Aims and scope

Publication date: August 2017
Source:Women and Birth, Volume 30, Issue 4





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Midwifery Education

Publication date: August 2017
Source:Women and Birth, Volume 30, Issue 4
Author(s): Linda Sweet




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Response to Edith Cowan students

Publication date: August 2017
Source:Women and Birth, Volume 30, Issue 4
Author(s): Ann Kinnear




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Response to Letter to the Editor by Council of Deans of Nursing and Midwifery

Publication date: August 2017
Source:Women and Birth, Volume 30, Issue 4
Author(s): Ann Kinnear




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KinFin: Software for Taxon-Aware Analysis of Clustered Protein Sequences

The field of comparative genomics is concerned with the study of similarities and differences between the information encoded in the genomes of organisms. A common approach is to define gene families by clustering protein sequences based on sequence similarity, and analyse protein cluster presence and absence in different species groups as a guide to biology. Due to the high dimensionality of these data, downstream analysis of protein clusters inferred from large numbers of species, or species with many genes, is non-trivial, and few solutions exist for transparent, reproducible and customisable analyses. We present KinFin, a streamlined software solution capable of integrating data from common file formats and delivering aggregative annotation of protein clusters. KinFin delivers analyses based on systematic taxonomy of the species analysed, or on user-defined groupings of taxa, for example sets based on attributes such as life history traits, organismal phenotypes, or competing phylogenetic hypotheses. Results are reported through graphical and detailed text output files. We illustrate the utility of the KinFin pipeline by addressing questions regarding the biology of filarial nematodes, which include parasites of veterinary and medical importance. We resolve the phylogenetic relationships between the species and explore functional annotation of proteins in clusters in key lineages and between custom taxon sets, identifying gene families of interest. KinFin can easily be integrated into existing comparative genomic workflows and promotes transparent and reproducible analysis of clustered protein data.

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Over-Expression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of the Troponin-T in Drosophila Indirect Flight Muscles

miRNAs are small non-coding endogenous RNAs, typically 21-23 nucleotides long, that regulate gene expression, usually post-transcriptionally by binding to the 3'-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure and other cardiac myopathies. Recent studies have implicated miR-9 in myocardial hypertrophy. However a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using the genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster. Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development. Troponin-T (TnT) was identified as major structural gene target of miR-9a. We show that flies over-expressing miR-9a in the IFMs have abnormal wing position and are flightless. These flies also exhibit loss of muscle integrity and sarcomeric organization causing an abnormal muscle condition known as "hypercontraction". Additionally, miR-9a over-expression resulted in the reduction of TnT protein levels while transcript levels were unaffected. Furthermore, muscle abnormalities associated with miR-9a over-expression were completely rescued by over-expression of TnT transgenes which lacked the miR-9a binding site. These findings indicate that miR-9a interacts with the 3'-UTR of the TnT mRNA and down-regulates the TnT protein levels by translational repression. The reduction in TnT levels leads to a cooperative down-regulation of other thin filament structural proteins. Our findings have implications for understanding the cellular pathophysiology of cardiomyopathies associated with miR-9 over-expression.

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Mutation of NRAS is a Rare Genetic Event in Ovarian Low-Grade Serous Carcinoma

Activating mutations involving the members of the RAS signaling pathway, including KRAS, NRAS, and BRAF, have been reported in ovarian low-grade serous carcinoma and its precursor lesion, serous borderline tumor (SBT). Whether additional genetic alterations in the RAS oncogene family accumulate during the progression of serous borderline tumor (SBT) to invasive low grade serous carcinoma (LGSC) remains largely unknown. While mutations of KRAS and BRAF occur at a very early stage of progression, even preceding the development of SBT, additional driving events, such as NRAS mutations, have been postulated to facilitate progression.

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Immunophenotypic Comparison of Testicular Sclerosing Sertoli Cell Tumors and Sertoli Cell Tumors Not Otherwise Specified

Testicular Sertoli cell tumors (SCT) are rare and most fall into the category of SCT-not otherwise specified (SCT-NOS). Only a few additional types of SCT are recognized. Sclerosing SCT (S-SCT), originally described in 1991, comprises a small fraction of SCTs and was considered a specific entity until the 2016 revision of the World Health Organization classification of non-germ cell tumors, where it was classified as a morphologic variant of SCT-NOS. In a recent study, differences in expression of PAX2/PAX8, inhibin, androgen receptor and S100 protein between SCT-NOS and S-SCT were noted in a small number of cases.

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Frequency and Pathological Characteristics of Drug-Induced Liver Injury in a Tertiary Medical Center

Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI.

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Pulmonary interstitial glycogenosis associated with a spectrum of neonatal pulmonary disorders

Primary or isolated pulmonary interstitial glycogenosis (PIG) is a rare disease presenting as tachypnea and hypoxemia during the perinatal period. A diffuse interstitial infiltrate with focal hyperinflation is visible on chest imaging. The biopsy findings include diffuse expansion of the interstitium by spindle-shaped cells with pale cytoplasm that, on electron microscopy (EM), are poorly differentiated mesenchymal cells containing abundant monoparticulate glycogen. This glycogenosis appears to be a transient abnormality, usually with a favorable prognosis.

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Primary Cutaneous NK/T-cell Lymphoma of Nasal Type: An Age-related Lymphoproliferative Disease?

Among extranodal NK/T-cell lymphoma of nasal type (NKTL), the extranasal variant (ENKTL) is known to have a worse prognosis with advanced clinical stage than the nasal variant of NKTL. However, detailed clinicopathological features of the localized extranasal disease have not been well documented in English literature. Here, we described the clinicopathological profiles of 14 patients with stage I ENKTL, including 7 in the skin, 5 in the gastrointestinal tract, and 2 in the central nervous system, highlighting the distinctiveness of the first.

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Histone deacetylases inhibition: a potential diagnostic and therapeutic target for cancers—reply

We thank Dr. Wu and colleagues for their interest in our manuscript on expression of histone deacetylases (HDACs) in pancreatic neuroendocrine tumors (pNET) [1] and for expressing further thoughts on HDACs as potential diagnostic and pharmacological inhibitors and as therapeutic targets for specific cancer types. We appreciate the opportunity to reply and further explain some of our observations.

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Follicular Lymphoma with Hyaline-vascular Castleman-like Features Analysis of 6 Cases and Review of the Literature

Follicular lymphoma (FL) with features reminiscent of hyaline-vascular Castleman disease (CD) is an unusual morphologic variant that may create diagnostic difficulties. To our knowledge, only 5 cases of this variant have been reported. We describe the clinicopathologic features of 6 cases including 2 men and 4 women with a median age of 63years (range, 41–77). Morphologically, all lymph node biopsy specimens showed at least a focal area of conventional FL; 4 cases showed neoplastic follicles with hyalinized blood vessels penetrating into germinal centers (lollipop-like lesions); 4 cases had interfollicular areas with increased vascular stroma, 2 cases showed small neoplastic follicles with prominent, onion skin-like mantle zones, and 1 case showed two or more germinal centers within follicles (twinning).

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Long-term effects of tDCS on fatigue, mood and cognition in multiple sclerosis

Fatigue is frequently reported by multiple sclerosis (MS) patients and remains one of their most debilitating and difficult to manage symptoms. It constitutes a great challenge to MS caregivers especially in face of the modest efficacy and numerous side effects of available medications. Apart from fatigue, cognitive and psychiatric manifestations could affect around 65% and 95% of MS patients, respectively (Chalah and Ayache, 2017).

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The Medial Plantar Sensory Response: A Sensitive Marker of Acute Inflammatory Demyelinating Polyneuropathy

Acute Inflammatory Demyelinating Polyneuropathy (AIDP) is an acute neuropathy characterized by ascending motor weakness that is often heralded by sensory symptoms. Diagnosis is confirmed by nerve conduction studies (NCS) that demonstrate the presence of widespread demyelination changes in motor nerves (Hadden et al., 1998). Sensory nerve involvement is early and often follows a typical pattern, the sural sparing pattern (Al-Shekhlee et al., 2007). This pattern is widely accepted as a specific marker of AIDP and is particularly useful when motor changes are not yet apparent (Hiew et al., 2016).

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Prefrontal cortical responses in children with prenatal alcohol-related neurodevelopmental impairment: A functional near-infrared spectroscopy study

Fetal Alcohol Spectrum Disorders (FASDS) is a term that refers to a cluster of physical and neurobehavioral abnormalities, including facial dysmorphology, growth retardation, and disruption to brain development, that have been investigated for over four decades in human and animal model studies of prenatal alcohol exposure (PAE) (Riley et al., 2011). Although public health awareness and prevention efforts have increased as a result of these findings, recent estimates of the prevalence of Fetal Alcohol Syndrome (FAS), the most severe FASD condition, have ranged from .6 to .9 percent of live births with the full range of FASDs estimated to fall between 2.4 to 4.8 percent (May et al., 2014).

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Electrophysiological correlates of performance monitoring in binge drinking: Impaired error-related but preserved feedback processing

Binge drinking is an alcohol consumption pattern characterized by alternations between intense alcohol intakes and abstinence periods (Courtney and Polich, 2009). Despite the lack of consensus regarding its definition, this habit is now widespread in young people in Western countries (e.g., Kanny et al., 2013). As a matter of fact, binge drinking is no longer considered as a recreational and occasional alcohol consumption activity, but rather as a risky behavior with major cognitive consequences (e.g., in memory or attentional processes; Hartley et al., 2004; Heffernan and O'Neill, 2012).

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A pitfall in magnetic stimulation for measuring central motor conduction time

An interesting electrophysiological study of patients with Hirayama disease using magnetic stimulation is published in the current issue of Clinical Neurophysiology. Zheng et al. (2017) measured two types of central motor conduction time (CMCT) in patients with Hirayama disease: one is CMCT using the F-wave technique (CMCTF) and another is CMCT using magnetic motor root stimulation (CMCTM) (Rossini et al. 2015). The authors compared CMCTF and CMCTM, and they showed that CMCTM was abnormally prolonged compared with CMCTF.

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S195 Physiological properties of the seizure onset zone and brain connectivity: Insights gained from callosotomy procedures

Rapidly propagating frontal lobe seizures that are difficult to lateralize may do so after corpus callosotomy. We performed callosotomy using laser interstitial thermal therapy (LITT) in three patients who were undergoing stereoelectroencephalography (SEEG) and examined both the electrocorticogram electrophysiology and neuroimaging connectivity measures.

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Effects of chronic exposure of X-ray on hematological parameters in human blood

Abstract

The aim of the study was to show how many X-ray technicians who work in radiology department at public-sector hospitals in Sulaimani city are affected by doses of X-ray from X-ray machines, fluoroscopy, and CT scan through examining 12 hematological parameters. The study group included 24 seemingly healthy female and male X-ray technicians. The group was subdivided into 12 female X-ray technicians having average ages of 39 and 14 years of 4 hourly per day of services. As well as, 12 male X-ray technicians having average ages of 41 and 15 years of 5 hourly per day of services. A group of 24 healthy control subjects was selected from outside of the hospitals; the group was subdivided into 12 females having average age of 33 years and 12 males having average of 39 years matched with the first group to reveal any alteration in hematological parameters. The statistical analysis of hematological parameters showed that among the female group, the parameter mean cell volume (MCV) was decreased significantly (P < 0.009) but the parameter mean cell hemoglobin concentration (MCHC) increased significantly (P < 0.049) compared to that among the control groups. The results showed that among the male group, the mean values of total white blood cells (tWBC) (P < 0.003) and platelet (PLT) counts (P < 0.03) decreased significantly compared with those among the control groups whereas no significant difference was observed between the rest of blood cell counts in the female and male groups. We concluded that chronic exposure to X-ray can produce significant increase in MCV and significant decrease in MCHC parameters in female X-ray technicians and significant decrease in the number of tWBC and PLT parameters in male X-ray technicians.

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A Complex Lens for a Complex Eye

Abstract

A key innovation for high resolution eyes is a sophisticated lens that precisely focuses light onto photoreceptors. The eyes of holometabolous larvae range from very simple eyes that merely detect light to eyes that are capable of high spatial resolution. Particularly interesting are the bifocal lenses of Thermonectus marmoratus larvae, which differentially focus light on spectrally-distinct retinas. While functional aspects of insect lenses have been relatively well studied, little work has explored their molecular makeup, especially in regard to more complex eye types. To investigate this question, we took a transcriptomic and proteomic approach to identify the major proteins contributing to the principal bifocal lenses of T. marmoratus larvae. Mass spectrometry revealed 10 major lens proteins. Six of these share sequence homology with cuticular proteins, a large class of proteins that are also major components of corneal lenses from adult compound eyes of Drosophila melanogaster and Anopheles gambiae. Two proteins were identified as house-keeping genes and the final two lack any sequence homologies to known genes. Overall the composition seems to follow a pattern of co-opting transparent and optically dense proteins, similar to what has been described for other animal lenses. To identify cells responsible for the secretion of specific lens proteins, we performed in situ hybridization studies and found some expression differences between distal and proximal corneagenous cells. Since the distal cells likely give rise to the periphery and the proximal cells to the center of the lens, our findings highlight a possible mechanism for establishing structural differences that are in line with the bifocal nature of these lenses. A better understanding of lens composition provides insights into the evolution of proper focusing, which is an important step in the transition between low-resolution and high-resolution eyes.

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Neural Versus Gonadal GnIH: Are they Independent Systems? A Mini-Review

Abstract

Based on research in protochordates and basal vertebrates, we know that communication across the first endocrine axes likely relied on diffusion. Because diffusion is relatively slow, rapid responses to some cues, including stress-related cues, may have required further local control of axis outputs (e.g., steroid hormone production by the gonads). Despite the evolution of much more efficient circulatory systems and complex nervous systems in vertebrates, production of many "neuro"transmitters has been identified outside of the hypothalamus across the vertebrate phylogeny and these neurotransmitters are known to locally regulate endocrine function. Our understanding of tissue-specific neuropeptide expression and their role coordinating physiological/behavioral responses of the whole organism remains limited, in part, due to nomenclature and historic dogma that ignores local regulation of axis output. Here, we review regulation of gonadotropin-inhibitory hormone (GnIH) across the reproductive axis in birds and mammals to bring further attention to context-dependent disparities and similarities in neuropeptide production by the brain and gonads. We find that GnIH responsiveness to cues of stress appears conserved across species, but that the response of specific tissues and the direction of GnIH regulation varies. The implications of differential regulation across tissues remain unclear in most studies, but further work that manipulates and contrasts function in different tissues has the potential to inform us about both organism-specific function and endocrine axis evolution.

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Introduction to Symposium: The Developmental and Proximate Mechanisms Causing Individual Variation in Cooperative Behavior

Abstract

Nearly all animals interact with members of their own species at some point during their lives. These behavioral interactions range from courtship, mating, and parental care to the complex cooperative behavior among related or unrelated individuals in group-living species. A number of theoretical models have attempted to explain how cooperation can evolve through natural selection. Although tremendously influential in animal behavior research, these traditional models have largely ignored individual variation in cooperative behavior and its underlying developmental and proximate mechanisms. However, a set of emerging models suggest that the evolution of cooperation can be heavily influenced by the degree of individual variation in cooperative behavior, as well as the complexity of the underlying mechanisms. Yet, while theoreticians argue the importance of studying individual variation in cooperation and the mechanisms underlying it, empiricists have not focused upon these aspects. The main objectives of our symposium at the 2017 meeting of the Society for Integrative and Comparative Biology is to establish new research avenues to study variation in cooperative behavior using both proximate and ultimate explanations and to produce a road map to study the developmental and proximate mechanisms in generating individual variation in cooperative behavior. This symposium brought together empiricists and theoreticians investigating cooperative behavior in diverse taxa and across multiple levels of analysis. Here we briefly describe the rationale for this symposium and why we thought it was needed as well as provide a brief overview of the contributions.

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Enrichment of putatively damaging rare variants in the DYX2 locus and the reading-related genes CCDC136 and FLNC

Abstract

Eleven loci with prior evidence for association with reading and language phenotypes were sequenced in 96 unrelated subjects with significant impairment in reading performance drawn from the Colorado Learning Disability Research Center collection. Out of 148 total individual missense variants identified, the chromosome 7 genes CCDC136 and FLNC contained 19. In addition, a region corresponding to the well-known DYX2 locus for RD contained 74 missense variants. Both allele sets were filtered for a minor allele frequency ≤0.01 and high Polyphen-2 scores. To determine if observations of these alleles are occurring more frequently in our cases than expected by chance in aggregate, counts from our sample were compared to the number of observations in the European subset of the 1000 Genomes Project using Fisher's exact test. Significant P values were achieved for both CCDC136/FLNC (P = 0.0098) and the DYX2 locus (P = 0.012). Taken together, this evidence further supports the influence of these regions on reading performance. These results also support the influence of rare variants in reading disability.

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Fabrication of Periodic Gold Nanocup Arrays Using Colloidal Lithography

We demonstrate the fabrication of periodic gold nanocup arrays using colloidal lithographic techniques and discuss the importance of nanoplasmonic films.

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Implementation and validation of the extended Hill-type muscle model with robust routing capabilities in LS-DYNA for active human body models

In the state of the art finite element AHBMs for car crash analysis in the LS-DYNA software material named *MAT_MUSCLE (*MAT_156) is used for active muscles modeling. It has three elements in parallel configur...

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Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma

Objective

Hippo signalling is a recently identified major oncosuppressive pathway that plays critical roles in inhibiting hepatocyte proliferation, survival and hepatocellular carcinoma (HCC) formation. Hippo kinase (Mst1 and Mst2) inhibits HCC proliferation by suppressing Yap/Taz transcription activities. As human HCC is mainly driven by chronic liver inflammation, it is not clear whether Hippo signalling inhibits HCC by shaping its inflammatory microenvironment.

Design

We have established a genetic HCC model by deleting Mst1 and Mst2 in hepatocytes. Functions of inflammatory responses in this model were characterised by molecular, cellular and FACS analysis, immunohistochemistry and genetic deletion of monocyte chemoattractant protein-1 (Mcp1) or Yap. Human HCC databases and human HCC samples were analysed by immunohistochemistry.

Results

Genetic deletion of Mst1 and Mst2 in hepatocytes (DKO) led to HCC development, highly upregulated Mcp1 expression and massive infiltration of macrophages with mixed M1 and M2 phenotypes. Macrophage ablation or deletion of Mcp1 in DKO mice markedly reduced hepatic inflammation and HCC development. Moreover, Yap removal abolished induction of Mcp1 expression and restored normal liver growth in the Mst1/Mst2 DKO mice. Finally, we showed that MCP1 is a direct transcription target of YAP in hepatocytes and identified a strong gene expression correlation between YAP targets and MCP-1 in human HCCs.

Conclusions

Hippo signalling in hepatocytes maintains normal liver growth by suppressing macrophage infiltration during protumoural microenvironment formation through the inhibition of Yap-dependent Mcp1 expression, providing new targets and strategies to treat HCCs.

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Post-tetanic transcranial motor evoked potentials augments the amplitude of compound muscle action potentials recorded from innervated and non-innervated muscles

Publication date: Available online 1 September 2017
Source:The Spine Journal
Author(s): Hideki Shigematsu, Masahiko Kawaguchi, Hironobu Hayashi, Tsunenori Takatani, Eiichiro Iwata, Masato Tanaka, Akinori Okuda, Yasuhiko Morimoto, Keisuke Masuda, Yuusuke Yamamoto, Yasuhito Tanaka
Background ContextTranscranial electrical stimulation used to produce motor evoked potentials (TES-MEP) and subsequent compound muscle action potential (CMAP) recording is widely used to monitor motor function during surgery when there is risk of damaging the spinal cord. Nonetheless, some muscles do not produce CMAP amplitudes sufficient for intraoperative monitoring.PurposeTo investigate the utility of tetanic stimulation at single and multiple peripheral nerve sites for augmenting CMAP amplitudes recorded from innervated and non-innervated muscles.Study Design/SettingRetrospective study.Patient SampleTwenty-four patients with cervical myelopathy who underwent decompression surgery at our department between November 2005 and March 2007.Outcome MeasuresCMAP amplitude as a physiologic measure.MethodsWe used two patterns of tetanic peripheral nerve stimulation for each patient. The first pattern consisted of tetanic stimulation of the left tibial nerve only (Pattern 1), and the second pattern consisted of tetanic stimulation of the bilateral median nerves and left tibial nerve (Pattern 2).ResultsCMAP amplitudes from all muscles were augmented by both tetanic stimulation patterns compared to conventional TES-MEP recording; however, Pattern 2 elicited the greatest augmentation of CMAP amplitudes, especially for CMAPs recorded from the bilateral abductor pollicis brevis muscles.ConclusionsAlthough tetanic stimulation of a single peripheral nerve increased CMAP amplitudes recorded from both innervated and non-innervated muscles, CMAP amplitudes were best augmented when the corresponding nerve received tetanic stimulation. Additionally, tetanic stimulation of multiple nerves rather than a single nerve appears to provide better augmentation.



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Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor

Summary

Aim

LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety, and tolerability profile.

Methods

Healthy subjects were randomised to receive LY3031207 (25, 75, and 275 mg), placebo, or celecoxib (400 mg) once daily for 28 days. The safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated.

Results

The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing.

Conclusions

This study emphasised the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.

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Evaluation of the pharmacokinetic drug interaction potential of tivantinib (ARQ 197) using cocktail probes in patients with advanced solid tumours

Summary

Aim

This phase 1, open-label, crossover study sought to evaluate drug–drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P-glycoprotein.

Methods

The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P-glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and after 5 days of treatment with tivantinib 360 mg twice daily.

Results

The ratios of geometric least squares mean (90% confidence interval) for the area under the concentration–time curve from time zero to the last quantifiable concentration in the presence/absence of tivantinib were 0.97 (0.89–1.05) for caffeine; 0.88 (0.76–1.02) for S-warfarin; 0.89 (0.60–1.31) for omeprazole; 0.83 (0.67–1.02) for midazolam; and 0.69 (0.51–0.94) for digoxin. Similar effects were observed for maximum plasma concentrations; the ratio for digoxin in the presence/absence of tivantinib was 0.75 (0.60–0.95).

Conclusions

The data suggest that tivantinib 360 mg twice daily has either a minimal or no effect on the pharmacokinetics of probe drugs for CYP1A2, CYP2C9, CYP2C19, and CYP3A4 substrates, and decreases the systemic exposure of P-glycoprotein substrates when administered with tivantinib.

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A frailty index from common clinical and laboratory tests predicts increased risk of death across the life course

Abstract

A frailty index (FI) based entirely on common clinical and laboratory tests might offer scientific advantages in understanding ageing and pragmatic advantages in screening. Our main objective was to compare an FI based on common laboratory tests with an FI based on self-reported data; we additionally investigated if the combination of subclinical deficits with clinical ones increased the ability of the FI to predict mortality. In this secondary analysis of the 2003–2004 and 2005–2006 National Health and Nutrition Examination Survey data, 8888 individuals aged 20+ were evaluated. Three FIs were constructed: a 36-item FI using self-reported questionnaire data (FI-Self-report); a 32-item FI using data from laboratory test values plus pulse and blood pressure measures (FI-Lab); and a 68-item FI that combined all items from each index (FI-Combined). The mean FI-Lab score was 0.15 ± 0.09, the FI-Self-report was 0.11 ± 0.11 and FI-Combined was 0.13 ± 0.08. Each index showed some typical FI characteristics (skewed distribution with long right tail, non-linear increase with age). Even so, there were fewer people with low frailty levels and a slower increase with age for the FI-Lab compared to the FI-Self-report. Higher frailty level was associated with higher risk of death, although it was strongest at older ages. Both FI-Lab and FI-Self-report remained significant in a combined model predicting death. The FI-Lab was feasible and valid, demonstrating that even subclinical deficit accumulation increased mortality risk. This suggests that deficit accumulation, from the subcellular to the clinically visible is a useful construct that may advance our understanding of the ageing process.

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Immune evasion mechanisms of human papillomavirus: An update

Abstract

Human papillomavirus (HPV) is the most frequently sexually transmitted agent in the world. It can cause cervical and other ano-genital malignancies, as well as oropharyngeal cancer. HPV has the unique ability to persist in the host's epithelium for a long time – longer than most viruses do – which is necessary to complete its replication cycle. To this end, HPV has developed a variety of immune evasion mechanisms, which unfortunately also favor the progression of the disease from infection to chronic dysplasia and eventually to cancer. This review summarizes the current knowledge about HPV immune evasion strategies. A special emphasis lies in HPV-mediated changes of the antigen processing machinery, which is generating epitopes for T-cells and contributes to the detection of infected cells. This article is protected by copyright. All rights reserved.

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Multimodular assessment of a calcified extraradicular deposit on the root surfaces of a mandibular molar

Abstract

Aim

To achieve a better understanding of a calcified extraradicular deposit on the apical root surfaces of a mandibular first molar associated with a radicular cyst and a sinus tract. A multimodular approach was applied using a combination of multiple investigation methods.

Summary

This case report presents a mandibular first molar with a calcified extraradicular deposit on the apical root surfaces of both roots. An apical periodontitis lesion was present and a sinus tract served as the only communication with the oral cavity. Diagnosis and treatment planning were based on clinical, radiographic (two and three dimensional) and ultrasound examination. The tooth was further analyzed after extraction using microscopic imaging, nano-computed tomography (nano-CT), hard- and soft tissue histology and electron probe microanalysis (EPMA). This multimodular approach revealed the calculus-like appearance and mineral composition of the extraradicular deposit. Multiple hypotheses about its aetiology are discussed.

This article is protected by copyright. All rights reserved.

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Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies

Abstract

Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC] and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression and functional studies, and applied network-based analytics in search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential- and hub-genes. In addition to disease-specific modules, we found a substantial overlap of disease neighborhoods, and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing STAT3, IL6, TNF and FOXP3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the AGE-RAGE pathway, and showed that RAGE activation induced cholangiocyte proliferation. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC and PSC. This article is protected by copyright. All rights reserved.

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Efficacy and Safety of Glecaprevir/Pibrentasvir in Japanese Patients with Chronic Genotype 2 Hepatitis C Virus Infection

ABSTRACT

Glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-acting anti-viral (DAA) regimen was evaluated for safety and efficacy in Hepatitis C Virus GT2-infected Japanese patients, including those with compensated cirrhosis. CERTAIN-2 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120mg) once daily (QD) in treatment-naïve and interferon (IFN) ± RBV treatment-experienced non-cirrhotic Japanese patients with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (Arm A) or 12 weeks of sofosbuvir (400 mg QD) + RBV (600 -1000 mg weight-based, BID) (Arm B). The primary endpoint was non-inferiority of G/P compared to SOF+RBV by assessing sustained virologic response at post-treatment week 12 (SVR12) among patients in the intent-to-treat (ITT) population. SVR12 was also assessed in treatment-naïve and IFN ± RBV treatment-experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the phase 3, open-label, multicenter CERTAIN-1 study. A total of 136 patients were enrolled in CERTAIN-2. SVR12 was achieved by 88/90 (97.8%) patients in Arm A and 43/46 (93.5%) patients in Arm B. No patient in Arm A experienced virologic failure, while two did in Arm B. The primary endpoint was achieved. In CERTAIN-1, 100% (18/18) of GT2-infected patients with compensated cirrhosis achieved SVR12. Treatment-emergent serious adverse events were experienced by two non-cirrhotic patients in each arm and no cirrhotic patient. Results demonstrate high efficacy and favorable tolerability of G/P in GT2-infected Japanese patients. This article is protected by copyright. All rights reserved.

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Chronic elevation of plasma FGF19 in long-term FXR agonist therapy, a happy marriage or cause for oncologic concern?

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Abstracts from the 2017 annual scientific meeting of the American Association of Clinical Anatomists, Minneapolis, Minnesota July 17-20.

http://ift.tt/2gyDDDN

Systematic Review of the Costs and Benefits of Prescribed Cannabis-Based Medicines for the Management of Chronic Illness: Lessons from Multiple Sclerosis

Abstract

Introduction

Cannabis-based medicines (CBMs) may offer relief from symptoms of disease; however, their additional cost needs to be considered alongside their effectiveness. We sought to review the economic costs and benefits of prescribed CBMs in any chronic illness, and the frameworks used for their economic evaluation.

Methods

A systematic review of eight medical and economic databases, from inception to mid-December 2016, was undertaken. MeSH headings and text words relating to economic costs and benefits, and CBMs were combined. Study quality was assessed using relevant checklists and results were synthesised in narrative form.

Results

Of 2514 identified records, ten studies met the eligibility criteria, all for the management of multiple sclerosis (MS). Six contained economic evaluations, four studies reported utility-based quality of life, and one was a willingness-to-pay study. Four of five industry-sponsored cost–utility analyses for MS spasticity reported nabiximols as being cost-effective from a European health system perspective. Incremental cost-effectiveness ratios per quality-adjusted life-year (QALY) gained for these five studies were £49,257 (UK); £10,891 (Wales); €11,214 (Germany); €4968 (Italy); and dominant (Spain). Nabiximols for the management of MS spasticity was not associated with statistically significant improvements in EQ-5D scores compared with standard care. Study quality was moderate overall, with limited inclusion of both relevant societal costs and discussions of potential bias.

Conclusions

Prescribed CBMs are a potentially cost-effective add-on treatment for MS spasticity; however, this evidence is uncertain. Further investment in randomised trials with in-built economic evaluations is warranted for a wider range of clinical indications.

Systematic review registration

PROSPERO Registration Number: CRD42014006370.

http://ift.tt/2wwvxPY

Sasang constitutional types for the risk prediction of metabolic syndrome: a 14-year longitudinal prospective cohort study

To examine whether the use of Sasang constitutional (SC) types, such as Tae-yang (TY), Tae-eum (TE), So-yang (SY), and So-eum (SE) types, increases the accuracy of risk prediction for metabolic syndrome.

http://ift.tt/2x0mTMG

Interventional Pulmonology: Determining an Ideal Technique, Phenotype-driven Management, and Finding Safer Alternatives

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 649-651, September 1, 2017.


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A Comparative Analysis of Pulmonary and Critical Care Medicine Guideline Development Methodologies

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 621-627, September 1, 2017.


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Obstructive Post-tracheotomy Granulation Tissue

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page e12-e13, September 1, 2017.


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Quantifying the Lung at Risk in Chronic Obstructive Pulmonary Disease. Does Emphysema Beget Emphysema?

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 535-536, September 1, 2017.


http://ift.tt/2etprb4

Reply: The ATS/JRS Guidelines on Lymphangioleiomyomatosis: Filling in the Gaps

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 660-661, September 1, 2017.


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What Is Menthol?

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page P9-P10, September 1, 2017.


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Gene Expression Signatures in Tuberculosis Have Greater Overlap with Autoimmune Diseases Than with Infectious Diseases

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 655-656, September 1, 2017.


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Applying Precision Medicine to Trial Design Using Physiology. Extracorporeal CO2 Removal for Acute Respiratory Distress Syndrome

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 558-568, September 1, 2017.


http://ift.tt/2gyvzmk

Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of Mycobacterium tuberculosis Infection

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 638-648, September 1, 2017.


http://ift.tt/2eOWKpw

Autophagy Traps Neutrophils into a Protective Alliance during Sepsis

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 537-538, September 1, 2017.


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Update in Asthma 2016

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 548-557, September 1, 2017.


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Partially Assisted Ventilation–induced Lung Injury in Early Acute Respiratory Distress Syndrome. When Real Life Is Different from Classical Physiology

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 538-539, September 1, 2017.


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Pneumonia and the Risk of Cardiovascular Death. Time to Change Our Strategy

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 541-543, September 1, 2017.


http://ift.tt/2gzWi1W

Randomized Double-Blind Controlled Trial of Roflumilast at Acute Exacerbations of Chronic Obstructive Pulmonary Disease

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 656-659, September 1, 2017.


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Volume-controlled Ventilation Does Not Prevent Injurious Inflation during Spontaneous Effort

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 590-601, September 1, 2017.


http://ift.tt/2eP5gom

Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 577-589, September 1, 2017.


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Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 609-620, September 1, 2017.


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Coexistence of Mediastinal Castleman Disease with Spindle Cell Carcinoma of the Lung

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 652-654, September 1, 2017.


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Effect of Continuous Positive Airway Pressure Therapy on Cardiovascular Outcomes: Risk Assessment

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 661-662, September 1, 2017.


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Assessing the Generalizability of the National Lung Screening Trial: Comparison of Patients with Stage 1 Disease

American Journal of Respiratory and Critical Care Medicine, Volume 196, Issue 5, Page 602-608, September 1, 2017.


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Issue Information

Cover of this issue. Increased matric stiffness promotes motility of HCC cells. See also Zhang et al. (pp. 1769-1777 of this issue)

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In This Issue

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Infection control at an urban hospital in Manila, Philippines: a systems engineering assessment of barriers and facilitators

Healthcare facilities in low- and middle-income countries, including the Philippines, face substantial challenges in achieving effective infection control. Early stages of interventions should include efforts ...

http://ift.tt/2xFioEf

Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study

Opioids and benzodiazepines are frequently used in the intensive care unit (ICU). Regular use and prolonged exposure to opioids in ICU patients followed by abrupt tapering or cessation may lead to iatrogenic w...

http://ift.tt/2eOELPT

Modelling the Survival Outcomes of Immuno-Oncology Drugs in Economic Evaluations: A Systematic Approach to Data Analysis and Extrapolation

Abstract

Background

New immuno-oncology (I-O) therapies that harness the immune system to fight cancer call for a re-examination of the traditional parametric techniques used to model survival from clinical trial data. More flexible approaches are needed to capture the characteristic I-O pattern of delayed treatment effects and, for a subset of patients, the plateau of long-term survival.

Objectives

Using a systematic approach to data management and analysis, the study assessed the applicability of traditional and flexible approaches and, as a test case of flexible methods, investigated the suitability of restricted cubic splines (RCS) to model progression-free survival (PFS) in I-O therapy.

Methods

The goodness of fit of each survival function was tested on data from the CheckMate 067 trial of monotherapy versus combination therapy (nivolumab/ipilimumab) in metastatic melanoma using visual inspection and statistical tests. Extrapolations were validated using long-term data for ipilimumab.

Results

Modelled PFS estimates using traditional methods did not provide a good fit to the Kaplan–Meier (K–M) curve. RCS estimates fit the K–M curves well, particularly for the plateau phase. RCS with six knots provided the best overall fit, but RCS with one knot performed best at the plateau phase and was preferred on the grounds of parsimony.

Conclusions

RCS models represent a valuable addition to the range of flexible approaches available to model survival when assessing the effectiveness and cost-effectiveness of I-O therapy. A systematic approach to data analysis is recommended to compare the suitability of different approaches for different diseases and treatment regimens.

http://ift.tt/2exGxbt

Carbon-ion radiotherapy for non-small cell lung cancer with interstitial lung disease: a retrospective analysis

Abstract

Background

Lung cancer is frequently complicated by interstitial lung disease (ILD). Treatment protocols for lung cancer patients with ILD have not been established; surgery, chemotherapy, and radiotherapy can all cause acute exacerbation of ILD. This study evaluated the toxicity and efficacy of carbon ion radiotherapy (CIRT) in patients with non-small cell lung cancer (NSCLC) and ILD.

Methods

Between June 2004 and November 2014, 29 patients diagnosed with NSCLC and ILD were treated with CIRT. No patient was eligible for curative surgery or conventional radiotherapy secondary to ILD. Owing to prior symptomology, radiation pneumonitis (RP) and symptom progression pre- and post-treatment were evaluated. The relationships between RP and clinical factors were investigated.

Results

Twenty-eight men and one woman, aged 62 to 90 years old, were followed for 2.7–77.1 months (median: 22.8 months). Single-grade symptomatic progression (grade 2–3) was observed in 4 patients, while 1 patient experiencedtwo-grade progression. Two patients experienced radiation-induced acute exacerbation. Local control at 3 years was 63.3% (72.2% for stage I disease); survival at 3 years was 46.3% (57.2% for stage I disease). Eighteen patients had died by the time of this writing, 10 of lung cancer progression. Radiation pneumonitis post-treatment progression correlated with dosimetric factors of the lungs (V5, V10) and a low pre-treatment serum surfactant protein-D.

Conclusions

We found that CIRT may be useful as a low-risk, curative option for NSCLC patients with ILD, a population that is typically ineligible for conventional therapy. The DVH analysis showed that minimizing the low-dose region is important for reducing the risk of severe RP.

Trial registration

NIRS-9404. Registered 1 March 1994.

http://ift.tt/2iRueYR

Protective Effects of Dietary Garlic Powder Against Cadmium-induced Toxicity in Sea Bass Liver: a Chemical, Biochemical, and Transcriptomic Approach

Abstract

To investigate the protective effect of garlic powder on cadmium-induced toxicity sea bass liver, juvenile fishes where maintained under three food diets (diet 1: normal without garlic supply, diet 2: 2% garlic powder; diet 3: 6% garlic powder). After 30 days of specific diets, each group was injected with 500 μg kg⁻¹of Cd. The control group was the one fed with normal diet and not injected with Cd. Liver Cd, Zn, and Se loads was assessed after 1 and 3 days of Cd injections. Moreover, antioxidant enzymes activities termed as catalase, superoxide dismutase, and glutathione peroxydase as well as their gene expression levels were monitored. Finally, metallothionein protein accumulation and its gene expression regulation (MTa) were determined. In fish fed with 2 and 6% garlic powder, the amounts of Cd, Zn, and Se significantly increase in liver tissues. Two percent garlic powder specific diet reversed the Cd-induced inhibition of catalase (CAT), superoxide dismutase (SOD), and gluthathione peroxydase (GPx) and restored the Cd-induced lipid peroxidation (MDA). The increase of liver metallothionein proteins as well as the MTa gene expression level under Cd influence was more pronounced in animals maintained for 30 days under garlic power 2% diet. Our data must be carefully considered in view of the garlic powder introduction in sea bass food composition at 2% since it is an efficient prevention against Cd-induced alterations.

http://ift.tt/2gzaZ5G

Association of the severity of diabetes-related complications with stage of breast cancer at diagnosis among elderly women with pre-existing diabetes

Abstract

Purpose

This study assessed the association between the severity of diabetes complications using diabetes complications severity index (DCSI) and stage of breast cancer (BC) at diagnosis among elderly women with pre-existing diabetes and incident BC.

Methods

Using Surveillance, Epidemiology and End Results-Medicare data, we identified women with incident BC during 2004–2011 and pre-existing diabetes (N = 7729). Chi-square tests were used to test for group differences in stage of BC at diagnosis. Multinomial logistic regression was used to examine the associations between the severity of diabetes complications and stage of BC at diagnosis.

Results

Overall, women with a DCSI = 2 and a DCSI ≥ 3 were more likely to be diagnosed at advanced stages as compared to those with no diabetes complications. In full adjusted association (after adding BC screening to the analysis model), the severity of diabetes complications was no longer an independent predictor of advanced stages at diagnosis. However, women with a DCSI = 2 were 26% more likely to be diagnosed at stage I (versus stage 0) of BC at diagnosis as compared to those without diabetes complications (OR 1.26, 95% CI 1.03–1.53).

Conclusion

The increased likelihood of having advanced-stage BC at diagnosis associated with severity of diabetes-related complications appears to be mediated by lower rates of breast cancer screening among elderly women with pre-existing diabetes complications. Therefore, reducing disparity in receiving breast cancer screening among elderly women with diabetes may reduce the risk of advanced-stage breast cancer diagnosis.

http://ift.tt/2iPuqHY

Association between self-perception of aging, view of cancer and health of older patients in oncology: a one-year longitudinal study

Abstract

Background

Identifying older people affected by cancer who are more at risk of negative health outcomes is a major issue in health initiatives focusing on medical effectiveness. In this regard, psychological risk factors such as patients' perception of their own aging and cancer could be used as indicators to improve customization of cancer care. We hypothesize that more negative self-perception of aging (SPA) and view of cancer could be linked to worse physical and mental health outcomes in cancer patients.

Methods

One hundred one patients diagnosed with cancer (breast, gynecological, lung or hematological) were followed for 1 year. They were evaluated on four occasions (baseline, 3, 6 and 12 months after the baseline). Their SPA, view of cancer and health (physical and mental) were assessed at each time of evaluation.

Results

Negative SPA and/or view of cancer at baseline are associated with negative evolution of patients' physical and mental health. Moreover, when the evolution of SPA and cancer view were taken into account, these two stigmas are still linked with the evolution of mental health. In comparison, only a negative evolution of SPA was linked to worse physical health outcomes.

Conclusions

Such results indicate that SPA and view of cancer could be used as markers of vulnerability in older people with cancer.

http://ift.tt/2wsJ395

Adjuvant chemotherapy versus chemoradiotherapy for small cell lung cancer with lymph node metastasis: a retrospective observational study with use of a national database in Japan

Abstract

Background

The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lymph node metastasis treated with postoperative adjuvant chemotherapy or chemoradiotherapy.

Methods

We retrospectively collected data on patients with postoperative SCLC diagnosed with N1 and N2 lymph node metastasis from the Diagnosis Procedure Combination database in Japan, between July 2010 and March 2015. We extracted data on patient age, sex, comorbidities, and TNM classification at lung surgery; operative procedures, chemotherapy drugs, and radiotherapy during hospitalization; and discharge status. Recurrence-free survival was compared between the chemotherapy and chemoradiotherapy groups using multivariable Cox regression analysis.

Results

Median recurrence-free survival was 1146 days (95% confidence interval [CI], 885–1407) in the chemotherapy group (n = 489) and 873 days (95% CI, 464–1282) in the chemoradiotherapy group (n = 75). There was no significant difference between these after adjusting for patient backgrounds (hazard ratio, 1.29; 95% CI, 0.91–1.84).

Conclusions

There was no significant difference in recurrence-free survival between patients with SCLC and N1-2 lymph node metastasis treated with postoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials are needed to address this issue.

http://ift.tt/2vTt00j

Role of adjuvant chemotherapy in locally advanced rectal cancer with ypT0-3N0 after preoperative chemoradiation therapy and surgery

Abstract

Background

We aimed to explore the clinical benefit of adjuvant chemotherapy (AC) with fluoropyrimidine in patients with ypT0-3N0 rectal cancer after preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME).

Methods

Patients with ypT0-3N0 rectal cancer after preoperative CRT and TME were included using prospectively collected tumor registry cohort between January 2001 and December 2013. Patients were categorized into two groups according to the receipt of AC. Disease-free survival (DFS) and overall survival (OS) were compared between the adjuvant and observation groups. To control for potential confounding factors, we also calculated propensity scores and performed propensity score-matched analysis for DFS and OS.

Results

Of the 339 evaluated patients, 87 patients (25.7%) did not receive AC. There were no differences in DFS (hazard ratio [HR], 0.921; 95% confidence interval [CI], 0.562–1.507; P = 0.742) and OS (HR, 0.835; 95% CI, 0.423–1.648; P = 0.603) between the adjuvant and observation groups. After propensity score matching, DFS (HR, 1.129; 95% CI, 0.626–2.035; P = 0.688) and OS (HR, 1.200; 95% CI, 0.539–2.669; P = 0.655) did not differ between the adjuvant and observation groups. Advanced T stage and positive resection margin were independently associated with inferior DFS and OS on multivariate analysis.

Conclusions

AC did not improve DFS and OS for patients with ypT0-3N0 rectal cancer after preoperative CRT followed by TME in this cohort study. The confirmative role of AC in locally advanced rectal cancer should be evaluated in prospective randomized trials with a larger sample size.

http://ift.tt/2wrYfmC

Uncommon presentation of a rare tumour - incidental finding in an asymptomatic patient: case report and comprehensive review of the literature on intrapericardial solitary fibrous tumours

Abstract

Background

A solitary fibrous tumour is a rare, mainly benign spindle cell mesenchymal tumour most commonly originating from the pleura. An intrapericardial location of a solitary fibrous tumour is extremely unusual. We present a case of an asymptomatic patient with a slow-growing massive benign cardiac solitary fibrous tumour.

Case presentation

A 37-year-old asymptomatic female patient was referred to our hospital with an enlarged cardiac silhouette found on her screening chest X-ray. The echocardiographic examination revealed pericardial effusion and an inhomogeneous mobile mass located in the pericardial sac around the left ventricle. Cardiac magnetic resonance (MRI) examination showed an intrapericardial, semilunar-shaped mass attached to the pulmonary trunk with an intermediate signal intensity on proton density-weighted images and high signal intensity on T2-weighted spectral fat saturation inversion recovery images. First-pass perfusion and early and late gadolinium-enhanced images showed a vascularized mass with septated, patchy, inhomogeneous late enhancement. Coronary computed tomography angiography revealed no invasion of the coronaries. Based on the retrospectively analysed screening chest X-rays, the mass had started to form at least 7 years earlier. Complete resection of the tumour with partial resection of the pulmonary trunk was performed. Histological evaluation of the septated, cystic mass revealed tumour cells forming an irregular patternless pattern; immunohistochemically, the cells tested positive for vimentin, CD34, CD99 and STAT6 but negative for keratin (AE1-AE3), CD31 and S100. Thus, the diagnosis of an intrapericardial solitary fibrous tumour was established. There has been no recurrence for 3 years based on the regular MRI follow-up.

Conclusion

Intrapericardial SFTs, showing slow growth dynamics, can present with massive extent even in completely asymptomatic patients. MRI is exceedingly useful for characterizing intrapericardial masses, allowing precise surgical planning, and is reliable for long-term follow up.

http://ift.tt/2vT7Z5P

Trends in risk classification and primary therapy of Japanese patients with prostate cancer in Nara urological research and treatment group (NURTG) – comparison between 2004–2006, 2007–2009, and 2010–2012

Abstract

Background

To assess the trends in risk classification and primary therapy of Japanese prostate cancer patients who were diagnosed between 2004 and 2012.

Methods

A total of 7768 patients who were newly diagnosed with prostate cancer at Nara Medical University and its 23 affiliated hospitals between 2004 and 2012 were enrolled. The trends in risk classification and primary therapy in 2004–2006 (prior period), 2007–2009 (middle period), and 2010–2012 (latter period) were compared.

Results

The proportion of high-risk and worse patients significantly decreased in the latter period compared to the prior period (p < 0.001), while that of intermediate-risk patients significantly increased over the years (p < 0.001). The proportion of primary androgen deprivation therapy (PADT) was 50% in the prior period, 40% in the middle period, and 30% in the latter period, respectively. The proportions of radiation therapy and active surveillance significantly increased. The proportion of radical prostatectomy remained similar over these periods (30%). The primary therapy was significantly different between the three periods (p < 0.001).

Conclusions

High-risk patients significantly decreased in the latter period. The use of PADT also significantly decreased, while radiation therapy and active surveillance significantly increased over these periods.

http://ift.tt/2wsflRm

Recent advances in assays for the fragile X-related disorders

Abstract

The fragile X-related disorders are a group of three clinical conditions resulting from the instability of a CGG-repeat tract at the 5′ end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55–200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP. This results in fragile X Syndrome (FXS), the most common heritable cause of intellectual disability and autism. The diagnosis and study of these disorders is challenging, in part because the detection of alleles with large repeat numbers has, until recently, been either time-consuming or unreliable. This problem is compounded by the mosaicism for repeat length and/or DNA methylation that is frequently seen in PM and FM carriers. Furthermore, since AGG interruptions in the repeat tract affect the risk that a FM allele will be maternally transmitted, the ability to accurately detect these interruptions in female PM carriers is an additional challenge that must be met. This review will discuss some of the pros and cons of some recently described assays for these disorders, including those that detect FMRP levels directly, as well as emerging technologies that promise to improve the diagnosis of these conditions and to be useful in both basic and translational research settings.

http://ift.tt/2exq9Yl

NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma

Abstract

Background

NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response. However, the roles of NLRP3 inflammasome in the tumorigenesis and development of cancer stem cells (CSCs) of squamous cell carcinoma of the head and neck (SCCHN) remain ambiguous.

Methods

In our study, tissue microarrays, ELISA, sphere-forming assay, colony formation assay and Western blot analysis were performed to evaluate the effect of NLRP3 inflammasome on the development of CSCs in human SCCHN tissue specimen, cell lines, and transgenic mouse SCCHN model.

Results

The components of NLRP3 inflammasome, namely, NLRP3, ASC, Caspase-1, and IL-18 were correlated with CSCs markers BMI1, ALDH1 and CD44 in human SCCHN specimens. Moreover, NLRP3, Caspase-1, IL-1β, and IL-18 were highly expressed in SCCHN cell lines. NLRP3 inflammasome activated by LPS and ATP promoted sphere-forming and colony formation capacities along with an upregulation of BMI1, ALDH1 and CD44. In addition, NLRP3 inflammasome blockade by NLRP3 inhibitor MCC950 reduced sphere and colony number, also decreased the expression of BMI1, ALDH1 and CD44 in SCCHN cell lines. Expression of NLRP3, ASC, Caspase-1, IL-1β, IL-18, BMI1, ALDH1 and CD44 was upregulated in Tgfbr1/Pten 2cKO mouse SCCHN model, and NLRP3 inflammasome expression was closely related to those CSCs makers in mice SCCHN. However, MCC950 treatment reduced the expression of NLRP3 inflammasome, CSCs markers BMI1, ALDH1 and CD44 in Tgfbr1/Pten 2cKO mice SCCHN. In addition, blockade of NLRP3 inflammasome can also delayed the tumor-burdened speed in SCCHN mice.

Conclusions

Our study demonstrates that NLRP3 inflammasome was upregulated and associated with the carcinogenesis and CSCs self-renewal activation in SCCHN. NLRP3 inflammasome can be a potential target in the development of novel approaches for head and neck squamous cell carcinoma therapy.

http://ift.tt/2gyq1IM

Ebola Virus Glycoprotein Induces an Innate Immune Response In vivo via TLR4.

Related Articles

Ebola Virus Glycoprotein Induces an Innate Immune Response In vivo via TLR4.

Front Microbiol. 2017;8:1571

Authors: Lai CY, Strange DP, Wong TAS, Lehrer AT, Verma S

Abstract
Ebola virus (EBOV), a member of the Filoviridae family, causes the most severe form of viral hemorrhagic fever. Although no FDA licensed vaccine or treatment against Ebola virus disease (EVD) is currently available, Ebola virus glycoprotein (GP) is the major antigen used in all candidate Ebola vaccines. Recent reports of protection as quickly as within 6 days of administration of the rVSV-based vaccine expressing EBOV GP before robust humoral responses were generated suggests that the innate immune responses elicited early after vaccination may contribute to the protection. However, the innate immune responses induced by EBOV GP in the absence of viral vectors or adjuvants have not been fully characterized in vivo. Our recent studies demonstrated that immunization with highly purified recombinant GP in the absence of adjuvants induced a robust IgG response and partial protection against EBOV infection suggesting that GP alone can induce protective immunity. In this study we investigated the early immune response to purified EBOV GP alone in vitro and in vivo. We show that GP was efficiently internalized by antigen presenting cells and subsequently induced production of key inflammatory cytokines. In vivo, immunization of mice with EBOV GP triggered the production of key Th1 and Th2 innate immune cytokines and chemokines, which directly governed the recruitment of CD11b(+) macrophages and CD11c(+) dendritic cells to the draining lymph nodes (DLNs). Pre-treatment of mice with a TLR4 antagonist inhibited GP-induced cytokine production and recruitment of immune cells to the DLN. EBOV GP also upregulated the expression of costimulatory molecules in bone marrow derived macrophages suggesting its ability to enhance APC stimulatory capacity, which is critical for the induction of effective antigen-specific adaptive immunity. Collectively, these results provide the first in vivo evidence that early innate immune responses to EBOV GP are mediated via the TLR4 pathway and are able to modulate the innate-adaptive interface. These mechanistic insights into the adjuvant-like property of EBOV GP may help to develop a better understanding of how optimal prophylactic efficacy of EBOV vaccines can be achieved as well as further explore the potential post-exposure use of vaccines to prevent filoviral disease.

PMID: 28861075 [PubMed]

http://ift.tt/2eOxdge

Combination therapy of PKCζ and COX-2 inhibitors synergistically suppress melanoma metastasis

Abstract

Background

Metastatic malignant melanoma is one of the most aggressive malignancies and its treatment remains challenging. Recent studies demonstrate that the melanoma metastasis has correlations with the heightened activations of protein kinase C ζ (PKCζ) and cyclooxygenase-2 (COX-2) signaling pathways. Targeted inhibitions for PKCζ and COX-2 have been considered as the promising strategies for the treatment of melanoma metastasis. Thus, the PKCζ inhibitor J-4 and COX-2 inhibitor Celecoxib were combined to treat melanoma metastasis in this study.

Methods

The Transwell assay, Wound-healing assay and Adhesion assay were used to evaluate the inhibition of combined therapy of J-4 and Celecoxib on melanoma cells invasion, migration and adhesion in vitro, respectively. The impaired actin polymerization was observed by confocal microscope and inactivated signal pathways about PKCζ and COX-2 were confirmed by the Western blotting assay. The B16-F10/C57BL mouse melanoma model was used to test the inhibition of combined therapy of J-4 and Celecoxib on melanoma metastasis in vivo.

Results

The in vitro results showed that the combination of J-4 and Celecoxib exerted synergistic inhibitory effects on the migration, invasion and adhesion of melanoma B16-F10 and A375 cells with combination index less than 1. The actin polymerization and phosphorylation of Cofilin required in cell migration were severely impaired, which is due to the inactivation of PKCζ related signal pathways and the decrease of COX-2. The combined inhibition of PKCζ and COX-2 induced Mesenchymal-Epithelial Transition (MET) in melanoma cells with the expression of E-Cadherin increasing and Vimentin decreasing. The secretion of MMP-2/MMP-9 also significantly decreased after the combination treatment. In C57BL/6 mice intravenously injected with B16-F10 cells (5 × 10⁴ cells/mouse), co-treatment of J-4 and Celecoxib also severely suppressed melanoma lung metastasis. The body weight monitoring and HE staining results indicated the low toxicity of the combination therapy.

Conclusions

This study demonstrates that the combination therapy of PKCζ and COX-2 inhibitors can significantly inhibit melanoma metastasis in vitro and in vivo, which will be an efficient strategy for treatment of melanoma metastasis in clinics.

http://ift.tt/2wsruWI

Much Ado about “Masculinity”: An Exploration of the Current State of Men and Masculinities Research

http://ift.tt/2vzLUOD

Gene Delivery in Neuro-Oncology

Abstract

Purpose of Review

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a dismal prognosis despite aggressive multimodal management thus novel treatments are urgently needed. Gene therapy is a versatile treatment strategy being investigated in multiple cancers including GBM. In gene therapy, a variety of vectors or "carriers" are used to deliver genes designed for different anti-tumoral effects. Gene delivery vehicles and approaches to treatment will be addressed in this review.

Recent Findings

The most commonly studied vectors are viral based, however, driven by advances in biomedical engineering, mesenchymal and neural stem cells, as well as multiple different types of nanoparticles have been developed to improve tumor tropism and also increase gene transfer into tumor cells. Different genes have been studied including suicide genes, which convert non-toxic prodrug into cytotoxic drug; immunomodulatory genes, which stimulate the immune system; and tumor suppressor genes which repair the defect that allow cells to divide unchecked.

Summary

Gene therapy may be a promising treatment strategy in neuro-oncology as it is versatile and flexible due to the ability to tailor vectors and genes for specific therapeutic activity. Pre-clinical studies and clinical trials have demonstrated feasibility and safety of gene therapy; however, further studies are required to determine efficacy.

http://ift.tt/2es1GQk

From mechanisms to therapy: RNA processing’s impact on human genetics

http://ift.tt/2gxAV1a

Copper, Manganese, Zinc, and Cadmium in Tea Leaves of Different Types and Origin

Abstract

Concentrations of selected metals (Cu, Mn, Zn, Cd) in tea leaves were investigated. Samples included black, green, and other (red, white, yellow, and oolong) teas. They were purchased on a local market but they covered different countries of origin. Beverages like yerba mate, rooibos, and fruit teas were also included in the discussion. Metal determinations were performed using atomic absorption spectrometry. In black teas, Mn/Cd ratio was found to be significantly higher (48,091 ± 35,436) vs. green (21,319 ± 16,396) or other teas (15,692 ± 8393), while Cd concentration was lower (31.4 ± 18.3 μg/kg) vs. other teas 67.0 (67.0 ± 24.4). Moreover, Zn/Cu and Cu/Cd ratios were, respectively, lower (1.1 ± 0.2 vs. 2.2 ± 0.5) and higher (1086 ± 978 vs. 261 ± 128) when comparing black teas with other teas. Intake of each metal from drinking tea was estimated based on the extraction levels reported by other authors. Contributions to recommended daily intake for Cu, Mn, and Zn were estimated based on the recommendations of international authorities. Except for manganese, tea is not a major dietary source of the studied elements. From the total number of 27 samples, three have shown exceeded cadmium level, according to local regulations.

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Clinical activity of eribulin in advanced desmoplastic small round-cell tumor.

Desmoplastic small round-cell tumor is a rare but highly aggressive tumor occurring mainly in adolescents and young adults. Prolonged progression-free survival has been documented in patients who have undergone aggressive multimodality therapy - that is, multiagent intensive chemotherapy, debulking surgery, and radiation therapy. Eribulin is a microtubule-dynamics inhibitor, and it has recently been shown to be active in liposarcomas. In preclinical models, eribulin activities have also been shown to occur in Ewing's sarcoma cell lines, rhabdomyosarcomas and osteosarcomas. In this study, we report three cases of male patients suffering from desmoplastic small round-cell tumor and the clinical response to eribulin in two of them. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A paradigm shift in surgical planning and simulation using 3Dgraphy: Experience of first 50 surgeries done using 3D-printed biomodels

Publication date: Available online 1 September 2017
Source:Injury
Author(s): Vaibhav Bagaria, Kshitij Chaudhary
IntroductionPreoperative planning is an important aspect of any orthopedic surgery. Traditionally, surgeons mentally rehearse the operation and anticipate problems based on data available from "radiography" like MRI and CT. 3D printed bio-models and tools, or "3Dgraphy" can simplify this mental exercise and provide a realistic and user-friendly portrayal of this radiographic data.MethodsFive surgeons participated in this multicenter study. 3D printed biomodels were obtained for 50 surgical cases that included periarticular trauma (24), pelvic trauma (11), complex primary (7), and revision arthroplasty (8). CT scan data was used to generate computer models which were then 3D printed in real size. These models were used to understand pathoanatomy and conduct simulated surgery as a part of preoperative planning. The models were sterilized and were used for intraoperative referencing. Following each case, the operating surgeon was asked to fill out a structured questionnaire to report on the perceived benefits of these tools.ResultsAll surgeons reported that the biomodels provided additional information to conventional imaging that enhanced their knowledge of the complex pathoanatomy. It was useful in preoperative planning, rehearsing the operation, surgical simulation, intraoperative referencing, surgical navigation, preoperative implant selection, and inventory management. This probably reduced surgical time and improved accuracy of the surgery. All surgeons reported that they would not only use it themselves but also recommend it to other surgeons.Conclusion3Dgraphy was found to be a valuable tool in orthopedic surgeries that involve complex pathoanatomy like pelvic trauma, revision arthroplasty, and periarticular fracture. As the technology evolves and improves, they are likely to become a standard component of many orthopedic procedures.



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Differences Between Orthopaedic Evaluation and Radiological Reports of Conventional Radiographs in Patients with Minor Trauma Admitted to the Emergency Department

Publication date: Available online 1 September 2017
Source:Injury
Author(s): Michele Catapano, Domenico Albano, Grazia Pozzi, Riccardo Accetta, Sergio Memoria, Fabrizio Pregliasco, Carmelo Messina, Luca Maria Sconfienza
IntroductionDuring night and on weekends, in our emergency department there is no radiologist on duty or on call: thus, X-ray examinations (XR) are evaluated by the orthopaedic surgeon on duty and reported the following morning/monday by radiologists. The aim of our study was to examine the discrepancy rate between orthopaedists and radiologists in the interpretation of imaging examinations performed on patients in our tertiary level orthopaedic institution and the consequences of delayed diagnosis in terms of patient management and therapeutic strategy.Materials andMethodsWe retrospectively reviewed all cases of discrepancy between orthopaedists and radiologists, which were categorized according to anatomical location of injury, initial diagnosis and treatment, change in diagnosis and treatment. We used the Chi square test to compare the frequencies of discrepancies between patients ≤14 and >14years of age.ResultsFrom January to December 2016, 19,512 patients admitted to our emergency department performed at least an imaging examination; among these patients, 13,561 underwent XR in absence of an attending radiologist. A discrepant diagnosis was found in 337/13,561 (2.5%; 184 males; mean age: 36.7±23.7, range 2-95); 151/337 (45%) discrepancies were encountered in the lower limbs, with ankle being the most common site of misdiagnosis (64/151), and 103/337 (30%) in the upper limbs, with the elbow being the most frequent site in this district (35/103). We found 293/337 false negatives (87%) and 44/337 false positives (13%), with 134 and 13 patients needing treatment change, respectively. We found 85/337 discrepancies (25%) in patients ≤14 years of age, and 252/337 (75%) in those >14years. The distribution of discrepancies per anatomic district was significantly different (P<0.001) in these two groups of patients.ConclusionsA low rate of discrepancy between orthopaedists and radiologists in evaluating images of patients admitted to our emergency department was found, although treatment change occurred in about half of cases. A thorough and accurate clinical evaluation is crucial to provide a correct treatment and prognosis.



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Reliable Anatomical Landmarks for Minimizing Leg-length Discrepancy during Hip Arthroplasty using the Lateral Transgluteal Approach for Femoral Neck Fracture

Publication date: Available online 1 September 2017
Source:Injury
Author(s): Jeung Kim, Nam Hoon Moon, Won Chul Shin, Kuen Tak Suh, Jae Yoon Jeong
BackgroundThe purpose of this study was to describe our experience of a preoperative templating technique, and to investigate the most reliable anatomical reference to minimize leg length discrepancy (LLD) during hip arthroplasty using the lateral transgluteal approach for femoral neck fractures. We hypothesized that the medial fracture tip and greater trochanter would be viable alternative anatomical ReferencesMethodsA total of 156 hip arthroplasty cases were enrolled in the present study (103 women, 114 hemiarthroplasties, 42 total hip arthroplasties). Preoperative acetate overlay templating was conducted based on pelvic anteroposterior radiographs. Three different anatomical references were used to determine the bony resection level, including the uppermost point of the lesser trochanter, uppermost point of the greater trochanter, and medial fracture tip. The accuracy of preoperative templating and the reliability of each anatomical reference for minimizing LLD were assessed.ResultsSignificant differences in postoperative LLD after hip arthroplasty between the three groups were identified. Post-hoc analysis showed that postoperative LLD in group A was significantly larger than that in groups B or C in hip arthroplasty.ConclusionThe results of this study suggest that the use of the lesser trochanter as an anatomical reference to determine the level of femoral neck osteotomy should be discouraged, and that the medial fracture tip and greater trochanter may be better alternatives when using the lateral transgluteal approach.



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Acute Traumatic Rupture of the Patellar Tendon in Pediatric Population: Case Series and Review of the Literature

Publication date: Available online 1 September 2017
Source:Injury
Author(s): Mohamed Abdelhamid Ali Yousef, Scott Rosenfeld
BackgroundIntact knee extensor mechanism is required for the normal function of the lower extremity. Patellar tendon rupture is a relatively rare injury with peak age incidence around 40 years and usually occurs midsubstance. The occurrence of pure patellar tendon rupture without bony avulsion is an extremely rare injury in the pediatric population with few cases reported in the literature with limited information regarding frequency, complications, and outcomes in children. However, due to increased participation in sports and high-energy recreational activities during childhood, the frequency of such injuries has progressively increased.ObjectiveTo evaluate the frequency of pediatric patellar tendon rupture injuries and describe the radiological findings, treatment modalities, and outcome of such injuries.MethodsDemographic and clinical data on a series of patients who sustained patellar tendon rupture were reviewed. These data included age at time of injury, sex, laterality, mechanism of injury, associated injuries, complications, presence or absence of Osgood-Schlatter disease, diagnostic imaging such as plain radiographs and magnetic resonance images (MRI), surgical technique, method of fixation, period of postoperative immobilization, total duration of physiotherapy, time to return to sports activities and follow-up duration. Insall-Salvati ratio was calculated on the preoperative lateral x-ray. The functional outcome was evaluated with regard to final knee active range of motion (AROM), manual quadriceps muscle testing, and presence or the absence of terminal extension lag. Clinical outcome rating using knee society score (KSS) was performed and functional outcome was further classified according to the calculated score.ResultsFive male patients with patellar tendon rupture (7%) were identified among 71 pediatric patients who sustained acute traumatic injury of the knee extensor mechanism. The mean age at the time of injury was 13.6 years (range: 12-15 years). The injury occurred in relation to sports activities in 4 patients. Osteogenesis imperfecta and Osgood-Schlatter disease were identified in 2 patients. High riding patella is the hallmark diagnostic sign detected in plain x-ray with preoperative Insall-Salvati ratio ranged from 1.7 to 2.5. Three patients had pure soft tissue avulsion distally from the proximal tibia, 1 patient had pure soft tissue avulsion proximally from the inferior patellar pole, and 1 patient with midsubstance tendinous disruption. No associated intra-articular lesions were identified. Suture bridge double row technique, transpatellar suturing, and transosseous suturing through the proximal tibia were used for patellar tendon reinsertion. After a mean follow-up period of 18. 4 weeks (range: 10–30 weeks), patients achieved AROM ranging from 0–120° to 0–137° without terminal extension lag. The mean time to return to sports activity was 22 weeks (range: 13–30 weeks). Quadriceps muscle strength was 5/5 at the final follow-up visit in all patients; however, relative muscle atrophy was noted in comparison to the other side in one patient. The mean KSS was 91.8 points (range: 79–100 points) with excellent outcome in 4 patients and good outcome in 1 patient.ConclusionPatellar tendon rupture is rare in the pediatric population and represents 7% of pediatric patients who sustained acute traumatic injury of the knee extensor mechanism. Ruptures may occur midsubstance, or from proximal or distal insertions. High riding patella is the hallmark diagnostic sign for such injury. Although rare, it is considered a serious injury that necessitates early diagnosis and surgical intervention. Functional range of motion was obtained in all patients with different modalities of treatment.



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How can we influence the incidence of secondary fragility fractures? A review on current approaches

Publication date: Available online 1 September 2017
Source:Injury
Author(s): H.-C. Pape, H.A. Bischoff-Ferrari
With the increasing number of elderly patients presenting with fragility fractures, their care has become a focus among trauma and orthopaedic surgeons. Protocols are ever evolving to improve the clinical pathways and treatment modalities targeting a more efficient and patient centred service.In this article, current approaches and their potential to reduce mortality and re-fracture in these patients are discussed.



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The outcome of intracapsular hip fracture fixation using the Targon Femoral Neck (TFN) locking plate system or cannulated cancellous screws: A comparative study involving 2004 patients

Publication date: Available online 1 September 2017
Source:Injury
Author(s): Zeiad Alshameeri, Mohamed Elbashir, Martyn J. Parker
AimThis study compares the outcome of intracapsular hip fracture fixation using the Targon Femoral Neck (TFN) locking plate system with the standard fixation using cannulated cancellous screws (CCS).Patients and MethodAnalyses of a prospectively collected data of all patients treated for intracapsular hip fractures using the TFN system and CCS at our department over a period of 28 years. Baseline characteristics and specific outcome measures where compared. The primary outcome measure was fracture revision during the 1st year. Secondary outcome measures were fracture complications, any revision surgery, mortality and mobility status at one year after surgery.ResultsA total of 2004 fractures were included, a third (n=725, 36.2%) were treated using the TFN system. There were higher rates of non-union (19.5% vs 9.5%) and revision surgery (19% vs 9%) during the first year in the CCS cohort. Revision surgery was also higher in the same group during the whole of the follow-up period (22.2% vs 14.9%). The first year's mortality rate was in the CCS cohort (21.1% vs 17.5%) but the reduction in mobility and mobility scores was the same in both cohorts.ConclusionThis study includes the largest cohort of cases treated for intracapsular hip fractures using the TFN system. It demonstrated that the TFN system was associated with lower rates of non-union, revisions and re-operations for any cause.



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In A Stable Battlefield, Avoid Using Austere Surgical Units to Meet the Golden Hour of Trauma Time to Care Goal

Publication date: Available online 1 September 2017
Source:Injury
Author(s): Richard Childers, Paul Parker




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Treating osteomyelitis of major limb amputations with a modified Lautenbach technique

Publication date: Available online 1 September 2017
Source:Injury
Author(s): Juliet M. Clutton, Oliver Donaldson, Anthony Perera, Rhidian Morgan-Jones
IntroductionMajor lower limb amputation significantly increases the energy cost of walking for patients. Complications such as osteomyelitis may require further surgery, and can lead to shortening of the stump. In these cases, the aim should be to treat infection without shortening the limb further. We present a series of patients with established osteomyelitis of the amputation stump, managed using a modified Lautenbach technique.MethodSix patients with either above or below knee amputations, in the practice of a single orthopaedic surgeon, were studied. Ages range from 39 to 64 years, and reasons for amputation included infection, pain, and necrosis. All patients had osteomyelitis in the amputation stump confirmed on MRI.ResultsAt a mean follow-up of 3.75 years (range 7 months to 6 years) all six patients had no clinical or haematological evidence of infection, and had returned to independent living. Stump length was preserved in all cases, including in one patient who underwent two procedures to ensure complete debridement.ConclusionsWe believe that this case series is the largest so far published regarding this modification of the Lautenbach Procedure. This operation treats infection effectively without further loss of bone length, and no patients so far have developed significant complications.



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Working Length and Proximal Screw Constructs in Plate Osteosynthesis of Distal Femur Fractures

Publication date: Available online 1 September 2017
Source:Injury
Author(s): William H. Harvin, Lasun O. Oladeji, Gregory J. Della Rocca, Yvonne M. Murtha, David A. Volgas, James P. Stannard, Brett D. Crist
BackgroundThe study purpose is to evaluate the working length, proximal screw density, and diaphyseal fixation mode and the correlation to fracture union after locking plate osteosynthesis of distal femoral fractures using bridge-plating technique.MethodsA four-year retrospective review was performed to identify patients undergoing operative fixation of distal femur fractures with a distal femoral locking plate using bridge-plating technique for the metadiaphyseal region. Primary variables included fracture union, secondary surgery for union, plate working length, and diaphyseal screw technique and configuration. Multiple secondary variables including plate metallurgy and coronal plane fracture alignment were also collected.ResultsNinety-six patients with distal femur fractures with a mean age 60 years met inclusion criteria. None of the clinical parameters were statistically significant indicators of union. Likewise, none of the following surgical technique parameters were associated with fracture union: plate metallurgy, the mean working length, screw density and number of proximal screws and screw cortices. However, diaphyseal screw technique did show statistical significance. Hybrid technique had a statistically significant higher chance of union when compared to locking (p=0.02). All proximal locking screw constructs were 2.9 times more likely to lead to nonunion.ConclusionsPlating constructs with all locking screws used in the diaphysis when bridge-plating distal femur locking plates were 2.9 times more likely to incur a nonunion. However, other factors associated with more flexible fixation constructs such as increased working length, decreased proximal screw number, and decreased proximal screw density were not significantly associated with union in this study.



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Development of fracture liaison services: What have we learned?

Publication date: Available online 1 September 2017
Source:Injury
Author(s): K.E. Shipman, A. Doyle, H. Arden, T. Jones, N.J. Gittoes
Due to dramatic improvements in life expectancy we are seeing a rapidly growing population of older people. Increasing frailty and susceptibility to fragility fractures are becoming pressing issues for both the individuals that suffer them as well as society, through pressures on health and social care budgets. The success of fracture liaison services, co-ordinated programmes enhancing the management of the fracture, osteoporosis, frailty and falls risk, is undisputed. To achieve optimal outcomes, however, it is important to have a standardisation of design, scope and structure of the service. Experience has taught us that by delegating responsibility for the holistic care of the patient to a trained and adequately resourced professional/team (fracture prevention practitioner) with clear standards against which benchmarking occurs, is the optimal model of delivery. Future challenges include how best to measure the success of services in imparting a reduction in fractures at a local population level as well as how to detect those patients with unmet need who do not uniformly present to health care services, such as those with vertebral fractures. The implementation of fracture liaison services however, is a clear demonstration of how collaboration between health care, social care and charity organisations, among others, has materially improved the health and well-being of the population.



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Updating vital status by tracking in the community among patients with epidemic Kaposi sarcoma who are lost to follow-up in sub-Saharan Africa

Abstract

Background

Throughout most of sub-Saharan Africa (and, indeed, most resource-limited areas), lack of death registries prohibits linkage of cancer diagnoses and precludes the most expeditious approach to determining cancer survival. Instead, estimation of cancer survival often uses clinical records, which have some mortality data but are replete with patients who are lost to follow-up (LTFU), some of which may be caused by undocumented death. The end result is that accurate estimation of cancer survival is rarely performed. A prominent example of a common cancer in Africa for which survival data are needed but for which frequent LTFU has precluded accurate estimation is Kaposi sarcoma (KS).

Methods

Using electronic records, we identified all newly diagnosed KS among HIV-infected adults at 33 primary care clinics in Kenya, Uganda, Nigeria, and Malawi from 2009 to 2012. We determined those patients who were apparently LTFU, defined as absent from clinic for ≥90 days at database closure and unknown to be dead or transferred. Using standardized protocols which included manual chart review, telephone calls, and physical tracking in the community, we attempted to update vital status amongst patients who were LTFU.

Results

We identified 1222 patients with KS, of whom 440 were LTFU according to electronic records. Manual chart review revealed that 18 (4.1%) were classified as LFTU due to clerical error, leaving 422 as truly LTFU. Of these 422, we updated vital status in 78%; manual chart review was responsible for updating in 5.7%, telephone calls in 26%, and physical tracking in 46%. Among 378 patients who consented at clinic enrollment to be tracked if they became LTFU and who had sufficient geographic contact/locator information, we updated vital status in 88%. Duration of LTFU was not associated with success of tracking, but tracking success was better in Kenya than the other sites.

Conclusion

It is feasible to update vital status in a large fraction of patients with HIV-associated KS in sub-Saharan Africa who have become LTFU from clinical care. This finding likely applies to other cancers as well. Updating vital status amongst lost patients paves the way towards accurate determination of cancer survival.

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Intervertebral Disc Degeneration in a Percutaneous Mouse Tail Injury Model.

Objectives: Intervertebral disc (IVD) degenerates progressively with age and after injuries. In this study, we aimed to characterize early molecular events underlying disc degeneration using a mouse tail IVD injury model. Design: We have established a transcutaneous minimally invasive approach to induce mouse tail IVD injury under fluoroscopic guidance. Morphological and molecular changes in the injured IVDs are compared with the baseline features of adjacent intact levels. Results: After needle puncture, tail IVDs exhibited time-dependent histological changes. The aggrecan neoepitope VDIPEN was evident from 2 days to 4 wks after injury. A disintegrin and metalloproteinase domain-containing protein 8 (adam8) is a surface protease known to cleave fibronectin in the IVD. Gene expression of adam8 was elevated at all time points after injury, whereas the increase of C-X-C motif chemokine ligand (cxcl)-1 gene expression was statistically significant at 2 days and 2 wks after injury. Type 1 collagen gene expression decreased initially at day 2 but increased at 2 wks after injury, whereas no significant change in type 2 collagen gene expression was observed. The extracellular matrix gene expression pattern is consistent with fibrocartilage formation after injury. Conclusions: Mouse tail IVDs degenerate after needle puncture, as demonstrated by histological changes and aggrecan degradation. The minimally invasive tail IVD injury model should prove useful to investigators studying mechanisms of IVD degeneration and repair. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Validating the Physiologic Model HumMod as a Substitute for Clinical Trials Involving Acute Normovolemic Hemodilution.

BACKGROUND: Blood conservation strategies and transfusion guidelines remain a heavily debated clinical topic. Previous investigational trials have shown that acute isovolemic hemodilution does not limit adequate oxygen delivery; however, a true critical hemoglobin level has never been investigated or defined due to safety concerns for human volunteers. Validated physiologic modeling may be useful to investigate hemodilution at critical hemoglobin levels without the ethical or safety hazards of clinical trials. Our hypothesis is that HumMod, an integrative physiological model, can replicate the cardiovascular and metabolic findings of previous clinical studies of acute isovolemic hemodilution and use coronary blood flow and coronary oxygen delivery in extreme hemodilution to predict a safety threshold. METHODS: By varying cardiovascular and sizing parameters, unique individuals were generated to simulate a population using HumMod, an integrative mathematical model of human physiology. Hemodilution was performed by simultaneously hemorrhaging 500 mL aliquots of blood while infusing equal volumes of hetastarch, 5% albumin balanced salt solution, or triple volumes of lactated Ringer's solution over 10 minutes. Five hemodilution protocols reported over 3 studies were directly replicated with HumMod to compare and validate essential cardiovascular and metabolic responses to hemodilution in moderately healthy, awake adults. Cardiovascular parameters, mental status, arterial and mixed venous oxygen content, and oxyhemoglobin saturation were recorded after the removal of each aliquot. The outputs of this simulation were considered independent variables and were stratified by hemoglobin concentration at the time of measurement to assess hemoglobin as an independent predictor of hemodynamic and metabolic behavior. RESULTS: The published reports exhibited discrepancies: Weiskopf saw increased heart rate and cardiac index, while Jones and Ickx saw no change in these variables. In HumMod, arterial pressure was maintained during moderate hemodilution due to decreases in peripheral resistance opposing increases in cardiac index. HumMod showed preserved ventilation through moderate hemodilution, compensated for by an increased oxygen extraction similar to the studies of Jones and Ickx. The simulation results qualitatively followed the clinical studies, but there were statistical differences. In more extreme hemodilution, HumMod had a lesser increase in cardiac index, which led to deficiencies in oxygen delivery and low venous saturation. In the simulations, coronary blood flow and oxygen delivery increase up to a critical hemoglobin threshold of 55-75 g/L in HumMod. In this range, coronary blood flow and oxygen delivery fell, leading to cardiac injury. The allowable amount of hemodilution before reaching the critical point is most closely correlated with nonmuscle mass (r = 0.69) and resting cardiac output (r = 0.67). CONCLUSIONS: There were significant statistical differences in the model population and the clinical populations, but overall, the model responses lay within the clinical findings. This suggests our model is an effective replication of hemodilution in conscious, healthy adults. A critical hemoglobin range of 5.5-7.5 g/L was predicted and found to be highly correlated with nonmuscle mass and resting cardiac output. (C) 2017 International Anesthesia Research Society

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The Effect of Head Position on the Cross-sectional Area of the Subclavian Vein.

In 41 healthy volunteers, we investigated the cross-sectional area (CSA) of the subclavian vein (SCV) in the following head positions: neutral and 30[degrees] head rotation toward the contralateral or ipsilateral sides. Significant differences were observed in the CSA of the SCV at 3 different head positions: contralateral 30[degrees] versus neutral, -0.05 cm2 (95% confidence interval, -0.08 to -0.03); contralateral 30[degrees] versus ipsilateral 30[degrees], -0.15 cm2 (-0.19 to -0.12); neutral versus ipsilateral 30[degrees], -0.10 cm2 (-0.13 to -0.07); all Pcorrected

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Transesohageal Echocardiographic-Guided Transapical Neochord Implantation.

No abstract available

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Evaluation of the Augmented Infant Resuscitator: A Monitoring Device for Neonatal Bag-Valve-Mask Resuscitation.

BACKGROUND: Annually, 6 million newborns require bag-valve-mask resuscitation, and providing live feedback has the potential to improve the quality of resuscitation. The Augmented Infant Resuscitator (AIR), a real-time feedback device, has been designed to identify leaks, obstructions, and inappropriate breath rates during bag-valve-mask resuscitation. However, its function has not been evaluated. METHODS: The resistance of the AIR was measured by attaching it between a ventilator and a ventilator tester. To test the device's reliability in training and clinical-use settings, it was placed in-line between a ventilation bag or ventilator and a neonatal manikin and a clinical lung model simulator. The lung model simulator simulated neonates of 3 sizes (2, 4, and 6 kg). Leaks, obstructions, and respiratory rate alterations were introduced. RESULTS: At a flow of 5 L/min, the pressure drop across the AIR was only 0.38 cm H2O, and the device had almost no effect on ventilator breath parameters. During the manikin trials, it was able to detect all leaks and obstructions, correctly displaying an alarm 100% of the time. During the simulated clinical trials, the AIR performed best on the 6-kg neonatal model, followed by the 4-kg model, and finally the 2-kg model. Over all 3 clinical models, the prototype displayed the correct indicator 73.5% of the time, and when doing so, took 1.6 +/- 0.9 seconds. CONCLUSIONS: The AIR is a promising innovation that has the potential to improve neonatal resuscitation. It introduces only marginal resistance and performs well on neonatal manikins, but its firmware should be improved before clinical use. (C) 2017 International Anesthesia Research Society

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