Factors associated with bronchiectasis in patients with uncontrolled asthma; the NOPES score: a study in 398 patients.

BACKGROUND: Some studies have reported a high prevalence of bronchiectasis in patients with uncontrolled asthma, but the factors associated with this condition are unknown. The objective of this study was to determine the prevalence of bronchiectasis in uncontrolled moderate-to-severe asthma and to identify risk factors and their correlation with bronchiectasis in these patients. METHODS: This is a prospective study of data from consecutive patients with uncontrolled moderate-to-severe asthma. Diagnosis of bronchiectasis was based on high-resolution computed tomography. A prognostic score was developed using a logistic regression model, which was used to determine the factors associated with bronchiectasis. RESULTS: A total of 398 patients (60% with severe asthma) were included. The prevalence of bronchiectasis was 28.4%. The presence of bronchiectasis was associated with a higher frequency of chronic expectoration (OR, 2.95; 95% CI, 1.49-5.84; p = 0.002), greater severity of asthma (OR, 2.43; 95% CI, 1.29-4.57; p = 0.006), at least one previous episode of pneumonia (OR, 2.42; 95% CI, 1.03-5.69; p = 0.044), and lower levels of FeNO (OR, 0.98; 95% CI, 0.97-0.99; p = 0.016). The NOPES score was developed on the basis of these variables (FeNO[cut off point 20.5 ppb], Pneumonia, Expectoration and asthma Severity), and it ranges from 0 to 4 points, where 0 means "no risk" and 4 corresponds to "high risk". The NOPES score yielded an AUC-ROC of 70% for the diagnosis of bronchiectasis, with a specificity of 95%. CONCLUSIONS: Almost a third of the patients with uncontrolled moderate-to-severe asthma had bronchiectasis. Bronchiectasis was related to the severity of asthma, the presence of chronic expectoration, a previous history of pneumonia, and lower levels of FeNO. The NOPES score is an easy-to-use scoring system with a high prognostic value for bronchiectasis in patients with uncontrolled moderate-to-severe asthma.

Oxygen metabolism in human placenta mitochondria.

Due to the high metabolic demands of the placental tissue during gestation, we decide to analyzed the mitochondrial bioenergetic functions in the human term placenta. Different mitochondrial morphological parameters, membrane potential and cardiolipin content were determined by flow cytometry. Oxygen uptake, hydrogen peroxide production and cytochrome P450 content, were also measured. Some apoptotic mitochondrial proteins were also analyzed by western blot. Two isolated mitochondrial fractions were observed: large/heavy and small/light with different functional characteristics. Oxygen uptake showed a respiratory control (RC) of 3.4 ± 0.3 for the heavy mitochondria, and 1.1 ± 0.4 for light mitochondria, indicating a respiratory dysfunction in the light fraction. Good levels of polarization were detected in the heavy fraction, meanwhile the light population showed a collapsed ΔΨm. Increased levels of cytochrome P450, higher levels of hydrogen peroxide, and low cardiolipin content were described for the light fraction. Three pro-apoptotic proteins p53, Bax, and cytochrome c were found increased in the heavy mitochondrial fraction; and deficient in the light fraction. The heavy mitochondrial fraction showed an improved respiratory function. This mitochondrial fraction, being probably from cytotrophoblast cells showed higher content of proteins able to induce apoptosis, indicating that these cells can effectively execute an apoptotic program in the presence of a death stimulus. Meanwhile the light and small organelles probably from syncytiotrophoblast, with a low oxygen metabolism, low level of ΔΨm, and increased hydrogen peroxide production, may not actively perform an apoptotic process due to their deficient energetic level. This study contributes to the characterization of functional parameters of human placenta mitochondria in order to understand the oxygen metabolism during the physiological process of gestation.

Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer.

OBJECTIVE: To evaluate the effect of all-trans retinoic acid (ATRA) as treatment for chemotherapy-induced peripheral neuropathy in an experimental animal model and in a randomized, double-blinded, controlled trial in patients with non-small-cell lung cancer (NSCLC). METHODS: Forty male Wistar rats were randomized in 5 groups: group A, control; groups B and C, treated with cisplatin; and groups D and E, treated with paclitaxel. ATRA (20 mg/kg PO) was administered for 15 days in groups C and E. We evaluated neuropathy and nerve regeneration-related morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)-α and RAR-ß expression. In addition, 95 patients with NSCLC under chemotherapy treatment were randomized to either ATRA (20 mg/m(2)/d) or placebo. Serum NGF, neurophysiologic tests, and clinical neurotoxicity were assessed. RESULTS: The experimental animals developed neuropathy and axonal degeneration, associated with decreased NGF levels in peripheral nerves. Treatment with ATRA reversed sensorial changes and nerve morphology; this was associated with increased NGF levels and RAR-ß expression. Patients treated with chemotherapy had clinical neuropathy and axonal loss assessed by neurophysiology, which was related to decreased NGF levels. ATRA reduced axonal degeneration demonstrated by nerve conduction velocity and clinical manifestations of neuropathy grades ≥2. CONCLUSIONS: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-ß expression in nerve. In patients, reduction of NGF in serum was associated with the severity of neuropathy; ATRA treatment reduced the electrophysiologic alterations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ATRA improves nerve conduction in patients with chemotherapy-induced peripheral neuropathy.

Surgical treatment for infective endocarditis in elderly patients.

OBJECTIVES: We evaluate the clinical, echographic and prognostic characteristics of infective endocarditis (IE) in a large population of elderly patients, and the results of surgical approach. METHODS: Multicentric, prospective, observational cohort study with 961 consecutive left-sided IE: 356 patients aged ≥65 years were compared with 605 younger. Indications for cardiac surgery, potential surgical risk, time and outcome, were compared. RESULTS: Hospital-acquired endocarditis, comorbidity, renal failure and septic shock were more frequent in elderly, but embolisms were less. Intracardiac destruction and ventricular failure were similar in both groups, but significantly fewer elderly patients underwent cardiac surgery (36% vs 51%; p < 0.01), and this group showed a worse outcome (43.2% of mortality vs 27% in younger; p < 0.01), resulting age as an independent predictor of mortality (OR: 1.02 CI95%: 1.01-1.03). Compared with medical treatment, surgery showed lower percentages of mortality compared with medical treatment (23.3% vs 31.3%; p = 0.03) in younger group, but a high mortality was observed with both procedures (47.6% vs 40.3%; p = 0.1) in the elderly. CONCLUSIONS: Although similar percentages of heart failure and intracardiac complications, increasing age is associated with higher mortality in IE. Lower rates of surgical treatment and a worse outcome after operation are common features in elderly patients.

Blood flow in the rabbit aortic arch and descending thoracic aorta.

The distribution of atherosclerotic lesions within the rabbit vasculature, particularly within the descending thoracic aorta, has been mapped in numerous studies. The patchy nature of such lesions has been attributed to local variation in the pattern of blood flow. However, there have been few attempts to model and characterize the flow. In this study, a high-order continuous Galerkin finite-element method was used to simulate blood flow within a realistic representation of the rabbit aortic arch and descending thoracic aorta. The geometry, which was obtained from computed tomography of a resin corrosion cast, included all vessels originating from the aortic arch (followed to at least their second generation) and five pairs of intercostal arteries originating from the proximal descending thoracic aorta. The simulations showed that small geometrical undulations associated with the ductus arteriosus scar cause significant deviations in wall shear stress (WSS). This finding highlights the importance of geometrical accuracy when analysing WSS or related metrics. It was also observed that two Dean-type vortices form in the aortic arch and propagate down the descending thoracic aorta (along with an associated skewed axial velocity profile). This leads to the occurrence of axial streaks in WSS, similar in nature to the axial streaks of lipid deposition found in the descending aorta of cholesterol-fed rabbits. Finally, it was observed that WSS patterns within the vicinity of intercostal branch ostia depend not only on local flow features caused by the branches themselves, but also on larger-scale flow features within the descending aorta, which vary between branches at different locations. This result implies that disease and WSS patterns in the vicinity of intercostal ostia are best compared on a branch-by-branch basis.

Effect of reverse flow on the pattern of wall shear stress near arterial branches.

Atherosclerotic lesions have a patchy distribution within arteries that suggests a controlling influence of haemodynamic stresses on their development. The distribution near aortic branches varies with age and species, perhaps reflecting differences in these stresses. Our previous work, which assumed steady flow, revealed a dependence of wall shear stress (WSS) patterns on Reynolds number and side-branch flow rate. Here, we examine effects of pulsatile flow. Flow and WSS patterns were computed by applying high-order unstructured spectral/hp element methods to the Newtonian incompressible Navier-Stokes equations in a geometrically simplified model of an aorto-intercostal junction. The effect of pulsatile but non-reversing side-branch flow was small; the aortic WSS pattern resembled that obtained under steady flow conditions, with high WSS upstream and downstream of the branch. When flow in the side branch or in the aortic near-wall region reversed during part of the cycle, significantly different instantaneous patterns were generated, with low WSS appearing upstream and downstream. Time-averaged WSS was similar to the steady flow case, reflecting the short duration of these events, but patterns of the oscillatory shear index for reversing aortic near-wall flow were profoundly altered. Effects of reverse flow may help explain the different distributions of lesions.

Streptococcus agalactiae left-sided infective endocarditis. Analysis of 27 cases from a multicentric cohort.

SUMMARY OBJECTIVE: To evaluate the current trends in the clinical characteristics and the prognosis of Streptococcus agalactiae infective endocarditis (IE), uncommon disease associated with high mortality. METHODS: Descriptive analysis of 27 cases of a large cohort (961 episodes) of infective endocarditis collected in seven hospitals of Andalusia (Spain) between 1984 and 2008. RESULTS: Native valves were affected in most cases (85. 2%), multiple valves were frequently involved (22.2%). The median age of the patients was 65 (51-76) years (59.3% men), with a comorbidity, according to the Charlson index, of 2.6+/-2.3. The most frequent underlying diseases were diabetes mellitus (25.9%), chronic obstructive pulmonary disease (14.8%), neoplasms (14.8%), urological disorders (11%) and chronic liver disease (11%). Clinical presentation was characterized by rapid worsening (median of 9 (5.7-15) days from onset of symptoms until diagnosis), a high rate of embolisms (37%) and cardiac complications (abscesses, fistulas or valve rupture) - 37% of cases. Surgery was performed in 12 patients (44.4%) and a high mortality (40.7%) was observed. CONCLUSION: S. agalactiae IE is a serious disease with aggressive course and high mortality rate and affects patients with debilitating diseases. We must be alert of the development of complications and consider early valve surgery when it is necessary.

Endothelial nitric oxide production and transport in flow chambers: The importance of convection.

A computational model of Nitric Oxide (NO) production and transport within a parallel-plate flow chamber coated with endothelial cells is presented. The relationship between NO concentration and Wall Shear Stress (WSS) at the endothelium is investigated in detail. An increase in WSS is associated with two phenomena: enhanced NO production by the endothelial cells, and an increase in the velocity at which NO is convected out of the chamber. These two phenomena have opposite effects on endothelial NO concentration. In physiologically realistic cases, the balance between them is found to vary as WSS is raised, resulting in a complex non-monotonic dependence of endothelial NO concentration on WSS. Also, it is found that a NO concentration boundary layer develops within the chamber, leading to substantial spatial variations in NO concentration along the length of the device. Finally, the implications of a negative feedback mechanism (that affects NO production) are presented. The results emphasize the role of convection on NO transport within flow chambers, which has been overlooked or misinterpreted in most previous theoretical studies. It is hoped that the conclusions of this study can be used to aid accurate interpretation of related experimental data.

Healthcare-associated infective endocarditis: an undesirable effect of healthcare universalization.

Invasive medical technology has led to an increase in the incidence of healthcare-associated infective endocarditis (HAIE). A prospective multicentre cohort study was conducted at seven hospitals in Andalusia, Spain, to establish the characteristics of HAIE and to compare them with those of community-acquired infective endocarditis (CAIE). HAIE was defined as either infective endocarditis (IE) manifesting >48 h after admission to hospital, or IE associated with a significant invasive procedure performed in the 6 months before diagnosis. Seven hundred and ninety-three cases of IE were investigated, and HAIE accounted for 127 (16%). As compared with patients with CAIE, patients with HAIE were older (60.1 ± 14.4 years vs. 53.6 ± 17.5 years) and had more comorbidities (Charlson index 3.3 ± 2.3 vs. 1.8 ± 2.3) and staphylococcal infections (58.3% vs. 24.8%). Vascular manipulation was the main cause of bacteraemia responsible for HAIE (63%). Peripheral vein catheter-associated bacteraemia accounted for 32.8% of the catheter-related bacteraemias. In-hospital mortality (44.9% vs. 24.2%) was higher in the HAIE group. Septic shock (OR 2.2, 95% CI 2.9-30.2) and surgery not performed because of high surgical risk (OR 1.6, 95% CI 1.2-20) were independent predictors of mortality in HAIE. The present study demonstrates that HAIE is a growing health problem associated with high mortality. Careful management of vascular devices is essential to minimize the risk of bacteraemias leading to HAIE.

Aged garlic extract delays the appearance of infarct area in a cerebral ischemia model, an effect likely conditioned by the cellular antioxidant systems.

Experimental evidence has shown that some garlic-derived products have a protective effect against ischemic brain injury. The present study was designed to investigate the effect of aged garlic extract (AGE), establish the therapeutic window, and determine its protective mechanism in a cerebral ischemia model. Animals were subjected to middle cerebral artery occlusion (MCAO) for 2h and treated with 1.2ml/kg body wt.(i.p.) of AGE 30min before, at the beginning of (0R), or 1h after reperfusion. The 0R treatment significantly reduced the size of the infarct area after 2h of reperfusion. Repeated doses subsequent to the 0R treatment (at 1, 2, or 3h after reperfusion) had no effect on the temporal window of protection. The protective 0R treatment with AGE prevented the increase in nitrotyrosine and the decrease in total superoxide dismutase, glutathione peroxidase, and extracellular superoxide dismutase activities induced by MCAO. These data indicate that AGE delays the effects of ischemia/reperfusion-induced neuronal injury. However, this treatment itself was not associated with a noticeable improvement in the neurological outcome, or with an effect on the inflammatory response. We conclude that the neuroprotective effect of AGE in the 0R treatment might be associated with control of the free-radical burst induced by reperfusion, preservation of antioxidant enzyme activity, and the delay of other pathophysiological processes.

Persistence of respiratory syncytial virus in macrophages alters phagocytosis and pro-inflammatory cytokine production.

Functions of macrophage are known to be altered by acute infection with respiratory syncytial virus (RSV). However, it is unknown whether the persistent presence and expression of the RSV genome have any effect on the functions of these cells. We used a murine macrophage-like cell line (P388D1) persistently infected with RSV to determine: (i) phagocytic activity mediated by Fcgamma receptors, (ii) expression of Fcgamma receptors, and (iii) production of IL-1beta, IL-6 and TNF-alpha. Viral persistence was found to increase phagocytosis, expression of Fcgamma receptors and the production of IL-1beta and IL-6. In contrast the biological activity of secreted TNF-alpha decreased. In this study we give novel evidence that RSV persistence alters the biological activities of macrophages.

Biosynthesis and functions of melanin in Sporothrix schenckii.

Sporothrix schenckii is a human pathogen that causes sporotrichosis, an important cutaneous mycosis with a worldwide distribution. It produces dark-brown conidia, which infect the host. We found that S. schenckii synthesizes melanin via the 1,8-dihydroxynaphthalene pentaketide pathway. Melanin biosynthesis in the wild type was inhibited by tricyclazole, and colonies of the fungus were reddish brown instead of black on tricyclazole-amended medium. Two melanin-deficient mutant strains were analyzed in this study: an albino that produced normal-appearing melanin on scytalone-amended medium and a reddish brown mutant that accumulated and extruded melanin metabolites into its medium. Scytalone and flaviolin obtained from cultures of the reddish brown mutant were identified by thin-layer chromatography, high-performance liquid chromatography, and UV spectra. Transmission electron microscopy showed an electron-dense granular material believed to be melanin in wild-type conidial cell walls, and this was absent in conidial walls of the albino mutant unless the albino was grown on a scytalone-amended medium. Melanized cells of wild-type S. schenckii and the albino grown on scytalone-amended medium were less susceptible to killing by chemically generated oxygen- and nitrogen-derived radicals and by UV light than were conidia of the mutant strains. Melanized conidia of the wild type and the scytalone-treated albino were also more resistant to phagocytosis and killing by human monocytes and murine macrophages than were unmelanized conidia of the two mutants. These results demonstrate that melanin protects S. schenckii against certain oxidative antimicrobial compounds and against attack by macrophages.

Stent placement for the diagnosis of upper tract obstruction.

The aim of this study was to evaluate the effectiveness of ureteral stent placement in diagnosing ureteropelvic junction (UPJ) obstruction in patients with negative or equivocal radiographic/nuclear studies and to assess relief of symptoms following definitive surgical procedures to relieve the obstruction. Patients undergoing ureteral stent placements performed by two attending urologists over an 18-month period were reviewed. All patients with equivocal or negative radiographic evaluations for ureteral obstruction in whom the stent was placed for diagnostic purposes were selected. Preoperative and postoperative information was obtained from the medical record or by telephone interview. Five patients were found who had equivocal radiographic studies along with symptoms of flank pain and who underwent diagnostic stent placement. All patients were female (average age 40 years, range 20-52). All had pain relief following stent placement and, on this basis, underwent an operative procedure to remove the presumed ureteral obstruction. Three underwent Acucise endopyelotomy, one had laparoscopic resection of the right ovarian vein, and one underwent nephrectomy. The average preoperative creatinine level was 0.9 mg/dL (range 0.8-1.0), and the average postoperative creatinine level was 1.0 mg/dL (range 0.9-1.1). All patients had relief of flank pain at a mean of 17 months following the surgical procedure. Relief of pain following stent placement in patients with clinical suspicion of ureteral obstruction portends a favorable outcome from procedures to relieve the presumed obstruction. In unusual cases where ureteral obstruction is suspected despite negative or equivocal radiographic findings, diagnostic stent placement appears to be useful.

Comparison of transurethral versus periurethral collagen injection in women with intrinsic sphincter deficiency.

Two different injection techniques for collagen injection have been described for the treatment of intrinsic sphincter deficiency (ISD) in women: periurethral and transurethral. The purpose of this review was-to compare these two different techniques to determine whether or not one method clearly is superior. Forty-five women, ages 43 to 88 years (mean 67 years), with ISD underwent collagen injection therapy using either the periurethral or transurethral route. A retrospective analysis was performed comparing initial and final incontinence grades, change in daily pad use, initial Valsalva leak point pressure (VLPP), total amount of collagen used, number of treatment sessions performed, anesthesia required, and complications related to injections. Twenty-four patients underwent transurethral injection, and 21 underwent periurethral injection. There was no significant difference in preoperative incontinence grade, initial VLPP, or age between the two groups. At a mean follow-up of 6.3 months, 11 (46%) of the transurethral group were cured, 12 (50%) improved, and 1 (4%) unchanged. The periurethral group with a mean follow-up of 8.8 months experienced a 33% cure rate and 67% improvement rate (p > .05). The average amount of collagen injected was 4.7 cc (1.5-12.5) transurethrally and 10.1 cc (5-20) periurethrally (p < .001). The number of treatment sessions was identical (1.3) regardless of the method used. Complications were minimal [minor bleeding (2), urinary tract infection (1) in periurethral vs. minor bleeding (2), urinary tract infection (1) in the transurethral group, and not significant between the two groups]. Overall, success was equivalent using either method. The amount of collagen injected was significantly more when utilizing the periurethral method. The transurethral method appears to offer similar results as the more commonly described periurethral technique. The transurethral method is an acceptable technique for collagen injection therapy in women.

Lenticular acral keratosis in washerwomen.

BACKGROUND: In 1952, a Brazilian dermatologist, Oswaldo Costa, described a dermatosis characterized by accentuation of the cutaneous folds on the knuckles of both hands and small horny papules on the thenar eminences, posterior surface of the wrists, and the interdigital space between thumb and index finger; he called this entity acrokeratoelastoidosis. Other similar entities, such as focal acral hyperkeratosis and marginal keratoelastoidosis, have been described. The features of the different types of lenticular acral keratosis are discussed. MATERIALS AND METHODS: Fifteen patients with lenticular acral keratosis and five controls were studied clinically and pathologically. The skin biopsies were processed for light and transmission electron microscopy. The clinical data were reviewed, and the following variables were recorded: age, sex, distribution and morphology of the lesions, history of exposure to sunlight and objective evidence of photodamage, familial incidence, occupation and hobbies, time of evolution, and response to previous treatments. The results were compared with samples taken at autopsy from five women without dermatoses. RESULTS: All patients were women, with flat, keratotic papules located on the transition between the dorsal and volar surfaces of the fingers and hands. Histologically, there was an increased amount of elastic fibers, which were coarse and tortuous, and appeared to be interrupted in some areas. In contrast, there were sparse, thin fibers in the mid and deep dermis in the skin of controls. Transmission electron microscopy of these papules showed enlarged, thickened elastic fibers, with deposits of electron-dense, coarse clumps. CONCLUSIONS: Our cases do not seem to correspond to any of the three entities which are manifested clinically by acral keratotic plaques. All of these women washed clothes by hand on a stone washboard for many hours every day. As there is no clinical or histologic evidence of actinic damage, chronic trauma seems to be the cause of the dermatosis in this type of patient. We propose the term "occupational lenticular acral keratosis" for our cases.

Ultrastructural changes in limb distal nerves of rats with alcoholism and/or malnutrition before and after dietary correction.

To study peripheral nerves changes in chronic alcoholism and in malnutrition, we examined ultrastructurally the distal nerve branches of the digits of rats treated with four different dietary schemes, as follows: controls (n = 22), fed standard rodent diet plus water ad libitum; alcoholism (n = 12), fed the standard diet and 2-12% ethanol in drinking water; malnutrition (n = 21), fed with corn tortillas instead of standard diet; and alcoholism and malnutrition combined (n = 22). After 10 months under these conditions, a proportion of animals from each group were sacrificed. The remaining rats of the malnutrition and alcoholism alone groups were deferred a standard diet. The combined alcohol + malnutrition group was subdivided into standard diet, malnutrition and ethanol. After a further 4 months under these new conditions, the animals were sacrificed. Ultrastructural examination of limb distal nerve branches showed that glycogen-like particles were more common in malnourished animals, whereas remyelinating axons were more numerous in ethanol-treated rats. Bands of regeneration were present in both groups, but were more common in animals treated with ethanol. These features decreased significantly when the respective nutritional factor was reversed. The results confirm that ethanol plays a definitive role in the development of alcoholic neuropathy and that malnutrition accentuates, the histopathological abnormalities.