Hereditary Basis Research Articles

Associations of high altitude polycythemia with polymorphisms in EPAS1, ITGA6 and ERBB4 in Chinese Han and Tibetan populations.

High altitude polycythemia (HAPC) is a common chronic disease at high altitude, which is characterized by excessive erythrocytosis (females, hemoglobin ≥ 190 g/L; males, hemoglobin ≥ 210 g/L). It is the most common disease in chronic mountain sickness casued primarily by persistent arterial hypoxia and ventilatory impairment. However, the disease is still unmanageable and related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. Subjects were screened for HAPC using the latest approved diagnostic criteria. To explore the hereditary basis of HAPC and investigate the association between three genes (EPAS1, ITGA6, ERBB4) and HAPC in Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). Subjects were screened for HAPC using the latest approved diagnostic criteria combined with excessive erythrocytosis and clinical symptoms. Analysis of variance was used to evaluate the impact of polymorphism on HAPC based on genetic variation. The Chi-squared test and analyses of genetic models, rs75591953 and rs75984373 in EPAS1, rs6744873 in ITGA6, rs17335043 in ERBB4 showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs3749148 in ITGA6, rs934607 and rs141267844 in ERBB4 showed a reduced risk of HAPC, whereas rs6710946 in ERBB4 increased the risk of HAPC. Our study suggest that the polymorphisms in the EPAS1, ITGA6 and ERBB4 correlate with susceptibility to HAPC.

Differences in photochemistry and response to heat stress between silver fir (Abies alba Mill.) provenances

The acclimation of silver fir to the conditions of the plantation sites has greater influence on PSII thermostability and performance than does on local adaptation. Forest ecosystems are frequently exposed to heat stress, which adversely affects their growth, performance, and ultimately survival. The knowledge of physiological responses to heat can help mitigate the effects of climate change by facilitating the choosing of suitable reproductive material for future reforestation programs. However, the intraspecific variation of adaptive traits, including the response to heat, has not been well documented. Therefore, we attempted to determine how PSII photochemistry of different silver fir (Abies alba Mill.) provenances varies in responses to heat stress and to reveal if intraspecific variation in PSII performance and thermostability is more affected by the climate of provenance origin or the plantation site. We tested 17 fir provenances sampled at two contrasting international provenance trial sites: Hertnik in Slovakia (390 m a.s.l.) and Kaprun in Austria (1100 m a.s.l.). Short-term heat stress was simulated for seven temperatures ranging from 20 to 51 °C using a water bath. The PSII thermotolerance was assessed via parameters of chlorophyll a fluorescence derived from the OKJIP transient. We observed several climatic variables of the provenances that significantly affected the photochemistry performance and thermostability of PSII, reflecting an additive hereditary basis. Almost all measured parameters varied significantly between trial plots and showed significant trial-by-provenance interactions pointing to acclimation triggered by the different conditions at the trial plots. Overall, the performance of PSII under non-stressing conditions and after heat treatment was better for provenances growing at the warmer trial site at Hertnik.

Identification and in silico characterization of p.G380R substitution in FGFR3, associated with achondroplasia in a non-consanguineous Pakistani family

BackgroundThe dimerization efficiency of FGFR3 transmembrane domain plays a critical role in the formation of a normal skeleton through the negative regulation of bone development. Recently, gain-of-function mutations in the transmembrane domain of FGFR3 has been described associated with an aberrant negative regulation, leading to the development of achondroplasia-group disorders, including achondroplasia (ACH), hypochondroplasia (HCH) and thanatophoric dysplasia (TD). Here, we describe a non-consanguineous Pakistani family with achondroplasia to explain hereditary basis of the disease.MethodsPCR-based linkage analysis using microsatellite markers was employed to localize the disease gene. Gene specific intronic primers were used to amplify the genomic DNA from all affected as well as phenotypically healthy individuals. Amplified PCR products were then subjected to Sanger sequencing and RFLP analysis to identify a potentially pathogenic mutation. The impact of identified mutation on FGFR3 protein’s structure and stability was highlighted through different bioinformatics tools.ResultsGenetic screening of the family revealed a previously reported heterozygous c.1138 G > A (p.G380R) mutation in the coding exon 8 of FGFR3 gene. Identified genetic variation was confirmed in all affected individuals while healthy individuals and controls were found genotypically normal. The results were further validated by RFLP analysis as c.1138 G > A substitution generates a unique recognition site for SfcI endonuclease. Following SfcI digestion, the electrophoretic pattern of three bands/DNA fragments for each patient is indicative of heterozygous status of the disease allele. In silico studies of the mutant FGFR3 protein predicted to adversely affect the stability of FGFR3 protein.ConclusionsMutation in the transmembrane domain may adversely affect the dimerization efficiency and overall stability of the FGFR3, leading to a constitutively active protein. As a result, an uncontrolled intracellular signaling or negative bone growth regulation leads to achondroplasia. Our findings support the fact that p.G380R is a common mutation among diverse population of the world and like other countries, can be used as a molecular diagnosis marker for achondroplasia in Pakistan.

Associations of high altitude polycythemia with polymorphisms in EPHA2 and AGT in Chinese Han and Tibetan populations.

High altitude polycythemia (HAPC) refers to the long-term living in the plateau of the hypoxia environment is not accustomed to cause red blood cell hyperplasia. The pathological changes are mainly the various organs and tissue congestion, blood stasis and hypoxia damage. Although chronic hypoxia is the main cause of HAPC, the related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). To explore the hereditary basis of HAPC and investigate the association between EPHA2 with AGT and HAPC in Chinese Han and Tibetan populations. Using the Chi-squared test and analyses of genetic models, rs2291804, rs2291805, rs3768294, rs3754334, rs6603856, rs6669624, rs11260742, rs13375644 and rs10907223 in EPHA2, and rs699, rs4762 and rs5051 in AGT showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs2478523 in AGT showed an increased the risk of HAPC. Our study suggest that polymorphisms in the EPHA2 and AGT correlate with susceptibility to HAPC in Chinese Han and Tibetan populations.

Clinical Impact of Mismatch Repair Protein Testing on Outcome of Early Staged Colorectal Carcinomas.

Colorectal cancer is the third most common cancer in men and second most common in women globally. In the present study, we aimed to analyse the proportion of patients with loss of immunostaining for mismatch repair (MMR) proteins in all newly diagnosed stage II cases of colorectal cancer for the purpose of prognostication, for determination of further chemotherapeutic strategy and for familial screening. From January 2014 to December 2015, 62 consecutive newly diagnosed cases of stage II colorectal cancer were included in the study. Details of each patient related to their demographic profile and tumour profile were recorded. All the cases were grossed and staged according to College of American Pathologist (CAP) guidelines. The expression of MMR proteins (which was earlier validated on normal as well as tumour tissue) in FFPE tumour tissue using IHC for mut L homologue 1 (MLH1), mut S homologue 2 (MSH2), mut S homologue 6 (MSH6) and post-meiotic segregation increased 2 (PMS2) was studied. Information regarding stage, treatment, clinical outcome and overall survival was retrieved when available. Out of a total of 371 cases, 62 (16.7%) cases were of stage II CRC, out of which 43 (12%) were treatment naive. Among the selected 62 cases, 26 (41.9%) demonstrated loss of MMR proteins and 36 (58.0%) cases had intact nuclear expression. Out of the cases with MMR loss, 38.4% showed loss of MLH1 and PMS2, 30.7% showed loss of MSH2 and MSH6, 26.9% showed isolated loss of PMS2 and 3.8% showed isolated loss of MSH6. Right-sided location (57.6%) was more common than left-sided (19.2%) and transverse colon (23.0%). Majority of the cases were moderately differentiated (65.3%) in morphology. There was no intratumoural infiltrate in most of the cases (53.8%), and only 3.8% cases showed marked intratumoural infiltrate. Also, peritumoural lymphocytic infiltrate was mild to moderate in most of the cases (26.9%) and marked Crohn's-like infiltrate was seen in only 7.6% cases. Our study shows that the routine evaluation of MMR proteins is achievable and essential for the purpose of prognostication, planning of treatment strategies and ascertaining a hereditary basis of CRC. The incidence of MMR protein loss was quite high in our study compared to other studies probably due to a difference in ethnicity. Though a right-sided predominance was supported, none of the typical morphological features of microsatellite instability (MSI) tumours were substantiated by our study, highlighting the lack of importance of histology for predicting MSI, and emphasising the point that MSI testing should be done as a routine procedure in all stage II CRC. A short follow-up was done for all our cases and comparison between the survival of the chemotherapy treated MSI cases versus those which were treatment naïve was performed and revealed that chemotherapy (CT) did not provide additional benefit to survival; MSI tumours in general are a better prognostic category and do not require additional chemotherapy.

Clinical and genetic basis of congenital myasthenic syndromes.

Neuromuscular junction disorders represent a wide group of neurological diseases characterized by weakness, fatigability and variable degrees of appendicular, ocular and bulbar musculature involvement. Its main group of disorders includes autoimmune conditions, such as autoimmune acquired myasthenia gravis and Lambert-Eaton syndrome. However, an important group of diseases include congenital myasthenic syndromes with a genetic and sometimes hereditary basis that resemble and mimick many of the classic myasthenia neurological manifestations, but also have different presentations, which makes them a complex clinical, therapeutic and diagnostic challenge for most clinicians. We conducted a wide review of congenital myasthenic syndromes in their clinical, genetic and therapeutic aspects.

Barriers and Facilitators to Adoption of Genomic Services for Colorectal Care within the Veterans Health Administration.

We examined facilitators and barriers to adoption of genomic services for colorectal care, one of the first genomic medicine applications, within the Veterans Health Administration to shed light on areas for practice change. We conducted semi-structured interviews with 58 clinicians to understand use of the following genomic services for colorectal care: family health history documentation, molecular and genetic testing, and genetic counseling. Data collection and analysis were informed by two conceptual frameworks, the Greenhalgh Diffusion of Innovation and Andersen Behavioral Model, to allow for concurrent examination of both access and innovation factors. Specialists were more likely than primary care clinicians to obtain family history to investigate hereditary colorectal cancer (CRC), but with limited detail; clinicians suggested templates to facilitate retrieval and documentation of family history according to guidelines. Clinicians identified advantage of molecular tumor analysis prior to genetic testing, but tumor testing was infrequently used due to perceived low disease burden. Support from genetic counselors was regarded as facilitative for considering hereditary basis of CRC diagnosis, but there was variability in awareness of and access to this expertise. Our data suggest the need for tools and policies to establish and disseminate well-defined processes for accessing services and adhering to guidelines.

NEW CANDIDATE GENES FOR SUSCEPTIBILITY TO TUBERCULOSIS IDENTIFIED THROUGH THE CONSTRUCTION AND ANALYSIS OF ASSOCIATIVE NETWORKS

Tuberculosis (TB) is a common disease caused by infection of Mycobacterium tuberculosis and influenced by host hereditary and environmental factors. Accumulated genomic data obtained through the use of new methodological approaches, including analysis of associative networks, contribute to the understanding of the hereditary basis of the disease. In the current study, we carried out the reconstruction and analysis of associative network representing molecular genetic links between proteins/genes involved in the development of TB. In the associative network, well studied proteins and genes with a decisive importance in the efficiency of the human immune response against a pathogen predominated. However, this approach identified 12 new genes encoding for the respective proteins in the associative network polymorphismsof which has not been studied regarding the development of TB.

The Open Mind: Cold War Politics and the Sciences of Human Nature by Jamie Cohen-Cole (review)

Jamie Cohen-Cole, Open Mind: Cold War Politics and the Sciences of Human Nature. Chicago: University of Chicago Press, 2014. 368 pp.It seems safe to say that in contemporary America, is a fairly ecumenical concept. We are told to keep an open mind to the cultural practices of others, to new technological innovations, to difference in all forms. However, open-mindedness cuts both ways: we can also hear frankly racist denunciations of mainstream unwillingness to consider the evidence for the hereditary bases of intelligence as a form of close-mindedness. Indeed, the very obviousness of the metaphor and its seeming lack of ideological specificity lend the concept a certain air of timelessness. open mind, however-at least in its specifically American form-is a surprisingly recent invention. Jamie Cohen-Cole's meticulously researched monograph does an excellent job of excavating the political and intellectual context in which the idiom emerged, demonstrating convincingly the powerful role that it played in shaping the intellectual landscape of post-war America. Indeed, its contemporary idiomatic ubiquity-however attenuated its positive content may appear-only serves to demonstrate how successfully it has infiltrated American ways of thinking about thinking. Open Mind lucidly charts the history of the concept, showing how it sutured creativity, rationality, autonomy, and willingness to embrace alternative viewpoints to a politically centrist, technocratic understanding of science and governance. Open-mindedness was used as both an evaluative standard for and scientific description of human activity in a surprisingly wide range of venues.Cohen-Cole argues that this open mind emerged as a quilting point for a whole host of projects and strategies within the ideology of a newly ascendant class of problem-oriented, interdisciplinary, Cold War intellectuals. These intellectuals found in the open mind the perfect expression of, and justification for, their particular experiences and understandings. Their participation in war-time working groups and policy planning, designed to rapidly mobilize America's intellectual capital to solve concrete problems, had forced them to learn to work together with experts from radically different disciplinary traditions and social locations. As they transitioned back to civilian life, they were faced with the dual challenges of transforming the networks of patronage and collegiality forged during World War II into durable institutions for the conduct of Cold War science, and-with millions of returning soldiers entering universities and the work force-of designing an educational system adequate for training a productive and cohesive citizenry. In Chapters 1 and 2 (Democratic Minds for a Complex Society and The Creative American, respectively), Cohen-Cole convincingly demonstrates how open-mindedness came to serve as perhaps the chief ethical virtue guiding each of these ventures, as the creativity, receptivity to alternative viewpoints, and problem-solving orientation required for success in intellectuals' earlier undertakings came to be held as a model for both academic and civic life more generally. As World War II turned into the Cold War, these elites used their particular war-time experiences to develop a new ethics and a new way of understanding their own practices as intellectuals. These self-understandings became the basis for a series of practical interventions into the way that all Americans learned, worked, and understood themselves both as citizens and human beings.Of course, the problems of coordination in complex organizations and societies were hardly novel. Indeed, Cohen-Cole also traces how the open mind presented a solution to longstanding fears in the educational establishment and early social sciences about the corrosive effects of the division of labor and stratification of society on national unity. In the Cold War context, however, these fears took on new urgency when dovetailed with the political concerns of a centrist, technocratic elite-fears of both an insidious international communism, as well as the home-grown specters of racism and reactionary paranoia. …

Abstract A06: ATM loss and KrasG12D cooperate to promote widely metastatic pancreatic ductal adenocarcinoma in mice

Abstract Invasive pancreatic adenocarcinoma (PDAC) is one of the most lethal solid malignancies. Mutational activation of Kras is nearly universal in preneoplastic pancreatic lesions (Pancreatic Intraepithelial Neoplasias-PanINs) and PDAC, whereas the progression of PanINs to PDAC is accompanied by both inactivating mutations in p16/CDKN2A, TP53, DPC4/SMAD4 and activating mutations in PI3K signaling. Although most PDAC cases represent a sporadic disease, about 5-10% of cases have a hereditary basis. Some of the loci responsible for inherited high-risk PDAC encode gene products implicated in DNA repair, such as BRCA2 and PALB2. The kinase Ataxia-Telangiectasia Mutated (ATM) plays a critical role in DNA damage responses activated by double-strand breaks, by triggering cell cycle checkpoints that repair DNA or induce p53-dependent apoptosis or senescence. ATM was recently identified as a novel predisposition gene for PDAC because deleterious ATM mutations were found in some families with hereditary PDAC, as well as in ~8% of sporadic PDAC cases. Thus far, the role of ATM as an anti-cancer barrier – especially in pancreatic cancer biology – is poorly understood. Here we sought to address this crucial issue using 3 different mouse strains expressing both an oncogenic version of Kras (KrasG12D) and variable ATM genetic dosage in the pancreas: 1) KC mice, express wild-type ATM, 2) KC;ATMcHET mice, carry deletion of one ATM-allele; and 3) KC;ATMcKO mice, carry deletion of both ATM-alleles. Our preliminary analysis of KrasG12D-induced PanIN formation uncovered that these lesions form earlier in pancreatic tissues carrying one functional ATM allele or lacking ATM in comparison to KC pancreata. In addition, we determined that the median survival due to metastatic tumor burden is considerably shorter in both KC;ATMcKO mice (~6 months) and KC;ATMcHET mice (~9 months) compared to KC mice (~15 months). We also began establishing primary cell lines from both PDAC and metastatic foci formed in KC, KC;ATMcKO and KC;ATMcHET mice. Preliminary analyses of 2 primary cell lines treated with ionizing radiation (IR) to induce DNA damage and processed for Western blot analysis showed lack of total ATM, phospho-ATM, phospho-KAP1 (an ATM-specific target), and phospho-p53 in ATM-deficient primary pancreatic cancer cells. In contrast, primary cell lines from KC;Cdkn2a+/- tumors and established human PDAC cell lines display functional ATM signaling after IR. In addition, primary cell lines from PDAC and liver metastases of KC;ATMcKO mice also exhibited genomic instability depicted by a high number of anaphase bridges. To complement the characterization of these primary cell lines, we will attempt to identify DNA repair pathway(s) compensating for the loss of ATM and exploit these findings to induce synthetic lethality. Likewise, additional signaling pathways that are activated or inactivated during PDAC progression in the context of ATM deficiency will be identified using both biased and unbiased approaches. To our knowledge, these preliminary results provide the first evidence in vivo that ATM activity poses an intrinsic barrier to oncogenic transformation in the pancreas. A comprehensive characterization of pancreatic tumor formation in the context of ATM deficiency using our generated mouse models is currently underway, together with experiments in primary cell lines attempting to identify vulnerabilities that could be exploited to develop adequate tailored treatments. Citation Format: Yiannis Drosos, Kathryn Roys, Emin Kuliyev, Peter McKinnon, Beatriz Sosa-Pineda. ATM loss and KrasG12D cooperate to promote widely metastatic pancreatic ductal adenocarcinoma in mice. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A06.

Covering the Cover

Covering the Cover

Congenital Cardiac Conduction Abnormalities

Abnormalities in cardiac conduction can occur due to a variety of factors. So called "idiopathic", conduction system degeneration develops without evident causes and may have hereditary basis. In the majority of cases it has no clinical manifestation, do not require treatment and have overall good prognosis. In this review we focus on congenital complete atrioventricular block and progressive cardiac conduction defect - rare but malignant and potentially lethal conditions that can be caused by genetic mutations and may be isolated or associated with structural heart disease. Cardiac involvement is relatively common in rare hereditary diseases - myodystrophies and mitochondrial cytopathies. Conduction abnormalities are among the most severe manifestations that may determine prognosis in these rare genetic disorders. These conditions deserve special consideration because of rapid progression of conduction defects and high prevalence of sudden cardiac death if no appropriate treatment applied.

A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase

Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. We found that small intestinal carcinoids can occur as an inherited autosomal-dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.

Prevalence of angle closure in siblings of patients with primary angle-closure glaucoma.

To determine the frequency of angle closure in siblings of patients with primary angle-closure glaucoma (PACG). In this cross-sectional observational study, siblings of consecutive patients with PACG underwent a comprehensive ophthalmologic examination, including slit-lamp biomicroscopy, measurement of intraocular pressure, stereoscopic optic nerve head examination, and dynamic gonioscopy. Ultrasonic pachymetry was obtained in all subjects; peripapillary retinal nerve fiber layer thickness measurement by optical coherence tomography and standard achromatic perimetry were performed in subjects with angle closure, categorized as primary angle-closure suspect (PACS), primary angle closure (PAC), and PACG, or any suspicion of glaucoma in the presence of open angles. Overall, 95 siblings from 47 families with at least 1 subject affected with PACG participated in the evaluations; 55 (57.9%) individuals were categorized within the spectrum of angle closure, including 34 (35.8%) subjects with PACS, 7 (7.4%)individuals with PAC, and 14 (14.7%) cases of PACG. Nine (9.5%) individuals with open angles demonstrated other abnormal features, these included 3 (3.2%) subjects with suspicious discs, 5 (5.3%) cases of primary open-angle glaucoma, and 1 patient (1.1%) with normal-tension glaucoma. The remaining 31 individuals (32.6%) had no evidence of glaucoma. Our findings indicate familial segregation of angle closure. Siblings of PACG patients are at high risk for the condition, such that two thirds of them demonstrate clinical findings related to glaucoma. These observations suggest a hereditary basis for angle closure; therefore, siblings of patients affected with angle closure should undergo targeted screening for glaucoma.

Deficiency of endothelium-specific transcription factor Sox17 induces intracranial aneurysm.

Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings. Our findings demonstrate that Sox17 deficiency in mouse can induce IA under hypertensive conditions, suggesting Sox17 deficiency as a potential genetic factor for IA formation. The Sox17-deficient mouse model provides a novel platform to develop therapeutics for incurable IA.

Paramastoid apophysis: case report

AbstractThe aim of this study was to report a case of a paramastoid apophysis of a human skull, identified during routine lessons at the Laboratory of Human Anatomy, Federal University of Pernambuco and Recife-PE, Brazil. The skull used in this study showed a morphological variation present only on the right side of the occipital bone, which had a height of 18.10 mm and had a facet joint with the transverse process of the atlas, being identified as paramastoid apophysis. Other anatomical variations in skull were found as: presence of sutural bone along the lambdoidal suture and persistent metopic suture. Thus, this study will be important for the health sciences and those who keep interest in pathologies associated with atlanto-occipital joint, because the description of the structures that deviate from the normal organogenesis resulting from disorders: hereditary basis or not, has a practical interest that prints the modification to the arrangement of the constituent elements of the region and possible functional alterations resulting therefrom.

Genetic structure and genetic diversity of single-variety Lonicera macranthoides populations in China, as indicated by SCoT markers.

Lonicera macranthoides is an important traditional Chinese herb. The lack of information regarding the genetic structure and genetic relationships among its cultivars has hindered the conservation and utilization of this resource. This study used start codon targeted markers to assess the genetic diversity and other genetic characteristics of five single-variety L. macranthoides populations in China. Using 22 primers produced a total of 266 bands, of which 227 were polymorphic, indicating a high level of polymorphism. At the species level, genetic diversity was high: percentage of polymorphic loci (PPB) = 85.34%, effective number of alleles (NE) = 1.3479, Nei's gene diversity (H) = 0.2075, and Shannon's information index (Hsp, species level) = 0.3198. However, at the varietal population level, genetic diversity was lower, with averages of: PPB = 19.74%, NE = 1.0946, H = 0.0561, Hpop = 0.0850 (population level). Nei's genetic differentiation coefficient was 0.7319, which is consistent with Shannon's population genetic differentiation coefficient (0.7324). This indicates that most of the genetic variation in this species exists among the varietal populations. The differentiation among varieties may have been caused by artificial selection, mode of reproduction, and barriers to gene flow (0.1831). The genetic similarity coefficient ranged from 0.7222 to 0.9419. Phylogenetic analysis showed the five varieties to form two major clades. Results suggest that cultivar breeders should strengthen the exchange of germplasm and increase the mutual penetration of useful genes, which would broaden the hereditary basis of L. macranthoides.

The hereditary basis of bicuspid aortic valve disease: a role for screening?

The hereditary basis of bicuspid aortic valve disease: a role for screening?

Patient profiling in diabetes and role of canagliflozin

Patient profiling in diabetes and role of canagliflozin Ambika Amblee1,2 1Division of Endocrinology, John H Stroger Jr Hospital of Cook County, 2Rush University Medical Center, Chicago, IL, USA Background: Physicians attempt to achieve glycemic goals in patients with type 2 diabetes mellitus (T2DM) through various means, including glucose-lowering medications. There is interindividual variability in response to medications, which can be partially explained by the presence of genetic polymorphisms that affect drug metabolism. Pharmacogenomics studies the hereditary basis of interpatient variations in drug response and aims to identify subgroups of patients whose drug management could be tailored accordingly. The aim of this review is to explore patient profiling in the management of T2DM with a focus on the sodium glucose transporter inhibitor canagliflozin. Methods: The PubMed database was searched using the terms “pharmacogenomics” and “diabetes” through May 31, 2014. Published articles and abstracts presented at national/international meetings were considered. Results and conclusion: Genome-wide association studies have opened the door for patient profiling and research into genetic variants in multifactorial T2DM. Clinically, it may be possible to tailor the type of medication used based on the presence or absence of the various genetic variants. However, the polymorphisms studied may only explain some of the variability in response to T2DM drugs and needs further validation to ensure its authenticity. There are still unidentified factors which appear to play a role in the interindividual variability seen in clinical practice. The potential exists for pharmacogenomics to promote efficacious, safe, and cost-effective individualized diabetes management. Pharmacogenomics is still in its early stages, and the idea of defining patients genetically to predict individual responses to drugs and obtain safe and effective T2DM management is promising, in spite of existing barriers. Currently, clinical profiling of patients with T2DM and using an individualized approach with most drugs, including canagliflozin, based on comorbid conditions still remains the most accepted approach for the management of T2DM. Keywords: personalized medicine, pharmacogenomics, genetic variants

Fibrous Dysplasia – A Case Report and Review of Literature

Fibrous dysplasia (FD) is a fibro-osseous lesion with no apparent familial, hereditary or congenital basis. It is a non-neoplastic developmental hamartomatous disease of the bone, characterised by a blend of fibrous and osseous elements in the region. It constitutes 2.5% of all bony neoplasms and 7% of all benign bony neoplasm. The treatment can be either conservative or complete resection. Here we report a case of fibrous dysplasia in a 64-year-old male patient on the right side of the face.