Significant association of SREBP-2 genetic polymorphisms with avascular necrosis in the Korean population

<p>Abstract</p> <p>Background</p> <p>It is known that steroid usage and alcohol abuse are major etiological factors in the development of avascular necrosis (AVN), a bone disease that produces osteonecrosis of the femoral head. The facilitation of fat biosynthesis by steroids and alcohol disrupts the blood supply into the femoral head. <it>SREBP-2 </it>plays a central role in the maintenance of lipid homeostasis through stimulating expression of genes associated with cholesterol biosynthetic pathways. The aim of this study was to examine the association between the polymorphisms of the <it>SREBP-2 </it>gene and AVN susceptibility in the Korean population.</p> <p>Methods</p> <p>Four single nucleotide polymorphisms (SNP) in the <it>SREBP-2 </it>gene, IVS1+8408 T>C (rs2267439), IVS3-342 G>T (rs2269657), IVS11+414 G>A (rs1052717) and IVS12-1667 G>A (rs2267443), were selected from public databases and genotyped in 443 AVN patients and 273 control subjects by using single-based extension (SBE) genotyping.</p> <p>Results</p> <p>The minor allele (C) frequency of rs2267439 showed a significant protective effect on AVN (P = 0.01, OR; 0.75, 95% CI; 0.604–0.935), and the genotype frequencies of this polymorphism were also different from the controls in all alternative analysis models (P range, 0.009–0.03, OR; 0.647–0.744). In contrast, rs1052717 and rs2267443 polymorphisms were significantly associated with AVN risk. Further analysis based on pathological etiology showed that the genotypes of rs2267439, rs1052717 and rs2267443 were also significantly associated with AVN susceptibility in each subgroup.</p> <p>Conclusion</p> <p>This study is the first report to evaluate the association between <it>SREBP-2 </it>gene polymorphisms and the susceptibility of AVN in the Korean population.</p

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported

Predicting Breast Cancer Response to Neoadjuvant Chemotherapy Using Pretreatment Diffuse Optical Spectroscopic-Texture Analysis

Purpose: Diffuse optical spectroscopy (DOS) has been demonstrated capable of monitoring response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC) patients. In this study, we evaluate texture features of pre-treatment DOS functional maps for predicting LABC response to NAC. Methods: LABC patients (n = 37) underwent DOS-breast imaging before starting neoadjuvant chemotherapy. Breast-tissue parametric maps were constructed and texture analyses were performed based on grey level co-occurrence matrices (GLCM) for feature extraction. Ground-truth labels as responders (R) or non-responders (NR) were assigned to patients based on Miller-Payne pathological response criteria. The capability of DOS-textural features computed on volumetric tumour data before the start of treatment (i.e. “pre-treatment”) to predict patient responses to NAC was evaluated using a leave-one-out validation scheme at subject level. Data were analysed using a logistic regression, naïve Bayes, and k-nearest neighbour (k-NN) classifiers. Results: Data indicated that textural characteristics of pre-treatment DOS parametric maps can differentiate between treatment response outcomes. The HbO2-homogeneity resulted in the highest accuracy amongst univariate parameters in predicting response to chemotherapy: sensitivity (%Sn) and specificity (%Sp) were 86.5 and 89.0%, respectively and accuracy was 87.8%. The highest predictors using multivariate (binary) combination features were the Hb-Contrast + HbO2-Homogeneity which resulted in a %Sn/%Sp = 78.0/81.0% and an accuracy of 79.5%. Conclusions: This study demonstrated that pre-treatment tumour DOS-texture features can predict breast cancer response to NAC and potentially guide treatments

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Understanding acute ankle ligamentous sprain injury in sports

This paper summarizes the current understanding on acute ankle sprain injury, which is the most common acute sport trauma, accounting for about 14% of all sport-related injuries. Among, 80% are ligamentous sprains caused by explosive inversion or supination. The injury motion often happens at the subtalar joint and tears the anterior talofibular ligament (ATFL) which possesses the lowest ultimate load among the lateral ligaments at the ankle. For extrinsic risk factors to ankle sprain injury, prescribing orthosis decreases the risk while increased exercise intensity in soccer raises the risk. For intrinsic factors, a foot size with increased width, an increased ankle eversion to inversion strength, plantarflexion strength and ratio between dorsiflexion and plantarflexion strength, and limb dominance could increase the ankle sprain injury risk. Players with a previous sprain history, players wearing shoes with air cells, players who do not stretch before exercising, players with inferior single leg balance, and overweight players are 4.9, 4.3, 2.6, 2.4 and 3.9 times more likely to sustain an ankle sprain injury. The aetiology of most ankle sprain injuries is incorrect foot positioning at landing – a medially-deviated vertical ground reaction force causes an explosive supination or inversion moment at the subtalar joint in a short time (about 50 ms). Another aetiology is the delayed reaction time of the peroneal muscles at the lateral aspect of the ankle (60–90 ms). The failure supination or inversion torque is about 41–45 Nm to cause ligamentous rupture in simulated spraining tests on cadaver. A previous case report revealed that the ankle joint reached 48 degrees inversion and 10 degrees internal rotation during an accidental grade I ankle ligamentous sprain injury during a dynamic cutting trial in laboratory. Diagnosis techniques and grading systems vary, but the management of ankle ligamentous sprain injury is mainly conservative. Immobilization should not be used as it results in joint stiffness, muscle atrophy and loss of proprioception. Traditional Chinese medicine such as herbs, massage and acupuncture were well applied in China in managing sports injuries, and was reported to be effective in relieving pain, reducing swelling and edema, and restoring normal ankle function. Finally, the best practice of sports medicine would be to prevent the injury. Different previous approaches, including designing prophylactice devices, introducing functional interventions, as well as change of games rules were highlighted. This paper allows the readers to catch up with the previous researches on ankle sprain injury, and facilitate the future research idea on sport-related ankle sprain injury

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances