Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists

Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC 50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.     

Non-proliferating plasma cells detected in the salivary glands and bone marrow of autoimmune NOD.B10.H2b mice,a model for primary Sjögren’s syndrome

Autoantibody secreting plasma cells (PCs) are essential contributors in the development of autoimmune conditions such as primary Sjögren’s syndrome (pSS). Particularly, the long-lived PC subset residing in the bone marrow has shown to continuously produce autoantibodies, whilst remaining unaffected by immunosuppressive treatment. We have previously shown accumulation of potentially long-lived PCs in chronically inflamed salivary glands of pSS patients. In this study, we aimed to characterise the PC compartment in the salivary glands (the target organ for pSS) and bone marrow before the onset of the murine pSS like disease versus advanced diseases progression. Bromodeoxyuridine (BrdU) was incorporated to distinguish the long-lived PCs. Double immunohistochemical staining and immunofluorescence were then conducted on submandibular gland and bone marrow sections from 8- and 40-week-old mice to identify BrdU and CD138. BrdU⁺ cells were detected in the submandibular glands of 8-week-old mice, and observed within all focal infiltrates by 40 weeks of age. Most CD138⁺ PCs were however BrdU^? and located predominantly on the periphery of these infiltrates. This observation was verified through immunofluorescence. A comparable staining pattern was observed in the bone marrow of 8- and 40-week-old NOD.B10.H2b mice, where some of the CD138⁺ cells also expressed BrdU. Interestingly, megakaryocytes in the bone marrow of NOD.B10.H2b mice were detected in close proximity to CD138⁺ cells, illustrating a possible presence of PC survival niches. Our results demonstrate the presence and accumulation of potentially long-lived PCs in NOD.B10.H2b mice as the disease advances.     

Evaluation of the irritancy and hypersensitivity potential following topical application of didecyldimethylammonium chloride

Didecyldimethylammonium chloride (DDAC) is a dialkyl-quaternary ammonium compound that is used in numerous products for its bactericidal, virucidal and fungicidal properties. There have been clinical reports of immediate and delayed hypersensitivity reactions in exposed individuals; however, the sensitization potential of DDAC has not been thoroughly investigated. The purpose of these studies was to evaluate the irritancy and sensitization potential of DDAC following dermal exposure in a murine model. DDAC induced significant irritancy (0.5 and 1%), evaluated by ear swelling in female Balb/c mice. Initial evaluation of the sensitization potential was conducted using the local lymph node assay (LLNA) at concentrations ranging from 0.0625–1%. A concentration-dependent increase in lymphocyte proliferation was observed with a calculated EC3 value of 0.17%. Dermal exposure to DDAC did not induce increased production of IgE as evaluated by phenotypic analysis of draining lymph node B-cells (IgE?⁺?B220⁺) and measurement of total serum IgE levels. Additional phenotypic analyses revealed significant and dose-responsive increases in the absolute number of B-cells, CD4?⁺?T-cells, CD8?⁺?T-cells and dendritic cells in the draining lymph nodes, along with significant increases in the percentage of B-cells (0.25% and 1% DDAC) at Day 10 following 4 days of dermal exposure. There was also a significant and dose-responsive increase in the number of activated CD44?⁺?CD4?⁺?and CD8?⁺?T-cells and CD86?⁺?B-cells and dendritic cells following exposure to all concentrations of DDAC. These results demonstrate the potential for development of irritation and hypersensitivity responses to DDAC following dermal exposure and raise concerns about the use of this chemical and other quaternary ammonium compounds that may elicit similar effects.     

Interaction of Proteasomes and Complement C3, Assay of Antisecretory Factor in Blood

Antisecretory factor (AF) is a protein complex which inhibits inflammation and regulates fluid transport. In this article, two new immunoassays (ELISA) are developed. The first ELISA establishes a 26S proteasome concentration of 0.41±0.03 μg/mL in normal plasma; the second ELISA discloses the binding of proteasomes to complement factor C3. The latter test values increased about tenfold following intake of processed cereals, paralleling with the old AF ELISA. The proteasome/C3 complex is purified and shown to expose hidden antisecretory peptide sequence and contain the inactive C3c protein. These findings might explain the antisecretory and anti-inflammatory effect during AF complex formation.     

Bone morphogenetic protein 6—a possible new player in pathophysiology of heart failure

Derangement of bone morphogenetic protein (BMP) signalling was observed in cardiovascular disorders. The present study assesses the diagnostic and prognostic value of BMP6 plasma concentration in chronic heart failure (CHF). 130 CHF patients and 32 controls participated in the study. BMP6 plasma level was measured at baseline. During 12‐month follow‐up death and hospitalisation with CHF exacerbation were recorded. BMP6 was significantly increased in CHF patients with highest concentration in most advanced disease. Individuals with pulmonary congestion or peripheral oedema had higher levels of BMP6 than isovolemic patients. BMP6 was not a predictor of all‐cause mortality or CHF hospitalisation. BMP6 may be involved in pathophysiology of systolic CHF. BMP6 plasma level is related to the disease severity and signs of exacerbation.     

Development of an instrument for measuring activities of daily living in persons with suspected cognitive impairment

Background According to the Swedish National Board of Health and Welfare, structured assessment of function and activity has high priority when evaluating suspected cognitive impairment or dementia. Aim/objectives The aim was to develop and psychometrically test an instrument to measure the ability to perform activities of daily living tasks in patients with suspected cognitive impairment. Material and methods The Cognitive Impairment in Daily Life (CID) instrument (for self-reported and informant-based assessments) has been developed in several phases. Content validity was achieved through five expert panels using a Content Validity Index (CVI). The content was tested further in a pilot study of 49 patients and 49 relatives from primary care or a specialist memory clinic. Results Content validity was good with a CVI index of 0.83. All patients considered that the included activities were relevant to them and reflected the difficulties they were experiencing. Most relatives considered the activities included in the instrument as adequate and captured the patients’ difficulties in daily life. Some adjustments of the tasks and scale were suggested and these were implicated after each phase. In general, relatives reported that patients had more difficulties performing the activities than the patients reported themselves. Conclusion The CID instrument seems promising in terms of content validity. Further testing of reliability and construct validity is ongoing.     

Diagnostic power of VEGF,MMP-9 and TIMP-1 in patients with breast cancer. A multivariate statistical analysis with ROC curve

PurposeVascular endothelial growth factor is an important factor in promoting angiogenesis in malignant processes, matrix metalloproteinase-9 in the degradation of extracellular matrix, which enhances metastasis, and tissue inhibitor of metalloproteinase-1 is its inhibitor. The aim of this study was to investigate the diagnostic power of these parameters in comparison to CA15-3 in breast cancer patients and in relation to the control group.Materials/methodsThe study included 120 breast cancer patients, 60 patients with benign breast tumors and 60 healthy women. Plasma levels of tested parameters were determined by enzyme-linked immunosorbent assay, CA15-3 by chemiluminescent microparticle immuno assay.ResultsTissue inhibitor of metalloproteinase-1 showed the highest value of sensitivity in breast cancer group (86.25%) and, more importantly, highest value in breast cancer stage I (85%). Vascular endothelial growth factor also showed high sensitivity (stage I and II–75%, III–85%, IV–70% and 76.25% in total breast cancer group) and the highest specificity (85%) from all tested parameters. It was also the only parameter which had statistically significant area under curve in all stages. In the total breast cancer group all tested parameters showed statistically significant area under curve, but the maximum range was obtained for combination: ‘vascular endothelial growth factor + CA15-3′. Vascular endothelial growth factor seems to be the best candidate for diagnosing breast cancer stage I and for differentiating between breast cancer and non-carcinoma cases.ConclusionsThe combined analysis of tested parameters and CA15-3 resulted in an increase in sensitivity and area under curve values, which provides hope for developing new panel of biomarkers that may be used in diagnosing breast cancer in the future.