Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients

Background Mutations in the PTPN11 gene are the main cause of Noonan syndrome (NS). The presence of some NS features is a frequent finding in children with idiopathic short stature (ISS). These children can represent the milder end of the NS clinical spectrum and PTPN11 is a good candidate for involvement in the pathogenesis of ISS. Objective To evaluate the presence of mutations in PTPN11 in ISS children who presented NS-related signs and in well-characterized NS patients. Patients and methods We studied 50 ISS children who presented at least two NS-associated signs but did not fulfil the criteria for NS diagnosis. Forty-nine NS patients diagnosed by the criteria of van der Burgt et al. were used to assess the adequacy of these criteria to select patients for PTPN11 mutation screening. The coding region of PTPN11 was amplified by polymerase chain reaction (PCR), followed by direct sequencing. Results No mutations or polymorphisms were found in the coding region of the PTPN11 gene in ISS children. Nineteen of the 49 NS patients (39%) presented mutations in PTPN11. No single characteristic enabled us to distinguish between NS patients with or without PTPN11 mutations. Conclusion Considering that no mutations were found in the present cohort with NS-related signs, it is unlikely that mutations would be found in unselected ISS children. The van der Burgt et al. criteria are adequate in attaining NS diagnosis and selecting patients for molecular studies. Mutations in the PTPN11 gene are commonly involved in the pathogenesis of NS but are not a common cause of ISS.

Two novel mutations in the EIF2AK3 gene in children with Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS, OMIM 226980) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, epiphyseal dysplasia, and other multisystemic clinical manifestations. We described two novel mutations in the EIF2AK3 gene in two consanguineous families with WRS from Brazil and Morocco. We have observed in case 1 a homozygous C > T replacement at base pair c.1192 at exon 7, generating a stop codon at position 398 (Gln398Stop). Both of his parents were found to be heterozygous for the mutation. We detected in both parents of case 2, a deceased Moroccan girl, a duplication of base pair c.851A at exon 5 (c.851dupA) leading to a frameshift and a stop codon at position 285 (p.Pro285AlafsX3). Both cases 1 and 2 had neonatal diabetes mellitus, multiple epiphyseal dysplasia, and growth delay, and presented episodes of acute hepatic dysfunction. Case 1 presented central hypothyroidism, developmental delay, and mild mental retardation. Case 2 presented a fatal episode of acute renal failure. The clinical phenotype associated with the syndrome can be variable, but a combination of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, and hepatic and/or renal dysfunction is the mainstay of diagnosis.

Association between tumoral GH-releasing peptide receptor type 1a mRNA expression and in vivo response to GH-releasing peptide-6 in ACTH-dependent Cushing`s syndrome patients

Objective: GH secretagogues (GHS) produce exaggerated ACTH and cortisol responses in Cushing`s disease (CD) patients, attributable to their direct action on GH-releasing peptide receptor type la (GHSR-1a). However, there are no studies correlating the ill vivo response to GHS and GHSR-1a mRNA expression in ACTH-dependent Cushing`s syndrome (CS) patients. The aim of this study is to correlate the patterns of ACTH and cortisol response to GH-releasing peptide-6 (GHRP-6) to GHSR-1a expression in ACTH-dependent CS patients Design: Prospective study in a tertiary referral hospital center. Fifteen CD patients and two ectopic ACTH syndrome (EAS) patients were studied. Methods: Tumor fragments were submitted to RNA extraction, and GHSR-1a expression was studied through real-time qPCR and compared with normal tissue samples. The patients were also submitted to desmopressin test and vasopressin receptor type 1B (AVPR1B) mRNA analysis by qPCR. Results: GHSR-1a expression was similar in normal pituitary samples and in corticotrophic tumor samples. GHSR-1a expression was higher in patients (CD and EAS) presenting ill vivo response to GHRP-6. Higher expression of AVPR1B was observed in the EAS patients responsive to desmopressin, as well as in corticotrophic tumors, as compared with normal pituitary samples, but no correlation between AVPR1B expression and response to desmopressin was observed in the CD patients. Conclusions: Our results revealed a higher expression of GHSR-1a in the ACTH-dependent CS patients responsive to GHRP-6, suggesting an association between receptor gene expression and ill vivo response to the secretagogue in both the CD and the EAS patients.

Real-time detection of pneumothorax using electrical impedance tomogyaphy

Objectives: Pneumothorax is a frequent complication during mechanical ventilation. Electrical impedance tomography (EIT) is a noninvasive tool that allows real-time imaging of regional ventilation. The purpose of this study was to 1) identify characteristic changes in the EIT signals associated with pneumothoraces; 2) develop and fine-tune an algorithm for their automatic detection; and 3) prospectively evaluate this algorithm for its sensitivity and specificity in detecting pneumothoraces in real time. Design: Prospective controlled laboratory animal investigation. Setting: Experimental Pulmonology Laboratory of the University of Sao Paulo. Subjects: Thirty-nine anesthetized mechanically ventilated supine pigs (31.0 +/- 3.2 kg, mean +/- SD). Interventions. In a first group of 18 animals monitored by EIT, we either injected progressive amounts of air (from 20 to 500 mL) through chest tubes or applied large positive end-expiratory pressure (PEEP) increments to simulate extreme lung overdistension. This first data set was used to calibrate an EIT-based pneumothorax detection algorithm. Subsequently, we evaluated the real-time performance of the detection algorithm in 21 additional animals (with normal or preinjured lungs), submitted to multiple ventilatory interventions or traumatic punctures of the lung. Measurements and Main Results: Primary EIT relative images were acquired online (50 images/sec) and processed according to a few imaging-analysis routines running automatically and in parallel. Pneumothoraces as small as 20 mL could be detected with a sensitivity of 100% and specificity 95% and could be easily distinguished from parenchymal overdistension induced by PEEP or recruiting maneuvers, Their location was correctly identified in all cases, with a total delay of only three respiratory cycles. Conclusions. We created an EIT-based algorithm capable of detecting early signs of pneumothoraces in high-risk situations, which also identifies its location. It requires that the pneumothorax occurs or enlarges at least minimally during the monitoring period. Such detection was operator-free and in quasi real-time, opening opportunities for improving patient safety during mechanical ventilation.

Goodpasture`s syndrome

Goodpasture`s syndrome (GS) is an auto-immune disease that is part of the pulmonary-renal syndrome spectrum. It is characterized by the linear deposition of anti-glomerular basement membrane antibodies (anti-GBM) in glomerular and alveolar basement membrane, resulting in alveolar hemorrhage and progressive glomerulonephritis. An early diagnosis is important to decrease clinical morbidity. In the present work, we illustrate a GS case, initially diagnosed as Wegener`s granulomatosis.The patient showed favorable clinical evolution with corticosteroid therapy associated with plasmapheresis and cyclophosphamide.

No association between the deficit syndrome in psychosis and summer birth in a Southern Hemisphere country (Correspondence)

This Article does not have an abstract.

Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity

The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 jig apolipoprotein B/ml) in the presence or absence of control HDL subfiractions (25 mu g protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p < 0.05) in MetS subjects (n = 16) relative to normolipidemic controls (n = 7). The attenuated anti-apoptotic activity of HDL3c correlated with abdominal obesity, atherogenic dyslipidemia and systemic oxidative stress (p < 0.05), and was intimately associated with altered physicochemical properties of apolipoprotein A-I (apoA-I-poor HDL3c, involving core cholesteryl ester depletion and triglyceride enrichment. We conclude that in MetS, apoA-I-poor, small, dense HDL3c exert defective protection of endothelial cells from oxLDL-induced apoptosis, potentially reflecting functional anomalies intimately associated with abnormal neutral lipid core content. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Burning mouth syndrome: Patient management

Burning mouth syndrome is an underdiagnosed and often poorly managed oral sensory disturbance. This paper discusses the recognition of the condition and suggests clinical approaches to ensure a correct diagnosis and appropriate management. The expansion of the traditional dental role of the dentist is reviewed in the context of overall oral and general health particularly with respect to the syndrome which demands an intensive work-up, open discussions with the patient,and a carefully planned long-term management strategy.

Magnetic resonance imaging of idiopathic carpal tunnel syndrome: Correlation with clinical findings and electrophysiological investigation

Objective: To compare clinical evaluation, electrophysiological investigation and magnetic resonance findings in assessing the severity of idiopathic carpal tunnel syndrome. Patients and methods: Seventy-four patients with idiopathic carpal tunnel syndrome were prospectively recruited. Clinical evaluation included symptoms severity score and two-point discrimination, sensory and motor nerve conduction velocities were determined by electroneuromyography and imaging parameters were obtained after wrist magnetic resonance. The Wilcoxon test was used to define the differences between measurements of median nerve area. The Pearson and Spearman correlation tests were used to determine the relationships between all the measured parameters. Results: Cross-sectional area of median nerve was smaller at hamate level than at radio-ulnar joint and pisiform levels (p < 0.001). With exception of median nerve area at hamate level, there was a lower degree of correlation between MRI parameters and findings obtained by clinical assessments and electrophysiological measurements. The median nerve area at hamate level correlated negatively with duration of symptoms, two-point discrimination, symptoms severity score and positively with sensory nerve conduction velocity (P < 0.01). Conclusion: In patients with idiopathic carpal tunnel syndrome, median nerve area measured by wrist magnetic resonance at hamate level may be considered as a valuable indicator to grading the severity of disease. (c) 2007 Elsevier B.V. All rights reserved.

Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue

Introduction: Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients. Methods: We retrospectively studied autopsy lung tissue from subjects who died with ARDS and from control subjects who died of non pulmonary causes. Using image analysis, we quantified the extension of epithelial changes (normal, abnormal and denudated epithelium expressed as percentages of the total epithelium length), bronchiolar inflammation, airway wall thickness, and extracellular matrix (ECM) protein content in distal airways. The Student`s t test or the Mann-Whitney test was used to compare data between the ARDS and control groups. Bonferroni adjustments were used for multiple tests. The association between morphological and clinical data was analyzed by Pearson rank test. Results: Thirty-one ARDS patients (A: PaO(2)/FiO(2) <= 200, 45 +/- 14 years, 16 males) and 11 controls (C:52 +/- 16 years, 7 males) were included in the study. ARDS airways showed a shorter extension of normal epithelium (A:32.9 +/- 27.2%, C:76.7 +/- 32.7%, P < 0.001), a larger extension of epithelium denudation (A:52.6 +/- 35.2%, C:21.8 +/- 32.1%, P < 0.01), increased airway inflammation (A:1(3), C:0(1), P = 0.03), higher airway wall thickness (A:138.7 +/- 54.3 mu m, C:86.4 +/- 33.3 mu m, P < 0.01), and higher airway content of collagen I, fibronectin, versican and matrix metalloproteinase-9 (MMP-9) compared to controls (P = 0.03). The extension of normal epithelium showed a positive correlation with PaO(2)/FiO(2) (r(2) = 0.34; P = 0.02) and a negative correlation with plateau pressure (r(2) = 0.27; P = 0.04). The extension of denuded epithelium showed a negative correlation with PaO(2)/FiO(2) (r(2) = 0.27; P = 0.04). Conclusions: Structural changes in small airways of patients with ARDS were characterized by epithelial denudation, inflammation and airway wall thickening with ECM remodeling. These changes are likely to contribute to functional airway changes in patients with ARDS.

SHOENFELD`S SYNDROME AFTER PANDEMIC INFLUENZA A/H1N1 VACCINATION

Recently, reports have suggested grouping different autoimmune conditions that are triggered by external stimuli as a single syndrome called autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This syndrome is characterized by the appearance of myalgia, myositis, muscle weakness, arthralgia, arthritis, chronic fatigue, sleep disturbances, cognitive impairment and memory loss, and the possible emergence of a demyelinating autoimmune disease caused by systemic exposure after vaccines and adjuvants. In the current study, the authors reported the first Brazilian case of a woman who developed ASIA, which was characterized by arthralgia, changes in inflammatory markers, and chronic fatigue, after the pandemic anti-influenza A/H1N1 vaccine without causing any other rheumatic disease, and it had a positive outcome.

Lipid goals among patients with diabetes or metabolic syndrome: Lipid Treatment Assessment Project (L-TAP) 2

Objective: This analysis of the Lipid Treatment Assessment Project 2 population compared lipid goal attainment by diabetes and metabolic syndrome status. Research design and methods: Dyslipidaemic patients aged >= 20 years on stable lipid lowering therapy had their lipid levels determined once during enrolment at investigation sites in nine countries between September 2006 and April 2007. Achievement of low-density lipoprotein (LDL) cholesterol success, triglycerides < 150 mg/dl (1.7 mmol/l), and high-density lipoprotein (HDL) cholesterol success (> 40 mg/dl [1.0 mmol/l] in men or > 50 mg/dl [1.3 mmol/l] in women) was compared using logistic regression. Results: A total of 9955 patients were evaluated. Patients with diabetes, compared with those without diabetes, had lower achievement of LDL cholesterol goals (according to National Cholesterol Education Program Adult Treatment Panel [NCEP ATP] III guidelines; 67% vs. 75%), triglycerides < 150 mg/dl (55% vs. 64%), and HDL cholesterol success (61% vs. 74%; p < 0.0001 for all comparisons). The significantly lower lipid goal attainment in patients with diabetes was consistent across participating world regions. Patients with metabolic syndrome, compared with those without metabolic syndrome, had lower achievement of NCEP ATP III LDL cholesterol goals (69% vs. 76%), triglycerides < 150 mg/dl (36% vs. 83%), and HDL cholesterol success (49% vs. 89%; p < 0.0001 for all comparisons). As the number of metabolic syndrome components increased, lipid success rates progressively decreased (p < 0.0001 for LDL cholesterol success, triglycerides < 150 mg/dl, and HDL cholesterol success). Conclusions: This analysis indicates that despite their increased cardiovascular risk, patients with diabetes or metabolic syndrome remain undertreated.

Repetitive Transcranial Magnetic Stimulation Is Efficacious as an Add-On to Pharmacological Therapy in Complex Regional Pain Syndrome (CRPS) Type I

Single session repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) is effective in the treatment of chronic pain patients but the analgesic effect of repeated sessions is still unknown We evaluated the effects of rTMS in patients with refractory pain due to complex regional pain syndrome (CRPS) type I Twenty three patients presenting CRPS type I of 1 upper limb were treated with the best medical treatment (analgesics and adjuvant medications physical therapy) plus 10 daily sessions of either real (r) or sham (s) 10Hz rTMS to the motor cortex (M1) Patients were assessed daily and after 1 week and 3 months after the last session using the Visual Analogical Scale (VAS) the McGill Pain Questionnaire (MPQ) the Health Survey 36 (SF 36) and the Hamilton Depression (HDRS) During treatment there was a significant reduction in the VAS scores favoring the r rTMS group mean reduction of 4 65 cm (50 9%) against 2 18 cm (24 7%) in the s rTMS group The highest reduction occurred at the tenth session and correlated to improvement in the affective and emotional subscores of the MPQ and SF 36 Real rTMS to the M1 produced analgesic effects and positive changes in affective aspects of pain in CRPS patients during the period of stimulation Perspective This study shows an efficacy of repetitive sessions of high frequency rTMS as an add on therapy to refractory CAPS type I patients It had a positive effect in different aspects of pain (sensory discriminative and emotional affective) It opens the perspective for the clinical use of this technique (C) 2010 by the American Pain Society

Prevalence of Metabolic Syndrome in Patients With Intermittent Claudication and its Correlation With the Segment of Arterial Obstruction

The metabolic syndrome (MetS) is associated with increased cardiovascular morbidity and mortality. Intermittent claudication reflects the presence of peripheral arterial disease (PAD). The aim of this study is to determine the prevalence of the MetS in claudicants and its correlation with age, gender, localization of arterial obstruction, and symptomatic coronary disease. Patients (n = 170) with intermittent claudication were studied. The mean age was 65 years (33-89). Metabolic syndrome was diagnosed in 98 patients (57.6%). The mean age of patients with MetS was 63.5 years compared with 67.0 years for patients without MetS (P = .027). Considering patients aged >= 65 years, MetS was present in 46 (48.9%) individuals and in 52 (68.4%) patients younger than 65 years (P = .011). Metabolic syndrome must be actively searched for in claudicant patients.