Sclerosing haemangioma of the lung is positive for MIB-1 in cell membrane and cytoplasmic staining pattern

AIMS: MIB-1 is a monoclonal antibody raised against the recombinant part of the Ki67 antigen, which is expressed in the nuclei of all the active part of the cell cycle. Recently, cell membrane and cytoplasmic pattern of staining with MIB-1 in hyalinizing trabecular adenoma of the thyroid was reported. Sclerosing haemangioma of the lung is a tumour of uncertain histogenesis with a usually benign course. The tumour is mainly composed of cuboidal cells that line the papillary or tubular structure and pale cells that are found in the stroma. METHODS AND RESULTS: We examined a cell membrane and cytoplasmic immunoreactive pattern for MIB-1 antibody in sclerosing haemangioma. In all of the five cases examined, distinct cell membrane and cytoplasmic MIB-1 positivity mainly in the pale cells was noted. None of the carcinomas of the lung showed this type of staining with MIB-1. CONCLUSION: This result shows that, although the staining may be a result of cross reaction, cell membrane and cytoplasmic MIB-1 positivity is unique in that it could distinguish sclerosing haemangioma from other malignant epithelial tumours of the lung.     

Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions

Paroxysmal kinesigenic dyskinesia (PKD (MIM128000)) is a neurological disorder characterized by recurrent attacks of involuntary movements. Benign familial infantile convulsion (BFIC) is also one of a neurological disorder characterized by clusters of epileptic seizures. The BFIC1 (MIM601764), BFIC2 (MIM605751) and BFIC4 (MIM612627) loci have been mapped to chromosome 19q, 16p and 1p, respectively, while BFIC3 (MIM607745) is caused by mutations in SCN2A on chromosome 2q24. Furthermore, patients with BFIC have been observed in a family concurrently with PKD. Both PKD and BFIC2 are heritable paroxysmal disorders and map to the same region on chromosome 16. Recently, the causative gene of PKD, the protein-rich transmembrane protein 2 (PRRT2), has been detected using whole-exome sequencing. We performed mutation analysis of PRRT2 by direct sequencing in 81 members of 17 families containing 15 PKD families and two BFIC families. Direct sequencing revealed that two mutations, c.649dupC and c.748C>T, were detected in all members of the PKD and BFIC families. Our results suggest that BFIC2 is caused by a truncated mutation that also causes PKD. Thus, PKD and BFIC2 are genetically identical and may cause convulsions and involuntary movements via a similar mechanism.     

Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin

Haemangioma is the most common tumour of endothelial origin, occurring in 4-10% of Caucasian infants. It is characterized by rapid growth during the first year of postnatal life, followed by spontaneous regression from 1 to 7 years of age. The cell surface adhesion molecule CD146 has been identified as an endothelial cell marker. Despite advances in understanding the functional role of CD146 in normal endothelial cells and tumour progression, its expression and a possible role in an endothelial tumour have not been studied. As part of an investigation of endothelial cell alterations in infantile haemangioma, differential expression studies were performed with several known antigens and endothelial cell markers. Using immunohistochemical and flow cytometric analyses, cultured human dermal microvascular endothelial cells isolated from newborn foreskin (HDMEC) were compared with endothelial cells derived from haemangioma tissue (HemECs). In addition, immunohistochemistry was used to compare haemangioma tissues with normal human skin. Unexpectedly, cultured HemECs showed a significantly lower level of CD146 than HDMECs by both flow cytometric analysis and immunofluorescence staining. Using immunohistochemical studies, it was further demonstrated that endothelia in all haemangioma tissues, regardless of the tumour phase, showed negative immunoreactivity for CD146. In contrast, strong positive staining for CD146 was observed in the pericyte-like cells that surround the endothelial layers. These findings are believed to be relevant to the molecular basis of haemangioma. Furthermore, it is possible that antibodies against CD146 may be useful for separating haemangioma-derived endothelial cells from normal endothelial cells and pericytes.     

Disease-associated Glut1 single amino acid substitute mutations S66F, R126C, and T295M constitute Glut1-deficiency states in vitro

Glucose transporter type 1 deficiency syndrome (Glut1DS) is the result of autosomal-dominant loss-of-function mutation of the glucose transporter type 1 gene (GLUT1) leading to brain energy failure and epileptic encephalopathy. In this study, the protein products of the Glut1DS-associated GLUT1 missense mutations, S66F, R126C, and T295M, were characterized using the Glut1-green fluorescent protein (GFP) fusion expressed in CHO cells. Glut1-GFP expression was confirmed by Western blot and confocal microscopy. The applicability of this Glut1-GFP expression model in reporting Glut1 functional deficits was validated by re-confirming the glucose transport defects of the previously reported pathogenic mutations R126H, R126L, and R333W. While S66F, R126C, and T295M mutants were expressed and targeted to the cell membrane, these Glut1 mutants have significantly diminished membrane association and glucose transport activity (p<0.05) relative to the wild-type Glut1 protein. Consistent with the reduced Glut1 membrane association, glucose transport kinetics studies showed that S66F, R126C, and T295M mutants have significantly reduced (p<0.05) Vmax but not Km. Thus, Glut1 single amino acid substitute mutants S66F, R126C, and T295M impair glucose transport function and constitute Glut1-deficiency states in vitro. These results support the pathogenicity of Glut1 S66F, R126C, and T295M in vivo.     

Immunohistochemical markers of carcinoma in situ of the testis also expressed in normal infantile germ cells

Carcinoma in situ of the testis is an intratubular, pre-invasive lesion preceding germ cell tumour. In adult men, carcinoma in situ cells differ in several aspects from normal germ cells. For example, placental-like alkaline phosphatase and/or the epitopes for the monoclonal antibodies M2A, 43-9F and TRA-1–60 are not seen in normal germ cells, whereas their presence is considered a specific sign of carcinoma in situ . As it is known that placental-like alkaline phosphatase and the epitope for TRA-1–60 are expressed in normal fetal germ cells it is possible that the markers could appear in normal infantile germ cells in a period after birth before they lose their expression. In children, carcinoma in situ cells may be difficult to identify morphologically and the use of the markers could be of great value. However, little information is available on the expression of the markers of adult carcinoma in situ in normal infantile germ cells. We investigated gonads from 66 boys less than 15 years old who died suddenly. Their deaths were unrelated to testicular disease. Immunohistochemical staining with anti-placental-like alkaline phosphatase antibody and monoclonal antibodies TRA-1–60 and 43–9F were performed. We found that these markers were expressed in some normal infantile germ cells until the age of 1 year. Therefore, these markers are not suitable for diagnosis of carcinoma in situ during the early postnatal period of life. Furthermore, our findings of placental-like alkaline phosphatase and the epitope for TRA-1–60 in normal germ cells before birth indicate that the markers of adult carcinoma in situ cells are of embryonic origin. This is in accordance with the hypothesis that carcinoma in situ cells are fetal germ cells malignantly transformed during fetal life, although re-expression of the antigens could provide an alternative explanation.     

Expression of the hyaluronan receptor LYVE-1 is not restricted to the lymphatic vasculature; LYVE-1 is also expressed on embryonic blood vessels

Expression of the hyaluronan receptor LYVE-1 is one of few available criteria used to discriminate lymphatic vessels from blood vessels. Until now, endothelial LYVE-1 expression was reported to be restricted to lymphatic vessels and to lymph node, liver, and spleen sinuses. Here, we provide the first evidence that LYVE-1 is expressed on blood vessels of the yolk sac during mouse embryogenesis. LYVE-1 is ubiquitously expressed in the yolk sac capillary plexus at E9.5, then becomes progressively down-regulated on arterial endothelium during vascular remodelling. LYVE-1 is also expressed on intra-embryonic arterial and venous endothelium at early embryonic stages and on endothelial cells of the lung and endocardium throughout embryogenesis. These findings have important implications for the use of LYVE-1 as a specific marker of the lymphatic vasculature during embryogenesis and neo-lymphangiogenesis. Our data are also the first demonstration, to our knowledge, that the mouse yolk sac is devoid of lymphatic vessels.     

An experimentally antithrombotic strawberry variety is also effective in humans

Prevention of arterial thrombotic diseases is of high priority in developed countries. As inappropriate diet is regarded as an important risk factor of thrombotic events, daily intake of an antithrombotic diet may offer a convenient and effective way of prevention. Earlier we used animal models of thrombosis to find fruits and vegetables with potential antithrombotic activity. Among various strawberry varieties tested, a particular variety (KYSt-4, Nohime) showed a significant antithrombotic effect. The aim of the present investigation was to extend this study to humans, by testing the experimentally active KYSt-4 and inactive KYSt-10 variety for effectiveness in humans after oral intake. Filtrates of strawberries were prepared and administered orally. Thrombotic status was tested by a novel global test (Gorog Thrombosis Test). The strawberry variety (KYSt-4; Nohime) which earlier inhibited experimental thrombosis showed antithrombotic effects in humans, while the experimentally inactive variety (KYSt-10) as well as the relevant control (water) were ineffective.     

LMO2 promotes angiogenesis probably by up-regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma

Sun Z‐J, Cai Y, Chen G, Wang R, Jia J, Chen X‐M, Zheng L‐W & Zhao Y‐F
(2010) Histopathology 57 , 622–632
LMO2 promotes angiogenesis probably by up‐regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma Aims: Infantile haemangiomas (IHs) are common benign vascular tumours distinctive for their perinatal presentation, rapid growth during the first year of life and subsequent slow involution. Recent research has indicated that endothelial cells of haemangiomas express LIM‐only protein 2 (LMO2). The aim of this study was to investigate the role of LMO2 in the pathogenesis of IHs was investigated. Methods and results: Immunoreactivity of LMO2 was assessed in specimens of 19 IH. Stable transfection of LMO2 into human endothelial cell lines (EAhy926) was performed to evaluate the role of LMO2 in terms of the change in cell proliferation, cell cycle and cell migration as well as the expression level of angiogenic factors. Immunoreactivity for LMO2 was detected in all IH specimens, specifically in the nucleus of the endothelial cells. The intensity of LMO2 immunostaining decreased significantly from proliferative to involuting stages. Furthermore, the overexpression of LMO2 enhanced the proliferation and migration of the endothelial cells and promoted G0/G1–S‐phase transition in vitro, together with an up‐regulation of bFGF expression. Conclusions: LMO2 probably promotes angiogenesis by up‐regulation of bFGF expression and thereby consequently influences progression of IH.     

DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia

Background

DISC1 is considered a susceptibility gene for schizophrenia and schizoaffective disorder, but little is known regarding the potential mechanisms through which it may confer increased risk. Given that DISC1 plays a role in cerebral cortex development, polymorphisms in this gene may have relevance for neurobiological models of schizophrenia that have implicated cortical deficits in its pathophysiology.

Methods

We investigated whether the DISC1 leu607phe polymorphism was associated with prefrontal gray matter volumes using magnetic resonance imaging in a cohort of patients with schizophrenia (N = 19) and healthy volunteers (N = 25) and positive and negative symptoms in 200 patients with schizophrenia.

Results

Among patients and healthy volunteers, phe carriers (N = 11) had significantly less gray matter in the superior frontal gyrus and anterior cingulate gyrus compared to leu/leu homozygotes (N = 33). Further, among patients left superior frontal gyrus gray matter volume was significantly negatively correlated with severity of hallucinations. In addition, patients who were phe carriers (N = 144) had significantly greater severity of positive symptoms (hallucinations) compared to patients who were leu/leu homozygotes (N = 56).

Discussion

These findings implicate DISC1 in variation of prefrontal cortical volume and positive symptoms, thus providing a potential mechanism through which DISC1 may confer increased risk for schizophrenia or schizoaffective disorder.