Primary cardiac sarcomas may develop from resident or bone marrow‐derived mesenchymal stem cells: use of immunohistochemistry including CD44 and octamer binding protein 3/4

Hegyi L, Thway K, Fisher C & Sheppard M N
(2012) Histopathology  61, 966–973 Primary cardiac sarcomas may develop from resident or bone marrow‐derived mesenchymal stem cells: use of immunohistochemistry including CD44 and octamer binding protein 3/4 Aims: To provide evidence that cardiac sarcomas ‘not otherwise specified’ express markers that might indicate their cellular origin or identify any lines of differentiation. Methods and results: We reviewed all 11 cases of primary undifferentiated cardiac sarcomas found in the archives of the Royal Marsden and Royal Brompton Hospitals, London, UK during the period 2000–2009. Five cases with appropriate consent and archived material were investigated using immunohistochemistry. We found that the spindle, pleomorphic or occasionally epithelioid cell sarcomas showed no lineage‐specific differentiation other than partial myofibroblastic or ‘myoid’ differentiation (all cases). All tumours showed some degree of cytoplasmic positivity for the mesenchymal stem cell marker CD44. In contrast, no nuclear octamer binding protein 3/4 (Oct3/4) expression was seen in any of the tumours, although very patchy cytoplasmic positivity was seen in some tumours. Conclusions: The cytoplasmic positivity for CD44 and the absence of nuclear Oct3/4 suggest that the cells of these sarcomas may represent ‘daughter’ stem cells that no longer have the capacity for tumour initiation, but have subsequently developed new lines of partial differentiation. Primary cardiac sarcomas may arise from mesenchymal stem cells with the ability to generate tumours with multilineage differentiation.     

Autochthonous hepatitis E in Southwest England: natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease

AIMS: To report the natural history of autochthonous hepatitis E and hepatitis E virus (HEV) IgG seroprevalence in Southwest England. METHODS: Patients with unexplained hepatitis were tested for hepatitis E and cases followed until recovery or death. Five hundred blood donors, 336 individuals over the age of 60 years and 126 patients with chronic liver disease were tested for HEV IgG. RESULTS: Forty cases of autochthonous hepatitis E (genotype 3) were identified. Hepatitis E was anicteric in 25% of cases and usually caused a self-limiting hepatitis predominantly in elderly Caucasian males. Six of 40 had a significant complication and three patients died, two of who had previously undiagnosed cirrhosis. Hepatitis E shows a seasonal variation with peaks in the spring and summer and no cases in November and December. HEV IgG prevalence increases with age, is more common in men and is 16% in blood donors, 13% in patients with chronic liver disease and 25% in individuals over 60 years. CONCLUSION: Autochthonous hepatitis E is more common than previously recognized, and should be considered in the differential diagnosis in patients with hepatitis, whatever their age or travel history. It carries a significant morbidity and when seen in the context of chronic liver disease carries an adverse prognosis.     

Vitamin D3 Supplementation Alleviates Left Ventricular Dysfunction in a Mouse Model of Diet-Induced Type 2 Diabetes: Potential Involvement of Cardiac Lipotoxicity Modulation

Cardiovascular Drugs and Therapy - To evaluate the effectiveness of vitamin D3 supplementation, in secondary prevention, on cardiac remodeling and function, as well as lipid profile, in a mouse...     

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine

Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis–an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the ‘subthreshold'' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 μg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.     

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.     

Influence of data filtering on reliability of respiratory impedance and derived parameters in children

Forced oscillation impedance (Zrs) measurements are frequently corrupted by noisy data in children. Our aim was to improve the reliability of respiratory resistance (Rrs) and routine identification of its flow (V') and volume (V) dependence during tidal breathing, according to Rrs = K1 + K2 x /V'/ + K3 x V. Zrs was measured at 12 Hz, using a head generator in 23 children aged 4-13 years undergoing methacholine (Mch) challenge. Rrs, K1, K2, K3, and residual mean square error (RMSD), as well as reproducibility of the parameters, were obtained. Calculations were performed separately in inspiration and expiration on the raw data, and after eliminating values lying outside confidence intervals ranging from 99% (F3SD) to 95% (F2SD) of the mean Zrs. Filtering decreased RMSD and Rrs, F3SD improved reproducibility of Rrs in expiration compared to raw data. F2SD increased K1 and decreased the amplitude of K2 and K3 before and after Mch compared to F3SD. Rrs and K2 were significantly larger and K3 significantly more negative in expiration than in inspiration at all levels of filtering, probably because of the upper airways. F3SD appeared efficient in eliminating aberrant data, while allowing the identification of physiological variations of Rrs.     

Low-grade Sarcomas with CD34-Positive Fibroblasts and Low-Grade Myofibroblastic Sarcomas

A subset of low-grade fibrosarcomas is composed of CD34-positive spindle cells. These include dermatofibrosarcoma, its morphologic variants, and its associated fibrosarcoma, solitary fibrous tumor, hemangiopericytoma and their malignant counterparts, and some cases of myxoinflammatory fibroblastic sarcoma. Dermatofibrosarcoma and related lesions are characterized by a t(17;22)(q22;q13) rearrangement resulting in fusion of the genes COL1A (17q21-22) and PDGFB1 (22q13). Solitary fibrous tumor displays varying cellularity and fibrosis and a peripheral hemangiopericytomatous pattern; most tumors formerly called hemangiopericytoma are now subsumed into the category of solitary fibrous tumor, although a few strictly defined examples are recognized; however, these are probably not composed of pericytes. Myofibroblastic malignancies are best identified by electron microscopy, with which varying degrees of differentiation, including the presence of fibronexus junctions, can be identified. Low-grade sarcomas showing myofibroblastic differentiation include myofibrosarcomas and inflammatory myofibroblastic tumors. Myofibrosarcomas are spindle cell neoplasms that occur in children or adults in the head and neck, trunk, and extremities as infiltrative neoplasms and that display a fascicular or fasciitis-like pattern with focal nuclear atypia and variable expression of myoid antigens. These sarcomas are prone to recurrence and a small number metastasize. Inflammatory myofibroblastic tumor (synonymous with inflammatory fibrosarcoma) is a neoplasm arising predominantly in childhood, and frequently in intraabdominal locations. It has spindle cells in fascicular, fasciitis-like and sclerosing patterns, with heavy chronic inflammation including abundant plasma cells. Many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset.     

Symptomatic isolated internal carotid artery occlusion with initial medical management: a monocentric cohort

Journal of Neurology - Symptomatic isolated carotid artery occlusions (ICAO) can lead to disability, recurrent stroke, and mortality, but natural history and best therapeutic management remain...