Chronic curcumin treatment improves spatial working memory but not recognition memory in middle-aged rhesus monkeys

Abstract

Studies of both humans and non-human primates have demonstrated that aging is typically characterized by a decline in cognition that can occur as early as the fifth decade of life. Age-related changes in working memory are particularly evident and mediated, in part, by the prefrontal cortex, an area known to evidence age-related changes in myelin that is attributed to inflammation. In recent years, several nutraceuticals, including curcumin, by virtue of their anti-inflammatory and antioxidant effects, have received considerable attention as potential treatments for age-related cognitive decline and inflammation. Accordingly, we assessed for the first time in a non-human primate model of normal aging the efficacy of dietary intervention using the natural phenol curcumin to ameliorate the effects of aging on spatial working and recognition memory. Results revealed that monkeys receiving daily administration of curcumin over 14–18 months demonstrated a greater improvement in performance on repeated administration of a task of spatial working memory compared to monkeys that received a control substance.

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Ral signaling pathway in health and cancer

Abstract

The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

Ral signaling pathway as an important effector pathway downstream of Ras plays an important role in health and diseases.

http://ift.tt/2yzfio1

A comprehensive genome-wide analysis of long noncoding RNA expression profile in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in East Asia and China. Long noncoding RNAs (lncRNAs) are emerging as critical regulators that may be involved in the development and progression of cancers in humans. However, the contributions of lncRNAs to HCC development, metastasis, and recurrence remain largely unknown. In this study, we comprehensively investigated lncRNA expression profile in HCC and normal tissues using TCGA RNA sequencing data, one RNA sequencing dataset, and two microarray datasets from GEO. By analyzing these four datasets, we identified hundreds of expression-dysregulated lncRNAs in HCC tissues compared with normal tissues. Genomic copy number variation analysis showed that many of those lncRNAs disorder are related to the copy number amplification or deletion. Moreover, several lncRNAs expression levels are associated with HCC patients' overall and recurrence-free survival, such as RP1-228H13.5, TMCC1-AS1, LINC00205, and RP11-307C12.11. Furthermore, we identified two lncRNAs termed PVT1 and SNHG7 that may be involved in HCC cells metastasis by comparing lncRNAs expression profiles between early recurrence HCC tissues with metastasis and late recurrence HCC tissues without metastasis. Finally, loss-of-function assays confirmed that knockdown of SNHG7 and PVT1 impaired HCC cells invasion. Taken together, these findings may provide a valuable resource for further identification of novel biomarkers and therapeutic targets for HCC patients.

lncRNAs are emerging as critical regulators that are involved in the development and progression of cancers in humans. We comprehensively investigated lncRNA expression profiling in HCC and normal tissues; these findings may provide a valuable resource to further identify novel biomarkers and therapeutic targets of HCC.

http://ift.tt/2xPtMfK

Birds of a Feather Flock Together: The Interpersonal Process of Objectification within Intimate Heterosexual Relationships

Abstract

On the basis that objectification is a self-perpetuating phenomenon, we tested two new hypotheses about the role of objectification within ongoing, intimate heterosexual relationships. First, individuals who self-objectify and objectify others tend to have partners who also self-objectify and objectify others. Second, objectification within relationships is associated with reduced relationship quality. Furthermore, rather than relying on the perspective of only one dyad member, we applied the Actor-Partner Interdependence Model (APIM: Kenny et al. 2006) as a framework for hypothesis testing. That is, we collected data from both partners within the relationship on the same variables (n = 59 heterosexual couples). We found support for both hypotheses, but negligible evidence of gender differences in relations between self-objectification, objectification, and relationship quality. Finally, we applied the APIM to replicate previous research on relations among self-objectification, objectification of partner, and body- and self-esteem. Self-objectification and objectification of partner was unrelated to body esteem for both men and women. Self-objectification was associated with reduced self-esteem, irrespective of gender, but objectification of partner was not associated with partner's self-esteem.

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Epilepsy and Psychiatric Comorbidities: Drug Selection

Abstract

Purpose of review The pharmacological treatment of patients with epilepsy and psychiatric comorbidities may sometimes represent a therapeutic challenge. This review is focused on the pharmacological management of patients with epilepsy and psychiatric problems in terms of rationalization of the antiepileptic drug (AED) treatment and the pharmacological management of the most clinically relevant psychiatric comorbidities, namely mood and anxiety disorders, psychoses, and attention deficit hyperactivity disorder (ADHD).

Recent findings Up to 8% of patients with drug-resistant epilepsy develop treatment-emergent psychiatric adverse events of AED regardless of the mechanism of action of the drug and this is usually related to an underlying predisposition given by the previous psychiatric history and the involvement of mesolimbic structures. Careful history taking, periodic screening for mood and anxiety disorders, low starting doses, and slow titration schedules can reduce the possibility of AED-related problems. A pragmatic checklist for the pharmacological management of patients with epilepsy and psychiatric disorders is presented.

Summary patients should be informed of potential behavioral effects of AEDs but no drugs should be excluded a priori. Any psychiatric comorbidity should be addressed in the appropriate setting and full remission and recovery should always represent the first goal of any therapeutic intervention. Neurologists should be aware of the side effects of major psychotropic drug classes in order to fully counsel their patients and other health professionals involved.

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Gastric cancer: immunohistochemical classification of molecular subtypes and their association with clinicopathological characteristics

Abstract

Gastric cancer is traditionally divided into intestinal and diffuse histological subtypes, but recent molecular analyses have led to novel classification proposals based on genomic alterations. While the intestinal- and diffuse-type tumours are distinguishable from each other at the molecular level, intestinal-type tumours have more diverse molecular profile. The technology required for comprehensive molecular analysis is expensive and not applicable for routine clinical diagnostics. In this study, we have used immunohistochemistry and in situ hybridisation in molecular classification of gastric adenocarcinomas with an emphasis on the intestinal subtype. A tissue microarray consisting of 244 gastric adenocarcinomas was constructed, and the tumours were divided into four subgroups based on the presence of Epstein-Barr virus, TP53 aberrations and microsatellite instability. The intestinal- and diffuse-type tumours were separately examined. The distribution of EGFR and HER2 gene amplifications was studied in the intestinal-type tumours. Epstein-Barr virus positive intestinal-type tumours were more common in male patients (p = 0.035) and most often found in the gastric corpus (p = 0.011). The majority of the intestinal-type tumours with TP53 aberrations were proximally located (p = 0.010). All tumours with microsatellite instability showed intestinal-type histology (p = 0.017) and were associated with increased overall survival both in the univariate (p = 0.040) and multivariate analysis (p = 0.015). In conclusion, this study shows that gastric adenocarcinomas can be classified into biologically and clinically different subgroups by using a simple method also applicable for clinical diagnostics.

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Caenorhabditis elegans BUB-3 and SAN-1/MAD3 Spindle Assembly Checkpoint Components Are Required for Genome Stability in Response to Treatment with Ionizing Radiation

Relatively little is known about the crosstalk between the spindle assembly checkpoint and the DNA damage response, especially in multicellular organisms. We performed a Caenorhabditis elegans forward genetic screen to uncover new genes involved in the repair of DNA damage induced by ionizing radiation. We isolated a mutation, gt2000 which confers hypersensitivity to ionizing radiation and showed that gt2000 introduces a premature stop in bub-3. BUB-3 is a key component of the spindle assembly checkpoint. We provide evidence that BUB-3 acts during development and in the germline; irradiated bub-3(gt2000) larvae are developmentally retarded and form abnormal vulvae. Moreover, bub-3(gt2000) embryos sired from irradiated worms show increased levels of lethality. Both bub-3 and san-1 (the Caenorhabditis elegans homologue of MAD3) deletion alleles confer hypersensitivity to ionizing radiation, consistent with the notion that the spindle assembly checkpoint pathway is required for DNA damage response. bub-3(gt2000) is moderately sensitive to the crosslinking drug cisplatin but not to UV light or methyl methanesulfonate. This is consistent with role in dealing with DNA double-strand breaks and not with base damage. Double mutant analysis revealed that bub-3 does not act within any of the three major pathways involved in the repair of double-strand breaks. Finally, the cdc-20 gain-of-function mutant cdc-20/fzy-1(av15), which is refractory to the cell cycle delay conferred by the spindle checkpoint showed phenotypes similar to bub-3 and san-1 mutants. We speculate that BUB-3 is involved in DNA damage response through regulation of cell cycle timing.

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Modulation of Global Transcriptional Regulatory Networks as a Strategy for Increasing Kanamycin Resistance of the Translational Elongation Factor-G Mutants in Escherichia coli

Evolve and resequence experiments have provided us a tool to understand bacterial adaptation to antibiotics. In our previous work, we had used short term evolution to isolate mutants resistant to the ribosome targeting antibiotic kanamycin, and reported that Escherichia coli develops low cost resistance to kanamycin via  different point mutations in the translation Elongation Factor-G (EF-G). Furthermore, we had shown that the resistance of EF-G mutants could be increased by second site mutations in the genes rpoD / cpxA / topA / cyaA. Mutations in three of these genes had been discovered in earlier screens for aminoglycoside resistance. In this work we expand our understanding of these second site mutations, the goal being to understand how these mutations affect the activities of the mutated gene products to confer resistance.  We show that the mutation in cpxA most likely results in an active Cpx stress response. Further evolution of an EF-G mutant in a higher concentration of kanamycin than what was used in our previous experiments identified the cpxA locus as a primary target for a significant increase in resistance. The mutation in cyaA results in a loss of catalytic activity and probably results in resistance via altered CRP function. Despite a reduction in cAMP levels, the CyaA^N600Y mutant has a transcriptome indicative of increased CRP activity, pointing to an unknown non-catalytic role for CyaA in gene expression. From the transcriptomes of double and single mutants we describe the epistasis between the mutation in EF-G and these second site mutations. We show that the large scale transcriptomic changes in the topoisomerase I (FusA^A608E-TopA^S180L) mutant likely result from increased negative supercoiling in the cell. Finally, genes with known roles in aminoglycoside resistance were present among the mis-regulated genes in the mutants.

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Cathepsin B is dispensable for cellular processing of cathepsin B-cleavable antibody-drug conjugates

Antibody-drug conjugates (ADCs) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline (VC(S)) linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload. Mass spectrometry studies of payload release suggested that other cysteine cathepsins can cleave the VC(S) linker. Also, ADCs with a non-protease-cleavable enantiomer, the VC(R) isomer, mediated effective cell killing with a cysteine-VC(R)-MMAE catabolite generated by lysosomal catabolism. Based on these observations, we altered the payload to a pyrrolo[2,1-c][1,4]benzodiazepine dimer (PBD) conjugate that requires linker cleavage in order to bind its DNA target. Unlike the VC-MMAE ADCs, the VC(S)-PBD ADC is at least 20-fold more cytotoxic than the VC(R)-PBD ADC. Our findings reveal that the VC(S) linker has multiple paths to produce active catabolites, and that antibody and intracellular targets are more critical to ADC efficacy. These results suggest that protease-cleavable linkers are unlikely to increase the therapeutic index of ADCs and that resistance based on linker processing is improbable.

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PP2A inactivation mediated by PPP2R4 haploinsufficiency promotes cancer development

Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of PPP2R4, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in PPP2R4. Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles. In Ppp2r4 gene-trapped (gt) mice showing residual PTPA expression, total PP2A activity and methylation were reduced, selectively affecting specific PP2A holoenzymes. Both PTPAgt/gt and PTPA+/gt mice showed higher rates of spontaneous tumors, mainly hematologic malignancies and hepatocellular adenomas and carcinomas. These tumors exhibited increased c-Myc phosphorylation and increased Wnt or Hedgehog signaling. We observed a significant reduction in lifespan in PTPA+/gt mice compared to wildtype mice. Additionally, chemical induced skin carcinogenesis was accelerated in PTPA+/gt compared to wildtype mice. Our results provide evidence for PPP2R4 as a haploinsufficient tumor suppressor gene, defining a high-penetrance genetic mechanism for PP2A inhibition in human cancer.

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Evidence for the presence in rainbow trout brain of amino acid sensing systems involved in the control of food intake

To assess the existence of central amino acid sensing systems in fish we carried out two experiments in rainbow trout. In the first one, we injected ICV two different branched-chain amino acids (BCAA), leucine and valine, and assessed food intake up to 48 h later. Leucine decreased and valine increased food intake. In a second experiment, 6h after similar ICV treatment we determined changes in parameters related to putative amino acid sensing systems. Amino acid sensing systems respond to leucine in hypothalamus and telencephalon, and to valine in telencephalon. The decreased food intake observed in fish treated ICV with leucine could relate to changes in mRNA abundance of hypothalamic neuropeptides (POMC, CART, NPY and AgRP). These in turn could relate to amino acid sensing systems present in the same area, related to BCAA and glutamine metabolism, as well as mechanistic target of rapamycin (mTOR), taste receptors and general control non-derepressible 2 (GCN2) kinase signalling. The treatment with valine did not affect amino acid sensing parameters in hypothalamus. These responses are comparable to those characterized in mammals. However, clear differences arise when comparing rainbow trout and mammals, in particular with respect to the clear orexigenic effect of valine, which could relate to the finding that valine partially stimulated two amino acid sensing systems in telencephalon. Another novel result is the clear effect of leucine on telencephalon, in which amino acid sensing systems, but not neuropeptides, were activated as in hypothalamus

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Vasoactivity of nitrite in the iliac artery of the toad, Rhinella marina

Nitrite (NO₂^-) causes vasodilation in mammals due to the formation of (nitric oxide) NO by endogenous NO₂^- reduction in the vascular wall. In this study, we determined if a similar mechanism operates in amphibians. Dual-wire myography of the iliac artery from Rhinella marina showed that applied NO₂^- caused a concentration-dependent vasodilation in normoxia (21% O₂; EC₅₀ 438 µM). Hypoxia (0.63% O₂) significantly increased the maximal dilation to NO₂^- by 5 % (P = 0.0398). The addition of oxyhemoglobin significantly increased the EC₅₀ (P = 0.0144; EC₅₀ 2236 µM), but did not affect the maximal vasodilation. In contrast, partially deoxygenated hemoglobin (90% desaturation) did not affect the EC₅₀ (P = 0.1189) but significantly (P = 0.0012) increased the maximal dilation to NO₂^- by 11%. The soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) completely abolished the response to NO₂- (P < 0.0001), and of the nitric oxide synthase inhibitors, only vinyl-L-NIO (P = 0.0028) significantly reduced the NO₂^- vasodilation. The xanthine oxidoreductase inhibitor, allopurinol (P = 0.927), the NO-scavenger C-PTIO (P = 0.478), and disruption of the endothelium (P = 0.094) did not affect the NO₂^- vasodilation. Incubation of iliac arteries with 1 mM NO₂^- did not a cause a change in cGMP concentration (P = 0.407). Plasma NO₂^- was found to be 0.86 ± 0.20 µmol.L^-1, while nitrate (NO₃^-) was 19.55 ± 2.55 µmol.L^-1. Both cygb and ngb mRNAs were expressed in the iliac artery and it is possible that these globins facilitate NO₂^- reduction in hypoxia. In addition, NO₂^- intracellular disproportionation processes could be important in the generation of NO from NO₂^-.

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Sex Differences in Maternal Gestational Hypertension-Induced Sensitization of Angiotensin II Hypertension in Rat Offspring: the Protective Effect of Estrogen

Recent studies demonstrate that maternal hypertension during pregnancy sensitizes an angiotensin (ANG) II-induced increase in blood pressure (BP) in adult male offspring that was associated with upregulation of mRNA expression of several renin-angiotensin-aldosterone system (RAAS) components and NADPH oxidase in the lamina terminalis (LT) and paraventricular nucleus (PVN). The purpose of the present study was to test whether there are sex differences in the maternal hypertension-induced sensitization of ANG II hypertension, and whether sex hormones are involved in the sensitization process. Male offspring of hypertensive dams showed an enhanced hypertensive response to systemic ANG II when compared to male offspring of normotensive dams and to female offspring of either normotensive or hypertensive dams. Castration did not alter the hypertensive response to ANG II in male offspring. Intact female offspring had no upregulation of RAAS components and NADPH oxidase in the LT and PVN. Whereas, ovariectomy (OVX) upregulated mRNA expression of several RAAS components and NADPH oxidase in these nuclei and induced a greater increase in the pressor response to ANG II in female offspring of hypertensive dams compared to female offspring of normotensive dams. This enhanced increase in BP was partially attenuated by E2 replacement in the OVX offspring of hypertensive dams. The results suggest that maternal hypertension induces a sex-specific sensitization of ANG II-induced hypertension and mRNA expression of brain RAAS and NADPH oxidase in offspring. Female offspring are protected from maternal hypertension-induced sensitization of ANG II hypertension and female sex hormones are partially responsible for this protective effect.

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Central serotonin and the control of arterial blood pressure and heart rate in infant rats: influence of sleep state and sex

Sudden Infant Death Syndrome (SIDS) is associated with serotonin (5-HT) neuron abnormalities. There is evidence of autonomic dysfunction during sleep in infants eventually succumbing to SIDS, as well as cardiovascular collapse prior to death. Neonatal rodents deficient in central 5-HT display hypotension and bradycardia. We hypothesized that central 5-HT reduces cardiac vagal tone and increases sympathetic vascular tone and, given the firing pattern of 5-HT neurons, that these effects are greater in quiet sleep (QS) than in active sleep (AS). We tested these hypotheses using two week-old, male and female rat pups lacking tryptophan hydroxylase 2 (TPH2-/-) and wildtype littermates (WT). Arterial blood pressure (ABP) and HR were measured over 3 hr, during periods of QS and AS. We also gave atropine or atenolol (each 1 mg/kg i.v.), or phentolamine (5, 50 and 500 ug/kg, i.v.) to separate groups to assess the effects 5-HT deficiency on autonomic tone to the heart or sympathetic vascular tone, respectively. Compared to WT, male and female TPH2-/- pups had reduced ABP in QS, but not in AS. Atropine induced a greater HR increase in female TPH2-/- compared to female WT pups, an effect absent in male TPH2-/- pups. Both genotypes experienced the same atenolol-induced drop in HR. In males only, phentolamine induced a smaller decrease in the ABP of TPH2-/- pups compared to WT. These data suggest that central 5-HT maintains ABP in QS, and HR in both states. In males, central 5-HT facilitates sympathetic vascular tone and in females, reduces cardiac vagal drive.

http://ift.tt/2zk3uTW

Dicarbonyl Stress and Glyoxalase Enzymatic System Regulation in Human Skeletal Muscle

Skeletal muscle insulin resistance is a hallmark of Type II Diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yrs; BMI: 32 ± 2 kg/m²) compared to lean healthy control subjects (LHC; age: 27 ± 1 yrs; BMI: 22 ± 1 kg/m²). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU/m²/min) -euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (-78.8%, p<0.05), which inversely correlated with BMI, percent body fat and HOMA-IR while positively correlating with clamp derived glucose disposal rates. T2DM also had lower NRF2 protein expression (-31.6%, p<0.05), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%, p<0.05). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1 and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.

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Activity of Muscle Sympathetic Neurons during Normotensive Pregnancy

In pathological populations, elevated sympathetic activity is associated with increased activity of individual sympathetic neurons. We used custom action potential detection software to analyze multi-unit sympathetic activity in 18 normotensive pregnant women (third trimester; 33 ± 5 weeks) and 19 non-pregnant women at rest and a subset (10 and 13 respectively) during a cold pressor challenge. Although the number of action potentials per burst, and number of active amplitude based "clusters" were not different between groups the total number of sympathetic action potentials per minute was higher in pregnant women at rest. Individual clusters were active predominately once per burst suggesting they represent single neurons. Action potentials occurred in closer succession in normotensive pregnant (inter-spike interval 36 ± 10 ms) versus non-pregnant women (50 ± 27 ms; P<0.001) at rest. Pregnant women had a lower total peripheral resistance (11.7 ± 3.0 mmHg/L/min) than non-pregnant women (15.1 ± 2.7 mmHg/L/min; P<0.001) indicating a blunted neurovascular transduction. The cold pressor reduced the number of action potentials per burst in both groups due to shortening of the R-R interval in conjunction with increased burst frequency, total neural firing per minute was unchanged. Thus, elevated sympathetic activity during normotensive pregnancy is specific to increased incidence of multi-unit bursts. This is likely due to decreased central gating of burst output as opposed to generalized increases in central drive. These data also reinforce the concept that pregnancy appears to be the only healthy state of chronic sympathetic hyperactivity that we are aware of.

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Relaxin mediated renal vasodilation in the rat is associated with falls in glomerular blood pressure

Relaxin (RLX) is a pleiotropic peptide hormone with marked renal vasodilatory actions which are physiologically important during pregnancy. RLX also has potent antifibrotic actions and is being tested therapeutically in various fibrotic diseases including chronic kidney disease (CKD). Since renal vasodilation may expose the glomerulus to increased blood pressure (P_GC), which exacerbates progression of CKD, we assessed the glomerular hemodynamic actions of RLX when administered acutely (75 min; 0.89 µg/100g body weight/hr, iv) and chronically (1.5µg/100g body weight/hr, sc). Both acute and chronic RLX produced marked renal vasodilation and increased renal plasma flow (RPF) in euvolemic, anesthetized male rats. GFR also increased with RLX but the magnitude of the rise was much less than the increase in RPF, due to concomitant falls in filtration fraction (FF). The fall in FF was the result of significant falls in glomerular blood pressure (P_GC) which occurred despite a slight rise in mean arterial blood pressure (MAP) with acute RLX, and no net change in MAP with chronic RLX. This fall in P_GC occurred because of the "in-series" arrangement of the afferent and efferent arteriolar resistance vessels (RA and RE) which can regulate P_GC independently of MAP. With both acute and chronic RLX RE relaxed to a greater extent than RA, thus producing falls in P_GC. Based on this finding, RLX has a beneficial hemodynamic impact on the kidney, which together with the antifibrotic actions suggest a strong therapeutic potential for use in CKD.

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Respiratory dysfunction following neonatal sustained hypoxia exposure during a critical window of brainstem extracellular matrix formation

The extracellular matrix (ECM) modulates brain maturation and plays a major role in regulating neuronal plasticity during critical periods of development. We examined: 1) whether there is a critical postnatal period of ECM expression in brainstem cardio-respiratory control regions; and 2) if the attenuated hypoxic ventilatory response (HVR) following neonatal sustained (5 days) hypoxia exposure (SH, 11% O₂, 24hrs/day) is associated with altered ECM formation. The nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV), the hypoglossal motor nucleus (XII), the cuneate nucleus (CN) and area postrema (AP) were immunofluorescently processed for aggrecan and Wisteria floribunda (WFA) agglutinin, a key proteoglycan of the ECM and the perineuronal net. From postnatal age 5 days (P5), aggrecan and WFA expression increased postnatally in all regions. Aggrecan expression in the nTS, a region that integrates and receives afferent inputs from the carotid body, increased abruptly between P10-15 followed by a distinct and transient plateau between P15-20. WFA expression in the nTS exhibited an analogous transient plateau, but it occurred earlier (plateauing between P10-P15). SH exposure between this period (P11-15) attenuated the HVR (assessed at P16) and increased aggrecan (but not WFA) expression in the nTS, DMNV and AP. An intracisternal micro-injection of chondroitinase ABC (ChABC), an enzyme that digests chondroitin sulfate proteoglycans, rescued the HVR and the increased aggrecan expression. These data indicate there are important stages of ECM formation that take place in key brainstem respiratory neural control regions that appear to be associated with a heightened vulnerability to hypoxia.

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Effect of Glycine, Pyruvate, and Resveratrol on the Regeneration Process of Postischemic Intestinal Mucosa

Background. Intestinal ischemia is often caused by a malperfusion of the upper mesenteric artery. Since the intestinal mucosa is one of the most rapidly proliferating organs in human body, this tissue can partly regenerate itself after the onset of ischemia and reperfusion (I/R). Therefore, we investigated whether glycine, sodium pyruvate, and resveratrol can either support or potentially harm regeneration when applied therapeutically after reperfusion injury. Methods. I/R of the small intestine was initiated by occluding and reopening the upper mesenteric artery in rats. After 60 min of ischemia and 300 min of reperfusion, glycine, sodium pyruvate, or resveratrol was administered intravenously. Small intestine regeneration was analyzed regarding tissue damage, activity of saccharase, and Ki-67 positive cells. Additionally, systemic parameters and metabolic ones were obtained at selected periods. Results. Resveratrol failed in improving the outcome after I/R, while glycine showed a partial beneficial effect. Sodium pyruvate ameliorated metabolic acidosis, diminished histopathologic tissue injury, and increased cell proliferation in the small intestine. Conclusion. While glycine could improve in part regeneration but not proliferation, sodium pyruvate seems to be a possible therapeutic agent to facilitate proliferation and to support mucosal regeneration after I/R injury to the small intestine.

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Cryoablation of Primary Breast Cancer in Patients with Metastatic Disease: Considerations Arising from a Single-Centre Data Analysis

Background. Patients presenting with stage IV breast cancer might benefit by removal of the primary tumor. We report our experience with CT-guided cryoablation of the primary tumor, with the aim of evaluating its role in this subgroup of patients. Patients and Methods. Data of 35 patients with mean age of 58 years with breast cancer at stage IV submitted to CT-guided cryoablation of the primary tumor between 2010 and 2016 were prospectively evaluated. All patients, except three, were preoperatively and postoperatively evaluated with breast MRI to assess the extent of tumor necrosis. Retreatment was performed in case of incomplete ablation. Results. Mean tumor size was 3.02 ± 1.4 cm. Six patients had multicentric disease. Complete tumor necrosis was 85.7% and 100% at 2-month and 6-month follow-up, respectively, as 5 patients with tumors > 3 cm required a redo cryoablation. No patient developed major complications. Minor side effects occurred in 30 patients (82%). All patients were discharged the same day of the procedure. During a mean follow-up of 46 months (range 3–84), 7 patients (20%) experienced local recurrences that were treated with redo cryoablation, and 7 (20%) died for disease progression. Conclusions. Our results suggest that cryoablation of the primary tumor is safe and effective in the treatment of patients presenting with stage IV breast cancer.

http://ift.tt/2gmrWg4

Lessons from the Latest ACA Battle

At the end of the 2017 Obamacare repeal-and-replace legislative battle (and before the next one begins), it is worth taking stock of why — defying the odds — the Affordable Care Act (ACA) still stands. From my perspective as an Obama administration veteran of every near-death experience of the law…

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Strengthening the ACA for the Long Term

Most complaints about the Affordable Care Act (ACA) (e.g. high and rising insurance premiums, large deductibles, and insurer exits) relate to nongroup insurance markets. These markets, the ones that were the most dysfunctional before the ACA, provide coverage to just 7% of the nonelderly population…

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Using Medicare Prices — Toward Equity and Affordability in the ACA Marketplace

As the U.S. Congress debates the future of the Affordable Care Act (ACA), the public has increasingly called for bipartisan solutions on health care reform. An immediate challenge is stabilizing the ACA marketplace, where 10.3 million people enroll in coverage. Given that certain areas of the…

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Endoscopic anti-reflux devices (with videos)

The American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee provides reviews of existing, new, or emerging endoscopic technologies that have the potential to affect the practice of GI endoscopy. Evidence-based methodology is used, with a MEDLINE literature search to identify pertinent preclinical and clinical studies on the topic and a MAUDE (Food and Drug Administration Center for Devices and Radiological Health) database search to identify the reported adverse events of a given technology.

http://ift.tt/2xOMBzU

Effect of Direct-Acting Antivirals on future occurrence of hepatocellular carcinoma in compensated cirrhotic patients

The achievement of high rates of sustained virological response (SVR) with direct-acting antivirals (DAAs) in hepatitis C virus (HCV) infected patients will reduce decompensating terminal events.

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Post-polypectomy bleeding after colonoscopy on uninterrupted aspirin/non steroideal antiflammatory drugs: systematic review and meta-analysis

The aim of this systematic review and meta-analysis was to assess the risk of post-polypectomy bleeding (PPB) in patients that underwent colorectal polypectomy and exposed to ASA/NSAIDs.

http://ift.tt/2zkMtt3

Quadruple, sequential, and concomitant first-line therapies for H. pylori eradication: a prospective, randomized study.

Current Italian guidelines recommend 10-day bismuth-based or bismuth-free (sequential and concomitant) regimens for first-line H. pylori eradication. However, comparison among these regimens is lacking in our country.

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Puerto Rico Audiology Program Requests Help

In the aftermath of Hurricane Irma's destruction, the University of Puerto Rico Audiology Program would like to make a heartfelt request for the following items:

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Immobilization of Caenorhabditis elegans to Analyze Intracellular Transport in Neurons

Caenorhabditis elegans (C. elegans) is a good model to study axonal and intracellular transport. Here, I describe a protocol for in vivo recording and analysis of axonal and intraflagellar transport in C. elegans.

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The Nematode Caenorhabditis Elegans - A Versatile In Vivo Model to Study Host-microbe Interactions

Here, we present the nematode Caenorhabditis elegans as a versatile host model to study microbial interaction.

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FirstNet applications for EMS connectivity, situational awareness

FirstNet, the nationwide wireless broadband network dedicated to public safety, is ahead of schedule, under budget and poised to change the practice of EMS

http://ift.tt/2ywaXjE

Metabolic Support of Excised, Living Brain Tissues During Magnetic Resonance Microscopy Acquisition

The current protocol describes a method by which users can maintain viability of acute hippocampal and cortical slice preparations during the collection of magnetic resonance microscopy data.

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Conditional Deletion of the L-Type Calcium Channel Cav1.2 in NG2-Positive Cells Impairs Remyelination in Mice

Exploring the molecular mechanisms that drive the maturation of oligodendrocyte progenitor cells (OPCs) during the remyelination process is essential to developing new therapeutic tools to intervene in demyelinating diseases such as multiple sclerosis. To determine whether L-type voltage-gated calcium channels (L-VGCCs) are required for OPC development during remyelination, we generated an inducible conditional knock-out mouse in which the L-VGCC isoform Cav1.2 was deleted in NG2-positive OPCs (Cav1.2^KO). Using the cuprizone (CPZ) model of demyelination and mice of either sex, we establish that Cav1.2 deletion in OPCs leads to less efficient remyelination of the adult brain. Specifically, Cav1.2^KO OPCs mature slower and produce less myelin than control oligodendrocytes during the recovery period after CPZ intoxication. This reduced remyelination was accompanied by an important decline in the number of myelinating oligodendrocytes and in the rate of OPC proliferation. Furthermore, during the remyelination phase of the CPZ model, the corpus callosum of Cav1.2^KO animals presented a significant decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons compared with controls. In addition, in a mouse line in which the Cav1.2^KO OPCs were identified by a Cre reporter, we establish that Cav1.2^KO OPCs display a reduced maturational rate through the entire remyelination process. These results suggest that Ca²⁺ influx mediated by L-VGCCs in oligodendroglial cells is necessary for normal remyelination and is an essential Ca²⁺ channel for OPC maturation during the remyelination of the adult brain.

SIGNIFICANCE STATEMENT Ion channels implicated in oligodendrocyte differentiation and maturation may induce positive signals for myelin recovery. Voltage-gated Ca²⁺ channels (VGCCs) are important for normal myelination by acting at several critical steps during oligodendrocyte progenitor cell (OPC) development. To determine whether voltage Ca²⁺ entry is involved in oligodendrocyte differentiation and remyelination, we used a conditional knockout mouse for VGCCs in OPCs. Our results indicate that VGCCs can modulate oligodendrocyte maturation in the demyelinated brain and suggest that voltage-gated Ca²⁺ influx in OPCs is critical for remyelination. These findings could lead to novel approaches for obtaining a better understanding of the factors that control OPC maturation in order to stimulate this pool of progenitors to replace myelin in demyelinating diseases.

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Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway

Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e.g., several hundred milliseconds). Here, we use a combination of electrophysiological, optogenetic, pharmacological, transgenic, and chemogenetic approaches to elucidate cellular mechanisms underlying this phenomenon in male and female mice. We find that knocking out D2Rs eliminates the ADP in a cell-autonomous fashion, confirming that this ADP depends on D2Rs. Hyperpolarizing current injection, but not AMPA receptor blockade, prevents synaptic stimulation from facilitating D2R-induced ADPs, suggesting that this phenomenon depends on the recruitment of voltage-dependent currents (e.g., NMDAR-mediated Ca²⁺ influx) by synaptic input. Finally, the D2R-induced ADP is blocked by inhibitors of cAMP/PKA signaling, insensitive to pertussis toxin or β-arrestin knock-out, and mimicked by G_s-DREADD stimulation, suggesting that D2R activation elicits the ADP by stimulating cAMP/PKA signaling. These results show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability in a manner that depends on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with G_s, rather than the G_i/o-associated mechanisms that have classically been ascribed to D2Rs.

SIGNIFICANCE STATEMENT Dopamine D2 receptors (D2Rs) in the prefrontal cortex (PFC) are thought to play important roles in behaviors, including working memory and cognitive flexibility. Variation in D2Rs has also been implicated in schizophrenia, Tourette syndrome, and bipolar disorder. Recently, we described a new mechanism through which D2R activation can enhance the excitability of pyramidal neurons in the PFC. Here, we explore the underlying cellular mechanisms. Surprisingly, although D2Rs are classically assumed to signal through G_i/o-coupled G-proteins and/or scaffolding proteins, such as β-arrestin, we find that the effects of D2Rs on prefrontal pyramidal neurons are actually mediated by pathways associated with G_s-mediated signaling. Furthermore, we show how, via this D2R-dependent phenomenon, synaptic input can enhance the excitability of prefrontal neurons over timescales on the order of seconds. These results elucidate cellular mechanisms underlying a novel signaling pathway downstream of D2Rs that may contribute to prefrontal function under normal and pathological conditions.

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Visual Motion Discrimination by Propagating Patterns in Primate Cerebral Cortex

Visual stimuli can evoke waves of neural activity that propagate across the surface of visual cortical areas. The relevance of these waves for visual processing is unknown. Here, we measured the phase and amplitude of local field potentials (LFPs) in electrode array recordings from the motion-processing medial temporal (MT) area of anesthetized male marmosets. Animals viewed grating or dot-field stimuli drifting in different directions. We found that, on individual trials, the direction of LFP wave propagation is sensitive to the direction of stimulus motion. Propagating LFP patterns are also detectable in trial-averaged activity, but the trial-averaged patterns exhibit different dynamics and behaviors from those in single trials and are similar across motion directions. We show that this difference arises because stimulus-sensitive propagating patterns are present in the phase of single-trial oscillations, whereas the trial-averaged signal is dominated by additive amplitude effects. Our results demonstrate that propagating LFP patterns can represent sensory inputs at timescales relevant to visually guided behaviors and raise the possibility that propagating activity patterns serve neural information processing in area MT and other cortical areas.

SIGNIFICANCE STATEMENT Propagating wave patterns are widely observed in the cortex, but their functional relevance remains unknown. We show here that visual stimuli generate propagating wave patterns in local field potentials (LFPs) in a movement-sensitive area of the primate cortex and that the propagation direction of these patterns is sensitive to stimulus motion direction. We also show that averaging LFP signals across multiple stimulus presentations (trial averaging) yields propagating patterns that capture different dynamic properties of the LFP response and show negligible direction sensitivity. Our results demonstrate that sensory stimuli can modulate propagating wave patterns reliably in the cortex. The relevant dynamics are normally masked by trial averaging, which is a conventional step in LFP signal processing.

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Sublaminar Subdivision of Mouse Auditory Cortex Layer 2/3 Based on Functional Translaminar Connections

The cerebral cortex is subdivided into six layers based on morphological features. The supragranular layers 2/3 (L2/3) contain morphologically and genetically diverse populations of neurons, suggesting the existence of discrete classes of cells. In primates and carnivores L2/3 can be subdivided morphologically, but cytoarchitectonic divisions are less clear in rodents. Nevertheless, discrete classes of cells could exist based on their computational requirement, which might be linked to their associated functional microcircuits. Through in vitro slice recordings coupled with laser-scanning photostimulation we investigated whether L2/3 of male mouse auditory cortex contains discrete subpopulations of cells with specific functional microcircuits. We use hierarchical clustering on the laminar connection patterns to reveal the existence of multiple distinct classes of L2/3 neurons. The classes of L2/3 neurons are distinguished by the pattern of their laminar and columnar inputs from within A1 and their location within L2/3. Cells in superficial L2 show more extensive columnar integration than deeper L3 cells. Moreover, L3 cells receive more translaminar input from L4. In vivo imaging in awake mice revealed that L2 cells had higher bandwidth than L3 cells, consistent with the laminar differences in columnar integration. These results suggest that similar to higher mammals, rodent L2/3 is not a homogenous layer but contains several parallel microcircuits.

SIGNIFICANCE STATEMENT Layer 2/3 of auditory cortex is functionally diverse. We investigated whether L2/3 cells form classes based on their functional connectivity. We used in vitro whole-cell patch-clamp recordings with laser-scanning photostimulation and performed unsupervised clustering on the resulting excitatory and inhibitory connection patterns. Cells within each class were located in different sublaminae. Superficial cells showed wider integration along the tonotopic axis and the amount of L4 input varied with sublaminar location. To identify whether sensory responses varied with sublaminar location, we performed in vivo Ca²⁺ imaging and found that L2 cells were less frequency-selective than L3 cells. Our results show that the diversity of receptive fields in L2/3 is likely due to diversity in the underlying functional circuits.

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Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus as an Independent Processor of Corollary Discharge Information in Mice

Understanding cerebellar contributions to motor coordination requires deeper insight into how the output structures of the cerebellum, the cerebellar nuclei, integrate their inputs and influence downstream motor pathways. The magnocellular red nucleus (RNm), a brainstem premotor structure, is a major target of the interposed nucleus (IN), and has also been described in previous studies to send feedback collaterals to the cerebellum. Because such a pathway is in a key position to provide motor efferent information to the cerebellum, satisfying predictions about the use of corollary discharge in cerebellar computations, we studied it in mice of both sexes. Using anterograde viral tracing, we show that innervation of cerebellum by rubrospinal neuron collaterals is remarkably selective for the IN compared with the cerebellar cortex. Optogenetic activation of the pathway in acute mouse brain slices drove IN activity despite small amplitude synaptic currents, suggesting an active role in IN information processing. Monosynaptic transsynaptic rabies tracing indicated the pathway contacts multiple cell types within the IN. By contrast, IN inputs to the RNm targeted a region that lacked inhibitory neurons. Optogenetic drive of IN inputs to the RNm revealed strong, direct excitation but no inhibition of RNm neurons. Together, these data indicate that the cerebellar nuclei are under afferent control independent of the cerebellar cortex, potentially diversifying its roles in motor control.

SIGNIFICANCE STATEMENT The common assumption that all cerebellar mossy fibers uniformly collateralize to the cerebellar nuclei and cortex underlies classic models of convergent Purkinje influence on cerebellar output. Specifically, mossy fibers are thought to both directly excite nuclear neurons and drive polysynaptic feedforward inhibition via Purkinje neurons, setting up a fundamental computational unit. Here we present data that challenge this rule. A dedicated cerebellar nuclear afferent comprised of feedback collaterals from premotor rubrospinal neurons can directly modulate IN output independent of Purkinje cell modulation. In contrast to the IN-RNm pathway, the RNm-IN feedback pathway targets multiple cell types, potentially influencing both motor output pathways and nucleo-olivary feedback.

http://ift.tt/2gORIdJ

Contralateral Bias of High Spatial Frequency Tuning and Cardinal Direction Selectivity in Mouse Visual Cortex

Binocular mechanisms for visual processing are thought to enhance spatial acuity by combining matched input from the two eyes. Studies in the primary visual cortex of carnivores and primates have confirmed that eye-specific neuronal response properties are largely matched. In recent years, the mouse has emerged as a prominent model for binocular visual processing, yet little is known about the spatial frequency tuning of binocular responses in mouse visual cortex. Using calcium imaging in awake mice of both sexes, we show that the spatial frequency preference of cortical responses to the contralateral eye is ~35% higher than responses to the ipsilateral eye. Furthermore, we find that neurons in binocular visual cortex that respond only to the contralateral eye are tuned to higher spatial frequencies. Binocular neurons that are well matched in spatial frequency preference are also matched in orientation preference. In contrast, we observe that binocularly mismatched cells are more mismatched in orientation tuning. Furthermore, we find that contralateral responses are more direction-selective than ipsilateral responses and are strongly biased to the cardinal directions. The contralateral bias of high spatial frequency tuning was found in both awake and anesthetized recordings. The distinct properties of contralateral cortical responses may reflect the functional segregation of direction-selective, high spatial frequency-preferring neurons in earlier stages of the central visual pathway. Moreover, these results suggest that the development of binocularity and visual acuity may engage distinct circuits in the mouse visual system.

SIGNIFICANCE STATEMENT Seeing through two eyes is thought to improve visual acuity by enhancing sensitivity to fine edges. Using calcium imaging of cellular responses in awake mice, we find surprising asymmetries in the spatial processing of eye-specific visual input in binocular primary visual cortex. The contralateral visual pathway is tuned to higher spatial frequencies than the ipsilateral pathway. At the highest spatial frequencies, the contralateral pathway strongly prefers to respond to visual stimuli along the cardinal (horizontal and vertical) axes. These results suggest that monocular, and not binocular, mechanisms set the limit of spatial acuity in mice. Furthermore, they suggest that the development of visual acuity and binocularity in mice involves different circuits.

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The Interplay between Long- and Short-Range Temporal Correlations Shapes Cortex Dynamics across Vigilance States

Increasing evidence suggests that cortical dynamics during wake exhibits long-range temporal correlations suitable to integrate inputs over extended periods of time to increase the signal-to-noise ratio in decision making and working memory tasks. Accordingly, sleep has been suggested as a state characterized by a breakdown of long-range correlations. However, detailed measurements of neuronal timescales that support this view have so far been lacking. Here, we show that the cortical timescales measured at the individual neuron level in freely behaving male rats change as a function of vigilance state and time awake. Although quiet wake and rapid eye movement (REM) sleep are characterized by similar, long timescales, these long timescales are abrogated in non-REM sleep. We observe that cortex dynamics exhibits rapid transitions between long-timescale states and sleep-like states governed by short timescales even during wake. This becomes particularly evident during sleep deprivation, when the interplay between these states can lead to an increasing disruption of long timescales that are restored after sleep. Experiments and modeling identify the intrusion of neuronal offline periods as a mechanism that disrupts the long timescales arising from reverberating cortical network activity. Our results provide novel mechanistic and functional links among behavioral manifestations of sleep, wake, and sleep deprivation and specific measurable changes in the network dynamics relevant for characterizing the brain's changing information-processing capabilities. They suggest a network-level function of sleep to reorganize cortical networks toward states governed by long timescales to ensure efficient information integration for the time awake.

SIGNIFICANCE STATEMENT Lack of sleep deteriorates several key cognitive functions, yet the neuronal underpinnings of these deficits have remained elusive. Cognitive capabilities are generally believed to benefit from a neural circuit's ability to reliably integrate information. Persistent network activity characterized by long timescales may provide the basis for this integration in cortex. Here, we show that long-range temporal correlations indicated by slowly decaying autocorrelation functions in neuronal activity are dependent on vigilance states. Although wake and rapid eye movement (REM) sleep exhibit long timescales, these long-range correlations break down during non-REM sleep. Our findings thus suggest two distinct states in terms of timescale dynamics. During extended wake, the rapid switching to sleep-like states with short timescales can lead to an overall decline in cortical timescales.

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Experimental System of Solar Adsorption Refrigeration with Concentrated Collector

With solar energy as the driving force, a novel adsorption refrigeration system has been developed and experimentally investigated. Water vapor and zeolite formed the working pair of the adsorption system. This manuscript describes the setup of the experimental rig, the operation procedure, and the important results.

http://ift.tt/2xOlMM0

Heparin-binding protein (HBP) improves prediction of sepsis-related acute kidney injury

Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-binding protein (HBP) is a promising biomarker in predicting development and prognosis of s...

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Whelen Engineering introduces SurfaceMax™ series Super-LED® lightheads

CHESTER, Conn. Whelen's SurfaceMax Series features the versatility and performance of the Hundred Series, with a full-fill optic and all-new patented mounting technology, providing easy installation and a clean look. The SurfaceMax Series mounts to a variety of applications and is available in Warning, Brake/Tail/Turn, and Turn Arrow models. Features SurfaceMax lightheads are Rated IP67 for ...

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Report of a case combining solitary Peutz-Jeghers polyp, colitis cystica profunda, and high-grade dysplasia of the epithelium of the colon

Abstract

Background

Colitis cystica profunda is a rare nonneoplastic disease defined by the presence of intramural cysts that contain mucus, usually situated in the rectosigmoid area, which can mimic various malignant lesions and polyps. Its etiology still remains not fully elucidated, and several mechanisms such as congenital, post-traumatic, and infectious have been implicated in the development of this rare entity.

Case presentation

Herein, we describe a unique case of colitis cystica profunda in the setting of Peutz-Jeghers-type polyp of the sigmoid colon, associated with high-grade dysplasia of the overlying epithelium in a 48-year-old female patient, who presented to the emergency room with signs of intestinal obstruction. To the best of our insight, this is the first manifestation ever reported in the literature regarding the coexistence of solitary Peutz-Jeghers-type polyp, colitis cystica profunda, and high-grade dysplasia of the epithelium of the colon.

Conclusions

The purpose of this case report is to highlight colitis cystica profunda and its clinical significance. An uncommon nonneoplastic entity, many times masquerading as malignant lesion of the rectosigmoid area of the colon. Clinicians and pathologists should be aware of this benign condition that is found incidentally postoperatively in patients undergoing colectomies, leading to unnecessary increase of morbidity and mortality in these patients, who otherwise could have been cured with conservative treatment only.

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What are the benefits, risks of binding a pelvic fracture?

World Trauma Symposium speaker describes pelvic fracture anatomy, pathophysiology and evidence for reducing bleeding and improving patient survival with a pelvic splint

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Using risk-tracing snowball approach to increase HIV case detection among high-risk populations in Cambodia: an intervention study

Early HIV diagnosis and initiation onto antiretroviral therapy may prevent ongoing spread of HIV. Risk Tracing Snowball Approach (RTSA) has been shown to be effective in detecting new HIV cases in other settin...

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Prevalence of congenital cytomegalovirus infection in symptomatic newborns under 3 weeks in Tehran, Iran

Cytomegalovirus (CMV) is a common cause of congenital infection worldwide and infants with symptomatic congenital CMV (cCMV) infection are at significantly increased risk of developing adverse long-term outcom...

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MapReduce particle filtering with exact resampling and deterministic runtime

Particle filtering is a numerical Bayesian technique that has great potential for solving sequential estimation problems involving non-linear and non-Gaussian models. Since the estimation accuracy achieved by ...

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Whelen Engineering introduces SurfaceMax lightheads

The SurfaceMax Series lightheads are compatible with the Scan-Lock app for Apple and Android devices

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Verathon launches portable handheld video laryngoscope system

GlideScope Go is designed to provide clear airway views in a wide variety of settings

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H&H Medical introduces the H*VENT vented chest dressing

The six-port design allows for multidirectional drainage toward gravity, allowing patients to be transported on their side

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H&H Medical announces acquisition of rights to SWAT-T tourniquet

The SWAT-T includes an elastic design to give the product the ability to treat a variety of injuries

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Recovery from Cogwheel Rigidity and Akinesia and Improvement in Vibration Sense and Olfactory Perception following Removal of an Epoxy-Oleic Acid DNA Adduct

The epoxy fatty acid cis-12,13-epoxy-oleic acid, which acts as a DNA adduct, may be generated during long-term storage of many seed oils, including those used in cooking, with frying oils and fried foods being a major source in the modern human diet. Removal of this epoxy fatty acid from the locus of the N-formyl peptide receptors was associated with recovery from cogwheel rigidity and akinesia as well as with improvement in vibration sense and olfactory perception.

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Overt Lower Gastrointestinal Bleeding and Pseudotumor: A Rare Presentation of Cytomegalovirus Infection

Cytomegalovirus (CMV) is a ubiquitous organism which can infect multiple organs of the body. In an immunocompromised patient, it can have a myriad of gastrointestinal manifestations. We report a case of recurrent hematochezia and concomitant pseudotumor in an AIDS (acquired immunodeficiency syndrome) patient attributable to CMV infection. A 62-year-old man with a history of AIDS, noncompliant with highly active antiretroviral therapy (HAART), presented with bright red blood per rectum. Index colonoscopy showed presence of multiple ulcers, colonic stenosis, and mass-like appearing lesion. Biopsy confirmed CMV infection and ruled out malignancy. Cessation of dual antiplatelet therapy and compliance with HAART lead to clinical cessation of bleeding and endoscopic healing of ulcers with complete resolution of colon mass on follow-up colonoscopy.

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A profound computational study to prioritize the disease-causing mutations in PRPS1 gene

Abstract

Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited congenital neurological disorders, affecting approximately 1 in 2500 in the US. About 80 genes were found to be in association with CMT. The phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is an essential enzyme in the primary stage of de novo and salvage nucleotide synthesis. The mutations in the PRPS1 gene leads to X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), PRS super activity, Arts syndrome, X-linked deafness-1, breast cancer, and colorectal cancer. In the present study, we obtained 20 missense mutations from UniProt and dbSNP databases and applied series of comprehensive in silico prediction methods to assess the degree of pathogenicity and stability. In silico tools predicted four missense mutations (D52H, M115 T, L152P, and D203H) to be potential disease causing mutations. We further subjected the four mutations along with native protein to 50 ns molecular dynamics simulation (MDS) using Gromacs package. The resulting trajectory files were analyzed to understand the stability differences caused by the mutations. We used the Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), solvent accessibility surface area (SASA), Covariance matrix, Principal Component Analysis (PCA), Free Energy Landscape (FEL), and secondary structure analysis to assess the structural changes in the protein upon mutation. Our study suggests that the four mutations might affect the PRPS1 protein function and stability of the structure. The proposed study may serve as a platform for drug repositioning and personalized medicine for diseases that are caused by the PRPS1 deficiency.

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Response to: ‘Lack of evidence for Zika virus transmission by Culex mosquitoes’

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Lack of evidence for Zika virus transmission by Culex mosquitoes

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Early Production of the Neutrophil-Derived Lipid Mediators LTB4 and LXA4 Is Modulated by Intracellular Infection with Leishmania major

Recruitment of neutrophil granulocytes to sites of infectious tissue damage is an early event in innate immune responses. Following chemotactic signals neutrophils establish a first line of defense in a swarm-like manner. Intracellular pathogens such as Leishmania major can, however, evade neutrophil-mediated killing and survive inside neutrophils. To achieve this the parasites evolved potent evasion mechanisms. Since neutrophils are a major source of inflammation regulating lipid mediators, we hypothesized that intracellular infection modifies the release of pro- and anti-inflammatory lipid mediators like leukotriene B4 (LTB4) and lipoxin A4 (LXA4), respectively. In the present study, we demonstrated in vitro that L. major-infected primary human neutrophils release an increased amount of LTB4, whereas LXA4 liberation is reduced during the first hours of infection. To investigate whether lipid mediator modulation is a common feature in intracellular infections, we tested the impact of an infection with Anaplasma phagocytophilum. Similarly to L. major, neutrophil infection with A. phagocytophilum led to an enhanced release of LTB4 and decreased LXA4 production. Together, our findings indicate that intracellular infections modulate the lipid mediator profile of neutrophils. This effect is likely to contribute to the survival of the pathogens in neutrophils and to the outcome of the infections.

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cAMP Response Element Binding Protein Expression in the Hippocampus of Rhesus Macaques with Chronic Ephedrine Addiction

Background. Drug addiction is classified as a chronic relapse nature brain disease with complicated neurobiology mechanisms. There are an increasing number of researchers that are investigating the possible mechanisms for solving the thorny problem. Methods. The model of chronic addiction of rhesus monkey ephedrine was established, where changes in body weight and behavior were monitored. The expression of cAMP response element binding protein (CREB) in the hippocampus of rhesus monkeys was identified by real-time PCR and Western blot. Results. We were successful in establishing the chronic ephedrine addiction model in the rhesus macaques. They exhibited changes in body weight and behavior. Immunofluorescence showed that CREB was expressed in the nucleus of the hippocampus, and the expression of CREB mRNA and protein in the hippocampus were increased by real-time PCR and Western blot. The CREB positive expression in the hippocampus of the modeling group was significantly higher than in the control group. Conclusions. The changes of body weight and behavior of the rhesus monkeys after ephedrine chronic addiction were significant. The changes of CREB in the hippocampus of rhesus macaques with ephedrine chronic addiction are important molecular mechanisms, and the upregulation of CREB may be involved in the physiological pathology and behavior process in individuals with chronic ephedrine addiction.

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Body Posture Asymmetry in Prematurely Born Children at Six Years of Age

Aims. The purpose of the study was to assess body posture asymmetries in the standing and sitting position in prematurely born children at six years of age. Study Design and Subjects. We measured trunk symmetry in coronal plane. The study was carried out in a group of 101 children, aged 6-7 years, mean age of 6.63, including 50 preterm children born at gestational age

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Modulating Neuroinflammation to Treat Neuropsychiatric Disorders

Neuroinflammation is recognised as one of the potential mechanisms mediating the onset of a broad range of psychiatric disorders and may contribute to nonresponsiveness to current therapies. Both preclinical and clinical studies have indicated that aberrant inflammatory responses can result in altered behavioral responses and cognitive deficits. In this review, we discuss the role of inflammation in the pathogenesis of neuropsychiatric disorders and ask the question if certain genetic copy-number variants (CNVs) associated with psychiatric disorders might play a role in modulating inflammation. Furthermore, we detail some of the potential treatment strategies for psychiatric disorders that may operate by altering inflammatory responses.

http://ift.tt/2xNOGvI

Calcium Ionophore, Calcimycin, Kills Leishmania Promastigotes by Activating Parasite Nitric Oxide Synthase

Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. There is no vaccine against human leishmaniasis and the treatment of the disease would benefit from a broader spectrum and a higher efficacy of leishmanicidal compounds. We analyzed the leishmanicidal activity and the mechanism of action of the calcium ionophore, calcimycin. L. major promastigotes were coincubated with calcimycin and the viability of the cells was assessed using resazurin assay. Calcimycin displayed dose-dependent effect with IC50 = 0.16 μM. Analysis of propidium iodide/LDS-751 stained promastigotes revealed that lower concentrations of calcimycin had cytostatic effect and higher concentrations had cytotoxic effect. To establish the mechanism of action of calcimycin, which is known to stimulate activity of mammalian constitutive nitric oxide synthase (NOS), we coincubated L. major promastigotes with calcimycin and selective NOS inhibitors ARL-17477 or L-NNA. Addition of these inhibitors substantially decreased the toxicity of calcimycin to Leishmania promastigotes. In doing so, we demonstrated for the first time that calcimycin has a direct leishmanicidal effect on L. major promastigotes. Also, we showed that Leishmania constitutive Ca2+/calmodulin-dependent nitric oxide synthase is involved in the parasite cell death. These data suggest activation of Leishmania nitric oxide synthase as a new therapeutic approach.

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The Modulatory Effect of Acupuncture on the Activity of Locus Coeruleus Neuronal Cells: A Review

The Locus Coeruleus (LC) is a small collection of noradrenergic neurons located in the pons. In the brain, noradrenaline (NE) is primarily produced by noradrenergic cell groups in the LC, which is the largest group of noradrenergic neurons in the central nervous system. Acupuncture, including the electroacupuncture which is a modified acupuncture method, is known to be effective in various kinds of diseases, and the involvement of noradrenergic system in the central nervous system has been reported by previous studies. However, on whether acupuncture can modulate the LC neuronal cells activities, results vary from studies to studies. In this paper, we included twelve articles, which observed the effect of acupuncture on the activities of LC in humans and animals. Our study shows that, among twelve included studies, six reported decrease of LC activities, whereas six showed increase of LC activities after acupuncture treatment. Although it is difficult to draw a firm conclusion, the authors suggest that the difference of frequencies may play an important role in the modulatory effect of acupuncture on LC. Further studies are needed to clarify the precise mechanism of acupuncture on LC, as it can lead to a new therapeutic method for various LC-NE related diseases.

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Predictors of Traditional Medical Practices in Illness Behavior in Northwestern Ethiopia: An Integrated Model of Behavioral Prediction Based Logistic Regression Analysis

This study aimed at investigating traditional medical beliefs and practices in illness behavior as well as predictors of the practices in Gondar city, northwestern Ethiopia, by using the integrated model of behavioral prediction. A cross-sectional quantitative survey was conducted to collect data through interviewer administered structured questionnaires from 496 individuals selected by probability proportional to size sampling technique. Unadjusted bivariate and adjusted multivariate logistic regression analyses were performed, and the results indicated that sociocultural predictors of normative response and attitude as well as psychosocial individual difference variables of traditional understanding of illness causation and perceived efficacy had statistically significant associations with traditional medical practices. Due to the influence of these factors, majority of the study population (85%) thus relied on both herbal and spiritual varieties of traditional medicine to respond to their perceived illnesses, supporting the conclusion that characterized the illness behavior of the people as mainly involving traditional medical practices. The results implied two-way medicine needs to be developed with ongoing research, and health educations must take the traditional customs into consideration, for integrating interventions in the health care system in ways that the general public accepts yielding a better health outcome.

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Anxiolytic Effect of Citrus aurantium L. in Crack Users

The objective of this study was to investigate the anxiolytic effects of the essential oil (EO) of Citrus aurantium L. in patients experiencing crack withdrawal. This was developed with internal users in therapeutic communities in Paraíba, Brazil. The test population consisted of 51 volunteers, subdivided into three groups. To elicit anxiety, the Simulated Public Speaking (SPS) method was used. Physiological measures were assessed at specific phases during the experiment using appropriate equipment. Psychological measures of anxiety were assessed using the Trait-State Anxiety Inventory (IDATE) and the Analog Smoke Scale (HAS). EO was administered by nebulization. The experiment was developed in individual sessions and consolidated to four phases. The results demonstrated that the test subjects in the groups that were given the EO maintained controlled anxiety levels during SPS, when compared to the Control Group (no treatment). Subjects who used the EO also maintained levels of "discomfort" and "cognitive impairment" during SPS. It was concluded that individuals who are experiencing internal crack cocaine withdrawal present high anxiety traits and that nebulization of the EO of Citrus aurantium L. provided an acute anxiolytic effect in crack cocaine users exposed to SPS.

http://ift.tt/2ywmjUI

Goreisan Inhibits Upregulation of Aquaporin 4 and Formation of Cerebral Edema in the Rat Model of Juvenile Hypoxic-Ischemic Encephalopathy

Secondary cerebral edema regulation is of prognostic significance in hypoxic-ischemic encephalopathy (HIE), and aquaporin 4 (AQP4) plays an important role in the pathogenesis of cerebral edema. The traditional Japanese herbal medicine Goreisan relieves brain edema in adults; however, its effect and pharmacological mechanism in children are unknown. We investigated the effects of Goreisan on HIE-associated brain edema and AQP4 expression in a juvenile rat model, established by combined occlusion of middle cerebral and common carotid arteries. Magnetic resonance imaging showed that the lesion areas were significantly smaller in the Goreisan- (2 g/kg) treated group than in the nontreated (saline) group at 24 and 48 h postoperatively. AQP4 mRNA levels in the lesion and nonlesion sides were significantly suppressed in the Goreisan group compared with the nontreated group 36 h postoperatively. Western blotting revealed that levels of AQP4 protein were significantly decreased in the Goreisan group compared with the nontreated group in the lesion side 72 h postoperatively, but not at 12 or 36 h. After 14 days, the Goreisan group had a significantly better survival rate. These findings suggest that Goreisan suppresses brain edema in HIE and improves survival in juvenile rats, possibly via regulation of AQP4 expression and function.

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Compression of the Fourth Ventricle Using a Craniosacral Osteopathic Technique: A Systematic Review of the Clinical Evidence

Compression of the fourth ventricle (CV4) is a well-known osteopathic procedure, utilized by osteopaths, osteopathic physicians, craniosacral therapists, physical therapists, and manual therapists as part of their healthcare practice based on some evidence suggesting impact on nervous system functions. The main objective of the study was to identify randomized controlled trials (RCTs) assessing the clinical benefits of CV4 and to show the evidence supporting clinical prescriptions, guides, and advice in treating. A computerized search of the PubMed, CINAHL Complete, Scopus, Web of Science, and ScienceDirect databases was performed. Two filters were used (article type: RCTs; species: humans). The methodological quality of the trials was assessed using the Downs and Black quality checklist for healthcare intervention studies. Only six studies met the inclusion criteria, of which four were RCTs and two were observational studies. The Downs and Black score ranged from 17 to 24 points out of a maximum of 27 points. The present review revealed the paucity of CV4 research in patients with different clinical problems, as five out of six included studies investigated healthy adults. According to the results of the included studies, CV4 may be beneficial for patients with different functional problems.

http://ift.tt/2zjPCJI

Effects of Whole-Body Electromyostimulation on Low Back Pain in People with Chronic Unspecific Dorsal Pain: A Meta-Analysis of Individual Patient Data from Randomized Controlled WB-EMS Trials

In order to evaluate the favorable effect of whole-body electromyostimulation (WB-EMS) on low back pain (LBP), an aspect which is frequently claimed by commercial providers, we performed a meta-analysis of individual patient data. The analysis is based on five of our recently conducted randomized controlled WB-EMS trials with adults 60 years+, all of which applied similar WB-EMS protocols (1.5 sessions/week, bipolar current, 16–25 min/session, 85 Hz, 350 μs, and 4–6 s impulse/4 s impulse-break) and used the same pain questionnaire. From these underlying trials, we included only subjects with frequent-chronic LBP in the present meta-analysis. Study endpoints were pain intensity and frequency at the lumbar spine. In summary, 23 participants of the underlying WB-EMS and 22 subjects of the control groups (CG) were pooled in a joint WB-EMS and CG. At baseline, no group differences with respect to LBP intensity and frequency were observed. Pain intensity improved significantly in the WB-EMS () and was maintained () in the CG. LBP frequency decreased significantly in the WB-EMS () and improved nonsignificantly in the CG (). Group differences for both LBP parameters were significant (). We concluded that WB-EMS appears to be an effective training tool for reducing LBP; however, RCTs should further address this issue with more specified study protocols.

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Therapy Effects of Wogonin on Ovarian Cancer Cells

Background. Wogonin is a plant monoflavonoid and has been reported to induce apoptosis of cancer cells and show inhibitory effect on cancer cell growth. However, the detailed and underlying molecular mechanisms are not elucidated. In this study, we investigated the molecular and biological effects of wogonin in human ovarian A2780 cancer cells. Materials and Methods. We determined the effects of wogonin on the changes of cell cycling and apoptotic responses of cells. Western blot analysis was used to measure the effects of wogonin on protein expressions. Results. Our results showed that treatment with wogonin inhibited the cancer cell proliferation, decreased the percentage of G0/G1 subpopulation, and reduced invasiveness of A2780 cells. Exposure to wogonin also resulted in downregulated protein levels of estrogen receptor alpha (ER-α), VEGF, Bcl-2, and Akt and increased expressions of Bax and p53. In addition, exposure to wogonin increased caspase-3 cleavage and induced apoptosis in A2780 cells. Our study further showed that MPP, a specific ER-α inhibitor, significantly enhanced antitumor effects of wogonin in A2780 cells. Conclusion. Our results suggest a potential clinical impact of wogonin on management of ovarian cancer.

http://ift.tt/2zixmQU

Isometric Tunnel Placement in Ulnar Collateral Ligament Reconstruction with Single CT Scan

Background. Isometric tunnel placement for anterior bundle of the medial collateral ligament (MCL) reconstruction is mandatory for successful surgery. Purpose. This study aimed to demonstrate a useful method for identifying isometric tunnel placement using a single computed tomography (CT) scan. Study Design. Descriptive Laboratory Study. Methods. Five normal elbows were scanned at 4 different flexion angles at 45° increment. Three-dimensional models were analyzed using 2 different approaches: single and multiple CT scans methods. Ligament footprints in the humerus and the ulna were registered. Ligament length and isometric points were defined. The locations of the isometric points were imported into both methods to be compared. Results. There was no significant difference between 2 methods in calculating the length in every zone. There was also no significant difference in determining isometric ligament's origin point, which is located approximately  mm and  mm for single and multiple CT, respectively, measured inferolaterally from medial epicondyle. Conclusions. A solid preoperative plan is critical when predicting tunnel locations due to the difficulty in finding isometric points and the individuality of optimal bone tunnel locations. Using single CT scan, optimal locations can be predicted with the same accuracy as a multiple CT scans with less radiation exposure.

http://ift.tt/2yuDVQU

Frozen section evaluation of sentinel lymph nodes in breast carcinoma: a retrospective analysis

Leonardo Russo, Luis Betancourt, Gabriel Romero, Ali Godoy, Laura Bergamo, Rafael Delgado, Ángela Ruiz, Marianna Gutiérrez, Eduardo Salas and Maria Puzzi

http://ift.tt/2gjcXDy

Book Review—Practical Hepatic Pathology: A Diagnostic Approach, 2nd Edition

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A STEP-DOWN PROTOCOL FOR OMALIZUMAB TREATMENT IN ORAL CORTICOSTEROID-DEPENDENT ALLERGIC ASTHMA PATIENTS

Abstract

Background

there are no specific criteria for a step-down or withdrawal dose of omalizumab. Our purpose was to evaluate the viability of a protocol for OMAlizumab DOse REduction (the OMADORE study) in severe allergic asthma (SAA).

Methods

the study population included 35 SAA patients treated during a minimum period of one year with oral corticosteroids (OC) equivalent to a mean daily dose of 4 mg of methyl-prednisolone. To qualify for the protocol, the patients had to have received treatment with OMA ≥ one year and a half, OC dose had to have reached the lowest tolerated dose and spirometry had to be ≥ at entry. Intervention: a) OMA dose was reduced by half; b) if patients were clinically stable after 6 months, the dose was halved again; c) if repeated OC boosters were needed and/or spirometry worsened ≥ 10%, OMA dose was raised to the previous figure until stabilization.

Results

Mean age was 52.5 (17) years, median monthly OC dose was 120 (IQR: 225) mg. Pulmonary function: FVC: 79.7 (20.2)%; FEV₁: 64.8 (21.7)%; FEV₁/ FVC: 61.7(13.8)%. OMA could be withdrawn in 34.3% of the patients; 22.9% tolerated a reduction, and in 42.9% the dose could not be modified. Follow-up time after reduction or withdrawal ranged from 12 to 30 months. There were no severe exacerbations requiring emergency assistance or admission.

Conclusions

The OMADORE study found that in more than 50% of SAA patients on OC, OMA dose can be safely reduced or withdrawn based on a progressive dose reduction protocol.

http://ift.tt/2yxlOM1

Atypical Presentation of Sjögren-Larsson Syndrome

Sjögren-Larsson syndrome is a rare neurocutaneous disorder characterized by ichthyosis, spastic diplegia or tetraplegia, and intellectual disability. Herein, we describe a case of a Greek patient with ichthyosis and spasticity of the legs but with normal intelligence (IQ 95). This syndrome should be suspected when a child presents with ichthyosis and spastic diplegia or tetraplegia, even if intelligence is normal.

http://ift.tt/2zhTtqy

Effectiveness of Nivolumab versus Docetaxel as Second-Line Treatment in Non-Small Cell Lung Cancer Patients in Clinical Practice

Aims: To evaluate the effectiveness of nivolumab as second-line treatment compared to standard therapy with docetaxel in adult patients with non-small cell lung cancer (NSCLC) in clinical practice. Methods: This is an observational, retrospective cohort study of adult patients diagnosed with NSCLC, stage III-IV, treated with docetaxel or nivolumab as second-line treatment. The end points evaluated were overall survival (OS) and progression-free survival (PFS). PFS and OS were described using the Kaplan-Meier method. The Cox proportional hazards model was applied to identify independent prognostic and predictive factors related to disease progression or death. Results: Thirty-three patients were included in this study (i.e., 14 in the nivolumab group and 19 in the docetaxel group). Nonsquamous NSCLC was the most frequent histological subtype. Cohorts were homogeneous. The follow-up time was 116 ± 87.3 days. The median PFS was 84 days (95% CI 39-300) for patients treated with nivolumab and 61 days (95% CI 48-76) for patients treated with docetaxel. The risk of progression was 60% lower for patients treated with nivolumab (HR 0.40; 95% CI 0.16-0.97; p = 0.043) compared to patients receiving docetaxel. Among the patients treated with docetaxel, the median OS was 129 days (95% CI 106-300). More than 50% of the patients treated with nivolumab were alive at the end of the follow-up period; nevertheless, the risk difference was not statistically significant (HR 0.55; 95% CI 0.20-1.51; p = 0.244). Conclusion: NSCLC patients treated with nivolumab as second-line therapy had a longer PFS compared to patients treated with docetaxel in a health care environment.
Chemotherapy 2017;62:374-380

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Long-Term Effectiveness of a Stress Management Intervention at Work: A 9-Year Follow-Up Study Based on a Randomized Wait-List Controlled Trial in Male Managers

Objective. Short- and medium-term effectiveness (up to 3 years) of individual level stress management interventions (SMI) at work were demonstrated, yet long-term effectiveness remains unexplored. We therefore aimed to address this research gap. Methods. 94 male middle managers participated in a randomized wait-list controlled trial between 2006 and 2008 and in a post-trial-follow-up survey in 2015. During the first two years, all received an 18-hour psychotherapeutic SMI intervention which was based on the Effort-Reward Imbalance (ERI) model: tackling stressor on mismatch between effort and reward and promoting recovery on overcommitment. Work stress (i.e., ERI indicators) was the primary outcome, and the secondary outcome was depressive symptoms. The long-term effectiveness of the SMI was examined by mixed modeling, using an external control group (). Results. Effort and reward were substantially improved with significant intervention time interaction effects () compared to the external control group; effects on overcommitment and depressive symptoms were also significant ( and , resp.), though their trajectories in the intervention group were less sustainable. Conclusions. The effectiveness of this psychotherapeutic SMI at work based on the ERI model was observed over a 9-year period, particularly on the effort-reward ratio.

http://ift.tt/2gpGDma

Preoperative C-Reactive Protein as a Risk Factor for Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Surgery for Colon Carcinoma

Background. Postoperative delirium (POD) is a very common complication in operative disciplines, especially in those elderly patients after cardiac surgery. This study aimed to investigate the relationship between C-reactive protein (CRP) and POD in elderly patients undergoing laparoscopic surgery for colon carcinoma. Methods. 160 elderly patients scheduled to undergo selective laparoscopic surgery for colon carcinoma were prospectively recruited in this present study. The preoperative demographic and medical characteristics, intraoperative variables, and postoperative complications were all recorded in detail. POD assessment was performed once a day for the first 3 days and at 7th day after surgery, respectively. CRP concentrations preoperatively and on postoperative days 1, 2, and 3 were measured by using human enzyme linked immunosorbent assay (ELISA). Results. Of all the 160 enrolled patients, 39 had suffered POD with a POD incidence of 24.4% within the first week after the operation. The univariate analysis and multiple logistic regression analysis suggested preoperative CRP concentrations as the only independent predicator for POD in patients undergoing laparoscopic surgery for colon carcinoma (OR: 5.87; 95% CI: 2.22–11.4; ). Conclusions. This present study highlighted the predictive role of preoperative CRP concentrations for POD in elderly patients undergoing laparoscopic surgery for colon carcinoma.

http://ift.tt/2gsBnhX

High-Dose Compound Heat Map for 3D-Cultured Glioblastoma Multiforme Cells in a Micropillar and Microwell Chip Platform

Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. To cure GBM patients, many target-specific chemotherapeutic agents have been developing. However, 2D monolayer cell-based toxicity and efficacy tests did not efficiently screen agents due to the pool reflection of in vivo microenvironments (cell-to-cell and cell-to-extracellular matrix interaction). In this study, we used a 3D cell-based, high-throughput screening method reflecting the microenvironments using a micropillar and microwell chip platform to draw a high-dose heat map of the cytotoxicity and efficacy of 70 compounds, with two DMSO controls. Moreover, the high-dose heat map model compared the responses of four 3D-cultured patient-derived GBM cells and astrocytes to high dosages of compounds with respect to efficacy and cytotoxicity, respectively, to discern the most efficacious drug for GBM. Among the 70 compounds tested, cediranib (a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases) exhibited the lowest cytotoxicity to astrocytes and high efficacy to GBM cells in a high-dose heat map model.

http://ift.tt/2yy0C90

Early identification of MCI converting to AD: a FDG PET study

Abstract

Purpose

Mild cognitive impairment (MCI) is a transitional pathological stage between normal ageing (NA) and Alzheimer's disease (AD). Although subjects with MCI show a decline at different rates, some individuals remain stable or even show an improvement in their cognitive level after some years. We assessed the accuracy of FDG PET in discriminating MCI patients who converted to AD from those who did not.

Methods

FDG PET was performed in 42 NA subjects, 27 MCI patients who had not converted to AD at 5 years (nc-MCI; mean follow-up time 7.5 ± 1.5 years), and 95 MCI patients who converted to AD within 5 years (MCI-AD; mean conversion time 1.8 ± 1.1 years). Relative FDG uptake values in 26 meta-volumes of interest were submitted to ANCOVA and support vector machine analyses to evaluate regional differences and discrimination accuracy.

Results

The MCI-AD group showed significantly lower FDG uptake values in the temporoparietal cortex than the other two groups. FDG uptake values in the nc-MCI group were similar to those in the NA group. Support vector machine analysis discriminated nc-MCI from MCI-AD patients with an accuracy of 89% (AUC 0.91), correctly detecting 93% of the nc-MCI patients.

Conclusion

In MCI patients not converting to AD within a minimum follow-up time of 5 years and MCI patients converting within 5 years, baseline FDG PET and volume-based analysis identified those who converted with an accuracy of 89%. However, further analysis is needed in patients with amnestic MCI who convert to a dementia other than AD.

http://ift.tt/2zxEDNF

Predictive value of 18 F-FDG PET/CT in adults with T-cell lymphoblastic lymphoma: post hoc analysis of results from the GRAALL-LYSA LLO3 trial

Abstract

Purpose

We examined whether FDG PET can be used to predict outcome in patients with lymphoblastic lymphoma (LL).

Methods

This was a retrospective post hoc analysis of data from the GRAAL-LYSA LL03 trial, in which the treatment of LL using an adapted paediatric-like acute lymphoblastic leukaemia protocol was evaluated. PET data acquired at baseline and after induction were analysed. Maximum standardized uptake values (SUV_max), total metabolic tumour volume and total lesion glycolysis were measured at baseline. The relative changes in SUV_max from baseline (ΔSUV_max) and the Deauville score were determined after induction.

Results

The population analysed comprised 36 patients with T-type LL. SUV_max using a cut-off value of ≤8.76 vs. >8.76 was predictive of 3-year event-free survival (31.6% vs. 80.4%; p = 0.013) and overall survival (35.0% vs. 83.7%; p = 0.028). ΔSUV_max using a cut-off value of ≤80% vs. >80% tended also to be predictive of 3-year event-free survival (40.0% vs. 76.0%; p = 0.054) and overall survival (49.2% vs. 85.6%; p = 0.085). Total metabolic tumour volume, baseline total lesion glycolysis and response according to the Deauville score were not predictive of outcome.

Conclusions

A low initial SUV_max was predictive of worse outcomes in our series of patients with T-type LL. Although relatively few patients were included, the study also suggested that ΔSUV_max may be useful for predicting therapeutic efficacy.

http://ift.tt/2zhsb3C

Heterogeneity index evaluated by slope of linear regression on 18 F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma

Abstract

Purpose

¹⁸F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of ¹⁸F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and ¹⁸F-FDG PET/CT parameters.

Methods

A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative ¹⁸F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each ¹⁸F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and ¹⁸F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence.

Results

Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the ¹⁸F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19–9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0.001, respectively) demonstrated significant results.

Conclusions

The heterogeneity index obtained using the linear regression slope, could be an effective predictor of pancreatic cancer recurrence after pancreatic cancer surgery, in addition to ¹⁸F-FDG PET/CT volumetric parameters and clinicopathologic parameters.

http://ift.tt/2zyuf8b

Impact of partial-volume correction in oncological PET studies: a systematic review and meta-analysis

Abstract

Purpose

Positron-emission tomography can be useful in oncology for diagnosis, (re)staging, determining prognosis, and response assessment. However, partial-volume effects hamper accurate quantification of lesions <2–3× the PET system's spatial resolution, and the clinical impact of this is not evident. This systematic review provides an up-to-date overview of studies investigating the impact of partial-volume correction (PVC) in oncological PET studies.

Methods

We searched in PubMed and Embase databases according to the PRISMA statement, including studies from inception till May 9, 2016. Two reviewers independently screened all abstracts and eligible full-text articles and performed quality assessment according to QUADAS-2 and QUIPS criteria. For a set of similar diagnostic studies, we statistically pooled the results using bivariate meta-regression.

Results

Thirty-one studies were eligible for inclusion. Overall, study quality was good. For diagnosis and nodal staging, PVC yielded a strong trend of increased sensitivity at expense of specificity. Meta-analysis of six studies investigating diagnosis of pulmonary nodules (679 lesions) showed no significant change in diagnostic accuracy after PVC (p = 0.222). Prognostication was not improved for non-small cell lung cancer and esophageal cancer, whereas it did improve for head and neck cancer. Response assessment was not improved by PVC for (locally advanced) breast cancer or rectal cancer, and it worsened in metastatic colorectal cancer.

Conclusions

The accumulated evidence to date does not support routine application of PVC in standard clinical PET practice. Consensus on the preferred PVC methodology in oncological PET should be reached. Partial-volume-corrected data should be used as adjuncts to, but not yet replacement for, uncorrected data.

http://ift.tt/2zhs3RG

Visualization of HER2-specific breast cancer intratumoral heterogeneity using 64 Cu-DOTA-trastuzumab PET

http://ift.tt/2zy1rwD

Interim FDG-PET in lymphoma, a questionable practice in hematology

http://ift.tt/2ziKFAP

Measurement uncertainty and clinical impact of target-to-background ratios derived by interim FDG-PET/CT in Hodgkin lymphoma: reply to Laffon and Martan

http://ift.tt/2zvNcZ7

Bone SPECT/CT in the postoperative spine: a focus on spinal fusion

Abstract

Low back pain is a global problem affecting one in 10 people. The management of low back pain varies from conservative to more invasive methods with a spectacular increase in the number of patients undergoing spinal fusion surgery during the last decade. Conventional radiological and radionuclide studies are often used in the assessment of persistent or recurring pain after spinal surgery with several advantages and limitations related to each technique. This article reviews the key contribution of integrated bone SPECT/CT in evaluating patients with persistent or recurring pain after spinal surgery, focusing on spinal fusion. Current literature supports the use of bone SPECT/CT as an adjunct imaging modality and problem-solving tool in evaluating patients with suspicion of pseudarthrosis, adjacent segment degeneration, and hardware failure. The role of bone SPECT/CT in post-operative orthopaedic scenarios is evolving, and this review highlights the need for further research on the role of bone SPECT/CT in these patients.

http://ift.tt/2ziKyVV

A rare case of thymoma first detected on gallium-68 PSMA PET/CT

http://ift.tt/2zx32CX

Poor predictive value of positive interim FDG-PET/CT in primary mediastinal large B-cell lymphoma

Abstract

Purpose

Though commonly used to assess response to therapy, the prognostic value of interim FDG-PET/CT in Primary Mediastinal Large B-cell Lymphoma (PMBCL) is unclear.

Methods

We conducted a retrospective study on 36 consecutive patients treated at our institution for a PMBCL between 2006 and 2014. All patients with a positive interim FDG-PET/CT had undergone histological restaging consisting either in a surgical debulking of the residual lesion (15 patients) or a CT-guided core needle biopsy (two patients). All FDG-PET/CT were secondarily reviewed according to the more recent Deauville criteria.

Results

Interim FDG-PET/CT was considered positive in 17/36 patients using visual evaluation. Among these patients, 14 had a Deauville score of 4. Histological restaging was negative in all but one case, showing inflammation and/or fibrosis. After a median follow-up of 48.5 months, a total of five patients have relapsed, two patients in the positive FDG-PET/CT group, and three patients in the negative FDG-PET/CT group, respectively.

Conclusions

These data indicate that a positive interim FDG-PET/CT does not reflect persistence of active disease in the vast majority of PMBCL cases. The relapse rate appears similar regardless of interim FDG-PET/CT results and interpretation criteria. This suggests that interim FDG-PET/CT has a poor positive predictive value, thus kt should be used with caution in PMBCL.

http://ift.tt/2ziKsO3

Single high dose versus repeated bone-targeted radionuclide therapy

http://ift.tt/2zyudNB

About the specificity of radiotracers for prostate cancer

http://ift.tt/2zhrCXy

Quantification: there is more to worry about than good scanner hardware and reliable calibration

http://ift.tt/2zx30ej

18 F-Florbetaben PET beta-amyloid binding expressed in Centiloids

Abstract

Purpose

The Centiloid (CL) method enables quantitative values from Aβ-amyloid (Aβ) imaging to be expressed in a universal unit providing pathological, diagnostic and prognostic thresholds in clinical practice and research and allowing integration of multiple tracers and methods. The method was developed for ¹¹C-PiB scans with zero CL set as the average in young normal subjects and 100 CL the average in subjects with mild Alzheimer's disease (AD). The method allows derivation of equations to convert the uptake value of any tracer into the same standard CL units but first requires head-to-head comparison with ¹¹C-PiB results. We derived the equation to express ¹⁸F-florbetaben (FBB) binding in CL units.

Methods

Paired PiB and FBB PET scans were obtained in 35 subjects. including ten young normal subjects aged under 45 years (33 ± 8 years). FBB images were acquired from 90 to 110 min after injection. Spatially normalized images were analysed using the standard CL method (SPM8 coregistration of PET data to MRI data and the MNI-152 atlas) and standard CL regions (cortex and whole cerebellum downloaded from http://www.gaain.org).

Results

FBB binding was strongly correlated with PiB binding (R ² = 0.96, SUVR_FBB = 0.61 × SUVR_PiB + 0.39). The equation to derive CL values from FBB SUVR was CL units = 153.4 × SUVR_FBB − 154.9. The CL value in the young normal subjects was −1.08 ± 6.81 for FBB scans compared to −0.32 ± 3.48 for PiB scans, giving a variance ratio of 1.96 (SD_{FBB CL}/SD_{PiB CL}).

Conclusions

¹⁸F-FBB binding is strongly correlated with PiB binding and FBB results can now be expressed in CL units.

http://ift.tt/2zhrAio