CYLD mutations in familial skin appendage tumours

Background: Germ-line mutations in CYLD are found in patients with familial skin appendage tumours. The protein product functions as a deubiquitinase enzyme, which negatively regulates NF-kappa B and c-Jun N-terminal kinase signalling. Brooke-Spiegler syndrome (BSS) is characterised by cylindromas, trichoepitheliomas and spiradenomas, whereas in familial cylindromatosis (FC) patients present with cylindromas and in multiple familial trichoepitheliomas (MFT) with trichoepitheliomas as the only skin tumour type. Although described as distinct entities, recent studies suggest that they are within the spectrum of a single entity. Objective: To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations. Methods: 25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene. Results: In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BSS, 100% for FC, and 44% for MFT. The majority of the mutations were insertions, deletions or nonsense mutations leading to formation of truncated proteins. All mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal a correlation between the types of mutations and their location within the gene and the patients` phenotypes and disease severity. Conclusions: This study provides further evidence on the role of CYLD in the pathogenesis of skin appendage tumours characterised by cylindromas, trichoepitheliomas and/or spiradenomas, but the molecular mechanisms of CYLD in skin tumorigenesis and the reasons for phenotypic variability remain to be explored.

Fatigue in amyotrophic lateral sclerosis: Frequency and associated factors

We aimed to quantify fatigue frequency and evolution in amyotrophic lateral sclerosis (ALS), and to correlate fatigue with factors such as age, sex, educational level, disease duration, functionality, quality of life, dyspnoea, depression and sleepiness. Sixty ALS patients (test group: TG) selected by El Escorial criteria and 60 normal individuals (control group: CG) matched according to sex and age, were followed every three months, during 9 months, by means of self-report scales: Fatigue Assessment Instrument (Fatigue Severity Scale plus three qualitative subscales); ALS Functional Rating Scale; McGill Quality of Life Questionnaire; dyspnoea analogical scale; Beck Depression Inventory and Epworth Sleepiness Scale. Fatigue was reported by 83% of TG (median: 3.6, interquartile range 1.5-5.4), compared with 20% of CG (median: 1, 1 - 1), and was significantly greater in the TG (p < 0.001, Mann-Whitney test). Fatigue severity increased by the ninth month of the study (p=0.0008, Friedman, Muller-Dunn post test). There was no correlation between fatigue and other parameters, except for an inverse correlation with age at disease onset (p=0.0395, Spearman rank correlation). In conclusion, fatigue was frequent in ALS, greater in the youngest patients and worsened during follow-up. Possibly, ALS related fatigue is an independent factor, which deserves individualized approach and treatment.

Scanning laser polarimetry with enhanced corneal compensation for detection of axonal loss in band atrophy of the optic nerve

PURPOSE: To compare the abilities of scanning laser polarimetry (SLP) with enhanced corneal compensation (ECC) and variable corneal compensation (VCC) modes for detection of retinal nerve fiber layer (RNFL) loss in eyes with band atrophy (BA) of the optic nerve. DESIGN. Cross-sectional study. METHODS: Thirty-seven eyes from 37 patients with BA and temporal visual field defect from chiasmal compression and 40 eyes from 40 healthy subjects were studied. Subjects underwent standard automated perimetry and RNFL measurements using an SLP device equipped with VCC and ECC. Receiver operating characteristic (ROC) curves were calculated for each parameter. Pearson correlation coefficients were obtained to evaluate the relationship between RNFL thickness parameters and severity of visual field loss, as assessed by the temporal mean defect. RESULTS: All RNFL thickness parameters were significantly lower in eyes with BA compared with normal eyes with both compensation modes. However, no statistically significant differences were observed in the areas under the ROC curves for the different parameters between GDx VCC and ECC (Carl Zeiss Meditec, Inc, Dublin, California, USA). Structure-function relationships also were similar for both compensation modes. CONCLUSIONS: No significant differences were found between the diagnostic accuracy of GDx ECC and that of VCC for detection of BA of the optic nerve. The use of GDx ECC does not seem to provide a better evaluation of RNFL loss on the temporal and nasal sectors of the peripapillary retina in subjects with BA of the optic nerve.

Dengue and dengue hemorrhagic fever among adults: Clinical outcomes related to viremia, serotypes, and antibody response

Background. Clinical manifestations of dengue vary in different areas of endemicity and between specific age groups, whereas predictors of outcome have remained controversial. In Brazil, the disease burden predominantly affects adults, with an increasing trend toward progression to dengue hemorrhagic fever (DHF) noted. Methods. A cohort of adults with confirmed cases of dengue was recruited in central Brazil in 2005. Patients were classified according to the severity of their disease. Associations of antibody responses, viremia levels (as determined by real-time polymerase chain reaction [PCR]), and serotypes (as determined by multiplex PCR) with disease severity were evaluated. Results. Of the 185 symptomatic patients > 14 years of age who had a confirmed case of dengue, 26.5% and 23.2% were classified as having intermediate dengue fever (DF)/ DHF (defined as internal hemorrhage, plasma leakage, manifested signs of shock, and/ or thrombocytopenia [platelet count, <= 50,000 platelets/mm(3)]) and DHF, respectively. The onset of intermediate DF/ DHF and DHF occurred at a late stage of disease, around the period of defervescence. Patients with DHF had abnormal liver enzyme levels, with a > 3-fold increase in aspartate aminotransferase level, compared with the range of values considered to be normal. Overall, 65% of patients presented with secondary infections with dengue virus, with such infection occurring in similar proportions of patients in each of the 3 disease category groups. Dengue virus serotype 3 (DV3) was the predominant serotype, and viremia was detected during and after defervescence among patients with DHF or intermediate DF/ DHF. Conclusions. Viremia was detected after defervescence in adult patients classified as having DHF or intermediate DF/ DHF. Secondary infection was not a predictor of severe clinical manifestation in adults with infected with the DV3 serotype.

Regression of glomerular injury by losartan in experimental diabetic nephropathy

Many features of chronic kidney disease may be reversed, but it is unclear whether advanced lesions, such as adhesions of sclerotic glomerular tufts to Bowman`s capsule (synechiae), can resolve during treatment. We previously showed, using a renal ablation model, that the renoprotective effect of the AT-1 receptor blocker, losartan, is dose-dependent. Here we determined if moderate and advanced glomerular lesions, associated with streptozotocin-induced diabetes, regress with conventional or high-dose losartan treatment. Using daily insulin injection for 10 months, we maintained diabetic adult male Munich-Wistar rats in a state of moderate hyperglycemia. Following this period, some rats continued to receive insulin with or without conventional or high-dose losartan for an additional 2 months. Diabetic rats pretreated with insulin for 10 months and age-matched non-diabetic rats served as controls. Mesangial expansion was found in the control diabetic rats and was exacerbated in those rats maintained on only insulin for an additional 2 months. Conventional and high-dose losartan treatments reduced this mesangial expansion and the severity of synechiae lesions below that found prior to treatment; however, the frequency of the latter was unchanged. There was no dose-response effect of losartan. Our results show that regression of mesangial expansion and contraction of sclerotic lesions is feasible in the treatment of diabetes, but complete resolution of advanced glomerulosclerosis may be hard to achieve.

Temporomandibular disorders and cutaneous allodynia are associated in individuals with migraine

The objective of this study was to estimate and contrast the occurrence of ictal and interictal cutaneous allodynia (CA) in individuals with migraine with and without temporomandibular disorders (TMD). Both TMD and CA are common in migraine and may be associated with migraine transformation from episodic into a chronic form. Herein we hypothesize that TMD contributes to the development of CA and to more severe headaches. In a clinic-based sample of individuals with episodic migraine, the presence of TMD was assessed using the research diagnostic criteria for myofascial or mixed (myofascial and arthralgic) TMD. Ictal CA was quantified using the validated Allodynia Symptom Checklist (ASC-12). The ASC-12 measures CA over the preceding month by asking 12 questions about the frequency of allodynia symptoms during headaches. Interictal CA was assessed in the domains of heat, cold and mechanical static allodynia using quantitative sensory testing. Our sample consists of 55 individuals; 40 (73%) had TMD (23 with myofascial TMD and 17 with the mixed type). CA of any severity (as assessed by ASC-12) occurred in 40% of those without TMD (reference group), 86.9% of those with myofascial TMD (P = 0.041, RR = 3.2, 95% CI = 1.5-7.0) and in 82.3% of those with mixed TMD (P = 0.02, RR = 2.5, 95% CI = 1.2-5.3). Individuals with TMD were more likely to have moderate or severe CA associated with their headaches. Interictally (quantitative sensory testing), thresholds for heat and mechanical nociception were significantly lower in individuals with TMD. Cold nociceptive thresholds were not significantly different in migraine patients with and without TMD. TMDs were also associated with change in extra-cephalic pain thresholds. In logistical regression, TMD remained associated with CA after adjusting for aura, gender and age. TMD and CA are associated in individuals with migraine.

Impact of a program for the prevention of traffic accidents in a Southern Brazilian city: a model for implementation in a developing country

Background: Traffic accidents constitute the main cause of death in the first decades of life. Traumatic brain injury is the event most responsible for the severity of these accidents. The SBN started an educational program for the prevention of traffic accidents, adapted from the American model ""Think First"" to the Brazilian environment, since 1995, with special effort devoted to the prevention of TBI by using seat belts and motorcycle helmets. The objective of the present study was to set up a traffic accident prevention program based on the adapted Think First and to evaluate its impact by comparing epidemiological variables before and after the beginning of the program. Methods: The program was executed in Maringa city, from September 2004 to August 2005, with educational actions targeting the entire population, especially teenagers and young adults. The program was implemented by building a network of information facilitators and multipliers inside the organized civil society, with widespread population dissemination. To measure the impact of the program, a specific software was developed for the storage and processing of the epidemiological variables. Results: The results showed a reduction of trauma severity due to traffic accidents after the execution of the program, mainly TBI. Conclusions: The adapted Think First was systematically implemented and its impact measured for the first time in Brazil, revealing the usefulness of the program for reducing trauma and TBI severity in traffic accidents through public education and representing a standardized model of implementation in a developing country. (C) 2009 Elsevier Inc. All rights reserved.

A morphometric study on the longitudinal and lateral symmetry of the sural nerve in mature and aging female rats

Aging affects peripheral nerve function and regeneration in experimental models but few literature reports deal with animals aged more than one year. We investigated morphological and morphometric aspects of the sural nerve in aging rats. Female Wistar rats 360, 640 and 720 days old were killed, proximal and distal segments of the right and left sural nerves were prepared for light microscopy and computerized morphometry. No morphometric differences between proximal and distal segments or between right and left sides at the same levels were found in all experimental groups. No increase in fiber and axon sizes was observed from 360 to 720 days. Likewise, no difference in total myelinated fiber number was observed between groups. Myelinated fiber population distribution was bimodal, being the 720-days old animals` distribution shifted to the left, indicating a reduction of the fiber diameters. The 9 ratio distribution of the 720-days old animals` myelinated fiber was also shifted to the left, which suggests axonal atrophy. Morphological alterations due to aging were observed, mainly related to the myelin sheath, which suggests demyelination. Large fibers were more affected than the smaller ones. Axon abnormalities were not as common or as obvious as the myelin changes and Wallerian degeneration was rarely found. These alterations were observed in all experimental groups but were much less pronounced in rats 360 days old and their severity increased with aging. in conclusion, the present study indicates that the aging neuropathy present in the sural nerve of female rats is both axonal and demyelinating. (C) 2008 Elsevier B.V. All rights reserved.

Management of acute psychostimulant toxicity

Psychostimulants produce a broad range of effects. Adverse effects can exist on a spectrum of severity from minor symptoms to life threatening toxicity. Although regular use or use of high doses increases risk of adverse events, many adverse events requiring emergency intervention may occur even in the naïve user.

Role of mixed Th1 and Th2 serum cytokines on pathogenesis and prognosis of hantavirus pulmonary syndrome

The hantavirus pulmonary syndrome (HPS) is an emerging syndrome in the Americas. The disease results from intense immune activation and changes in vascular permeability. The aim of this study was to determine the profile of serum cytokines in HPS patients looking for correlation with the clinical parameters, severity and outcome of illness. Studying 21 HPS patients, we found that IL-6 may have an important role in the pathogenesis of HPS, being associated with fatal outcome. Our results also support a mixed Th1/Th2 immune response during the course of HPS and that the magnitude of Th1 response effector cytokines is correlated to HPS severity. The decreased levels of TGF-beta observed in HPS patients suggest that immunoregulatory activity could be damaged in these patients. (c) 2008 Elsevier Masson SAS. All rights reserved.

Effects of changing blood viscosity and heart rate on vena contracta width as evaluated by color Doppler flow mapping. An in vitro study with a pulsatile flow model

Background: There is only limited knowledge on how the quantification of valvular regurgitation by color Doppler is affected by changing blood viscosity. This study was designed to evaluate the effect of changing blood viscosity on the vena contracta width using an in vitro model of valvular insufficiency capable of providing ample variation in the rate and stroke volume. Methods: We constructed a pulsatile flow model filled with human blood at varying hematocrit (15%, 35%, and 55%) and corresponding blood viscosity (blood/water viscosity: 2.6, 4.8, 9.1) levels in which jets were driven through a known orifice (7 mm(2)) into a 110 mL compliant receiving chamber (compliance: 2.2 mL/mmHg) by a pulsatile pump. In addition, we used variable pump stroke volumes (5, 7.5, and 10 mL) and rates (40, 60, and 80 ppm). Vena contracta region was imaged using a 3.5 MHz transducer. Pressure and volume in the flow model were kept constant during each experimental condition, as well as ultrasound settings. Results: Blood viscosity variation in the experimental range did not induce significant changes in vena contracta dimensions. Also, vena contracta width did not change from normal to low hematocrit and viscosity levels. A very modest increase only in vena contracta dimension was observed at very high level of blood viscosity when hematocrit was set to 55% . Pump rate, in the evaluated range, did not influence vena contracta width. These results in controlled experimental settings suggest that the vena contracta is an accurate quantitative method for quantifying valvular regurgitation even when this condition is associated with anemia, a frequent finding in patients with valvular heart disease.

Liver HLA-G expression is associated with multiple clinical and histopathological forms of chronic hepatitis B virus infection

As the mechanisms leading to the persistence of hepatitis B virus (HBV) infection are poorly understood and as the histocompatibility leucocyte antigen (HLA)-G is well described as a tolerogenic molecule, we evaluated HLA-G expression in 74 specimens of HBV liver biopsies and in 10 specimens obtained from previously healthy cadaver liver donors. HBV specimens were reviewed and classified by the METAVIR score, and HLA-G expression was assessed by immunohistochemistry. No HLA-G expression was observed in control hepatocytes. In contrast, 57 (77%) of 74 HBV specimens showed soluble and membrane-bound HLA-G expression in hepatocytes, biliary epithelial cells or both. No associations between the intensity of HLA-G expression and patient age or gender, HBeAg status, severity of liver fibrosis, and grade of histological findings were observed. Although significance was not reached (P = 0.180), patients exhibiting HLA-G expression presented a higher median HBV DNA viral load (105 copies/mL) than those who did not express HLA-G (103.7 copies/mL). These results indicate that HLA-G is expressed in most cases of chronic HBV infection in all stages and may play a role in the persistency of HBV infection.

A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family

Background: Hereditary angioedema is an autosomal dominant disease characterized by episodes of subcutaneous and submucosal edema. It is caused by deficiency of the C1 inhibitor protein, leading to elevated levels of bradykinin. More than 200 mutations in C1 inhibitor gene have been reported. The aim of this study was to analyze clinical features of a large family with an index case of hereditary angioedema and to determine the disease-causing mutation in this family. Methods: Family pedigree was constructed with 275 individuals distributed in five generations. One hundred and sixty-five subjects were interviewed and investigated for mutation at the C1 inhibitor gene. Subjects reporting a history of recurrent episodes of angioedema and/or abdominal pain attacks underwent evaluation for hereditary angioedema. Results: We have identified a novel mutation at the C1 inhibitor gene, c.351delC, which is a single-nucleotide deletion of a cytosine on exon 3, resulting in frameshift with premature stop codon. Sequencing analysis of the hypothetical truncated C1 inhibitor protein allowed us to conclude that, if transcription occurs, this protein has no biological activity. Twenty-eight members of the family fulfilled diagnostic criteria for hereditary angioedema and all of them presented the c.351delC mutation. Variation in clinical presentation and severity of disease was observed among these patients. One hundred and thirty-seven subjects without hereditary angioedema did not have the c.351delC mutation. Conclusion: The present study provides definitive evidence to link a novel genetic mutation to the development of hereditary angioedema in patients from a Brazilian family.

Perception of dysphagia: lack of correlation with objective measurements of esophageal function

Background The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically-induced esophageal hypocontractility, and in patients with gastro-esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM). Methods Combined manometry-impedance was performed in 10 HV, 19 GERD patients without IEM and nine patients with IEM. Additionally, nine HV were studied after 50 mg sildenafil, which induced esophageal peristaltic failure. Perception of each 5 mL viscous swallow was evaluated using a 5-point scale. Manometry identified hypocontractility (contractions lower than 30 mmHg) and impedance identified incomplete bolus clearance. Key Results In HV and in GERD patients with and without IEM, there was no association between either manometry or impedance and perception on per swallow analysis (OR: 0.842 and OR: 2.017, respectively), as well as on per subject analysis (P = 0.44 and P = 0.16, respectively). Lack of correlation was also found in HV with esophageal hypocontractility induced by sildenafil. Conclusions & Inferences There is no agreement between objective measurements of esophageal function and subjective perception of bolus passage. These results suggest that increased bolus passage perception in patients without mechanical obstruction might be due to esophageal hypersensitivity.

The H63D genetic variant of the HFE gene is independently associated with the virological response to interferon and ribavirin therapy in chronic hepatitis C

Background Conflicting results have been reported in studies evaluating the relationship between serum markers of iron overload, liver iron deposits, and HFE mutations (C282Y and H63D) in chronic hepatitis C patients, and also their impact on the response to therapy in these patients. Aim To evaluate the role of HFE mutations in the severity of liver disease and in the response to therapy in chronic hepatitis C. Methods Two hundred and sixty-four hepatitis C patients treated with standard interferon and ribavirin were divided into two groups according to type of antiviral response: sustained virological response (SVR) and nonresponse or relapse. We evaluated the relationship between HFE mutation and the type of antiviral response, clinical data, biochemical tests, liver histopathology, virological data, and HFE mutations. Results Of the 264 patients, 88 (32.1%) had SVR whereas 67.9% had nonresponse or relapse. Liver iron deposits were observed in 49.2% of the patients. The factors associated with SVR were hepatitis C virus genotype 2 or 3, transferrin saturation value of 45% or less, and detection of the H63D mutation. HFE mutation was more frequent in patients with iron deposits, but without association with serum iron biochemistry or severity of liver disease. Steatosis was more frequent in patients with liver iron deposits. Conclusion The H63D mutation was an independent factor associated with SVR in chronic hepatitis C patients, as also were hepatitis C virus genotype 2 or 3 and transferrin saturation value of 45% or less. Moreover, the H63D mutation was associated with liver iron deposits. Eur J Gastroenterol Hepatol 22: 1204-1210 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.