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To describe the signalment, clinicopathological findings and outcome in dogs presenting with acute kidney injury (AKI) and skin lesions between November 2012 and March 2014, in whom cutaneous and renal glomerular vasculopathy (CRGV) was suspected and renal thrombotic microangiopathy (TMA) was histopathologically confirmed. The medical records of dogs with skin lesions and AKI, with histopathologically confirmed renal TMA, were retrospectively reviewed. Thirty dogs from across the UK were identified with clinicopathological findings compatible with CRGV. These findings included the following: skin lesions, predominantly affecting the distal extremities; AKI; and variably, anaemia, thrombocytopaenia and hyperbilirubinaemia. Known causes of AKI were excluded. The major renal histopathological finding was TMA. All thirty dogs died or were euthanised. Shiga toxin was not identified in the kidneys of affected dogs. Escherichia coli genes encoding shiga toxin were not identified in faeces from affected dogs. CRGV has previously been reported in greyhounds in the USA, a greyhound in the UK, without renal involvement, and a Great Dane in Germany. This is the first report of a series of non-greyhound dogs with CRGV and AKI in the UK. CRGV is a disease of unknown aetiology carrying a poor prognosis when azotaemia develops.

Proper evaluation of lung nodules is a difficult issue for clinical management of patients. Discrim-inating metastatic endometrial stromal sarcoma (ESS) from other primary spindle cell neoplasms of the lung using histological analysis can be challenging. This is particularly true when an adequate clinical history is lacking, because ESS metastasis can be delayed by a couple of decades. To empha-size the importance of the correlation of pathological findings with clinical history and imaging studies, we investigated 11 cases of ESS (seven low grade and four high grade) metastatic to the lung. All cases presented with one to multiple unilateral or bilateral lung nodules that were detected by chest computed tomography. Primary ESS was diagnosed from hysterectomy specimens except for one by endometrial biopsy, 0.5 to 23 years prior to metastasis. Immunohistochemical studies showed that all ESS cases were moderately to strongly positive for Bcl-2 and CD10 with > 50% of tumor cells stained, except for one high grade ESS that was negative for CD10. Eight (72.7%) and seven (63.6) of the 11 cases showed positive estrogen and progesterone receptors, respectively, with a majority of positive cases showing diffuse and moderate to strong staining. Strong but patchy staining for CD34 was detected in one (9.1%) case with smooth muscle differentiation. CK7 and TTF-1 were negative in all cases. Two (18.2%) cases exhibited patchy and strong positivity for cal-desmon. Two (18.2%) low grade ESS cases showed moderate to strong AE1 / AE3 positivity in > 50% of tumor cells, one of which also showed moderate CK19 and Cam 5.2 staining in > 30% of tumor cells. One should be cautious when assessing spindle cell neoplasms of the lung in women with a history of hysterectomy. Correlation of clinical history and imaging studies with histological and immunohistochemical findings is essential to diagnosis of metastatic ESS to the lung. [ABSTRACT FROM AUTHOR]

TTF-1 and napsin A are useful biomarkers for differentiating primary lung adenocarcinoma from metastatic tumors. Studies have shown, however, that TTF-1 and napsin A also can be expressed in extrapulmonary carcinomas, and that a small fraction of primary lung adenocarcinomas do not co-express these two markers. We attempted to determine whether a tissue-specific transcriptional factor, PAX8, can help determine primary sites of lung carcinomas. Immunohistochemical stains for PAX8, TTF-1 and napsin A were performed on 103 cases of metastatic lung carcinomas from a variety of origins and 120 cases of primary lung adenocarcinomas. Our data demonstrated that all 103 metastatic carcinomas were negative for napsin A, while 14 (13.6%; four thyroid, two endometrium, three colon, one prostate, one salivary adenoid cystic, two renal cell carcinomas, and one ovary) showed weak to strong TTF-1 nuclear staining in 5-60% of the tumor cells. All primary lung adenocarcinomas were negative for PAX8, whereas 46 (44.7%) metastatic carcinomas from the kidney (29/33), ovary (6/8), endometrium (5/5), endocervix (1/1), thyroid (4/5) and urinary tract (1/3) were positive for PAX8. Our data demonstrate that of combined use of PAX8, TTF-1 and napsin A is reliable to separate reliably lung primary from metastatic tumors. [ABSTRACT FROM AUTHOR]

Abstract Background Anaemia of chronic kidney disease increases the risk of death and adverse events, but can be managed using erythropoiesis stimulating agents (ESAs). However, recent evidence suggests that targeting a higher haemoglobin concentration ([Hb]) increases mortality risk, and both higher [Hb] targets and ESA doses have been implicated. Nonetheless, a causative role has not been demonstrated, and this potential relationship requires further appraisal in such a complex patient group. Methods The relationship between the haematopoietic response to ESAs and patient survival in 302 stable, prevalent dialysis patients was explored in a prospective, single-centre study. Clinical and laboratory parameters influencing mortality and ESA resistance were analysed. Patients were stratified into 5 groups, according to their [Hb] and ESA dosage, and were followed for 2 years. Results Little difference in co-morbidities between groups was identified. 73 patients died and 36 were transplanted. Initial analysis suggested a direct relationship between mortality and ESA dosage. However, Cox proportional hazards multivariate analysis demonstrated mortality risk was associated only with age (adjusted HR per year: 1.061, 95% CI 1.031-1.092), dialysis duration (adjusted HR: 1.010, 95% CI 1.004-1.016), peripheral vascular disease (adjusted HR: 1.967, 95% CI 1.083-3.576) and CRP (adjusted HR: 1.024, 95% CI 1.011-1.039). Mortality was increased in patients poorly responsive to ESAs (55.5%). Conclusion ESA dose does not appear to contribute substantially to mortality risk in dialysis patients. Instead, age and co-morbidities appear to be the critical determinants. A poor response to ESAs is a marker of overall poor health status.

Abstract Background Anemia is common among peritoneal dialysis (PD) patients, and most patients require erythropoiesis-stimulating agents (ESA) to maintain their hemoglobin concentrations within current guideline recommendations. Darbepoetin alfa is an ESA with a 3-fold longer half-life and greater in vivo biological activity than recombinant human erythropoietin, allowing less frequent dosing that may simplify anemia management in these patients, providing benefits to patients, care givers and health care providers. Clinical studies have confirmed the efficacy and safety of darbepoetin alfa administered at extended dosing intervals. However, there are limited data on the management of anemia with ESAs in PD patients in routine clinical practice. The aim of this multicenter observational study in European and Australian dialysis patients was to evaluate darbepoetin alfa administered once every 2 weeks (Q2W) in routine clinical practice for 12 months. Methods PD patients ≥18 years old and converting to treatment with darbepoetin alfa Q2W were eligible for enrollment regardless of previous or current ESA use. Patients enrolled in the study were treated according to local usual clinical practice. Data were collected up to 6 months prior to and 12 months after conversion to darbepoetin alfa Q2W. The primary endpoint was hemoglobin concentration 12 months after conversion to darbepoetin alfa Q2W. Results Of the 741 eligible PD patients (mean age, 61 years; male, 57%), 640 (86%) completed the study. Mean hemoglobin concentration (g/dL) was 11.69 (95% CI, 11.53-11.86) 6 months before the conversion, 12.25 (95% CI, 12.13-12.38) at conversion, and 11.88 (95% CI, 11.74-12.02) 12 months after conversion to darbepoetin alfa Q2W. The weekly equivalent ESA dose (μg/wk) was a geometric mean of 25.24 (95% CI, 23.46-27.15) 6 months before conversion, 20.90 (95% CI, 19.13-22.83) immediately before conversion, 18.89 (95% CI, 18.13-19.68) at conversion and 19.04 (95% CI, 17.69-20.49) 12 months after conversion. Twelve months after conversion, 70% of patients were receiving darbepoetin alfa Q2W and 73% had hemoglobin concentrations >11.0 g/dL. Conclusion In this large observational study, PD patients were able to maintain mean hemoglobin concentrations >11.0 g/dL after conversion to extended dosing of darbepoetin alfa Q2W, with no mean dose increase.

Abstract Background Many hospitalizations for residents of skilled nursing facilities are potentially avoidable. Factors that could prevent hospitalization for urinary tract infection (UTI) were investigated, with focus on patient mobility. Methods A retrospective cohort study was conducted using 2003–2004 data from the Centers for Medicare and Medicaid Services. The study included 408,192 residents of 4267 skilled nursing facilities in California, Florida, Michigan, New York, and Texas. The patients were followed over time, from admission to the skilled nursing facility to discharge or, for those who were not discharged, for 1 year. Cox proportional hazards regression was conducted with hospitalization for UTI as the outcome. Results The ability to walk was associated with a 69% lower rate of hospitalization for UTI. Maintaining or improving walking ability over time reduced the risk of hospitalization for UTI by 39% to 76% for patients with various conditions. For residents with severe mobility problems, such as being in a wheelchair or having a missing limb, maintaining or improving mobility (in bed or when transferring) reduced the risk of hospitalization for UTI by 38% to 80%. Other potentially modifiable predictors included a physician visit at the time of admission to the skilled nursing facility (Hazard Ratio (HR), 0.68), use of an indwelling urinary catheter (HR, 2.78), infection with Clostridium difficile or an antibiotic-resistant microorganism (HR, 1.20), and use of 10 or more medications (HR, 1.31). Patient characteristics associated with hospitalization for UTI were advancing age, being Hispanic or African-American, and having diabetes mellitus, renal failure, Parkinson's disease, dementia, or stroke. Conclusion Maintaining or improving mobility (walking, transferring between positions, or moving in bed) was associated with a lower risk of hospitalization for UTI. A physician visit at the time of admission to the skilled nursing facility also reduced the risk of hospitalization for UTI.

Objectives: Autoimmune metaplastic atrophic gastritis (AMAG) is an underrecognized entity, especially in its early stage. This study assessed whether the use of gastrin immunohistochemistry would increase sensitivity for diagnosing early AMAG., Methods: Three-hundred gastric biopsies were prospectively stained for gastrin by immunohistochemistry. Inclusion criteria included well-oriented gastric mucosa with mucus glands and minimal plasma cell infiltrate not suspected to represent pyloric metaplasia. Patient age, sex, designated location of biopsy, presence or absence of intestinal metaplasia, and clinical information were not criteria. Any case with absence of gastrin-positive endocrine cells reflexed to chromogranin immunohistochemistry. Maloriented biopsies or cases with current Helicobacter infection were excluded., Results: The 298-patient study cohort comprised 222 females (mean age, 47 years; range, 16-80 years) and 76 males (mean age, 49 years; range, 7-80 years). Biopsies were designated as "antral/antral nodules" (61%), and the rest were labeled "gastric/random stomach" (39%). Nine cases (3%) exhibited absence of gastrin-positive endocrine cells; one of those showed endocrine cell hyperplasia by chromogranin staining., Conclusions: Pathologists should be aware of the histologic features of early AMAG and meticulously analyze tissue regardless of specimen labeling. Gastrin immunostain is a supplemental diagnostic tool when encountering inflamed antral-appearing specimens., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Health care-associated infections (HAIs) are avoidable through good hand hygiene (HH) practices. Hand hygiene compliance systems (HHCSs) have been shown to reliably measure HH adherence, but data on their effectiveness at reducing HAI rates are limited., Methods: This nonrandomized, pre-post intervention study was conducted at a community hospital in the United States. HAI rates were examined before and after implementation of a HHCS. Preintervention began in January 2014 and intervention began in March 2015; data were collected through September 2017. Additional infection-specific interventions were carried out. HAIs were calculated as incidence rate ratios., Results: The preintervention and intervention periods included 14,297 and 36,890 patients, respectively. The HHCS recorded an average of 696,928 HH opportunities/month. A significant reduction in the rate of catheter-associated urinary tract infections was observed during the intervention: IRR, 0.55; 95% CI, 0.35-0.87. Similarly, a significant reduction in the rate of central line-associated bloodstream infections was observed: IRR, 0.45; 95% CI, 0.23-0.89., Discussion and Conclusions: These findings suggest that monitoring HH practices with an automated system, in addition to other infection control measures, may be an effective means of reducing HAIs. Further studies are needed to isolate the potential role of HHCSs in the reduction of HAIs., (Copyright © 2018 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Identifying strategies to protect patients most at risk for hospital-acquired pressure ulcers (HAPU) is essential. HAPUs have significant impact on patients and their families and have profound cost and reimbursement implications., Aims: This article describes the successful implementation of a hospital-wide mattress switch-out program using a Multidisciplinary Task Force, which resulted in a decrease in HAPUs and significant cost savings., Results: As a result of this quality improvement project supported by evidence, the hospital realized a 66.6% decrease in Stage III and IV HAPUs, a 50% reduction in patient complaints about mattress comfort, a cost savings of $714,724, and an endorsement of bedside nurse clinical autonomy by nursing and executive leaders., Linking Evidence to Action: Nursing leaders can effectively realize large-scale initiatives by developing and implementing wide-ranging operational projects, like this 2.5-day, 275-bed hospital mattresses switch-out., (© 2018 Sigma Theta Tau International.)

Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3), is an oncofetal protein whose aberrant expression has previously been detected in multiple malignant neoplasms. Pulmonary neuroendocrine carcinomas demonstrate increased expression compared with pulmonary carcinoid tumors, but this relationship has not been studied in gastrointestinal neuroendocrine tumors (GINETs). This study examined IMP3 expression in GINETs, with a focus on correlation with established grading criteria. Fifty-four GINETs were immunohistochemically studied using a monoclonal antibody against IMP3. Using established World Health Organization criteria, the cases were stratified by grade and included 31 grade 1 neuroendocrine tumors (G1 GINETs), 15 grade 2 neuroendocrine tumors (G2 GINETs), and 8 neuroendocrine carcinomas (GINECs). The majority (51/54, 94.4%) of GINETs demonstrated IMP3 staining. Thirty cases (55.6%) showed IMP3 cytoplasmic/membranous staining in 60% or greater of tumor cells, with moderate to strong staining in nearly all of these cases (29/30; 96.7%). Of the remaining 24 cases, 3 cases showed no staining, whereas 17 (81%) demonstrated weak staining. When stratified by grade, there was no statistically significant difference in IMP3 staining among the 3 grades of GINETs; of the G1 GINETs, 14 (45.2%) demonstrated staining in at least 60% of tumor cells, compared with 10 (66.7%) G2 GINETs and 6 (75%) GINECs. Hindgut neoplasms of any grade were the most likely to show significant IMP3 staining. Unlike what has been demonstrated in neuroendocrine neoplasms in the lungs, GINETs appear to have a consistent IMP3 expression profile among all tumors grades, which may be reflective of their unique tumor biology.

Objectives: To determine whether histologic features could help identify gastric carcinomas with lymphoid stroma associated with microsatellite instability (MSI) (ie, "medullary carcinomas"), Epstein-Barr virus (EBV) infection (termed lymphoepithelioma-like carcinomas in other organ systems), or neither., Methods: We identified 17 solid-type gastric carcinomas with lymphoid stroma, assessed EBV and MSI status, and compared features across groups. We also compared them with 51 solid-type colorectal adenocarcinomas., Results: In the stomach, EBV-associated carcinomas (n = 8) contained intratumoral germinal centers (P = .024) and eosinophils (P = .030) and lacked necrosis (P = .019) compared with MSI-associated carcinomas (n = 5) and non-EBV, non-MSI carcinomas (n = 4). In the colon, MSI-driven carcinomas (n = 40) more frequently contained intratumoral lymphocytes (P = .017) and neutrophils (P = .0050) and less often metastasized to distant sites (P = .0040) than poorly differentiated carcinomas lacking MSI (n = 11)., Conclusions: Morphology may help classify gastric carcinomas with lymphoid stroma, although ancillary testing appears more reliable. Lymphoepithelioma-like carcinoma and medullary carcinoma should not be used interchangeably., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background Chorionic histiocytic hyperplasia (CHH) is a cellular proliferation at the base of the chorion that was identified by the authors in examining placentas for chronic chorioamnionitis (CC). This study is a retrospective review of cases diagnosed with CHH, describing its incidence alone and with associated lesions, and the immunophenotype of lesional cells. Design In this retrospective study, a laboratory information system search over a 34-month period using the key phrase "chorionic stromal" was performed. Cases identified were reviewed for presence of the following: CC, chronic villitis (CV), chronic deciduitis (CD), maternal (MIR), and fetal (FIR) acute inflammatory responses, meconium deposition; and whether CD3 immunostaining was performed. Incidences were tabulated and compared with known prevalences in our population. Select cases were stained with various immunostains to identify cell lineage and X and Y fluorescent probes to identify fetal or maternal cell origin in cases with male infants. Results Eighty cases of CHH were identified during the study period. Incidences of inflammatory lesions associated with CHH were: CV (54/80, 68%), CD (32/80, 40%), CC (25/80, 31%), MIR (39/80, 49%), and FIR (9/80, 11%). Only chronic inflammatory lesions had a significant correlation with the co-incidence of CHH. CC was identified alongside CHH in 12 of 22 cases in which a CD3 immunostain was performed. The cell population in CHH was vimentin+, CD68+, CD3-, CD45-, CD56-, hPL-, SMA-, OCT 3/4- and, in some cases, variably mixed with CD3+ lymphocytes. The cells had a male genotype by fluorescent in situ hybridization analysis. Conclusion The association of CHH with acute and chronic inflammatory conditions and its immunophenotype suggest that it may be a reactive process. CD3 immunostaining is helpful to identify concurrent CC.

GPS telemetry markedly enhances the temporal and spatial resolution of animal location data, and recent advances in micro-GPS receivers permit their deployment on small mammals. One such technological advance, snapshot technology, allows for improved battery life by reducing the time to first fix via postponing recovery of satellite ephemeris (satellite location) data and processing of locations. However, no previous work has employed snapshot technology for small, terrestrial mammals. We evaluated performance of two types of micro-GPS (< 20 g) receivers (traditional and snapshot) on a small, semi-fossorial lagomorph, the pygmy rabbit (Brachylagus idahoensis), to understand how GPS errors might influence fine-scale assessments of space use and habitat selection. During stationary tests, microtopography (i.e., burrows) and satellite geometry had the largest influence on GPS fix success rate (FSR) and location error (LE). There was no difference between FSR while animals wore the GPS collars above ground (determined via light sensors) and FSR generated during stationary, above-ground trials, suggesting that animal behavior other than burrowing did not markedly influence micro-GPS errors. In our study, traditional micro-GPS receivers demonstrated similar FSR and LE to snapshot receivers, however, snapshot receivers operated inconsistently due to battery and software failures. In contrast, the initial traditional receivers deployed on animals experienced some breakages, but a modified collar design consistently functioned as expected. If such problems were resolved, snapshot technology could reduce the tradeoff between fix interval and battery life that occurs with traditional micro-GPS receivers. Our results suggest that micro-GPS receivers are capable of addressing questions about space use and resource selection by small mammals, but that additional techniques might be needed to identify use of habitat structures (e.g., burrows, tree cavities, rock crevices) that could affect micro-GPS performance and bias study results.

Inflammatory hepatocellular adenoma (IHA) is characterized by sinusoidal dilation, inflammation, and bile ductular reaction. However, these changes can also be seen in nonneoplastic liver tissue adjacent to a mass lesion. This differential may arise in biopsy tissue attempting to sample a liver mass. Serum amyloid A (SAA) immunostaining is useful for the diagnosis of IHA but is not entirely specific. In addition, the histologic pattern of mass effect (ME) has received little formal scrutiny. We compared the clinical, morphologic, and immunohistochemical findings in 18 IHA and 36 livers with ME. Several histologic findings were evaluated in all cases. SAA and CD34 staining were also performed. Patients with IHA were younger (P<.0001) and more often female (P=.0044) than patients with specimens showing ME, but lesions were multifocal on imaging in two-thirds of patients in each category. Unpaired arteries were only seen in IHA (P<.0001), whereas ductular reaction was more common in ME (P=.012). Strong SAA immunostaining was observed in 100% of IHAs and 56% of ME cases (P=.0004), and CD34 staining was seen in 95% of IHAs and 6% of ME cases (P<.0001). Unpaired arteries and staining for SAA and CD34 best distinguish IHA from ME. However, unpaired arteries may be absent because of sampling, and SAA is not available in all laboratories. Ductular reaction can occur in IHA but is more common in ME., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cardiac arrest in the perioperative period is associated with significant morbidity and mortality. Novel resuscitation devices may afford patients improved survival and limit neurologic injury. We report a case of cardiac arrest in the postanesthesia care unit that required an extensive period of cardiopulmonary resuscitation assisted by the ResQPOD impedance threshold device to optimize coronary perfusion and a LUCAS chest compression system to maintain optimal cardiopulmonary resuscitation while transporting the patient to the cardiac catheterization laboratory. Furthermore, after stabilization for an occluded left anterior descending artery with stent placement, an institutional hypothermia protocol was initiated using Thermogard XP Temperature Management system for 24 hours., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The Cancer Genome Atlas Research Network recently classified gastric adenocarcinoma into 4 molecular subtypes: Epstein-Barr virus-positive tumors, microsatellite-unstable tumors, tumors with chromosomal instability, and genomically stable tumors. We theorized that immunohistochemistry might be useful in similar categorization and that that HER2 expression might relate to subtype. We stained 104 gastric adenocarcinomas for MLH1, p53, and EBER in situ hybridization. We grouped them based on staining pattern and compared the groups. Cases were categorized as follows: group 1 (EBER positive), 7 cases (7%); group 2 (MLH1 deficient), 17 cases (16%); group 3 (aberrant p53 staining, EBER negative, retained MLH1), 40 cases (38%); group 4 (unremarkable staining), 40 cases (38%). This distribution was comparable to that found by the Research Network after accounting for the TP53 mutation rate in the chromosomal instability group. Group 1 patients had significantly longer follow-up times (median, 70 months versus 13 months for other groups; P = .0324). No group 2 cases overexpressed HER2. In group 3, 3 of 40 cases were HER2 immunohistochemistry positive, but 7 of 27 were HER2 positive by fluorescence in situ hybridization. Staining offers an efficient, reasonably accurate alternative for molecular subtyping of gastric adenocarcinoma, although some cases with chromosomal instability cannot be identified. These findings have potential prognostic and therapeutic implications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Maspin, a member of the serpin family of protease inhibitors, has been shown to inhibit tumor growth and suppress metastasis in several malignancies, including lung cancer. Previous studies have reported that p63 and p53 control maspin expression by transactivating the promoter. The present study analyzed immunohistochemical studies to determine the expression and coexpression patterns of maspin, p63 and p53 in non-small cell lung carcinoma, specifically squamous cell carcinoma and adenocarcinoma. The results showed that 83/86 cases (96.5%) of squamous cell carcinoma and 82/161 cases (50.9%) of adenocarcinoma included in this study were positive for maspin. There were 79/86 cases (91.9%) of squamous cell carcinoma and 16/161 cases (9.9%) of adenocarcinoma with positive expression for p63. In addition, 77/86 cases (89.5%) of squamous cell carcinoma and 99/161 cases (61.5%) of adenocarcinoma were positive for p53. Maspin, p63 and p53 expression were each significantly higher in squamous cell carcinoma than adenocarcinoma. Squamous cell carcinomas more highly coexpress maspin and p63, as well as maspin and p53, when compared with adenocarcinomas. The high frequency of coexpression of maspin and p63, as well as maspin and p53, in squamous cell carcinoma, suggests that p63 and p53 may be involved in the pathway to control maspin expression. Therapeutic targeting on maspin, p63 and p53 molecules might be beneficial in the management of patients with squamous cell carcinomas of the lung in the future.

Although GATA binding protein 3, a zinc finger transcription factor and an estrogen receptor-regulated gene, has recently been suggested as a marker for urothelium, prognostic significance of GATA binding protein 3 expression in bladder tumor remains unclear. We immunohistochemically stained for GATA binding protein 3 in urothelial neoplasm and matched nonneoplastic bladder tissue specimens. GATA binding protein 3 was positive in 125 (86%; 13 [9%] weak, 44 [30%] moderate, and 68 [47%] strong) of 145 bladder tumors, which was significantly lower than in benign urothelium (104/106 [98%]; 3 [3%] weak, 30 [28%] moderate, and 71 [67%] strong) (P=.001). Fifty (98%) of 51 low-grade tumors were GATA binding protein 3 positive, whereas 75 (80%) of 94 high-grade carcinomas were GATA binding protein 3 positive (P=.002). Similarly, 78 (98%) of 80 non-muscle-invasive tumors expressed the GATA binding protein 3, compared with 47 (72%) of 65 muscle-invasive tumors (P<.001). Conversely, among 68 cases treated with cystectomy, significantly lower expression of GATA binding protein 3 was found in pN0 tumors (32/47 [68%]) than in node-positive tumors (20/21 [95%]) (P=.027). Kaplan-Meier and log-rank tests further revealed that overall positivity (P=.048) or strong positivity (P=.025) of GATA binding protein 3 correlated with progression of muscle-invasive tumors. Multivariate analysis identified high GATA binding protein 3 expression as a strong prognosticator for progression (P=.052) and cancer-specific survival (P=.040) of muscle-invasive tumors. Moreover, there were significant correlations between GATA binding protein 3 expression vs androgen receptor overexpression, estrogen receptor α overexpression, or loss of estrogen receptor β expression. Thus, compared with benign urothelium, a significant decrease in the expression of GATA binding protein 3 in urothelial neoplasms was seen. Loss of GATA binding protein 3 was associated with high-grade and/or muscle-invasive tumors, whereas strong expression was an independent predictor of poor prognosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Osteoclasts (OC) are bone-resorbing, multinucleated cells that are generated via fusion of OC precursors (OCP). The frequency of OCP is elevated in patients with erosive inflammatory arthritis and metabolic bone diseases. Although many cytokines and cell surface receptors are known to participate in osteoclastogenesis, the molecular mechanisms underlying the regulation of this cellular transformation are poorly understood. Herein, we focused our studies on the dendritic cell-specific transmembrane protein (DC-STAMP), a seven-pass transmembrane receptor-like protein known to be essential for cell-to-cell fusion during osteoclastogenesis. We identified an immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic tail of DC-STAMP, and developed an anti-DC-STAMP monoclonal antibody 1A2 that detected DC-STAMP expression on human tumor giant cells, blocked OC formation in vitro, and distinguished four patterns of human PBMC with a positive correlation to OC potential. In freshly isolated monocytes, DC-STAMP(high) cells produced a higher number of OC in culture than DC-STAMP(low) cells and the surface expression of DC-STAMP gradually declined during osteoclastogenesis. Importantly, we showed that DC-STAMP is phosphorylated on its tyrosine residues and physically interacts with SHP-1 and CD16, an SH2-domain-containing tyrosine phosphatase and an ITAM-associated protein, respectively. Taken together, these data show that DC-STAMP is a potential OCP biomarker in inflammatory arthritis. Moreover, in addition to its effect on cell fusion, DC-STAMP dynamically regulates cell signaling during osteoclastogenesis., (Copyright © 2012 American Society for Bone and Mineral Research.)

Differentiation of primary from metastatic adenocarcinoma in the lung can be challenging, and it demands sensitive and specific biomarkers, especially when the tissue for diagnosis is limited. Thyroid transcription factor-1 (TTF-1) has been considered a reliable marker for adenocarcinoma of lung origin. However, several recent studies have shown that TTF-1 immunostaining is also positive in adenocarcinomas arising in different organs including colon, endometrium, endocervix, and ovary. In addition, approximately 20% of lung primary adenocarcinomas are negative for TTF-1 immunostaining, and napsin A immunostaining has slightly higher sensitivity in detecting lung primary adenocarcinoma. We performed TTF-1 and napsin A immunostaining on 120 cases of primary lung adenocarcinomas and 37 cases of metastatic carcinomas in the lung. The results showed that 95 (79.2%) of 120 lung primary adenocarcinomas showed napsin A+/TTF-1+ double-positive immunostaining pattern. TTF-1⁻/napsin A+, TTF-1+/napsin A⁻, and TTF-1⁻/napsin A⁻ were seen in 8.3%, 3.3%, and 9.2% lung primary adenocarcinomas, respectively. Eight (21.6%) of the 37 metastatic carcinomas were positive for TTF-1 and they include clear-cell renal cell carcinomas completely negative for napsin A although napsin A was detected in 12 (80.0%) of 15 primary papillary and 3 (33.3%) of 9 primary clear-cell renal cell carcinomas. All renal epithelial neoplasms were TTF-1 negative. These findings indicate that double napsin A and TTF-1-positive immunostaining is highly specific for lung primary adenocarcinoma and the combination of these 2 biomarkers is warranted to help segregating primary lung adenocarcinoma from metastatic carcinoma in the lung.

Enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, is a histone methyltransferase and plays an important role in cell proliferation and cell cycle regulation. It has been shown to be overexpressed in a number of malignant neoplasms. This study aimed to determine the expression pattern of enhancer of zeste homolog 2 in neuroendocrine tumors of the lung and the potential of enhancer of zeste homolog 2 to serve as a biomarker to segregate carcinoids from high-grade neuroendocrine carcinomas. Fifty-four cases, including 25 typical carcinoids, 7 atypical carcinoids, 9 large-cell neuroendocrine carcinomas, and 13 small-cell lung carcinomas, were immunohistochemically studied using a monoclonal antibody against enhancer of zeste homolog 2. All 13 small-cell lung carcinomas demonstrated moderate to strong nuclear staining with 12 exhibiting more than 90% of tumor cells staining. All 9 large-cell neuroendocrine carcinomas were moderately to strongly positive for enhancer of zeste homolog 2, with 6 cases having staining in more than 80% of tumor cells. In contrast, all 25 typical carcinoids and 6 atypical carcinoids showed only rare scattered enhancer of zeste homolog 2-positive tumor cells, with 1 case of atypical carcinoid exhibiting moderate staining in 40% of tumor cells. A subsequent validation study of the 14 specimens of lung or mediastinal lymph node biopsy and fine-needle aspiration, including 6 small-cell lung carcinomas, 2 large-cell neuroendocrine carcinomas, 5 typical carcinoids, and 1 atypical carcinoid, was performed. Enhancer of zeste homolog 2 was diffusely and strongly positive in all small-cell lung carcinomas and large-cell neuroendocrine carcinomas, even with severe crush artifact, whereas it was only positive in rare tumor cells in carcinoids. These findings support the formulation that enhancer of zeste homolog 2 may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas and as a diagnostically useful marker in distinguishing high-grade neuroendocrine carcinomas from carcinoids., (Copyright © 2011 Elsevier Inc. All rights reserved.)

D2-40 is a new monoclonal antibody recognizing podoplanin and it is selective for lymphatic endothelium. Several studies have confirmed the reliability of D2-40 in the diagnosis of pleural malignant mesothelioma, but the evaluation of this antibody in other pleural neoplasms is limited. The aim of this study was to determine the diagnostic value of D2-40 in segregation of malignant mesothelioma from other pleural or lung neoplasms. Sixty-seven cases, including 36 pleural malignant mesotheliomas, 15 solitary fibrous tumors, 13 pleomorphic carcinomas, and 3 synovial sarcomas, were immunohistochemically studied using a D2-40 monoclonal antibody. Twenty-five (21 epithelioid and 4 biphasic) of 36 (69%) malignant mesotheliomas and 2 of 15 (13%) solitary fibrous tumors were positive for D2-40. The difference of D2-40 positivity between these 2 types of tumor was significant (P<0.001). No D2-40 positivity was detected in pleomorphic carcinomas (n=13) or synovial sarcomas (n=3). These findings showed that D2-40 was frequently positive in malignant mesothelioma, but could also be positive in a small portion of solitary fibrous tumor. These results indicate that D2-40 is a valuable marker for malignant mesothelioma, but caution should be taken when evaluating D2-40-positive pleural spindle cell neoplasms in limited small biopsy specimens, especially when the differential diagnosis includes solitary fibrous tumor and malignant mesothelioma.

There is growing evidence that aberrant innate immune responses towards the bacterial flora of the gut play a role in the pathogenesis of canine inflammatory bowel disease (IBD). Toll-like receptors (TLR) play an important role as primary sensors of invading pathogens and have gained significant attention in human IBD as differential expression and polymorphisms of certain TLR have been shown to occur in ulcerative colitis (UC) and Crohn's disease (CD). The aim of the current study was to evaluate the expression of two TLR important for recognition of commensals in the gut. TLR2 and TLR4 mRNA expression in duodenal biopsies from dogs with IBD was measured and correlated with clinical and histological disease severity. Endoscopic duodenal biopsies from 20 clinical cases and 7 healthy control dogs were used to extract mRNA. TLR2 and TLR4 mRNA expression was assessed using quantitative real-time PCR. TLR2 mRNA expression was significantly increased in the IBD dogs compared to controls, whereas TLR4 mRNA expression was similar in IBD and control cases. In addition, TLR2 mRNA expression was mildly correlated with clinical severity of disease, however, there was no correlation between TLR2 expression and histological severity of disease., (Copyright 2009 Elsevier B.V. All rights reserved.)

Depending on the Breslow depth of the primary melanoma, sentinel lymph node biopsy is considered as standard of care for the staging of cutaneous melanoma, and is one of the most important prognostic factors. The histologic analysis of these specimens becomes difficult to interpret when benign intranodal nevic cells mimic metastases. Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP3), also known as K homology domain-containing protein overexpressed in cancer or L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and has been shown to have diagnostic utility in distinguishing cutaneous melanoma from benign nevi. In this study, 43 sentinel lymph node biopsy specimens, including 13 with benign intranodal nevi and 30 with metastatic melanoma (two cases containing both benign nevi and metastatic melanoma), from 41 patients were immunohistochemically analyzed with a monoclonal antibody against IMP3. None of the benign intranodal nevi expressed IMP3, whereas 21 out of 30 (70%) of the lymph nodes containing metastatic melanoma did. It seems that IMP3 is helpful in distinguishing benign intranodal nevi from metastatic melanoma in sentinel lymph node biopsy specimens, and could be a valuable diagnostic adjunct in sentinel lymph node biopsy assessment in which questions arise as to the malignancy of the melanocytes present.

Tissue engineering often involves seeding cells into porous scaffolds and subjecting the scaffold to mechanical stimulation. Current experimental techniques have provided a plethora of data regarding cell responses within scaffolds, but the quantitative understanding of the load transfer process within a cell-seeded scaffold is still relatively unknown. The objective of this work was to develop a finite element representation of the transient and heterogeneous nature of a cell-seeded collagen-GAG-scaffold. By undertaking experimental investigation, characteristics such as scaffold architecture and shrinkage, cellular attachment patterns, and cellular dimensions were used to create a finite element model of a cell-seeded porous scaffold. The results demonstrate that a very wide range of microscopic strains act at the cellular level when a sample value of macroscopic (apparent) strain is applied to the collagen-GAG-scaffold. An external uniaxial strain of 10% generated a cellular strain as high as 49%, although the majority experienced less than approximately 5% strain. The finding that the strain on some cells could be higher than the macroscopic strain was unexpected and proves contrary to previous in vitro investigations. These findings indicate a complex system of biophysical stimuli created within the scaffolds and the difficulty of inducing the desired cellular responses from artificial environments. Future in vitro studies could also corroborate the results from this computational prediction to further explore mechanoregulatory mechanisms in tissue engineering.

Marrow stromal cell (MSC) populations, which are a potential source of undifferentiated mesenchymal cells, and culture scaffolds that mimic natural extracellular matrix are attractive options for orthopaedic tissue engineering. A type I collagen-glycosaminoglycan (CG) scaffold that has previously been used clinically for skin regeneration was recently shown to support expression of bone-associated proteins and mineralisation by MSCs cultured in the presence of osteogenic supplements. Here we follow RNA markers of osteogenic differentiation in this scaffold. We demonstrate that transcripts of the late stage markers bone sialoprotein and osteocalcin are present at higher levels in scaffold constructs than in two-dimensional culture, and that considerable gene induction can occur in this scaffold even in the absence of soluble osteogenic supplements. We also find that bone-related gene expression is affected by pore size, mechanical constraint, and uniaxial cyclic strain of the CG scaffold. The data presented here further establish the CG scaffold as a potentially valuable substrate for orthopaedic tissue engineering and for research on the mechanical interactions between cells and their environment, and suggest that a more freely-contracting scaffold with larger pore size may provide an environment more conducive to osteogenesis than constrained scaffolds with smaller pore sizes.

An 11-year-old female domestic shorthair cat with a previous history of having been spayed, presented with signs of abdominal distension, lethargy and anorexia of 1 week's duration. On the basis of radiological and ultrasonographic findings a tentative diagnosis of pyometra was made. Exploratory coeliotomy revealed a 900 degrees left horn uterine torsion along the longitudinal axis. Ovariohysterectomy was performed without correction of the torsion. To the authors' knowledge this is the first case report of uterine torsion in a non-gravid cat.

Adult mesenchymal stem cells (MSCs) are under investigation as an alternative cell source for the engineering of cartilage tissue in three-dimensional (3D) scaffolds. However, little is known about the intracellular mechanisms involved in the chondrogenic differentiation of MSCs. This study investigated the signaling pathways evoked by TGF-beta1 and IGF-1 that mediated chondrogenic differentiation in adult rat bone-marrow derived MSCs in (i) monolayer on plastic and (ii) a 3D collagen-GAG scaffold. The data demonstrated involvement of the p38 pathway, but not ERK1/2 or PI3K in TGF-beta1-induced chondrogenic differentiation in monolayer. Similarly, when the MSCs were seeded onto a collagen-GAG scaffold and treated with TGF-beta1, the chondrogenic differentiation was dependent upon p38. In contrast, IGF-1-induced chondrogenic differentiation in monolayer involved p38, ERK1/2, as well as PI3K. The phosphorylation of Akt occurred downstream of PI3K and phospho-Akt was found to accumulate in the nucleus of IGF-1-treated cells. When MSCs were seeded onto the collagen-GAG scaffold and exposed to IGF-1, PI3K was required for chondrogenesis. These findings highlight the respective and differential involvement of p38, ERK1/2 and PI3K in growth factor-induced chondrogenesis of MSCs and demonstrates that intracellular signaling pathways are similar when differentiation is stimulated in a 2D or 3D environment.

The effective treatment of cartilage defects by tissue engineering requires an improved understanding of the effect of mechanical forces on cell differentiation within three-dimensional (3D) matrices. The objective of this study was to investigate the effects of mechanical constraint and cyclic tensile strain on the chondrogenic differentiation of mesenchymal stem cells (MSCs) in a 3D collagen type I-glycosaminoglycan (GAG) scaffold. A multi-station uniaxial stretching bioreactor was fabricated to facilitate application of cyclic strain to the constructs cultured in a chondrogenic medium. Mechanical constraint, created by uniaxial clamping, prevented the cell-mediated contraction of the scaffolds and resulted in a reduction in the rate of GAG synthesis as measured by [35S] sulfate incorporation relative to unconstrained controls. However, the rate of GAG synthesis was increased following application of continuous 10% cyclic tensile loading at 1 Hz for 7 days. A poroelastic finite element analysis of the 3D scaffold computed a maximum fluid flow of 19 microm/s and maximum principal strains of 8% under 10% stretch suggesting these magnitudes were sufficient to mechano-regulate the chondrogenic differentiation process.

The objective of this study was to determine if cyclic tensile strain would regulate the rate of glycosaminoglycan synthesis via stretch-activated ion channels in adult mesenchymal stem cells seeded in a collagen type I-glycosaminoglycan scaffold and treated with TGF-beta1. The application of 10% cyclic tensile loading at 1Hz for 7 days significantly increased the rate of glycosaminoglycan synthesis, as assessed using [(35)S] sulphate incorporation. This increase was attenuated in the presence of a stretch-activated ion channel inhibitor (10microM gadolinium chloride) demonstrating the involvement, in part, of these ion channels in the mechanotransduction pathway that couples cyclic tensile loading to matrix synthesis.