Citations

AbstractBackgroundTo date, genetic‐association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune‐related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk.MethodsWe conducted two independent case–control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta‐analysis which included 12 additional, earlier studies. The meta‐analysis comprised a total of 2894 patients (839 IBS‐C, 1073 IBS‐D, 502 IBS‐M), and 3138 healthy volunteers with self‐reported Caucasian ancestry.Key ResultsThe association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta‐analysis: IBS (OR 1.19, 95% CI 1.08–1.31), and IBS‐C (OR 1.24, 95% CI 1.08–1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes.Conclusions & InferencesOur meta‐analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS‐C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.

The discrete two‐dimensional (2D) S‐transform (ST‐2D) is a space‐frequency representation that provides the local spectrum at each pixel in an image. The inherent localisation properties of the ST‐2D make it a preferred candidate for space‐frequency analysis. However, the ST‐2D is sensitive to the image rotation. This limits its use in many image processing applications such as texture analysis. This study describes the rotational sensitivity of the ST‐2D, and explains how this limits its application. To overcome these problems, a novel rotationally invariant S‐transform (RIST) is formulated, and its rotational invariance is investigated. The RIST can provide approximate rotational invariance for magnitudes and complex values over a wide range of rotation angles, but with a trade‐off of higher computation time. The RIST may be useful for many medical, scientific and industrial applications.

This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans.

Abstract Purpose: Oncolytic herpes simplex viruses (oHSV) represent a promising therapy for glioblastoma (GBM), but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GBM. Experimental Design: Quantitative flow cytometry of mice with intracranial gliomas (±oHSV) was used to examine macrophage/microglia infiltration and activation. In vitro coculture assays of infected glioma cells with microglia/macrophages were used to test their impact on oHSV replication. Macrophages from TNFα-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNFα on virus replication. TNFα blocking antibodies were used to evaluate the impact of TNFα on oHSV therapy in vivo. Results: Flow-cytometry analysis revealed a 7.9-fold increase in macrophage infiltration after virus treatment. Tumor-infiltrating macrophages/microglia were polarized toward a M1, proinflammatory phenotype, and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNFα in response to infected glioma cells in vitro and in vivo. Using TNFα-blocking antibodies and macrophages derived from TNFα-knockout mice, we discovered TNFα-induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFα from the tumor microenvironment with TNFα-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors. Conclusions: The results of these studies suggest that FDA approved TNFα inhibitors may significantly improve the efficacy of oncolytic virus therapy. Clin Cancer Res; 21(14); 3274–85. ©2015 AACR.

OBJECT The transoral approach is the gold standard for ventral decompression of the brainstem caused by craniovertebral junction (CVJ) pathology. This approach is often associated with significant morbidity, related to swallowing and respiratory complications. The endoscopic endonasal approach was introduced to reduce the rate of these complications. However, the exact role of this approach in the treatment of CVJ pathology is not well defined. METHODS A comprehensive literature search was performed to identify series of patients with pathology of the CVJ treated via the endoscopie endonasal approach. Data on patient characteristics, indications for treatment, complications, and outcome were obtained and analyzed. RESULTS Twelve studies involving 72 patients were included. The most common indications for treatment were rheumatoid pannus (38.9%) and basilar invagination (29.2%). Cerebrospinal fluid leak was found in 18% of cases intraoperatively and 4.2% of cases postoperatively. One case of meningitis complicated by sepsis and death represents the procedure-related mortality of 1.4%. Of the patients without preoperative swallowing impairment, 95% returned to oral feeding on the 3rd postoperative day. Ninety-three percent of patients experienced improvement in neurological symptoms after the procedure. CONCLUSIONS The endonasal endoscopie approach is effective for the treatment of neural compression caused by CVJ pathology. It offers advantages such as lower rates of postoperative dysphagia and respiratory complications when compared with the more traditional transoral approach. However, these 2 approaches should be seen as complementary rather than alternatives. Patient-related factors as well as the surgeon’s expertise must be considered when making treatment decisions.

NISHIMURA, R.A. et al.: Hemodynamic and symptomatic consequences of ventricular pacing. After implantation of a ventricular demand pacemaker (VVI), occasional patients continue to have dizziness, syncope, or near syncope (“pacemaker syndrome”). To identify patients in whom VVI pacing may have deleterious effects, we compared cuff blood pressure responses to VVI pacing with blood pressure responses to atrioventricsler sequential pacing (DVI) or sinus rhythm in 50 consecutive patients. Patients with intact ventriculoatrial conduction had a much greater decrease in systolic blood pressure with VVI pacing (24 ± 11 mm Hg) than those with ventriculoatrial dissociation (−4 ± 15 mm Hg) (P<0.005). Patients who were in heart failure had a lesser decrease in blood pressure with VVI pacing than did those without failure (P<0.05); 13 of the 14 heart failure patients lacked ventriculoatrial conduction. Ten patients had symptomatic dizziness after VVI pacing; the incidence of symptoms was higher in patients with ventriculoatrial conduction (9 of 23) than in those without ventriculoatrial conduction (1 of 27) (P<0.003). We conclude that the presence of intact ventriculoatrial conduction appears to be a crucial determinent of the hemodynamic response to VVI pacing, and its presence may identify patients who are at risk for “pacemaker syndrome.”

Hidradenocarcinoma is a rare malignancy of the sweat glands with only a few cases reported in literature. The management of these tumors is based on the extent of disease with local disease managed with surgical resection. These can tumors carry a high potential of lymphatic and vascular spread and local and distant metastases are not uncommon. Given the rarity of the tumor and lack of genetic and clinical data about these tumors, there is no consensus on the proper management of metastatic disease. Here in we report the first case of metastatic hidradenocarcinoma with detailed molecular profiling including whole exome sequencing. We identified mutations in multiple genes including two that are potentially targetable: PTCH1 and TCF7L1. Further work is necessary to not only confirm the presence of these mutations but also to confirm the clinical significance.