Cyclooxygenase-1 is involved in endothelial dysfunction of mesenteric small arteries from angiotensin II-infused mice

Angiotensin II induces endothelial dysfunction by reducing NO availability and increasing reactive oxygen species. We assessed whether cyclooxygenase (COX)-1 or COX-2 participate in the angiotensin II-induced endothelial dysfunction in murine mesenteric small arteries and examined the role of reduced nicotinamide-adenine dinucleotide phosphate-dependent reactive oxygen species production. Mice received angiotensin II (600 ng/kg per minute, SC), saline (controls), angiotensin II + apocynin (reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, 2.5 mg/day), or apocynin alone for 2 weeks. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In controls, acetylcholine-induced relaxation was inhibited by NG-monomethyl-L-arginine and unaffected by DFU (COX-2 inhibitor), SC-560 (COX-1 inhibitor), or ascorbic acid. In angiotensin II-infused animals, the attenuated response to acetylcholine was less sensitive to NG-monomethyl-L-arginine, unaffected by DFU, and enhanced by SC-560 and, similarly, by SQ-29548, a thromboxane-prostanoid receptor antagonist. Moreover, response to acetylcholine was unchanged by ozagrel, a thromboxane synthase inhibitor, and normalized by ascorbic acid. Apocynin prevented the angiotensin II-induced vascular dysfunctions. In angiotensin II-infused mice, RT-PCR analysis showed a significant COX-2 downregulation, whereas COX-1 expression was upregulated. These changes were unaffected by apocynin. Modulation of COX isoform by angiotensin II was also documented by immunohistochemistry. In small mesenteric vessels, the reduced NO availability and oxidant excess, which characterize endothelial dysfunction secondary to angiotensin II, are associated with a reduced COX-2 and an increased COX-1 function and expression. Angiotensin II causes an oxidative stress-independent COX-1 overexpression, whereas angiotensin II-mediated oxidant excess production stimulates COX-1 activity to produce a contracting prostanoid endowed with agonist activity on thromboxane-prostanoid receptors.     

Mild ocular myopathy associated with a novel mutation in mitochondrial twinkle helicase

Autosomal dominant PEO is associated with mutations in a number of nuclear genes affecting the intergenomic communication with mitochondrial DNA. We report a Spanish family showing a mild phenotype characterized by autosomal dominant ocular myopathy and morphological signs of mitochondrial dysfunction, that harboured a novel c.1071G>C (p.R357P) mutation in the hot-spot linker region of the twinkle protein.     

A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form

Background  

More than 90% of Congenital Adrenal Hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the HLA class III area on the short arm of chromosome 6p21.3. In this region, a 30 kb deletion produces a non functional chimeric gene with its 5' and 3' ends corresponding to CYP21A1P pseudogene and CYP21A2, respectively. To date, five different CYP21A1P/CYP21A2 chimeric genes have been found and characterized in recent studies. In this paper, we describe a new CYP21A1P/CYP21A2 chimera (CH-6) found in an Italian CAH patient.     

Uterine and ovarian carcinosarcomas overexpressing Trop-2 are sensitive to hRS7, a humanized anti-Trop-2 antibody

Background

We evaluated the expression of human trophoblastic cell-surface marker (Trop-2) and the potential of hRS7 - a humanized monoclonal anti-Trop-2 antibody - as a therapeutic strategy against treatment-refractory human uterine (UMMT) and ovarian (OMMT) carcinosarcoma cell lines.

Materials and methods

Trop-2 expression was evaluated by immunohistochemistry (IHC) in paraffin-embedded tumor tissues, by real-time polymerase-chain-reaction (RT-PCR) and flow-cytometry in cell lines. Sensitivity to hRS7 antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested using 5-hour chromium-release assays against UMMT and OMMT cells.

Results

Trop-2 expression was elevated in 9 of 26 (35%) UMMT and 8 of 14 (57%) OMMT tissues tested by IHC. Positivity for Trop-2 mRNA by RT-PCR and surface expression by flow cytometry were detected in 2 of 4 cell lines, with high positivity noted in OMMT-ARK-2. OMMT-ARK-2 was highly sensitive to hRS7 ADCC (range: 34.7-41.0%; P < 0.001) with negligible cytotoxicity seen in the absence of hRS7 or in the presence of control antibody (range: 1.1-2.5%). Human IgG did not significantly inhibit ADCC while human complement increased, hRS7-mediated-cytotoxicity against OMMT-ARK-2.

Conclusion

Trop-2 is overexpressed in a proportion of UMMT and OMMT, and hRS7 may represent a novel, potentially highly effective treatment option for patients with treatment-refractory carcinosarcomas overexpressing Trop-2.     

Función familiar y salud mental del cuidador de familiares con dependencia

ObjectiveTo analyse the influence of family function on the caregiver's perceived mental health.DesignCross-sectional study.SettingTwo primary care urban health centres.Participants153 caregivers of dependent people.MeasurementSociodemographic variables of caregiver and dependent relative and psychoactive drugs prescribed to caregiver. Caregiver questionnaires: mental health evaluated with General Health Questionnaire (GHQ-12), family function with adaptation, partnership, growth, affection and resolve (APGAR), and Duke University-University of North Carolina functional social support questionnaire. Care-recipient questionnaires: cognitive disorders with Pfeiffer and functional dependence level with Barthel.ResultsCaregiver's mean age was 63.8 years; 72.5% (n=111) were female; 57.5% have only primary school studies; and 37.1% take psychoactive drugs. More than 40% of the care-receivers have cognitive disorders and 49.7% have total functional impairment. According to the GHQ-12, 27% of the caregivers had mental health disorders; 31.3% of the families were dysfunctional and 32.7% had poor social support. The variables that significantly contributed to the explanation of caregiver's mental health have been: psychoactive drug intake, family function, social support and educational level.ConclusionFamily function is an important predictor of caregiver's mental health.     

On the construction of an inter-subject diffusion tensor magnetic resonance atlas of the healthy human brain

Voxel based morphometry (VBM) has been increasingly applied to detect diffusion tensor (DT) image abnormalities in patients for different pathologies. An important requisite for a robust VBM analysis is the availability of a high-dimensional non-rigid coregistration technique that is able to align both the spatial and the orientational DT information. Consequently, there is a need for an inter-subject DTI atlas as a group specific reference frame that also contains this orientational DT information. In this work, a population based DTI atlas has been developed that incorporates such orientational DT information with high accuracy and precision. The proposed methodology for constructing such an atlas is compared with a subject based DTI atlas, in which a single subject is selected as the reference image. Our results demonstrate that the population based atlas framework is more accurate with respect to the underlying diffusion information.     

Proposal for reclassification of the TNM staging system in patients with locally advanced (pT3-4) renal cell carcinoma according to the cancer-related outcome

OBJECTIVES: The optimal stratification of locally advanced renal cell carcinoma (RCC) is controversial, with the prognostic relevance of ipsilateral adrenal gland invasion and cranial extension of vena cava thrombosis being the most debatable issues. We evaluated the prognosis of patients with locally advanced RCC and identified a new model to stratify their outcome. MATERIALS AND METHODS: We analyzed the data of 227 patients who had undergone partial or radical nephrectomy for pT3-4 RCC at two academic centers between 1986 and 2002. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analysis, respectively. RESULTS: At a median follow-up of 29 mo, we censored 108 (47.6%) cancer-related deaths. On univariate analysis, the 2002 T stage was not statistically significant. According to cancer-related outcome, we identified three subgroups of patients with different prognoses: pT3a(n): tumors with perirenal fat invasion or renal vein thrombosis or thrombosis within the vena cava below the diaphragm; pT3b(n): tumors with renal vein thrombosis or thrombosis within the vena cava below the diaphragm and concomitant perirenal fat invasion; pT4(n): adrenal gland or Gerota fascia invasion or thrombosis within the vena cava above the diaphragm. The three subgroups had significantly different prognoses. The new reclassification was an independent predictive variable on multivariate analysis, as well as the pathologic lymph node stage. CONCLUSIONS: The 2002 version of TNM of locally advanced RCC did not stratify patient outcome. The present study suggests the possibility of reclassifying pT3-4 RCC into three categories capable of predicting cancer-specific survival, regardless of all other prognostic factors.