Pulmonary function and histological impairment in mice after acute exposure to aluminum dust

Along the aluminum refining process, alumina (Al(2)O(3)) constitutes the main source of dust. Although aluminum refinery workers present respiratory symptoms with lung functional changes, no conclusive data about lung function impairment after alumina exposure has been so far reported. We examined the pulmonary alterations of exposure to material collected in an aluminum refinery in Brazil. BALB/c mice were exposed in a whole-body chamber for 1 h to either saline (CTRL, n = 11) or to a suspension (in saline) of 8 mg/m(3) of the dust (ALUM, n = 11) both delivered by an ultrasonic nebulizer. Twenty-four hours after exposure lung mechanics were measured by the end-inflation method. Lungs were prepared for histology. ALUM showed significantly higher static elastance (34.61 +/- 5.76 cmH(2)O/mL), elastic component of viscoelasticity (8.16 +/- 1.20 cmH(2)O/mL), pressure used to overcome the resistive component of viscoelasticity (1.62 +/- 0.24 cmH(2)O), and total resistive pressure (2.21 +/- 0.49 cmH(2)O) than CTRL (27.95 +/- 3.63 cmH(2)O/mL, 6.12 +/- 0.99 cmH(2)O/mL, 1.23 +/- 0.19 cmH(2)O, and 1.68 +/- 0.23 cmH(2)O, respectively). ALUM also presented significantly higher fraction area of alveolar collapse (69.7 +/- 1.2%) and influx of polymorphonuclear cells (27.5 +/- 1.1%) in lung parenchyma than CTRL (27.2 +/- 1.1% and 14.6 +/- 0.7%, respectively). The composition analysis of the particulate matter showed high concentrations of aluminum. For the first time it was demonstrated in an experimental model that an acute exposure to dust collected in an aluminum producing facility impaired lung mechanics that could be associated with inflammation.

A NEUROECONOMIC MODELING OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)

In this paper we present a new neuroeconomics model for decision-making applied to the Attention-Deficit/Hyperactivity Disorder (ADHD). The model is based on the hypothesis that decision-making is dependent on the evaluation of expected rewards and risks assessed simultaneously in two decision spaces: the personal (PDS) and the interpersonal emotional spaces (IDS). Motivation to act is triggered by necessities identified in PDS or IDS. The adequacy of an action in fulfilling a given necessity is assumed to be dependent on the expected reward and risk evaluated in the decision spaces. Conflict generated by expected reward and risk influences the easiness (cognitive effort) and the future perspective of the decision-making. Finally, the willingness (not) to act is proposed to be a function of the expected reward (or risk), adequacy, easiness and future perspective. The two most frequent clinical forms are ADHD hyperactive (AD/HDhyp) and ADHD inattentive (AD/HDdin). AD/HDhyp behavior is hypothesized to be a consequence of experiencing high rewarding expectancies for short periods of time, low risk evaluation, and short future perspective for decision-making. AD/HDin is hypothesized to be a consequence of experiencing high rewarding expectancies for long periods of time, low risk evaluation, and long future perspective for decision-making.

Implications of prevalent and incident diabetes mellitus on left ventricular geometry and function in the ageing heart: The MONICA/KORA Augsburg cohort study

Background and Aim: It is unclear to what extent diabetes modulates the ageing-related adaptations of cardiac geometry and function. Methods and Results: We examined 1005 adults, aged 25-74 years, from a population-based survey at baseline in 1994/5 and at follow-up in 2004/5. We compared persistently non-diabetic individuals (ND; no diabetes at baseline and at follow-up, n = 833) with incident (ID; non-diabetic at baseline and diabetic at follow-up, n = 36) and with prevalent diabetics (PD; diabetes at baseline and follow-up examination, n = 21). Left ventricular (LV) geometry and function were evaluated by echocardiography. Statistical analyses were performed with multivariate linear regression models. Over ten years the PD group displayed a significantly stronger relative increase of LV mass (+9.34% vs. +23.7%) that was mediated by a more pronounced increase of LV end-diastolic diameter (+0% vs. +6.95%) compared to the ND group. In parallel, LA diameter increased (+4.50% vs. +12.7%), whereas ejection fraction decreased (+3.02% vs. -4.92%) more significantly in the PD group. Moreover, at the follow-up examination the PD and ID groups showed a significantly worse diastolic function, indicated by a higher E/EM ratio compared with the ND group (11.6 and 11.8 vs. 9.79, respectively). Conclusions: Long-standing diabetes was associated with an acceleration of age-related changes of left ventricular geometry accumulating in an eccentric remodelling of the left ventricle. Likewise, echocardiographic measures of systolic and diastolic ventricular function deteriorated more rapidly in individuals with diabetes. (C) 2009 Elsevier B.V. All rights reserved.

Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function

Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the CNS, where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF has become a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have consistently reported altered levels of BDNF in the circulation (i.e., serum or plasma) of patients with major depression, bipolar disorder, Alzheimer`s disease, Huntington`s disease and Parkinson`s disease. Correlations between serum BDNF levels and affective, cognitive and motor symptoms have also been described. BDNF appears to be an unspecific biomarker of neuropsychiatric disorders characterized by neurodegenerative changes.

Transcranial Electrocortical Stimulation to Monitor the Facial Nerve Motor Function During Cerebellopontine Angle Surgery

OBJECTIVE: This study was conducted to investigate the success rate of using the facial motor evoked potential (FMEP) of orbicularis oculi and oris muscles for facial nerve function monitoring with use of a stepwise protocol, and its usefulness in predicting facial nerve outcome during cerebellopontine angle (CPA) surgeries. METHODS: FMEPs were recorded intraoperatively from 60 patients undergoing CPA surgeries. Transcranial electrocortical stimulation (TES) was performed using corkscrew electrodes positioned at hemispheric montage (C3/C4 and CZ). The contralateral abductor pollicis brevis muscle was used as the control response. Stimulation was always applied contralaterally to the affected side using 1, 3, or 5 rectangular pulses ranging from 200 to 600 V with 50 mu s of pulse duration and an interstimulus interval of 2 ms. Facial potentials were recorded from needles placed in the orbicularis oculi and oris muscles. RESULTS: FMEP from the orbicularis oris and oculi muscles could be reliably monitored in 86.7% and 85% of the patients, respectively. The immediate postoperative facial function correlated significantly with the FMEP ratio in the orbicularis oculi muscle at 80% amplitude ratio (P =.037) and orbicularis oris muscle at 35% ratio (P =.000). FMEP loss was always related to postoperative facial paresis, although in different degrees. CONCLUSION: FMEPs can be obtained reliably by using TES with 3 to 5 train pulses. Stable intraoperative FMEPs can predict a good postoperative outcome of facial function. However, further refinements of this technique are necessary to minimize artifacts and to make this method more reliable.

Recovery of Renal Function in Heart Transplantation Patients After Conversion From a Calcineurin Inhibitor-Based Therapy to Sirolimus

Background. Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation. Methods. The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance <50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up. Conclusion. The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.

Salbutamol improves markers of epithelial function in mice with chronic allergic pulmonary inflammation

We investigated the effects of salbutamol on the markers of epithelial function in a murine model of chronic allergic pulmonary inflammation by recording the ciliary beat frequency (CBF) and the transepithelial potential difference (PD) in vivo. Mice were sensitized and received four challenges of ovalbumin (OVA group) or 0.9% saline (control group). Forty-eight hours after the 4th inhalation, we observed eosinophilia in the bronchoalveolar lavage and epithelium remodeling with stored acid mucus in the OVA group (P < 0.001). No difference in the baseline CBF was noticed between the groups; however, the OVA group had a significantly lower baseline PD (P = 0.013). Salbutamol increased the CBF in all groups studied, and the dose response curve to salbutamol increased the PD in the OVA group from 10(-4) M to 10(-2) M. We suggest that salbutamol affects the CBF and the depth of the periciliary layer, which, in great part, determines the ability of the cilia to propel the mucus layer. This effect may have a positive impact on airway mucociliary transport in asthma and may have clinical implications. (C) 2011 Elsevier B.V. All rights reserved.

Increased number and function of natural killer cells in human immunodeficiency virus 1-positive subjects co-infected with herpes simplex virus 2

P>Natural killer (NK) cells bridge the interface between innate and adaptive immunity and are implicated in the control of herpes simplex virus 2 (HSV-2) infection. In subjects infected with human immunodeficiency virus 1 (HIV-1), the critical impact of the innate immune response on disease progression has recently come into focus. Higher numbers of NK cells are associated with lower HIV-1 plasma viraemia. Individuals with the compound genotype of killer cell immunoglobulin-like receptor (KIR) 3DS1 and human leucocyte antigen (HLA)-Bw4-80I, or who have alleles of KIR3DL1 that encode proteins highly expressed on the NK cell surface, have a significant delay in disease progression. We studied the effect of HSV-2 co-infection in HIV-1-infected subjects, and show that HSV-2 co-infection results in a pan-lymphocytosis, with elevated absolute numbers of CD4+ and CD8+ T cells, and NK cells. The NK cells in HSV-2 co-infected subjects functioned more efficiently, with an increase in degranulation after in vitro stimulation. The number of NK cells expressing the activating receptors NKp30 and NKp46, and expressing KIR3DL1 or KIR3DS1, was inversely correlated with HIV-1 plasma viral load in subjects mono-infected with HIV-1, but not in subjects co-infected with HSV-2. This suggests that HSV-2 infection mediates changes within the NK cell population that may affect immunity in HIV-1 infection.

Kidney Function and 24-Hour Proteinuria in Patients with Fabry Disease during 36 Months of Agalsidase Alfa Enzyme Replacement Therapy: A Brazilian Experience

Background. Prior to the introduction of enzyme replacement therapy (ERT), management of Fabry disease (FD) consisted of symptomatic and palliative measures. ERT has been available for several years using recombinant human agalsidase alfa, an analogue of alpha-galactosidase A (GALA). However, the limitations of ERT in improving kidney function have not been established. This study evaluates the safety and therapeutic effect of agalsidase alfa replacement in terms of kidney function and reduction in 24-hour proteinuria. Methods. During the period between January 1, 2002, and August 1, 2005, nine Fabry patients (7 male, 2 female) were treated according to protocol, receiving 0.2 mg/kg agalsidase alfa IV every two weeks. Kidney function was evaluated by measuring the glomerular filtration rate (GFR) using chromium ethylene diamine tetra-acetate clearance ((51)Cr-EDTA mL/min/1.73 m(2)) at baseline, 12, 24, and 36 months. 24-hour proteinuria was measured at baseline, 3, 6, 12, 18, 24, and 36 months of ERT. Kidney disease was classified according to National Kidney Foundation Disease Outcome Quality Initiative (NKF/DOQI) Advisory Board criteria, which define stage I chronic kidney disease (CKD) as GFR >= 90mL/min/1.73 m(2), stage II as 60-89 mL/min/1.73m(2), stage III as 30-59 mL/min/1.73 m(2), stage IV as 15-29 mL/min/1.73m(2), and stage V as < 15 mL/min/1.73m(2). Results. Six patients completed 36 months of therapy, 2 patients completed 18 months, and 1 patient completed 12 months. Mean patient age at baseline was 34.6 +/- 11.3 years. During the study period, kidney function remained stable in patients with stages I, II, or III CKD. One patient, who entered the study with stage IV CKD, progressed to end-stage chronic kidney disease, beginning hemodialysis after 7 months and receiving a kidney transplant after 12 months of ERT. Proteinuria also remained stable in the group of patients with pathologic proteinuria. The use of agalsidase alfa was well tolerated in 99.5% of the infusions administered. Conclusion. Over the course of 36 months of ERT, there was no change in kidney function and 24-hour proteinuria. This suggests thatagalsidase alfa may slow or halt the progression of kidney disease when used before extensive kidney damage occurs. No significant side effects were observed with ERT during the course of the study.

Suicide behavior and neuropsychological assessment of type I bipolar patients

Background: Neuropsychological deficits are often described in patients with bipolar disorder (BID). Some symptoms and/or associated characteristics of BD can be more closely associated to those cognitive impairments. We aimed to explore cognitive neuropsychological characteristics of type I bipolar patients (BPI) in terms Of lifetime Suicide attempt history. Method: We studied 39 BPI Outpatients compared with 53 healthy controls (HC) matched by age, educational and intellectual level. All Subjects were submitted to a neuropsychological assessment of executive functions, decision-making and declarative episodic memory. Results: When comparing BD1 patients, regardless of suicide attempt history or HC, we observed that bipolar patients performed worse than controls oil measures of memory, attention, executive functions and decision-making, Patients with a history of suicide attempt performed worse than non-attempters on measures of decision-making and there were a significant negative correlation between the number of suicide attempts and decision-making results (block 3 and net score). We also found significant Positive correlation between the number Of Suicide attempts and amount Of errors in Stroop Color Word Test (part 3). Limitations: The sample Studied call be considered small and a potentially confounding variable - medication status - were not controlled. Conclusion: Our results show the presence of neuropsychological deficits in memory, executive functions, attention and decision-making in BPI patients. Suicide attempts BPI scored worse than non-suicide attempt Bill oil measures of decision-making. More suicide attempts were associated with a worse decision-making process. Future research should explore the relationship between the association between this specific cognitive deficits in BPIs, serotonergic function and suicide behavior in bipolar patients as well other diagnostic groups. (C) 2009 Elsevier B.V. All rights reserved.

Cost-Effectiveness of Palliation of Unresectable Esophageal Cancer

Introduction Different modalities of palliation for obstructive symptoms in patients with unresectable esophageal cancer (EC) exist. However, these therapeutic alternatives have significant differences in costs and effectiveness. Methods A Markov model was designed to compare the cost-effectiveness (CE) of self-expandable stent (SES), brachytherapy and laser in the palliation of unresectable EC. Patients were assigned to one of the strategies, and the improvement in swallowing function was compared given the treatment efficacy, probability of survival, and risks of complications associated to each strategy. Probabilities and parameters for distribution were based on a 9-month time frame. Results Under the base-case scenario, laser has the lowest CE ratio, followed by brachytherapy at an incremental cost-effectiveness ratio (ICER) of $4,400.00, and SES is a dominated strategy. In the probabilistic analysis, laser is the strategy with the highest probability of cost-effectiveness for willingness to pay (WTP) values lower than $3,201 and brachytherapy for all WTP yielding a positive net health benefit (NHB) (threshold $4,440). The highest probability of cost-effectiveness for brachytherapy is 96%, and consequently, selection of suboptimal strategies can lead to opportunity losses for the US health system, ranging from US$ 4.32 to US$ 38.09 million dollars over the next 5-20 years. Conclusion Conditional to the WTP and current US Medicare costs, palliation of unresectable esophageal cancers with brachytherapy provides the largest amount of NHB and is the strategy with the highest probability of CE. However, some level of uncertainly remains, and wrong decisions will be made until further knowledge is acquired.

New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder-Robinson X-linked recessive mental retardation syndrome

We report the identification of a novel mutation at a highly conserved residue within the N-terminal region of spermine synthase (SMS) in a second family with Snyder-Robinson X-linked mental retardation syndrome ( OMIM 309583). This missense mutation, p.G56S, greatly reduces SMS activity and leads to severe epilepsy and cognitive impairment. Our findings contribute to a better delineation and expansion of the clinical spectrum of Snyder-Robinson syndrome, support the important role of the N-terminus in the function of the SMS protein, and provide further evidence for the importance of SMS activity in the development of intellectual processing and other aspects of human development.

The role of BPH, lower urinary tract symptoms, and PSA levels on erectile function of Brazilian men who undergo prostate cancer screening

Introduction. Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are common problems in middle-aged and older men. Recently, epidemiologic studies have shown significant associations between severity of LUTS and male sexual dysfunction. Aim. We analyzed the role of prostate enlargement, LUTS, and prostate specific antigen (PSA) levels in the erectile function of Brazilian men who underwent prostate cancer (PCa) screening. Method. We analyzed data from 1,008 consecutive patients enrolled in a PCa screening program. Benign prostatic hyperplasia (BPH) was defined as a prostate weight greater than 30 g as defined by digital rectal examination. For statistical analysis, we used the chi-squared and analysis of variance tests. The odds ratios (OR) for correlation of ED with prostate volume LUTS and PSA were estimated using logistic regression models. Main Outcome Measure. The American Urological Association (AUA) symptom score for LUTS and the International Index of Erectile Function. Results. Mean patient age was 61.2 years (45-87) and median PSA value was 1.9 ng/mL. BPH was identified in 48.5% of patients. Mild, moderate, and severe LUTS were found in 52.3%, 30.9%, and 16.8% of cases, respectively. ED was classified as absent, mild, mild to moderate, moderate, and severe in 18.6%, 23.1%, 18.6%, 15.2%, and 24.5%, respectively. While only 5.4% of the patients with no ED presented severe LUTS, this finding was observed in 27.1% of patients with severe ED (P<0.001). Univariate logistic regression analysis demonstrated that age, prostate volume, AUA symptom score, and PSA levels were significant predictors of ED. However, when controlled for patient age, only LUTS remained as an independent predictor of ED. Conclusions. Controlling for patient age, LUTS are independent risk factors for the development of ED among Brazilian men who undergo PCa screening.

Quantitative parameters of facial motor evoked potential during vestibular schwannoma surgery predict postoperative facial nerve function

Background Facial motor evoked potential (FMEP) amplitude ratio reduction at the end of the surgery has been identified as a good predictor for postoperative facial nerve outcome. We sought to investigate variations in FMEP amplitude and waveform morphology during vestibular schwannoma (VS) resection and to correlate these measures with postoperative facial function immediately after surgery and at the last follow-up. Methods Intraoperative orbicularis oculi and oris muscles FMEP data from 35 patients undergoing surgery for VS resection were collected, then analysed by surgical stage: initial, dural opening, tumour dissection (TuDis), tumour resection (TuRes) and final. Findings Immediately after surgery, postoperative facial function correlated significantly with the FMEP amplitude ratio during TuDis, TuRes and final stages in both the orbicularis oculi (p = 0.003, 0.055 and 0.028, respectively) and oris muscles (p = 0.002, 0.104 and 0.014, respectively). At the last follow-up, however, facial function correlated significantly with the FMEP amplitude ratio only during the TuDis (p = 0.005) and final (p = 0.102) stages for the orbicularis oris muscle. At both time points, postoperative facial paresis correlated significantly with FMEP waveform deterioration in orbicularis oculi during the final stage (immediate, p = 0.023; follow-up, p = 0.116) and in orbicularis oris during the TuDis, TuRes and final stages (immediate, p = 0.071, 0.000 and 0.001, respectively; follow-up, p = 0.015, 0.001 and 0.01, respectively). Conclusions FMEP amplitude ratio and waveform morphology during VS resection seem to represent independent quantitative parameters that can be used to predict postoperative facial function. Event-to-baseline FMEP monitoring is quite useful to dictate when intraoperative changes in surgical strategy are warranted to reduce the chances of facial nerve injury.

A decision support system to facilitate management of patients with acute gastrointestinal bleeding

Objective: To develop a model to predict the bleeding source and identify the cohort amongst patients with acute gastrointestinal bleeding (GIB) who require urgent intervention, including endoscopy. Patients with acute GIB, an unpredictable event, are most commonly evaluated and managed by non-gastroenterologists. Rapid and consistently reliable risk stratification of patients with acute GIB for urgent endoscopy may potentially improve outcomes amongst such patients by targeting scarce health-care resources to those who need it the most. Design and methods: Using ICD-9 codes for acute GIB, 189 patients with acute GIB and all. available data variables required to develop and test models were identified from a hospital medical records database. Data on 122 patients was utilized for development of the model and on 67 patients utilized to perform comparative analysis of the models. Clinical data such as presenting signs and symptoms, demographic data, presence of co-morbidities, laboratory data and corresponding endoscopic diagnosis and outcomes were collected. Clinical data and endoscopic diagnosis collected for each patient was utilized to retrospectively ascertain optimal management for each patient. Clinical presentations and corresponding treatment was utilized as training examples. Eight mathematical models including artificial neural network (ANN), support vector machine (SVM), k-nearest neighbor, linear discriminant analysis (LDA), shrunken centroid (SC), random forest (RF), logistic regression, and boosting were trained and tested. The performance of these models was compared using standard statistical analysis and ROC curves. Results: Overall the random forest model best predicted the source, need for resuscitation, and disposition with accuracies of approximately 80% or higher (accuracy for endoscopy was greater than 75%). The area under ROC curve for RF was greater than 0.85, indicating excellent performance by the random forest model Conclusion: While most mathematical models are effective as a decision support system for evaluation and management of patients with acute GIB, in our testing, the RF model consistently demonstrated the best performance. Amongst patients presenting with acute GIB, mathematical models may facilitate the identification of the source of GIB, need for intervention and allow optimization of care and healthcare resource allocation; these however require further validation. (c) 2007 Elsevier B.V. All rights reserved.