Behavioral and cognitive impact of early life stress: Insights from an animal model.
Children subjected to traumatic events during childhood are reported to exhibit behavioral and cognitive deficits later in life, often leading to post-traumatic stress disorder (PTSD) and major depression. Interestingly, some children continue to remain normal despite being exposed to the same risk factors. These trauma-related behavioral and cognitive profiles across different stages of life are not well understood. Animal studies can offer useful insights. The goal of this study was to determine the impact of early life exposure to traumatic events on behavioral and cognitive profile in rats by tracking the behavior of each rat at different ages. We utilized the single prolonged stress (SPS), a rodent model of PTSD, to study the effects of early life stress. Male Sprague-Dawley rats were exposed to SPS on post-natal day (PND) 25. Tests to assess anxiety- and depression-like behavior, as well as learning and memory function were performed at PND32, 60 and 90. Rats exposed to SPS exhibited both anxiety- and depression-like behavior at PND32. And, short-term (STM) but not long-term memory (LTM) was impaired. Rats exposed to SPS at PND60 exhibited anxiety- but not depression-like behavior. STM but not LTM was impaired. Rats exposed to SPS at PND90 exhibited fearful (as indicated by elevated plus maze test) but not an overall anxiety-like behavior (in light and dark test). These rats also displayed significant depression-like behavior with no changes in STM or LTM. Interestingly, when data was further analyzed, two subsets of PND90 rats exposed to SPS were identified, "susceptible": with depression-like behavior and "resilient": without depression-like behavior. Importantly, while resilient group expressed early signs of anxiety- (at PND32 and PND60) and depression-like behavior (at PND32), these behavioral deficits were absent at PND90. On the other hand, susceptible PND90 rats exposed to SPS expressed later onset of anxiety-like behavior (at PND60), while depression-like phenotype was evident only later on at PND90. Our findings suggest that early life stress caused co-occurrence of anxiety and depression-like behavior at PND32 (mimics human early-adolescent period). This co-occurrence was lost at PND60 with demonstration of anxiety- but not depression-like behavior. Later, depression but not anxiety-like behavior was observed at PND90. It seems that behavioral adaptations occur at the critical PND60 stage (mimics human late-adolescent period), where behavioral and cognitive switching occurs, thereby, expressing susceptible and resilient phenotypes.


Uropathogenic Escherichia coli induces serum amyloid a in mice following urinary tract and systemic inoculation.
Serum amyloid A (SAA) is an acute phase protein involved in the homeostasis of inflammatory responses and appears to be a vital host defense component with protective anti-infective properties. SAA expression remains poorly defined in many tissues, including the urinary tract which often faces bacterial challenge. Urinary tract infections (UTIs) are usually caused by strains of uropathogenic Escherichia coli (UPEC) and frequently occur among otherwise healthy individuals, many of whom experience bouts of recurrent and relapsing infections despite the use of antibiotics. To date, whether SAA is present in the infected urothelium and whether or not the induction of SAA can protect the host against UPEC is unclear. Here we show, using mouse models coupled with immunofluorescence microscopy and quantitative RT-PCR, that delivery of UPEC either directly into the urinary tract via catheterization or systemically via intraperitoneal injection triggers the expression of SAA. As measured by ELISA, serum levels of SAA1/2 were also transiently elevated in response to UTI, but circulating SAA3 levels were only up-regulated substantially following intraperitoneal inoculation of UPEC. In in vitro assays, physiological relevant levels of SAA1/2 did not affect the growth or viability of UPEC, but were able to block biofilm formation by the uropathogens. We suggest that SAA functions as a critical host defense against UTIs, preventing the formation of biofilms both upon and within the urothelium and possibly providing clinicians with a sensitive serological marker for UTI.


Deposition of poly(styrene/alpha-tert-butoxy-omega-vinyl-benzyl-polyglycidol) microspheres on mica plates crossing the liquid-air interface: formation of stripe pattern.
Formation of stripelike assemblies of poly(styrene/alpha-tert-butoxy-omega-vinyl-benzyl-polyglycidol) microspheres adsorbed on nonpatterned mica plates moving perpendicularly from suspension of particles through the water-air interface has been observed. It was found that ordered assemblies were formed by capillary forces acting on particles crossing the water-air boundary. At sufficiently high rates of plate movement (i.e., at appropriate dynamic loading conditions) the adsorbed microspheres approaching the water surface begin sliding on the plate, due to capillary forces, in the direction opposite to the plate movement and are kept below the water surface. Plate movement brings new adsorbed particles to the water-air interface, where particles are assembled into aggregates. When particle aggregates are large, the capillary forces cannot overcome shearing forces and the particle assemblies are withdrawn on the plate above the water surface. This process repeated during continuous movement of the plate results in the formation of the quite regularly distributed stripes of adsorbed microspheres. Formation of the regularly distributed particle assemblies depends on concentration of microspheres in suspension.


Practical IMRT QA dosimetry using Gafchromic film: a quick start guide.
This work outlines a method for using Gafchromic film for dosimetry purposes, by scanning it with currently available commercial scanners. The scanners used were: Epson V800, Epson V700, Epson V37 series, specifically a V370 and a Canon multi-function office printer/scanner. The Epson scanners have 16 bit RGB resolution, the Canon has 8 bit RGB (Red Green Blue) resolution, and the V800 and V700 allow scanning in transmission mode. The V700 uses an Epson White Cold Cathode Florescent Lamp; the recently released V800 uses an Epson light emitting diode (LED) light source, while the V37 series uses a reflective mode and the Epson LED light source. The Epson V37 series scanners are designed for non-professional use so the cost has been kept at a low "entry level" point, so they would be a suitable option for a department wanting to use Gafchromic film or with limited needs that did not justify a more sophisticated and expensive unit. Note that the V800 or V700 scanners are not expensive in context, costing approximately the same as a 25 sheet box of Gafchromic film. The Canon was included to demonstrate that a scanner with 8 bit RGB resolution can be used for dosimetry. These general multi-function units are available in most departments, and they would allow Gafchromic film to be evaluated as a dosimetry tool without a significant investment. Furthermore, they are generally capable of scanning large format film (425 × 350 mm) in one part. Although this is not necessary for dosimetry, it is often useful for machine QA, where dividing the film into two parts to ensure accurate measurements is not practical. Moreover, this analytical method uses software that is freely or commonly available, particularly the image processing package ImageJ. Note ImageJ v1.48 was the version used. The results demonstrate that this method used with the scanners evaluated is a practical method of using Gafchromic film as a dosimeter for IMRT QA.


Knowledge and attitudes of parents and professionals to neonatal BCG vaccination in light of recent UK policy changes: a questionnaire study.
Universal BCG vaccination in the UK ended in 2005. The new vaccination policy instead offers a number of different forms of selective vaccination to newborns based on risk of acquiring TB. We set out to assess the attitudes and knowledge of both parents and professionals to the new policy for neonatal BCG vaccination. A short questionnaire was designed, made up of demographic and attitude questions, as well as very basic knowledge questions. The researchers handed out the questionnaire to all parents and professionals in the antenatal and postnatal areas, as well as the paediatric and neonatal units during a 6-week period. The site was the Royal Oldham hospital, a district general hospital with 3250 deliveries per year and multi-ethnic in its population mix. A total of 253 completed questionnaires were collected. The ethnic origin of responders was 50.6% White British, 18.2% Bangladeshi, 8.7% Indian, 4% White/Asian, the remaining 18.5% of other origins. 71.5% of responders said they had heard of BCG vaccine. When asked if they knew the new policy for its use, 33.2% answered yes. 24.5% gave the most accurate response when asked who now receives BCG. We have found that amongst parents and professionals alike there is a lack of knowledge of the new policy. This has lead to confusion and as knowledge amongst the professionals who identify neonates for vaccination is low, uptake may be sub-optimal. We suggest that units investigate the issue and ensure that the new policy is understood and implemented correctly.


Predictors of blood pressure control among hypertensives in community health centers.
The correlates of blood pressure (BP) control among hypertensive individuals who have access to care in community-based health-care settings are poorly characterized, particularly among minority and immigrant populations. Using data extracted from electronic medical records in four federally qualified health centers in New York, we investigated correlates of hypertension (HTN) control in cross-sectional analyses. The sample consisted of adult, nonobstetric patients with a diagnosis of HTN and a clinic visit between June 2007 and October 2008 (n = 2,585). Forty-nine percent of hypertensive patients had controlled BP at their last visit. Blacks had a higher prevalence of HTN (B, 32.8%; W, 16.2%; H, 11.5%) and were less likely to have controlled BP (B, 42.2%; W, 50.9%; H, 50.8%) compared with Hispanics and whites. Medication intensification did not differ by race/ethnicity. In multivariate analyses higher body mass index (BMI), black race, diabetes, fewer clinical encounters, and male gender were associated with poor BP control. However, when we applied the Seventh Report of the Joint National Committee (JNC 7) definition for BP control for nondiabetic patients (systolic blood pressure (SBP) <140, diastolic blood pressure (DBP) <90) to all patients with HTN, we found no difference in BP control between those with and without diabetes. Blacks had poorer HTN control compared with whites and Hispanics. Significant discrepancies in BP control between hypertensive patients with and without diabetes may be related to a lack of provider adherence to JNC 7 guidelines that define BP control in this population as <130/80. Further research is needed to understand racial disparities in BP control as well as factors influencing clinician's management of BP among patients with diabetes.


Insomnia treatment by olanzapine. Is sleep state misperception a psychotic disorder?
Offering a new perspective on sleep state misperception, we discuss a patient who presented with sleep state misperception and was ultimately diagnosed with delusional disorder. A 60-year-old woman with chief complaints of insomnia, agitation, and suicidal ideation, was admitted to an inpatient psychiatric ward. Based on information from her family and a mental state examination, her primary diagnosis was sleep state misperception. She was treated with Trazodone. Because she was unresponsive to the treatment, a full psychiatric evaluation and wrist actigraphy report were undertaken, resulting in a revised diagnosis of delusional disorder. She was started on Olanzapine and, after 6 weeks was discharged with good improvement. Sleep state misperception might be considered not just as a sleep disorder, but also as a psychiatric disorder with psychotic symptoms. Further research is recommended.


Local humoral immunity in patients with pollen allergy.
All classes of immunoglobulins and albumin have been studied in different phases of disease, both in blood and in the nasal secretions of 75 patients with pollen allergy. There were 20 healthy persons in the test group. Total correlational analysis was done to determine interdependence of the researched indexes. The percentage of local synthesis of immunoglobulins in the nasal secretion was calculated with the help of Donovan's formula. The results obtained allowed us to find out that the local origin was responsible for 74% of total IgE, 97% of IgA and 10% of IgG in the nasal secretion in patients with pollen allergy. While comparing the results of skin tests with RAST, both in blood and in the nasal secretion, a positive coincidence was found considering the results of skin tests and RAST in serum in 93.8% cases, and in the nasal secretion in 91% of the cases. Coincidence between negative skin tests and the results of RAST in serum was as high as 89% of the cases. In some cases with negative skin test, specific IgE to the corresponding pollen allergens was found in the nasal secretion. In most of the cases there was correlation between allergen specific IgE in blood and in the nasal secretion in the phase of remission (88% of cases) and in the phase of exacerbation (100%). Total and allergen specific IgE in the nasal secretion can be widely used to diagnose allergy "in vitro".


Protective Modifications in Ophthalmology Practice during COVID-19 Pandemic: Challenges and Lessons Learned.
Ophthalmology is a specialty which involves close contact with patients. Personal protective equipment (PPE) along with modifications in examination techniques and equipment are needed to avoid spread of coronavirus infectious disease (COVID-19) to health professionals. This communication aims to highlight and critically analyse the measures suggested to control this spread. We also highlighted our experience with protective gear modifications. As with any practice, triage is cornerstone. Use of disinfectants, good personal hygiene practices and PPE for patients and staff, must be adopted for safe ophthalmology practices. Key Words: COVID-19, Ophthalmology, Personal protective equipment (PPE).


Identification of eosinophil lineage-committed progenitors in the murine bone marrow.
Eosinophil lineage-committed progenitors (EoPs) are phenotypically isolatable in the steady-state murine bone marrow. Purified granulocyte/monocyte progenitors (GMPs) gave rise to eosinophils as well as neutrophils and monocytes at the single cell level. Within the short-term culture of GMPs, the eosinophil potential was found exclusively in cells activating the transgenic reporter for GATA-1, a transcription factor capable of instructing eosinophil lineage commitment. These GATA-1-activating cells possessed an IL-5Ralpha(+)CD34(+)c-Kit(lo) phenotype. Normal bone marrow cells also contained IL-5Ralpha(+)CD34(+)c-Kit(lo) EoPs that gave rise exclusively to eosinophils. EoPs significantly increased in number in response to helminth infection, suggesting that the EoP stage is physiologically involved in eosinophil production in vivo. EoPs expressed eosinophil-related genes, such as the eosinophil peroxidase and the major basic protein, but did not express basophil/mast cell-related mast cell proteases. The enforced retroviral expression of IL-5Ralpha in GMPs did not enhance the frequency of eosinophil lineage read-outs, whereas IL-5Ralpha(+) GMPs displayed normal neutrophil/monocyte differentiation in the presence of IL-5 alone. Thus, IL-5Ralpha might be expressed specifically at the EoP stage as a result of commitment into the eosinophil lineage. The newly identified EoPs could be the cellular target in the treatment of a variety of disorders mediated by eosinophils.


Early-stage microvascular alterations of a new model of controlled cortical traumatic brain injury: 3D morphological analysis using scanning electron microscopy and corrosion casting.
This study was performed to study the microvascular changes that occur during the first 12 hours after traumatic brain injury (TBI) using the corrosion casting technique. The authors performed a qualitative and quantitative morphological study of the changes in cerebral vessels at acute (3 hours) and subacute (12 hours) stages after experimental TBI. They used a model of controlled cortical impact (CCI) injury induced by a recently developed electromagnetic device (impactor), focusing their observations mainly on the microvascular alterations responsible for the formation and maintenance of tissue edema and consequent brain swelling during the first hours after TBI. They used corrosion casting, scanning electron microscopy (SEM), light microscopy, and transmission electron microscopy (TEM) to obtain a morphological qualitative map with both 2D and 3D details. Scanning electron microscopy analysis of vascular casts documented in 3 dimensions the typical injuries occurring after a TBI: subdural, subarachnoid, and intraparenchymal hemorrhages, along with alterations of the morphological characteristics and architecture of both medium-sized and capillary vessels, including ectasia of pial vessels, sphincter constrictions at the origin of the perforating vessels, focal swelling of perforating vessels, widening of intercellular junctions, and some indirect evidence of structural impairment of endothelial cells. All of these vascular alterations were confirmed in 2D analyses using light microscopy and TEM. The corrosion casting-SEM technique applied to a CCI experimental model proved to be a reliable method for studying the pathophysiology of the vascular alterations occurring at acute and subacute stages after CCI injury. It was also possible to obtain topographical localization of the vascular and cellular events that usually lead to hyperemia, edema, and brain swelling. Moreover, by applying informatic software to anatomical images it was possible to perform quantification and statistical analysis of the observed events.


Effect of gluten-free diet on cerebellar MR spectroscopy in gluten ataxia.
To evaluate the effect of gluten free diet (GFD) on magnetic resonance spectroscopy (MRS) of the cerebellum in patients with gluten ataxia (GA). Patients with GA, defined as sporadic ataxia with positive antigliadin antibodies in the absence of an alternative cause, routinely undergo MRS at baseline and after the introduction of GFD as part of their clinical care. We present our experience of the effect of GFD on MRS of the cerebellum. A total of 117 consecutive patients with GA were included in this report. Sixty-three were on strict GFD with elimination of antigliadin antibodies, 35 were on GFD but were still positive for antigliadin antibodies, and 19 patients opted not to go on GFD. The N-acetylaspartate (NAA)/creatine (Cr) area ratio from the cerebellar vermis increased in 62 out of 63 (98%) patients on strict GFD, in 9 of 35 (26%) patients on GFD but positive antibodies, and in only 1 of 19 (5%) patients not on GFD. The NAA/Cr ratio decreased in all 14 ataxia control patients (cerebellar variant of multisystem atrophy). There were no differences in the MRS results between those patients who had and those who did not have enteropathy (celiac disease) within each group. The demonstration of increased NAA/Cr ratio on repeat scanning following strict GFD strengthens previous findings of clinical improvement of the ataxia in patients with GA. The presence of enteropathy is not a prerequisite for such improvement; therefore patients with positive serology and negative duodenal biopsy should still be treated with strict GFD.


Regulations of miR-183-5p and Snail-Mediated Shikonin-Reduced Epithelial-Mesenchymal Transition in Cervical Cancer Cells.
Shikonin, the main ingredient of Lithospermum erythrorhizon, has been reported to have antitumor effects via multiple targets and signaling pathways. However, the detailed mechanism underlying the effects in cervical cancer still remained unknown. MTT, wound-healing, transwell assays and flow cytometry experiments were used to measure cell growth, migration, invasion, and cell cycle analysis. Western blot was used to examine protein levels of Snail, Vimentin and E-cadherin. The expression level of miR-183-5p was measured via qRT-PCR. The E-cadherin promoter activity was detected via Secrete-PairTM Dual Luminescence Assay Kit. The transient transfection experiments were used for silencing of E-cadherin and overexpression of Snail genes. Tumor xenograft and bioluminescent imaging experiments were carried out to confirm the in vitro findings. We showed that shikonin inhibited cell viability, migration and invasion, and induced cell cycle arrest in a dose-dependent manner in cervical cancer Hela and C33a cells. Mechanistically, we found that shikonin increased miR-183-5p expression and inhibited expression of transcription factor Snail protein. The mimics of miR-183-5p reduced, while the inhibitors of miR-183-5p reversed shikonin-inhibited Snail protein expression. In addition, shikonin decreased Vimentin, increased E-cadherin protein expressions and E-cadherin promoter activity, the latter was reversed in cells transfected with exogenous Snail overexpression vectors. Moreover, silencing of E-cadherin significantly abolished shikonin-inhibited cervical cancer cell growth. Similar findings were also observed in vivo using one xenograft mouse model. Our results show that shikonin inhibits EMT through inhibition of Snail and stimulation of miR-183-5p expressions, which resulted in induction of E-cadherin expression. Thus, blockade of EMT could be a novel mechanism underlying the anti-cervical cancer effects of shikonin.


Carbohydrate Staple Food Modulates Gut Microbiota of Mongolians in China.
Gut microbiota is a determining factor in human physiological functions and health. It is commonly accepted that diet has a major influence on the gut microbial community, however, the effects of diet is not fully understood. The typical Mongolian diet is characterized by high and frequent consumption of fermented dairy products and red meat, and low level of carbohydrates. In this study, the gut microbiota profile of 26 Mongolians whom consumed wheat, rice and oat as the sole carbohydrate staple food for a week each consecutively was determined. It was observed that changes in staple carbohydrate rapidly (within a week) altered gut microbial community structure and metabolic pathway of the subjects. Wheat and oat favored bifidobacteria (Bifidobacterium catenulatum, Bifodobacteriumbifidum, Bifidobacterium adolescentis); whereas rice suppressed bifidobacteria (Bifidobacterium longum, Bifidobacterium adolescentis) and wheat suppresses Lactobaciilus, Ruminococcus and Bacteroides. The study exhibited two gut microbial clustering patterns with the preference of fucosyllactose utilization linking to fucosidase genes (glycoside hydrolase family classifications: GH95 and GH29) encoded by Bifidobacterium, and xylan and arabinoxylan utilization linking to xylanase and arabinoxylanase genes encoded by Bacteroides. There was also a correlation between Lactobacillus ruminis and sialidase, as well as Butyrivibrio crossotus and xylanase/xylosidase. Meanwhile, a strong concordance was found between the gastrointestinal bacterial microbiome and the intestinal virome. Present research will contribute to understanding the impacts of the dietary carbohydrate on human gut microbiome, which will ultimately help understand relationships between dietary factor, microbial populations, and the health of global humans.


How to make head or tail of 'bridging' and 'bonding'?: addressing the methodological ambiguity.
A distinction has recently been proposed between bridging (or encompassing) and bonding (or inward-looking) social networks. However, existing theoretical contributions remain vague as to the fundamental meaning of both concepts. As a consequence, two distinct interpretations have developed alongside each other. In the present paper, we employ data on voluntary association membership in Flanders to empirically illustrate that both approaches can lead to substantially different outcomes and therefore appear to tap into different dimensions of bridging versus bonding. These findings underline the problematic nature of the current conceptual ambiguity. We conclude that should the bridging/bonding distinction add meaningfully to our understanding of the external effects of social networks, it is essential to resolve the conceptual and methodological imprecision.


Surface characterization and platelet adhesion studies on fluorocarbons prepared by plasma-induced graft polymerization.
It is believed that the interactions between the biological environment and biomaterial surface are the key factors influencing its biocompatibility. Therefore, plasma processing, which can vary the surface properties without altering the bulk properties, has been considered as one of the important techniques for improving a materials' biocompatibility. In this investigation, plasma-induced grafting polymerization of vinylidene fluoride (VDF) and chlorotrifluoroethylene (CTFE), instead of direct plasma polymerization, was attempted with an aim to improve the substrate blood compatibility. Contact angle measurement indicated both fluorocarbon-grafted Pdyethylenes (PEs) are hydrophobic. Due to the additional fluorine and chlorine atoms on the CTFE chain, the PCTFE-grafted PE exhibited a higher hydrophobicity than the PVDF-grafted one. ESCA analysis has revealed that these two plasma-induced fluorocarbon deposits contain almost no CFx (x > 2) binding on the surface layer, indicating the grafting polymerization mainly follows the free radical mechanism instead of the molecule-highly-fragmented reaction steps commonly seen in the direct plasma polymerization treatment. In addition, ATR-FTIR has shown the surface chemical configuration of these PVDF- and PCTFE-grafted PEs to be very similar to those of the bulk samples of PVDF and PCTFE. The surface roughness decreased after oxygen plasma treatment and was further reduced by VDF and CTFE grafting polymerization. In vitro platelet adhesion testing indicated these two fluorocarbon grafted PEs are less platelet-activating than the nontreated PE control and oxygen plasma activated one.


Detecting overlapping protein complexes based on a generative model with functional and topological properties.
Identification of protein complexes can help us get a better understanding of cellular mechanism. With the increasing availability of large-scale protein-protein interaction (PPI) data, numerous computational approaches have been proposed to detect complexes from the PPI networks. However, most of the current approaches do not consider overlaps among complexes or functional annotation information of individual proteins. Therefore, they might not be able to reflect the biological reality faithfully or make full use of the available domain-specific knowledge. In this paper, we develop a Generative Model with Functional and Topological Properties (GMFTP) to describe the generative processes of the PPI network and the functional profile. The model provides a working mechanism for capturing the interaction structures and the functional patterns of proteins. By combining the functional and topological properties, we formulate the problem of identifying protein complexes as that of detecting a group of proteins which frequently interact with each other in the PPI network and have similar annotation patterns in the functional profile. Using the idea of link communities, our method naturally deals with overlaps among complexes. The benefits brought by the functional properties are demonstrated by real data analysis. The results evaluated using four criteria with respect to two gold standards show that GMFTP has a competitive performance over the state-of-the-art approaches. The effectiveness of detecting overlapping complexes is also demonstrated by analyzing the topological and functional features of multi- and mono-group proteins. Based on the results obtained in this study, GMFTP presents to be a powerful approach for the identification of overlapping protein complexes using both the PPI network and the functional profile. The software can be downloaded from http://email@example.com/dai/others/GMFTP.zip.


Using MRI art, poetry, photography and patient narratives to bridge clinical and human experiences of stroke recovery.
Integrating co-produced humanities-based pedagogy into patient and workforce education is of growing interest. The aim of our Depth of Field: Exploring Stroke Recovery project grew from a strong commitment to use patients' lived experiences as a voice to educate new stroke patients and the health professional staff who will care for them. The aim of the initial Quality Improvement project at a West Australian Stroke Rehabilitation Unit (SRU) was to co-produce a reflective learning resource with stroke patients and their families to help navigate the stroke recovery journey. A series of artefacts (documentary-style photographs, audio-narrated vignettes, MRI images and poetry) were collected from four stroke patients and their families at differing stages of recovery over 12 months as they recounted the honest and raw reality of what life is really like following a stroke. These artefacts were used in a pilot qualitative project to explore new stroke patients, their families and SRU health professional staff perceptions towards the artefacts in order to inform the final educational resource. These findings enhance our understandings of how we can use art and patient (healthcare consumers) voice to widen the lens of stroke recovery and provides a valuable template to co-produce peer-to-peer and health professions education reflective learning resources to promote more human- centred approaches to care.


Ghrelin's Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction.
Understanding the intricate pathways that modulate appetite and subsequent food intake is of particular importance considering the rise in the incidence of obesity across the globe. The serotonergic system, specifically the 5-HT2C receptor, has been shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor that is well-known for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signaling is not due to coupling to GαS, as no increase in cAMP signaling is observed. Next, flow cytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT2C receptor. In addition, we demonstrate colocalized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signaling is blocked ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into a biologically significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management.


Description of immatures of the genus Tropisternus Solier, subgenus Pristoternus Orchymont (Coleoptera: Hydrophilidae), with emphasis on the chaetotaxy and morphometry of larval forms.
The egg cases, larvae, and pupae of Tropisternus (Pristoternus) latus (Brullé, 1837), T. (P.) ovalis Castelnau, 1840, and T. (P.) laevis (Sturm, 1826) are illustrated and described for the first time. The egg cases are built with or without a mast, which can be ribbon-like or globular; all larval instars have seven anterior denticles in the anterior margin of nasale, and the antennal seta AN8 is present; the pupae bear 6 or 8 styli on the abdominal segments II-VI, the pleural styli can be either short or very long, and horn-like projections may be present on the abdominal segments II-VI. A comparison of the morphology of the egg cases, pupae and larval chaetotaxic and morphometric characters within the genus Tropisternus is presented.


One platform solid multicolour emission of terthiophene compounds controlled by mixed self-assembly.
Via the mixed self-assembling procedure, solid multicolour emission materials based on an amphiphilic terthiophene compound are obtained from a unimolecular platform. Upon controlling the concentration of the cationic surfactant dodecyltriethyl ammonium bromide (DEAB) in the precipitate-monomer equilibrium system of the terthiophene compound TTC4L, mixed self-assembly of TTC4L-DEAB results in diverse structures (including plates, spheres, and needles) with different emission colours. The multicolour emissions are triggered by the different distances between the terthiophene groups in these mixed self-assemblies. Each distance corresponds to a specific molecular state of terthiophene groups, so that emissions corresponding to the monomers, excimers, and aggregates are obtained. Upon variation of the ratio of DEAB and TTC4L, the relative fraction of emissions corresponding to the monomers, excimers, and aggregates of TTC4L changes. This approach may act as a simple method to control the stacking mode of the oligothiophene group which is anticipated to realize unimolecular-platform multicolour emissions.


Histamine H(3)-receptor antagonists inhibit gastroprotection by (R)-alpha-methylhistamine in the rat.
(R)-alpha-methylhistamine, a selective agonist of histamine H(3) receptors, is capable of protecting the gastric mucosa against differently acting damaging agents. The objective of the present study was to determine whether H(3) receptors mediate its protective action in the rat. Gastric mucosal lesions were induced intragastrically (i.g.) by 0.6 N HCl, 1 ml rat(-1). (R)-alpha-methylhistamine, 100 mg kg(-1) i.g., substantially reduced the severity of macroscopically and histologically assessed damage caused by concentrated acid. Prior treatment with highly selective H(3)-receptor antagonists, ciproxifan (0.3, 1 and 3 mg kg(-1) i.g.) and clobenpropit (3, 10 and 30 mg kg(-1) i.g.), dose-dependently inhibited the protection exerted by (R)-alpha-methylhistamine up to a complete reversal. When given alone at high doses, both antagonists tended to worsen the HCl-induced histologic damage. During basal conditions, (R)-alpha-methylhistamine, 100 mg kg(-1) i. g., caused a significant increase in titratable acidity of the gastric juice. Prior treatment with ciproxifan (3 mg kg(-1) i.g.) and clobenpropit (30 mg kg(-1) i.g.) did not alter the secretory response to (R)-alpha-methylhistamine. Clobenpropit alone, but not ciproxifan, increased the volume of gastric juice, and both compounds alone had no effect on titratable acid. Present findings support evidence that H(3) receptors are actively involved in the maintenance of gastric mucosal integrity, with no apparent role in the regulation of basal gastric acid secretion.


Addressing self-injury in the school setting.
A growing number of students presenting with nonlethal self-injury has recently captured the attention of school nurses. The purpose of intentional self-harm is aimed at reducing emotional distress. This is not a new phenomenon, but what is alarming is the increasing incidence of self-injurious behavior among adolescents. This behavior is raising many questions for school staff. School nurses, along with guidance department staff, are searching for information and direction needed to address this behavior. School nurses, educated about self-injury, can serve as resources for other school staff members. Prevention strategies for all adolescents can be developed as well as strategies targeted at groups of at-risk adolescents. Because mental health care is critical for the treatment of self-injury, referral and early access to counseling is an important role for school nurses. In addition, a plan that includes educating staff members and parents can be developed. Included in this comprehensive plan is developing a protocol to be used to guide the care of adolescents who self-injure.


The degree of calcification and the weight of pineal glands in Ugandan Africans.
Two hundred formalin fixed, isolated pineal glands from Ugandan Africans have been X-rayed in consecutive unselected post mortems using a laboratory X-ray machine. The degree of calcification has been divided into four stages and according to this up to 43% of all pineal glands after the age of 10 years are likely to be detected in an ordinary skull X-ray. In females the pineal glands have been more often calcified and heavier than in males, however the stalk of pineal glands in males has shown more frequent calcifications than in females. The average weight per decade has been almost constant throughout the life span. In Ugandan Africans the pineal glands were significantly lighter than in Caucasians and possible reasons for this feature are discussed.


Enhancing Structure Prediction and Design of Soluble and Membrane Proteins with Explicit Solvent-Protein Interactions.
Solvent molecules interact intimately with proteins and can profoundly regulate their structure and function. However, accurately and efficiently modeling protein solvation effects at the molecular level has been challenging. Here, we present a method that improves the atomic-level modeling of soluble and membrane protein structures and binding by efficiently predicting de novo protein-solvent molecule interactions. The method predicted with unprecedented accuracy buried water molecule positions, solvated protein conformations, and challenging mutational effects on protein binding. When applied to homology modeling, solvent-bound membrane protein structures, pockets, and cavities were recapitulated with near-atomic precision even from distant homologs. Blindly refined atomic-level structures of evolutionary distant G protein-coupled receptors imply strikingly different functional roles of buried solvent between receptor classes. The method should prove useful for refining low-resolution protein structures, accurately modeling drug-binding sites in structurally uncharacterized receptors, and designing solvent-mediated protein catalysis, recognition, ligand binding, and membrane protein signaling.


Diagnostic Accuracy of Single-Lead Electrocardiograms Using the Kardia Mobile App and the Apple Watch 4: Validation Study.
To date, the 12-lead electrocardiogram (ECG) is the gold standard for cardiological diagnosis in clinical settings. With the advancements in technology, a growing number of smartphone apps and gadgets for recording, visualizing, and evaluating physical performance as well as health data is available. Although this new smart technology is innovative and time- and cost-efficient, less is known about its diagnostic accuracy and reliability. This study aimed to examine the agreement between the mobile single-lead ECG measurements of the Kardia Mobile App and the Apple Watch 4 compared to the 12-lead gold standard ECG in healthy adults under laboratory conditions. Furthermore, it assessed whether the measurement error of the devices increases with an increasing heart rate. This study was designed as a prospective quasi-experimental 1-sample measurement, in which no randomization of the sampling was carried out. In total, ECGs at rest from 81 participants (average age 24.89, SD 8.58 years; n=58, 72% male) were recorded and statistically analyzed. Bland-Altman plots were created to graphically illustrate measurement differences. To analyze the agreement between the single-lead ECGs and the 12-lead ECG, Pearson correlation coefficient (r) and Lin concordance correlation coefficient (CCCLin) were calculated. The results showed a higher agreement for the Apple Watch (mean deviation QT: 6.85%; QT interval corrected for heart rate using Fridericia formula [QTcF]: 7.43%) than Kardia Mobile (mean deviation QT: 9.53%; QTcF: 9.78%) even if both tend to underestimate QT and QTcF intervals. For Kardia Mobile, the QT and QTcF intervals correlated significantly with the gold standard (rQT=0.857 and rQTcF=0.727; P<.001). CCCLin corresponded to an almost complete heuristic agreement for the QT interval (0.835), whereas the QTcF interval was in the range of strong agreement (0.682). Further, for the Apple Watch, Pearson correlations were highly significant and in the range of a large effect (rQT=0.793 and rQTcF=0.649; P<.001). CCCLin corresponded to a strong heuristic agreement for both the QT (0.779) and QTcF (0.615) intervals. A small negative correlation between the measurement error and increasing heart rate could be found of each the devices and the reference. Smart technology seems to be a promising and reliable approach for nonclinical health monitoring. Further research is needed to broaden the evidence regarding its validity and usability in different target groups.


Twenty-first century graduate education in clinical psychology: a four level matrix model.
Clinical psychology is positioned to play key roles in mental and physical health issues of 21st century America. In this regard, however, the present Boulder model of educating clinical psychologists is not preparing our graduates to meet the diverse demands of either today's or tomorrow's marketplaces. Accordingly, we introduce a new, four level "matrix model" for the education of future clinical psychologists. The core focus of the proposed matrix model is on the weaknesses and strengths of people in their personalities and their environments. Moreover, this matrix model operates at the individual, interpersonal, institutional, and societal-community levels of analyses. The details and implications of this proposed educational curriculum are described.


A survey of infectious bovine keratoconjunctivitis in the Gisborne and Hunterville regions of New Zealand.
A postal survey of 400 beef farmers in the Hunterville and Gisborne districts sought to identify features of farms or management procedures that might influence the occurrence, transmission or severity of infectious bovine keratoconjunctivitis (IBK). The overall response rate was 72%. The annual incidence of IBK outbreaks rose from 10% to 28% between the years 1977 to 1981 and was similar for both districts. Prevalence was highest during mid-summer and lowest in mid-winter. Larger properties were more prone to outbreaks. In both districts, farmers of IBK-free properties purchased fewer cattle than those who had experienced IBK and this distinction was more evident in the Hunterville area. Only in the Gisborne district did a Hereford breed predisposition to infection become apparent. All age groups were affected with IBK but the attack rate was highest in the younger cattle. Eleven percent of farmers routinely treated their cattle for IBK and that produced an earlier resolution of lesions and fewer cattle in which healing extended longer than four weeks. Most farmers considered IBK to be an inconvenience which limited livestock production through reducing growth rates and lowering monetary returns when stock had to be sold at unsuitable times. Eye disfigurement caused loss of value in stud and export stock.


Erythro-PmBs: A Selective Polymyxin B Delivery System Using Antibody-Conjugated Hybrid Erythrocyte Liposomes.
As a result of the growing worldwide antibiotic resistance crisis, many currently existing antibiotics have become ineffective due to bacteria developing resistive mechanisms. There are a limited number of potent antibiotics that are successful at suppressing microbial growth, such as polymyxin B (PmB); however, these are often deemed as a last resort due to their toxicity. We present a novel PmB delivery system constructed by conjugating hybrid erythrocyte liposomes with antibacterial antibodies to combine a high loading efficiency with guided delivery. The retention of PmB is enhanced by incorporating negatively charged lipids into the red blood cells' cytoplasmic membrane (RBCcm). Anti-Escherichia coli antibodies are attached to these hybrid erythrocyte liposomes by the inclusion of DSPE-PEG maleimide linkers. We show that these erythro-PmBs have a loading efficiency of ∼90% and are effective in delivering PmB to E. coli, with values for the minimum inhibitory concentration (MIC) being comparable to those of free PmB. The MIC values for Klebsiella aerogenes, however, significantly increased well beyond the resistant breakpoint, indicating that the inclusion of the anti-E. coli antibodies enables the erythro-PmBs to selectively deliver antibiotics to specific targets.


Thermal and nonthermal signatures of the Unruh effect in Casimir-Polder forces.
We show that Casimir-Polder forces between two relativistic uniformly accelerated atoms exhibit a transition from the short distance thermal-like behavior predicted by the Unruh effect to a long distance nonthermal behavior, associated with the breakdown of a local inertial description of the system. This phenomenology extends the Unruh thermal response detected by a single accelerated observer to an accelerated spatially extended system of two particles, and we identify the characteristic length scale for this crossover with the inverse of the proper acceleration of the two atoms. Our results are derived separating at fourth order in perturbation theory the contributions of vacuum fluctuations and radiation reaction field to the Casimir-Polder interaction between two atoms moving in two generic stationary trajectories separated by a constant distance and linearly coupled to a scalar field. The field can be assumed in its vacuum state or at finite temperature, resulting in a general method for the computation of Casimir-Polder forces in stationary regimes.


A Tn10-lacZ-kanR-URA3 gene fusion transposon for insertion mutagenesis and fusion analysis of yeast and bacterial genes.
We describe here a new variant of transposon Tn10 especially adapted for transposon analysis of cloned yeast genes; it can equally well be used for analysis of prokaryotic genes. We have applied this element to analysis of the LEU2, RAD50, and CDC48 genes of Saccharomyces cerevisiae. This transposon, nicknamed mini-Tn10-LUK, contains a lacZ gene without efficient transcription or translation start signals, an intact URA3 gene, and a kanR determinant. The lacZ gene can be activated by appropriate insertion of the element into an actively expressed gene. Other yeast genes can easily be substituted for URA3 in the available constructs. The mini-Tn10-LUK system has several important advantages. Transposition events occur in Escherichia coli at high frequency and into many different sites in yeast DNA. It is easy to obtain enough insertions to sensitively define the functional limits of a gene. Transposon insertions can be obtained in a single step by standard transposon procedures and can be screened immediately for phenotype either in yeast or in E. coli. The LacZ phenotypes of the insertion mutations provide a good circumstantial indication of the orientation of the target gene. Under favorable circumstances, usable lacZ protein fusions are created. Transposon insertion mutations obtained by this method directly facilitate additional genetic, functional, physical and DNA sequence analysis of the gene or region of interest.


Studies of competing evaporation rates of multiple volatile components from a single binary-component aerosol droplet.
The simultaneous evaporation and condensation of multiple volatile components from multicomponent aerosol droplets leads to changes in droplet size, composition and temperature. Measurements and models that capture and predict these dynamic aerosol processes are key to understanding aerosol microphysics in a broad range of contexts. We report measurements of the evaporation kinetics of droplets (initially ∼25 μm radius) formed from mixtures of ethanol and water levitated within a electrodynamic balance over timescales spanning 500 ms to 6 s. Measurements of evaporation into a gas phase of varied relative humidity and temperature are shown to compare well with predictions from a numerical model. We show that water condensation from the gas phase can occur concurrently with ethanol evaporation from aqueous-ethanol droplets. Indeed, water can condense so rapidly during the evaporation of a pure ethanol droplet in a humid environment, driven by the evaporative cooling the droplet experiences, that the droplet becomes pure water within 0.4 s.


Intensive versus conventional therapy to slow the progression of idiopathic glomerular diseases.
Chronic kidney disease (CKD) caused by idiopathic glomerular diseases usually is progressive. Inhibition of the renin-angiotensin system (RAS) retards, but does not abrogate, CKD progression. Statins and spironolactone may decrease the rate of CKD progression independently or in addition to RAS inhibition. Randomized open-label study. We recruited 128 patients (82 men and 46 women) with a clinical diagnosis of idiopathic chronic glomerulonephritis and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) (range, 36-102 mL/min/1.73 m(2)), and urine protein-creatinine ratio ranging from 1.1-5.2 g/g. Intensive therapy (a combination of RAS inhibitors [angiotensin-converting enzyme [ACE] inhibitors plus angiotensin receptor blockers [ARBs] plus a high-dose statin and spironolactone) versus conventional therapy (a regimen based on ACE inhibitors with a low-dose statin). Changes in eGFR, proteinuria, and adverse events after 3 years of therapy. With intensive therapy, urine protein-creatinine ratio decreased from 2.65 (range, 1.1-5.2) to 0.45 (0.14-1.51) g/g (P < 0.001) and eGFR did not significantly change over time (64.6 +/- 2.1 vs 62.9 +/- 2.9 mL/min/1.73 m(2)). With conventional therapy, urine protein-creatinine ratio decreased from 2.60 (range, 1.32-5.4) to 1.23 (0.36-3.42) g/g (P < 0.001) and eGFR decreased from 62.5 +/- 1.7 to 55.8 +/- 1.9 mL/min/1.73 m(2) (P < 0.001). Comparison of the decreases in proteinuria and GFR between intensive versus conventional therapy was significantly different starting in the 1st and 12th months, respectively. Systolic blood pressure was lower with intensive than conventional therapy (113.5 +/- 1.4 vs 122.7 +/- 1.2 mm Hg; P < 0.01). We found an inverse relationship between percentage of decrease in proteinuria and change in eGFR (P < 0.001). Patients on intensive therapy were more likely to develop adverse events, such as hyperkalemia (9 vs 3 patients in the conventional therapy group) and discontinue therapy (15 vs 8 patients in the conventional therapy group). Open-label design. A more intensive therapy that includes a combination of ACE inhibitors and ARBs plus high-dose statins and spironolactone may retard CKD progression more effectively than conventional therapy based on ACE inhibitors plus low-dose statin, but may lead to more adverse effects and discontinuation of therapy.


Dynamics of sodium channel Nav1.5 expression in astrocytes in mouse models of multiple sclerosis.
Astrocytes actively participate in the response of the central nervous system to injury, including in multiple sclerosis. Astrocytes can play both beneficial and detrimental roles in response to neuroinflammation; however, in extreme cases, astrogliosis can result in the formation of a glial scar, which can impede the regeneration of injured neurons. Although astrocytes do not express the voltage-gated sodium channel Nav1.5 in the nonpathological human brain, they exhibit robust upregulation of Nav1.5 within acute and chronic multiple sclerosis lesions. Recent work has indicated that Nav1.5 contributes to the pathways that regulate glial scar formation in vitro through modulation of intracellular Ca levels. However, the temporal dynamics of astrocytic Nav1.5 channel expression in response to neuroinflammatory pathologies has not been investigated. We examined astrocytes from mice with monophasic and chronic-relapsing (CR) experimental autoimmune encephalomyelitis (EAE) by immunohistochemical analysis to determine whether Nav1.5 is expressed in these cells, and whether the expression correlates with the severity of disease and/or phases of relapse and remission. Our results demonstrate that Nav1.5 is upregulated in astrocytes in situ in a temporal manner that correlates with disease severity in both monophasic and CR EAE. Further, in CR EAE, Nav1.5 expression is upregulated during relapses and subsequently attenuated during periods of remission. These observations are consistent with the suggestion that Nav1.5 can play a role in the response of astrocytes to inflammatory pathologies in the central nervous system and suggest Nav1.5 may be a potential therapeutic target to modulate reactive astrogliosis in vivo.


Index and adjacent level kinematics after cervical disc replacement and anterior fusion: in vivo quantitative radiographic analysis.
Prospective, randomized trial. To assess the in vivo kinematics of the cervical spine after cervical fusion and arthroplasty. Compared with spinal fusion, disc replacement may impede the development of adjacent segment disease. To achieve this goal, any arthroplasty device should achieve desired spinal alignment while maintaining physiologic spinal motion at both the operated and surrounding motion segments. As part of a multicenter, prospective, randomized Food and Drug Administration IDE clinical evaluation of the porous coated motion artificial cervical disc, patients underwent either a single-level total disc replacement (TDR; 272 patients) or anterior cervical discectomy and fusion (ACDF; 182 patients) for treatment of cervical radiculopathy or myelopathy. Neutral, flexion, and extension radiographs of the cervical spine obtained before surgery, and at 3, 6, and 12 months after surgery were assessed. Quantitative assessments and comparisons of motion patterns were produced using validated computer-assisted methods. Kinematic parameters, including segmental rotation, translation, center of rotation (COR), disc height, and disc angle were calculated. Cervical TDR preserved angular motion at the operated level, although the range was reduced from 8.0° before surgery to 6.2° at 12 months after surgery (P < 0.001). Significantly after TDR, adjacent-level angular motion was unchanged. In patients treated with fusion, angular motion at the superior adjacent level increased from 9.6° before surgery to 11.0° (P = 0.003) at 12 months, with a trend toward increased postoperative translation (P = 0.07). For the TDR group, the horizontal COR averaged 0.8 mm posterior to the disc center before surgery and 0.2 mm anterior to the center at 12 months after TDR (P < 0.001), and the vertical COR averaged 2.5 mm below the endplate before surgery and 4.0 mm below at 12 months (P = 0.001). COR at the adjacent levels was unaltered by fusion or TDR. Lordotic alignment and disc height at the index level increased after intervention in both groups. TDR with the porous coated motion implant is able to restore and maintain lordotic alignment and disc height and maintain angular motion while allowing for similar translation to that seen before surgery. In contrast, after ACDF, the superior adjacent level developed increased angular motion compared with preoperative range of motion. This study provides in vivo data regarding the functioning of TDR and ACDF and their impact on adjacent-level kinematics.


Nurses' decision on seclusion: patient characteristics, contextual factors and reflexivity in teams.
While many characteristics of patients, professionals and facilities with relevance to seclusion rates have been investigated, their relative importance is unclear. Virtually no attention has been paid to team processes and reflexivity in relation to decision making on seclusion. The aim of this paper is to estimate the effects of these factors on nurse decision making on seclusion. Sixty Dutch psychiatric nurses of four closed wards reported team reflexivity and their tendency to seclude a theoretical patient. Approachability (whether there was a good or hardly any possibility to communicate with the patient), staffing level and confidence within the team had the greatest impact on the decision to seclude. Intra class correlation was 0.30. There was a large interaction effect of reflexivity with team 4, and team reflexivity was highly correlated with team tendency to avoid seclusion. In nurses' decision on seclusion, the effects of 'pure' patient characteristics are small as compared with the effects of interpersonal and contextual factors, and nurses vary widely in their judgement. Team reflexivity is related to the tendency to prevent seclusion.


Relationships between exercise-induced reductions in thigh intermuscular adipose tissue, changes in lipoprotein particle size, and visceral adiposity.
Small LDL and HDL particle size are characteristic of a proatherogenic lipoprotein profile. Aerobic exercise increases these particle sizes. Although visceral adipose tissue (VAT) has been strongly linked with dyslipidemia, the importance of intermuscular adipose tissue (IMAT) to dyslipidemia and exercise responses is less well understood. We measured exercise-associated changes in thigh IMAT and VAT and examined their relationships with changes in LDL and HDL particle size. Sedentary, dyslipidemic, overweight subjects (n = 73) completed 8-9 mo of aerobic training. Linear regression models were used to compare the power of IMAT change and VAT change to predict lipoprotein size changes. In men alone (n = 40), IMAT change correlated inversely with both HDL size change (r = -0.42, P = 0.007) and LDL size change (r = -0.52, P < 0.001). That is, reduction of IMAT was associated with a shift toward larger, less atherogenic lipoprotein particles. No significant correlations were observed in women. After adding VAT change to the model, IMAT change was the only significant predictor of either HDL size change (P = 0.034 for IMAT vs. 0.162 for VAT) or LDL size change (P = 0.004 for IMAT vs. 0.189 for VAT) in men. In conclusion, in overweight dyslipidemic men, exercise-associated change in thigh IMAT was inversely correlated with both HDL and LDL size change and was more predictive of these lipoprotein changes than was change in VAT. Reducing IMAT through aerobic exercise may be functionally related to some improvements in atherogenic dyslipidemia in men.


Changes of cyclic AMP concentration to isoproterenol after abrupt cessation of propranolol in rats.
Because the mechanism of adverse reactions to abrupt cessation of propranolol in patients with coronary heart disease was an enigma, we studied the effect of cessation of propranolol on beta-adrenergic receptor reactivity to catecholamine stimulation. The cyclic AMP concentrations in plasma and left ventricular muscle after the administration of isoproterenol (5 mg/Kg) were measured in rats before, during, 2 days after, and 4 days after of the administration of propranolol (5 mg/Kg). Two days after withdrawal from propranolol, the cyclic AMP concentrations in plasma and left ventricular muscle were significantly increased (p less than 0.005, p less than 0.01). Four days after withdrawal from propranolol, the cyclic AMP concentration in plasma was significantly increased (p less than 0.001). On the other hand, that of left ventricular muscle showed a tendency to have higher value, although, this was statistically not significant. From these results, this study suports that there is a hypersensitivity to adrenergic stimultion after abrupt cessation of long-term propranolol treatment. The explanation of propranolol withdrawal phenomenon most likely lies in lthe nature of beta adrenergic receptors that become activated during long-term blockade.


Putting perception into action with inverse optimal control for continuous psychophysics.
Psychophysical methods are a cornerstone of psychology, cognitive science, and neuroscience where they have been used to quantify behavior and its neural correlates for a vast range of mental phenomena. Their power derives from the combination of controlled experiments and rigorous analysis through signal detection theory. Unfortunately, they require many tedious trials and preferably highly trained participants. A recently developed approach, continuous psychophysics, promises to transform the field by abandoning the rigid trial structure involving binary responses and replacing it with continuous behavioral adjustments to dynamic stimuli. However, what has precluded wide adoption of this approach is that current analysis methods do not account for the additional variability introduced by the motor component of the task and therefore recover perceptual thresholds that are larger compared to equivalent traditional psychophysical experiments. Here, we introduce a computational analysis framework for continuous psychophysics based on Bayesian inverse optimal control. We show via simulations and previously published data that this not only recovers the perceptual thresholds but additionally estimates subjects' action variability, internal behavioral costs, and subjective beliefs about the experimental stimulus dynamics. Taken together, we provide further evidence for the importance of including acting uncertainties, subjective beliefs, and, crucially, the intrinsic costs of behavior, even in experiments seemingly only investigating perception.


PAMAM-dendrimer Enhanced Antibacterial Effect of Vancomycin Hydrochloride Against Gram-Negative Bacteria.
The antibacterial activity of some antibiotics is specific to either Gram-positive or Gram-negative bacteria. There are different mechanisms behind such insensitivities like inability of antibiotics to permeate through some bacterial membranes, as is the case for vancomycin in Gram-negative bacteria. The present investigation tries to overcome this problem by dendrimers, in order to make Gram-negative bacteria responsive to vancomycin. The effects of generations 3 (G3) and 5 (G5) polyamidoamine amine-terminated dendrimers (NH2-PAMAM), on the antibacterial activity of vancomycin, were evaluated. Vancomycin-PAMAM dendrimers complexes were prepared and their antibacterial activities were evaluated by determination of their "minimum inhibitory concentration (MIC)", "minimum bactericidal concentration" and "fractional inhibitory concentration index" values against two Gram-positive and four Gram-negative bacteria, using broth micro-dilution method. The complexation of vancomycin and dendrimers was also assessed by in vitro release studies across dialysis tubing using a developed HPLC method. Results showed that vancomycin solution was effective against Gram-positive bacteria, but, was not effective in Gram-negative ones. Vancomycin-PAMAM dendrimers exhibited significant antibacterial efficacy against Gram-negative bacteria resulting in a decline of vancomycin MIC values by about 2, 2, 4 and 64 times in E. coli, K. pneumonia, S. typhimurium and P. aeruginosa, respectively. Results also showed that enhanced effect by G5 is more than G3. Dendrimers did not affect antibacterial activity of vancomycin in Gram-positive bacteria, as no permeation problem exists here. The present study revealed that both G3 and G5 cationic PAMAM dendrimers are able to make Gram-negative bacteria sensitive to vancomycin, resulting in decline of MIC values up to 64 times, possibly by increasing its permeation through bacterial membrane. These results look promising for broadening the antibacterial spectrum of vancomycin and such a strategy might be used for increasing the overall life of antibiotics.


Pictorial cues and enhancement of patient recall of instructions or information.
Optometrists utilize handouts and pamphlets to facilitate information and instruction recall by their patients. A study was conducted to determine the effect of using pictorial cues. Thirty-six college students learned fifteen nouns in numerical order. In one condition subjects perceived the nouns alone, in another they perceived the nouns with illustrations. Half of the subjects in each condition were tested immediately after stimuli presentation; the remaining subjects were tested after a one-hour delay. It was determined that a picture-word association occurred, and decreased memory decay (longer memory) occurred for compound stimuli. This indicated that visual stimuli can facilitate word memory and pictorial cues would, therefore, be beneficial.


Invasive cervical resorption of central incisor during orthodontic treatment.
Invasive cervical resorption (ICR) is a relatively rare type of ERR (External Root Resorption), in which a localized resorption begins in the cervical area of the tooth, below the epithelial junction and above the ridge crest. Describe the clinical case of an 11-year-old boy with no dental trauma history, presenting moderate crowding and ectopic eruption of the maxillary right central incisor. He had been undergoing orthodontic treatment elsewhere, and his family was dissatisfied with the results. A new treatment was indicated, which included rapid maxillary expansion followed by extraction of four premolars. During routine panoramic evaluation, a radiolucid image was detected and a periapical radiograph was requested. At this point, an ICR of the maxillary right central incisor was found. The treatment was cautiously finalized and despite the use of light forces, central incisor was severally compromised by ICR and was therefore extracted. This clinical example discusses the importance of routine radiographs for the early diagnoses of ICR.


Mimosine, a plant-derived amino acid induces apoptosis in human pancreatic cancer xenografts.
Several studies have indicated that mimosine, a plant amino acid, is a potential inhibitor of the cell cycle giving rise to growth arrest in G1-phase. These results were mainly derived from in vitro investigations. To date only one paper is available about its applicability in xenografted lung tumor. This study revealed a tumor growth suppression and an increased apoptotic index. Our experiment was aimed at investigating the influence of mimosine in human pancreatic cancer. Subcutaneously growing human pancreatic cancer xenografts in immunosuppressed mice were treated with 30 mg/kg b.w. mimosine for 34 days and the apoptosis was assessed by flow cytometry. Mimosine treatment resulted in a significant tumor growth suppression and the sub-G1 fraction was doubled (10.82 +/- 1.18% vs. 4.65 +/- 1.65 % in controls, p < 0.01). This is the first evidence that mimosine exerts an apoptotic activity in xenotransplanted human pancreatic cancer and suppresses its growth.


Heart rate variability analysis as an index of emotion regulation processes: interest of the Analgesia Nociception Index (ANI).
Autonomic Nervous System (ANS) variations are strongly influence by emotion regulation processes. Indeed, emotional stimuli are at the origin of an activation of the ANS and the way an individual pass from a state of alert in the case of emotional situation to a state of calm is closely coupled with the ANS flexibility. We have previously described and developed an Analgesia Nociception Index (ANI) for real time pain measurement during surgical procedure under general anesthesia. This index, based on heart rate variability analysis, constitutes a measure of parasympathetic tone and can be used in several other environments. In this paper, we hypothesized that such an index could be used as a tool to investigate the processes of emotional regulation of a human subject. To test this hypothesis, we analyzed ANI's response to a negative emotional stimulus. This analysis showed that the index decreases during the emotion induction phase and returns to its baseline after 2 minutes. This result confirms that ANI could be a good indicator of parasympathetic changes in emotional situation.


Pheromone perception and behavior in Drosophila.
Pheromones have essential roles in the social behavior of most animals. Studies of pheromone-driven behaviors are especially attractive in Drosophila melanogaster, because these insects are genetically and molecularly well characterized, have relatively simple central nervous systems compared with vertebrates, and yet they display complex behaviors controlled by sophisticated sensory systems. Like most other aspects of biology, studies on pheromone-driven behaviors have entered a new area, as candidate pheromone receptors and signaling molecules have been identified through the deciphering of the Drosophila genome. These advances have made it possible to make specific manipulations of pheromone pathways for further investigation.


Alternative bearings in total knee arthroplasty.
Total knee arthroplasty (TKA) is durable and reliable to relieve pain and improve function in patients with end stage arthritis of the knee joint. However, the demographics of patients undergoing TKA is changing; younger and more active patients are electing to undergo knee replacement surgery. In recent years, improvements in design, polyethelyne, and materials promise to reduce wear and improve the durability of TKA further. In this article we review these improvements, including cross-linked polyethelyne, mobile bearings, and alternative bearing surfaces used in TKA.


Post Neurosurgical Meningitis due to Colistin Heteroresistant Acinetobacter baumannii.
Recently Acinetobacter baumannii isolates have emerged as a problematic infectious agent that causes meningitis in neurosurgical patients. Colistin has been used successfully for the treatment of A. baumannii meningitis but colistin resistant isolates have been reported worldwide. Two isolates of A. baumannii were cultured during a five-day period from cerebrospinal fluid (CSF) samples of a 20-year-old man with a gunshot trauma in the abdomen, which had exited from his back. Antimicrobial susceptibility tests of isolates were performed. Multiplex PCR was performed for detection of bla OXA-23-like, bla OXA-24-like and bla OXA-58-like genes. Metallo-β-lactamase genes such as: bla VIM, bla IMP, bla SPM and bla NDM were sought by singleplex PCR. In order to evaluate the genetic relationship, two isolates were examined by the repetitive extragenic palindromic-polymerase chain reaction (REP_PCR) method. E-test results showed that the isolates were sensitive to colistin and tigecycline with minimum inhibitory concentration of (MIC) 0.25 µg/mL and 1.5 µg/mL, respectively. Secondly the isolates were resistant to colistin with MIC > 256 µg/mL but remained sensitive to tigecycline with MIC 1.5 µg/mL. On the basis of the multiplex PCR, both of the isolates were positive for bla OXA-23-like. Other investigated genes such as bla OXA-24-like, bla OXA-58-like, bla VIM, bla IMP, bla SPM and bla NDM were negative. REP-PCR results showed that two isolates were derived from a single strain and both were the same. The results of our study revealed that the firs isolate of A. baumannii was colistin heteroresistant and was changed to completely resistant during therapy. Diagnosis and treatment of A. baumannii meningitis is very important and to avoid treatment failure we suggest that all A. baumannii isolates obtained from CSF should be evaluated properly for colistin heteroresistance.


Excystation of Cryptosporidium parvum at temperatures that are reached during solar water disinfection.
Species belonging to the genera Cryptosporidium are recognized as waterborne pathogens. Solar water disinfection (SODIS) is a simple method that involves the use of solar radiation to destroy pathogenic microorganisms that cause waterborne diseases. A notable increase in water temperature and the existence of a large number of empty or partially excysted (i.e. unviable) oocysts have been observed in previous SODIS studies with water experimentally contaminated with Cryptosporidium parvum oocysts under field conditions. The aim of the present study was to evaluate the effect of the temperatures that can be reached during exposure of water samples to natural sunlight (37-50 degrees C), on the excystation of C. parvum in the absence of other stimuli. In samples exposed to 40-48 degrees C, a gradual increase in the percentage of excystation was observed as the time of exposure increased and a maximum of 53.81% of excystation was obtained on exposure of the water to a temperature of 46 degrees C for 12 h (versus 8.80% initial isolate). Under such conditions, the oocyst infectivity evaluated in a neonatal murine model decreased statistically with respect to the initial isolate (19.38% versus 100%). The results demonstrate the important effect of the temperature on the excystation of C. parvum and therefore on its viability and infectivity.


The neurobiology of moral behavior: review and neuropsychiatric implications.
Morality may be innate to the human brain. This review examines the neurobiological evidence from research involving functional magnetic resonance imaging of normal subjects, developmental sociopathy, acquired sociopathy from brain lesions, and frontotemporal dementia. These studies indicate a "neuromoral" network for responding to moral dilemmas centered in the ventromedial prefrontal cortex and its connections, particularly on the right. The neurobiological evidence indicates the existence of automatic "prosocial" mechanisms for identification with others that are part of the moral brain. Patients with disorders involving this moral network have attenuated emotional reactions to the possibility of harming others and may perform sociopathic acts. The existence of this neuromoral system has major clinical implications for the management of patients with dysmoral behavior from brain disorders and for forensic neuropsychiatry.


Body composition changes in preterm infants following hospital discharge: comparison with term infants.
Infants experiencing catch-up growth devote a greater proportion of their energy to fat deposition, potentially at the expense of gains in lean body mass. The objective of the present study was to compare the body composition of preterm and term infants after hospital discharge and to determine the effect of gestational age (GA), birth size, nutrition, and illness on growth in fat-free mass (FFM) after hospitalization. Anthropometric measurements and body composition testing via air displacement plethysmography were performed on 26 appropriate-for-gestational-age (AGA) preterm (mean GA 31.5 ± 2.7 weeks) and 97 AGA term (mean GA 39.8 ± 1.0 weeks) infants at term corrected age (CA) and at 3 to 4 months CA. At term CA, preterm infants had lower FFM (3.0 vs 3.3 kg, P = 0.001), higher percentage of body fat (18.7% vs 15.2%, P < 0.0001), lower weight (P =0.04), and shorter length (P = 0.001) than term infants. By 3 to 4 months CA, weight, length, percentage of body fat, and FFM were similar in the 2 groups. GA, inpatient nutrition, and illness were associated with FFM at 4 months CA in the preterm infants (P < 0.05). Markedly lower FFM and higher adiposity were observed in preterm infants at term CA, but these differences had lessened and were no longer statistically significant at 3 to 4 months CA. Although early nutrition was associated with growth trajectories in the hospital, the continuing influence of early illness on postdischarge growth suggests that nonnutritional factors (eg, disturbances in the growth hormone axis) also may affect body composition trajectories of preterm infants.


Asymmetric mRNA localization contributes to fidelity and sensitivity of spatially localized systems.
Although many proteins are localized after translation, asymmetric protein distribution is also achieved by translation after mRNA localization. Why are certain mRNA transported to a distal location and translated on-site? Here we undertake a systematic, genome-scale study of asymmetrically distributed protein and mRNA in mammalian cells. Our findings suggest that asymmetric protein distribution by mRNA localization enhances interaction fidelity and signaling sensitivity. Proteins synthesized at distal locations frequently contain intrinsically disordered segments. These regions are generally rich in assembly-promoting modules and are often regulated by post-translational modifications. Such proteins are tightly regulated but display distinct temporal dynamics upon stimulation with growth factors. Thus, proteins synthesized on-site may rapidly alter proteome composition and act as dynamically regulated scaffolds to promote the formation of reversible cellular assemblies. Our observations are consistent across multiple mammalian species, cell types and developmental stages, suggesting that localized translation is a recurring feature of cell signaling and regulation.


[Isolation and some properties of rat skeletal muscle polysomes].
Possibility was investigated to prepare polysomes from microsomal fraction of rat sceletal muscles. Centrifugation in sucrose gradient showed that approximately 60 percent of UV-absorbing material in the preparation obtained was in polysomic region of the gradient. Mild treatment with pancreatic ribonuclease led to disintegration of polysomes and respective increase in content of monosomic component. The use of combined gradient permitted to obtain two fractions of polysomes, one of which was readily sedimented by centrifugation. This fraction contained significant amount of protein and incorporated relatively low quantity of 32-P within 2 hrs after administration of the label in vivo. The data obtained suggest that the fraction of polysomes carried out the biosynthesis of myosin.


Fibrinogen and the risk of thrombosis.
Fibrinogen contributes to thrombosis risk in different ways. Indeed, various mutations in the fibrinogen genes predispose to thrombosis. At the same time, high levels of fibrinogen are also associated with thrombotic complications. Although the underlying causative mechanisms are not clear, this most likely involves the associated inflammatory and hypercoagulable states. In the last few years, particular attention has focused on the polymorphisms of fibrinogen genes involved in increased fibrinogen levels or fibrinogen qualitative changes. The association between dysfibrinogenemia and risk of thrombosis is well known, and some mechanisms have been clearly identified. Paradoxically, some patients with either hypofibrinogenemia or afibrinogenemia may also suffer from severe thromboembolic complications. The management of these patients is particularly challenging because they are not only at risk of thrombosis but also of bleeding. This review discusses the various quantitative and qualitative defects of fibrinogen associated with thrombosis, the tests that may predict the thrombotic risk, as well as some preventive or therapeutic approaches.


Dilatation and nontraumatic rupture of the urinary tract during pregnancy: a review.
Rupture of the urinary tract during pregnancy is uncommonly reported. Nevertheless, pregnancy-induced changes in the urinary tract predispose to tears and leaks in the renal parenchyma or collecting system. Pyelonephritis, painful overdistension, and rupture are consequences of the effects of pregnancy on the urinary tract. Thirteen cases of urinary tract rupture from the literature and one from the authors' experience illustrate the clinical manifestations of this serious complication of pregnancy.


Primary care providers advising smokers to quit: comparing effectiveness between those with and without alcohol, drug, or mental disorders.
Individuals with alcohol, drug, or mental (ADM) disorders combined make up over 40% of all smokers in the U.S. Primary care providers (PCPs) play an important role in smoking cessation counseling, but their effectiveness with this population is unclear. This study evaluated the effectiveness of PCP smoking cessation counseling for smokers with ADM disorders. Probit regressions conducted in 2009-2010 examined the relationship between past year PCP smoking cessation counseling and successful quitting among 1,356 adults who reported smoking in the 1998-1999 Community Tracking Study survey and who reported seeing a PCP in the past year in the follow-up 2000-2001 Healthcare for Communities Survey. Past year PCP exercise counseling was used as an instrumental variable for past year PCP smoking cessation counseling to account for potential hidden bias between smoking status and receipt of smoking cessation counseling. Smokers with and without ADM disorders were equally likely to receive smoking cessation counseling (72.9% vs. 69.9%). Using the instrumental variable approach, smoking cessation counseling by PCPs was significantly associated (p < .01) with quitting among both groups. Predicted probabilities of quitting without smoking cessation counseling were 6.0% for smokers with ADM disorders and 10.5% for smokers without ADM disorders. Predicted probabilities of quitting with smoking cessation counseling were 31.3% for smokers with ADM disorders and 34.9% for smokers without ADM disorders. This study shows that PCPs can help smokers with ADM disorders successfully quit. These smokers should be targeted for smoking cessation counseling to reduce the health burden of tobacco.


The Role of TGF-β Receptors in Fibrosis.
Recent advances in defining TGF-β signaling pathways have provided a new level of understanding of the role of this pleiotropic growth factor in the development of fibrosis. Here, we review selected topics related to the profibrotic role of TGF-β . We will discuss new insights into the mechanisms of ligand activation and the contribution of Erk1/2 MAPK, PI3K/FAK, and Endoglin/Smad1 signaling pathways to the process of fibrosis. There is growing evidence of the disease-specific alterations of the downstream components of the TGF-β signaling pathway that may be explored for the future therapeutic interventions.


Membrane-bound melatonin receptor MT1 down-regulates estrogen responsive genes in breast cancer cells.
Melatonin possesses anti-estrogenic effects on estrogen receptor expressing (ER+) breast cancer cells in culture by reducing cell cycle progression and cell proliferation. There is increasing agreement that on a cellular level the effects of melatonin are primarily induced by the membrane-bound receptor MT1. The participation of a second, nuclear receptor of the group of ligand-dependent transcription factors, called RZRalpha, is under debate. In this study we used a number of breast cancer cell lines differing in their expression of the estrogen receptor and the two known melatonin receptors. In MCF-7 breast cancer cells transfected with a vector carrying the MT1 gene (MCF-7Mel1a) binding of CREB-protein to the cAMP-responsive element of the breast cancer suppressing gene BRCA-1 was more strongly reduced by treatment with melatonin than in the parental cells. Expression of estrogen responsive genes was determined in serum-starved cells, cells stimulated for 16 hr with estradiol and cells subsequently treated with melatonin. Expression of BRCA-1, p53, p21(WAF) and c-myc were up-regulated by estradiol. Treatment of the stimulated cells with melatonin counteracted the increase induced by estradiol almost completely. The more MT1 a cell line expressed, the stronger was the reduction of the expression of the estradiol-induced genes. There was no correlation between the expression of the nuclear receptor RZRalpha and the effects of melatonin on these genes.


Factors associated with health care professionals' choice of written asthma management plans.
The objective of this descriptive-comparative study was to determine what factors were associated with health care professionals' choice of written asthma management plans (WAMP) for health care practice. A convenience sample of medical and nursing students and practicing health care professionals was asked to choose the preferred WAMP and give a brief explanation for the choice on the questionnaire. Comparative groups were formed based on the WAMP choice. Independent sample chi2 and content analysis were used to analyze data. Ninety-five percent (n = 192) of all survey respondents (N = 202) preferred the highly readable Global Initiative for Asthma Sample Patient Asthma Management Plan, as compared to the Veterans Administration/Department of Defense (DoD) WAMP. Major themes as to why respondents preferred the Global Initiative for Asthma WAMP include "pictures," "readability," "user-friendliness," and "simplicity." Use of the current DoD/Veterans Health Administration WAMP within the DoD Military Health System may need to be re-evaluated.


Incarceration and compulsory rehabilitation impede use of medication for opioid use disorder and HIV care engagement in Vietnam.
Non-prescribed opioid use is illegal in Vietnam. People who are apprehended for use of non-prescribed opioids may be arrested and incarcerated or sent to compulsory rehabilitation centers. For those on medication to treat opioid use disorder (MOUD), incarceration in either setting may disrupt treatment. This study estimates the effects of incarceration and compulsory rehabilitation on MOUD and HIV treatment outcomes in Vietnam. Data are from a clinical trial testing the effects of MOUD on HIV viral suppression in six Vietnamese HIV clinics. Participants were assessed quarterly for 12 months. We assessed the associations between incarceration or compulsory rehabilitation during months 0-9 and study outcomes of receipt of MOUD, HIV clinic engagement, and antiretroviral therapy prescription during months 9-12, among those who were released by month 9 of the study, using logistic regression and zero-inflated negative binomial models. At nine months, 25 of 258 participants (9.7%) were incarcerated or sent to compulsory rehabilitation at least once and completed the month 9 assessment. Of those, 19 (76.0%) did not receive MOUD in months 9 through 12. Both incarceration and compulsory rehabilitation were negatively associated with subsequent receipt of MOUD (aOR = 0.05, 95% CI = (0.01, 0.24); 0.14 (0.04, 0.50), respectively) and HIV clinic engagement (aOR = 0.13, 95% CI = (0.03, 0.71); 0.09 (0.02, 0.39), respectively). In the final three months of the study, participants who were incarcerated had 42.5 fewer days of MOUD (95% CI = 23.1, 61.9), and participants in compulsory rehabilitation had 46.1 fewer days of MOUD (95% CI = 33.8, 58.4) than those not incarcerated or in compulsory rehabilitation. Our findings suggest that both incarceration and compulsory rehabilitation disrupt MOUD and HIV treatment among people with HIV and Opioid Use Disorder in Vietnam. Prioritization of evidence-based strategies to support engagement in care for people who use drugs could potentially expand HIV and Opioid Use Disorder treatment access and curb substance use more effectively than reliance on incarceration or compulsory rehabilitation.


[Promotion of media competence and prevention of cyberbullying using the Medienhelden program: results from an evaluation study ].
The manualized Medienhelden (engl. Media Heroes) program (Schultze-Krumbholz, Zagorscak, Siebenbrock, Scheithauer, 2012) is implemented in the school environment either as a ten-week program during lessons (curriculum; IGL) or as a single project day with reduced content of the long version (IGK). In consecutive lessons, topics of the program are, for example: definition of cyberbullying, its negative impact, how to protect oneself on the internet, and opportunities to react in appropriate ways. The program utilizes mainly cognitive-behavioral methods. In the present contribution the program and selected results from a controlled, pre-follow-up evaluation study with 570 adolescents (Ncontrolgroup = 289, NIGK = 98 and NIGL = 183), from one general high school and four college preparatory high schools from a German major city will be presented. Results show that cyberbullying decreased in both intervention groups (project day, curriculum) compared to the control group while at the same time an increase of social competencies, self-esteem, and subjective health was observed. These effects were more pronounced for the curriculum intervention group. An opposite pattern was found for the control group: Cyberbullying and empathy worsened, and no change was found for perspective-taking, self-esteem, and subjective health. The program shows both preventive and intervention effects.


Neuromuscular electrical stimulation prevents muscle wasting in critically ill comatose patients.
Fully sedated patients, being treated in the intensive care unit (ICU), experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully sedated ICU patients admitted for acute critical illness [n=3 males, n=3 females; age 63 ± 6 y; APACHE II (Acute Physiology and Chronic Health Evaluation II) disease-severity-score: 29 ± 2]. One leg was subjected to twice-daily NMES of the quadriceps muscle for a period of 7 ± 1 day whereas the other leg acted as a non-stimulated control (CON). Directly before the first and on the morning after the final NMES session, quadriceps muscle biopsies were collected from both legs to assess muscle fibre-type-specific cross-sectional area (CSA). Furthermore, phosphorylation status of the key proteins involved in the regulation of muscle protein synthesis was assessed and mRNA expression of selected genes was measured. In the CON leg, type 1 and type 2 muscle-fibre-CSA decreased by 16 ± 9% and 24 ± 7% respectively (P<0.05). No muscle atrophy was observed in the stimulated leg. NMES increased mammalian target of rapamycin (mTOR) phosphorylation by 19 ± 5% when compared with baseline (P<0.05), with no changes in the CON leg. Furthermore, mRNA expression of key genes involved in muscle protein breakdown either declined [forkhead box protein O1 (FOXO1); P<0.05] or remained unchanged [muscle atrophy F-box (MAFBx) and muscle RING-finger protein-1 (MuRF1)], with no differences between the legs. In conclusion, NMES represents an effective and feasible interventional strategy to prevent skeletal muscle atrophy in critically ill comatose patients.


Angiopoietin-2 May Be Involved in the Resistance to Bevacizumab in Recurrent Glioblastoma.
Despite encouraging response rate of bevacizumab (BVZ) in recurrent glioblastoma, many patients do not respond to this schedule and most of the responders develop an early relapse. Plasma concentrations of VEGF, PlGF, Ang2, and sTie2 were assessed by ELISA before and during BVZ treatment in seventy patients. Baseline levels of VEGF-A, and PlGF were higher in patients than in healthy volunteers, whereas no difference was found for Ang2, and sTie2. No biomarker at baseline was associated with response, PFS or OS. At recurrence, the authors observed an increase of Ang2 suggesting that Ang2/sTie2 could be involved in the resistance to BVZ.


Transparent and Flexible Electronics Assembled with Metallic Nanowire-Layered Nondrying Glycerogel.
There has been increasing demand for transparent and mechanically durable electrical conductors for their uses in wearable electronic devices. It is common to layer metallic nanowires on transparent but stiff poly(dimethylsiloxane) (PDMS) or stretchable but opaque Ecoflex-based substrates. Here, we hypothesized that layering metallic nanowires on a stretchable and hygroscopic gel would allow us to assemble a transparent, stretchable, and durable conductor. The hygroscopic property of the gel was attained by partially replacing water in the preformed polyacrylamide hydrogel with glycerol. The resulting gel, denoted as a glycerogel, could remain hydrated for over 6 months in air by taking up water molecules from the air. The glycerogel was tailored to be stretchable up to 8 times its original length by tuning the amount of the cross-linker and acrylamide. The resulting glycerogel allowed for deposition of wavy silver nanowires using the prestrain method up to 400% prestrain, without causing kinks and interfacial cracks often found with nanowires layered onto PDMS. With a prestrain of 100%, the resulting nanowire-gel conductor exhibited optical transparency (85%) and electrical conductivity (17.1 ohm/sq) even after 5000 cycles of deformation. The results of this study would broadly be useful to improve the performance of the next generation of flexible electronic devices.


Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway.
Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-κB pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-κB activation through inhibition of IκBα phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKKα/β. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-κB pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).


Preservation of FoxP3+ regulatory T cells in the peripheral blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation.
Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain normal CD4(+) T-cell counts and control viremia to levels that are below the limit of detection of current assays. The mechanisms involved in long-term control of viremia have not been fully elucidated. CD4(+) CD25(+) regulatory T cells (Tregs) downmodulate chronic inflammation by suppressing the activation and proliferation of effector lymphocytes. We found that while Tregs were functional in ES and patients on highly active antiretroviral therapy (HAART), ES maintained high levels of Tregs in peripheral blood mononuclear cells whereas patients on HAART had evidence of Treg depletion. We also demonstrated that Tregs can serve as reservoirs for HIV-1 in vivo. These data suggest that both direct infection by HIV-1 and tissue redistribution are possible explanations for declining FoxP3(+) Tregs in progressive HIV-1 infection. Furthermore, the maintenance of Tregs may be one mechanism associated with the nonprogressive nature of HIV-1 infection in ES.


Repression and somatization: a case history of hemodynamic activation.
A 52-year-old woman presented to the office about 2 and 1/2 years after the death of her husband from cancer. She had multiple hemodynamic and cardiovascular disorders such as hypertension, angina, tachycardia, dysmenorrhea, cardiac ectopics, and very cold hands and feet. The patient complained of tension and insomnia but refused to take any medications because of allergic responses to them. Hence, a relaxation and psychotherapeutic approach was adopted. Psychometric testing revealed extreme defensiveness (including repression). The patient had never mourned for her husband. Therapy helped her overcome her bereavement, tension, and insomnia. In addition, many of her physical manifestations subsided considerably during therapy.


Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: a population-based study.
Smoking has been posited as a possible risk factor for amyotrophic lateral sclerosis (ALS), but large population-based studies of patients with incident disease are still needed. The authors performed a population-based case-control study in the Netherlands between 2006 and 2009, including 494 patients with incident ALS and 1,599 controls. To prove the relevance of population-based incidence cohorts in case-control studies, the authors compared results with those from cohorts including patients with prevalent ALS and referral patients. Subjects were sent a questionnaire. Multivariate analyses showed an increased risk of ALS among current smokers (odds ratio = 1.38, 95% confidence interval (CI): 1.02, 1.88) in the incident patient group only. Cox regression models showed that current smoking was also independently associated with shorter survival (hazard ratio = 1.51, 95% CI: 1.07, 2.15), explaining the lack of association in the prevalent and referral patient groups. Current alcohol consumption was associated with a reduced risk of ALS (incident patient group: odds ratio = 0.52, 95% CI: 0.40, 0.75). These findings indicate that current smoking is associated with an increased risk of ALS, as well as a worse prognosis, and alcohol consumption is associated with a reduced risk of ALS, further corroborating the role of lifestyle factors in the pathogenesis of ALS. The importance of population-based incident patient cohorts in identifying risk factors is highlighted by this study.