Do the cardiovascular effects of angiotensin-converting enzyme (ACE) I involve ACE-independent mechanisms? new insights from proline-rich peptides of Bothrops jararaca

Angiotensin-converting enzyme (ACE) inhibitors were developed based on proline-rich oligopeptides found in the venom of Bothrops jararaca (Bj) previously known as bradykinin-potentiating peptides (BPPs). However, the exact mechanism of action of BPPs remains unclear. The role of the ACE in the cardiovascular effects of two of naturally proline-rich oligopeptides (Bj-BPP-7a and Bj-BPP-10c) was evaluated in vitro and in vivo. Bj-BPP-7a does not potentiate the cardiovascular response to bradykinin and is a weak inhibitor of ACE C and N sites (K(i) = 40,000 and 70,000 nM, respectively), whereas Bj-BPP-10c is a strong bradykinin potentiator and inhibitor of the ACE C site (K(i) = 0.5 versus 200 nM for N site). Strikingly, both peptides, in doses ranging from 0.47 to 71 nmol/kg, produced long-lasting reduction (>6 h) in the mean arterial pressure of conscious spontaneously hypertensive rats (maximal change, 45 +/- 6 and 53 +/- 6 mm Hg for Bj-BPP-7a and Bj-BPP-10c, respectively). The fall in blood pressure was accompanied by variable degrees of bradycardia. In keeping with the absence of relationship between ACE-inhibitory and antihypertensive activities, no changes in the pressor effect of angiotensin I or in the hypotensive effect of bradykinin were observed at the peak of the cardiovascular effects of both peptides. Our results indicate that the antihypertensive effect of two Bj-BPPs containing the motif Ile-Pro-Pro is unrelated to their ability for inhibiting ACE or potentiating bradykinin (BK), indicating as a major component ACE and BK-independent mechanisms. These results are in line with previous observations suggesting ACE inhibition-independent mechanisms for angiotensin I-converting enzyme inhibitor.     

Dying at home for terminal cancer patients: differences by level of education and municipality of residence in Spain

ObjectiveTo measure and assess differences by educational level in the place of death for cancer patients, and to determine whether patterns of geographical disparities are associated with access to palliative care services in the municipality of residence.MethodWe analysed the death certificates of adults (older than 24) who died of cancer (ICD-10 C00 to C97) in Spain during 2015, either at home, in hospital or in a long-term care centre. Of the 105,758 individuals included in the study population, 75.2% lived in one of the 746 identifiable municipalities (more than 10,000 inhabitants). This individual database was combined with three economic databases at municipal level and with a directory of palliative care resources published by the Sociedad Española de Cuidados Paliativos. Multilevel models were estimated to predict the place of death according to individual characteristics. Generalised least squares regression models were then applied to the municipal effects estimated in the first stage.ResultsThe probability of dying in long-term care centre decreases as levels of education increase; the probability of dying at home, rather than in hospital, is higher for patients with higher education. Dying in hospital is an urban phenomenon. There are large differences between Spanish regions. Access to palliative services is only of marginal significance in accounting for the systematic differences observed between municipalities.ConclusionsDeveloping specific plans for palliative care, with an active role being played by primary care teams, may help improve end-of-life care in Spain.     

The relationship between body mass index and body fat percentage and periodontal status in Mexican adolescents

Objective. To assess the association between obesity indicators and the periodontal status of high school students. Materials and methods. High school students (15-year-olds) in Mexico City participated in the survey (n = 257). International Obesity Task Force cut-off values (ISO-BMI) were applied to identify overweight and obesity. Also, bioelectrical impedance analysis was performed to estimate body fat percentage (BF%). The simplified detritus index (DI-S) was used to evaluate oral hygiene. The periodontal community index (CPI) was obtained to assess the periodontal status of the participants. Results. Overweight/obesity was identified in 30.0% of the students. BF% was 37.5% in women and 21.2% in men and 16.7% of the participants smoked and 33.5% of the students presented DI-S >1. Based on CPI, 59.5% of the participants showed good periodontal status (CPI = 0); bleeding on probing without further periodontal involvement was found in 13.6% of the participants (CPI = 1), 23.8% showed a CPI = 2 (dental calculus) and a CPI = 3 (shallow periodontal pockets) was detected in 3.1% of the participants. The results of the multinomial logistical regression model fitting CPI ≥2 identified an association BF% (OR = 1.06), having poor oral hygiene (OR = 20.09) and smoking (OR = 2.49). Similarly, overweight/obesity was associated with CPI ≥2 (OR = 1.78) adjusting for school attended (public school OR = 0.35), oral hygiene (DI-S >1, OR = 23.92) and tobacco consumption (smoker OR = 1.81). Conclusions. Excess body fat indicators were associated with bleeding on probing and dental calculus in adolescents. The relationship between overweight/obesity and periodontal status in adolescents should be considered in oral health preventive programs.     

Comparison between embossed digital imaging and unprocessed film-based radiography in detecting periodontal bone defects: an in vitro study

Objectives

Our aim was to compare bone-loss measurements between embossed digital radiographic imaging and unprocessed film-based radiography.

Methods

Forty two-wall bone defects were made in the proximal region of the premolar in dry pig mandibles. Digital and conventional radiographs were taken using a Schick sensor and Kodak InSight F-speed intraoral dental film stabilized by a fixing device. Image manipulation was done using Adobe Photoshop 7.0 software with an embossing tool. Four trained examiners made all the radiographic measurements in millimeters a total of three times??from the cementoenamel junction to the most apical extension of the bone loss??with both types of imaging (embossed digital and unprocessed film). As a gold standard, the measurements were also made in dry mandibles using a periodontal probe and digital caliper. Analysis of variance was applied to compare the measurements with both types of imaging and from the dry mandibles. The level of significance was 0.05 for a 95?% confidence interval.

Results

The mean values of the measurements for embossed digital imaging, unprocessed film-based imaging, and visual measurement in the dry mandible were, respectively, 5.91, 6.62, and 6.67?mm. There was a statistically significant difference among the three methods (p?=?0.007). Tukey??s post hoc analysis indicated a similarity between the mean values for unprocessed film-based imaging and dry mandible measurement, but not with embossed imaging.

Conclusions

Bone-loss measurement using embossed digital imaging was inferior to unprocessed film-based imaging, and it underestimated the amount of bone loss.     

Differential CB1 and CB2 cannabinoid receptor-inotropic response of rat isolated atria: endogenous signal transduction pathways

In this study, we have determined the contractile effects of CB1 and CB2 cannabinoid receptor activation on rat isolated atria and the different signaling pathways involved. Anandamide did not has significantly effect on atria contractility, however, the treatment with both CB1 (AM251) or CB2 (AM630) receptor antagonists, the endocannabinoids triggered stimulation or inhibition on contractility respectively. The ACEA stimulation of CB1 receptor exerted decrease on contractility, that significantly correlated with the decrement of cAMP and the stimulation of nitric oxide synthase (NOS) and the accumulation of cyclic GMP (cGMP). On the contrary, JWH 015 stimulation of CB2 receptor triggered positive contractile response that significantly correlated with the increase cAMP production. The inhibiton of adenylate cyclase activity impaired the JWH 015 activation of CB1 receptor induced positive contractile effect, while inhibitors of phospholipase C (PLC), NOS and soluble nitric oxide (NO)-sensitive guanylate cyclase blocked the dose-response curves of ACEA on contractility. Those inhibitors also attenuated the CB1 receptor-dependent increase in activation of NOS and cGMP accumulation. These results suggest that CB2 receptor agonist mediated positive contractile effect associated with increased production on cAMP while CB1 receptor agonist mediated decrease on contractility associated with decreased cAMP accumulation and increase production of NO and cGMP; that occur secondarily to stimulation of PLC, NOS and soluble guanylate cyclase. Data give pharmacological evidence for the existence of functional CB1 and CB2 cannabinoid receptors in rat isolated atria and may contribute to a better understanding the effects of cannabinoids in the cardiovascular system.     

In vitro induction of apoptosis and in vivo effects of a flavone nitroderivative in murine mammary adenocarcinoma cells

We explored the in vitro and in vivo mechanism of antitumor action of the synthetic flavonoid 2′‐nitroflavone on LM3 murine mammary adenocarcinoma cells. In vitro assays showed that 2′‐nitroflavone increased the population of LM3 hypodiploid cells and produced a typical ladder of DNA fragmentation. Apoptotic cell death was also characterized by the activation of caspase‐8, ‐9 and ‐3, by an increment in the expression levels of the proapoptotic protein Bax and by the release of cytochrome c to cytosol. The in vivo effect of 2′‐nitroflavone on tumor growth was studied in BALB/c mice injected subcutaneously with LM3 cells. Results showed that tumor volume and weight were significantly reduced at doses of 10 and 40 mg/kg of 2′‐nitroflavone, respectively. Apoptotic cells were identified by TUNEL assay in tumor slices from mice treated with 10 mg/kg of 2′‐nitroflavone. Western blot analysis of tumor lysate supernatants from treated mice revealed an upregulation of the total levels of Bax and Fas receptor. In addition, administration of 40 mg/kg of 2′‐nitroflavone to nontumor‐bearing mice showed no histopathological effects on different organ tissues. This is the first report of the in vivo growth inhibitory effect of 2′‐nitroflavone as an apoptotic agent likely useful for mammary adenocarcinoma treatment. © 2009 UICC     

Necrotizing Fasciitis of the Skull Base and Neck in a Patient with AIDS and Non-Hodgkin's Lymphoma.

Necrotizing fasciitis is a rapidly progressing, life-threatening soft tissue bacterial infection found more frequently in immunocompromised subjects and rarely in the head and neck. We report a rare case of a patient with acquired immunodeficiency syndrome (AIDS) and non-Hodgkin's lymphoma (NHL) who presented with a high fever and supraorbital cellulitis 1 week after undergoing chemotherapy. He received intravenous antibiotic therapy but soon developed dyspnea and trismus with rapid extension of the cellulitis to the face, ipsilateral infratemporal fossa (ITF), and bilateral neck. An awake tracheotomy was followed by surgical exploration and drainage and debridement of the supraorbital and ITF areas, parotid gland, and bilateral neck. He received intravenous antibiotic therapy and the surgical wound was regularly debrided for 10 days. Following a gradual recovery, the patient was discharged 2 weeks later. Early antibiotic therapy, wide surgical exploration, and a secured airway are the therapeutic mainstay for necrotizing fasciitis of the skull base and neck.     

Predictors of response to cardiac resynchronization therapy--importance of left ventricular dyssynchrony.

BACKGROUND: Cardiac resynchronization therapy (CRT) is currently used in selected patients with dilated cardiomyopathy and heart failure. However, 30% of patients do not respond to CRT when selection is based on clinical and electrocardiographic criteria. Left ventricular dyssynchrony can be evaluated by tissue Doppler imaging and it has been described as a useful precdictor of response to CRT. OBJECTIVE: To evaluate whether left ventricular dyssynchrony, as measured by tissue Doppler imaging, can be used to predict response to CRT. METHODS: 23 consecutive patients (age 67 +/- 10 years, 13 male) with heart failure refractory to medical therapy and who underwent CRT were studied. Before and six months after the procedure, various characteristics - clinical (including NYHA functional class), electrocardiographic (QRS interval) and echocardiographic (left ventricular ejection fraction [EF] and respective volumes)--were evaluated. In addition, pulsed wave tissue Doppler imaging was used to assess the time interval (QS) between the beginning of the QRS complex and the beginning of the systolic wave on the Doppler signal, in the basal segments of the septal, lateral, anterior and inferior walls. Left ventricular dyssynchrony was quantified as the difference between the maximum and minimum QS interval (QS(max-min)). The patients were divide into two groups: responders, if functional class improved by at least one and EF increased by more than 10%, and non-responders for the remainder. Differences between groups were assessed and predictors of response to CRT were determined. RESULTS: CRT improved functional class by at least one in 87% of patients and EF improved from 21 +/- 6 to 33 +/- 9% (p < 0.001). QS(max-min) was reduced from 80 +/- 38 to 38 +/- 14 ms (p < 0.001). In 15 patients (65%), classified as responders, there was an improvement in functional class and an increase in EF of more than 10%. There were no differences between groups, except for QS(max-min). Patients in the responder group had greater left ventricular dyssynchrony (QS(max-min) 94 +/- 39 vs. 54 +/- 16 ms, p = 0.002). QSmix-min was an independent predictor of response to CRT and a cut-off of 60 ms identified responders with a sensitivity of 87% and specificity of 75%. CONCLUSION: Despite the good results achieved with CRT, about one third of patients do not benefit from it. Left ventricular dyssynchrony can be quantified by tissue Doppler imaging using QS(max-min) and values greater than 60 ms can identify responders to CRT.     

Uniaxial yield strains for bovine trabecular bone are isotropic and asymmetric.

Although evidence suggests that yield strains for trabecular bone are isotropic, i.e., independent of loading direction, decisive support for this hypothesis has remained elusive. To explicitly test whether yield strains for trabecular bone are isotropic, compressive and tensile yield strains of 51 specimens of bovine tibial trabecular bone (0.41 +/- 0.08 g/cm3 [mean apparent density +/- SD]) were measured without end artifacts in on-axis (along the principal trabecular orientation) and off-axis (30-40 degrees oblique to on-axis) orientations. Yield strains for the on-axis and off-axis orientations were similar in tension (0.80 +/- 0.03% compared with 0.85 +/- 0.04%, p = 0.21) and compression (0.97 +/- 0.05% compared with 0.96 +/- 0.07%, p > 0.99); as expected, modulus and strength depended on loading direction. When considered with an ancillary experiment on bovine tibial trabecular bone that showed yield strains to be similar between on-axis and 90 degrees off-axis bone, these results firmly establish the isotropy of uniaxial yield strains for bovine tibial trabecular bone. This bone is of high density and has a strong, plate-type, anisotropic architecture. Therefore, yield strains for uniaxial loading are expected to be isotropic, or nearly so, for other types of dense trabecular bone, although further work is required to confirm this and to establish this behavior for bone of lower density.     

COMPARISON BETWEEN INVERTED AND UNPROCESSED DIGITIZED RADIOGRAPHIC IMAGING IN PERIODONTAL BONE LOSS MEASUREMENTS

The advances in digital imaging technology in dentistry have provided an alternative to film-based radiography and have given new options to detect periodontal bone loss. The purpose of this study was to compare inverted and unprocessed digitized radiographic imaging in periodontal bone loss measurements. Thirty-five film-based periapical radiographs of patients suffering from moderate to advanced untreated periodontal bone loss associated to lower premolar and molars was selected from the department files, with 40 bone loss areas. The film-based radiographs were digitized with a flatbed scanner with a transparency and radiograph adapter used for transilluminating the radiograph imaging. Digitization was performed at 600 dpi and in gray scale. The images were digitized using Image Tool software by applying image inversion, that is, transformation of radiopaque structures into radiolucent structures and vice-versa. The digital data were saved as JPEG files. The images were displayed on a 15-inch and 24-bit video monitor under reduced room lighting. One calibrated examiner performed all radiographic measurements, three times, from the cementoenamel junction to the most apical extension of the bone loss, in both types of image (inverted and unprocessed). Brightness and contrast were adjusted according to the examiner''s individual demand. Intraclass correlation coefficient was used to compare the measurements from both types of images. The means of radiographic measurements, in mm, for inverted and unprocessed digitized imaging were 6.4485 and 6.3790, respectively. The intraclass correlation coefficient was significant (0.99) The inverted and unprocessed digitized radiographic images were reliable and there was no difference in the diagnostic accuracy between these images regarding periodontal bone loss measurements.