Carmen Morales

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.

Prognostic significance of clinical and angiogenesis-related factors in low-grade oligodendrogliomas

BACKGROUND Keeping in mind that oligodendrogliomas have unpredictable biological behavior, the aim of this study is to investigate the prognostic significance of VEGF expression and microvessel density in a homogeneous series of low-grade oligodendrogliomas. METHODS For this study 36 patients with a low-grade oligodendroglioma treated by surgical resection and radiotherapy were selected. At the time of surgery, in all cases the Karnofsky Performance Scale (KPS) score was more than 70, and the study of the resected tumor disclosed a Ki-67/MIB-1 labeling index (MBI-1 LI) less than 1%. In this homogeneous series, immunohistochemical studies were performed using monoclonal antibodies against VEGF in order to study the expression of this cytokine, and against vascular endothelial CD-34 antigen, in order to identify microvessels. RESULTS Our results show that in contrast to low-grade astrocytomas, low-grade oligodendrogliomas lacked immunoreactive VEGF. Oligodendrogliomas with low vascular density (less than 20 microvessels per microscopical field, at 200 x) or high vascular density (more than 100 microvessels per field, at 200 x) were identified, but this factor had no influence on the survival rate of patients. On the other hand, analysis of the present series showed that clinical factors, such as age or extent of surgical resection, were not significantly associated with survival. CONCLUSIONS In contrast to low-grade astrocytomas, the angiogenesis score of low-grade oligodendrogliomas (counting the number of microvessels in tumor tissue) adds little information to help predict tumor behavior.

Expression of Vascular Permeability Factor in Glioblastoma Specimens: Correlation with Tumor Vascular Endothelial Surface and Peritumoral Edema

Keeping in mind that the expression of vascular permeability factor (VPF) in astrocytic tumors has been related to tumor angiogenesis and peritumoral edema (PE), the aim of this study is to investigate the correlation between degree of VPF expression by tumor cells, and degree of PE and vascular endothelial surface (VES) in glioblastoma. Tumor tissue and neuroimaging data were studied in a series of 38 patients with glioblastoma. For each tumor, immunohistochemical and morphometric studies were performed in order to obtain a score of VPF expression, and a VES score, expressed as the CD-34 immunostained endothelial surface per each 1000 tumor cells. These parameters were related to the degree of PE. The results show that in glioblastomas there exist a clear correlation between the tumor-cell expression of VPF and VES, but we failed to obtain a significant correlation between degree of PE and degree of VES, or between degree of VPF expression and degree of PE. Our present results suggest that in glioblastomas, tumor angiogenesis is clearly related to the expression of VPF by tumor cells, but factors other than intratumoral presence of VPF may contribute to the development of PE.

Signo del halo en la tomografía computarizada de tórax: diagnóstico diferencial con correlación anatomopatológica

El signo del halo consiste en un area circular de atenuacion en vidrio deslustrado que rodea un nodulo pulmonar. Aunque la causa mas frecuente es la hemorragia pulmonar, dicho signo se asocia a numerosas entidades, que corresponden a diferentes procesos anatomopatologicos: nodulos hemorragicos de etiologia infecciosa (aspergilosis invasiva —la causa mas frecuente de nodulos pulmonares con halo—, mucormicosis, candidiasis, tuberculosis, neumonias viricas), nodulos hemorragicos de etiologia no infecciosa (gra-nulomatosis de Wegener, sarcoma de Kaposi, metastasis hemorragicas), nodulos con halo debido a infiltracion de celulas neoplasicas (carcinoma bronquioloalveolar, linfoma, metastasis con crecimiento tumoral intraalveolar) y nodulos con halo debido a lesiones inflamatorias no hemorragicas (sarcoidosis, neumonia organizada). Por lo tanto, el diagnostico debe realizarse integrando todos los hallazgos de la tomografia computarizada de torax en el contexto clinico del paciente. El objetivo de la presente revision es describir e ilustrar enfermedades que pueden manifestarse como nodulos pulmonares con el signo del halo, analizando su utilidad diagnostica y discutiendo su correlacion radiopatologica.

The Halo Sign in Computed Tomography Images: Differential Diagnosis and Correlation With Pathology Findings

The halo sign is a circular area of ground-glass attenuation that is seen around pulmonary nodules at computed tomography (CT). Although the sign is most often an indication of pulmonary hemorrhage, it may also accompany other lesions associated with different disease processes. Examples are hemorrhagic nodules of infectious origin (mucormycosis, candidiasis, tuberculosis, viral pneumonia, and invasive aspergillosis--the last being the most common cause of the CT halo sign); hemorrhagic nodules of noninfectious origin (Wegener granulomatosis, Kaposi sarcoma, and hemorrhagic metastases); tumor cell infiltration (bronchioloalveolar carcinoma, lymphoma, and metastasis with intra-alveolar tumor growth); and nonhemorrhagic lesions (sarcoidosis and organizing pneumonia). Diagnosis must therefore be based on careful consideration of all the CT chest findings within the context of the patients clinical state. The aim of this review was to describe and illustrate different disease processes that appear as a halo sign on CT scans, to analyze the value of this diagnostic tool, and to assess its correlation with pathology findings.

Prognostic Significance of Endothelial Surface Score and MIB-1 Labeling Index in Glioblastoma

The aim of this study is to investigate the usefulness of a vascular endothelial surface score (VESS) and MIB-1 labeling index (MIB-1 LI), in a defined series of glioblastomas, as biological markers with prognostic significance of survival. Tumor tissue and survival were studied in a series of 38 patients with glioblastoma, previously treated by surgical resection and radiotherapy. For each tumor, immunohistochemical and morphornetric studies were performed in order to study MIB-1 LI, and VESS, expressed as the CD-34 immunostained endothelial surface per 1000 tumor cells. The survival for the entire patient population of the series was 48.1 ± 14.1 weeks, and the mean VESS for the tumors of the series ranged from 16.7 to 107 µm2 per 1000 tumor cells (mean: 38.7 ± 18.2). Factors such as age or MIB-1 LI were not significatively associated with survival, but the median survival for the 18 patients with a VESS less than 35 was 50.7 ± 3.7 weeks, versus 45.9 ± 2.8 weeks for the 20 patients showing a VESS higher than 36 (p < 0.05). Our present results suggest that tumor VESS, expressed as the CD-34 immunostained endothelial surface per each 1000 tumor cells, may have usefulness, as angiogenic-related factor influencing survival, in patients with glioblastoma.

Effect of recombinant human growth hormone on peripheral nerve regeneration: experimental work on the ulnar nerve of the rat.

Neurotrophic factors may be used to improve the growth and repair of injured peripheral nerves. In this study we determined the effectiveness of recombinant human growth hormone on peripheral nerve injury in the Wistar rat. The ulnar nerve of the rat was sectioned and its proximal and distal ends were sutured to either end of a silastic tube, with the aim of encouraging regeneration through the tube. 32 ulnar nerve specimens were randomized into two groups: 18 nerves regenerating under the influence of recombinant growth hormone, and 14 nerves regenerating in its absence. The study was performed over a period of 8 weeks and progression of regeneration was assessed with regular surface electroneurography every 1-2 weeks after surgery. In the group receiving recombinant growth hormone, it comprised a significant improvement in the recovery of conduction velocity, and a more gradual increase in the amplitude of motor potential from the fifth week onwards was observed. Histological analysis of study specimens in the recombinant hormone group revealed an improved architecture of the regenerating nerve, a greater density of nerve fibers, and increased myelination with a lesser degree of endoneural fibrosis. Our work demonstrates the positive effect of the administration of recombinant human growth hormone in obtaining significantly improved conduction velocities, and a greater improvement in nerve regeneration from the fifth week of monitoring when compared to the control group. Histological analysis in the group receiving hormone showed acceptable degree of myelination with little granulation tissue and fibrosis.

Laurin–Sandrow syndrome: Review and redefinition

We report on a newborn infant with characteristics of Laurin–Sandrow syndrome (LSS). She had hypertelorism, flat nose with grooved collumella, “V” shaped mouth with thin lips, 7 well‐recognized and fused digits and 1 additional postaxial bilateral appendix on each hand. The right and left feet had 12 and 11 toes, respectively, the 4 external ones were recognizable, and the rest were fused in a uniform mass but with independent nails. There was also a 2.3 cm‐long digitiform appendix in the internal part of both feet. Radiographs showed seven metacarpals and seven metatarsals with similar morphology; both hands lacking thumbs. The four lateral‐most toes had regular shaped phalanges and the rest were irregular. The left digitiform appendix had three bones and the right only two. Tibiae were shorter than fibulae. Central Nervous System examination showed an abnormally shaped olivary nucleus, cerebellar cortical heterotopias, gray matter ectopias in both spinal cord and hemispheric white matter, marked ventricular dilatation, and moderate diffuse white matter gliosis. Karyotype was 46XX. A complete necropsy study is presented and all reported cases are reviewed focusing on their phenotypic differences and their nosologic classification. We propose the entity LSS only in cases with symmetric tetramelic polysyndactyly, especially cup‐shaped hands and mirror feet, in association with nasal anomalies.

Antitumor Effect of TNP-470 is not Associated to Decrease of Angiogenesis in an Experimental Malignant Neuroectodermic Tumor

The hypothesis that tumor growth depends on neovascularization has been broadly used in oncology research. TNP-470 is a fumagillin synthetic analog that is isolated from Aspergillus fumigatus, and experimental studies suggested that it shows antitumor effect mediated by its strong antiangiogenic effect. Because limited experience exists about the antitumoral effect of TNP-470 in cerebral tumors, we have carried out a study in order to evaluate the effect of TNP-470 on tumor growth and the vascular area in an experimental malignant neuroectodermic tumor growing in the subcutaneous space of immunocompetent Wistar rats. Our results showed a significant tumor growth inhibition in animals treated with TNP-470 when compared to those in the control group (intratumoral injections were administered in 30 mg/kg dose, three times a week on alternate days during four consecutive weeks). Since the quantitative analysis of tumor vascular parameters – number of microvessels and total intratumor vascular area – in the experimental groups did not show significant statistical differences, we conclude that TNP-470 has a significant antitumor effect on our neuroectodermic tumor, but this effect is mediated by other antineoplastic mechanisms that are independent of its previously described angiostatic capacity.

Apoptosis-related proteins are potential markers of neonatal hypoxic-ischemic encephalopathy (HIE) injury.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes high mortality and long-term morbidity rates. The magnitude of the neuronal damage depends on the duration and severity of the initial insult combined with the deleterious effects of reperfusion and apoptosis. Currently, a diagnosis of HIE is based largely on the neurological and histological findings. Therefore, the aim of this study was to identify apoptosis-related proteins that might serve as potential markers of HIE injury. As an initial step toward reaching this objective, we analyzed changes in protein levels in an in vitro model of hypoxia using antibody arrays, and we have identified changes in the expression level of two proteins involved in apoptosis, Smac-DIABLO and cathepsin D. We obtained brain sections from eight neonatal HIE patients and performed histological staining, TUNEL assays and Smac-DIABLO and cathepsin D immunolocalization. Our results revealed a high number of TUNEL-positive cells, including neurons, astrocytes and ependymal cells, in the various regions that were analyzed. Interestingly, many of the areas that were positive for TUNEL staining did not appear to be damaged in the histological evaluation. In addition, using immunostaining, we found that Smac-DIABLO and cathepsin D had the same regional distribution pattern. Taken together, these findings indicate that these two proteins could serve as markers to identify injured regions that might not to be detectable using histological observations alone.