Pharmacodynamics of PEG-IFN-alpha-2a and HCV Response as a Function of IL28B Polymorphism in HIV/HCV-Coinfected Patients

We examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models. African Americans and whites had a similar distribution of IL28B genotypes (P = 0.5). The IL28B CC genotype was overrepresented (P = 0.015) in patients infected with HCV genotype-3 compared with genotype-1. In both genotype-1 and genotype-3, the first-phase viral decline and the average pegylated interferon-alpha-2a effectiveness during the first week of therapy were larger (trend P <= 0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second slower phase of viral decline (days 2-29) and infected cells loss rate, delta, were larger (P = 0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.

Fascicular Topography of the Suprascapular Nerve in the C5 Root and Upper Trunk of the Brachial Plexus: A Microanatomic Study From a Nerve Surgeon`s Perspective

BACKGROUND: In patients with supraclavicular injuries of the brachial plexus, the suprascapular nerve (SSN) is frequently reconstructed with a sural nerve graft coapted to C5. As the C5 cross-sectional diameter exceeds the graft diameter, inadequate positioning of the graft is possible. OBJECTIVE: To identify a specific area within the C5 proximal stump that contains the SSN axons and to determine how this area could be localized by the nerve surgeon, we conducted a microanatomic study of the intraplexal topography of the SSN. METHODS: The right-sided C5 and C6 roots, the upper trunk with its divisions, and the SSN of 20 adult nonfixed cadavers were removed and fixed. The position and area occupied by the SSN fibers inside C5 were assessed and registered under magnification. RESULTS: The SSN was monofascicular in all specimens and derived its fibers mainly from C5. Small contributions from C6 were found in 12 specimens (60%). The mean transverse area of C5 occupied by SSN fibers was 28.23%. In 16 specimens (80%), the SSN fibers were localized in the ventral (mainly the rostroventral) quadrants of C5, a cross-sectional area between 9 o`clock and 3 o`clock from the surgeon`s intraoperative perspective. CONCLUSION: In reconstruction of the SSN with a sural nerve graft, coaptation should be performed in the rostroventral quadrant of C5 cross-sectional area (between 9 and 12 o`clock from the nerve surgeon`s point of view in a right-sided brachial plexus exploration). This will minimize axonal misrouting and may improve outcome.

Glial cell line-derived neurotrophic factor added to a sciatic nerve fragment grafted in a spinal cord gap ameliorates motor impairments in rats and increases local axonal growth

Purpose: The aversive nature of regenerative milieu is the main problem related to the failure of neuronal restoration in the injured spinal cord which however might be addressed with an adequate repair intervention. We evaluated whether glial cell line-derived neurotrophic factor (GDNF) may increase the ability of sciatic nerve graft, placed in a gap promoted by complete transections of the spinal cord, to enhance motor recovery and local fiber growth. Methods: Rats received a 4 mm-long gap at low thoracic level and were repaired with a fragment of the sciatic nerve. GDNF was added (NERVE+GDNF) or not to the grafts (NERVE-GDNF). Motor behavior score (BBB) and sensorimotor tests-linked to the combined behavior score (CBS), which indicate the degree of the motor improvement and the percentage of functional deficit, respectively, and also the spontaneous motor behavior in an open field by means of an infrared motion sensor activity monitor were analyzed. At the end of the third month post surgery, the tissue composed by the graft and the adjacent regions of the spinal cord was removed and submitted to the immunohistochemistry of the neurofilament-200 (NF-200), growth associated protein-43 (GAP-43), microtubule associated protein-2 (MAP-2), 5-hidroxytryptamine (serotonin, 5-HT) and calcitonin gene related peptide (CGRP). The immunoreactive fibers were quantified at the epicenter of the graft by means of stereological procedures. Results: Higher BBB and lower CBS levels (p < 0.001) were found in NERVE+GDNF rats. GDNF added to the graft increased the levels of individual sensorimotor tests mainly at the third month. Analysis of the spontaneous motor behavior showed decreases in the time and number of small movement events by the third month without changes in time and number of large movement events in the NERVE+GDNF rats. Immunoreactive fibers were encountered inside the grafts and higher amounts of NF-200, GAP-43 and MAP-2 fibers were found in the epicenter of the graft when GDNF was added. A small amount of descending 5-HT fibers was seen reentering in the adjacent caudal levels of the spinal cords which were grafted in the presence of GDNF, event that has not occurred without the neurotrophic factor. GDNF in the graft also led to a large amount of MAP-2 perikarya and fibers in the caudal levels of the cord gray matter, as determined by the microdensitometric image analysis. Conclusions: GDNF added to the nerve graft favored the motor recovery, local neuronal fiber growth and neuroplasticity in the adjacent spinal cord.

Influence of Suture on Peripheral Nerve Regeneration and Collagen Production at the Site of Neurorrhaphy: An Experimental Study

BACKGROUND: Restoration of nerve continuity and effective maintenance of coaptation are considered fundamental principles of end-to-end peripheral nerve repair. OBJECTIVE: To evaluate the influence of the number of stitches on axonal regeneration and collagen production after neurorrhaphy. METHODS: Thirty male Wistar rats were equally divided into 3 groups and were all operated on with the right sciatic nerve exposed. In 2 groups, the nerve was sectioned and repaired by means of 3 (group B) or 6 (group C) epineurium sutures with 100 monofilament nylon. One group (group A) was used as a control. Each animal from groups B and C underwent electrophysiological evaluation with motor action potential recordings before nerve section and again at an 8-week interval after neurorrhaphy. Nerve biopsy specimens were used for histomorphometric assessment of axonal regeneration and quantification of collagen at the repair site. RESULTS: Animals from group C had significantly lower motor action potential conduction velocities compared with control animals (P = .02), and no significant difference was seen between groups B and C. Parameters obtained from morphometric evaluation were not significantly different between these 2 groups. Type I collagen and III collagen in the epineurium were significantly higher in group C than in either the control group (P = .001 and P = .003) or group B (P = .01 and P = .02). No differences were identified for collagen I and III in the endoneurium. CONCLUSION: Using 6 sutures for nerve repair is associated with worse electrophysiological outcomes and higher amounts of type I and III collagen in the epineurium compared with control. Neurorraphy with 6 stitches is also related to a significant increase in epineurium collagen I and III compared with 3-stitch neurorraphy.

Cor pulmonale in a patient with Brown-Vialetto-Van Laere syndrome: A case report

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare neurological disease characterized by sensorineural hearing loss and multiple cranial nerve palsies, usually involving the VIIth and IXth to XIIth cranial nerves. We describe the clinical and pathological features of a 33-year-old woman with BVVLS. The patient developed progressive exertional dyspnea, with clinical and laboratory findings of right-sided heart failure and pulmonary hypertension. She developed status epilepticus in the setting of cardiac deterioration and respiratory infection, and died of cardiogenic and septic shock. Autopsy disclosed bilateral neuronal loss and gliosis in the inferior colliculi, locus coeruleus and facial and vestibular nuclei. Cor pulmonale is a complication of hypoventilation-induced hypoxia and hypercapnia and had not yet been reported in BVVLS. (C) 2010 Elsevier B.V. All rights reserved.

Evaluation of retinal nerve fiber layer thickness measurements using optical coherence tomography in patients with tobacco-alcohol-induced toxic optic neuropathy

Three patients with progressive visual loss, chronic alcoholism and tabagism were submitted to a complete neuro-ophthalmic examination and to retinal nerve fiber layer (RNFL) measurements using optical coherence tomography (OCT) scanning. Two patients showed marked RNFL loss in the temporal sector of the optic disc. However, a third patient presented RNFL measurements within or above normal limits, based on the Stratus-OCT normative database. Such findings may be due to possible RNFL edema similar to the one that may occur in the acute phase of toxic optic neuropathies. Stratus-OCT was able to detect RNFL loss in the papillomacular bundle of patients with tobacco-alcohol-induced toxic optic neuropathy. However, interpretation must be careful when OCT does not show abnormality in order to prevent diagnostic confusion, since overestimation of RNFL thickness measurements is possible in such cases.

Comparison of Quantitative Imaging Devices and Subjective Optic Nerve Head Assessment by General Ophthalmologists to Differentiate Normal From Glaucomatous Eyes

Purpose: To compare the ability of Subjective assessment of optic nerve head (ONH) and retinal nerve fiber layer (RNFL) by general ophthalmologists and by a glaucoma expert with objective measurements by optical coherence tomography (Stratus OCT, Carl Zeiss Meditec Inc), confocal scanning laser ophthalmoscope (HRT III; Heidelberg Engineering, Heidelberg. Germany), and scanning laser polarimetry (GDx enhanced corneal compensation; Carl Zeiss Meditec Inc, Dublin, CA) in discriminating glaucomatous and normal eyes. Methods: Sixty-one glaucomatous and 57 normal eyes or 118 subjects Were included in the study. Three independent general ophthalmologists and I glaucoma expert evaluated ONH stereo-photographs. Receiver operating characteristic curves were constructed for each imaging technique and sensitivity at fixed specificity was estimated. Comparisons or areas under these curves (aROCs) and agreement (k) were determined between stereophoto grading and best parameter from each technique. Results: Best parameter from each technique showed larger aROC (Stratus OCT RNFL 0.92; Stratus OCT ONH vertical integrated area = 0.86; Stratus OCT macular thickness = 0.82; GDx enhanced corneal compensation = 0.91, HRT3 global cup-to-disc ratio = 0.83; HRT3 glaucoma probability score numeric area score 0.83) compared with stereophotograph grading by general ophthalmologists (0.80) in separating glaucomatous and normal eyes. Glaucoma expert stereophoto grading provided equal or larger aROC (0.92) than best parameter of each computerized imaging device. Stereophoto evaluated by a glaucoma expert showed better agreement with best parameter of each quantitative imaging technique in classifying eyes either as glaucomatous or normal compared with stereophoto grading by general ophthalmologists, The combination Of Subjective assessment of the optic disc by general ophthalmologists with RNFL objective parameters improved identification of glaucoma patients in a larger proportion than the combination of these objective parameters with Subjective assessment of the optic disc by a glaucoma expert (29.5% vs. 19.7%, respectively). Conclusions: Diagnostic ability of all imaging techniques showed better performance than subjective assessment of the ONH by general ophthalmologists, but not by It glaucoma expert, Objective RNFL measurements may provide improvement in glaucoma detection when combined with subjective assessment of the optic disc by general ophthalmologists or by a glaucoma expert.

Comparison of the GDx VCC scanning laser polarimeter and the stratus optical coherence tomograph in the detection of band atrophy of the optic nerve

Aim To compare the ability of scanning laser polarimeter (SLP) with variable corneal compensation (GDx VCC) and optical coherence tomograph (Stratus OCT) to discriminate between eyes with band atrophy (BA) of the optic nerve and healthy eyes. Methods The study included 37 eyes with BA and temporal visual field (VF) defects from chiasmal compression, and 29 normal eyes. Subjects underwent standard automated perimetry (SAP) and retinal nerve fibre layer (RNFL) scans using GDx VCC and Stratus OCT. The severity of the VF defects was evaluated by the temporal mean defect (TMD), calculated as the average of 22 values of the temporal total deviation plot on SAP. Receiver operating characteristic (ROC) curves were calculated. Pearson`s correlation coefficients were used to evaluate the relationship between RNFL thickness parameters and the TMD. Results No significant difference was found between the ROC curves areas (AUCs) for the GDx VCC and Stratus OCT with regard to average RNFL thickness (0.98 and 0.99, respectively) and the superior (0.94; 0.95), inferior (0.96; 0.97), and nasal (0.92; 0.96) quadrants. However, the AUC in the temporal quadrant (0.77) was significantly smaller (P < 0.001) with GDx VCC than with Stratus OCT (0.98). Lower TMD values were associated with smaller RNFL thickness in most parameters from both equipments. Conclusion Adding VCC resulted in improved performance in SLP when evaluating eyes with BA, and both technologies are sensitive in detecting average, superior, inferior, and nasal quadrant RNFL loss. However, GDx VCC still poorly discriminates RNFL loss in the temporal quadrant when compared with Stratus OCT.

Long-term follow-up of children with extrahepatic portal vein obstruction: impact of an endoscopic sclerotherapy program on bleeding episodes, hepatic function, hypersplenism, and mortality

Background: Endoscopic sclerotherapy (ES) has been the standard treatment for children with idiopathic extrahepatic portal vein obstruction (EHPVO). Portosystemic shunts are indicated when variceal bleeding cannot be controlled by ES. Recently, mesenteric left portal vein bypass was indicated as a surgical intervention and preventative measure for hepatic dysfunction in children with long-term EHPVO. Nevertheless, there is a lack Of published data confirming the extent of hepatic dysfunction, hypersplenism, and physical development in children with long-term follow-up. Method: We retrospectively verified the long-term outcomes in 82 children with EHPVO treated with ES protocol, focusing on mortality, control of bleeding, hypersplenism, and consequent hepatic dysfunction. Results: Of the children, 56% were free from bleeding after the initiation of ES. The most frequent cause of rebleeding was gastric varices (30%). Four patients had recurrent bleeding from esophageal varices (4.6%). Four patients underwent surgery as a consequence of uncontrolled gastric varices. There were no deaths. Most patients showed good physical development. We observed a mild but statistically significant drop in factor V motion, as well as leukocyte and platelet count. Conclusion: Endoscopic sclerotherapy is an efficient treatment for children with EHPVO. The incidence of rebleeding is low, and there was no mortality. Children develop mild liver dysfunction and hypersplenism with long-term follow-up. Only a few patients manifest symptoms of hypersplenism, portal biliopathy, or liver dysfunction before adolescence. (C) 2009 Elsevier Inc. All rights reserved.

Patients Receiving Physical Rehabilitation: Records of Sexual Function Before the Introduction of Erectogenic Drugs

The objective of this study is to evaluate the entries associated to the sexual function of patients undergoing physical disability rehabilitation, as well as the course of changes and medical approach through a retrospective review of medical charts. Methods: Medical records referring to the period between July and September, 1998 were evaluated. The data was divided into two groups, records containing physician`s entries on sexual function and/or entries of other health care professionals. The following aspects were investigated: whether complaints were spontaneously voiced by the patient, and whether diagnosis had been reached, with corresponding management. Results: Out of 245 medical records investigated, 17 (6.9%) contained clinical observations on the sexual function; out of those, 14 reached diagnosis. Twelve records (4.9%) had information by non-medical healthcare professionals. Out of 17 entries by doctors, 16 referred to male patients, which was found to be significant (p = 0.0202). Conclusions: Records for the sexual function of patients undergoing physical rehabilitation are scarce. In this population, the sexual function of male patients had more extensive investigation on the part of physicians when compared to other health care professionals.

Prevalence of Erectile Dysfunction as Defined by the International Index of Erectile Function (IIEF) and Self-Reported Erectile Dysfunction in a Sample of Brazilian Men Who Consider Themselves Healthy

A cross-sectional study was carried out with 288 male blood donors, aged between 40 and 60 years old, with the aim of comparing the prevalence of erectile dysfunction (ED) as defined by the International Index of Erectile Function (IIEF) and that resulting from the simple questioning of the presence of ED. Socio-demographic, clinical, and behavioral factors that are associated with the presence of ED were considered. Erectile dysfunction prevalence in the IIEF was 31.9%, while self-reported ED prevalence was 3.1%. The factors associated to ED, as reported by the IIEF were: professional inactivity, suspected depression and/or anxiety, reduced sexual desired, and self-reported ED.

POLYETHYLENE GLYCOL ADDITION DOES NOT IMPROVE EXOGENOUS SURFACTANT FUNCTION IN AN EXPERIMENTAL MODEL OF MECONIUM ASPIRATION SYNDROME

Meconium (MEC) is a potent inactivator of pulmonary surfactant. The authors studied the effects of polyethylene glycol addition to the exogenous surfactant over the lung mechanics and volumes. Human meconium was administrated to newborn rabbits. Animals were ventilated for 20 minutes and dynamic compliance, ventilatory pressure, and tidal volume were recorded. Animals were randomized into 3 study groups: MEC group (without surfactant therapy); S100 group (100 mg/kg surfactant); and PEG group (100 mg/kg porcine surfactant plus 5% PEG). After ventilation, a pulmonary pressure-volume curve was built. Histological analysis was carried out to calculate the mean alveolar size (Lm) and the distortion index (DI). Both groups treated with surfactant showed higher values of dynamic pulmonary compliance and lower ventilatory pressure, compared with the MEC group (P .05). S100 group had a larger maximum lung volume, V30, compared with the MEC group (P .05). Lm and DI values were smaller in the groups treated with surfactant than in the MEC group (P .05). No differences were observed between the S100 and PEG groups. Animals treated with surfactant showed significant improvement in pulmonary function as compared to nontreated animals. PEG added to exogenous surfactant did not improve lung mechanics or volumes.

Expression of smooth muscle and extracellular matrix proteins in relation to airway function in asthma

Background: Smooth muscle content is increased within the airway wall in patients with asthma and is likely to play a role in airway hyperresponsiveness. However, smooth muscle cells express several contractile and structural proteins, and each of these proteins may influence airway function distinctly. Objective: We examined the expression of contractile and structural proteins of smooth muscle cells, as well as extracellular matrix proteins, in bronchial biopsies of patients with asthma, and related these to lung function, airway hyperresponsiveness, and responses to deep inspiration. Methods: Thirteen patients with asthma (mild persistent, atopic, nonsmoking) participated in this cross-sectional study. FEV1 % predicted, PC20 methacholine, and resistance of the respiratory system by the forced oscillation technique during tidal breathing and deep breath were measured. Within 1 week, a bronchoscopy was performed to obtain 6 bronchial biopsies that were immunuhistochemically stained for alpha-SM-actin, desmin, myosin light chain kinase (MLCK), myosin, calponin, vimentin, elastin, type III collagen, and fibronectin. The level of expression was determined by automated densitometry. Results: PC20 methacholine was inversely related to the expression of alpha-smooth muscle actin (r = -0.62), desmin (r = -0.56), and elastin (r = -0.78). In addition, FEV1% predicted was positively related and deep inspiration-induced bronchodilation inversely related to desmin (r = -0.60), MLCK (r = -0.60), and calponin (r = -0.54) expression. Conclusion: Airway hyperresponsiveness, FEV1% predicted, and airway responses to deep inspiration are associated with selective expression of airway smooth muscle proteins and components of the extracellular matrix.

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.

Baroreflex deficit blunts exercise training-induced cardiovascular and autonomic adaptations in hypertensive rats

P>1. Baroreceptors regulate moment-to-moment blood pressure (BP) variations, but their long-term effect on the cardiovascular system remains unclear. Baroreceptor deficit accompanying hypertension contributes to increased BP variability (BPV) and sympathetic activity, whereas exercise training has been associated with an improvement in these baroreflex-mediated changes. The aim of the present study was to evaluate the autonomic, haemodynamic and cardiac morphofunctional effects of long-term sinoaortic baroreceptor denervation (SAD) in trained and sedentary spontaneously hypertensive rats (SHR). 2. Rats were subjected to SAD or sham surgery and were then further divided into sedentary and trained groups. Exercise training was performed on a treadmill (five times per week, 50-70% maximal running speed). All groups were studied after 10 weeks. 3. Sinoaortic baroreceptor denervation in SHR had no effect on basal heart rate (HR) or BP, but did augment BPV, impairing the cardiac function associated with increased cardiac hypertrophy and collagen deposition. Exercise training reduced BP and HR, re-established baroreflex sensitivity and improved both HR variability and BPV. However, SAD in trained SHR blunted all these improvements. Moreover, the systolic and diastolic hypertensive dysfunction, reduced left ventricular chamber diameter and increased cardiac collagen deposition seen in SHR were improved after the training protocol. These benefits were attenuated in trained SAD SHR. 4. In conclusion, the present study has demonstrated that the arterial baroreflex mediates cardiac disturbances associated with hypertension and is crucial for the beneficial cardiovascular morphofunctional and autonomic adaptations induced by chronic exercise in hypertension.