Extreme appraisals of internal states and bipolar symptoms: The Hypomanic Attitudes and Positive Predictions Inventory.

The Hypomanic Attitudes and Positive Predictions Inventory (HAPPI; W. Mansell, 2006) was developed to assess multiple, extreme, self-relevant appraisals of internal states. The present study aimed to validate the HAPPI in a clinical sample. Participants (N = 50) with a diagnosis of bipolar disorder (confirmed by a structured clinical interview) completed a series of questionnaires pertaining to clinical factors, reward motivation, cognitive style, symptoms, and functioning at baseline, in addition to the HAPPI. Over the following 4 weeks, participants were asked to complete self-report measures of symptoms (activation, perceived conflict, depression, and well-being), as well as work and social functioning, twice weekly. The authors hypothesized that the HAPPI would be associated with prospective bipolar symptoms and functioning, when controlling for baseline symptoms and potentially confounding measures. The HAPPI was positively, independently associated with activation and conflict after 4 weeks. Furthermore, individual HAPPI factors were associated with activation, conflict, and depression. The results provided preliminary support for the predictive validity of the HAPPI in a clinical sample. The HAPPI could be used in the future as a tool in cognitive behavioral therapy for bipolar disorder to identify problematic beliefs and guide formulation. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Inhibition of hIAPP Amyloid Aggregation and Pancreatic β‐Cell Toxicity by OH‐Terminated PAMAM Dendrimer

Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type‐2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation‐3 OH‐terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT‐1 cells as well as in mouse islets. This finding is supported by high‐throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c‐terminal portion of the peptide, where the amyloidogenic sequence (residues 22–29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self‐association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type‐2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation.     

Improvement of Glycaemia and Endothelial Function by a New Low-Dose Curcuminoid in an Animal Model of Type 2 Diabetes

Curcumin has been suggested as a promising treatment for metabolic diseases, but the high doses required limit its therapeutic use. In this study, a new curcuminoid is synthesised to increase curcumin anti-inflammatory and antioxidant potential and to achieve hypoglycaemic and protective vascular effects in type 2 diabetic rats in a lower dose. In vitro, the anti-inflammatory effect was determined through the Griess reaction, and the antioxidant activity through ABTS and TBARS assays. In vivo, Goto-Kakizaki rats were treated for 2 weeks with the equimolar dose of curcumin (40 mg/kg/day) or curcuminoid (52.4 mg/kg/day). Fasting glycaemia, insulin tolerance, plasma insulin, insulin signalling, serum FFA, endothelial function and several markers of oxidative stress were evaluated. Both compounds presented a significant anti-inflammatory effect. Moreover, the curcuminoid had a marked hypoglycaemic effect, accompanied by higher GLUT4 levels in adipose tissue. Both compounds increased NO-dependent vasorelaxation, but only the curcuminoid exacerbated the response to ascorbic acid, consistent with a higher decrease in vascular oxidative and nitrosative stress. SOD1 and GLO1 levels were increased in EAT and heart, respectively. Altogether, these data suggest that the curcuminoid developed here has more pronounced effects than curcumin in low doses, improving the oxidative stress, endothelial function and glycaemic profile in type 2 diabetes.     

First-Void Urine Microbiome in Women with Chlamydia trachomatis Infection

Background: Chlamydia trachomatis (CT) is the agent of the most common bacterial sexually transmitted infection worldwide. Until now, little information is available about the microbial composition of urine samples during CT urethritis. Therefore, in this study, we characterized the microbiome and metabolome profiles of first-void urines in a cohort of women with CT urethral infection attending an STI clinic. Methods: Based on CT positivity by nucleic acid amplification techniques on urine samples, the enrolled women were divided into two groups, i.e., “CT-negative” (n = 21) and “CT-positive” (n = 11). Urine samples were employed for (i) the microbiome profile analysis by means of 16s rRNA gene sequencing and (ii) the metabolome analysis by ¹H-NMR. Results: Irrespective of CT infection, the microbiome of first-void urines was mainly dominated by Lactobacillus, L. iners and L. crispatus being the most represented species. CT-positive samples were characterized by reduced microbial biodiversity compared to the controls. Moreover, a significant reduction of the Mycoplasmataceae family—in particular, of the Ureaplasma parvum species—was observed during CT infection. The Chlamydia genus was positively correlated with urine hippurate and lactulose. Conclusions: These data can help elucidate the pathogenesis of chlamydial urogenital infections, as well as to set up innovative diagnostic and therapeutic approaches.     

Therapeutic Vaccines for HPV-Associated Oropharyngeal and Cervical Cancer: The Next De-Intensification Strategy?

The rise in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has prompted a quest for further understanding of the role of high-risk HPV in tumor initiation and progression. Patients with HPV-positive OPSCC (HPV+ OPSCC) have better prognoses than their HPV-negative counterparts; however, current therapeutic strategies for HPV+ OPSCC are overly aggressive and leave patients with life-long sequalae and poor quality of life. This highlights a need for customized treatment. Several clinical trials of treatment de-intensification to reduce acute and late toxicity without compromising efficacy have been conducted. This article reviews the differences and similarities in the pathogenesis and progression of HPV-related OPSCC compared to cervical cancer, with emphasis on the role of prophylactic and therapeutic vaccines as a potential de-intensification treatment strategy. Overall, the future development of novel and effective therapeutic agents for HPV-associated head and neck tumors promises to meet the challenges posed by this growing epidemic.     

A Second Life for MAP,a Model Amphipathic Peptide

Cell-penetrating peptides (CPP) have been shown to be efficient in the transport of cargoes into the cells, namely siRNA and DNA, proteins and peptides, and in some cases, small therapeutics. These peptides have emerged as a solution to increase drug concentrations in different tissues and various cell types, therefore having a relevant therapeutic relevance which led to clinical trials. One of them, MAP, is a model amphipathic peptide with an α-helical conformation and both hydrophilic and hydrophobic residues in opposite sides of the helix. It is composed of a mixture of alanines, leucines, and lysines (KLALKLALKALKAALKLA). The CPP MAP has the ability to translocate oligonucleotides, peptides and small proteins. However, taking advantage of its unique properties, in recent years innovative concepts were developed, such as in silico studies of modelling with receptors, coupling and repurposing drugs in the central nervous system and oncology, or involving the construction of dual-drug delivery systems using nanoparticles. In addition to designs of MAP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy, this review will be focused on unique molecular structure and how it determines its cellular activity, and also intends to address the most recent and frankly motivating issues for the future.     

Voxelized Minkowski sum computation on the GPU with robust culling

We present a new approach for computing the voxelized Minkowski sum (excluding any enclosed voids) of two polyhedral objects using programmable Graphics Processing Units (GPUs). We first cull out surface primitives that will not contribute to the final boundary of the Minkowski sum, analyzing and adaptively bounding the rounding errors of the culling algorithm to solve the floating point error problem. The remaining surface primitives are then rendered to depth textures along six orthogonal directions to generate an initial solid voxelization of the Minkowski sum. Finally we employ fast flood fill to find all the outside voxels. We generate both solid and surface voxelizations of Minkowski sums without enclosed voids and support high volumetric resolution of 1024³ with low video memory cost. The whole algorithm runs on the GPU and is at least one order of magnitude faster than existing boundary representation (B-rep) based algorithms. It avoids the large number of 3D Boolean operations needed in most existing algorithms and is easy to implement. The voxelized Minkowski sums can be used in a variety of applications including motion planning and penetration depth computation.