A case report of iatrogenic gas gangrene post colonoscopy successfully treated with conservative management- is surgery always necessary?

Background: Colonoscopy is a routine procedure in diagnosis and treatment of colonic disease. While generally regarded as a safe procedure, potentially fatal complications can occur. Gas gangrene is one such complication, with very high mortality. There are few cases of gas gangrene occurring after colonoscopy, making it one of the rarer complications of this procedure. There have been no previously reported cases of a patient surviving such an infection and the optimal treatment strategy is contentious. This report describes a case of intramural gas gangrene of the colon, treated conservatively with antibiotic therapy in which the patient survived with full recovery. Case presentation: A 71-year-old, previously healthy male presented 6 h post apparently uncomplicated colonoscopic polypectomy with rigors, nausea, vomiting and right upper quadrant pain. At presentation he was febrile at 40.1 °C but hemodynamically stable. Abdominal computed tomography revealed substantial colonic thickening and several focal intramural gas bubbles (pneumatosis intestinalis) surrounding the polypectomy site. Within 24 h post procedure he became hypotensive and was admitted to ICU in frank septic shock requiring inotropes, and with demonstrable septic myocardial depression. Bloods showed multi-organ derangement with leukocytosis, lactic acidosis, haemolytic anaemia and hyperbilirubinemia. A diagnosis of presumed Clostridial gas gangrene was made, and treatment was initiated with benzylpenicillin, clindamycin, metronidazole and vancomycin. After 4 days in ICU he was stepped down, and discharged after a further 10 days with no surgical or endoscopic interventions. At three-month review he reported being back to full health. Conclusions: This case demonstrates that gas gangrene infection is a possible complication of colonoscopic polypectomy. This is a cause of rapid deterioration in post-colonoscopy patients and has been misdiagnosed as colonic perforation in previously reported cases of retroperitoneal gas gangrene. Such misdiagnosis delays antibiotic therapy, which likely plays a role in the high mortality of this condition. Early diagnosis and initiation of antibiotic therapy with benzylpenicillin and clindamycin as seen in this case is essential for patient survival. While surgery is typically performed, non-operative management of pneumatosis intestinalis, and potentially gas gangrene is becoming more common and was utilized effectively in this patient

Evidence for Placoderms from the Mid-Palaeozoic Sandon Beds of North-western New South Wales, Australia

Armoured jawed fishes known as placoderms are a well-documented group with a fossil record spanning the Silurian to end-Devonian. They have a global distribution and a marked diversity within Devonian deposits of Australia. Despite their notable Gondwanan fossil record, new material is occasionally identified and can present important stratigraphic information for otherwise under-explored deposits. A unique find from the so-called Sandon beds is presented here and expands the record of placoderms from New South Wales. This specimen presents insight into a previously unknown macrofossil record from the deposit and suggests a more Devonian age for the unit, rather than the previously suggested Carboniferous date. We also summarise the macrovertebrate record of Devonian placoderms from Australia, highlighting and discussing changes in their Gondwanan taxonomic diversity across the time period

Macro- to Microscale Strain Transfer in Fibrous Tissues is Heterogeneous and Tissue-Specific

AbstractMechanical deformation applied at the joint or tissue level is transmitted through the macroscale extracellular matrix to the microscale local matrix, where it is transduced to cells within these tissues and modulates tissue growth, maintenance, and repair. The objective of this study was to investigate how applied tissue strain is transferred through the local matrix to the cell and nucleus in meniscus, tendon, and the annulus fibrosus, as well as in stem cell-seeded scaffolds engineered to reproduce the organized microstructure of these native tissues. To carry out this study, we developed a custom confocal microscope-mounted tensile testing device and simultaneously monitored strain across multiple length scales. Results showed that mean strain was heterogeneous and significantly attenuated, but coordinated, at the local matrix level in native tissues (35–70% strain attenuation). Conversely, freshly seeded scaffolds exhibited very direct and uniform strain transfer from the tissue to the local matrix level (15–25% strain attenuation). In addition, strain transfer from local matrix to cells and nuclei was dependent on fiber orientation and tissue type. Histological analysis suggested that different domains exist within these fibrous tissues, with most of the tissue being fibrous, characterized by an aligned collagen structure and elongated cells, and other regions being proteoglycan (PG)-rich, characterized by a dense accumulation of PGs and rounder cells. In meniscus, the observed heterogeneity in strain transfer correlated strongly with cellular morphology, where rounder cells located in PG-rich microdomains were shielded from deformation, while elongated cells in fibrous microdomains deformed readily. Collectively, these findings suggest that different tissues utilize distinct strain-attenuating mechanisms according to their unique structure and cellular phenotype, and these differences likely alter the local biologic response of such tissues and constructs in response to mechanical perturbation

Isisfordia molnari sp. nov., a new basal eusuchian from the mid-Cretaceous of Lightning Ridge, Australia

The Australian Mesozoic crocodyliform record is sparse in comparison to other Gondwanan localities. A single formally-named taxon is known from this interval; Isisfordia duncani (Winton Formation, Albian–Turonian, Queensland). We present a previously undescribed crocodyliform braincase from the Griman Creek Formation (Cenomanian), New South Wales, which we assign to Isisfordia molnari sp. nov. Assignment to the genus is based on the possession of a newly-defined autapomorphy of Isisfordia: a broadly exposed prootic within the supratemporal foramen. A second autapomorphy of I. duncani (maximum diameter of the caudal aperture of the cranioquadrate siphonium approximately one-third the mediolateral width of the foramen magnum, with the lateral wall of the caudal aperture formed exclusively by the quadrate) may also be present in I. molnari; however, definitive recognition of this feature is marred by incomplete preservation. The new taxon is differentiated from I. duncani based on the absence of a median ridge on the parietal, and the lack of characteristic ridges on the parietal that form the medial margin of the supratemporal foramina. Reanalysis of a second specimen (the former holotype of the nomen dubium,‘Crocodylus (Bottosaurus) selaslophensis’) allows for its referral to the genus Isisfordia. Crucial to this reappraisal is the reinterpretation of the specimen as a partial maxilla, not the dentary as previously thought. This maxillary fragment possesses specific characteristics shared only with I. duncani; namely an alveolar groove. However, several key features differentiate the maxillary fragment from I. duncani, specifically the presence of continuous alveolar septa, the thickening of the medial alveolar rim, and the alveolar and crown base morphology. These findings constitute the first evidence of Isisfordia outside of the type locality and indicate its widespread occurrence on the freshwater floodplains along the eastern margin of the epeiric Eromanga Sea during the Albian–Cenomanian

Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites

The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target

Small Deletion Variants Have Stable Breakpoints Commonly Associated with Alu Elements

Copy number variants (CNVs) contribute significantly to human genomic variation, with over 5000 loci reported, covering more than 18% of the euchromatic human genome. Little is known, however, about the origin and stability of variants of different size and complexity. We investigated the breakpoints of 20 small, common deletions, representing a subset of those originally identified by array CGH, using Agilent microarrays, in 50 healthy French Caucasian subjects. By sequencing PCR products amplified using primers designed to span the deleted regions, we determined the exact size and genomic position of the deletions in all affected samples. For each deletion studied, all individuals carrying the deletion share identical upstream and downstream breakpoints at the sequence level, suggesting that the deletion event occurred just once and later became common in the population. This is supported by linkage disequilibrium (LD) analysis, which has revealed that most of the deletions studied are in moderate to strong LD with surrounding SNPs, and have conserved long-range haplotypes. Analysis of the sequences flanking the deletion breakpoints revealed an enrichment of microhomology at the breakpoint junctions. More significantly, we found an enrichment of Alu repeat elements, the overwhelming majority of which intersected deletion breakpoints at their poly-A tails. We found no enrichment of LINE elements or segmental duplications, in contrast to other reports. Sequence analysis revealed enrichment of a conserved motif in the sequences surrounding the deletion breakpoints, although whether this motif has any mechanistic role in the formation of some deletions has yet to be determined. Considered together with existing information on more complex inherited variant regions, and reports of de novo variants associated with autism, these data support the presence of different subgroups of CNV in the genome which may have originated through different mechanisms

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Assessing the performance of maternity care in Europe: A critical exploration of tools and indicators

Background: This paper critically reviews published tools and indicators currently used to measure maternity care performance within Europe, focusing particularly on whether and how current approaches enable systematic appraisal of processes of minimal (or non-) intervention in support of physiological or "normal birth". The work formed part of COST Actions IS0907: "Childbirth Cultures, Concerns, and Consequences: Creating a dynamic EU framework for optimal maternity care" (2011-2014) and IS1405: Building Intrapartum Research Through Health - an interdisciplinary whole system approach to understanding and contextualising physiological labour and birth (BIRTH) (2014-). The Actions included the sharing of country experiences with the aim of promoting salutogenic approaches to maternity care. Methods: A structured literature search was conducted of material published between 2005 and 2013, incorporating research databases, published documents in english in peer-reviewed international journals and indicator databases which measured aspects of health care at a national and pan-national level. Given its emergence from two COST Actions the work, inevitably, focused on Europe, but findings may be relevant to other countries and regions. Results: A total of 388 indicators were identified, as well as seven tools specifically designed for capturing aspects of maternity care. Intrapartum care was the most frequently measured feature, through the application of process and outcome indicators. Postnatal and neonatal care of mother and baby were the least appraised areas. An over-riding focus on the quantification of technical intervention and adverse or undesirable outcomes was identified. Vaginal birth (no instruments) was occasionally cited as an indicator; besides this measurement few of the 388 indicators were found to be assessing non-intervention or "good" or positive outcomes more generally. Conclusions: The tools and indicators identified largely enable measurement of technical interventions and undesirable health (or pathological medical) outcomes. A physiological birth generally necessitates few, or no, interventions, yet most of the indicators presently applied fail to capture (a) this phenomenon, and (b) the relationship between different forms and processes of care, mode of birth and good or positive outcomes. A need was identified for indicators which capture non-intervention, reflecting the reality that most births are low-risk, requiring few, if any, technical medical procedures

Controversies in spine research: organ culture versus in vivo models for studies of the intervertebral disc

Intervertebral disc degeneration is a common cause of low back pain, the leading cause of disability worldwide. Appropriate preclinical models for intervertebral disc research are essential to achieving a better understanding of underlying pathophysiology and for the development, evaluation, and translation of more effective treatments. To this end, in vivo animal and ex vivo organ culture models are both widely used by spine researchers; however, the relative strengths and weaknesses of these two approaches are a source of ongoing controversy. In this article, members from the Spine and Preclinical Models Sections of the Orthopedic Research Society, including experts in both basic and translational spine research, present contrasting arguments in support of in vivo animal models versus ex vivo organ culture models for studies of the disc, supported by a comprehensive review of the relevant literature. The objective is to provide a deeper understanding of the respective advantages and limitations of these approaches, and advance the field toward a consensus with respect to appropriate model selection and implementation. We conclude that complementary use of several model types and leveraging the unique advantages of each is likely to result in the highest impact research in most instances