Showing papers by "Stephen J. O'Brien published in 2014"

Whole-genome analyses resolve early branches in the tree of life of modern birds

Abstract: To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.

Comparative genomics reveals insights into avian genome evolution and adaptation.

Abstract: Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.

Evaluation and Integration of Genetic Signature for Prediction Risk of Nasopharyngeal Carcinoma in Southern China

Abstract: Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC). A number of single nucleotide polymorphisms (SNPs) have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs in ITGA9 at 3p21.3 and 9 SNPs within the 6p21.3 HLA region were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC). Results. The reported associations between ITGA9 variants and NPC were not replicated. Multiple loci of GABBR1, HLA-F, HLA-A, and HCG9 were statistically significant in both cohorts (Pcombined range from 5.96 × 10−17 to 0.02). We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC.

Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication

Abstract: Little is known about the genetic changes that distinguish domestic cat populations from their wild progenitors. Here we describe a high-quality domestic cat reference genome assembly and comparative inferences made with other cat breeds, wildcats, and other mammals. Based upon these comparisons, we identified positively selected genes enriched for genes involved in lipid metabolism that underpin adaptations to a hypercarnivorous diet. We also found positive selection signals within genes underlying sensory processes, especially those affecting vision and hearing in the carnivore lineage. We observed an evolutionary tradeoff between functional olfactory and vomeronasal receptor gene repertoires in the cat and dog genomes, with an expansion of the feline chemosensory system for detecting pheromones at the expense of odorant detection. Genomic regions harboring signatures of natural selection that distinguish domestic cats from their wild congeners are enriched in neural crest-related genes associated with behavior and reward in mouse models, as predicted by the domestication syndrome hypothesis. Our description of a previously unidentified allele for the gloving pigmentation pattern found in the Birman breed supports the hypothesis that cat breeds experienced strong selection on specific mutations drawn from random bred populations. Collectively, these findings provide insight into how the process of domestication altered the ancestral wildcat genome and build a resource for future disease mapping and phylogenomic studies across all members of the Felidae.

Minke whale genome and aquatic adaptation in cetaceans

Abstract: The shift from terrestrial to aquatic life by whales was a substantial evolutionary event. Here we report the whole-genome sequencing and de novo assembly of the minke whale genome, as well as the whole-genome sequences of three minke whales, a fin whale, a bottlenose dolphin and a finless porpoise. Our comparative genomic analysis identified an expansion in the whale lineage of gene families associated with stress-responsive proteins and anaerobic metabolism, whereas gene families related to body hair and sensory receptors were contracted. Our analysis also identified whale-specific mutations in genes encoding antioxidants and enzymes controlling blood pressure and salt concentration. Overall the whale-genome sequences exhibited distinct features that are associated with the physiological and morphological changes needed for life in an aquatic environment, marked by resistance to physiological stresses caused by a lack of oxygen, increased amounts of reactive oxygen species and high salt levels.

Genome-wide Mycobacterium tuberculosis variation (GMTV) database: a new tool for integrating sequence variations and epidemiology

Abstract: Tuberculosis (TB) poses a worldwide threat due to advancing multidrug-resistant strains and deadly co-infections with Human immunodeficiency virus. Today large amounts of Mycobacterium tuberculosis whole genome sequencing data are being assessed broadly and yet there exists no comprehensive online resource that connects M. tuberculosis genome variants with geographic origin, with drug resistance or with clinical outcome. Here we describe a broadly inclusive unifying Genome-wide Mycobacterium tuberculosis Variation (GMTV) database, ( http://mtb.dobzhanskycenter.org ) that catalogues genome variations of M. tuberculosis strains collected across Russia. GMTV contains a broad spectrum of data derived from different sources and related to M. tuberculosis molecular biology, epidemiology, TB clinical outcome, year and place of isolation, drug resistance profiles and displays the variants across the genome using a dedicated genome browser. GMTV database, which includes 1084 genomes and over 69,000 SNP or Indel variants, can be queried about M. tuberculosis genome variation and putative associations with drug resistance, geographical origin, and clinical stages and outcomes. Implementation of GMTV tracks the pattern of changes of M. tuberculosis strains in different geographical areas, facilitates disease gene discoveries associated with drug resistance or different clinical sequelae, and automates comparative genomic analyses among M. tuberculosis strains.

The dynamic proliferation of CanSINEs mirrors the complex evolution of Feliforms

Abstract: Repetitive short interspersed elements (SINEs) are retrotransposons ubiquitous in mammalian genomes and are highly informative markers to identify species and phylogenetic associations. Of these, SINEs unique to the order Carnivora (CanSINEs) yield novel insights on genome evolution in domestic dogs and cats, but less is known about their role in related carnivores. In particular, genome-wide assessment of CanSINE evolution has yet to be completed across the Feliformia (cat-like) suborder of Carnivora. Within Feliformia, the cat family Felidae is composed of 37 species and numerous subspecies organized into eight monophyletic lineages that likely arose 10 million years ago. Using the Felidae family as a reference phylogeny, along with representative taxa from other families of Feliformia, the origin, proliferation and evolution of CanSINEs within the suborder were assessed. We identified 93 novel intergenic CanSINE loci in Feliformia. Sequence analyses separated Feliform CanSINEs into two subfamilies, each characterized by distinct RNA polymerase binding motifs and phylogenetic associations. Subfamily I CanSINEs arose early within Feliformia but are no longer under active proliferation. Subfamily II loci are more recent, exclusive to Felidae and show evidence for adaptation to extant RNA polymerase activity. Further, presence/absence distributions of CanSINE loci are largely congruent with taxonomic expectations within Feliformia and the less resolved nodes in the Felidae reference phylogeny present equally ambiguous CanSINE data. SINEs are thought to be nearly impervious to excision from the genome. However, we observed a nearly complete excision of a CanSINEs locus in puma (Puma concolor). In addition, we found that CanSINE proliferation in Felidae frequently targeted existing CanSINE loci for insertion sites, resulting in tandem arrays. We demonstrate the existence of at least two SINE families within the Feliformia suborder, one of which is actively involved in insertional mutagenesis. We find SINEs are powerful markers of speciation and conclude that the few inconsistencies with expected patterns of speciation likely represent incomplete lineage sorting, species hybridization and SINE-mediated genome rearrangement.

Mammalian Keratin Associated Proteins (KRTAPs) Subgenomes: Disentangling Hair Diversity and Adaptation to Terrestrial and Aquatic Environments

Abstract: Adaptation of mammals to terrestrial life was facilitated by the unique vertebrate trait of body hair, which occurs in a range of morphological patterns. Keratin associated proteins (KRTAPs), the major structural hair shaft proteins, are largely responsible for hair variation. We exhaustively characterized the KRTAP gene family in 22 mammalian genomes, confirming the existence of 30 KRTAP subfamilies evolving at different rates with varying degrees of diversification and homogenization. Within the two major classes of KRTAPs, the high cysteine (HS) subfamily experienced strong concerted evolution, high rates of gene conversion/recombination and high GC content. In contrast, high glycine-tyrosine (HGT) KRTAPs showed evidence of positive selection and low rates of gene conversion/recombination. Species with more hair and of higher complexity tended to have more KRATP genes (gene expansion). The sloth, with long and coarse hair, had the most KRTAP genes (175 with 141 being intact). By contrast, the “hairless” dolphin had 35 KRTAPs and the highest pseudogenization rate (74% relative to the 19% mammalian average). Unique hair-related phenotypes, such as scales (armadillo) and spines (hedgehog), were correlated with changes in KRTAPs. Gene expression variation probably also influences hair diversification patterns, for example human have an identical KRTAP repertoire as apes, but much less hair. We hypothesize that differences in KRTAP gene repertoire and gene expression, together with distinct rates of gene conversion/recombination, pseudogenization and positive selection, are likely responsible for micro and macro-phenotypic hair diversification among mammals in response to adaptations to ecological pressures.

Sympatric Asian felid phylogeography reveals a major Indochinese–Sundaic divergence

Abstract: The dynamic geological and climatological history of Southeast Asia has spawned a complex array of ecosystems and 12 of the 37 known cat species, making it the most felid-rich region in the world. To examine the evolutionary histories of these poorly studied fauna, we compared phylogeography of six species (leopard cat Prionailurus bengalensis, fishing cat P. viverrinus, Asiatic golden cat Pardofelis temminckii, marbled cat P. marmorata, tiger Panthera tigris and leopard P. pardus) by sequencing over 5 kb of DNA each from 445 specimens at multiple loci of mtDNA, Y and X chromosomes. All species except the leopard displayed significant phylogenetic partitions between Indochina and Sundaland, with the central Thai–Malay Peninsula serving as the biogeographic boundary. Concordant mtDNA and nuclear DNA genealogies revealed deep Indochinese–Sundaic divergences around 2 MYA in both P. bengalensis and P. marmorata comparable to previously described interspecific distances within Felidae. The divergence coincided with serial sea level rises during the late Pliocene and early Pleistocene, and was probably reinforced by repeated isolation events associated with environmental changes throughout the Pleistocene. Indochinese–Sundaic differentiations within P. tigris and P. temminckii were more recent at 72–108 and 250–1570 kya, respectively. Overall, these results illuminate unexpected, deep vicariance events in Southeast Asian felids and provide compelling evidence of species-level distinction between the Indochinese and Sundaic populations in the leopard cat and marbled cat. Broader sampling and further molecular and morphometric analyses of these species will be instrumental in defining conservation units and effectively preserving Southeast Asian biodiversity.

The biomechanics of throwing: simplified and cogent.

Abstract: The majority of shoulder injuries occur due to repetitive overhead movements, with baseball pitching being the most common mechanism for overuse injury. Before studying the treatment of these shoulder injuries, it is paramount that the health professional have an understanding of the etiology of and the underlying mechanisms for shoulder pathology. The act of overhead throwing is an eloquent full-body motion that requires tremendous coordination from the time of force generation to follow-through. The shoulder complex is a crucial component of the upper body kinetic chain as it transmits force created in the lower body to the arm and hand to produce velocity and accuracy with ball release. The focus of this article is on the biomechanics of the throwing motion, with emphasis on the kinematics of the shoulder. The established phases of the throwing motion will be reviewed in a stepwise manner and the contributions of osseous and soft-tissue structures to the successful completion of each phase will be discussed.

Endogenous Retrovirus Insertion in the KIT Oncogene Determines White and White spotting in Domestic Cats

Abstract: The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. We performed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1) as the feline W locus. Segregation and sequence analysis of the KIT gene in two pedigrees (P1 and P2) revealed the remarkable retrotransposition and evolution of a feline endogenous retrovirus (FERV1) as responsible for two distinct phenotypes of the W locus, Dominant White, and white spotting. A full-length (7125 bp) FERV1 element is associated with white spotting, whereas a FERV1 long terminal repeat (LTR) is associated with all Dominant White individuals. For purposes of statistical analysis, the alternatives of wild-type sequence, FERV1 element, and LTR-only define a triallelic marker. Taking into account pedigree relationships, deafness is genetically linked and associated with this marker; estimated P values for association are in the range of 0.007 to 0.10. The retrotransposition interrupts a DNAase I hypersensitive site in KIT intron 1 that is highly conserved across mammals and was previously demonstrated to regulate temporal and tissue-specific expression of KIT in murine hematopoietic and melanocytic cells. A large-population genetic survey of cats (n = 270), representing 30 cat breeds, supports our findings and demonstrates statistical significance of the FERV1 LTR and full-length element with Dominant White/blue iris (P < 0.0001) and white spotting (P < 0.0001), respectively.

The combination of hyper-CVAD plus nelarabine as frontline therapy in adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson Cancer Center experience.

Abstract: The combination of hyper-CVAD plus nelarabine as frontline therapy in adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson Cancer Center experience

Phylogeography and population history of Leopardus guigna , the smallest American felid

Abstract: The guigna (Leopardus guigna) is the smallest and most-restricted New World cat species, inhabiting only around 160,000 km2 of temperate rain forests in southern South America and is currently threatened by habitat loss, fragmentation and human persecution. We investigated phylogeographic patterns of genetic diversity, demographic history and barriers to gene flow with 116 individuals sampled across the species geographic range by analyzing 1,798 base pairs of the mtDNA (496 bp HVSI region, 720 bp NADH-5 gene, 364 bp from 16S gene and 218 bp from ATP-8 gene) and 15 microsatellite loci. Mitochondrial DNA data revealed a clear phylogeographic pattern with moderate separation between northern and southern Chilean populations supporting recognized subspecific partitions based on morphology. A recent demographic expansion was inferred for the southern-most group (San Rafael Lake), presumably due to the complete coverage of this area during the last glacial period, 28000–16000 years BP. Geographical barriers such as the Andes Mountains and the Chacao Channel have partially restricted historic and more-recent gene flow and the Chiloe Island population has diverged genetically since being separated from the mainland 7000 years BP. This is the first study of the genetic structure of this threatened species throughout its whole geographic range.

Annotated features of domestic cat - Felis catus genome.

Abstract: Domestic cats enjoy an extensive veterinary medical surveillance which has described nearly 250 genetic diseases analogous to human disorders. Feline infectious agents offer powerful natural models of deadly human diseases, which include feline immunodeficiency virus, feline sarcoma virus and feline leukemia virus. A rich veterinary literature of feline disease pathogenesis and the demonstration of a highly conserved ancestral mammal genome organization make the cat genome annotation a highly informative resource that facilitates multifaceted research endeavors. Here we report a preliminary annotation of the whole genome sequence of Cinnamon, a domestic cat living in Columbia (MO, USA), bisulfite sequencing of Boris, a male cat from St. Petersburg (Russia), and light 30× sequencing of Sylvester, a European wildcat progenitor of cat domestication. The annotation includes 21,865 protein-coding genes identified by a comparative approach, 217 loci of endogenous retrovirus-like elements, repetitive elements which comprise about 55.7% of the whole genome, 99,494 new SNVs, 8,355 new indels, 743,326 evolutionary constrained elements, and 3,182 microRNA homologues. The methylation sites study shows that 10.5% of cat genome cytosines are methylated. An assisted assembly of a European wildcat, Felis silvestris silvestris, was performed; variants between F. silvestris and F. catus genomes were derived and compared to F. catus. The presented genome annotation extends beyond earlier ones by closing gaps of sequence that were unavoidable with previous low-coverage shotgun genome sequencing. The assembly and its annotation offer an important resource for connecting the rich veterinary and natural history of cats to genome discovery.

Evolutionary Genomics and Adaptive Evolution of the Hedgehog Gene Family ( Shh, Ihh and Dhh ) in Vertebrates

Abstract: The Hedgehog (Hh) gene family codes for a class of secreted proteins composed of two active domains that act as signalling molecules during embryo development, namely for the development of the nervous and skeletal systems and the formation of the testis cord. While only one Hh gene is found typically in invertebrate genomes, most vertebrates species have three (Sonic hedgehog – Shh; Indian hedgehog – Ihh; and Desert hedgehog – Dhh), each with different expression patterns and functions, which likely helped promote the increasing complexity of vertebrates and their successful diversification. In this study, we used comparative genomic and adaptive evolutionary analyses to characterize the evolution of the Hh genes in vertebrates following the two major whole genome duplication (WGD) events. To overcome the lack of Hh-coding sequences on avian publicly available databases, we used an extensive dataset of 45 avian and three non-avian reptilian genomes to show that birds have all three Hh paralogs. We find suggestions that following the WGD events, vertebrate Hh paralogous genes evolved independently within similar linkage groups and under different evolutionary rates, especially within the catalytic domain. The structural regions around the ion-binding site were identified to be under positive selection in the signaling domain. These findings contrast with those observed in invertebrates, where different lineages that experienced gene duplication retained similar selective constraints in the Hh orthologs. Our results provide new insights on the evolutionary history of the Hh gene family, the functional roles of these paralogs in vertebrate species, and on the location of mutational hotspots.

Intra-operative and short term outcome of total knee arthroplasty in morbidly obese patients

Abstract: Background Longer operation times, poorer patient outcomes and increased early post-operative complications are reasons cited for not undertaking Total Knee Arthroplasty (TKA) on morbidly obese patients. This study tests the hypothesis that there is no difference in intra-operative parameters between morbidly obese and non-obese patients, and no difference in patient outcome. Methods Intra-operative parameters, post-operative complications, patient outcomes and knee range of motion were compared between morbidly obese patients (BMI>40kg/m 2 ) and individually age and gender matched non-obese patients (BMI 2 ) undergoing cementless rotating platform TKA. Results Anaesthetic times and length of hospital stay were not significantly different between the morbidly obese and non-obese patients. Surgical time was significantly greater in morbidly obese patients. Improvements in patient outcomes following TKA were not significantly different between the morbidly obese and non-obese patients at early and short-term follow-up. Conclusions In contrast to previous studies, post-operative complication rates within three months of surgery and up to one year post-operatively were not significantly higher for morbidly obese patients. Level of evidence III

Genetic variations affecting serum carcinoembryonic antigen levels and status of regional lymph nodes in patients with sporadic colorectal cancer from Southern China.

Abstract: Background Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients However, the genetic determinants of sCEA level in healthy and CRC population remains unclear Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications Methods and Findings Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform Eight candidate SNPs were validated in CRC patients The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1427, 95% CI: 1005~1843, P = 0006) It was also one of the risk factors for regional lymph node metastasis (OR = 2266, 95% CI: 1196~4293, P = 0012) The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0006) The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0022) In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0023) Conclusions We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China

Midterm Clinical Outcomes for Arthroscopic Subdeltoid Transfer of the Long Head of the Biceps Tendon to the Conjoint Tendon

Abstract: Purpose The aim of this study was to assess the midterm functional outcomes for arthroscopic subdeltoid transfer of the long head of the biceps tendon (LHBT) to the conjoint tendon. Methods Fifty-six shoulders in 54 patients (46 men, 8 women; mean age, 42 years) who underwent isolated arthroscopic subdeltoid LHBT transfer to the conjoint tendon by a single surgeon with a minimum of 4 years follow-up were evaluated with American Society of Shoulder and Elbow Surgeons (ASES) and L'Insalata scores. A subset of patients was available for physical examination. Results At an average of 6.4 years postoperatively, ASES and L'Insalata scores were 86 and 85, respectively, corresponding to 88% of patients rated good to excellent. Twelve shoulders (10 from men patients, 2 from women patients; mean age 41 years; average follow-up, 6.3 years) underwent physical examination. Mean University of California, Los Angeles (UCLA) score was 31, and there were no significant differences in side-to-side elbow flexion strength or endurance using a 10-pound weight. One patient had a Popeye sign. There were no major complications reported in this cohort. Conclusions Arthroscopic transfer of the LHBT to the conjoint tendon is a safe and durable intervention for chronic refractory biceps tendinitis. Level of Evidence Level IV, therapeutic case series.

HIV in (and out of) the clinic: Biomedicine, traditional medicine and spiritual healing in Harare

Abstract: Contemporary lived experiences of the human immunodeficiency virus (HIV) are shaped by clinical and cultural encounters with illness. In sub-Saharan countries such as Zimbabwe, HIV is treated in very different ways in various therapeutic contexts including by biomedical experts, traditional medicine and faith healers. The co-existence of such expertise raises important questions around the potencies and limits of medicalisation and alternative healing practices in promoting HIV recovery. First, in this study, drawing on in-depth qualitative interviews with 60 people from poor urban areas in Harare, we explore the experiences of people living with and affected by HIV. Specifically, we sought to document, interrogate and reflect on their perceptions and experiences of biomedicine in relation to traditional medicine and spiritual healing. Their accounts indicate that traditional medicine and spiritual beliefs continue to significantly influence the way in which HIV is understood, and the forms of help and care people seek. Second, we observe the dramatic and overwhelmingly beneficial impact of Antiretroviral Therapy and conclude through Zimbabwean's own stories that limitations around delivery and wider structural inequalities impede its potential. Lastly, we explore some practical implications of the biomedical clinic (and alternative healing practices) being understood as sites of ideological and expert contestation. This paper aimed to add to our knowledge of the relationships between traditional medicine and spiritual healing in connection with biomedicine and how this may influence HIV treatment and prevention.

The influence of immediate knee flexion on blood loss and other parameters following total knee replacement

Abstract: In an initial randomised controlled trial (RCT) we segregated 180 patients to one of two knee positions following total knee replacement (TKR): six hours of knee flexion using either a jig or knee extension. Outcome measures included post-operative blood loss, fall in haemoglobin, blood transfusion requirements, knee range of movement, limb swelling and functional scores. A second RCT consisted of 420 TKR patients randomised to one of three post-operative knee positions: flexion for three or six hours post-operatively, or knee extension. Positioning of the knee in flexion for six hours immediately after surgery significantly reduced blood loss (p = 0.002). There were no significant differences in post-operative range of movement, swelling, pain or outcome scores between the various knee positions in either study. Post-operative knee flexion may offer a simple and cost-effective way to reduce blood loss and transfusion requirements following TKR. We also report a cautionary note regarding the potential risks of prolonged knee flexion for more than six hours observed during clinical practice in the intervening period between the two trials, with 14 of 289 patients (4.7%) reporting lower limb sensory neuropathy at their three-month review. Cite this article: Bone Joint J 2014;96-B:201–9.

Bacteria: Other Pathogenic Enterobacteriaceae – Enterobacter and Other Genera

Abstract: The family Enterobacteriaceae includes a number of genera ( Cronobacter , Escherichia coli , Salmonella , and Yersinia ) that are well-known bacterial causes of food-borne disease. Other species including Enterobacter , Klebsiella , Pantoea , and Serratia may on occasion cause food-borne illness. These species have the ability to cause infection in immunocompromised individuals along with nosocomial infections in hospitals environments. Here the authors review their general characteristics and links to food contamination along with associated clinical signs. In addition they comment on current laboratory-based methodologies used for isolation, identification, and subtyping.

Intestinal Expression of Fas and Fas Ligand Is Upregulated by Bacterial Signaling through TLR4 and TLR5, with Activation of Fas Modulating Intestinal TLR-Mediated Inflammation

Abstract: TLRs play an important role in mediating intestinal inflammation and homeostasis. Fas is best studied in terms of its function in apoptosis, but recent studies demonstrate that Fas signaling may mediate additional functions such as inflammation. The role of Fas, and the Fas ligand (FasL), in the intestine is poorly understood. The aim of this study was to evaluate potential cross-talk between TLRs and Fas/FasL system in intestinal epithelial cells (IECs). IECs were stimulated with TLR ligands, and expression of Fas and FasL was investigated. Treatment with TLR4 and TLR5 ligands, but not TLR2 and 9 ligands, increased expression of Fas and FasL in IECs in vitro. Consistent with this finding, expression of intestinal Fas and FasL was reduced in vivo in the epithelium of TLR4 knockout (KO), 5KO, and germ-free mice, but not in TLR2KO mice. Modulating Fas signaling using agonistic anti-Fas augmented TLR4- and TLR5-mediated TNF-α and IL-8 production by IECs. In addition, suppression of Fas in IECs reduced the ability of TLR4 and TLR5 ligands and the intestinal pathogens Salmonella typhimurium and Listeria monocytogenes to induce the expression of IL-8. In conclusion, this study demonstrates that extensive cross-talk in IECs occurs between the Fas and TLR signaling pathways, with the FasL/Fas system playing a role in TLR-mediated inflammatory responses in the intestine.

The birds of Genome10K.

Abstract: Everyone loves the birds of the world. From their haunting songs and majesty of flight to dazzling plumage and mating rituals, bird watchers – both amateurs and professionals - have marveled for centuries at their considerable adaptations. Now, we are offered a special treat with the publication of a series of papers in dedicated issues of Science, Genome Biology and GigaScience (which also included pre-publication data release). These present the successful beginnings of an international interdisciplinary venture, the Avian Phylogenomics Project that lets us view, through a genomics lens, modern bird species and the evolutionary events that produced them.

Development of MHC-Linked Microsatellite Markers in the Domestic Cat and Their Use to Evaluate MHC Diversity in Domestic Cats, Cheetahs, and Gir Lions.

Abstract: Diversity within the major histocompatibility complex (MHC) reflects the immunological fitness of a population. MHClinked microsatellite markers provide a simple and an inexpensive method for studying MHC diversity in large-scale studies. We have developed 6 MHC-linked microsatellite markers in the domestic cat and used these, in conjunction with 5 neutral microsatellites, to assess MHC diversity in domestic mixed breed (n = 129) and purebred Burmese (n = 61) cat populations in Australia. The MHC of outbred Australian cats is polymorphic (average allelic richness = 8.52), whereas the Burmese population has significantly lower MHC diversity (average allelic richness = 6.81; P < 0.01). The MHC-linked microsatellites along with MHC cloning and sequencing demonstrated moderate MHC diversity in cheetahs (n = 13) and extremely low diversity in Gir lions (n = 13 ). Our MHC-linked microsatellite markers have potential future use in diversity and disease studies in other populations and breeds of cats as well as in wild felid species.

Metal-carbon fiber composite femoral stems in hip replacements: a randomized controlled parallel-group study with mean ten-year follow-up.

Abstract: Background: Attempts to improve proximal load transfer and minimize stress shielding have included reducing the stiffness of femoral stems and using alternative stem materials, including carbon fiber composites. An uncemented implant (SR71) composed of a carbon-fiber-composite distal section and a porous-coated titanium-alloy proximal section, designed to improve proximal load transfer and provide good fixation, was clinically evaluated in a prospective randomized study. Methods: Sixty patients were enrolled and randomized to receive either the SR71 stem or an all-metal stem (Stability). All patients received a cemented all-polyethylene acetabular component and a 28-mm metal femoral head. All uncemented stems were implanted by the same surgeon. Patients were followed for up to ten years with repeated assessments of bone mineral density, radiographs, Harris hip scores (HHS), and visual analog scale (VAS) pain scores. Results: Ten years postoperatively, nineteen patients who had been treated with the SR71 stem and not lost to follow-up showed a significantly greater increase in proximal bone mineral density (Gruen zones 1 [p = 0.003] and 7 [p = 0.0007]) from baseline than did the twenty-two who had been treated with the Stability stem and not lost to follow-up. In contrast, the Stability group showed a significantly greater increase in distal bone mineral density (Gruen zones 2 [p = 0.0004], 3 [p = 0.0001], and 5 [p = 0.0035]) compared with the SR71 group. Radiographs demonstrated one case of progressive migration of an acetabular component used with an SR71 stem and one case of bone resorption in Gruen zones 7 and 14 in a patient treated with a Stability stem. There was no significant difference between the SR71 and Stability stems in terms of changes in the total HHS, HHS for pain, HHS for range of motion, or VAS pain scores ten years postoperatively relative to preoperative levels. There was one reported revision of an SR71 femoral stem at the ten-year review. Conclusions: The investigational SR71 implant provided increased proximal bone density and reduced distal bone density. The implant showed promising results at the time of early follow-up, and the clinical outcomes were similar to those of an all-metal stem at the time of a ten-year follow-up. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Allergy/hypersensitivity reactions as a predisposing factor to complex regional pain syndrome I in orthopedic patients.

Abstract: Several predisposing conditions have been associated with complex regional pain syndrome I (CRPS I). The purpose of this study was to determine the relationship between a history of allergy/hypersensitivity reactions and CRPS I in orthopedic patients. Orthopedic patients with CRPS I (n=115) who experienced pain relief after a successful sympathetic nerve blockade were identified for study inclusion; a control group (n=115) matched to the CRPS I group by age, sex, and location of injury was also included. All patients in the study had an average age of 42 years. In the CRPS I group, all participants were Caucasian and the majority (80.8%) were women. The skin of patients with CRPS I was described as fair (57.7%), mottled (57.7%), or sensitive (80.8%). Of the patients with CRPS I, 78 (67.8%) reported a statistically significant history of allergies compared with the 39 (33.9%) patients in the control group (P<.0001). Patients with CRPS I who experienced complete pain relief for at least 1 month following a single sympathetic nerve block were asked to answer a questionnaire (n=35), and some then underwent immediate hypersensitivity testing using a skin puncture technique (n=26). Skin hypersensitivity testing yielded an 83.3% positive predictive value with an accuracy of 76.9%. Based on these results, a positive history for allergy/hypersensitivity reactions is a predisposing condition for CRPS I in this subset of orthopedic patients. These hypersensitivity reactions may prove important in gaining a better understanding in the pathophysiology of CRPS I as a regional pain syndrome.

Arthroscopic Subscapularis Bankart Technique as a Salvage Procedure for Failed Anterior Shoulder Stabilization

Abstract: Background Shoulder instability is a relatively common problem. Even with contemporary surgical techniques, instability can recur following both open and arthroscopic fixation. Surgical management of capsular insufficiency in anterior shoulder stabilization represents a significant challenge, particularly in young, active patients. There are a limited number of surgical treatment options. The Laterjet technique can present with a number of intraoperative challenges and postoperative complication.

Visualization, sharing and analysis of large data sets

Abstract: Systems and methods for visualization, sharing and analysis of large data sets are described. Systems and methods may include receiving an input data set, wherein the input data set includes data that can be classified in classification dimensions wherein a first classification dimension is a linear ordering of data entries and a second classification dimension represents analysis criteria, traits of the data entries, or aspects of the data entries; obtaining an unabridged data table listing results for each combination of coordinates in the first classification dimension and the second classification dimension; and displaying contents of the unabridged data table as a visual array wherein two axes correspond to the coordinates and a third axis corresponds to a third classification dimension, wherein the third classification dimension represents an actual value of the respective data point for the coordinates. Methods may also assess the visual array, such as by identifying one or more regions of high density of signals.

GWATCH: a web platform for automated gene association discovery analysis

Abstract: Background: As genome-wide sequence analyses for complex human disease determinants are expanding, it is increasingly necessary to develop strategies to promote discovery and validation of potential disease-gene associations. Findings: Here we present a dynamic web-based platform – GWATCH – that automates and facilitates four steps in genetic epidemiological discovery: 1) Rapid gene association search and discovery analysis of large genome-wide datasets; 2) Expanded visual display of gene associations for genome-wide variants (SNPs, indels, CNVs), including Manhattan plots, 2D and 3D snapshots of any gene region, and a dynamic genome browser illustrating gene association chromosomal regions; 3) Real-time validation/replication of candidate or putative genes suggested from other sources, limiting Bonferroni genome-wide association study (GWAS) penalties; 4) Open data release and sharing by eliminating privacy constraints (The National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB), informed consent, The Health Insurance Portability and Accountability Act (HIPAA) of 1996 etc.) on unabridged results, which allows for open access comparative and meta-analysis. Conclusions: GWATCH is suitable for both GWAS and whole genome sequence association datasets. We illustrate the utility of GWATCH with three large genome-wide association studies for HIV-AIDS resistance genes screened in large multicenter cohorts; however, association datasets from any study can be uploaded and analyzed by GWATCH.