Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection.

OBJECTIVES: The most recent survey conducted by the World Health Organization described Tuberculosis (TB) as one of the top 10 causes of death and the leading cause of death from a single infectious agent. The increasing number of TB-resistant cases has contributed to this scenario. In light of this, new strategies to control and treat the disease are necessary. Our research group has previously described furoxan derivatives as promising scaffolds to be explored as new antitubercular drugs. RESULTS: Two of these furoxan derivatives, (14b) and (14c), demonstrated a high selectivity against Mycobacterium tuberculosis. The compounds (14b) and (14c) were also active against a latent M. tuberculosis strain, with MIC90 values of 6.67 µM and 9.84 µM, respectively; they were also active against monoresistant strains (MIC90 values ranging from 0.61 to 20.42 µM) and clinical MDR strains (MIC90 values ranging from 3.09 to 42.95 µM). Time-kill experiments with compound (14c) showed early bactericidal effects that were superior to those of the first- and second-line anti-tuberculosis drugs currently used in therapy. The safety of compounds (14b) and (14c) was demonstrated by the Ames test because these molecules were not mutagenic under the tested conditions. Finally, we confirmed the safety, and high efficacy of compounds (14b) and (14c), which reduced M. tuberculosis to undetectable levels in a mouse aerosol model of infection. CONCLUSION: Altogether, we have identified two advanced lead compounds, (14b) and (14c), as novel promising candidates for the treatment of TB infection.

[Olmesartan-associated enteropathy: attention to an emerging iatrogenic phenomenon]. / Enteropatía asociada a olmesartán: atención a un fenómeno iatrogénico emergente.

Olmesartan is an angiotensin II type 1 receptor blocker commonly used in the treatment of hypertension. Several cases of sprue-like enteropathy associated with the use of this drug have been described which, even with important signs and limitations for the patient, present a full recovery after discontinuing the use of olmesartan. The case of a 64 year-old patient is presented, diagnosed with hypertension, under treatment with olmesartan-amlodipine, with chronic diarrhoea and villous atrophy on intestinal biopsies without diagnostic criteria for celiac disease and with complete remission after suspending discontinuing the use of olmesartan. Based on the clinical features presented by the case reported, the clinical and anatomopathological findings are described as well as the evolution of drug-induced enteropathy.

Dynamics of interacting electrons under effect of a Morse potential.

We consider interacting electrons moving in a nonlinear Morse lattice. We set the initial conditions as follows: electrons were initially localized at the center of the chain and a solitonic deformation was produced by an impulse excitation on the center of the chain. By solving quantum and classical equations for this system numerically, we found that a fraction of electronic wave function was trapped by the solitonic excitation, and trapping specificities depend on the degree of interaction among electrons. Also, there is evidence that the effective electron velocity depends on Coulomb interaction and electron-phonon coupling in a nontrivial way. This association is explained in detail along this work. In addition, we briefly discuss the dependence of our results with the type of initial condition we choose for the electrons and lattice.

Enhanced localization, energy anomalous diffusion and resonant mode in harmonic chains with correlated mass-spring disorder.

In this work, we study the vibrational modes and energy spreading in a harmonic chain model with diluted second-neighbors couplings and correlated mass-spring disorder. While all nearest neighbor masses are coupled by an elastic spring, second neighbors springs are introduced with a probability pD. The masses are randomly distributed according to the site connectivity mi = m0 (1 + 1/n(α)(I), where ni is the connectivity of the site i and α is a tunable exponent. We show that maximum localization of the vibrational modes is achieved for α ≃ 3/4. The time-evolution of the energy wave-packet is followed after an initial localized excitation. While the participation number remains finite, the energy spread is shown to be sub-diffusive after a displacement and super-diffusive after an impulse excitation. These features are related to the development of a power-law tail in the wave-packet distribution. Further, we unveil that the spring dilution leads to the emergence of a resonant localized state which is signaled by a van Hove singularity in the density of states.

Recent insights on the medicinal chemistry of sickle cell disease.

Sickle Cell Disease (SCD) is one of the most prevalent hematological diseases in the world. SCD is a genetic disease characterized by punctual mutation that basis on the exchange of glutamic acid to valine in a beta chain of hemoglobin. In deoxygenated state, the interaction among the beta chains leads to hemoglobin polymerization carrying out to deformation of cytoskeleton structure of red blood cells to a sickle shape. Currently, the treatment is performed with the antineoplasic drug hydroxyurea. This review summarizes current knowledge about possible targets and the approaches to discover new compounds to treat the SCD symptoms. Drug design based on therapeutical application and molecular modifications strategies will be discussed.

TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis.

Tumor necrosis factor-stimulated gene 14 (TSG-14)/PTX3 was identified originally as a TNF-alpha and IL-1beta-stimulated gene from normal, human foreskin fibroblasts and vascular endothelial cells, respectively. TSG-14 gene encodes a 42-kDa-secreted glycoprotein with a carboxy-terminal half that shares homology with the entire sequence of C-reactive protein (CRP) and serum amyloid P component (SAP), acute-phase proteins of the pentraxin family. Some experimental evidence suggests that TSG-14 plays a role in inflammation, yet its function and mechanism of action remain unclear. We have generated transgenic mice that overexpress the murine TSG-14 gene under the control of its own promoter. From eight transgenic founders, two lineages were derived and better characterized: Tg2 and Tg4, carrying two and four copies of the transgene, respectively. TSG-14 transgenic mice were found to be more resistant to the endotoxic shock induced by LPS and to the polymicrobial sepsis caused by cecal ligation and puncture (CLP). Moreover, macrophages derived from the transgenic mice produced higher amounts of nitric oxide in response to IFN-gamma, TNF-alpha, and LPS as compared with macrophages from wild-type animals, and the augmented response appears to be the consequence of a higher responsiveness of transgenic macrophages to IFN-gamma. The data shown here are the first in vivo evidence of the involvement of TSG-14 in the inflammatory process and suggest a role for TSG-14 in the defense against bacterial infections.

[Risk stratification in acute myocardial infarction survivors. Exercise stress test versus coronary angiography]. / Estratificação prognóstica em sobreviventes ao infarto agudo do miocárdio. Teste ergométrico versus cinecoronariografia.

PURPOSE: To compare the predictive accuracy for future ischemic events of heart rate limited treadmill exercise test (HET) and coronary angiography (CA) applied to survivors of an uncomplicated myocardial infarction. METHODS: 142 consecutive patients (55 +/- 11 years, 80% males), presenting a non complicated acute myocardial infarction (AMI) were included. HET was performed 10 +/- 3 days after AMI, and CA during hospital stay or within 4-6 weeks. HET positivity criteria were: 1) horizontal or down-sloping ST segment displacement > or = 1 mm; 2) angina; 3) arterial pressure drop during exercise; 4) low workload (< 6 METS); 5) complex ventricular arrhythmia. At CA lesions causing > or = 50% of luminal reduction were considered significant. HET and CA results were correlated to ischemic events occurring during the follow-up (unstable angina in 20%, cardiac death 6%, and reinfarction 6%). RESULTS: HET was positive in 69 (49%) patients, exhibiting a positive predictive value for ischemic events (PV+) of 26% and a negative predictive value (PV-) of 77%. The mean event-free time was 43 +/- 3 months for positive HET and 46 +/- 3 months for a negative one (p = 0.48). CA showed 0-1 vessel involvement in 93 (66%) patients and > or = 2 vessels in 49 (34%) patients. The presence of multivascular disease at CA presented a PV+ of 37% and PV- of 82%; the mean event-free time was 37 +/- 4 months for patients with multivascular involvement and 48 +/- 2 months for patients without this pattern (p = 0.007). CONCLUSION: The predictive accuracy of HET for future ischemic events in the thrombolytic era is markedly reduced. This population of AMI survivors presents an overall good prognosis that seems to justify the poor predictive accuracy of this test.

[Neonatal cholestasis: the delay in referring patients for differential diagnosis]. / Colestase neonatal - atraso no encaminhamento de crianças para diagnóstico diferencial.

OBJECTIVE: An efficient treatment of extrahepatic biliary atresia demands that the diagnostic differentiation between intra- and extrahepatic neonatal cholestasis be performed by the eighth week of life. This study aimed at evaluate the age of the patients admitted to a general hospital for differential diagnosis of cholestatic jaundice. METHODS: Forty nine children from the Pediatric Service at Hospital de Clínicas, in Porto Alegre, have been studied between 1984 and 1991, according to the protocol for diagnostic elucidation followed by this hospital, which includes biliary tract scintigraphy with Tc-99m DISIDA and, depending on its results, an wedge or percutaneous liver biopsy. The ages of the children have been compared on the occasion of the procedures. Twenty six cases have been studied retrospectively and 23, prospectively. RESULTS: Both the patients with intrahepatic and extrahepatic cholestasis underwent scintigraphy, on average at over eight weeks (age 77.94 +/- 42.98 days) and the histopathological study of the liver was performed approximately two weeks after scintigraphy. Only six patients (12.8% of the 47 cases) underwent the liver biopsy before the first eighth week of life. CONCLUSIONS: A delay was observed in referring patients for differential diagnosis of neonatal cholestasis and the performance of tests. The need of hospitalization in order to conduct these procedures delays even further this diagnosis, which should be concluded by the eighth week of life.

[Nonfatal traumatic lesions in victims of being run over. The medicolegal aspects]. / Lesões traumáticas não mortais em vítimas de atropelamento. Aspectos médico-legais.

Road traffic accidents represent one of the greatest causes of morbidity and mortality, mainly in countries like Portugal, where the accident rate is one of the highest in Europe. The constant increasing number and variety of circulating vehicles tends to amplify the phenomenon dimension, with resulting human and social costs. Although, in our country, there have been several reports on injuries to occupants of cars in read traffic accidents, there are no more than a few studies on injuries to pedestrians in such accidents. With this goal, a retrospective study of all lawsuits concerning these victims of being run over [correction of trampling], which were examined and concluded at the Clinical Department of the Institute of Legal Medicine of Lisbon during the quinquennium 1985-1989. The population satisfying these requirements consists of 324 persons of both sexes and the results are presented on the basis of some parameters considered helpful to a better understanding of this kind of victims, injuries sustained and medico-legal consequences. In conclusion, we try to define the main injury patterns and to discuss several aspects of medico-legal and social nature concerning this particular road traffic accidents.

[Survival after aorto-femoral shunt with Dacron prosthesis]. / Sobrevivência após derivação aorto-femoral com próteses de Dacron.

The purpose of this paper is to establish the survival rate of patients submitted to aorto-femoral bypass grafting and compare it with the general mortality rate of the population in the State of São Paulo. The records of 210 patients with aorto-femoral bypass grafts and mean age of 54 years were analysed according the Kaplan and Meyer method. The survival curves of the normal population with the age of 55 and 70 years were used for comparison. Our results are comparable with those reported in the international literature. The aorto-femoral atherosclerotic disease Hás the same features wherever lives the patient. The death is caused mainly by cardiac disease. In our patients, however, the infection of the prosthesis was also an important factor in the fatal outcome of the disease. After ten years about half of the patients submitted to an aorto-femoral bypass grafting are still alive.

Giant aneurysm of the ascending aorta secondary to medial agenesis in infancy.

A 14-month-old infant was found to have a giant aneurysm of the ascending aorta at the time he underwent angiography. At the time of autopsy, a saccular chamber was found to take the place of the aorta. Histologic examination of the aneurysm revealed absence of the medial layer. Thus, medial genesis may be another cause of aneurysm of the ascending aorta.

[Percutaneous transluminal coronary angioplasty in patients with prior surgical revascularization]. / Angioplastia coronária transluminal percutânea em pacientes com revascularização cirúrgica prévia.

PURPOSE: To show the author's experience with percutaneous transluminal coronary angioplasty (PTCA) in patients with prior coronary bypass surgery. METHODS: Between January 1989 and January 1991, 629 PTCA in 572 patients were performed. Forty-eight had previous revascularization surgery with interval range of 4 days to 10 years. The PTCA sites were divided in three groups: A) native arterial segments, not affected by surgery (26 patients); B) native arterial segments proximal (4 patients) and distal (2 patients) to graft anastomosis; C) in the coronary vein graft (16 patients). RESULTS: The overall primary success was 78%. In groups B and C, 16 procedures were successfully dilated (72%). All failures in group C were due to unstable problems in reaching (4 patients) or crossing (2 patients) the stenosis with the balloon. There was one death in group A and another in group C. CONCLUSION: Angioplasty is an effective alternative for treatment of recurrent ischemia in patients with prior myocardial revascularization surgery and in early results are comparable to the general angioplasty population.

[Coronary angioplasty in patients over 70. An analysis of 115 dilatations]. / Angioplastia coronária em pacientes acima de 70 anos. Análise de 115 dilatações.

PURPOSE: To verify the validity of transluminal coronary angioplasty (PTCA) in the population over 70 years old. METHODS: Retrospectively, were analysed 115 PTCA performed in 89 elderly patients (70 to 85 years old) from January 1988 to January 1991. Three groups were defined: A) single vessel-77 (86.5%) patients; B) double vessel-9 (10.1%) patients; C) three vessel-3 (3.4%) patients. RESULTS: Of the 89 treated patients, 81.8% in group A, 72.2% in group B and 75% in group C were successfully dilated. The learning curve had showed increase in success rate after the first 250 angioplasties (from 60.6% to 82.5%). Treatment of acute myocardial infarction by direct thrombolysis was made in 7 patients (6 S, 1 I). Major complications included: deaths (4.4%), ventricular fibrillation (1.08%), acute coronary occlusion (6.6%). Emergency coronary artery bypass grafting was required in 4.4% with one death. CONCLUSION: Coronary angioplasty is an effective treatment in elderly patients and may be performed with acceptable success and with low complications.

[Constrictive pericarditis as differential diagnosis of hepatic disease]. / Pericardite constrictiva como diagnóstico diferencial de doença hepática.

Constrictive chronic pericarditis in a 13-year-old male patient was previously treated as chronic hepatitis for seven years, with the use of furosemide and spironolactone. Investigation for diagnosis included chest radiography, echo-doppler-cardiography, thoracocentesis with pleural biopsy and computerized tomography of chest, and showed ventricular diastolic restriction due to constrictive chronic pericarditis. After eight weeks of tuberculostatic treatment, the patient was submitted to hemodynamic study that confirmed the diagnosis and a pericardiectomy was performed. Long-term follow-up showed regression of diastolic restriction and decrease of hepatosplenomegaly and of jugular stasis. Tuberculostatic drugs were given for 12 months postoperatively, associated to corticosteroids.

[Superior vena cava compression syndrome]. / Síndrome de compressão da veia cava superior.

The superior vena cava syndrome that causes difficulties on venous return to the heart is a uncommon clinical entity and actually, more than 90% of the cases are secondary to a malignant intrathoracic process, rather than the intrinsic diseases of the aorta that is a rare etiology of the compression. The present report documents an aortic ascending atherosclerotic aneurysm that developed a superior vena cava compression syndrome. The literature was reviewed, stressing some important aspects about the etiology, physiopathology, diagnostic procedures, prognostic and treatment of this syndrome.

[Percutaneous transluminal coronary angioplasty. Analysis of 305 dilatations]. / Angioplastia coronária transluminal percutânea. Análise de 305 dilatações.

PURPOSE: To show the initial experience of this service with the technique of percutaneous transluminal coronary angioplasty. PATIENTS AND METHODS: Between january 1988 and december 1989, 305 coronary angioplasties were performed in 280 patients with age range of 33 to 82 years (being 49% above 60 years old) and 71% male. Among those, 212 (75%) experienced clinical picture of stable angina and 68 (25%) of unstable angina or myocardial infarction. Patients were divided in three groups: group A--those with lesions of 70% or worse in more than one vessel or in the same vessel with or without any other vessel total occlusion (multiple lesions or multiple vessels: 36 patients; group B--those with lesions of 70% or worse in one vessel with at least one occluded vessel: 64 patients; group C--those with lesions of 70% or worse isolated in a single vessel: 180 patients. RESULTS: Of the 280 treated patients, 229 were considered successful (75%). There has been 22 complications (7%) and 9 deaths (3%). The late follow-up (from 1 to 24 months), displayed 28 new procedures based on clinical suspicion of restenosis. Obstruction or occlusion were present in 16 of the later, with 10 being selected to undergo new procedure, one of those twice. The remaining 12 patients received clinical or surgical treatment. CONCLUSION: Aside from the fact that early and midterm results indeed are promising, the procedure is not safe from immediate risks, and limiting late restenosis. Nevertheless, the lesions might be redilated by the same technique, with success rates comparable to the initial one.