The central pathway of primary olfactory axons is abnormal in mice lacking the N-CAM-180 isoform

Although N-CAM has previously been implicated in the growth and fasciculation of axons, the development of axon tracts in transgenic mice with a targeted deletion of the 180-kD isoform of the neural cell adhesion molecule (N-CAM-180) appears grossly normal in comparison to wild-type mice. We examined the organization of the olfactory nerve projection from the olfactory neuroepithelium to glomeruli in the olfactory bulb of postnatal N-CAM-180 null mutant mice. Immunostaining for olfactory marker protein revealed the normal presence of fully mature primary olfactory neurons within the olfactory neuroepithelium of mutant mice. The axons of these neurons form an olfactory nerve, enter the nerve fiber layer of the olfactory bulb, and terminate in olfactory glomeruli as in wild-type control animals. The olfactory bulb is smaller and the nerve fiber layer is relatively thicker in mutants than in wild-type mice. Previous studies have revealed that the plant lectin Dolichos biflorus agglutinin (DBA) clearly stains the perikarya and axons of a subpopulation of primary olfactory neurons. Thus, DBA staining enabled the morphology of the olfactory nerve pathway to be examined at higher resolution in both control and mutant animals. Despite a normal spatial pattern of DBA-stained neurons within the nasal cavity, there was a distorted axonal projection of these neurons onto the surface of the olfactory bulb in N-CAM-180 null mutants. In particular, DBA-stained axons formed fewer and smaller glomeruli in the olfactory bulbs of mutants in comparison to wild-type mice. Many primary olfactory axons failed to exit the nerve fiber layer and contribute to glomerular formation. These results indicate that N-CAM-180 plays an important role in the growth and fasciculation of primary olfactory axons and is essential for normal development of olfactory glomeruli. (C) 1997 John Wiley & Sons, Inc.

Presence of novel N-CAM glycoforms in the rat olfactory system

The functional activity of the neural cell adhesion molecule N-CAM can be modulated by posttranslational modifications such as glycosylation. For instance, the long polysialic acid side chains of N-CAM alter the adhesion properties of the protein backbone. In the present study, we identified two novel carbohydrates present on N-CAM, NOC-3 and NOC-4. Both carbohydrates were detected on N-CAM glycoforms expressed by subpopulations of primary sensory olfactory neurons in the rat olfactory system. Based on the expression of NOC-3 and NOC-4 and the olfactory marker protein (OMP), four independent subpopulations of primary sensory olfactory neurons were characterized. These neurons expressed: both NOC-3 and NOC-4 but not OMP; both NOC-4 and OMP but not NOC-3; NOC-3, NOC-4, and OMP together; and OMP alone. The NOC-3- and NOC-4-expressing neurons were widely dispersed in the olfactory neuroepithelium lining the nasal cavity. The axons of NOC-4 expressing neurons innervated all glomeruli in the olfactory bulb, whereas the NOC-3 expressing axons terminated in a discrete subset of glomeruli scattered throughout the whole olfactory bulb. We propose that both NOC-3 and NOC-4 are part of a chemical code of olfactory neurons which is used in establishing the topography of connections between the olfactory neuroepithelium and the olfactory bulb. (C) 1997 John Wiley & Sons, Inc.

Molecular characterization of the Hepatitis B virus genotypes in Colombia: A Bayesian inference on the genotype F

Hepatitis B is a worldwide health problem affecting about 2 billion people and more than 350 million are chronic carriers of the virus. Nine HBV genotypes (A to I) have been described. The geographical distribution of HBV genotypes is not completely understood due to the limited number of samples from some parts of the world. One such example is Colombia, in which few studies have described the HBV genotypes. In this study, we characterized HBV genotypes in 143 HBsAg-positive volunteer blood donors from Colombia. A fragment of 1306 bp partially comprising HBsAg and the DNA polymerase coding regions (S/POL) was amplified and sequenced. Bayesian phylogenetic analyses were conducted using the Markov Chain Monte Carlo (MCMC) approach to obtain the maximum clade credibility (MCC) tree using BEAST v.1.5.3. Of all samples, 68 were positive and 52 were successfully sequenced. Genotype F was the most prevalent in this population (77%) - subgenotypes F3 (75%) and Fib (2%). Genotype G (7.7%) and subgenotype A2 (15.3%) were also found. Genotype G sequence analysis suggests distinct introductions of this genotype in the country. Furthermore, we estimated the time of the most recent common ancestor (TMRCA) for each HBV/F subgenotype and also for Colombian F3 sequences using two different datasets: (i) 77 sequences comprising 1306 bp of S/POL region and (ii) 283 sequences comprising 681 bp of S/POL region. We also used two other previously estimated evolutionary rates: (i) 2.60 x 10(-4) s/s/y and (ii) 1.5 x 10(-5) s/s/y. Here we report the HBV genotypes circulating in Colombia and estimated the TMRCA for the four different subgenotypes of genotype F. (C) 2010 Elsevier B.V. All rights reserved.

Molecular epidemiology and genetic diversity of hepatitis B virus genotype E in an isolated Afro-Colombian community

Hepatitis B virus (HBV) infection is a significant public health concern with 350 million chronic carriers worldwide. Eight HBV genotypes (A-H) have been described so far. Genotype E (HBV/E) is widely distributed in West Africa and has rarely been found in other continents, except for a few cases in individuals with an African background. In this study, we characterized HBV genotypes in Quibdo, Colombia, by partial S/P gene sequencing, and found, for the first time, HBV/E circulating in nine Afro-Colombian patients who had no recent contact with Africa. The presence of HBV/E in this community as a monophyletic group suggests that it was a result of a recent introduction by some Afro-descendent contact or, alternatively, that the virus came with slaves brought to Colombia. By using sequences with sampling dates, we estimated the substitution rate to be about 3.2x10(-4) substitutions per site per year, which resulted in a time to the most recent common ancestor (TMRCA) of 29 years. In parallel, we also estimated the TMRCA for HBV/E by using two previously estimated substitution rates (7.7x10(-4) and 1.5x10(-5) substitutions per site per year). The TMRCA was around 35 years under the higher rate and 1500 years under the slower rate. In sum, this work reports for the first time the presence of an exclusively African HBV genotype circulating in South America. We also discuss the time of the entry of this virus into America based on different substitution rates estimated for HBV.

A phylogenetic study of hepatitis B virus in chronically infected Brazilian patients of Western and Asian descent

Hepatitis B virus (HBV) causes one of the most important chronic viral infections worldwide. HBV is classified into eight genotypes whose epidemiology varies geographically. In Brazil, genotypes A, D, and F are more frequent, while in East Asia, genotypes B and C predominate. Several studies showed that immigrants retain the HBV infection pattern of their ancestral country. To identify HBV genotypes infecting chronic carriers in Brazilian families of Western and Asian descent by Hepatitis B surface antigen gene sequencing and analyze the route of viral transmission by phylogenetic analysis of viral sequences. Eighty-seven people chronically infected with HBV were separated into two groups: Western descent (27) and Asian descent (60). Surface and pre-core/core genes were amplified from serum HBV-DNA and sequences were subjected to phylogenetic analysis. HBV genotype A was found in 74% of Western subjects, while genotype C was found in 94% of Asian patients. Thirty-eight percent of Western families were infected with HBV with similar pre-core/core sequences, while only 25% of Asian families showed similarity in these sequences. Phylogenetical analysis of pre-core/core HBV gene suggested intra-familial transmission of HBV in 38% of Western families and 25% of Asian families. Analysis of HBsAg gene sequences helped to define the HBV genotype but did not allow inferring route of transmission as its sequences showed a smaller phylogenetic signal than pre-core/core sequences. Chronic HBV carriers of Asian descent born in or living in Brazil were infected with the same HBV genotype predominant in their ancestral country.

Sphenoid sinus symmetry and differences between sexes

Objectives: To evaluate the anatomic variations of neurovascular structures adjacent to the sphenoid sinus and their agreement between right and left sides as well as differences between sexes. Methods: Forty-five cadavers were dissected (24 men, and differences between sexes and agreement of anatomic variations of the sphenoid sinus between sides were analyzed. Results: The mean distance from the sphenoid sinus ostium to the anterior nasal spine was greater in males than in females by an average of 3.0 mm (p = 0.001) while the mean difference of distances between the right and left side was -1.1 +/- 3.1 mm. Female cadavers had a greater frequency of optic-carotid recess (p = 0.04) and dehiscence over the maxillary nerve (p = 0.02), as well as greater relative risk of optic nerve protrusion (p < 0.001), and dehiscence over the internal carotid artery (ICA) (p = 0.002). In male cadavers the intersinus septum was inserted on the course of the ICA 3.5 times more often than in female (p = 0.02). Agreement of anatomic variations between sides ranged from moderate to almost perfect depending on the structures evaluated. Conclusions: There are anatomic differences of the sphenoid sinus between sexes and between right and left sides, and these differences should be taken into consideration during surgery.

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.

Severe Posterior Epistaxis-Endoscopic Surgical Anatomy

Objective: To describe the anatomy of the sphenopalatine foramen (SPF) region and possible anatomical variations. Study Design: Prospective study accomplished from September, 2006, to January, 2007. Methods: The sphenopalatine foramen (SPF) of 61 cadavers were carefully dissected. Presence of the ethmoidal crest, location of sphenopalatine and accessory foramens, and the number of arterial branches emerging through foramens were observed. Data were analyzed in relation to gender, racial group, and symmetry of the cadaver. Prediction of the presence of accessory foramen was evaluated. Results: Mixed race cadavers prevailed in 122 nasal fossae dissected (75% males). Ethmoidal crest was present in 100% of the cadavers, being anterior to the SPF in 98.4% of the cases. The most frequent SPF location was the transition of the middle and superior meatus (86.9%). Mean distance from the SPF and accessory foramen to anterior nasal spine was 6.6 cm and 6.7 cm, respectively. Accessory foramen was present in 9.83% of the cases. A single arterial stem emerged through the SPF in 67.2% of the cases, and 100% through accessory foramens. The prevalence analyses showed no differences that were statistically significant (P > 0.05) between gender and racial group. The symmetry analyses showed a strong conformity (P < 0.01) between nasal fossae in relation to the SPF location. There was no statistically significant conformity between nasal fossae and accessory foramen (P = 0.53). None of the variables of interest presents any statistically significant (P > 0.05) association with the presence of the accessory foramen. Conclusions: There are anatomical variations in the lateral nose wall that should be considered for successful endoscopic surgical treatment of severe epistaxis.

The efficacy of functional endoscopic sinus surgery in the evolution of fever of unknown origin in ICU patients

Conclusion: Functional endoscopic sinus surgery (FESS) was found to be effective in treating fever of unknown origin (FUO) in intensive care unit (ICU) patients with rhinosinusitis, with 62% of patients showing improvement within 5 days of the procedure. Objective: To correlate improvement in FUO with FESS drainage of the paranasal sinuses. Methods: Fifty patients that developed FUO during ICU stay, with CT findings suggestive of rhinosinusitis, and showed no improvement in fever after clinical treatment underwent FESS for drainage of the paranasal sinuses and were evaluated for postoperative improvement of fever. Results: The study sample consisted of 50 patients (74% of whom were male, mean age 48.1 years). The most frequent diagnoses at ICU admission were tetanus, pulmonary disease, and cardiovascular disease. In all, 68% of patients underwent nasogastric or enteral intubation. CT scanning most commonly showed involvement of the sphenoid sinus. In 54% of cases, sinusitis was bilateral and extended throughout the maxillary, ethmoidal, and sphenoidal sinuses. Sinusectomy was performed in all patients, and pathological secretion in the paranasal sinuses was seen in 52% of patients during surgery. Gram-negative bacteria were the most commonly isolated organisms, followed by Gram-positive bacteria and fungi. Improvement of fever was found in 82% of patients after FESS; 38% of these improved within the first 48 h post-procedure, and the remaining 62% within the first 5 postoperative days.

Endoscopic ligation of the anterior ethmoidal artery: a cadaver dissection study

Anterior ethmoidal artery (AEA) ligation may be necessary in cases of severe epistaxis not controllable with traditional therapy. Endoscopic endonasal ligation of the AEA is not used frequently; there are few studies in the literature for standardization of the endoscopic technique for this vessel. Aim: To demonstrate the feasibility of periorbital AEA ligation in a transethmoidal endoscopic approach. Methods: A prospective study where 50 nasal cavities were dissected. After anterior ethmoidectomy and partial removal of lamina papyracea, the periorbital area was carefully dissected along a subperiosteal plane to identify the AEA. The vessel was exposed within the orbit and dissected. Results: Data on technical difficulties, complications, the learning curve and anatomical variations were gathered. Conclusion: An endonasal endoscopic approach to the AEA within the orbit was shown to be feasible. Identifying the artery is not difficult, and this technique avoids external incisions. This approach appears to be an excellent alternative for approaching the AEA. Further clinical studies are needed to demonstarte the benefits of this technique.

Model-Predicted Performance of Second-Trimester Down Syndrome Screening With Sonographic Prenasal Thickness

Objective. The purpose of this study was to estimate the Down syndrome detection and false-positive rates for second-trimester sonographic prenasal thickness (PT) measurement alone and in combination with other markers. Methods. Multivariate log Gaussian modeling was performed using numerical integration. Parameters for the PT distribution, in multiples of the normal gestation-specific median (MoM), were derived from 105 Down syndrome and 1385 unaffected pregnancies scanned at 14 to 27 weeks. The data included a new series of 25 cases and 535 controls combined with 4 previously published series. The means were estimated by the median and the SDs by the 10th to 90th range divided by 2.563. Parameters for other markers were obtained from the literature. Results. A log Gaussian model fitted the distribution of PT values well in Down syndrome and unaffected pregnancies. The distribution parameters were as follows: Down syndrome, mean, 1.334 MoM; log(10) SD, 0.0772; unaffected pregnancies, 0.995 and 0.0752, respectively. The model-predicted detection rates for 1%, 3%, and 5% false-positive rates for PT alone were 35%, 51%, and 60%, respectively. The addition of PT to a 4 serum marker protocol increased detection by 14% to 18% compared with serum alone. The simultaneous sonographic measurement of PT and nasal bone length increased detection by 19% to 26%, and with a third sonographic marker, nuchal skin fold, performance was comparable with first-trimester protocols. Conclusions. Second-trimester screening with sonographic PT and serum markers is predicted to have a high detection rate, and further sonographic markers could perform comparably with first-trimester screening protocols.

A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Background: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35). Methods: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies. Results: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08-1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95-1.09, P = 0.66; P-heterogeneity (P(het)) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12-1.34, P = 7 x 10(-6)) but not males (OR = 1.02, 95% CI = 0.97-1.08, P = 0.35; P(het) = 6 x 10(-4)). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P(het) = 0.86). Conclusions: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers. Impact: Further research is warranted to elucidate the mechanisms underlying these observations. Cancer Epidemiol Biomarkers Prev; 20(4); 658-64. (C) 2011 AACR.

Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies

Introduction Associations between systemic lupus erythematosus (SLE) and primary immunodeficiencies (PIDs) were analyzed to gain insight into the physiopathology of SLE. Some PIDs have been consistently associated with SLE or lupus-like manifestations: (a) homozygous deficiencies of the early components of the classical complement pathway in the following decreasing order: in C1q, 93% of affected patients developed SLE; in C4, 75%; in C1r/s, 57%; and in C2, up to 25%; (b) female carriers of X-linked chronic granulomatous disease allele; and (c) IgA deficiency, present in around 5% of juvenile SLE. Discussion In the first two groups, disturbances of cellular waste-disposal have been proposed as the main mechanisms of pathogenesis. On the other hand and very interestingly, there are PIDs systematically associated with several autoimmune manifestations in which SLE has not been described, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), immunedys-regulation polyendocrinopathy enteropathy X-linked (IPEX), and autoinumme lymphoproliferative syndrome (ALPS), suggesting that mechanisms considered as critical players for induction and maintenance of tolerance to autoantigens, such as (1) AME-mediated thymic negative selection of lymphocytes, (2) Foxp3+ regulatory T cell-mediated peripheral tolerance, and (3) deletion of auto-reactive lymphocytes by Fas-mediated apoptosis, could not be relevant in SLE physiopathology. The non-description of SLE and neither the most characteristic SLE clinical features among patients with agammaglobulinemia are also interesting observations, which reinforce the essential role of B lymphocytes and antibodies for SLE pathogenesis. Conclusion Therefore, monogenic PIDs represent unique and not fully explored human models for unraveling components of the conundrum represented by the physiopathology of SLE, a prototypical polygenic disease.

Primary ciliary dyskinesia: evaluation using cilia beat frequency assessment via spectral analysis of digital microscopy images

Olm MA, Kogler JE Jr, Macchione M, Shoemark A, Saldiva PH, Rodrigues JC. Primary ciliary dyskinesia: evaluation using cilia beat frequency assessment via spectral analysis of digital microscopy images. J Appl Physiol 111: 295-302, 2011. First published May 5, 2011; doi:10.1152/japplphysiol.00629.2010.-Ciliary beat frequency (CBF) measurements provide valuable information for diagnosing of primary ciliary dyskinesia (PCD). We developed a system for measuring CBF, used it in association with electron microscopy to diagnose PCD, and then analyzed characteristics of PCD patients. 1 The CBF measurement system was based on power spectra measured through digital imaging. Twenty-four patients suspected of having PCD (age 1-19 yr) were selected from a group of 75 children and adolescents with pneumopathies of unknown causes. Ten healthy, nonsmoking volunteers (age >= 17 yr) served as a control group. Nasal brush samples were collected, and CBF and electron microscopy were performed. PCD was diagnosed in 12 patients: 5 had radial spoke defects, 3 showed absent central microtubule pairs with transposition, 2 had outer dynein arm defects, 1 had a shortened outer dynein arm, and 1 had a normal ultrastructure. Previous studies have reported that the most common cilia defects are in the dynein arm. As expected, the mean CBF was higher in the control group (P < 0.001) and patients with normal ultrastructure (P < 0.002), than in those diagnosed with cilia ultrastructural defects (i.e., PCD patients). An obstructive ventilatory pattern was observed in 70% of the PCD patients who underwent pulmonary function tests. All PCD patients presented bronchial wall thickening on chest computed tomography scans. The protocol and diagnostic techniques employed allowed us to diagnose PCD in 16% of patients in this study.

Is Chlamydia-infected tubal fimbria the origin of ovarian cancer?

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. Prophylactic salpingo-oophorectomies in BRCA + women have recently implicated the fimbria as a site of origin for high-grade serous carcinoma and its intraepithelial precursors. This suggests that at least some ovarian cancers, probably the most aggressive ones, may not originate in the ovary itself, but rather may arise in the uterine tubes. Chronic inflammation is associated with carcinogenesis in several tissues, including liver, esophagogastric junction (cardia), and the uterine cervix. The mechanisms underlying the relationship between inflammation and cancer are complex and involve common pathways, in addition to DNA damage. A critical source of uterine tube inflammation is infection with Chlamydia trachomatis. We hypothesize that C. trachomatis infection may be involved in chronic tubal, inflammation and subsequent fimbrial carcinogenesis. Fimbrial intraepithelial precursors can evolve into high grade serous carcinomas that spread rapidly to the ovarian surface and peritoneum; such tumors may appear to be primary ovarian neoplasia, though in reality being a secondary malignancy. This hypothesis must be further investigated to understand the intracellular signaling pathways involved in Chlamydia infection and its heating, and their relationship to carcinogenesis in order to discover potential therapeutic molecular targets. If our hypothesis were confirmed, salpingectomy instead of ovariectomy may also become the recommended surgery for high risk women. (C) 2008 Elsevier Ltd. All rights reserved.