Structural relationship between link proteins and proteoglycan monomers

AbstractStructural homologies between link proteins and proteoglycan monomers are demonstrated. A possible redundancy in the proteoglycan monomers structure is discussed and the link proteins domains homologous to other proteins are specified

Integrated problem-based learning in the neuroscience curriculum – the SUNY Downstate experience

BACKGROUND: This paper reports the author's initial experience as Block Director in converting a Conventional Curriculum into a problem-based learning model (PBL) for teaching Psychopathology. As part of a wide initiative in curriculum reform, Psychopathology, which was a six-week course in the second-year medical school curriculum, became integrated into a combined Neuroscience block. The study compares curriculum conversion at State University of New York (SUNY), Downstate, with the experiences at other medical centres that have instituted similar curricula reform. METHODS: Student satisfaction with the Conventional and PBL components of the Neuroscience curriculum was compared using questionnaires and formal discussions between faculty and a body of elected students. The PBL experience in Psychopathology was also compared with that of the rest of the Neuroscience Block, which used large student groups and expert facilitators, while the Psychopathology track was limited to small groups using mentors differing widely in levels of expertise. RESULTS: Students appeared to indicate a preference toward conventional lectures and large PBL groups using expert facilitators in contrast to small group mentors who were not experts. Small PBL groups with expert mentors in the Psychopathology track were also rated favorably. CONCLUSION: The study reviews the advantages and pitfalls of the PBL system when applied to a Neuroscience curriculum on early career development. At SUNY, conversion from a Conventional model to a PBL model diverged from that proposed by Howard S. Barrows where student groups define the learning objectives and problem-solving strategies. In our model, the learning objectives were faculty-driven. The critical issue for the students appeared to be the level of faculty expertise rather than group size. Expert mentors were rated more favorably by students in fulfilling the philosophical objectives of PBL. The author, by citing the experience at other major Medical Faculties, makes a cautious attempt to address the challenges involved in the conversion of a Psychopathology curriculum into a PBL dominated format

The skeletal phenotype of chondroadherin deficient mice

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their a2b1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the a1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth

Measuring educational needs among patients with rheumatoid arthritis using the Dutch version of the Educational Needs Assessment Tool (DENAT)

The Educational Needs Assessment Tool (ENAT) was developed in the United Kingdom (UK) to systematically assess the educational needs of patients with arthritis. The aim of the present study was to describe the educational needs of Dutch patients with rheumatoid arthritis (RA) by using the Dutch version of the ENAT (DENAT). The original UK version of the ENAT, comprising 39 items grouped into seven domains, was translated into Dutch according to international guidelines for cross-cultural translation and adaptation. The DENAT was then sent to a random sample of 319 RA patients registered at the outpatient clinic of a university hospital. For each domain (score range 1–5, equalling low–high educational needs), a median score with the inter-quartile range was computed. The Kruskal–Wallis test was used to determine possible associations between educational needs and age, disease duration, gender and educational background. The response rate was 165 out of 319 (52%). The median educational needs scores were 2.5 for “managing pain”, 3.0 for “movement”, 2.0 for “feelings”, 4.0 for “arthritis process”, 4.0 for “treatments from health professionals”, 3.5 for “self-help measures” and 2.5 for “support systems”. Lower age and shorter disease duration were associated with more educational needs in the domain “support systems”. In addition, younger patients had more educational needs regarding managing pain and feelings than older patients. There were no associations between gender or educational background and educational needs. The DENAT has demonstrated its ability to identify individual educational needs of Dutch patients with RA. The lower age and shorter disease duration were associated with more educational needs. The practical applicability of the DENAT needs further research

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

Human induced pluripotent stem cell-derived microglia-like cells harboring TREM2 missense mutations show specific deficits in phagocytosis

Dysfunction of microglia, the brain’s immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals

Thrombocytopenia in the experimental leptospirosis of guinea pig is not related to disseminated intravascular coagulation

BACKGROUND: Thrombocytopenia is commonly observed in severe leptospirosis. However, previous studies on coagulation alterations during leptospirosis resulted in inconsistent conclusions. Some findings showed that the prominent levels of thrombocytopenia observed in severe leptospirosis did not reflect the occurrence of disseminated intravascular coagulation (DIC) syndrome, while the others reached the conclusion that the hemorrhages observed in leptospirosis were due to DIC. The aim of this study is to elucidate whether DIC is an important feature of leptospirosis. METHODS: The leptospirosis model of guinea pig was established by intraperitoneal inoculation of Leptospira interrogans strain Lai. Hematoxylin and eosin (HE) staining, electron microscopy and immunohistochemistry staining were used to detect the pathologic changes. Platelet thrombus or fibrin thrombus was detected by HE, Martius Scarlet Blue (MSB) staining and electron microscopy. Hemostatic molecular markers such as 11-dehydrogenate thromboxane B2 (11-DH-TXB2), thrombomodulin (TM), thrombin-antithrombin III complex (TAT), D-Dimer and fibrin (ogen) degradation products (FDPs) in the plasma were examined by quantitative enzyme-linked immunosorbent assay (ELISA) to evaluate the hematological coagulative alterations in leptospirosis models. RESULTS: Pulmonary hemorrhage appeared in the model guinea pig 24 hours after leptospires intraperitoneal inoculation, progressing to a peak at 96 hours after the infection. Leptospires were detected 24 hours post-inoculation in the liver, 48 hours in the lung and 72 hours in the kidney by immunohistochemistry staining. Spiral form of the bacteria was initially observed in the liver, lung and kidney suggestive of intact leptospires, granular form of leptospires was seen as the severity increased. Platelet aggregation in hepatic sinusoid as well as phagocytosis of erythrocytes and platelets by Kupffer cells were both observed. Neither platelet thrombus nor fibrin thrombus was found in the liver, lung or kidney via morphological observation. Thrombocytopenia was observed in all infected guinea pigs of our experimental leptospirosis study. Analysis of hematologic molecular markers showed that 11-DH-TXB2 and TM in the plasma were elevated significantly. TAT that reflects the thrombin activation had a trend of decline after infection. Although D-dimer and FDPs increased statistically, the increasing may not bear clinical significance. CONCLUSION: Pathologic and hematological studies for experimental leptospirosis of guinea pig indicated that the thrombocytopenia found in guinea pigs did not correlate with the occurrence of DIC. The platelet aggregation and Kupffer cells phagocytosis might be the potential causes of thrombocytopenia in severe leptospirosis