Physiology of the prion protein

Prion diseases are transmissible spongiform encephalopathies (TSEs), attributed to conformational conversion of the cellular prion protein (PrP(C)) into an abnormal conformer that accumulates in the brain. Understanding the pathogenesis of TSEs requires the identification of functional properties of PrP(C). Here we examine the physiological functions of PrP(C) at the systemic, cellular, and molecular level. Current data show that both the expression and the engagement of PrP(C) with a variety of ligands modulate the following: 1) functions of the nervous and immune systems, including memory and inflammatory reactions; 2) cell proliferation, differentiation, and sensitivity to programmed cell death both in the nervous and immune systems, as well as in various cell lines; 3) the activity of numerous signal transduction pathways, including cAMP/protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, as well as soluble non-receptor tyrosine kinases; and 4) trafficking of PrP(C) both laterally among distinct plasma membrane domains, and along endocytic pathways, on top of continuous, rapid recycling. A unified view of these functional properties indicates that the prion protein is a dynamic cell surface platform for the assembly of signaling modules, based on which selective interactions with many ligands and transmembrane signaling pathways translate into wide-range consequences upon both physiology and behavior.     

Immunolocalization and expression of lubricin in the bilaminar zone of the human temporomandibular joint disc

Lubricin, which is a boundary joint lubricant, was investigated immunohistochemically in the bilaminar zone (BZ) of the human temporomandibular joint (TMJ), without any degenerative changes. Immunohistochemistry for lubricin detection was carried out on 33 TMJ discs obtained from 17 cadavers. Sections were incubated with diluted rabbit polyclonal anti-lubricin antibody and scored according to the percentage of lubricin immunopositive cells. Three different TMJ disc tissue compartments were analyzed, namely: the upper lamina, the inferior lamina and the loose connective tissue in the space between the laminae. The Mann-Whitney U test was used to compare protein expression (lubricin) among disc specimens’ regions. Staining was noted within the TMJ disc cell populations in every disc tissue sample, with almost every cell immunolabeled by the lubricin antibody. The number of disc cells immunolabeled was almost the same in the 3 bilaminar zone regions. Positive extracellular matrix staining was also seen. The results of the present study suggest that lubricin is expressed in the TMJ disc bilaminar zone. Lubricin may have a role in normal disc posterior attachment physiology through the prevention of cellular adhesion as well as providing lubrication during normal bilaminar zone function.     

De-escalation therapy in ventilator-associated pneumonia

OBJECTIVE: To evaluate de-escalation of antibiotic therapy in patients with ventilator-associated pneumonia. DESIGN: Prospective observational study during a 43-month period. SETTING: Medical-surgical intensive care unit. PATIENTS: One hundred and fifteen patients admitted to the intensive care unit with clinical diagnosis of ventilator-associated pneumonia. All the episodes of ventilator-associated pneumonia received initial broad-spectrum coverage followed by reevaluation according to clinical response and microbiology. Quantitative cultures obtained by bronchoscopic examination or tracheal aspirates were used to modify therapy. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS: One hundred and twenty-one episodes of ventilator-associated pneumonia were diagnosed. Change of therapy was documented in 56.2%, including de-escalation (the most frequent cause) in 31.4% (increasing to 38% if isolates were sensitive). Overall intensive care unit mortality rate was 32.2%. Inappropriate antibiotic therapy was identified in 9% of cases and was associated with 14.4% excess intensive care unit mortality. Quantitative tracheal aspirates and bronchoscopic samples (58 protected specimen brush and three bronchoalveolar lavage) were associated with 32.7% and 29.5% intensive care unit mortality and 29.3% and 34.4% de-escalation rate. De-escalation was lower (p < .05) in the presence of nonfermenting Gram-negative bacillus (2.7% vs. 49.3%) and in the presence of late-onset pneumonia (12.5% vs. 40.7%). When the pathogen remained unknown, half of the patients died and de-escalation was not performed. CONCLUSION: De-escalation was the most important cause of antibiotic modification, being more feasible in early-onset pneumonia and less frequent in the presence of nonfermenting Gram-negative bacillus. The impact of quantitative tracheal aspirates or bronchoscopic techniques was comparable in terms of mortality.     

Immunohistochemical overexpression of platelet-derived growth factor receptor-beta (PDGFR-β) is associated with PDGFRB gene copy number gain in sarcomatoid non-small-cell lung cancer

Introduction

Sarcomatoid non-small cell lung cancer (NSCLC) is an uncommon histologic variant that has not been molecularly well-characterized. We hypothesized that the PDGF-B/PDGF-Rβ pathway may be dysregulated in sarcomatoid lung cancer.

Methods

We conducted immunohistochemical (IHC) and gene copy number gain studies of PDGF-B/PDGFR-β on archived surgically resected specimens, 43 sarcomatoid NSCLCs and 42 control NSCLCs that were age, gender and stage-matched. Biomarkers were correlated to patient demographics, tumor characteristics, and survival.

Results

Sarcomatoid tumors had higher PDGFR-β IHC expression than control NSCLC (median score 2.69 vs. 1.93; P < 0.0001). No difference was seen between the two groups of PDGF-B IHC expression; and neither PDGF-B nor PDGFR-β IHC levels correlated with gender, age, clinical or pathologic TNM status, or overall survival. PDGFRB gene copy number was evaluated by FISH using three ways: presence of amplification, gene copy number gain, and gene copy ratio between tumor and normal tissue. PDGFRB gene copy number gain was associated with sarcomatoid histology (P = 0.006), lower clinical and pathologic T-stage (P = 0.07, P = 0.048), and higher pathologic N-stage (P = 0.013). Sarcomatoid NSCLC patients (P = 0.006) and female patients (P = 0.03) had higher gene copy ratios above 1.83. Higher PDGFR-β IHC expression in tumor cells was associated with gene copy number gain (P = 0.021) and higher gene copy ratio status (P = 0.005).

Conclusion

This is the first study to demonstrate high PDGFR-β IHC expression and gene copy number gain in sarcomatoid NSCLC tumors and suggests that further studies are warranted to determine whether PDGFR-β is a feasible therapeutic target in this population.     

A population based assessment of the use of orthopedic surgery in patients with rheumatoid arthritis

OBJECTIVE: To describe the use of orthopedic surgery, including joint replacement surgery, in a well defined population based cohort of patients with rheumatoid arthritis (RA) and to identify characteristics that predict such use. METHODS: A retrospective medical record review was performed of cases of RA incident in Rochester, MN, during the years 1955-85. Patients were followed until 1998. All joint surgeries were recorded, including joint reconstructive surgeries, total joint arthroplasty (TJA), and other joint reconstructive procedures (JRP) such as tendon transfers and resections, joint fusions, and surgeries for fractures and infections involving joints. RESULTS: Of the total 424 RA incident cases, 148 (34.9%) patients underwent one or more (maximum of 20/patient) surgical procedures involving joints during their followup (median 14.8 yrs, range 0.2-42.8 yrs). Overall, this RA cohort had 9.7 surgeries per 100 person-yrs of followup. The estimated cumulative incidence of surgical procedures for RA at 30 yrs was 52.7% +/- SE 4.2. Surgeries for arthritis related joint disease of RA included: primary TJA 76 patients (31.3 +/- 4.1); JRP joint fusion 78 patients (29.4 +/- 3.5); JRP soft tissue 92 patients (29.8 +/- 3.3); and cervical spine fusion one patient. Non-RA (trauma and other) joint surgeries included TJA 26 patients (13.5 +/- 3.4) and arthrotomy for septic arthritis 8 patients (2.4 +/- 0.9). Based on Cox proportional hazards regression, the risk of having a disease related joint surgery for RA is increased in patients who are younger (p < 0.001), have positive rheumatoid factor (p = 0.01), and those with rheumatoid nodules (p < 0.001). There was a borderline significant increase in the risk of first joint surgery in women (p = 0.09). Women also had significantly more joint surgeries (11.5/100 person-yrs) than men (4.9/100 person-yrs; p < 0.001). Survival of patients who had surgery for RA related joint disease was similar to those who did not. CONCLUSION: This is the first population based assessment of joint surgeries performed in patients with RA. Reconstructive surgeries were common, and women had significantly more surgeries than men. Survivorship among patients with RA undergoing surgeries was similar to that of the RA patient population at large.     

Enhanced neural progenitor/stem cells self-renewal via the interaction of stress-inducible protein 1 with the prion protein

Prion protein (PrP(C) ), when associated with the secreted form of the stress-inducible protein 1 (STI1), plays an important role in neural survival, neuritogenesis, and memory formation. However, the role of the PrP(C) -STI1 complex in the physiology of neural progenitor/stem cells is unknown. In this article, we observed that neurospheres cultured from fetal forebrain of wild-type (Prnp(+/+) ) and PrP(C) -null (Prnp(0/0) ) mice were maintained for several passages without the loss of self-renewal or multipotentiality, as assessed by their continued capacity to generate neurons, astrocytes, and oligodendrocytes. The homogeneous expression and colocalization of STI1 and PrP(C) suggest that they may associate and function as a complex in neurosphere-derived stem cells. The formation of neurospheres from Prnp(0/0) mice was reduced significantly when compared with their wild-type counterparts. In addition, blockade of secreted STI1, and its cell surface ligand, PrP(C) , with specific antibodies, impaired Prnp(+/+) neurosphere formation without further impairing the formation of Prnp(0/0) neurospheres. Alternatively, neurosphere formation was enhanced by recombinant STI1 application in cells expressing PrP(C) but not in cells from Prnp(0/0) mice. The STI1-PrP(C) interaction was able to stimulate cell proliferation in the neurosphere-forming assay, while no effect on cell survival or the expression of neural markers was observed. These data suggest that the STI1-PrP(C) complex may play a critical role in neural progenitor/stem cells self-renewal via the modulation of cell proliferation, leading to the control of the stemness capacity of these cells during nervous system development.     

FRAIL Questionnaire Screening Tool and Short-Term Outcomes in Geriatric Fracture Patients

Objectives

There are limited screening tools to predict adverse postoperative outcomes for the geriatric surgical fracture population. Frailty is increasingly recognized as a risk assessment to capture complexity. The goal of this study was to use a short screening tool, the FRAIL scale, to categorize the level of frailty of older adults admitted with a fracture to determine the association of each frailty category with postoperative and 30-day outcomes.

Locally advanced breast cancer: comparison of mammography,sonography and MR imaging in evaluation of residual disease in women receiving neoadjuvant chemotherapy

The accuracy of mammography, sonography and magnetic resonance imaging (MRI) in identifying residual disease after neoadjuvant chemotherapy is evaluated and imaging findings are correlated with pathologic findings. Fifteen patients enrolled in an experimental protocol of preoperative neoadjuvant chemotherapy underwent clinical examination, mammography, sonography and dynamic MRI, performed in this order, before and respectively after 2 and 4 cycles of neoadjuvant chemotherapy. Four radiologists, two for mammography, one for sonography and one for MR, examined the images, blinded to the results of the other examinations. All patients underwent radical or conservative surgery, and imaging findings were compared with pathologic findings. MRI identified 2/15 (13.3.%) clinically complete response (CR), 9/15 (60%) partial response (PR), 3/15 (20%) stable disease (SD) and 1/15 (6.7%) progressive disease. Mammography identified 1/15 (6.7%) clinically CR, 8/15 (53.3%) PR and 4/15 (27%) SD, and was not able to evaluate the disease in 2/15 (13%) cases. Sonography presented the same results as MRI. Therefore, MRI and sonography compared to mammography correctly identified residual disease in 100 vs. 86%. MRI resulted in two false-negative results because of the presence of microfoci of in situ ductal carcinoma (DCIS) and invasive lobular carcinoma (LCI). MRI was superior to mammography in cases of multifocal or multicentric disease (83 vs. 33%). Sonography performed after MRI improves the accuracy in evaluation of uncertain foci of multifocal disease seen on MR images with an increase of diagnostic accuracy from 73 to 84.5%. MRI assesses response to neoadjuvant chemotherapy better than traditional methods of physical examination and mammography.