Treatment of Granuloma Annulare With Pentoxifylline and Oral Vitamin E: A Case Series.

Granuloma annulare (GA) is a difficult-to-treat granulomatous skin disorder characterized by multiple annular, raised, and erythematous lesions. While numerous therapies have been proposed, there is currently no clear gold standard of treatment. We present a series of five patients with biopsy-proven generalized GA who were treated with pentoxifylline and oral vitamin E. Each patient in this series had at least a one-year history of GA refractory to other treatments. After three months of treatment, four of the five patients demonstrated objective improvement in their lesions through before and after clinical photographs. No patients suffered any adverse events on this treatment regimen. As our series has demonstrated modest benefits in concurrence with previously published studies, we recommend combination therapy with pentoxifylline and vitamin E as a strong contender for first- or second-line treatment for generalized GA. Pentoxifylline and vitamin E are advantageous for their tolerability, cost-effectiveness, minimal drug interactions, and convenience.

Treatment of acrodermatitis continua of hallopeau with ixekizumab.

Acrodermatitis continua of hallopeau (ACH) is a rare chronic inflammatory variant of pustular psoriasis often restricted to the distal portions the digits in the hands and feet. ACH is of a chronic relapsing nature and is invariably recalcitrant to many available topical and systemic anti-psoriatic therapies. On account of its low prevalence and high resistance to treatments, no clinical guideline of ACH exists. We present a patient with ACH resistant to multiple therapies, including the biologic adalimumab, who was successfully treated with an IL-17 inhibitor (ixekizumab). We believe our unique treatment with an excellent outcome may assist other dermatologists if faced with this condition.

Water balloon-induced orbital fracture in an aviator.

BACKGROUND: Orbital fractures are common injuries found in facial trauma. Typical etiologies of orbital fractures include motor vehicle collisions and assault. We report the case of a 32-year-old male who suffered an orbital fracture from a water balloon. Additionally, we describe the aeromedical complications that may result from this injury. Finally, we attempt to answer the question of when a patient may return to flying after sustaining such an injury through review of the literature. CASE PRESENTATION: A 32-year-old male pilot with the United States Air Force was at an outdoor event with his unit when he was struck with a water balloon launched from a sling shot into his left orbit. Shortly afterwards, he had an onset of subcutaneous emphysema and was escorted to a nearby Emergency Department. Computed tomography identified an orbital fracture with associated orbital and subcutaneous emphysema. The patient was evaluated by a plastic surgeon and was determined not to be a surgical candidate. Four weeks later, he returned to flying status. CONCLUSIONS: Water balloons are thought to be safe and harmless toys. However, when coupled with slingshots, water balloons can become formidable projectiles capable of significant orbital injury including orbital fractures. These injuries are concerning to aviators, as the most common sites for fractures of the orbit are the thin ethmoid and maxillary bones adjacent to the sinuses. At altitude, gases in the sinuses may expand and enter the orbit through these fractures, which may suddenly incapacitate the flyer. It is important for flight surgeons to identify and assess these individuals to determine suitability for flying.

Unique pelvic fin in a tetrapod-like fossil fish, and the evolution of limb patterning.

All living tetrapods have a one-to-two branching pattern in the embryonic proximal limb skeleton, with a single element at the base of the limb (the humerus or femur) that articulates distally with two parallel radials (the ulna and radius or the tibia and fibula). This pattern is also seen in the fossilized remains of stem-tetrapods, including the fishlike members of the group, in which despite the absence of digits, the proximal parts of the fin skeleton clearly resemble those of later tetrapods. However, little is known about the developmental mechanisms that establish and canalize this highly conserved pattern. We describe the well-preserved pelvic fin skeleton of Rhizodus hibberti, a Carboniferous sarcopterygian (lobe-finned) fish, and member of the tetrapod stem group. In this specimen, three parallel radials, each robust with a distinct morphology, articulate with the femur. We review this unexpected morphology in a phylogenetic and developmental context. It implies that the developmental patterning mechanisms seen in living tetrapods, now highly constrained, evolved from mechanisms flexible enough to accommodate variation in the zeugopod (even between pectoral and pelvic fins), while also allowing each element to have a unique morphology.

Distal tibial triplane fracture with ipsilateral tibial shaft fracture: A case series.

BACKGROUND & PURPOSE: Distal tibial Triplane fracture with ipsilateral tibial shaft fracture is a rare but important problem. This rarely reported combination of injuries if not recognised may lead to deleterious consequences. METHODS/PATIENTS: The local database of all emergency admissions was scrutinised to identify subjects before interrogation of the clinical notes and relevant radiographic imaging. FINDINGS: This paper reports a series of five children who were found to have triplane fracture of the distal tibia with concomitant ipsilateral fracture of the tibial shaft. CONCLUSIONS: We suggest that a high index of suspicion for concomitant fractures should be maintained in the presence of either triplane fracture of the distal tibia or tibial shaft fractures in the peri-adolescent child. Minimum appropriate imaging should include orthogonal full length plain radiographs of the tibia as well as formal ankle radiographs.

The Newcomer Health Clinic in Nova Scotia: A Beacon Clinic to Support the Health Needs of the Refugee Population.

Refugees tend to have greater vulnerability compared to the general population reporting greater need for physical, emotional, or dental problems compared to the general population. Despite the importance of creating strong primary care supports for these patients, it has been demonstrated that there is a significant gap in accessing primary care providers who are willing to accept the refugee population. These have resulted in bottlenecks in the transition or bridge clinics and have left patients orphaned without a primary care provider. This in turn results in higher use of emergency service and other unnecessary costs to the healthcare system. Currently there are few studies that have explored these challenges from primary care provider perspectives and very few to none from patient perspectives. A novel collaborative implementation initiative in primary healthcare (PHC) is seeking to improve primary medical care for the refugee population by creating a globally recommended transition or beacon clinic to support care needs of new arrivals and transitions to primary care providers. We discuss the innovative elements of the clinic model in this paper.

NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism.

Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c +/-(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.

Computational Metabolomics Operations at BioCyc.org.

BioCyc.org is a genome and metabolic pathway web portal covering 5500 organisms, including Homo sapiens, Arabidopsis thaliana, Saccharomyces cerevisiae and Escherichia coli. These organism-specific databases have undergone variable degrees of curation. The EcoCyc (Escherichia coli Encyclopedia) database is the most highly curated; its contents have been derived from 27,000 publications. The MetaCyc (Metabolic Encyclopedia) database within BioCyc is a "universal" metabolic database that describes pathways, reactions, enzymes and metabolites from all domains of life. Metabolic pathways provide an organizing framework for analyzing metabolomics data, and the BioCyc website provides computational operations for metabolomics data that include metabolite search and translation of metabolite identifiers across multiple metabolite databases. The site allows researchers to store and manipulate metabolite lists using a facility called SmartTables, which supports metabolite enrichment analysis. That analysis operation identifies metabolite sets that are statistically over-represented for the substrates of specific metabolic pathways. BioCyc also enables visualization of metabolomics data on individual pathway diagrams and on the organism-specific metabolic map diagrams that are available for every BioCyc organism. Most of these operations are available both interactively and as programmatic web services.

The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases.

The MetaCyc database (MetaCyc.org) is a comprehensive and freely accessible database describing metabolic pathways and enzymes from all domains of life. MetaCyc pathways are experimentally determined, mostly small-molecule metabolic pathways and are curated from the primary scientific literature. MetaCyc contains >2100 pathways derived from >37,000 publications, and is the largest curated collection of metabolic pathways currently available. BioCyc (BioCyc.org) is a collection of >3000 organism-specific Pathway/Genome Databases (PGDBs), each containing the full genome and predicted metabolic network of one organism, including metabolites, enzymes, reactions, metabolic pathways, predicted operons, transport systems and pathway-hole fillers. Additions to BioCyc over the past 2 years include YeastCyc, a PGDB for Saccharomyces cerevisiae, and 891 new genomes from the Human Microbiome Project. The BioCyc Web site offers a variety of tools for querying and analysis of PGDBs, including Omics Viewers and tools for comparative analysis. New developments include atom mappings in reactions, a new representation of glycan degradation pathways, improved compound structure display, better coverage of enzyme kinetic data, enhancements of the Web Groups functionality, improvements to the Omics viewers, a new representation of the Enzyme Commission system and, for the desktop version of the software, the ability to save display states.

PortEco: a resource for exploring bacterial biology through high-throughput data and analysis tools.

PortEco (http://porteco.org) aims to collect, curate and provide data and analysis tools to support basic biological research in Escherichia coli (and eventually other bacterial systems). PortEco is implemented as a 'virtual' model organism database that provides a single unified interface to the user, while integrating information from a variety of sources. The main focus of PortEco is to enable broad use of the growing number of high-throughput experiments available for E. coli, and to leverage community annotation through the EcoliWiki and GONUTS systems. Currently, PortEco includes curated data from hundreds of genome-wide RNA expression studies, from high-throughput phenotyping of single-gene knockouts under hundreds of annotated conditions, from chromatin immunoprecipitation experiments for tens of different DNA-binding factors and from ribosome profiling experiments that yield insights into protein expression. Conditions have been annotated with a consistent vocabulary, and data have been consistently normalized to enable users to find, compare and interpret relevant experiments. PortEco includes tools for data analysis, including clustering, enrichment analysis and exploration via genome browsers. PortEco search and data analysis tools are extensively linked to the curated gene, metabolic pathway and regulation content at its sister site, EcoCyc.

Groups: knowledge spreadsheets for symbolic biocomputing.

Knowledge spreadsheets (KSs) are a visual tool for interactive data analysis and exploration. They differ from traditional spreadsheets in that rather than being oriented toward numeric data, they work with symbolic knowledge representation structures and provide operations that take into account the semantics of the application domain. 'Groups' is an implementation of KSs within the Pathway Tools system. Groups allows Pathway Tools users to define a group of objects (e.g. groups of genes or metabolites) from a Pathway/Genome Database. Groups can be transformed (e.g. by transforming a metabolite group to the group of pathways in which those metabolites are substrates); combined through set operations; analysed (e.g. through enrichment analysis); and visualized (e.g. by painting onto a metabolic map diagram). Users of the Pathway Tools-based BioCyc.org website have made extensive use of Groups, and an informal survey of Groups users suggests that Groups has achieved the goal of allowing biologists themselves to perform some data manipulations that previously would have required the assistance of a programmer. Database URL: BioCyc.org.

Synaptic protein α1-takusan mitigates amyloid-ß-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites.

The synaptic toxicity of soluble amyloid-ß (Aß) oligomers plays a critical role in the pathophysiology of Alzheimer's disease (AD). Here we report that overexpressed α1-takusan, which we previously identified as a protein that enhances synaptic activity via interaction with PSD-95, mitigates oligomeric Aß-induced synaptic loss. In contrast, takusan knockdown results in enhanced synaptic damage. α1-Takusan interacts with tau either directly or indirectly, and prevents Aß-induced tau hyperphosphorylation and mitochondrial fragmentation. Deletion analysis identified the second domain (D2) within the takusan protein that is required for PSD-95 clustering and synaptic protection from Aß. A 51 aa sequence linking D2 to the PDZ-binding C terminus was found to be as effective as full-length takusan in protecting synapses from Aß-induced damage. Moreover, a sequence containing the D2 from the human protein discs large homolog 5, when linked to a C-terminal PDZ-binding motif, can also increase the clustering of PSD-95 in cortical dendrites. In summary, α1-takusan protects synapses from Aß-induced insult via interaction with PSD-95 and tau. Thus, takusan-based protein sequences from either mouse or human may be of potential therapeutic benefit in AD.

Pectoral girdle and fin anatomy of Gogonasus andrewsae Long, 1985: implications for tetrapodomorph limb evolution.

Recently discovered material has yielded new information on the pectoral girdle and fin endoskeleton of Gogonasusandrewsae (Frasnian Gogo Formation, Kimberley Region, Western Australia). These elements permit the first comprehensive description of the anocleithrum, cleithrum, scapulocoracoid, and lepidotrichia. New autapomorphies of Gogonasus include a square exposed region on the supracleithrum, an unusual knob-like process on the scapulocoracoid, a relatively small entepicondyle, and lepidotrichia with I-beam-shaped cross sections. Several poorly ossified regions on the scapulocoracoid and humerus indicate an early ontogenetic state, as with other immature tetrapodomorph fish specimens. A phylogenetic analysis indicates a more stemward position for Gogonasus in a weakly supported clade with other "osteolepidid" taxa, compared to other recent studies placing Gogonasus crownward of osteolepidid fishes and the Tristichopteridae, as the sister taxon to the "Elpistosteglia" + Tetrapoda. A phylogenetic position among megalichthyid fishes is suggested for Sterropterygion, while radiographs of the megalichthyid Cladarosymblema show a scythe-like radius terminating distally with that of the intermedium. New data on the scapulocoracoid of the rhizodontid Barameda reveals a coroacoid crest and small supraglenoid foramen.

First ceratosaurian dinosaur from Australia.

The basal theropod dinosaur clade Ceratosauria, and its subclade Abelisauroidea, is characteristic of late Mesozoic terrestrial vertebrate faunas in western Gondwana (South America, Africa, Madagascar, and India) and Europe. Yet unambiguous records of ceratosaurs have hitherto been absent from Australia, where the theropod assemblage appears to include several typically Laurasian clades. Here, we report the first evidence of ceratosaurs (and potentially abelisauroids) from eastern Gondwana--a diagnostic astragalocalcaneum from the Aptian (121-125 Ma) of Victoria, Australia. Ceratosauria thus occurred in both western and eastern Gondwana during the Early Cretaceous. This fossil adds to the poorly known dinosaur fauna of Australia, a major clade of basal theropods, emphasising that its mid-Cretaceous theropod diversity was surprisingly cosmopolitan despite relative geographic isolation, including clades that have been thought to be typical of both Gondwana and Laurasia--Ceratosauria, Spinosauridae, Carcharodontosauria, Tyrannosauroidea, and Deinonychosauria. Such a contemporaneous association of theropod clades is unknown from other Gondwanan continents and questions the views that the late Mesozoic dinosaur fauna of Australia was dominated by Gondwanan or Laurasian elements, extreme isolation, relictualism, and/or novelty as a 'centre of origin'. The cosmopolitan theropod fauna of Australia probably reflects the global distribution of these clades early in their history, prior to significant continental breakup.

Bone and joint tuberculosis in children in the Blackburn area since 2006: a case series.

This report describes a series of four cases of children between the ages 5 and 14 years with bone or joint infection with Mycobacterium tuberculosis diagnosed between June 2006 and March 2008 in the Blackburn area of England. All of the cases were of South Asian descent. The diagnosis was confirmed by the presence of M. tuberculosis on the culture of bone, synovium or joint fluid, or by the presence of the typical histology of tuberculosis (TB). The sites of tuberculous disease were the hip joint, the sacro-iliac joint and the talus. A recent paper by Sandher et al. (J Bone Joint Surg Br 89:1379-1381, 2007) illustrated only two cases of childhood bone and joint TB in the same geographical area in the preceding 17 years.

Partitioning protein structures into domains: why is it so difficult?

This analysis takes an in-depth look into the difficulties encountered by automatic methods for domain decomposition from three-dimensional structure. The analysis involves a multi-faceted set of criteria including the integrity of secondary structure elements, the tendency toward fragmentation of domains, domain boundary consistency and topology. The strength of the analysis comes from the use of a new comprehensive benchmark dataset, which is based on consensus among experts (CATH, SCOP and AUTHORS of the 3D structures) and covers 30 distinct architectures and 211 distinct topologies as defined by CATH. Furthermore, over 66% of the structures are multi-domain proteins; each domain combination occurring once per dataset. The performance of four automatic domain assignment methods, DomainParser, NCBI, PDP and PUU, is carefully analyzed using this broad spectrum of topology combinations and knowledge of rules and assumptions built into each algorithm. We conclude that it is practically impossible for an automatic method to achieve the level of performance of human experts. However, we propose specific improvements to automatic methods as well as broadening the concept of a structural domain. Such work is prerequisite for establishing improved approaches to domain recognition. (The benchmark dataset is available from http://pdomains.sdsc.edu).

Life on the edge: gastrointestinal parasites from the forest edge and interior primate groups.

Humans are responsible for massive changes to primate habitats, and one unanticipated consequence of these alterations may be changes in host-parasite interactions. Edges are a ubiquitous aspect of human disturbance to forest landscapes. Here we examine how changes associated with the creation of edges in Kibale National Park, Uganda, alter the parasite community that is supported by two species of African colobines: the endangered red colobus (Piliocolobus tephrosceles) and the black-and-white colobus (Colobus guereza). An analysis of 822 fecal samples from edge and forest interior groups revealed no difference in the richness of parasite communities (i.e., the number of parasite species recovered from the host's fecal sample). However, for both species the proportion of individuals with multiple infections was greater in edge than forest interior groups. The prevalence of specific parasites also varied between edge and forest interior groups. Oesophagostomum sp., a potentially deleterious parasite, was 7.4 times more prevalent in red colobus on the edge than in those in the forest interior, and Entamoeba coli was four times more prevalent in red colobus on the edge than in animals from the forest interior. Environmental contamination with parasites (measured as parasite eggs/gm feces) by red colobus from the edge and forest interior differed in a similar fashion to prevalence for red colobus, but it did not differ for black-and-white colobus. For example, egg counts of Oesophagostomum sp. were 10 times higher in red colobus from the edge than in those from the interior. The less severe infections in the black-and-white colobus relative to the red colobus may reflect the fact that black-and-white colobus raid agricultural crops while red colobus do not. This nutritional gain may facilitate a more effective immune response to parasites by the black-and-white colobus. The fact that animals on the edge are likely not nutritionally stressed raises an intriguing question as to what facilitates the elevated infections in edge animals. We speculate that interactions with humans may be linked to the observed patterns of infections, and hence that understanding the ecology of infectious diseases in nonhuman primates is of paramount importance for conservation and potentially for human-health planning.