Heart Failure With Preserved Ejection Fraction in Diabetes: Mechanisms and Management

Diabetes mellitus (DM) is a major cause of heart failure in the Western world, either secondary to coronary artery disease or from a distinct entity known as “diabetic cardiomyopathy.” Furthermore, heart failure with preserved ejection fraction (HFpEF) is emerging as a significant clinical problem for patients with DM. Current clinical data suggest that between 30% and 40% of patients with HFpEF suffer from DM. The typical structural phenotype of the HFpEF heart consists of endothelial dysfunction, increased interstitial and perivascular fibrosis, cardiomyocyte stiffness, and hypertrophy along with advanced glycation end products deposition. There is a myriad of mechanisms that result in the phenotypical HFpEF heart including impaired cardiac metabolism and substrate utilization, altered insulin signalling leading to protein kinase C activation, advanced glycated end products deposition, prosclerotic cytokine activation (eg, transforming growth factor-β activation), along with impaired nitric oxide production from the endothelium. Moreover, recent investigations have focused on the role of endothelial-myocyte interactions. Despite intense research, current therapeutic strategies have had little effect on improving morbidity and mortality in patients with DM and HFpEF. Possible explanations for this include a limited understanding of the role that direct cell-cell communication or indirect cell-cell paracrine signalling plays in the pathogenesis of DM and HFpEF. Additionally, integrins remain another important mediator of signals from the extracellular matrix to cells within the failing heart and might play a significant role in cell-cell cross-talk. In this review we discuss the characteristics and mechanisms of DM and HFpEF to stimulate potential future research for patients with this common, and morbid condition.     

Initial Clinical Guidelines for Co-Occurring Autism Spectrum Disorder and Gender Dysphoria or Incongruence in Adolescents

Evidence indicates an overrepresentation of youth with co-occurring autism spectrum disorders (ASD) and gender dysphoria (GD). The clinical assessment and treatment of adolescents with this co-occurrence is often complex, related to the developmental aspects of ASD. There are no guidelines for clinical care when ASD and GD co-occur; however, there are clinicians and researchers experienced in this co-occurrence. This study develops initial clinical consensus guidelines for the assessment and care of adolescents with co-occurring ASD and GD, from the best clinical practices of current experts in the field. Expert participants were identified through a comprehensive international search process and invited to participate in a two-stage Delphi procedure to form clinical consensus statements. The Delphi Method is a well-studied research methodology for obtaining consensus among experts to define appropriate clinical care. Of 30 potential experts identified, 22 met criteria as expert in co-occurring ASD and GD youth and participated. Textual data divided into the following data nodes: guidelines for assessment; guidelines for treatment; six primary clinical/psychosocial challenges: social functioning, medical treatments and medical safety, risk of victimization/safety, school, and transition to adulthood issues (i.e., employment and romantic relationships). With a cutoff of 75% consensus for inclusion, identified experts produced a set of initial guidelines for clinical care. Primary themes include the importance of assessment for GD in ASD, and vice versa, as well as an extended diagnostic period, often with overlap/blurring of treatment and assessment.     

Spirituelle Erfahrungsqualität

Scenic thinking and action involves a fundamental commitment to a comprehensive concept of human nature. One of the six content-related dimensions of a scene is the axiological dimension, which is methodically implemented in Axiodrama, but is basically included in any scene. Spiritual qualities of experience are regarded as the outcome of integration at all role levels, and are systematically catalogued. In the next step, a critical distinction is made from esoteric practices. Finally, the ways that clients deal with spiritual experiences are outlined.     

Immunohistochemical assessment of CD1a‐positive Langerhans cells and their relationship with E‐cadherin in minor salivary gland tumors

J Oral Pathol Med (2012) 41 : 47–53 Objective: The aim of this study was to investigate the presence of CD1a‐positive Langerhans cells and their relationship with E‐cadherin in minor salivary gland tumors. Methods: Twenty‐seven minor salivary gland tumors were investigated using immunohistochemistry for CD1a and E‐cadherin. Results: A significant difference regarding the mean density of CD1a‐positive Langerhans cells was observed between pleomorphic adenomas and malignant tumors studied (P = 0.001). No CD1a‐positive cells were detected in most cases (n = 5) of cystic adenoid carcinomas. CD1a‐positive cells were detected in one mucoepidermoid carcinoma case, and six low‐grade polymorphous adenocarcinomas cases. Comparison of the mean density of CD1a‐positive cells between the three malignant tumors showed no significant difference (P = 0.127). No significant difference was observed in the presence of E‐cadherin between tumors (P = 0.73), but it was detected in 24 cases. Conclusions: The lack of CD1a‐positive in malignant salivary gland tumors facilitates the neoplastic development and suggests that these cells might be useful as auxiliary diagnostic and prognostic tool in minor salivary gland tumors. Furthermore, it is suggested that E‐cadherin mediates cell adhesion in these tumors although we did not demonstrate significance.     

Surgical management of ileosigmoid fistulas in Crohn's disease

Ileosigmoid fistulas are found in Crohn's disease and may present a surgical dilemma. PURPOSE: This study was designed to examine surgical practice to determine types of intervention, enumerate complications, and elicit guidelines for surgical management. METHOD: The medical records of patients with ileosigmoid fistula and Crohn's disease from 1975 to 1995 were reviewed. RESULTS: Ninety patients (44 men) were studied. A preoperative diagnosis of ileosigmoid fistula was made in 77 percent of patients. Sigmoid repair was performed in 43 patients (47.8 percent), sigmoid resection in 32 patients (35.6 percent), 12 patients (13.3 percent) underwent more extensive procedures, and 3 patients (3.3 percent) either had surgery elsewhere or were observed. The fistula was never directly responsible for a stoma. The repair and resection groups were similar with respect to age, length of Crohn's disease, and preoperative symptoms. There was no significant difference between groups in the incidence of postoperative complications; there were no postoperative deaths. Average length of stay was 8.3 days following repair and 9.9 days after resection. Reasons for resection included significant purulence or inflammation, a large fistula defect, a defect on the mesenteric border of the sigmoid, and active sigmoid Crohn's disease. Surgeon's assessment of the presence of Crohn's disease in the sigmoid correlated with pathologic examination and was aided by knowledge of recent endoscopic appearance and biopsy results; intraoperative frozen section and colonoscopy were helpful in distinguishing serosal inflammation from active Crohn's disease. CONCLUSION: Contrast studies identified 77 percent of ileosigmoid fistulas preoperatively. Performing repair rather than resection does not increase the risk of complications, if standard surgical principles are followed. Preoperative or intraoperative endoscopy assists the surgical evaluation of the sigmoid.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Seattle, Washington, June 9 to 14, 1996.     

Enhancement of MHC-I Antigen Presentation via Architectural Control of pH-Responsive,Endosomolytic Polymer Nanoparticles

Protein-based vaccines offer a number of important advantages over organism-based vaccines but generally elicit poor CD8⁺ T cell responses. We have previously demonstrated that pH-responsive, endosomolytic polymers can enhance protein antigen delivery to major histocompatibility complex class I (MHC-I) antigen presentation pathways thereby augmenting CD8⁺ T cell responses following immunization. Here, we describe a new family of nanocarriers for protein antigen delivery assembled using architecturally distinct pH-responsive polymers. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize linear, hyperbranched, and core-crosslinked copolymers of 2-(N,N-diethylamino)ethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) that were subsequently chain extended with a hydrophilic N,N-dimethylacrylamide (DMA) segment copolymerized with thiol-reactive pyridyl disulfide (PDS) groups. In aqueous solution, polymer chains assembled into 25 nm micellar nanoparticles and enabled efficient and reducible conjugation of a thiolated protein antigen, ovalbumin. Polymers demonstrated pH-dependent membrane-destabilizing activity in an erythrocyte lysis assay, with the hyperbranched and cross-linked polymer architectures exhibiting significantly higher hemolysis at pH ≤ 7.0 than the linear diblock. Antigen delivery with the hyperbranched and cross-linked polymer architecture enhanced in vitro MHC-I antigen presentation relative to free antigen, whereas the linear construct did not have a discernible effect. The hyperbranched system elicited a four- to fivefold increase in MHC-I presentation relative to the cross-linked architecture, demonstrating the superior capacity of the hyperbranched architecture in enhancing MHC-I presentation. This work demonstrates that the architecture of pH-responsive, endosomolytic polymers can have dramatic effects on intracellular antigen delivery, and offers a promising strategy for enhancing CD8⁺ T cell responses to protein-based vaccines.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9697-1) contains supplementary material, which is available to authorized users.KEY WORDS: MHC-I antigen presentation, pH-responsive nanoparticle, polymer architecture, RAFT polymerization, vaccine     

Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib

Resistance toward imatinib and other BCR/ABL tyrosine kinase inhibitors remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CML). We recently have identified the heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) as a BCR/ABL-dependent survival molecule in CML cells. We here show that silencing Hsp32/HO-1 in CML cells by an siRNA approach results in induction of apoptosis. Moreover, targeting Hsp32/HO-1 by either pegylated zinc protoporphyrine (PEG-ZnPP) or styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP) resulted in growth inhibition of BCR/ABL-transformed cells. The effects of PEG-ZnPP and SMA-ZnPP were demonstrable in Ba/F3 cells carrying various imatinib-resistant mutants of BCR/ABL, including the T315I mutant, which exhibits resistance against all clinically available BCR/ABL tyrosine kinase inhibitors. Growth-inhibitory effects of PEG-ZnPP and SMA-ZnPP also were observed in the CML-derived human cell lines K562 and KU812 as well as in primary leukemic cells obtained from patients with freshly diagnosed CML or imatinib-resistant CML. Finally, Hsp32/HO-1-targeting compounds were found to synergize with either imatinib or nilotinib in producing growth inhibition in imatinib-resistant K562 cells and in Ba/F3 cells harboring the T315I mutant of BCR/ABL. In summary, these data show that HO-1 is a promising novel target in imatinib-resistant CML.