Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in murine Kras(G12D)-induced skin carcinogenesis in vivo.
The Ras and Notch signaling pathways are frequently activated during development to control many diverse cellular processes and are often dysregulated during tumorigenesis. To study the role of Notch and oncogenic Kras signaling in a progenitor cell population, Pdx1-Cre mice were utilized to generate conditional oncogenic Kras(G12D) mice with ablation of Notch1 and/or Notch2. Surprisingly, mice with activated Kras(G12D) and Notch1 but not Notch2 ablation developed skin papillomas progressing to squamous cell carcinoma providing evidence for Pdx1 expression in the skin. Immunostaining and lineage tracing experiments indicate that PDX1 is present predominantly in the suprabasal layers of the epidermis and rarely in the basal layer. Further analysis of keratinocytes in vitro revealed differentiation-dependent expression of PDX1 in terminally differentiated keratinocytes. PDX1 expression was also increased during wound healing. Further analysis revealed that loss of Notch1 but not Notch2 is critical for skin tumor development. Reasons for this include distinct Notch expression with Notch1 in all layers and Notch2 in the suprabasal layer as well as distinctive p21 and β-catenin signaling inhibition capabilities. Our results provide strong evidence for epidermal expression of Pdx1 as of yet not identified function. In addition, this finding may be relevant for research using Pdx1-Cre transgenic strains. Additionally, our study confirms distinctive expression and functions of Notch1 and Notch2 in the skin supporting the importance of careful dissection of the contribution of individual Notch receptors.


Role of cytokines in pathogenesis of endometriosis.
Sampson's theory stating that endometrial cells and fragments desquamate during the menstrual period are transported through Fallopian tubes into the peritoneal cavity where they implant, proliferate and develop into endometriotic lesions is generally accepted [1]. Accumulating data suggest that deficient immunity against retrograde endometrium during menstruation may be involved in the pathophysiology of endometriosis. Recent studies in women with endometriosis have demonstrated functional changes in several immunologic components in the peritoneal fluid as well as in sera of those patients. It was shown, for instance, that a wide pattern of cytokines are involved during endometrial cells implantation, proliferation and forming of endometriotic lesions. Those factors play a critical role in decreased immunologic surveillance, recognition and destruction of ectopic endometrial cells and possible facilitation of the implantation of ectopic endometrial tissues. The present review summarises the current knowledge on the role of different cytokines in the pathophysiology of endometriosis.


Structural differences between hip endoprostheses, and implications on a hip kinetics.
We compared kinetic characteristic of unipolar, bipolar and total hip endoprostheses, implanted after dislocated femoral neck fracture. Ninety patients were divided into three groups (30 patients in each group); a group with unipolar partial hip endoprosthesis (UPEP), a group with bipolar partial hip endoprosthesis (BPEP) and a group with total hip endoprosthesis (TEP). The patients from different groups were paired by parameters which could influence the long term functional result: follow up period, comorbidities, functional capabilities before injury, etc. After the average follow up 3.8 +/- 1.9 years, a measuring of range of hip motions (ROM) was conducted. The largest mean amplitudes in flexion (104 degrees), extension (13 degrees), abduction (35 degrees) and external rotation (38 degrees) was achieved BPEP, the largest adduction (14 degrees) was achieved UPEP, and internal rotation (34 degrees) TEP. Differences in ROMs are partially related to the clinical parameters such as: level of the hip pain, gait pattern, age and rehabilitation period (P < 0.05). Measuring of ROMs is the most reliable part of the clinical exam and it does not depend on subjectivity of patient, as opposed to other clinical parameters (level of pain, walking distance, aids usage, etc). The results obtained are favorable for the bipolar hip endoprosthesis, and they can be related to the biomechanical differences between the three types of hip endoprostheses. Kinetic advantages of the BPEP as compared to the UPEP, can be explained by the BPEP's structure: two-level mobility and a thinner neck which delays impingement in the late motion phase. In comparison to the TEP, clinical advantages of the BPEP can be attributed to less extensive surgery and scarring.


Application of a pH Electrode Incorporating an Ionic Liquid Salt Bridge to the Measurement of Rainwater Samples.
A pH electrode incorporating a reference electrode different from that in conventional electrodes was applied to the measurement of rainwater pH. The reference electrode utilizes a recently proposed ionic liquid salt bridge instead of a conventional potassium chloride salt bridge. The response time of this electrode was remarkably improved in rain sample pH measurements compared to that of conventional pH electrodes. In addition, the measured pH values of rain samples seemed to be more accurate with this electrode.


Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.
Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.


Evaluation of a dentifrice containing 8% arginine, calcium carbonate, and sodium monofluorophosphate to repair acid-softened enamel using an intra-oral remineralization model.
An intra-oral remineralization study was conducted to compare the ability of a dentifrice containing 8% arginine and calcium carbonate (Pro-Argin Technology), and 1450 ppm fluoride as sodium monofluorophosphate (MFP) to remineralize acid-softened bovine enamel specimens compared to a silica-based dentifrice with 1450 ppm fluoride as MFP. The intra-oral clinical study employed a double blind, two-treatment, crossover design, and used an upper palatal retainer to expose the enamel specimens to the oral environment during product use and periods of remineralization. The retainer was designed to house three partially demineralized bovine enamel samples. The study population was comprised of 30 adults, ages 18 to 70 years. The study consisted of two treatment phases with a washout period lasting seven (+/- three) days preceding each treatment phase. A silica-based dentifrice without fluoride was used during the washout period. The Test Dentifrice used in this study contained 8% arginine, calcium carbonate, and 1450 ppm fluoride as sodium monofluorophosphate (MFP). The Control Dentifrice was silica-based and contained 1450 ppm fluoride as MFP. The treatment period consisted of a three-day lead-in period with the assigned product. The panelists brushed two times per day during the three-day lead-in period with the assigned product. On the fourth day, the panelists began brushing with the assigned product with the retainer in their mouth. The panelists brushed for one minute, followed by a one-minute swish with the slurry and a rinse with 15 ml of water in the morning, in the afternoon, and night with the retainer in the mouth. The panelists brushed only their teeth and not the specimens directly. Changes in mineral content before and after treatment were measured using a Knoop microhardness tester. The results of the study showed that percent remineralization values for the Test Dentifrice and Control Dentifrice were 14.99% and 8.66%, respectively. A statistical analysis showed that the Test Dentifrice was statistically significantly more effective at remineralizing acid-softened enamel in comparison to the Control Dentifrice (p < 0.05). This study demonstrated that the Test Dentifrice with 8% arginine, calcium carbonate, and 1450 ppm fluoride as MFP is highly effective treatment for promoting remineralization of enamel that has been softened by an erosive challenge.


The Effect of Energy Patches on Substrate Utilization in Collegiate Cross-Country Runners.
It is well established that an increased capacity of skeletal muscle to oxidize fatty acids can spare glycogen and delay the onset of fatigue in mild- to moderate-intensity exercise. The purpose of the following study was to examine the effect of LifeWave® energy patches on non-protein substrate utilization in Division-1 cross-country runners. To determine the effect of the patches subjects were pretested to establish baselines and randomly assigned to an experimental (EX) or placebo (PL) group. Twenty-two trained male (n = 11; mean ± SD, age = 21.1 ± 2.6years, height = 179.6 ± 4.2cm, body mass = 71.4 ± 7.4kg, VO2max = 72.6 ± 7.1mL·kg-1·min-1) and female (n = 11; mean ± SD, age = 21.5 ± 2.4years, height = 166.7 ± 5.7cm, body mass = 53.7 ± 3.2kg, VO2max = 63.6 ± 6.9mL·kg-1·min-1) cross-country runners volunteered to participate in the study. Dependent variables included maximal oxygen consumption (VO2max), rating of perceived exertion (RPE), respiratory exchange ratio (RER), maximum heart rate (HRmax), and time to exhaustion (TTE). Results indicated there were no significant differences between the EX and PL groups at posttesting for RPE, TTE, HRmax, or VO2max. RER was found to be significantly higher for the EX group compared to the PL group during stage 1 of the Bruce-protocol graded exercise test (p = 0.02). Based on the limited available research regarding LifeWave® energy patches effect on non-protein substrate utilization during aerobic exercise there appears to be no performance enhancing benefits.


Cognition as coordinated non-cognition.
We propose that cognition is more than a collection of independent processes operating in a modular cognitive system. Instead, we propose that cognition emerges from dependencies between all of the basic systems in the brain, including goal management, perception, action, memory, reward, affect, and learning. Furthermore, human cognition reflects its social evolution and context, as well as contributions from a developmental process. After presenting these themes, we illustrate their application to the process of anticipation. Specifically, we propose that anticipations occur extensively across domains (i.e., goal management, perception, action, reward, affect, and learning) in coordinated manners. We also propose that anticipation is central to situated action and to social interaction, and that many of its key features reflect the process of development.


Anorectal swabs as a marker of male-to-male sexual exposure in STI surveillance systems.
Identification of priority populations such as men who have sex with men (MSM) is important in surveillance systems to monitor trends of sexually transmitted infections (STIs). We explored using routinely collected non-behavioural data as a means to establish MSM status in surveillance by assessing anorectal swab as a marker of male-to-male sexual exposure. We used chlamydia testing data from a sexual health clinic, 2007-2012. Men reporting any male sexual partner(s) in the previous 12 months were considered MSM. The dataset was split into development and validation samples to develop a univariate predictive model and assess the model fit. The dataset included 30 358 individual men and 48 554 episodes of STI testing; 45% were among reported MSM and an anorectal swab was performed in 40% of testing episodes. Anorectal swabbing had good diagnostic performance as a marker for MSM status (sensitivity = 87%, specificity = 99%, positive predictive value = 98·6%, negative predictive value = 90·3%). The model showed good fit against the internal validation sample (area under the curve = 0·93). Anorectal swabs are a valid marker of MSM behaviour in surveillance data from sexual health clinics, and they are likely to be particularly useful for monitoring STI trends among MSM with higher risk behaviour.


Healthcare Workers Who Work With COVID-19 Patients Are More Physically Exhausted and Have More Sleep Problems.
In this survey study of 7,208 Dutch healthcare workers, we investigate whether healthcare workers dealing with COVID-19 patients experience lower general health, more physical and mental exhaustion and more sleep problems than other healthcare workers. Additionally, we study whether there are differences in well-being within the group of healthcare workers working with COVID-19 patients, based on personal and work characteristics. We find healthcare workers who are in direct contact with COVID-19 patients report more sleep problems and are more physically exhausted than those who are not in direct contact with COVID-19 patients. Mental exhaustion and general health do not significantly differ between healthcare workers who are in direct contact with COVID-19 patients and those who are not. Among healthcare workers in direct contact with COVID-19 patients, lower well-being on one or more indicators is reported by those who are female, living alone, without leadership role, or without sufficient protective equipment. Regarding age, physical exhaustion is more prevalent under healthcare workers older than 55 years, whereas mental exhaustion is more prevalent under healthcare workers younger than 36 years. These results stress the need of mental and physical support of healthcare workers during a pandemic, catered to the needs of healthcare workers themselves.


Potential bias in meta-analyses of effect sizes in imaging genetics.
The penetrance of genetic variation has been assumed to be higher at the level of neural phenotypes than at the level of behavioral phenotypes. One of the few attempts to validate this assumption is the study of Rose and Donohoe published in this issue. In this article, we will address 2 methodological issues we believe have to be considered for a better understanding of the present results. We briefly discuss potential solutions that might also help improve future meta-analyses of effect sizes in neuroimaging data.


Iron deficiency and risk factors for lower iron stores in 6-24-month-old New Zealanders.
To determine the prevalence of biochemical iron deficiency and identify factors associated with ferritin levels among 6-24-month-old urban South Island New Zealand children. Cross-sectional survey conducted from May 1998 to March 1999. The cities of Christchurch, Dunedin and Invercargill. A total of 323 randomly selected 6-24-month-old children participated (response rate 61%) of which 263 provided a blood sample. A complete blood cell count, zinc protoporphyrin, serum ferritin and C-reactive protein were measured on nonfasting venipuncture blood samples, 3-day weighed food records and general questionnaire data were collected. Among children with C-reactive protein<10 mg/l (n=231), 4.3% had iron deficiency anaemia, 5.6% had iron deficiency without anaemia, and 18.6% had depleted iron stores, when a ferritin cutoff of < or =12 g/l was used. Age (negative), sex (girls>boys), ethnicity (Caucasian>non-Caucasian), weight-for-age percentiles (negative) and birth weight (positive) were associated with ferritin after adjusting for infection and socioeconomic status. When current consumption of iron fortified formula and >500 ml of cows' milk per day were included, these were associated with a 22% increase and 25% decrease in ferritin, respectively (R2=0.28). The presence of suboptimal iron status (29%) among young New Zealand children is cause for concern, even though severe iron deficiency is rare, because children with marginal iron status are at risk of developing severe iron deficiency if exposed to a physiological challenge.


A little more conversation please? Qualitative study of researchers' and patients' interview accounts of training for patient and public involvement in clinical trials.
Training in patient and public involvement (PPI) is recommended, yet little is known about what training is needed. We explored researchers' and PPI contributors' accounts of PPI activity and training to inform the design of PPI training for both parties. We used semi-structured qualitative interviews with researchers (chief investigators and trial managers) and PPI contributors, accessed through a cohort of clinical trials, which had been funded between 2006 and 2010. An analysis of transcripts of audio-recorded interviews drew on the constant comparative method. We interviewed 31 researchers and 17 PPI contributors from 28 trials. Most researchers could see some value in PPI training for researchers, although just under half had received such training themselves, and some had concerns about the purpose and evidence base for PPI training. PPI contributors were evenly split in their perceptions of whether researchers needed training in PPI. Few PPI contributors had themselves received training for their roles. Many informants across all groups felt that training PPI contributors was unnecessary because they already possessed the skills needed. Informants were also concerned that training would professionalise PPI contributors, limiting their ability to provide an authentic patient perspective. However, informants welcomed informal induction 'conversations' to help contributors understand their roles and support them in voicing their opinions. Informants believed that PPI contributors should be confident, motivated, intelligent, focussed on helping others and have relevant experience. Researchers looked for these qualities when selecting contributors, and spoke of how finding 'the right' contributor was more important than accessing 'the right' training. While informants were broadly receptive to PPI training for researchers, they expressed considerable reluctance to training PPI contributors. Providers of training will need to address these reservations. Our findings point to the importance of reconsidering how training is conceptualised, designed and promoted and of providing flexible, learning opportunities in ways that flow from researchers' and contributors' needs and preferences. We also identify some areas of training content and the need for further consideration to be given to the selection of PPI contributors and models for implementing PPI to ensure clinical trials benefit from a diversity of patient perspectives.


Skin CD4+ Memory T Cells Play an Essential Role in Acquired Anti-Tick Immunity through Interleukin-3-Mediated Basophil Recruitment to Tick-Feeding Sites.
Ticks, blood-sucking arthropods, serve as vectors for transmission of infectious diseases including Lyme borreliosis. After tick infestation, several animal species can develop resistance to subsequent infestations, reducing the risk of transmission. In a mouse model, basophils reportedly infiltrate tick-feeding sites during the second but not first infestation and play a crucial role in the expression of acquired tick resistance. However, the mechanism underlying basophil recruitment to the second tick-feeding site remains ill-defined. Here, we investigated cells and their products responsible for the basophil recruitment. Little or no basophil infiltration was detected in T-cell-deficient mice, and adoptive transfer of CD4+ but not CD8+ T cells reconstituted it. Il3 gene expression was highly upregulated at the second tick-feeding site, and adoptive transfer of interleukin-3 (IL-3)-sufficient but not IL-3-deficient CD4+ T cells conferred the basophil infiltration on T-cell-deficient mice, indicating that the CD4+ T-cell-derived IL-3 is essential for the basophil recruitment. Notably, IL-3+ resident CD4+ memory T cells were detected even before the second infestation in previously uninfested skin distant from the first tick-feeding site. Taken together, IL-3 produced locally by skin CD4+ memory T cells appears to play a crucial role in basophil recruitment to the second tick-feeding site.


Ocins database: a database of bug-busters from Bifidobacterium, Lactobacillus, and Enterococcus.
The ocins are antimicrobial polypeptides produced by probiotic microbes, such as Lactobacillus , Enterococcus , Streptococcus , Leuconostoc and Bifidobacterium . They are produced in response to stress and for the self-defense of the bacterium. It is indispensable to understand their mechanistic characteristics, structures, and functions, if the food industry is to reduce contamination levels and produce germfree foods. Databases of the ocins that are readily accessible to the food industry are scarce, but urgently required. Therefore, we established a very useful, unique, and a simple ocin database, which not merely provides information about ocins, but also directs their utilisation in the food industry. The database includes information about each ocin, its amino acid sequence, molecular weight, and isoelectric point. The database also possesses all the currently known ocin (probiotic origin only) sequences and structures, target organisms, and relevant to food industries (aqua culture, dairy and meat industries), which is hard to obtain in other databases. The database is free for public and accessed at http://ocins.cftri.com/ocins/.


Origin and nature of measurement bias in catadioptric parallel goniophotometers.
We briefly categorize and compare parallel goniophotometers, which are instruments capable of simultaneously measuring the far-field distribution of light scattered by a surface or emitted by a source over a large solid angle. Little is known about the accuracy and reliability of an appealing category, the catadioptric parallel goniophotometers (CPGs), which exploit a curved reflector and a lens system. We analyzed the working principle common to all the different design configurations of a CPG and established the specifications implicitly imposed on the lens system. Based on heuristic considerations, we show that the properties of a real (thick) lens system are not fully compatible with these specifications. This causes a bias to the measurements that increases with the acceptance angle of the lens system. Depending on the angular field, the measured sample area can be drastically reduced and shifted relative to the center of the sample. To gain insights into the nature and importance of the measurement bias, it was calculated with our model implemented in MATLAB for the CPG configuration incorporating a lens system with a very large acceptance angle (fisheye lens). Our results demonstrate that, due to the spatio-angular-filtering properties of the fisheye lens, this category of CPGs is so severely biased as to give unusable measurements. In addition, our findings raise the question of the importance of the bias in the other types of CPGs that rely on a lens system with a lower acceptance angle.


Uric acid increases fibronectin synthesis through upregulation of lysyl oxidase expression in rat renal tubular epithelial cells.
Urate is produced as the major end product of purine metabolism. In the last decade, the incidence of hyperuricemia increased markedly, and similar trends in the epidemiology of metabolic syndrome have been observed. Hyperuricemia is associated with renal disease, and recent studies have reported that mild hyperuricemia results in hypertension, intrarenal vascular disease, and renal injury. This has led to the hypothesis that uric acid may contribute to renal fibrosis and progressive renal disease. Our purpose was to investigate the relationship between uric acid and renal tubular injury. We applied the method of intraperitoneal injection of uric acid to generate the hyperuricemic mouse model. Compared with the saline injection group, the expression of lysyl oxidase (LOX) and fibronectin in kidneys was increased significantly in hyperuricemic groups. In vitro, uric acid significantly induced NRK-52E cells to express the ECM marker fibronectin, as well as LOX, which plays a pivotal role in ECM maturation, in a time- and dose-dependent manner. Upregulation of the urate transporter URAT1, which is located in the apical membrane of proximal tubules, sensitized the uric acid-induced fibronectin and LOX induction, while both knocking down URAT1 expression in tubular epithelial cells by RNA interference and inhibiting URAT1 function pharmacologically attenuated LOX and fibronectin expression. Furthermore, knockdown of LOX expression by a small interfering RNA strategy led to a decrease in fibronectin abundance induced by uric acid treatment. In addition, evidence of a uric acid-induced activation of the NF-kappaB signaling cascade was observed. Our findings highlight a need for carefully reevaluating our previous view on the pathological roles of hyperuricemia in the kidney and nephropathy induced by uric acid in clinical practice.


Heritability of different forms of memory in the Late Onset Alzheimer's Disease Family Study.
The study aim was to estimate the genetic contribution to individual differences in different forms of memory in a large family-based group of older adults. As part of the Late Onset Alzheimer's Disease Family Study, 899 persons (277 with Alzheimer's disease, 622 unaffected) from 325 families completed a battery of memory tests from which previously established composite measures of episodic memory, semantic memory, and working memory were derived. Heritability in these measures was estimated using the maximum likelihood variance component method, controlling for age, gender, and education. In analyses of unaffected family members, the adjusted heritability estimates were 0.62 for episodic memory, 0.49 for semantic memory, and 0.72 for working memory, where a heritability estimate of 1 indicates that genetic factors explain all of the phenotypic variance and a heritability of 0 indicates that genetic factors explain none. Adjustment for APOE genotype had little effect on these estimates. When analyses included affected and unaffected family members, adjusted heritability estimates were lower (0.47 for episodic memory, 0.32 for semantic memory, 0.42 for working memory). Adjusting for APOE slightly reduced the estimate for episodic memory (0.40) but had no effect on the remaining estimates. The results indicate that memory functions are under strong genetic influence in older persons with and without AD, and are only partly attributable to APOE. This suggests that genetic analyses of memory endophenotypes may help to identify genetic variants associated with AD.


Dietary ALA from Spinach Enhances Liver n-3 Fatty Acid Content to Greater Extent than Linseed Oil in Mice Fed Equivalent Amounts of ALA.
Although several works have reported absorption rate differences of n-3 polyunsaturated fatty acids (PUFA) bound to different lipid forms, such as ethyl ester, triacylglycerol (TAG), and phospholipids, no studies have investigated the effect of n-3 PUFA from glycolipids (GL). The present study compared the fatty acid contents of tissue and serum lipids from normal C57BL/6J mice fed two types of α-linolenic acid (ALA)-rich lipids, spinach lipid (SPL), and linseed oil (LO). ALA was primarily present as the GL form in SPL, while it existed as TAG in LO. Supplementation of both lipids increased ALA and its n-3 metabolites, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid, and decreased n-6 PUFA, linoleic acid and arachidonic acid, in the livers, small intestines, and sera of the treated mice compared with those of the control group. When the comparison between the SPL and LO diets containing the same amount of ALA was conducted, the EPA and DPA levels in the liver lipids from mice fed the SPL diet were significantly higher than those fed the LO diet. Additionally, the total contents of n-3 PUFA of lipids from the livers, small intestines, and sera of the SPL group were higher than those of the LO group.


Sodium-dependent GABA-induced currents in GAT1-transfected HeLa cells.
1. HeLa cells were infected with recombinant vaccinia virus containing the T7 RNA polymerase gene and transfected with the cDNA for a rat GABA transporter, GAT1, cloned downstream of a T7 RNA polymerase promoter. Six to sixteen hours after transfection, whole-cell recording with a voltage ramp in the range -90 to 50 mV revealed GABA-induced currents (approximately -100 pA at -60 mV in 100 microM GABA, 16 h after transfection at room temperature). No GABA-induced currents were observed in parental HeLa cells or in mock-transfected cells. 2. GABA-induced currents were suppressed by extracellular perfusion with GABA-free solutions or addition of GAT1 inhibitors SKF89976-A or SKF100330-A. At fixed voltage the GABA dependence of the inward current fitted the Michaelis-Menten equation with a Hill coefficient, n, near unity and an equilibrium constant, K(m), near 3 microM. The Na+ dependence of the inward currents fitted the Michaelis-Menten equation with n approximately equal to 2 and K(m) approximately equal to 10 mM. The constants n and K(m) for GABA and Na+ were independent of voltage in the range -90 to -30 mV. 3. GABA-induced currents reverse direction in the range 5-10 mV. The implication of this result is that GAT1 can mediate electrogenic (electrophoretic) influx or efflux of GABA depending on the membrane voltage. The presence of an outward current in our experiments is consistent with radioactive-labelled flux data from resealed vesicle studies. However, it is inconsistent with frog oocyte expression experiments using the sample clone. In oocytes, GAT1 generates no outward current in a similar voltage range. Smaller intracellular volume or higher turnover rates in the mammalian expression system may explain the outward currents. 4. External GABA induces inward current, and internal GABA induces outward current. However, in cells initially devoid of internal GABA, external GABA can also facilitate an outward current. This GAT1-mediated outward current occurs only after applying negative potentials to the cell. These data are consistent with the concept that negative potentials drive GABA and Na+ into the cell, which then leads to electrogenic efflux through GAT1 at positive voltages. 5. Assuming coupled transport, we estimate the number of transporters, N, times the turnover rate, r, to be Nr approximately 10(9) s-1 under nominal conditions (V = -60 mV, 30 microM GABA, 130 mM Na+ and room temperature). This indicates either very high levels of expression (approximately 10(4) microns-2), assuming published turnover rates (approximately 10 s-1), or turnover rates that are significantly greater than previously reported. As an alternative, a channel may exist in the GAT1 protein that is gated by GABA and Na+ and blocked by GAT1 antagonists. The channel mode of conduction would exist in addition to the coupled, fixed-stoichiometry transporter mode of conduction.


A megavoltage scatter correction technique for cone-beam CT images acquired during VMAT delivery.
Kilovoltage cone-beam CT (kV CBCT) can be acquired during the delivery of volumetric modulated arc therapy (VMAT), in order to obtain an image of the patient during treatment. However, the quality of such CBCTs is degraded by megavoltage (MV) scatter from the treatment beam onto the imaging panel. The objective of this paper is to introduce a novel MV scatter correction method for simultaneous CBCT during VMAT, and to investigate its effectiveness when compared to other techniques. The correction requires the acquisition of a separate set of images taken during VMAT delivery, while the kV beam is off. These images--which contain only the MV scatter contribution on the imaging panel--are then used to correct the corresponding kV/MV projections. To test this method, CBCTs were taken of an image quality phantom during VMAT delivery and measurements of contrast to noise ratio were made. Additionally, the correction was applied to the datasets of three VMAT prostate patients, who also received simultaneous CBCTs. The clinical image quality was assessed using a validated scoring system, comparing standard CBCTs to the uncorrected simultaneous CBCTs and a variety of correction methods. Results show that the correction is able to recover some of the low and high-contrast signal to noise ratio lost due to MV scatter. From the patient study, the corrected CBCT scored significantly higher than the uncorrected images in terms of the ability to identify the boundary between the prostate and surrounding soft tissue. In summary, a simple MV scatter correction method has been developed and, using both phantom and patient data, is shown to improve the image quality of simultaneous CBCTs taken during VMAT delivery.


High-efficiency 1.5 microm thick optical axis grating and its use for laser beam combining.
We demonstrate an optical axis grating (OAG) recorded in a nematic liquid crystal that yields a higher than 80% diffraction efficiency and over 800:1 switching contrast between diffraction orders for a laser beam of a red wavelength in a material layer only 1.5 microm thick. The grating was used for combining two laser beams with high efficiency. These observations prove the feasibility of new generation high-efficiency diffractive optical components, which are most promising for infrared and high-power applications owing to their enhanced transparency and reduced thermal effects in thin material layers.


Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer.
APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246. APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg. MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response. We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.


Integration of genome-wide computation DRE search, AhR ChIP-chip and gene expression analyses of TCDD-elicited responses in the mouse liver.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor (TF) that mediates responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Integration of TCDD-induced genome-wide AhR enrichment, differential gene expression and computational dioxin response element (DRE) analyses further elucidate the hepatic AhR regulatory network. Global ChIP-chip and gene expression analyses were performed on hepatic tissue from immature ovariectomized mice orally gavaged with 30 μg/kg TCDD. ChIP-chip analysis identified 14,446 and 974 AhR enriched regions (1% false discovery rate) at 2 and 24 hrs, respectively. Enrichment density was greatest in the proximal promoter, and more specifically, within ± 1.5 kb of a transcriptional start site (TSS). AhR enrichment also occurred distal to a TSS (e.g. intergenic DNA and 3' UTR), extending the potential gene expression regulatory roles of the AhR. Although TF binding site analyses identified over-represented DRE sequences within enriched regions, approximately 50% of all AhR enriched regions lacked a DRE core (5'-GCGTG-3'). Microarray analysis identified 1,896 number of TCDD-responsive genes (|fold change| ≥ 1.5, P1(t) > 0.999). Integrating this gene expression data with our ChIP-chip and DRE analyses only identified 625 differentially expressed genes that involved an AhR interaction at a DRE. Functional annotation analysis of differentially regulated genes associated with AhR enrichment identified overrepresented processes related to fatty acid and lipid metabolism and transport, and xenobiotic metabolism, which are consistent with TCDD-elicited steatosis in the mouse liver. Details of the AhR regulatory network have been expanded to include AhR-DNA interactions within intragenic and intergenic genomic regions. Moreover, the AhR can interact with DNA independent of a DRE core suggesting there are alternative mechanisms of AhR-mediated gene regulation.


CALIFORNIA STATE UNIVERSITY CATASTROPHIC (CAT) LEAVE DONATION PROGRAM: DEMOGRAPHICS, ECONOMIC SECURITY, AND SOCIAL EQUITY.
The California State University (CSU) Chancellor's Office reached an agreement with all CSU collective bargaining units and Employee Relations on a uniform Catastrophic (CAT) Leave Donation Program in 1992. The CAT Leave Donation Program allows employees to donate sick and/or vacation leave credits to employees who are incapacitated due to a catastrophic illness or injury and have exhausted all of their own leave credits. This also extends to employees with whom family illnesses are deemed catastrophic, thus requiring the employee to care for an immediate family member. Stakeholders include union represented employees who accrue leave credits as well as any employee who receives or donates hours of leave credits in the program. Other stakeholders include the family members and program administrators.


Auditory imagery modulates frequency-specific areas in the human auditory cortex.
Neural responses in early sensory areas are influenced by top-down processing. In the visual system, early visual areas have been shown to actively participate in top-down processing based on their topographical properties. Although it has been suggested that the auditory cortex is involved in top-down control, functional evidence of topographic modulation is still lacking. Here, we show that mental auditory imagery for familiar melodies induces significant activation in the frequency-responsive areas of the primary auditory cortex (PAC). This activation is related to the characteristics of the imagery: when subjects were asked to imagine high-frequency melodies, we observed increased activation in the high- versus low-frequency response area; when the subjects were asked to imagine low-frequency melodies, the opposite was observed. Furthermore, we found that A1 is more closely related to the observed frequency-related modulation than R in tonotopic subfields of the PAC. Our findings suggest that top-down processing in the auditory cortex relies on a mechanism similar to that used in the perception of external auditory stimuli, which is comparable to early visual systems.


Identification of Candida species by randomly amplified polymorphic DNA fingerprinting of colony lysates.
We have characterized a method that produces simple yet diagnostic fingerprints that are unique to isolates of Candida species. DNA from individual colonies can be amplified from crude single-colony lysates. Randomly amplified polymorphic DNA (RAPD) fingerprints generated from a single primer correctly identified the species of most (>98%) of the isolates identified with CHROMagar Candida plates as non-Candida albicans Candida species. RAPD fingerprints were much more informative than the plates, since they distinguished between all tested species and required less time. Most (91%) of these identifications agreed with those assigned by API 20C tests. In almost every incident of species identity mismatch, electrophoretic karyotyping showed that the RAPD fingerprint was correct. This underscores the improved objectivity and reliability of this method over those of conventional diagnostic tools. The identities of approximately 30% of C. albicans isolates identified in clinical laboratories by positive germ tube tests are not verified by either testing on CHROMagar Candida plates or RAPD fingerprinting. Data suggest that clinical isolates conventionally identified as C. albicans in clinical settings are heterogeneous, consisting of both misidentified and atypical yeasts. RAPD fingerprints obtained from primary culture plate colonies allows for rapid, highly accurate determinations of Candida species, hence permitting earlier selection of appropriate antifungal agents in the clinical setting.


The endothelin-converting enzyme-1/endothelin-1 pathway plays a critical role in inflammation-associated premature delivery in a mouse model.
Premature delivery occurs in 12% of all births and accounts for nearly half of long-term morbidity. Current therapeutic approaches to preterm delivery are ineffective and present serious risks to both mother and fetus. The single most common cause of preterm birth is infection. Previous in vitro investigations have shown that endothelin-1 (ET-1) is induced by inflammatory cytokines and that it increases myometrial smooth muscle tone. Furthermore, we have previously shown that both the endothelin-converting enzyme-1 (ECE-1) inhibitor, phosphoramidon, as well as a novel ET-1 receptor A antagonist synthesized by our group, control premature delivery in a mouse model of inflammation-associated preterm delivery. In the current work, we show that levels of both ET-1 and ECE-1 are increased in gestational tissues in E16.5 mice induced to deliver prematurely after lipopolysaccharide administration. We also show that premature delivery is controlled by treatment with the selective endothelin receptor A antagonist BQ-123 in a dose-dependent manner. Finally, we show here for the first time that premature delivery can be controlled using RNA silencing, by hydrodynamic transfection of E15 mice with ECE-1 RNAi. Taken together, these data support a critical role for the ECE-1/ET-1 system in inflammation-associated premature delivery. The ability to control premature delivery by antagonizing or silencing the ECE-1/ET-1 system offers a novel approach to an unmet clinical need.


Grooming and growing with microglia.
Microglia mediate neuroprotection and neuropathogenesis but have not been directly associated with behavior. As gatekeepers of the brain's immune system, microglia protect the brain from pathogens but also contribute to inflammation, which may negatively affect neurons. A recent study demonstrates a role for Hoxb8-expressing microglia in modulating behavior, a finding that is interesting from both the pathology and developmental biology perspectives.


Poverty and childhood undernutrition in developing countries: a multi-national cohort study.
The importance of reducing childhood undernutrition has been enshrined in the United Nations' Millennium Development Goals. This study explores the relationship between alternative indicators of poverty and childhood undernutrition in developing countries within the context of a multi-national cohort study (Young Lives). Approximately 2000 children in each of four countries - Ethiopia, India (Andhra Pradesh), Peru and Vietnam - had their heights measured and were weighed when they were aged between 6 and 17 months (survey one) and again between 4.5 and 5.5 years (survey two). The anthropometric outcomes of stunted, underweight and wasted were calculated using World Health Organization 2006 reference standards. Maximum-likelihood probit estimation was employed to model the relationship within each country and survey between alternative measures of living standards (principally a wealth index developed using principal components analysis) and each anthropometric outcome. An extensive set of covariates was incorporated into the models to remove as much individual heterogeneity as possible. The fully adjusted models revealed a negative and statistically significant coefficient on wealth for all outcomes in all countries, with the exception of the outcome of wasted in India (Andhra Pradesh) and Vietnam (survey one) and the outcome of underweight in Vietnam (surveys one and two). In survey one, the partial effects of wealth on the probabilities of stunting, being underweight and wasting was to reduce them by between 1.4 and 5.1 percentage points, 1.0 and 6.4 percentage points, and 0.3 and 4.5 percentage points, respectively, with each unit (10%) increase in wealth. The partial effects of wealth on the probabilities of anthropometric outcomes were larger in the survey two models. In both surveys, children residing in the lowest wealth quintile households had significantly increased probabilities of being stunted in all four study countries and of being underweight in Ethiopia, India (Andhra Pradesh) and Peru in comparison to children residing in the highest wealth quintile households. Random effects probit models confirmed the statistical significance of increased wealth in reducing the probability of being stunted and underweight across all four study countries. We conclude that, although multi-faceted, childhood undernutrition in developing countries is strongly rooted in poverty.


A framework for planning of sustainable water and sanitation systems in peri-urban areas.
There are billions of people around the world that lack access to safe water supply and basic sanitation, a situation which puts the affected in severe health conditions as well as economical and social despair. Many of those lacking adequate water supply and sanitation systems can be found at the fringe of the cities in so called peri-urban areas, especially in the developing world. Planning in these areas is highly complex due to challenging environmental and physical conditions, high population density and unclear institutional boundaries. This article presents a framework aiming to support the planning process for sustainable water and sanitation systems in peri-urban areas. The suggested framework is based on different available planning approaches from a review of literature and websites of organisations and companies. It consists of a recommendation of important steps in the planning process as well as supporting tools. Further, it incorporates a set of sustainability criteria important for the peri-urban context and allows for the development of site specific systems. The framework has the aim to be flexible for different planning situations, and for suiting planners with different perspectives and amount of resources.


Generation of experimental allergic airways inflammation in the absence of draining lymph nodes.
The objective of this study was to investigate the contribution of secondary lymphoid organs in the generation and maintenance of experimental allergic airway inflammation. We employed a previously reported murine model of respiratory mucosal allergic sensitization, induced by repeated aerosolizations of ovalbumin in the context of a GM-CSF airway environment. We executed this protocol in wild-type (WT) and lymphotoxin-alpha-deficient mice (LTalpha-KO) mice, which are devoid of lymph nodes (LNs) and possess rudimentary spleen structures. Despite the lack of pulmonary LNs draining the airway compartment, LTalpha-KO mice were fully capable of mounting a robust inflammatory response in the airways, consisting of Th2 polarized CD4+ T cells and eosinophils. This was accompanied by IL-5, IL-13, and IFN-gamma production by splenocytes and generation of ovalbumin-specific serum IgE. Exposure to the same antigen 7 weeks after complete resolution of airway inflammation once again induced a Th2 polarized infiltrate, demonstrating intact immunological memory. To investigate inherent plasticity in establishing antigen-specific immunity, mice were splenectomized before sensitization. Allergic sensitization was completely abrogated in splenectomized LTalpha-KO mice, compared with eusplenic LTalpha-KO controls. These data demonstrate that secondary lymphoid organs, either LN or spleen, are essential for the generation of allergic airway responses.


Synergistic silencing of α-globin and induction of γ-globin by histone deacetylase inhibitor, vorinostat as a potential therapy for β-thalassaemia.
β-Thalassaemia is one of the most common monogenic diseases with no effective cure in the majority of patients. Unbalanced production of α-globin in the presence of defective synthesis of β-globin is the primary mechanism for anaemia in β-thalassaemia. Clinical genetic data accumulated over three decades have clearly demonstrated that direct suppression of α-globin and induction of γ-globin are effective in reducing the globin chain imbalance in erythroid cells hence improving the clinical outcome of patients with β-thalassaemia. Here, we show that the histone deacetylase inhibitor drug, vorinostat, in addition to its beneficial effects for patients with β-thalassaemia through induction of γ-globin, has the potential to simultaneously suppress α-globin. We further show that vorinostat exhibits these synergistic beneficial effects in globin gene expression at nanomolar concentrations without perturbing erythroid expansion, viability, differentiation or the transcriptome. This new evidence will be helpful for the interpretation of existing clinical trials and future clinical studies that are directed towards finding a cure for β-thalassaemia using vorinostat.


Filled Skutterudite Antimonides: A New Class of Thermoelectric Materials
A class of thermoelectric materials has been synthesized with a thermoelectric figure of merit ZT (where T is temperature and Z is a function of thermopower, electrical resistivity, and thermal conductivity) near 1 at 800 kelvin. Although these materials have not been optimized, this value is comparable to the best ZT values obtained for any previously studied thermoelectric material. Calculations indicate that the optimized material should have ZT values of 1.4. These ternary semiconductors have the general formula RM4X12 (where R is lanthanum, cerium, praseodymium, neodymium, or europium; M is iron, ruthenium, or osmium; and X is phosphorus, arsenic, or antimony) and represent a new approach to creating improved thermoelectric materials. Several alloys in the composition range CeFe4-xCoxSb12 or LaFe4-xCoxSb12 (0 < x < 4) have large values of ZT.


Development of a reverse transcription-PCR-DNA enzyme immunoassay for detection of "Norwalk-like" viruses and hepatitis A virus in stool and shellfish.
Outbreaks of food- and waterborne gastroenteritis are being increasingly reported throughout the world. The analysis of environmental samples by newer diagnostic techniques such as reverse transcription-PCR (RT-PCR) amplification of nucleic acid has begun to identify human enteric viruses (predominantly "Norwalk-like" viruses [NLVs]) as the cause of many of these outbreaks. To streamline NLV detection from environmental samples such as shellfish, we have developed an RT-PCR-oligoprobe amplification and detection method using several new procedures that enable confirmed RT-PCR amplification and product detection in 1 day. The new steps include replacing reverse transcriptase and Taq polymerase with rTth polymerase, a heat-stable enzyme that functions as both a reverse transcriptase and DNA polymerase, in a single-tube, single-buffer, elevated temperature reaction. An internal standard Norwalk virus (NV) RNA control is added to each RT-PCR to identify sample inhibition, and thermolabile uracil N-glycosylase is incorporated into the reaction to prevent PCR product carryover contamination. Finally, RT-PCR-generated amplicons are detected in microtiter wells using virus-specific biotinylated oligoprobes in an enzyme-linked immunosorbent assay-based format. The DNA enzyme immunoassay is based on the capture of PCR product by biotinylated probes fixed onto individual streptavidin-coated wells. Using this method, low levels of NV were detected in stool and both NLV and hepatitis A virus were detected in bivalve mollusks following bioaccumulation. The method also successfully detected NLV in oysters implicated in an outbreak of NLV gastroenteritis. This method dramatically decreases the time needed for analysis and is amenable to automation.


Visibly transparent polymer solar cells produced by solution processing.
Visibly transparent photovoltaic devices can open photovoltaic applications in many areas, such as building-integrated photovoltaics or integrated photovoltaic chargers for portable electronics. We demonstrate high-performance, visibly transparent polymer solar cells fabricated via solution processing. The photoactive layer of these visibly transparent polymer solar cells harvests solar energy from the near-infrared region while being less sensitive to visible photons. The top transparent electrode employs a highly transparent silver nanowire-metal oxide composite conducting film, which is coated through mild solution processes. With this combination, we have achieved 4% power-conversion efficiency for solution-processed and visibly transparent polymer solar cells. The optimized devices have a maximum transparency of 66% at 550 nm.


The heterodimeric assembly of the CD94-NKG2 receptor family and implications for human leukocyte antigen-E recognition.
The CD94-NKG2 receptor family that regulates NK and T cells is unique among the lectin-like receptors encoded within the natural killer cell complex. The function of the CD94-NKG2 receptors is dictated by the pairing of the invariant CD94 polypeptide with specific NKG2 isoforms to form a family of functionally distinct heterodimeric receptors. However, the structural basis for this selective pairing and how they interact with their ligand, HLA-E, is unknown. We describe the 2.5 A resolution crystal structure of CD94-NKG2A in which the mode of dimerization contrasts with that of other homodimeric NK receptors. Despite structural homology between the CD94 and NKG2A subunits, the dimer interface is asymmetric, thereby providing a structural basis for the preferred heterodimeric assembly. Structure-based sequence comparisons of other CD94-NKG2 family members, combined with extensive mutagenesis studies on HLA-E and CD94-NKG2A, allows a model of the interaction between CD94-NKG2A and HLA-E to be established, in which the invariant CD94 chain plays a more dominant role in interacting with HLA-E in comparison to the variable NKG2 chain.


Environmental and physical controls on northern terrestrial methane emissions across permafrost zones.
Methane (CH4 ) emissions from the northern high-latitude region represent potentially significant biogeochemical feedbacks to the climate system. We compiled a database of growing-season CH4 emissions from terrestrial ecosystems located across permafrost zones, including 303 sites described in 65 studies. Data on environmental and physical variables, including permafrost conditions, were used to assess controls on CH4 emissions. Water table position, soil temperature, and vegetation composition strongly influenced emissions and had interacting effects. Sites with a dense sedge cover had higher emissions than other sites at comparable water table positions, and this was an effect that was more pronounced at low soil temperatures. Sensitivity analysis suggested that CH4 emissions from ecosystems where the water table on average is at or above the soil surface (wet tundra, fen underlain by permafrost, and littoral ecosystems) are more sensitive to variability in soil temperature than drier ecosystems (palsa dry tundra, bog, and fen), whereas the latter ecosystems conversely are relatively more sensitive to changes of the water table position. Sites with near-surface permafrost had lower CH4 fluxes than sites without permafrost at comparable water table positions, a difference that was explained by lower soil temperatures. Neither the active layer depth nor the organic soil layer depth was related to CH4 emissions. Permafrost thaw in lowland regions is often associated with increased soil moisture, higher soil temperatures, and increased sedge cover. In our database, lowland thermokarst sites generally had higher emissions than adjacent sites with intact permafrost, but emissions from thermokarst sites were not statistically higher than emissions from permafrost-free sites with comparable environmental conditions. Overall, these results suggest that future changes to terrestrial high-latitude CH4 emissions will be more proximately related to changes in moisture, soil temperature, and vegetation composition than to increased availability of organic matter following permafrost thaw.


Genome-wide meta-analysis of systolic blood pressure in children with sickle cell disease.
In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0 x 10(-8)), a number of suggestive candidate loci were identified. The most significant SNP, rs7952106 (P-value=8.57 x 10(-7)), was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene (P-value=5.2 x 10(-5)). Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5' CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.


Lateralized electrodermal dysfunction and complexity in patients with schizophrenia and depression.
Recent evidence indicates that in psychiatric patients with schizophrenia and depression, lateralized EDA changes linked to temporal-limbic electrophysiological dysfunction occur. These clinical findings provide evidence for brain asymmetry and disruptions related to integrative brain activity in pathological conditions. These changes in brain asymmetry may be assessed by linear analysis of EDA measurement and nonlinear analysis of brain complexity calculated as information entropy. Two groups of patients with established diagnosis of paranoid schizophrenia (N=35), unipolar depression (N=35) and a control group of 35 healthy controls were examined by measurement of bilateral electrodermal activity (EDA). In non-linear data analysis of the EDA time series in resting state the method of recurrence quantification analysis was applied. In these patients significant right-left EDA asymmetry and asymmetry of information entropy calculated by non-linear recurrence quantification analysis of EDA records have been found. Similar asymmetry has not been observed in the group of healthy controls. Because information entropy reflects the complexity of the deterministic structure in the system, then unilaterally increased entropy in patients with schizophrenia and depression likely indicates specific nonlinear disturbances in limbic circuits that modulate EDA. These data are in accordance with recent findings that indicate apparent differences in nonlinear neural patterns in the psychiatric diseases and nonlinear behavior of healthy brain.


Wearable Improved Vision System for Color Vision Deficiency Correction.
Color vision deficiency (CVD) is an extremely frequent vision impairment that compromises the ability to recognize colors. In order to improve color vision in a subject with CVD, we designed and developed a wearable improved vision system based on an augmented reality device. The system was validated in a clinical pilot study on 24 subjects with CVD (18 males and 6 females, aged 37.4 ± 14.2 years). The primary outcome was the improvement in the Ishihara Vision Test score with the correction proposed by our system. The Ishihara test score significantly improved ([Formula: see text]) from 5.8 ± 3.0 without correction to 14.8 ± 5.0 with correction. Almost all patients showed an improvement in color vision, as shown by the increased test scores. Moreover, with our system, 12 subjects (50%) passed the vision color test as normal vision subjects. The development and preliminary validation of the proposed platform confirm that a wearable augmented-reality device could be an effective aid to improve color vision in subjects with CVD.


Theory of mind: did evolution fool us?
Theory of Mind (ToM) is the ability to attribute mental states (e.g., beliefs and desires) to other people in order to understand and predict their behaviour. If others are rewarded to compete or cooperate with you, then what they will do depends upon what they believe about you. This is the reason why social interaction induces recursive ToM, of the sort "I think that you think that I think, etc.". Critically, recursion is the common notion behind the definition of sophistication of human language, strategic thinking in games, and, arguably, ToM. Although sophisticated ToM is believed to have high adaptive fitness, broad experimental evidence from behavioural economics, experimental psychology and linguistics point towards limited recursivity in representing other's beliefs. In this work, we test whether such apparent limitation may not in fact be proven to be adaptive, i.e. optimal in an evolutionary sense. First, we propose a meta-Bayesian approach that can predict the behaviour of ToM sophistication phenotypes who engage in social interactions. Second, we measure their adaptive fitness using evolutionary game theory. Our main contribution is to show that one does not have to appeal to biological costs to explain our limited ToM sophistication. In fact, the evolutionary cost/benefit ratio of ToM sophistication is non trivial. This is partly because an informational cost prevents highly sophisticated ToM phenotypes to fully exploit less sophisticated ones (in a competitive context). In addition, cooperation surprisingly favours lower levels of ToM sophistication. Taken together, these quantitative corollaries of the "social Bayesian brain" hypothesis provide an evolutionary account for both the limitation of ToM sophistication in humans as well as the persistence of low ToM sophistication levels.


Cost-effectiveness of coronary artery calcium testing for coronary heart and cardiovascular disease risk prediction to guide statin allocation: the Multi-Ethnic Study of Atherosclerosis (MESA).
The Multi-Ethnic Study of Atherosclerosis (MESA) showed that the addition of coronary artery calcium (CAC) to traditional risk factors improves risk classification, particularly in intermediate risk asymptomatic patients with LDL cholesterol levels <160 mg/dL. However, the cost-effectiveness of incorporating CAC into treatment decision rules has yet to be clearly delineated. To model the cost-effectiveness of CAC for cardiovascular risk stratification in asymptomatic, intermediate risk patients not taking a statin. Treatment based on CAC was compared to (1) treatment of all intermediate-risk patients, and (2) treatment on the basis of United States guidelines. We developed a Markov model of first coronary heart disease (CHD) and cardiovascular disease (CVD) events. We modeled statin treatment in intermediate risk patients with CAC≥1 and CAC≥100, with different intensities of statins based on the CAC score. We compared these CAC-based treatment strategies to a "treat all" strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. Clinical and economic outcomes were modeled over both five- and ten-year time horizons. Outcomes consisted of CHD and CVD events and Quality-Adjusted Life Years (QALYs). Sensitivity analyses considered the effect of higher event rates, different CAC and statin costs, indirect costs, and re-scanning patients with incidentalomas. We project that it is both cost-saving and more effective to scan intermediate-risk patients for CAC and to treat those with CAC≥1, compared to treatment based on established risk-assessment guidelines. Treating patients with CAC≥100 is also preferred to existing guidelines when we account for statin side effects and the disutility of statin use. Compared to the alternatives we assessed, CAC testing is both effective and cost saving as a risk-stratification tool, particularly if there are adverse effects of long-term statin use. CAC may enable providers to better tailor preventive therapy to patients' risks of CVD.


Unproved and controversial methods and theories in allergy/immunology.
Unproved methods and controversial theories in the diagnosis and management of allergy/immunology are those that lack scientific credibility. Some definitions are provided for perspective, as in chronic medical conditions, frequently nonscientifically based treatments are developed that can have a profound psychological effect on the patients in the absence of objective physical benefit. Standard practice uses methods of diagnosis and treatment used by reputable physicians in a particular subspecialty or primary care practice, with the understanding that diagnosis and treatment options are consistent with established mechanisms of conditions or diseases. Conventional medicine (Western or allopathic medicine) is that which is practiced by the majority of physicians, osteopaths, psychologists, registered nurses, and physical therapists. Complementary medicine involves diverse practices or products that are used with the practice of conventional medicine, such as using acupuncture in addition to opioids for pain relief. Alternative medicine implies use of complementary practices in place of conventional medicine. Unproved and controversial methods and theories do not have supporting data, validation, or sufficient scientific scrutiny, and they should not be used in the practice of allergy/immunology. Some examples of unproven theories about allergic/immunologic conditions include allergic toxemia, idiopathic environmental intolerance, and toxic disease from indoor molds. Unconventional diagnostic methods for allergic conditions include cytotoxic tests, provocation-neutralization, electrodermal diagnosis, applied kinesiology assessments, chemical analysis of body fluids, and serum immunoglobulin G (IgG) or IgG4 testing. Unproven treatments and intervention methods for allergic/immunologic conditions include acupuncture, homeopathy, halotherapy, and autogenous urine injections.


A threefold approach including quantum chemical, molecular docking and molecular dynamic studies to explore the natural compounds from Centaurea jacea as the potential inhibitors for COVID-19.
In the current report, we studied the possible inhibitors of COVID-19 from bioactive constituents of Centaurea jacea using a threefold approach consisting of quantum chemical, molecular docking and molecular dynamic techniques. Centaurea jacea is a perennial herb often used in folk medicines of dermatological complaints and fever. Moreover, anticancer, antioxidant, antibacterial and antiviral properties of its bioactive compounds are also reported. The Mpro (Main proteases) was docked with different compounds of Centaurea jacea through molecular docking. All the studied compounds including apigenin, axillarin, Centaureidin, Cirsiliol, Eupatorin and Isokaempferide, show suitable binding affinities to the binding site of SARS-CoV-2 main protease with their binding energies -6.7 kcal/mol, -7.4 kcal/mol, -7.0 kcal/mol, -5.8 kcal/mol, -6.2 kcal/mol and -6.8 kcal/mol, respectively. Among all studied compounds, axillarin was found to have maximum inhibitor efficiency followed by Centaureidin, Isokaempferide, Apigenin, Eupatorin and Cirsiliol. Our results suggested that axillarin binds with the most crucial catalytic residues CYS145 and HIS41 of the Mpro, moreover axillarin shows 5 hydrogen bond interactions and 5 hydrophobic interactions with various residues of Mpro. Furthermore, the molecular dynamic calculations over 60 ns (6×106 femtosecond) time scale also shown significant insights into the binding effects of axillarin with Mpro of SARS-CoV-2 by imitating protein like aqueous environment. From molecular dynamic calculations, the RMSD and RMSF computations indicate the stability and dynamics of the best docked complex in aqueous environment. The ADME properties and toxicity prediction analysis of axillarin also recommended it as safe drug candidate. Further, in vivo and in vitro investigations are essential to ensure the anti SARS-CoV-2 activity of all bioactive compounds particularly axillarin to encourage preventive use of Centaurea jacea against COVID-19 infections.


A Randomized Feasibility Trial Comparing Surveillance Regimens for Patients with Low and Low-Intermediate Risk Non-Muscle Invasive Bladder Cancer.
Surveillance regimens for non-muscle invasive bladder cancer (NMIBC) are disparate and controlled trials could inform guidelines. The feasibility of randomizing patients to variable frequency surveillance is unknown. To determine patient willingness to randomization to high frequency (HF) versus low frequency (LF) surveillance regimen for NMIBC and compare patient comfort and healthcare costs across regimens. A non-blinded, two-arm, randomized-controlled study of patients with low or low-intermediate risk NMIBC was conducted at two institutions where patients were offered randomization to HF vs. LF surveillance following initial tumor resection. The HF group underwent cystoscopy every three months for 2 years, then every 6 months for 2 years, then annually. The LF group underwent cystoscopy at 9 months following the 3-month cystoscopy, then annually. Assuming 75% of patients approached would agree to enrollment, a sample size of n = 35 patients per arm provided a one-sided 95% exact Clopper-Pearson confidence lower-limit of 60%. Of 70 patients approached, 45 (64.3%) agreed to participate and 25 (35.7%) declined enrollment due to preference for HF. Twelve biopsies were performed, including 4 (19%) of 21 patients in the HF group and 8 (33.3%) of 24 patients in the LF group. Disease recurrence (low grade Ta) was observed in 3 (14.3%) and 5 (20.8%) patients in the HF and LF groups, respectively. No patients experienced high grade recurrence or progression. Both groups had similar patient-reported procedure-related discomfort and quality of life measures over time. Patient out-of-pocket cost and healthcare systems costs were $383.80 more per patient annually in the HF group. Randomization to variable frequency surveillance is challenging as over a third of patients declined participation. However, these data provide important preliminary insights into the potential effects of surveillance frequency on oncologic and economic outcomes in patients with low and low-intermediate risk bladder cancer.


Extracellular vesicles in the biology of brain tumour stem cells--Implications for inter-cellular communication, therapy and biomarker development.
Extracellular vesicles (EVs) act as carriers of molecular and oncogenic signatures present in subsets of tumour cells and tumour-associated stroma, and as mediators of intercellular communication. These processes likely involve cancer stem cells (CSCs). EVs represent a unique pathway of cellular export and cell-to-cell transfer of insoluble molecular regulators such as membrane receptors, signalling proteins and metabolites, thereby influencing the functional integration of cancer cell populations. While mechanisms that control biogenesis, cargo and uptake of different classes of EVs (exosomes, microvesicles, ectosomes, large oncosomes) are poorly understood, they likely remain under the influence of stress-responses, microenvironment and oncogenic processes that define the biology and heterogeneity of human cancers. In glioblastoma (GBM), recent molecular profiling approaches distinguished several disease subtypes driven by distinct molecular, epigenetic and mutational mechanisms, leading to formation of proneural, neural, classical and mesenchymal tumours. Moreover, molecularly distinct clonal cellular lineages co-exist within individual GBM lesions, where they differentiate according to distinct stem cell hierarchies resulting in several facets of tumour heterogeneity and the related potential for intercellular interactions. Glioma stem cells (GSCs) may carry signatures of either proneural or mesenchymal GBM subtypes and differ in several biological characteristics that are, at least in part, represented by the output and repertoire of EV production (vesiculome). We report that vesiculomes differ between known GBM subtypes. EVs may also reflect and influence the equilibrium of the stem cell hierarchy, contain oncogenic drivers and modulate the microenvironment (vascular niche). The GBM/GSC subtype-specific differentials in EV cargo of proteins, transcripts, microRNA and DNA may enable detection of the dynamics of the stem cell compartment and result in biological effects that remain to be fully characterized.


Ecologic correlates of obesity in rural obese adults.
We examined relationships of individual and environmental factors with obesity and trying to lose weight in rural residents. The joint contributions of individual and environmental factors on obesity status (obese vs. morbidly obese) and trying to lose weight (yes vs. no) were evaluated using generalized estimating equations. Patients at 29 clinics in rural areas (N = 414, M age 55.0 years (SD = 15.4), 66.3% female) completed anthropometric assessments of weight and height along with survey assessments of individual sociodemographics and trying to lose weight. Rural environments were assessed on aggregated physician access, and sociodemographic context. Most participants (70%, M BMI = 38.3) were obese and 30% morbidly obese. A majority (73%, n = 302) of the sample was trying to lose weight. Compared to obese, morbidly obese participants were more likely to be younger, disproportionately female, not have private insurance, have more comorbid conditions, and rate themselves in worse health in comparison to their obese peers. Compared to not trying to lose weight, trying to lose weight participants were more likely to be younger, disproportionately female, have fewer comorbid conditions, and have attempted to lose weight more times through exercise. Few relationships were seen between environmental variables and obesity or trying to lose weight. There was no consistent pattern of relationships between environment factors and obesity or trying to lose weight was seen. Unique aspects of rural living may not be captured by traditionally available neighborhood measures.


Urinary estrogens and estrogen metabolites and mammographic density in premenopausal women.
Mammographic density is a strong and independent risk factor for breast cancer and is considered an intermediate marker of risk. The major predictors of premenopausal mammographic density, however, have yet to be fully elucidated. To test the hypothesis that urinary estrogen metabolism profiles are associated with mammographic density, we conducted a cross-sectional study among 352 premenopausal women in the Nurses' Health Study II (NHSII). We measured average percent mammographic density using a computer-assisted method. In addition, we assayed 15 estrogens and estrogen metabolites (jointly termed EM) in luteal-phase urine samples. We used multivariable linear regression to quantify the association of average percent density with quartiles of each individual EM as well as the sum of all EM (total EM), EM groups defined by metabolic pathway, and pathway ratios. In multivariable models controlling for body mass index and other predictors of breast density, women in the top quartile of total EM had an average percent density 3.4 percentage points higher than women in the bottom quartile (95 % confidence interval: -1.1, 8.0; p trend = 0.08). A non-significant positive association was noted for the 2-hydroxylation pathway catechols (breast density was 4.0 percentage points higher in top vs. bottom quartile; p trend = 0.06). In general, we observed no associations with parent estrogens or the 4- or 16-hydroxylation pathways or pathway ratios. These results suggest that urinary luteal estrogen profiles are not strongly associated with premenopausal mammographic density. If these profiles are associated with breast cancer risk, they may not act through influences on breast density.


A novel finding of sentinel lymphatic channels in early stage breast cancer patients: which may influence detection rate and false-negative rate of sentinel lymph node biopsy.
The exact lymphatic drainage pattern of the breast hasn't been explained clearly. The aim of this study was to investigate the sentinel lymphatic channels (SLCs) in the cancerous breast. Whether the type of SLCs influenced the detection rate and false-negative rate of SLNB was also assessed. Mimic SLNB was performed in 110 early-stage breast cancer patients with subareolar injection of blue methylene dye intraoperatively. Postoperatively, 110 specimens of modified radical mastectomy were examined for all blue SLCs after additional injection of methylene dye in peritumoral parenchyma. Interestingly, three types of SLCs, including superficial sentinel lymphatic channel (SSLC), deep sentinel lymphatic channel (DSLC), and penetrating sentinel lymphatic channel (PSLC) were found in 107 patients. Six lymphatic drainage patterns based on the three types of SLCs were observed in these 107 patients. The proportions of the drainage pattern SSLC, DSLC, PSLC, SSLC+DSLC, SSLC+PSLC, and DSLC+PSLC in the breast were 43%, 0.9%, 15.9%, 33.6%, 3.7% and 2.8%, respectively. The lymphatic drainage pattern in the breast was a significant risk factor for unsuccessful identification of sentinel lymph nodes (P<0.001) and false-negatives in SLNB (P = 0.034) with the subareolar injection technique. Three kinds of SLCs are the basis of six lymphatic drainage patterns from the breast to the axilla. The type of SLCs is the factor influencing the detection rate and false-negative rate of SLNB. These findings suggest the optimal injection technique of the combination of superficial and deep injection in SLNB procedures. Future clinical studies are needed to confirm our novel findings.


Screening of Pesticide and Biocide Patterns As Risk Drivers in Sediments of Major European River Mouths: Ubiquitous or River Basin-Specific Contamination?
Pesticides and biocides (PaB) are ubiquitously present in aquatic ecosystems due to their widespread application and have been detected in rivers at concentrations that may cause distress to aquatic life. Many of these compounds accumulate in sediments acting as long-term source for aquatic ecosystems. However, data on sediment contamination with current-use PaB in Europe are scarce. Thus, in this study, we elucidated PaB patterns and associated risks in sediments of seven major European rivers focusing on their last stretch as an integrative sink of particles transported by these rivers. Sediments were extracted with pressurized liquid extraction (PLE) using a broad-spectrum method recovering many compound classes with a wide range of physicochemical properties. Altogether 126 compounds were analyzed and 81 of them were detected with LC-HRMS and GC-NCI-MS/MS at least in one of the sediments. The highest number of compounds was detected (59) in River Elbe sediments close to Cuxhaven with outstanding concentrations ranging from 0.8 to 1691 mg/g organic carbon. Multivariate analysis identified a cluster with 3 ubiquitous compounds (cyhalothrin, carbendazim, fenpropimorph) and three clusters of chemicals with higher variability within and between rivers. Risk assessment indicates an acute toxic risk to benthic crustaceans at all investigated sites with the pyrethroids tefluthrin and cyfluthrin together with the fungicide carbendazim as the main drivers. Risks to algae were driven at most sites almost exclusively by photosynthesis inhibitors with estuary-specific herbicide mixtures, while in the rivers Po and Gironde cell division inhibitors played an important role at some sites. Mixtures of specific concern have been defined and suggested for integration in future monitoring programs.


Current pesticide suicide surveillance methods used across the African continent: a scoping review protocol.
Every year, more than 800 000 people die from suicides of which an estimated 20% are from pesticide ingestion. Multiple studies have estimated that around 77%-80% of these pesticide suicides occur in low/middle-income countries. The full burden of pesticide suicides in African countries remains poorly documented, one reason being the lack of systematic data collection. It is essential to know the number of pesticide suicide cases to guide prevention of further cases occurring. This can be done by informing policy and legislation, and the implementation of targeted bans, as well as raising community awareness around the use of these pesticides, training of healthcare personnel, and influencing the type and level of clinical facility investments into this area of healthcare. The scoping review aims to investigate how pesticide suicide deaths in Africa are recorded by exploring the various surveillance systems in place, as well as highlighting key limitations and data collection barriers. A scoping review will be carried out with the five-stage methodological frameworks set out by Arksey and O'Malley and the Joanna Briggs Institute. Studies in English that looked at pesticide suicide in African countries will be extracted and screened independently by two reviewers against the inclusion and exclusion criteria of this review. Studies' data will be extracted, and a descriptive synthesis developed of their main findings, as guided by the approach of Levac and colleagues. Ethics approval is not required for this review as no human participants will be involved. The study findings will be distributed in a peer-reviewed publication. This protocol has been submitted for publication to BMJ Open.


The genetic basis of modularity in the development and evolution of the vertebrate dentition.
The construction of organisms from units that develop under semi-autonomous genetic control (modules) has been proposed to be an important component of their ability to undergo adaptive phenotypic evolution. The organization of the vertebrate dentition as a system of repeated parts provides an opportunity to study the extent to which phenotypic modules, identified by their evolutionary independence from other such units, are related to modularity in the genetic control of development. The evolutionary history of vertebrates provides numerous examples of both correlated and independent evolution of groups of teeth. The dentition itself appears to be a module of the dermal exoskeleton, from which it has long been under independent genetic control. Region-specific tooth loss has been a common trend in vertebrate evolution. Novel deployment of teeth and reacquisition of lost teeth have also occurred, although less frequently. Tooth shape differences within the dentition may be discontinuous (referred to as heterodonty) or graded. The occurrence of homeotic changes in tooth shape provides evidence for the decoupling of tooth shape and location in the course of evolution. Potential mechanisms for region-specific evolutionary tooth loss are suggested by a number of mouse gene knockouts and human genetic dental anomalies, as well as a comparison between fully-developed and rudimentary teeth in the dentition of rodents. These mechanisms include loss of a tooth-type-specific initiation signal, alterations of the relative strength of inductive and inhibitory signals acting at the time of tooth initiation and the overall reduction in levels of proteins required for the development of all teeth. Ectopic expression of tooth initiation signals provides a potential mechanism for the novel deployment or reacquisition of teeth; a single instance is known of a gene whose ectopic expression in transgenic mice can lead to ectopic teeth. Differences in shape between incisor and molar teeth in the mouse have been proposed to be controlled by the region-specific expression of signalling molecules in the oral epithelium. These molecules induce the expression of transcription factors in the underlying jaw mesenchyme that may act as selectors of tooth type. It is speculated that shifts in the expression domains of the epithelial signalling molecules might be responsible for homeotic changes in tooth shape. The observation that these molecules are regionally restricted in the chicken, whose ancestors were not heterodont, suggests that mammalian heterodonty may have evolved through the use of patterning mechanisms already acting on skeletal elements of the jaws. In general, genetic and morphological approaches identify similar types of modules in the dentition, but the data are not yet sufficient to identify exact correspondences. It is speculated that modularity may be achieved by gene expression differences between teeth or by differences in the time of their development, causing mutations to have cumulative effects on later-developing teeth. The mammalian dentition, for which virtually all of the available developmental genetic data have been collected, represents a small subset of the dental diversity present in vertebrates as a whole. In particular, teleost fishes may have a much more extensive dentition. Extension of research on the genetic control of tooth development to this and other vertebrate groups has great potential to further the understanding of modularity in the dentition.


Association Between Consumption of Ultraprocessed Foods and Cognitive Decline.
Although consumption of ultraprocessed food has been linked to higher risk of cardiovascular disease, metabolic syndrome, and obesity, little is known about the association of consumption of ultraprocessed foods with cognitive decline. To investigate the association between ultraprocessed food consumption and cognitive decline in the Brazilian Longitudinal Study of Adult Health. This was a multicenter, prospective cohort study with 3 waves, approximately 4 years apart, from 2008 to 2017. Data were analyzed from December 2021 to May 2022. Participants were public servants aged 35 to 74 years old recruited in 6 Brazilian cities. Participants who, at baseline, had incomplete food frequency questionnaire, cognitive, or covariate data were excluded. Participants who reported extreme calorie intake (<600 kcal/day or >6000 kcal/day) and those taking medication that could negatively interfere with cognitive performance were also excluded. Daily ultraprocessed food consumption as a percentage of total energy divided into quartiles. Changes in cognitive performance over time evaluated by the immediate and delayed word recall, word recognition, phonemic and semantic verbal fluency tests, and Trail-Making Test B version. A total of 15 105 individuals were recruited and 4330 were excluded, leaving 10 775 participants whose data were analyzed. The mean (SD) age at the baseline was 51.6 (8.9) years, 5880 participants (54.6%) were women, 5723 (53.1%) were White, and 6106 (56.6%) had at least a college degree. During a median (range) follow-up of 8 (6-10) years, individuals with ultraprocessed food consumption above the first quartile showed a 28% faster rate of global cognitive decline (β = -0.004; 95% CI, -0.006 to -0.001; P = .003) and a 25% faster rate of executive function decline (β = -0.003, 95% CI, -0.005 to 0.000; P = .01) compared with those in the first quartile. A higher percentage of daily energy consumption of ultraprocessed foods was associated with cognitive decline among adults from an ethnically diverse sample. These findings support current public health recommendations on limiting ultraprocessed food consumption because of their potential harm to cognitive function.


The health care provider's role and patient compliance to health promotion advice from the user's perspective: analysis of the 2006 National Health Interview Survey data.
The recommendations of health care providers have been shown to be a predictor of future healthy behaviors. However, patient adherence to these recommendations may differ based upon the type of health care professional providing the information. This study explored patient compliance in the United States over a 12-month period and contracted the patient response to recommendations given by chiropractors versus medical doctors. Multiple logistic regression models were used for analyses of data from the Sample Adult Core component of the 2006 National Health Interview Survey (n = 24 275). Analyses were performed separately for recommendation and compliance of weight loss, increase exercise, and diet change by health profession subtype (chiropractor and medical doctor). About 30.5% of the respondents reported receiving advice from their provider. Among these, 88.0% indicated they complied with the advice they received. Patients who were advised were more likely to comply (odds ratio [OR] [95% CI], 10.41[9.34-11.24]). Adjusting for seeing a physical therapist, age, and body mass index, chiropractors were less likely to advice patients compared to medical doctors (OR [95% CI], 0.38 [0.30-0.50]). In general, there was a 21% increased odds that patients who received and complied with health promotion advice from their health care provider would report an improved health status (OR [95% CI], 1.21 [1.10-1.33]) compared with those who did not comply or were not advised. Chiropractors in the United States give health promotion recommendation to their patients but are less likely to do so than general medical doctors. Patients tend to comply with health providers' recommendations and those who do report better health.


The effect of surface conditioning on the bond strength of resin composite to amalgam.
This study evaluated the effect of different surface conditioning methods on the tensile bond strength (TBS) and integrity of the amalgam-resin composite interface, using commercially available restoration repair systems. One hundred and sixty Gamma 2 amalgam specimens were stored in artificial saliva for 2 weeks and then randomly assigned to one of the following conditioning groups (n=20/group): Group 1: air abrasion, alloy primer and 'Panavia 21', Group 2: air abrasion and 'Amalgambond Plus', Group 3: air abrasion and 'All-Bond 3', Group 4: diamond bur, alloy primer and 'Panavia 21', Group 5: diamond bur and 'Amalgambond Plus', Group 6: diamond bur and 'All-Bond 3', Group 7: silica coating technique, and Group 8: non-conditioned amalgam surfaces (control group). Subsequently, resin composite material was added to the substrate surfaces and the amalgam-resin composite specimens were subjected to TBS testing. Representative samples from the test groups were subjected to scanning electron microscopy and surface profilometry. The data was analysed statistically with one-way ANOVA and post hoc Tukey's tests (α=0.05). The mean TBS of amalgam-resin composite ranged between 1.34 and 5.13MPa and varied with the degree of amalgam surface roughness and the type of conditioning technique employed. Significantly highest TBS values (5.13±0.96MPa) were obtained in Group 1 (p=0.013). Under the tested conditions, significantly greater tensile bond strength of resin composite to amalgam was achieved when the substrate surface was conditioned by air abrasion followed by the application of the Panavia 21 adhesive system. Effecting a repair of an amalgam restoration with resin composite via the use of air abrasion and application of Panavia 21 would seem to enhance the integrity of the amalgam-resin composite interface. Clinical trials involving the implementation of this technique are indicated to determine the usefulness of this technique.


Improving accountability through alignment: the role of academic health science centres and networks in England.
As in many countries around the world, there are high expectations on academic health science centres and networks in England to provide high-quality care, innovative research, and world-class education, while also supporting wealth creation and economic growth. Meeting these expectations increasingly depends on partnership working between university medical schools and teaching hospitals, as well as other healthcare providers. However, academic-clinical relationships in England are still characterised by the "unlinked partners" model, whereby universities and their partner teaching hospitals are neither fiscally nor structurally linked, creating bifurcating accountabilities to various government and public agencies. This article focuses on accountability relationships in universities and teaching hospitals, as well as other healthcare providers that form core constituent parts of academic health science centres and networks. The authors analyse accountability for the tripartite mission of patient care, research, and education, using a four-fold typology of accountability relationships, which distinguishes between hierarchical (bureaucratic) accountability, legal accountability, professional accountability, and political accountability. Examples from North West London suggest that a number of mechanisms can be used to improve accountability for the tripartite mission through alignment, but that the simple creation of academic health science centres and networks is probably not sufficient. At the heart of the challenge for academic health science centres and networks is the separation of accountabilities for patient care, research, and education in different government departments. Given that a fundamental top-down system redesign is now extremely unlikely, local academic and clinical leaders face the challenge of aligning their institutions as a matter of priority in order to improve accountability for the tripartite mission from the bottom up. It remains to be seen which alignment mechanisms are most effective, and whether they are strong enough to counter the separation of accountabilities for the tripartite mission at the national level, the on-going structural fragmentation of the health system in England, and the unprecedented financial challenges that it faces. Future research should focus on determining the comparative effectiveness of different alignment mechanisms, developing standardised metrics and key performance indicators, evaluating and assessing academic health science centres and networks, and empirically addressing leadership issues.