IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2−/−). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2−/− podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2−/− podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.

Diagnostic value of increased sensitivity by massively parallel sequencing

Routine molecular diagnostics modalities are unable to confidently detect low frequency mutations (<5-15%) that may indicate response to targeted therapies. We confirm the presence of a low frequency NRAS mutation in a rectal cancer patient using massively parallel sequencing when previous Sanger sequencing results proved negative and Q-PCR testing inconclusive. There is increasing evidence that these low frequency mutations may confer resistance to anti-EGFR therapy. In view of negative/inconclusive Sanger sequencing and Q-PCR results for NRAS mutations in a KRAS wt rectal case, the diagnostic biopsy and 4 distinct subpopulations of cells in the resection specimen after conventional chemo/radiotherapy were massively parallel sequenced using the Ion Torrent PGM. DNA was derived from FFPE rectal cancer tissue and amplicons produced using the Cancer Hotspot Panel V2 and sequenced using semiconductor technology. NRAS mutations were observed at varying frequencies in the patient biopsy (12.2%) and all four subpopulations of cells in the resection with an average frequency of 7.3% (lowest 2.6%). The results of the NGS also provided the mutational status of 49 other genes that may have prognostic or predictive value, including KRAS and PIK3CA. NGS technology has been postulated in diagnostics because of its capability to generate results in large panels of clinically meaningful genes in a cost-effective manner. This case illustrates another potential advantage of this technology: its use for detecting low frequency mutations that may influence therapeutic decisions in cancer treatment.

Impact of age, various forms of cataract, and visual acuity on whole-field scotopic sensitivity screening for glaucoma in rural Taiwan.

OBJECTIVE: To evaluate the impact of age, various forms of cataract, and visual acuity on whole-field scotopic sensitivity screening for glaucoma in a rural population. DESIGN: Clinic-based study with population-based recruitment. SETTING: Jin Shan Township near Taipei, Taiwan. SUBJECTS: Three hundred forty-six residents (ages, > or = 40 years) of Jin Shan Township. INTERVENTIONS: Whole-field scotopic testing, ophthalmoscopy with dilation of the pupils, cataract grading against photographic standards, and screening visual field testing in a random one-third subsample. MAIN OUTCOME MEASURES: Whole-field scotopic sensitivity (in decibels) and diagnostic status as a case of glaucoma, glaucoma suspect, or normal. RESULTS: Participants in Jin Shan Township did not differ significantly in the rate of blindness, low visual acuity, or family history of glaucoma from a random sample of nonrespondents. Scotopic sensitivity testing detected 100% (6/6) of subjects with open-angle glaucoma at a specificity of 80.2%. The mean +/- SE scotopic sensitivity for six subjects with open-angle glaucoma (32.78 +/- 1.51 dB) differed significantly from that of 315 normal individuals (38.51 +/- 0.22 dB), when adjusted for age and visual acuity (P = .05, t test). With linear regression modeling, factors that correlated significantly with scotopic sensitivity were intraocular pressure, screening visual field, best corrected visual acuity, presence of cortical cataract, and increasing age. CONCLUSIONS: Although cataract affects the whole-field scotopic threshold, it appears that scotopic testing may be of value in field-based screening for glaucoma.

Logic Brightens My Day: Evidence for Implicit Sensitivity to Logical Validity.

A key assumption of dual process theory is that reasoning is an explicit, effortful, deliberative process. The present study offers evidence for an implicit, possibly intuitive component of reasoning. Participants were shown sentences embedded in logically valid or invalid arguments. Participants were not asked to reason but instead rated the sentences for liking (Experiment 1) and physical brightness (Experiments 2-3). Sentences that followed logically from preceding sentences were judged to be more likable and brighter. Two other factors thought to be linked to implicit processing-sentence believability and facial expression-had similar effects on liking and brightness ratings. The authors conclude that sensitivity to logical structure was implicit, occurring potentially automatically and outside of awareness. They discuss the results within a fluency misattribution framework and make reference to the literature on discourse comprehension. 

Os ambientes artísticos interativos na inclusão de alunos com necessidades educativas especiais

Com o objetivo de sublinhar a habilidade e o direito à criação do indivíduo com necessidades especiais este projeto deriva da beleza do território da arte e dos paradigmas de interação e imersão, hoje potencializados pelo feedback multimodal e multissensorial dos ambientes multimédia responsivos. Enfatizando o atual contexto da escola inclusiva, este estudo teve lugar num estabelecimento de ensino, em Portugal, envolvendo um grupo de alunos com Necessidades Educativas Especiais — NEE — de Currículo Específico Individual — CEI. Num contexto real, intentámos avaliar que tipo de impacto poderão ter os ambientes artísticos interativos nestes alunos, enquanto meio de autoexpressão e de inclusão. O estudo realizado assumiu um carácter exploratório. Special INPUT foi o conceito proposto por diferentes ambientes e abordagens de interação, implementados em sessões individuais com os participantes, que permitiu observar e promover, sob um contexto artístico, as habilidades intelectual, emocional, de personalidade, interpessoal, intrapessoal, psicomotora e, artística. Conceptualizámos, prototipámos e implementámos oito ambientes interativos, artísticos e lúdicos, que enfatizaram de formas diversas a experiência imersiva mediada pela técnica. Daí emergiram três grupos de ambientes – Special SOUND, Special MOVEMENT e Special ME – que intentaram promover nestes alunos a descoberta de si mesmos através do input de som, movimento e/ou vídeo processados em tempo real. O feedback visual e/ou sonoro visou o “engajamento lúdico” e a “ressonância estética” enquanto meios de descoberta e desenvolvimento da habilidade e valor pessoais. Numa perspetiva de diferenciação e individualização curricular, reconhecemos as vantagens dos ambientes artísticos interativos na inclusão de alunos com NEE, tendo-se observado um impacto positivo derivado da autoria e do controlo propiciados aos participantes nestes contextos. Hoje, a possibilidade de recorrer ao multimédia e a toda uma panóplia de interfaces não invasivas, explorando a poética de som e imagem interativos, em contexto artístico, inspira abordagens originais, centradas na pessoa, atentando às potencialidades e plasticidades das vigentes ferramentas de autor para a programação de interação, promovendo a dignificação da diferença, a autoexpressão e sensibilidade individuais, e os processos de autoobservação, autodescoberta e autoconsciência da capacidade expressiva que promovem a ideia positiva do “self” e o desenvolvimento de diferentes aptidões pessoais.

Emotional Responses to Disfigured Faces: The Influences of Perceived Anonymity, Empathy, and Disgust Sensitivity

Two experiments investigated self-reported emotional reactions to photographs of people with attractive, unattractive or structurally disfigured faces. In Experiment 1 participants viewing disfigured faces reported raised levels of sorrow and curiosity but not raised levels of negative emotions. In Experiment 2 there was more negative emotion and less positive emotion reported under conditions of relatively high anonymity, compared to low anonymity, specific to disfigured faces, suggesting that self-reports are influenced by social desirability. Trait empathy was associated with sorrow and negative emotions when viewing disfigured faces. Disgust sensitivity was associated with negative emotions and inversely associated with positive emotions.

Interpersonal Relationships in the Primary Classroom: an Analysis of Social and Affective Outcomes

Recent research regarding the quality of relationships in primary classrooms has focused largely on the enhancement and development of cognitive skills. The study reported here focused on a range of social and affective outcomes with the intention of broadening our understanding of the classroom as an interactive system, from the child's perspective. This paper provides empirical evidence on children's perceptions at Key Stage 2 (pupil age 7-11 years) of their relationships with teachers, other adults and children. Data were collected via an attitudinal questionnaire survey in nine primary schools in England. Results indicate that, in addition to the development of social skills, children also valued academic confidence, learning and the involvement of their parents in homework, and that these were associated with the interactions and routines established within the primary classroom settings. Some variations in terms of pupil age, teacher career phase, and the socio-economic context of the school were identified; however, the importance of the relationship between pupil and teacher remained consistent across schools.

Acute hypoxia improves insulin sensitivity (SI2*) and β cell function in individuals with Type 2 Diabetes

Type 2 diabetes is a multifactorial metabolic disease characterized by defects in β-cells function, insulin sensitivity, glucose effectiveness and endogenous glucose production (1). It is widely accepted that insulin and exercise are potent stimuli for glucose transport (2). Acute exercise is known to promote glucose uptake in skeletal muscle via an intact contraction stimulated mechanism (3), while post-exercise improvements in glucose control are due to insulin-dependant mechanisms (2). Hypoxia is also known to promote glucose uptake in skeletal muscle using the contraction stimulated pathway. This has been shown to occur in vitro via an increase in β-cell function, however data in vivo is lacking. The aim of this study was to examine the effects of acute hypoxia with and without exercise on insulin sensitivity (SI2*), glucose effectiveness (SG2*) and β-cell function in individuals with type 2 diabetes. Following an overnight fast, six type 2 diabetics, afer giving informed written consent, completed 60 min of the following: 1) normoxic rest (Nor Rest); 2) hypoxic rest [Hy Rest; O2 = 14.6 (0.4)%]; 3) normoxic exercise (Nor Ex); 4) hypoxic exercise [Hy Ex; O2 = 14.6 (0.4)%]. Exercise trails were set at 90% of lactate threshold. Each condition was followed by a labelled intravenous glucose tolerance test (IVGTT) to provide estimations of SI2*, SG2* and β-cell function. Values are presented as means (SEM). Two-compartmental minimal model analysis showed SI2* to be higher following Hy Rest when comparisons were made with Nor Rest (P = 0.047). SI2* was also higher following Hy Ex [4.37 (0.48) x10-4 . min-1 (μU/ml)] compared to Nor Ex [3.24 (0.51) x10-4 . min-1 (μU/ml)] (P = 0.048). Acute insulin response to glucose (AIRg) was reduced following Hy Rest vs. Nor Rest (P = 0.014 - Table 1). This study demonstrated that 1) hypoxia has the ability to increase glucose disposal; 2) hypoxic-induced improvements in glucose tolerance in the 4 hr following exposure can be attributed to improvements in peripheral SI2*; 3) resting hypoxic exposure improves β-cell function and 4) exercise and hypoxia have an additive effect on SG2* in type 2 diabetics. These findings suggest a possible use for hypoxia both with and without exercise in the clinical treatment of type 2 diabetes.

Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism

Aims/hypothesis - It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. Subjects and methods - We randomised 17 sedentary overweight male subjects (age 50 ± 2.6 years, BMI 27.6 ± 0.5 kg/m2) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic–euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg−1 min−1]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. Results - After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group. Conclusions/interpretation - Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise.

Image quality optimization, via application of contextual contrast sensitivity and discrimination functions

What is the best luminance contrast weighting-function for image quality optimization? Traditionally measured contrast sensitivity functions (CSFs), have been often used as weighting-functions in image quality and difference metrics. Such weightings have been shown to result in increased sharpness and perceived quality of test images. We suggest contextual CSFs (cCSFs) and contextual discrimination functions (cVPFs) should provide bases for further improvement, since these are directly measured from pictorial scenes, modeling threshold and suprathreshold sensitivities within the context of complex masking information. Image quality assessment is understood to require detection and discrimination of masked signals, making contextual sensitivity and discrimination functions directly relevant. In this investigation, test images are weighted with a traditional CSF, cCSF, cVPF and a constant function. Controlled mutations of these functions are also applied as weighting-functions, seeking the optimal spatial frequency band weighting for quality optimization. Image quality, sharpness and naturalness are then assessed in two-alternative forced-choice psychophysical tests. We show that maximal quality for our test images, results from cCSFs and cVPFs, mutated to boost contrast in the higher visible frequencies.

The immediate effects of atlanto-occipital joint manipulation and suboccipital muscle inhibition technique on active mouth opening and pressure pain sensitivity over latent myofascial trigger points in the masticatory muscles

DESIGN: A randomized controlled trial.OB JECTIVE: To investigate the immediate effects on pressure pain thresholds over latent trigger points (TrPs) in the masseter and temporalis muscles and active mouth opening following atlanto-occipital joint thrust manipulation or a soft tissue manual intervention targeted to the suboccipital muscles. BACKGROUND : Previous studies have described hypoalgesic effects of neck manipulative interventions over TrPs in the cervical musculature. There is a lack of studies analyzing these mechanisms over TrPs of muscles innervated by the trigeminal nerve. METHODS: One hundred twenty-two volunteers, 31 men and 91 women, between the ages of 18 and 30 years, with latent TrPs in the masseter muscle, were randomly divided into 3 groups: a manipulative group who received an atlanto-occipital joint thrust, a soft tissue group who received an inhibition technique over the suboccipital muscles, and a control group who did not receive an intervention. Pressure pain thresholds over latent TrPs in the masseter and temporalis muscles, and active mouth opening were assessed pretreatment and 2 minutes posttreatment by a blinded assessor. Mixed-model analyses of variance (ANOVA) were used to examine the effects of interventions on each outcome, with group as the between-subjects variable and time as the within-subjects variable. The primary analysis was the group-by-time interaction. RESULTS: The 2-by-3 mixed-model ANOVA revealed a significant group-by-time interaction for changes in pressure pain thresholds over masseter (P<.01) and temporalis (P =.003) muscle latent TrPs and also for active mouth opening (P<.001) in favor of the manipulative and soft tissue groups. Between-group effect sizes were small. CONCLUSIONS: The application of an atlanto-occipital thrust manipulation or soft tissue technique targeted to the suboccipital muscles led to an immediate increase in pressure pain thresholds over latent TrPs in the masseter and temporalis muscles and an increase in maximum active mouth opening. Nevertheless, the effects of both interventions were small and future studies are required to elucidate the clinical relevance of these changes. LEVEL OF EVIDENCE : Therapy, level 1b. J Orthop Sports Phys Ther 2010;40(5):310-317. doi:10.2519/jospt.2010.3257. KEYWORDSDS: cervical manipulation, muscle trigger points, neck, TMJ, upper cervical.