Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions

Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five‐class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align‐Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], MutPred, PolyPhen‐2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen‐2.1 provided the best‐combined model (R² = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen‐2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.     

Can Different Subsets of Ineffective Esophageal Motility Influence the Outcome of Nissen Fundoplication?

Background

Ineffective esophageal motility (IEM) in patients with gastroesophageal reflux disease includes three different subsets that may affect symptom profiles. Our aim was to assess symptoms and functional outcome in patients with erosive esophagitis according to different subsets of IEM, before and after Nissen fundoplication (NF).

Methodology

A retrospective study with prospective follow-up of 72 patients with reflux esophagitis and IEM in whom open NF was performed. Based on principal manometric esophageal body motility disorder, patients were divided in three groups: predominantly low-amplitude (LAC, N?=?38), non-propulsive (NPC, N?=?18), and simultaneous low-amplitude esophageal contractions (SC, N?=?16). Patients underwent symptomatic questionnaire and stationary esophageal manometry before and 6 months, 1 year, and 3 years after surgery.

Results

Preoperatively, patients in NPC and SC groups had higher mean scores of dysphagia, without statistical significance as opposed to the LAC group (p?=?0.239). Postoperative dysphagia occurred in 36 patients, without statistical significance between groups regarding dysphagia grades (p?=?0.390). A longer duration of postoperative dysphagia was noted in the SC group (p?p?Conclusion Three years after NF, successful symptomatic and functional outcome was achieved in analyzed groups of patients with erosive esophagitis regardless of IEM subtype.     

Cryoglobulinemic vasculitis in systemic sclerosis successfully treated with mycophenolate mofetil

Cryoglobulinemic vasculitis is extremely rare in patients with systemic sclerosis (SSc). So far, only two cases of cryoglobulinemic vasculitis in SSc were described in the literature. This report is about a patient with SSc and secondary Sj?gren’s syndrome, who developed typical clinical features of small-vessel vasculitis, including arthritis, purpura, microhaematuria, gangrene of fingers, and toes and myocardial ischemia, in the presence of mixed cryoglobulinemia, ANA, rheumatoid factor, and anti-SSA/Ro antibodies. Symptoms and signs of vasculitis worsened despite initial treatment with corticosteroids and cyclophosphamide, but improved significantly when mycophenolate mofetil was used instead cyclophosphamide.     

Alveolar Bone Grafting in Cleft Patients from Bone Defect to Dental Implants

Cleft lip and palate is the most common congenital deformity affecting craniofacial structures. Orofacial clefts have great impact on the quality of life which includes aesthetics, function, psychological impact, dental development and facial growth. Incomplete fusion of facial prominences during the fourth to tenth week of gestation is the main cause. Cleft gaps are closed with alveolar bone grafts in surgical procedure called osteoplasty. Autogenic bone is taken from the iliac crest as the gold standard. The time of grafting can be divided into two stages: primary and secondary. The alveolar defect is usually reconstructured between 7 and 11 years and is often related to the development of the maxillary canine root. After successful osteoplasty, cleft defect is closed but there is still a lack of tooth. The space closure with orthodontic treatment has 50-75% success. If the orthodontic treatment is not possible, in order to replace the missing tooth there are three possibilities: adhesive bridgework, tooth transplantation and implants. Dental implant has the role of holding dental prosthesis, prevents pronounced bone atrophy and loads the augmentation material in the cleft area. Despite the fact that autologous bone from iliac crest is the gold standard, it is not a perfect source for reconstruction of the alveolar cleft. Bone morphogenic protein (BMP) is appropriate as an alternative graft material. The purpose of this review is to explain morphology of cleft defects, historical perspective, surgical techniques and possibilities of implant and prosthodontic rehabilitation.Key words: Cleft Lip, Cleft Palate, Alveolar bone grafting, Bone Morphogenic Proteins, Dental implants, Dental prosthesis, Orthodontic Space Closure     

Altruism costs—the cheap signal from amygdala

When people state their willingness to pay for something, the amount usually differs from the behavior in a real purchase situation. The discrepancy between a hypothetical answer and the real act is called hypothetical bias. We investigated neural processes of hypothetical bias regarding monetary donations to public goods using fMRI with the hypothesis that amygdala codes for real costs. Real decisions activated amygdala more than hypothetical decisions. This was observed for both accepted and rejected proposals. The more the subjects accepted real donation proposals the greater was the activity in rostral anterior cingulate cortex—a region known to control amygdala but also neural processing of the cost-benefit difference. The presentation of a charitable donation goal evoked an insula activity that predicted the later decision to donate. In conclusion, we have identified the neural mechanisms underlying real donation behavior, compatible with theories on hypothetical bias. Our findings imply that the emotional system has an important role in real decision making as it signals what kind of immediate cost and reward an outcome is associated with.     

Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: The EVOLVE trial

Tobramycin inhalation solution is used to treat chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients. We evaluated the efficacy and safety of a novel, light‐porous particle, dry‐powder formulation of tobramycin, which was developed to improve delivery efficiency to the airways and substantially reduce the delivery time. In this randomized, double‐blind study, patients with CF (age 6–21 years) received tobramycin inhalation powder (112 mg tobramycin) twice daily (n = 46) or placebo (n = 49) via the T‐326 Inhaler for one cycle, followed by two open‐label cycles (all patients). Cycles were 28 days on, 28 days off treatment. The primary endpoint was change in forced expiratory volume in 1 sec (FEV₁) % predicted from baseline to Day 28 of Cycle 1. The study was terminated early based on positive results in the interim analysis. Tobramycin inhalation powder significantly improved FEV₁ % predicted versus placebo at Day 28 (difference 13.3, 95% CI: 5.31–21.28; P = 0.0016). Similar changes in FEV₁ were seen in patients switching from placebo to tobramycin inhalation powder in Cycle 2; improvements were maintained over time. Tobramycin inhalation powder also reduced sputum P. aeruginosa density, respiratory‐related hospitalization and antipseudomonal antibiotic use versus placebo. The most common adverse event was cough; the frequency of cough was higher in patients receiving placebo (26.5%) versus tobramycin inhalation powder (13.0%) in Cycle 1. Tobramycin inhalation powder was not associated with ototoxicity or nephrotoxicity. Administration time was between 4 and 6 min. In conclusion, tobramycin inhalation powder was effective and well tolerated in CF patients, and may offer an important treatment option to decrease the treatment burden of CF pseudomonas lung infections. Pediatr Pulmonol. 2011; 46:230–238. © 2011 Wiley‐Liss, Inc.     

Ruptured intramural intestinal hematoma in an adolescent patient with severe hemophilia A

We report on a 17-year-old patient with severe hemophilia A without inhibitors who developed abdominal bleeding after an episode of severe cough. Abdominal ultrasound showed intramural intestinal hematoma as well as large amount of peritoneal fluid appearing as blood and right hematocele. Abdominal CT revealed markedly thickened intestinal wall in sigmoidal region. Patient was managed with replacement therapy as well as peritoneal drainage with favorable outcome. This is the first report on a hematoperitoneum in a hemophiliac due to ruptured intramural sigmoidal hematoma.