Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations

X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials

Use of preoperative apparent diffusion coefficients to predict brain tumor grade

Introduction: The apparent diffusion coefficient (ADC) sequence is based on the diffusion properties of water molecules within tissues and correlates with tissue cellularity. ADC may have a role in predicting tumor grade for gliomas, and may in turn assist in identifying tumor biopsy sites. The purpose of this investigation was to assess the competence of preoperative ADC values in predicting tumor grades.Methods: This was a retrospective investigation. We calculated the ADC values in the areas of greatest restriction in solid tumor components, and we recorded the pattern of contrast enhancement. Pathology reports masked to the imaging results were reviewed independently. We calculated the differences in the mean values of different tumor grades and high-grade and low-grade gliomas. A receiver operator curve (ROC) analysis assessed the predictive potential of ADC values for low-grade gliomas.Results: Forty-eight cases of glioma were included in our study. We noted a statistically significant difference in the lowest mean ADC values for the tumor regions of Grade IV lesions (333.83 ± 295.47) compared with Grade I lesions (653.20 ± 145.07). On ROC analysis, we noted an area under the curve (AUC) of 0.80 for the lowest ADC value in the whole tumor region, which was a predictor of low-grade glioma with 95 % confidence interval (CI) of 0.675-0.926. The sensitivity of the lowest ADC value was 84.5% for high-grade lesions.Conclusion: Given our findings that the means of the lowest ADC value are significantly different between low and high-grade gliomas with an AUC of 0.80 for ADC as a predictor of low-grade lesions and a sensitivity of 84.5% for high-grade lesions, ADC values contain some predictive properties of tumor grading. ADC values may be a valuable parameter in the assessment and treatment of tumors

Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10-3 to <1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid

<p>Abstract</p> <p>Background</p> <p>Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of <it>SMN </it>gene (<it>SMN1</it>) and clinical severity is in part determined by the copy number of the centromeric copy of the <it>SMN </it>gene (<it>SMN2</it>). The <it>SMN2 </it>mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of <it>SMN2 </it>gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor.</p> <p>Methods</p> <p>Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index.</p> <p>Results</p> <p>After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period.</p> <p>Conclusion</p> <p>Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01033331">NCT01033331</a></p

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Association between Variants on Chromosome 4q25, 16q22 and 1q21 and Atrial Fibrillation in the Polish Population

Genome-wide studies have shown that polymorphisms on chromosome 4q25, 16q22 and 1q21 correlate with atrial fibrillation (AF). However, the distribution of these polymorphisms differs significantly among populations.To test the polymorphisms on chromosome 4q25, 16q22 and 1q21 in a group of patients (pts) that underwent catheter ablation of AF.Four hundred and ten patients with AF that underwent pulmonary vein isolation were included in the study. Control group (n = 550) was taken from healthy population, matched for age, sex and presence of hypertension. All participants were genotyped for the presence of the rs2200733, rs10033464, rs17570669, rs3853445, rs6838973 (4q25), rs7193343 (16q22) and rs13376333 (1q21) polymorphisms.All the polymorphisms tested (except rs17570669) correlated significantly with AF in univariate analysis (p values between 0.039 for rs7193343 and 2.7e-27 for rs2200733), with the odds ratio (OR) 0.572 and 0.617 for rs3853445 and rs6838973, respectively (protective role) and OR 1.268 to 3.52 for the other polymorphisms. All 4q25 SNPs tested but rs3853445 were independently linked with AF in multivariate logistic regression analysis. In haplotype analysis six out of nine 4q25 haplotypes were significantly linked with AF. The T allele of rs2200733 favoured increased number of episodes of AF per month (p = 0.045) and larger pulmonary vein diameter (recessive model, p = 0.032).Patients qualified for catheter ablation of AF have a significantly higher frequency of 4q25, 16q22 and 1q21 variants than the control group. The T allele of rs2200733 favours larger pulmonary veins and increased number of episodes of AF

Signal-averaged P wave analysis for delineation of interatrial conduction – Further validation of the method

<p>Abstract</p> <p>Background</p> <p>The study was designed to investigate the effect of different measuring methodologies on the estimation of P wave duration. The recording length required to ensure reproducibility in unfiltered, signal-averaged P wave analysis was also investigated. An algorithm for automated classification was designed and its reproducibility of manual P wave morphology classification investigated.</p> <p>Methods</p> <p>Twelve-lead ECG recordings (1 kHz sampling frequency, 0.625 <it>μ</it>V resolution) from 131 healthy subjects were used. Orthogonal leads were derived using the inverse Dower transform. Magnification (100 times), baseline filtering (0.5 Hz high-pass and 50 Hz bandstop filters), signal averaging (10 seconds) and bandpass filtering (40–250 Hz) were used to investigate the effect of methodology on the estimated P wave duration. Unfiltered, signal averaged P wave analysis was performed to determine the required recording length (6 minutes to 10 s) and the reproducibility of the P wave morphology classification procedure. Manual classification was carried out by two experts on two separate occasions each. The performance of the automated classification algorithm was evaluated using the joint decision of the two experts (i.e., the consensus of the two experts).</p> <p>Results</p> <p>The estimate of the P wave duration increased in each step as a result of magnification, baseline filtering and averaging (100 ± 18 vs. 131 ± 12 ms; P < 0.0001). The estimate of the duration of the bandpass-filtered P wave was dependent on the noise cut-off value: 119 ± 15 ms (0.2 <it>μ</it>V), 138 ± 13 ms (0.1 <it>μ</it>V) and 143 ± 18 ms (0.05 <it>μ</it>V). (P = 0.01 for all comparisons).</p> <p>The mean errors associated with the P wave morphology parameters were comparable in all segments analysed regardless of recording length (95% limits of agreement within 0 ± 20% (mean ± SD)). The results of the 6-min analyses were comparable to those obtained at the other recording lengths (6 min to 10 s).</p> <p>The intra-rater classification reproducibility was 96%, while the interrater reproducibility was 94%. The automated classification algorithm agreed with the manual classification in 90% of the cases.</p> <p>Conclusion</p> <p>The methodology used has profound effects on the estimation of P wave duration, and the method used must therefore be validated before any inferences can be made about P wave duration. This has implications in the interpretation of multiple studies where P wave duration is assessed, and conclusions with respect to normal values are drawn.</p> <p>P wave morphology and duration assessed using unfiltered, signal-averaged P wave analysis have high reproducibility, which is unaffected by the length of the recording. In the present study, the performance of the proposed automated classification algorithm, providing total reproducibility, showed excellent agreement with manually defined P wave morphologies.</p

Potassium channel gene mutations rarely cause atrial fibrillation

BACKGROUND: Mutations in several potassium channel subunits have been associated with rare forms of atrial fibrillation. In order to explore the role of potassium channels in inherited typical forms of the arrhythmia, we have screened a cohort of patients from a referral clinic for mutations in the channel subunit genes implicated in the arrhythmia. We sought to determine if mutations in KCNJ2 and KCNE1-5 are a common cause of atrial fibrillation. METHODS: Serial patients with lone atrial fibrillation or atrial fibrillation with hypertension were enrolled between June 1, 2001 and January 6, 2005. Each patient underwent a standardized interview and physical examination. An electrocardiogram, echocardiogram and blood sample for genetic analysis were also obtained. Patients with a family history of AF were screened for mutations in KCNJ2 and KCNE1-5 using automated sequencing. RESULTS: 96 patients with familial atrial fibrillation were enrolled. Eighty-three patients had lone atrial fibrillation and 13 had atrial fibrillation and hypertension. Patients had a mean age of 56 years at enrollment and 46 years at onset of atrial fibrillation. Eighty-one percent of patients had paroxysmal atrial fibrillation at enrollment. Unlike patients with an activating mutation in KCNQ1, the patients had a normal QT(c )interval with a mean of 412 ± 42 ms. Echocardiography revealed a normal mean ejection fraction of 62.0 ± 7.2 % and mean left atrial dimension of 39.9 ± 7.0 mm. A number of common polymorphisms in KCNJ2 and KCNE1-5 were identified, but no mutations were detected. CONCLUSION: Mutations in KCNJ2 and KCNE1-5 rarely cause typical atrial fibrillation in a referral clinic population

Blood flow changes using a 3D xenogeneic collagen matrix or a subepithelial connective tissue graft for root coverage procedures: a pilot study.

BACKGROUND: The study investigated the early healing process following the treatment of single Miller class I and II recessions with a 3D xenogeneic collagen matrix (CMX) or connective tissue graft (CTG). METHODS: This pilot investigation was designed as a single-center randomized controlled parallel trial. A total of eight subjects (four per group) were treated with either CMX or CTG in the anterior maxilla. Vascular flow changes were assessed by laser Doppler flowmetry (LDF) before and after surgery and at days 1, 2, 3, 7, 14, and 30 while clinical evaluations took place at baseline and at days 60 and 180. Pain intensity perception was evaluated by the short-form McGill pain questionnaire (SF-MPQ), at days 1 and 14. RESULTS: The vascular flow fluctuated similarly in both groups pre- and post-operatively, but the CTG exhibited a more homogeneous pattern as opposed to CMX that showed a second phase of increased blood flow at 14 days. Clinically, the CTG led to greater change in mean root coverage and keratinized tissue gain but CMX was associated with lower early pain intensity scores. CONCLUSIONS: Within the limits of the study, the vascular flow alterations during the early healing of both graft types followed a similar pattern. The CMX was associated with a second peak of increased blood flow. CLINICAL RELEVANCE: The vascular flow changes after the application of CMX for single tooth recession root coverage did not show major differences from those observed after the use of a CTG. A trend for better clinical performance in terms of root coverage and keratinized tissue gain was noted for the CTG, but the initial patient morbidity was less for CMX

PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation

BackgroundAtrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.MethodsRight atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies.ResultsIn human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (P=2.0×10-2; n=12 and 12 in each group) with &gt;40% reduction in MLC2a phosphorylation (P=1.4×10-6; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10-2 and 6.7×10-3, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (P=5.0×10-6; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (P=1.8×10-2 and 4.1×10-2, respectively; n=6, 6, and 5).ConclusionsPatients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF