needed to improve long-term outcomes among PHIVY.


Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo.
Dopamine signaling encodes reward learning and motivated behavior through modulation of synaptic signaling in the nucleus accumbens, and aberrations in these processes are thought to underlie obsessive behaviors associated with alcohol abuse. The nucleus accumbens is divided into core and shell sub-regions with overlapping but also divergent contributions to behavior. Here we optogenetically targeted dopamine projections to the accumbens allowing us to isolate stimulation of dopamine terminals ex vivo. We applied 5 pulse (phasic) light stimulations to probe intrinsic differences in dopamine release parameters across regions. Also, we exposed animals to 4weeks of chronic intermittent ethanol vapor and measured phasic release. We found that initial release probability, uptake rate and autoreceptor inhibition were greater in the accumbens core compared to the shell, yet the shell showed greater phasic release ratios. Following chronic ethanol, uptake rates were increased in the core but not the shell, suggesting region-specific neuronal adaptations. Conversely, kappa opioid receptor function was upregulated in both regions to a similar extent, suggesting a local mechanism of kappa opioid receptor regulation that is generalized across the nucleus accumbens. These data suggest that dopamine axons in the nucleus accumbens core and shell display differences in intrinsic release parameters, and that ethanol-induced adaptations to dopamine neuron terminal fields may not be homogeneous. Also, chronic ethanol exposure induces an upregulation in kappa opioid receptor function, providing a mechanism for potential over-inhibition of accumbens dopamine signaling which may negatively impact downstream synaptic function and ultimately bias choice towards previously reinforced alcohol use behaviors.


Effect of Addition of Multiwalled Carbon Nanotubes on the Piezoelectric Properties of Polypropylene Filaments.
The effect of addition of multiwalled carbon nanotubes (CNTs) on the piezoelectric properties of polypropylene (PP) monofilaments has been investigated. Various amounts of CNTs (0%, 0.01%, 0.1% and 1% weight ratios) were melt-blended with PP and the resulting nanocomposites were extruded in a continuous process with simultaneous on-line poling to produce monofilaments. Concurrent stretching at a draw ratio of 5:1 and polarisation at applied electric fields of 15 kV of PP/CNT filaments was observed to enhance the piezoelectric properties. The microstructure and crystallinity of the filaments was analysed using scanning electron microscopy (SEM), differential scanning calorimetric (DSC) and Fourier transform infrared spectroscopy (FTIR) techniques. Voltage generation by the CNT-modified PP filaments was determined by the application of predetermined load impact. The results show that the incorporation of CNTs in the PP fibre structure has a considerable impact on the enhancement of piezoelectric properties of the PP filament obtained that the peak voltage generation was almost four fold (from 0.76 V to 2.92 V) when 0.1 wt% of CNTs added into the polymer. This is owing to the fact that carbon nanotubes act as nucleating agent for enhancing the crystallisation during the melt extrusion process.


Norwalk gastroenteritis: a community outbreak associated with bakery product consumption.
From 23 to 26 August 1982, a gastrointestinal illness occurred among 129 of 248 (52%) persons interviewed who had attended four social events in the Minneapolis-St. Paul area. The median incubation period was 36 hours, and symptoms included diarrhea, nausea, headache, and vomiting. Findings of a food-specific questionnaire given to attendants of the four events confirmed that consumption of cake and frosting was significantly associated with development of the illness (odds ratio, 7.9 to 48.3; p = 0.006 to 0.00001). All cake items were purchased from a single bakery, where the employee who had prepared the frosting had had onset of diarrhea and vomiting on August 20. Given an approximate 60% attack rate among persons who ate frosted items, we estimate that 3000 outbreak-associated cases occurred. Serologic analysis confirmed that 17 of 25 ill persons had fourfold or greater rises in their antibody titer to Norwalk virus. Thus, foodborne transmission of Norwalk virus can result from contamination by a single foodhandler.


Regulation of stress-activated MAP kinase pathways during cell fate decisions.
Mammalian cells are frequently exposed to a variety of environmental stresses, such as ultraviolet rays, ionizing radiation, genotoxins, heat shock, and oxidative stress. In coping with the barrage of these and other stresses, multi-cellular eukaryotic organisms have developed a strategy as to how damaged cells will respond to stresses. In general, if the intensity of the damage is moderate, the cell will seek to repair the damage. If, however, the damage to a cell is too severe to be repaired, the affected cells are eliminated by apoptosis. This cell death reduces the risk to the organism as a whole, such as development of a cancer. Such a crucial decision between survival and death is, at least in part, mediated by the stress-activated MAP kinase (SAPK) pathways. SAPKs are a group of serine/threonine protein kinases that convert extracellular stress stimuli into diverse cellular responses, including cell cycle arrest, apoptotic cell death, and cytokine production, through phosphorylation of specific target proteins. Recent progress in the identification of molecules that participate in the SAPK pathways, such as GADD45 proteins and Wipl, has provided new insights, not only into the molecular basis of the cellular response to environmental stress, but also into the etiology of human diseases including cancer.


New approaches to treating Alzheimer's disease.
To date, no truly efficacious drugs for Alzheimer's disease (AD) have been developed; moreover, all new anti-AD drugs developed since 2003 have failed. To succeed where previous ones have failed in drug development, new approaches for AD therapy are needed. Here we discuss the potential application of network medicine as a new approach to AD treatment. Unlike traditional approaches focused on a single target/pathway, network medicine targets and restores disease-disrupted networks through simultaneous modulation of numerous proteins (targets)/pathways involved in AD pathogenesis. We consider several drug candidates under development for AD therapy, including Keap1-Nrf2 regulators, endogenous neurogenic agents, and hypoxia-inducible factor 1 (HIF-1) activators. These drug candidates are multi-target ligands with the potential to further develop as network medicines, since they act as master regulators to initiate a broad range of cellular defense mechanisms/cytoprotective genes that exert their efficacy in a holistic way. We also explore their diverse mechanisms of action and potential disease-modifying effects, which may have profound implications for drug discovery.


Cognitive and Motor Perseveration Are Associated in Older Adults.
Aging causes perseveration (difficulty to switch between actions) in motor and cognitive tasks, suggesting that the same neural processes could govern these abilities in older adults. To test this, we evaluated the relation between independently measured motor and cognitive perseveration in young (21.4 ± 3.7 y/o) and older participants (76.5 ± 2.9 y/o). Motor perseveration was measured with a locomotor task in which participants had to transition between distinct walking patterns. Cognitive perseveration was measured with a card matching task in which participants had to switch between distinct matching rules. We found that perseveration in the cognitive and motor domains were positively related in older, but not younger individuals, such that participants exhibiting greater perseveration in the motor task also perseverated more in the cognitive task. Additionally, exposure reduces motor perseveration: older adults who had practiced the motor task could transition between walking patterns as proficiently as naïve, young individuals. Our results suggest an overlap in neural processes governing cognitive and motor perseveration with aging and that exposure can counteract the age-related motor perseveration.


Obstructive sleep apnea syndrome: the diagnostic strategy dilemma.
Obstructive sleep apnea syndrome is a major public health hazard affecting 2-4% of the adult population; only 10% of these patients are recognized by healthcare providers. In the last decade the number of referrals for polysomnography increased threefold in Israel, compared to 12-fold worldwide, and is expected to increase even more in the coming years. This constant demand for PSG studies is beyond the current capacity of sleep laboratories, thus preventing diagnosis for most patients with suspected OSAS. In the current review, we examine problems facing decision-makers on how to treat the increasing flood of patients presenting with symptoms suggestive of sleep-disordered breathing. We evaluate the cost-effectiveness of current technologies for OSA diagnosis, i.e., laboratory versus at-home technologies. We conclude that no current alternative exists to the use of PSG for OSA diagnosis. When at-home technologies are suggested for OSAS diagnosis, data should be provided on factors influencing its cost-effectiveness, e.g., accuracy rates of diagnosis, relative cost of human resources, and case-mix of patients tested. Since PSG remains the gold standard for diagnosis of OSAS, in Israel resources should be allocated to increasing the volume of beds for PSG studies in order to increase access to diagnosis and treatment, which in turn provides better quality of life, saves scarce resources of the healthcare system, prevents unnecessary accidents and increases workers' productivity.


Ethical analysis in HTA of complex health interventions.
In the field of health technology assessment (HTA), there are several approaches that can be used for ethical analysis. However, there is a scarcity of literature that critically evaluates and compares the strength and weaknesses of these approaches when they are applied in practice. In this paper, we analyse the applicability of some selected approaches for addressing ethical issues in HTA in the field of complex health interventions. Complex health interventions have been the focus of methodological attention in HTA. However, the potential methodological challenges for ethical analysis are as yet unknown. Six of the most frequently described and applied ethical approaches in HTA were critically assessed against a set of five characteristics of complex health interventions: multiple and changing perspectives, indeterminate phenomena, uncertain causality, unpredictable outcomes, and ethical complexity. The assessments are based on literature and the authors' experiences of developing, applying and assessing the approaches. The Interactive, participatory HTA approach is by its nature and flexibility, applicable across most complexity characteristics. Wide Reflective Equilibrium is also flexible and its openness to different perspectives makes it better suited for complex health interventions than more rigid conventional approaches, such as Principlism and Casuistry. Approaches developed for HTA purposes are fairly applicable for complex health interventions, which one could expect because they include various ethical perspectives, such as the HTA Core Model® and the Socratic approach. This study shows how the applicability for addressing ethical issues in HTA of complex health interventions differs between the selected ethical approaches. Knowledge about these differences may be helpful when choosing and applying an approach for ethical analyses in HTA. We believe that the study contributes to increasing awareness and interest of the ethical aspects of complex health interventions in general.