Clinical characteristics of patients with sustained ventricular arrhythmias after sacubitril/valsartan initiation.

Our aim was to describe the clinical profile of patients presenting sustained ventricular arrhythmias after sacubitril/valsartan (SV) initiation. All cases of sustained ventricular arrhythmias in patients receiving SV were consecutively recorded in two centers. Nineteen patients had sustained ventricular arrhythmias after SV. All were men and were previously receiving angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers before SV initiation. Fifteen patients (78.9%) had electrical stability in the previous 6 months. Nine patients (47.4%) initiated SV at the lowest available dose (24/26 mg). Globally, in all but five patients alive at discharge, SV was discontinued after the event. Six patients presented new arrhythmic events after discontinuation of SV. Two deaths and three heart transplants occurred (one due to heart failure and the other two due to persistent ventricular arrhythmias). All patients had a high arrhythmic risk, and 17 (89.5%) had an implanted cardioverter defibrillator. No specific triggers for the arrhythmic event were found. Male sex and previous episodes of ventricular arrhythmias could be associated with an increased risk of sustained ventricular tachycardia after SV initiation. Discontinuation of the drug might be an additional approach to enable a better control of ventricular arrhythmias in some patients.

Influence of total hip arthroplasty and physicians advices in the sports activity performed after the surgery. / Influencia de la artroplastia total de cadera y el consejo médico en la actividad deportiva realizada después de la intervención.

BACKGROUND AND OBJECTIVES: There are no randomized prospective studies that evaluate sports activity after total hip arthroplasty (THA). The objective of this study is to assess the level and type of sports activity in patients undergoing THA and to assess the recommendations given by physicians. MATERIALS AND METHODS: We performed a descriptive study that analyzes 46 patients (the average age was 41 years, range 37 - 48) under 50 years of age who underwent THA (58 hips) in our center. The average follow-up was 7.5 (1 - 11) years. Age, sex, sports activity according to the UCLA scale, sports activities practiced before and after the intervention, complications and recommendations given by doctors were evaluated. RESULTS: The average time to resume sport activity after the surgery was 5 (3-10) months. There were no differences in the UCLA scale before and after the operation (P> 0.05). The most practiced sport before the surgery was swimming (17%). The 31% of patients did not receive advice from their physician and the 65.2% were dissuaded from playing sports after ATC. The recommended sports were swimming (44%) and the static bicycle (17.5%), correlating with the most practiced sports after the operation. CONCLUSION: The patients modified their sport activity after having undergone a total hip arthroplasty. The surgery and the physician's advice were the ones that influenced the choice of the sports activity performed after being operated on.

Structure-composition relationships in ternary solvents containing methylbenzoate.

Thermophysical properties of the hexane+1-chlorohexane (or hexanoic acid or diisopropylether)+methylbenzoate ternary systems and their binary constituents are reported at 298.15 K and 0.1 MPa over the whole composition range. The properties and the optimized geometry of the gas-phase components were appraised from the density functional theory. To find out the causal link between the thermophysical measurements and the molecular level features, the derived mixing and excess functions of the ternary systems were looked into according to the scaled particle and Kirkwood-Buff analyses. The hydrogen bonding and dipole interactions along with the geometry effects brought about by the very different size and shape of the components give rise to complex mixed structures. Application of semiempirical models and use of simple cubic equations of state combined with a one-parameter van der Waals mixing rule has led to prediction of the ternary properties with variable degree of precision.

Techniques used to identify the Brazilian variant of HIV-1 subtype B.

The purpose of the present study was to compare the sensitivity and specificity of V3 enzyme immunoassay (solid phase EIA and EIA inhibition) and restriction fragment length polymorphism (RFLP) with the DNA sequencing "gold standard" to identify the Brazilian HIV-1 variants of subtype B and B"-GWGR. Peripheral blood mononuclear cells were collected from 61 HIV-1-infected individuals attending a clinic in São Paulo. Proviral DNA was amplified and sequentially cleaved with the Fok I restriction enzyme. Plasma samples were submitted to a V3-loop biotinylated synthetic peptide EIA. Direct partial DNA sequencing of the env gene was performed on all samples. Based on EIA results, the sensitivity for detecting B-GPGR was 70%, compared to 64% for the Brazilian variant B"-GWGR while, the specificity of B-GPGR detection was 85%, compared to 88% for GWGR. The assessment of RFLP revealed 68% sensitivity and 94% specificity for the B-GPGR strain compared to 84 and 90% for the B"-GWGR variant. Moreover, direct DNA sequencing was able to detect different base sequences corresponding to amino acid sequences at the tip of the V3 loop in 22 patients. These results show a similar performance of V3 serology and RLFP in identifying the Brazilian variant GWGR. However, V3 peptide serology may give indeterminate results. Therefore, we suggest that V3 serology be used instead of DNA sequencing where resources are limited. Samples giving indeterminate results by V3 peptide serology should be analyzed by direct DNA sequencing to distinguish between B-GPGR and the Brazilian variant B"-GWGR.

Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption.

Angiogenesis inhibitor TNP-470, 6-O-(N-chloroacetyl-carbamoyl)-fumagillol, semisynthetic analogue of fumagillin, has strong inhibitory activities against in vivo tumor growth and metastasis in a wide variety of tumors. However, it is still unknown whether this agent inhibits bone metastasis. We examined the effects of TNP-470 in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-MB-231 (MDA-231) produced osteolytic bone metastasis. After inoculation of MDA-231 cells into the left heart ventricle, TNP-470 (30 mg/kg, three times a week) or PBS was s.c. administrated for 4 weeks. After this period, the TNP-470 had reduced not only the number and area of osteolytic bone metastases (approximately 60 and 70%, respectively) but also their radiolucency. Histological examination of the femurs of the untreated group revealed that most of the cancellous bone had been replaced by the metastatic cancer. Numerous active osteoclasts were present along the trabecular bone surface surrounded by the metastatic MDA-231 cancer cells aggressively invading the bone marrow. In contrast, in the bone from TNP-470-treated mice, bone destruction was markedly inhibited, and there were much fewer osteoclasts. In a murine bone marrow culture under 1,25-dihydroxyvitamin D3 in which mature functional osteoclasts formed in vitro, TNP-470 significantly inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells. And also, TNP-470 suppressed the in vivo bone resorption in calvaria treated with interleukin-1beta, an osteoclast stimulator. These data suggested that TNP-470 inhibited bone metastasis through not only antitumor action by its angiogenesis inhibition but also by the inhibition of osteoclastic bone resorption. Our results indicate that TNP-470 should be a potentially beneficial drug to be used in the treatment of osteolytic metastasis.

Characterization and preferential solvation of the hexane/hexan-1-ol/methylbenzoate ternary solvent.

The thermophysical properties of the hexane/hexan-1-ol/methylbenzoate ternary system and its binary constituents were studied at 298.15 K over the whole composition range. The excess and mixing properties calculated from the experimental values combined with the mixture activity coefficients deduced from the UNIFAC group contribution method were used to calculate the integrals of the Kirkwood-Buff fluctuation theory for the ternary system and the binary constituents. Also the local composition and the excess or deficit number of molecules around a central molecule have been determined. The volumetric properties for the ternary system and its binary constituents were correlated and predicted successfully with several cubic equations of state combined with two simple mixing rules. The structural and intermolecular interactions of the mixtures were analyzed on the basis of the measured and derived properties.

Extracellular matrices expression in invasion area of adenoid cystic carcinoma of salivary glands.

Adenoid cystic carcinoma (ACC) is a salivary malignant tumor with poor long-term prognosis, that is known to have predilection for invasion of the adjacent stroma and neural tissues. This carcinoma has shown a high incidence of recurrence and distal metastasis. Invasive carcinomas have been associated with the distributions of extracellular matrices (ECM). Cell proliferation as a marker of tumor growth has been related to poor prognosis in oral carcinomas. Immunohistochemical analysis of 15 cases of ACC was done using antibodies to laminin, type IV collagen, fibronectin, tenascin and anti-proliferating nuclear antigen (PCNA). Laminin and type IV collagen were totally or partially absent in the ACC invasive areas. Tenascin was expressed in the stroma and cytoplasm and was associated with tumor cell proliferation. It can be concluded that basement membrane represents a barrier that is lost during cell invasion and tenascin may be involved in the detachment of cancer cells, increasing the invasive potential of ACC.

Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma.

Immunohistochemical analysis of erbB3, as the third member of epidermal growth factor receptor gene family, was performed on 41 cases of oral squamous cell carcinoma, correlating the staining pattern with clinical outcome. High expression of erbB3 protein (ERBB3) was significantly associated with lymph node metastasis (P < 0.05), survival rate (P < 0.05) and mode of invasion (P < 0.01) in this series. These results demonstrated that ERBB3 expression may be helpful in identifying those oral squamous cell carcinomas with higher malignant potential.

Sequential expression of myc-, ras-, oncogene products and EGF receptor during DMBA-induced tongue carcinogenesis.

The mechanism leading to development of oral cancer has not been completely understood. It is currently believed that alternation of a number of genes can result in the development of epidermoid carcinomas. In this investigation, we used a 9,10-dimethyl 1,2-benzanthracene (DMBA)-induced carcinogenesis in a hamster tongue model to investigate the expression of c-myc, c-Ha-ms proteins and epidermal growth factor receptor (EGFr). During the DMBA-carcinogenesis of the tongue, the number of c-myc protein positive cells were increased in epithelial dysplasia and elevated throughout the process of tumorigenesis. The expression of c-Ha-ras protein was detected in normal epithelium. The level of c-Ha-ras protein expression was decreased in the dysplastic stage, and it was almost negative in squamous cell carcinomas. Detection of EGFr overexpression occurred only after 1-4 weeks of DMBA treatment, at a very early stage of tumor development, and increased through carcinogenesis varying individually within the malignant tissues. These results suggest that c-myc protein and c-Ha-ras protein expression may have an important role in malignant transformation, and the overexpression of EGFr can be correlated to very early stages of tumor development in the DMBA-induced in vivo tongue carcinogenesis.

The role of caspase family protease, caspase-3 on cisplatin-induced apoptosis in cisplatin-resistant A431 cell line.

PURPOSE: Cisplatin (cis-diamminedichloro-platinum(II), CDDP) has been reported to induce apoptosis in cancer cells. the mechanism of the apoptosis in cancer cells induced by CDDP is still unclear. Recent studies have revealed that caspase family of cystine proteases play an important role in the regulation of several apoptotic processes. In this study, whether apoptosis induced by CDDP could be mediated by the activation of caspase-3, a caspase family protease, was investigated. METHODS: The CDDP-resistant subline A431/CDDP2 from the previously established human epidermoid carcinoma cell line A431 was used. The parent A431 cells (A431/P) and the A431/CDDP2 were exposed to CDDP with or without a caspase family protease inhibitor (Z-Asp-CH2-DCB), and cellular sensitivity to CDDP was determined. DNA fragmentation was then analyzed, and the caspase-3 protein levels determined by Western blotting following exposure of the cells to CDDP with or without Z-Asp-CH2-DCB. RESULTS: In the A431/P cells, the cytotoxicity of CDDP was clearly reduced by Z-Asp-CH2-DCB compared with its cytotoxicity in A431/CDDP2 cells. Furthermore, quantitative analysis of DNA fragmentation revealed that Z-Asp-CH2-DCB inhibited DNA fragmentation induced by CDDP in A431/P cells, but not in A431/CDDP2 cells. Western blotting analysis demonstrated a marked reduction in procaspase-3 protein levels in A431/P cells treated with Z-Asp-CH2-DCB. In the A431/CDDP2 cells, procaspase-3 protein levels were no different with and without Z-Asp-CH2-DCB. CONCLUSIONS: These findings suggest that caspase-3 may mediate apoptosis induced by CDDP, and its induction could represent a novel approach to the effective treatment of malignant tumors.

The influence of blood arterial oxygen condition on the tumor response to preoperative radiation therapy in oral cancer patients.

The relationship between clinicopathological factors and response of radiation therapy in oral squamous cell carcinoma has been studied. It has been suggested that factors such as tumor site, extent and tumor differentiation determine the response to radiation therapy. It is known that oxygenation is related to the therapeutic effects of radiation therapy. However, there are few reports on the relationship between oxygen condition and the response to radiation therapy. The present study was carried out to assess whether any clinicopathological factors, including an evaluation of the oxygen condition can be used to predict the effects of preoperative radiation therapy in oral squamous cell carcinomas. Forty-seven patients with oral cancer treated with external radiation therapy preoperatively were evaluated. There were no significant differences in response to the radiation with respect to age, sex, tumor site, stage, macroscopic shape of tumors, and the histological factors. The hemoglobin (Hb) and arterial oxygen content (CaO(2)) levels of favorable cases (Hb: 14.4 g/dl, CaO(2) 19.1 ml/dl) were significantly higher than those of unfavorable cases (Hb: 11.0 g/dl, CaO(2): 16.1 ml/dl). These findings suggest that oxygen conditions of oral cancer patients predict tumor response to preoperative radiation therapy.

Effects of bisphosphonate on experimental jaw metastasis model in nude mice.

The mechanism of osteolysis associated with metastatic cancer of the jaws is essentially osteoclast-mediated. Therefore, it is likely that potent osteoclastic bone resorption inhibitors such as bisphosphonates would be efficacious for the treatment of jaw metastasis. We examined the effects of a third generation bisphosphonate, YM175, in a nude mice jaw metastasis model with intracardiac injection of a human breast cancer cell line, MDA-MB-231. The metastatic lesions in untreated mice were radiographically observed at the body and angle of the mandible. Histology of the mandible of untreated mice revealed that most of the bone marrow cavities had been occupied by the metastatic tumor with active osteoclasts along the trabecular bone. The experimental group showed that YM175 markedly reduced the size of tumor and the number of osteoclasts. These results suggest that YM175 may suppress metastasis formation and tumor growth in jaw through inhibition of osteoclastic bone resorption.

Cell proliferation and tumor angiogenesis in oral squamous cell carcinoma.

Cell proliferation and vascularization play an important role in the metabolic functions of normal and malignant tissues. Tumor cell proliferation and density of microvessels (DM) in 33 specimens of oral squamous cell carcinoma (SCC) were assessed by immunohistochemical staining of proliferating nuclear cell antigen (PCNA) and JC/70A, respectively. Their staining patterns were compared to the clinicopathologic findings. The PCNA labeling index (LI) showed significantly higher values in advanced carcinomas (T3 and T4) (mean, 20.19 +/- 12.79) than in early carcinomas (T1 and T2) (mean, 9.58 +/- 4.01; P < 0.01). The DM (mean, 105.92 +/- 22.65) and PCNA LI (mean, 25.69 +/- 13.32) of tumors with lymph node metastasis were significantly higher than in tumors without nodal involvement (DM, mean, 72.6 +/- 24.30; P < 0.01) (PCNA LI, mean, 10.25 +/- 3.99; P < 0.001). Marginal DM values were significantly correlated and directly proportional to the mode of tumor invasion. Evaluation of PCNA and DM at the periphery of the tumor may help to identify oral SCC that have higher malignant potential.

Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study.

The tyrosine kinase receptor family, including the epidermal growth factor receptor (EGF-R), c-erbB2 and, more recently, the c-erbB3, has been recognized as being of particular importance in many human malignancies. This study was undertaken to define the role of c-erb B2 and c-erbB3 in adenoid cystic carcinomas (A.C.C.) of the salivary glands. Sixteen cases of A.C.C. were studied immunohistochemically, using antibodies against each erbB gene family product. EGF-R was not detected in any of these samples but c-erbB2 and c-erbB3 gene products (ERBB2and ERBB3) were demonstrated in all A.C.C. sections with some degree of straining. Tubular and cribriform patterns overexpressed particularly large amounts of ERBB2 and ERBB3. Strong staining was mainly demonstrated in tumor cells of the invasive area. These results suggested that overexpression of ERBB2 and ERBB3 is related to tumor differentiation and invasion in adenoid cystic carcinomas.

Experimental bone metastasis model of the oral and maxillofacial region.

Metastasis of the oral and maxillofacial region frequently causes serious morbidity. Despite the importance of the clinical problem, little is known about the pathophysiological mechanisms of this metastatic process. Therefore, we examined whether the intracardiac injection of human breast cancer cells reproductively leads to jaw metastases developing an adequate experimental model. Human breast cancer MDA-MB-231 (MDA-231) cells (1 x 10(5)) were injected into the left heart ventricle of 4-week-old, female nude mice. Jaw metastases were examined radiographically and histologically 4 weeks after the cancer cell inoculation. At this time, the nude mice showed a marked body weight loss and cachexia. Osteolytic bone metastases were commonly observed in limbs, vertebral bone, pelvis and scapulae. In maxillofacial bones, breast cancer cells metastasized in 11 of 12 nude mice (91.7%). The lesions were radiographically determined at the mandible (11/12), maxilla (8/12) and zygomatic arch (2/12). Metastasis frequently occurred at the molar and angle regions of the mandible and at the palatal suture as well as around the root of the incisal teeth of the maxilla respectively. Histological examination revealed that numerous osteoclasts were present along the trabecular bone surfaces with aggressive bone resorption. This experimental model may be useful not only for the investigation of the mechanism of jaw metastasis formation but also for the screening of potential therapeutic agents for osteolytic bone metastasis.

Heavy metals in the vicinity of a chlor-alkali factory in the Upper Negro River ecosystem, Northern Patagonia, Argentina.

A study on heavy metal contents was performed in sediments and biota of the Upper Negro River (Alto Valle) aquatic system, Northern Patagonia, Argentina. The irrigation system of the Neuquén and Negro Rivers runs alongside these rivers for 150 km, supporting intensive agricultural and economical activities, mainly related to fruit production. A mercury cell chlor-alkali factory operated between 1951 and 1995. Close attention was given to the surroundings of the plant, located next to the Main Irrigation Channel, and to the PII drainage channel which received the plant's effluents between 1951 and 1979. From 1979 until its closure, the effluents were pumped above a ravine to a series of evaporation and decantation pools. Mercury and other heavy metals and metalloids (Ag, As, Ba, Co, Cr, Cs, Ni, Sb, Se, U and Zn) contents were measured for bottom sediments of the river and irrigation and drainage channels, for two widespread species of macrophytes (Potamogeton pectinatus and Myriophyllum brasiliensi), and for liver and muscle of native fish Odontesthes microlepidotus. River bed sediments show no evidence of heavy metal accumulation, however, biota might indicate that contaminants are entering the rivers. Mercury was the only element accumulated in the Main Irrigation channel sediments, the highest contents occurring in the surroundings of the nowadays shut-down chlor-alkali plant, returning to background values approximately 40 km downstream the plant. At the plant site, sediments from the center of the channel showed a decrease in Hg content in the upper 10 cm layer, ranging from 0.8 to 3.4 microg g(-1), and from 2.8 to 13.7 microg g(-1) in the next 10 cm lower layer. Conversely, the PII drainage channel sediments showed accumulation of Hg (2-4 microg g(-1)), distributed uniformly at different depths and along the channel, until its mouth at Negro river. Mercury contents of macrophytes downstream the chlor-alkali plant are higher than the baseline for the area, and macrophytes and fish liver from the PII drainage channel present the highest content in this element. The drainage channel system showed different degrees of impact, those channels flowing through densely populated areas being the most affected.

Influencia de la artroplastia total de cadera y el consejo médico en la actividad deportiva realizada después de la intervención / Influence of total hip arthroplasty and physicians advices in the sports activity performed after the surgery

ANTECEDENTES Y OBJETIVOS: No hay estudios prospectivos aleatorizados que evalúen la actividad deportiva tras una artroplastia total de cadera (ATC). El objetivo de este estudio es evaluar el nivel y el tipo de actividad deportiva en pacientes intervenidos de ATC y valorar las recomendaciones dadas por los médicos. MATERIALES Y MÉTODOS: Estudio descriptivo que analiza a 46 pacientes (edad media 41 años, rango 37-48) menores de 50 años que fueron intervenidos de ATC (58 caderas) en nuestro centro. El seguimiento medio fue 7,5 (1-11) años. Se evaluó la edad, el sexo, la actividad deportiva según la escala UCLA, las actividades deportivas practicadas antes y después de la intervención, las complicaciones y las recomendaciones dadas por los médicos. RESULTADOS: La media del tiempo para retomar la actividad deportiva tras la intervención fue de 5 (3-10) meses. No hubo diferencias en la escala UCLA antes y después de la intervención (p > 0,05). El deporte más practicado antes de la intervención fue la natación (17%). El 31% de los pacientes no recibió consejos de su médico y el 65,2% fue disuadido de realizar deporte tras la ATC. Los deportes aconsejados fueron la natación (44%) y la bicicleta estática (17,5%), correlacionándose con los deportes más practicados tras la intervención. CONCLUSIÓN: Los pacientes modificaron su actividad deportiva tras ser intervenidos de ATC, siendo la propia intervención y el consejo del médico los que influyeron en la elección de la actividad deportiva realizada tras ser intervenido

BACKGROUND AND OBJECTIVES: There are no randomized prospective studies that evaluate sports activity after total hip arthroplasty (THA). The objective of this study is to assess the level and type of sports activity in patients undergoing THA and to assess the recommendations given by physicians. MATERIALS AND METHODS: We performed a descriptive study that analyzes 46 patients (the average age was 41 years, range 37 - 48) under 50 years of age who underwent THA (58 hips) in our center. The average follow-up was 7.5 (1 - 11) years. Age, sex, sports activity according to the UCLA scale, sports activities practiced before and after the intervention, complications and recommendations given by doctors were evaluated. RESULTS: The average time to resume sport activity after the surgery was 5 (3-10) months. There were no differences in the UCLA scale before and after the operation (P> 0.05). The most practiced sport before the surgery was swimming (17%). The 31% of patients did not receive advice from their physician and the 65.2% were dissuaded from playing sports after ATC. The recommended sports were swimming (44%) and the static bicycle (17.5%), correlating with the most practiced sports after the operation. CONCLUSION: The patients modified their sport activity after having undergone a total hip arthroplasty. The surgery and the physician's advice were the ones that influenced the choice of the sports activity performed after being operated on

Angiogenesis and expression of platelet-derived endothelial cell growth factor in oral squamous cell carcinoma.

It has been demonstrated that angiogenesis is required in the process of tumor progression and metastasis. Microvessel density (MVD) estimates tumor angiogenesis and is an independent indicator for predicting tumor metastasis in a variety of carcinomas. Platelet-derived endothelial cell growth factor (PD-ECGF) is known to be an angiogenic factor in vitro and in vivo. Of 55 patients with oral squamous cell carcinoma (OSCC), regional metastasis was absent in 35 and present in 20. Cases with lymph node metastasis showed significantly higher MVD (mean 61.0 +/- 28.8) than those without metastasis (mean 29.3 +/- 15.1; p < 0.001). A total of 37 cases (67.3%) were PD-ECGF-positive with a high MVD (mean 47.8 +/- 27.9) and 18 (32.7%) showed a negative PD-ECGF expression with a low MVD (mean 26.6 +/- 13.2). PD-ECGF expression was significantly correlated with the increment of MVD (p < 0.01). We suggest that MVD can be used as an independent prognostic indicator for predicting metastasis and that PD-ECGF activity plays an important role in the neovascularization of OSCC.

Immunohistochemical analysis of nucleoside diphosphate kinases in oral squamous cell carcinomas.

The nm23 gene is a potential metastasis suppressor gene originally identified using a murine melanoma cell line. The nm23 proteins are nucleoside diphosphate (NDP) kinases, and there are two isotypes in human and other mammalian cells. Immunohistochemical analysis with anti-rat NDP kinase (NDP kinase alpha, NDP kinase beta) monoclonal antibodies was performed in deparaffinized sections of 56 specimens of oral squamous cell carcinoma. Detection of these NDP kinases in tissue samples was correlated with clinical and histopathological factors. The NDP kinase A (nm23 H1 protein)-positive group was apt to have a lower frequency of neck metastasis than the negative one (p < 0.01). Consequently, it is suggested that NDP kinase A might be a metastasis suppressor factor that may be useful for predicting tumor metastases in patients with oral squamous cell carcinoma.