Common and rare alleles of the serotonin transporter gene,SLC6A4, associated with Tourette's disorder

To evaluate the hypothesis that functionally over‐expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT‐linked polymorphic region 5‐HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine‐to‐valine at position 425 (I425V). The higher expressing 5‐HTTLPR/rs25531 L_A allele was more prevalent in TD probands than in controls (χ² = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing L_AC haplotype (5‐HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 0.0013; OR, 2.14). Furthermore, the rare gain‐of‐function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family‐adjusted significance of χ² = 15.03 (P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 Movement Disorder Society     

Anatomical surgical planning for oral and oropharyngeal primary carcinoma combined with adjuvant treatment where indicated is associated with improved local control

We aimed to find out whether surgical tactics that lead to a reduction in tumour-involved surgical margins also improve local control. We retrospectively reviewed a consecutive case series (n = 162) of previously untreated patients who had operations for squamous cell carcinoma (SCC) of the oral cavity or oropharynx. Extensive use was made of computed tomographic multiplanar imaging to plan primary resections. Nine patients (6%) had tumour at the resection margin. Local control at 36 months was 96%, disease-specific survival (DSS) was 86%, and overall survival (OS) was 77%. Carefully planned primary operation for SCC of the oral cavity and oropharynx to minimise tumour-involved margins combined with conventional adjuvant treatment where indicated, is associated with a high probability of local control and disease-specific survival.     

Anxiety disorders are associated with verbal memory impairment in patients with Parkinson’s disease without dementia

Journal of Neurology - Preliminary evidence has demonstrated a link between anxiety and memory impairment in Parkinson’s disease (PD). This study further investigated this association using...     

Is cardiac catheterization a prerequisite in all patients undergoing bidirectional cavopulmonary anastomosis?

Traditionally, all patients undergo cardiac catheterization before bidirectional cavopulmonary anastomosis (BCPA). The purpose of this study was to determine if preoperative catheterization is necessary when echocardiographic parameters appear favorable. A retrospective review was performed of all patients who underwent BCPA (n = 142) between February 1996 and May 2001. Echocardiographic criteria defining a favorable BCPA candidate included good ventricular function, moderate or less atrioventricular and semilunar valve regurgitation, absence of ventricular outflow tract obstruction, normal proximal branch pulmonary artery (PA) size, and low PA pressures estimated by PA band gradient or systemic PA shunt velocity. The median age at operation was 7 months (range: 2-11) and weight was 6.2 kg (range: 2.7-7.1). There were 73 unfavorable candidates. Patients with hypoplastic left heart syndrome (n = 23) and pulmonary atresia with intact septum (n = 15) predominated among the unfavorable group. All patients were catheterized. This provided additional information on PA pressures in 3 patients in the favorable group but did not defer operation or influence outcome (no mortality, prolonged pleural drainage, or longer intensive care department stay). All 3 patients are alive at a mean follow-up of 51 months. The 30-day mortality was 2% (4 of 151 patients), all in the unfavorable group. Overall, 20 patients (13%) required arterioplasty of PAs at the time of BCPA. BCPA can be performed with a low risk of morbidity and mortality in a wide range of patients. By using commonly acquired echocardiographic parameters, a low-risk subgroup of patients can be identified who can safely avoid preoperative cardiac catheterization.     

Accuracy of patient-specific instrumentation in anatomic and reverse total shoulder arthroplasty

Purpose:Glenoid component malposition is associated with poor function and early failure of both anatomic and reverse total shoulder arthroplasty. Glenoid positioning is challenging particularly in the setting of bone loss or deformity. Recently, the use of computer assistance has been shown to reduce implantation error. The aim of this study is to evaluate the accuracy of patient-specific instrumentation in cases of anatomic and reverse shoulder replacement in vivo.Methods:Twenty patients underwent total shoulder arthroplasty using a computed tomography (CT)-based patient-specific instrumentation (PSI) system, ten anatomic and ten reverse. Preoperative three-dimensional digital templating of glenoid component position was undertaken and surgery then performed using a custom-made guide. Postoperative CT scans were used to compare final implanted component position to the preoperatively planned position in the same patient.Results:Final component position and orientation closely reflected the preoperatively templated position. Mean deviation in the glenoid version from planned was 1.8° ±1.9° (range, 0.1°–7.3°). Mean deviation in inclination was 1.3° ±1.0° (range, 0.2°–4.5°). Mean deviation in position on the glenoid face was 0.5 ± 0.3 mm (range, 0.0–1.3 mm) in the anteroposterior plane and 0.8 ± 0.5 mm (range, 0.0–1.9 mm) in the superoinferior plane. Actual achieved version was within 7° of neutral in all cases except for one where it was deliberately planned to be outside of this range.Conclusion:PSI in both anatomic and reverse shoulder arthroplasty is highly accurate in guiding glenoid component implantation in vivo. The system can reliably correct bony deformity.     

4D DMLC leaf sequencing to minimize organ at risk dose in moving anatomy

The most favorable treatment for moving body anatomy should aim at utilizing organ motion to minimize the dose to sensitive structures without compromising the dose delivered to the target. The solution of the problem of appropriate intensity redistribution over different phases of body motion is achievable in dynamic multileaf collimator (DMLC) intensity modulated radiation therapy delivery, due to the fact that multiple solutions are admissible for imposing the same intensity map over a moving target in this technique of irradiation. The realization of this type of delivery provides a treatment methodology that delivers treatment plans for moving patient anatomy that are superior to any treatments possible for static patient body anatomy. This paper is devoted to exploring this idea. To this end, a simple, though clinically realistic example is developed and presented that shows modified DMLC leaf motions that deliver a predetermined intensity to a moving target while reducing the dose delivered to organs at risk.     

Safety and efficacy of tranexamic acid in children with cerebral palsy undergoing femoral varus derotational osteotomy: a double cohort study

European Journal of Orthopaedic Surgery & Traumatology - The safety and efficacy of tranexamic acid (TXA) in reducing blood loss after total joint arthroplasty and spinal fusion surgery has...     

Sequencing of LRP2 Reveals Multiple Rare Variants Associated with Urinary Trefoil Factor-3

Novel biomarkers are being investigated to identify patients with kidney disease. We measured a panel of 13 urinary biomarkers in participants from the Offspring Cohort of the Framingham Heart Study. Using an Affymetrix chip with imputation to 2.5 M single-nucleotide polymorphisms (SNPs), we conducted a GWAS of these biomarkers (n=2640) followed by exonic sequencing and genotyping. Functional studies in zebrafish were used to investigate histologic correlation with renal function. Across all 13 biomarkers, there were 97 significant SNPs at three loci. Lead SNPs at each locus were rs6555820 (P=6.7×10⁻⁴⁹; minor allele frequency [MAF]=0.49) in HAVCR1 (associated with kidney injury molecule-1), rs7565788 (P=2.15×10⁻¹⁶; MAF=0.22) in LRP2 (associated with trefoil factor 3 [TFF3]), and rs11048230 (P=4.77×10⁻⁸; MAF=0.10) in an intergenic region near RASSF8 (associated with vascular endothelial growth factor). Validation in the CKDGen Consortium (n=67,093) showed that only rs7565788 at LRP2, which encodes megalin, was associated with eGFR (P=0.003). Sequencing of exons 16–72 of LRP2 in 200 unrelated individuals at extremes of urinary TFF3 levels identified 197 variants (152 rare; MAF<0.05), 31 of which (27 rare) were nonsynonymous. In aggregate testing, rare variants were associated with urinary TFF3 levels (P=0.003), and the lead GWAS signal was not explained by these variants. Knockdown of LRP2 in zebrafish did not alter the renal phenotype in static or kidney injury models. In conclusion, this study revealed common variants associated with urinary levels of TFF3, kidney injury molecule-1, and vascular endothelial growth factor and identified a cluster of rare variants independently associated with TFF3.Serum creatinine, as used in most GFR estimating equations, is the primary biomarker of CKD.¹ Creatinine has significant limitations as a biomarker. It is insensitive to early declines in kidney function, and there are important extrarenal factors that influence its concentration, thus increasing the potential for misclassification when it is used to diagnose renal disease.² As a result, novel biomarkers are being investigated that could allow earlier and more accurate diagnosis of CKD.³ It is likely, however, that these biomarkers also have non-GFR determinants, including genetic factors. For example, levels of cystatin C, a novel GFR biomarker, are known to be influenced by both nongenetic factors, such as adiposity and the metabolic syndrome,⁴ and the presence of specific genetic variants in the cystatin C-gene cluster.⁵Genome-wide association studies (GWAS) allow for the evaluation of genetic associations of biomarkers in an unbiased manner. These studies could illuminate previously unrecognized pathways for CKD pathogenesis, thus identifying new potential molecular targets for therapeutic intervention. Multiple variants have been identified in association with kidney function through GWAS,⁶ whereas a variant in CUBN encoding cubilin, a proximal tubular transport protein, has been associated with albuminuria.⁷ Recently, a GWAS identified a locus at PTGDS in association with another kidney biomarker, β-trace protein.⁸To gain additional insight into biologic pathways of renal function and kidney injury, we measured a panel of 13 urinary biomarkers in participants from the Framingham Heart Study (FHS) and performed a GWAS of their levels. Here, we report the primary results from these studies as well as follow-up work to identify whether rare variants in LRP2 are associated with levels of trefoil factor 3 (TFF3).