bmj;358/sep28_6/j4153/FAF1faBiographyBen Maruthappu, 29, is a public health registrar in northwest London and cofounder of Cera, a technology enabled social care provider. Cera aims to link patients...
The Rho GTPase Rac1 is a multifunctional protein involved in distinct pathways ranging from development to pathology. The aim of the present study was to unravel the contribution of neuronal Rac1 in regulating the response to brain injury induced by permanent focal cerebral ischemia (pMCAO). Our results show that pMCAO significantly increased total Rac1 levels in wild type mice, mainly through rising nuclear Rac1, while a reduction in Rac1 activation was observed. Such changes preceded cell death induced by excitotoxic stress. Pharmacological inhibition of Rac1 in primary neuronal cortical cells prevented the increase in oxidative stress induced after overactivation of glutamate receptors. However, this was not sufficient to prevent the associated neuronal cell death. In contrast, RNAi-mediated knock down of Rac1 in primary cortical neurons prevented cell death elicited by glutamate excitotoxicity and decreased the activity of NADPH oxidase. To test whether in vivo down regulation of neuronal Rac1 was neuroprotective after pMCAO, we used tamoxifen-inducible neuron-specific conditional Rac1-knockout mice. We observed a significant 50% decrease in brain infarct volume of knockout mice and a concomitant increase in HIF-1α expression compared to littermate control mice, demonstrating that ablation of Rac1 in neurons is neuroprotective. Transmission electron microscopy performed in the ischemic brain showed that lysosomes in the infarct of Rac1- knockout mice were preserved at similar levels to those of non-infarcted tissue, while littermate mice displayed a decrease in the number of lysosomes, further corroborating the notion that Rac1 ablation in neurons is neuroprotective.
Our results demonstrate that Rac1 plays important roles in the ischemic pathological cascade and that modulation of its levels is of therapeutic interest. This article is protected by copyright. All rights reserved.
Objective: To test the hypothesis that Lewy body pathology (LBs) is present in the spinal cord of older community-dwelling adults without a clinical diagnosis of Parkinson's disease (PD).
Methods: We studied 162 prospective autopsies from older adults with PD (N=6) and without PD (N=156). We documented the presence of LBs in cerebrum and brainstem structures from each of the 6 regions used for Braak PD staging and 4 spinal cord levels (C5/6, T7, L4/5 and S4/5). Parkinsonism proximate to death was based on a previously validated measure present if 2 or more of the 4 signs of parkinsonism were present based on a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS).
Results: Fifty-three of 156 individuals without PD (34%) had LBs in a least one site within the CNS. About half of cases with LBs in the cerebrum or brainstem, (25/53, 47%) also had spinal LBs. Almost 90% (22/25 88%) of cases with spinal LBs had LBs in the cerebrum (Braak stages 4-6) and about 10% (3/25, 12%) had only brainstem LBs (Braak stages 1-3). Four of 6 cases with PD showed LBs in cerebrum, brainstem and spinal cord. Individuals with LBs in the spinal cord were more likely to have clinical parkinsonism proximate to death compared to individuals with LBs in brainstem and cerebrum alone (52% vs 32%; Chi-Square х2 = 5.368, df = 1, p = 0.0.021) and more severe nigral neuronal loss (48%% vs 11%; Chi-Square х2 = 9.049, df = 1, p = 0.003). These findings were unchanged when we included cases with a history of PD.
Conclusion: Older community-dwelling adults without a clinical diagnosis of PD have evidence of LBs throughout the CNS including the spinal cord which is associated with parkinsonism and more severe nigral neuronal loss. This article is protected by copyright. All rights reserved.
Selling off unused or underused estate sounds like a good idea for any organisation in need of funds, and the NHS is certainly that. The Naylor Review, published in March (doi:10.1136/bmj.j2072),...
A 64 year old woman presented with left upper abdominal pain, which was first felt as a "pins and needles" sensation five years earlier and gradually evolved to stabbing pain. There was no abdominal...
A 50 year old man presented to a clinic with a two year history of multiple hypopigmented patches spread over the trunk and all four limbs (fig 1). The patches were variable in size with central...
Seismic changes in the organisation, delivery, and funding of health and social care services have been underway since the secretary of state's duty to provide key services throughout England was...
Osteolytic bone lesions can be a consequence of leukemic bone infiltration or focal bone destruction by inflammatory factors released from leukemic cells. Destructive bone lesions have a negative impact on the quality of life of leukemia patients, causing unbearable pain and, in some cases, limb paralysis. However, the mechanism, by which leukemic cells produce destructive bone lesions, and the effect of therapeutics on osteolytic lesions have not been fully elucidated yet and, thus, stand to benefit from an in vivo model. To that end, HL-60 cells were transformed by retrovirus-mediated constitutively active (CA) STAT5 expression and injected into nonobese diabetic (NOD)/SCID mice via the tail vein. After three weeks, lumbar spines were subjected to histocytometric analysis. Xenograft mice developed hind limb paralysis in 2-3 weeks, which was consistent with the consequences of spinal bone destruction by extramedullary invasion of leukemia cells. The in vivo model will improve the understanding and treatment of osteolytic bone lesions caused by myeloid leukemic cells.
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Acute kidney injury (AKI) is a multifactorial entity that occurs in a variety of clinical settings. Although AKI is not a usual reason for intensive care unit (ICU) admission, it often complicates critically ill patients' clinical course requiring renal replacement therapy progressing sometimes to end-stage renal disease and increasing mortality. The causes of AKI in the group of ICU patients are further complicated from damaged metabolic state, systemic inflammation, sepsis, and hemodynamic dysregulations, leading to an imbalance that generates oxidative stress response. Abundant experimental and to a less extent clinical data support the important role of oxidative stress-related mechanisms in the injury phase of AKI. The purpose of this article is to present the main pathophysiologic mechanisms of AKI in ICU patients focusing on the different aspects of oxidative stress generation, the available evidence of interventional measures for AKI prevention, biomarkers used in a clinical setting, and future perspectives in oxidative stress regulation.
from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2fsHBdn
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Adenoid cystic carcinoma (ACC) is a rare malignant tumor, mostly involving the minor salivary glands. Herein, we present a case of ACC in a 43-year-old man with symptoms of dental abscess as the initial presentation of the tumor. In spiral computed tomography (CT) scan, soft tissue mass with the erosion of maxillary sinus wall on the right side of the alveolar ridge was evident. Histopathological examination of the excised tumor with immunohistochemical studies (C-kit, Vimentin, pan-cytokeratin, p53, p63, and ki67 positive reaction) confirmed grade 2 ACC in the maxillary sinus. The patient underwent hemimaxillectomy and right-neck dissection. Due to the extension of tumor cells excessively into the surrounding tissues and involvement of orbital bone, complete and total resection of the tumor with safe margins could not be done. After surgery, adjuvant radiotherapy was considered for the patient. At the end of treatment, the patient lost his eye vision. Seventeen months from initial diagnosis, he was still alive without lung or distant metastasis.
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Background. Acute postoperative pain delays recovery and increases morbidity and mortality. Traditional administration of postoperative analgesics by nurses is often inefficient. The present study evaluated the safety, efficacy, and usability of a novel, patient-controlled analgesic dispenser, the PCoA Acute. Methods. A controlled pilot study was conducted at three medical centers. Patients scheduled for elective surgery were enrolled into two groups, both taking oral analgesics: a control group (), opioids dispensed by nurses, and a test group (), opioids dispensed via the PCoA Acute. Pill intake data were recorded. Pain ratings at rest and during movement were surveyed. Results. No severe adverse events were recorded. Average pill intake time was reduced from 8 : 58 minutes in the control group to 1 : 17 minutes in the test group ( value
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Silybin is one of the effective, traditional Chinese medicines used as a hepatoprotective agent in nonalcoholic fatty liver disease (NAFLD) therapy worldwide, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been recognized as an important factor involved in NAFLD development. However, little is known about the mechanisms of silybin in the regulation of high-fat diet (HFD)–induced liver inflammation. In our study, we found that silybin inhibited endoplasmic reticulum stress and NLRP3 inflammasome activation in the livers of HFD-fed mice and in cultured hepatocytes. Phosphorylation of inositol-requiring enzyme (IRE)1α and eIF2α, expression of thioredoxin-interacting protein and cleaved caspase-1, and release of IL-1β were reduced by silybin. In addition, silybin inhibited the approach of calreticulin and translocase of outer membrane 20 (Tom20), prevented assembly of the NLRP3 inflammasome complex, and suppressed the accumulation of acetylated α-tubulin in the perinuclear region. Both MEC-17 and sirtuin 2 (SIRT2) were influenced by palmitate and silybin, whereas histone deacetylase 6 was not affected. In addition, supplementing NAD+ directly or increasing NAD+ concentration with silybin could maintain the activity of SIRT2. The anti-inflammatory effect of silybin was blocked by SIRT2 silencing or by the SIRT2 inhibitor AGK2, as evidenced by NLRP3/ASC colocalization, AC-α-tubulin expression, and IL-1β release. These findings indicate that the NAD+/SIRT2 pathway is an important mediator through which silybin prevents NLRP3 inflammasome activation during NAFLD.—Zhang, B., Xu, D., She, L., Wang, Z., Yang, N., Sun, R., Zhang, Y., Yan, C., Wei, Q., Aa, J., Liu, B., Wang, G., Xie, Y. Silybin inhibits NLRP3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease.
Trypanosoma brucei, protozoan parasites that cause human African trypanosomiasis (HAT), depend on ornithine uptake and metabolism by ornithine decarboxylase (ODC) for survival. Indeed, ODC is the target of the WHO "essential medicine" eflornithine, which is antagonistic to another anti-HAT drug, suramin. Thus, ornithine uptake has important consequences in T. brucei, but the transporters have not been identified. We describe these amino acid transporters (AATs). In a heterologous expression system, TbAAT10-1 is selective for ornithine, whereas TbAAT2-4 transports both ornithine and histidine. These AATs are also necessary to maintain intracellular ornithine and polyamine levels in T. brucei, thereby decreasing sensitivity to eflornithine and increasing sensitivity to suramin. Consistent with competition for histidine, high extracellular concentrations of this amino acid phenocopied a TbAAT2-4 genetic defect. Our findings established TbAAT10-1 and TbAAT2-4 as the parasite ornithine transporters, one of which can be modulated by histidine, but both of which affect sensitivity to important anti-HAT drugs.—Macedo, J. P., Currier, R. B., Wirdnam, C., Horn, D., Alsford, S., Rentsch, D. Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei.
Clinically, low and moderate alcohol intake improves human health with protection against metabolic syndromes, including type 2 diabetes; however, mechanisms that are associated with these effects remain to be elucidated. The aims of this study were to investigate the effects of moderate alcohol intake on thermogenic brown/beige adipocyte formation and glucose and lipid homeostasis, as well as the involvement of retinoic acid (RA) signaling in the entire process. C57BL6 male mice were supplemented with 8% (w/v) alcohol in water for 1 or 4 mo. Alcohol intake prevented body weight gain, induced the formation of uncoupling protein 1–positive beige adipocytes in white adipose tissue, and increased thermogenesis in mice, which is associated with decreased serum glucose and triacylglycerol levels. Mechanistically, alcohol intake increased RA levels in serum and adipose tissue, which was associated with increased expression of aldehyde dehydrogenase family 1 subfamily A1 (Aldh1a1). When RA receptor-α signaling was conditionally blocked in platelet-derived growth factor receptor-α-positive adipose progenitors, the effects of alcohol on beige adipogenesis were largely abolished. Finally, moderate alcohol prevented high-fat diet-induced obesity and metabolic dysfunction. In conclusion, moderate alcohol intake induces thermogenic brown/beige adipocyte formation and promotes glucose and lipid oxidation via elevation of RA signaling.—Wang, B., Wang, Z., de Avila, J. M., Zhu, M.-J., Zhang, F., Gomez, N. A., Zhao, L., Tian, Q., Zhao, J., Maricelli, J., Zhang, H., Rodgers, B. D., Du, M. Moderate alcohol intake induces thermogenic brown/beige adipocyte formation via elevating retinoic acid signaling.
Silver nanoparticles (AgNPs) are employed in a variety of consumer products; however, in vivo rodent studies indicate that AgNPs can cause lung inflammation and toxicity in a strain- and particle type–dependent manner, but mechanisms of susceptibility remain unclear. The aim of this study was to assess the variation in AgNP-induced lung inflammation and toxicity across multiple inbred mouse strains and to use genome-wide association (GWA) mapping to identify potential candidate susceptibility genes. Mice received doses of 0.25 mg/kg of either 20-nm citrate-coated AgNPs or citrate buffer using oropharyngeal aspiration. Neutrophils in bronchoalveolar lavage fluid (BALF) served as markers of inflammation. We found significant strain- and treatment-dependent variation in neutrophils in BALF. GWA mapping identified 10 significant single-nucleotide polymorphisms (false discovery rate, 15%) in 4 quantitative trait loci on mouse chromosomes 1, 4, 15, and 18, and Nedd4l (neural precursor cell expressed developmentally downregulated gene 4-like; chromosome 18), Ano6 (anocatmin 6; chromosome 15), and Rnf220 (Ring finger protein 220; chromosome 4) were considered candidate genes. Quantitative RT-PCR revealed significant inverse associations between mRNA levels of these genes and neutrophil influx. Nedd4l, Ano6, and Rnf220 are candidate susceptibility genes for AgNP-induced lung inflammation that warrant additional exploration in future studies.—Scoville, D. K., Botta, D., Galdanes, K., Schmuck, S. C., White, C. C., Stapleton, P. L., Bammler, T. K., MacDonald, J. W., Altemeier, W. A., Hernandez, M., Kleeberger, S. R., Chen, L.-C., Gordon, T., Kavanagh, T. J. Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice.
Loss of the epithelial intermediate filament protein keratin 8 (K8) in murine β cells leads to irregular insulin vesicles and decreased insulin levels. Because mitochondria are central in glucose-stimulated insulin secretion, the relationship between keratins and β-cell mitochondrial function and morphology was investigated. β cells in murine K8-knockout (K8–/–) islets of Langerhans have increased numbers of mitochondria, which are rounder and have diffuse cristae, as seen by electron microscopy. The mitochondrial network in primary cultured K8–/– β cells is more fragmented compared with K8+/+ mitochondria, correlating with decreased levels of mitofusin 2 and the mitofusin 2- and keratin-binding protein trichoplein. K8–/– β-cell mitochondria have decreased levels of total and mitochondrial cytochrome c, which correlates with a reduction in electron transport complexes I and IV. This provokes loss of mitochondrial membrane potential and reduction of ATP and insulin amount, as seen in K8–/– β cells. Mitochondria in K8 wild-type β cells and MIN6 insulinoma cells overexpressing K8 and 18 are more stationary compared with mitochondria in keratin-deficient cells. In conclusion, keratins, likely through trichoplein–mitofusin interactions, regulate both structural and dynamic functions of β-cell mitochondria, which could have implications for downstream insulin secretion.—Silvander, J. S. G., Kvarnström, S. M., Kumari-Ilieva, A., Shrestha, A., Alam, C. M., Toivola, D. M. Keratins regulate β-cell mitochondrial morphology, motility, and homeostasis.
Subclinical hypothyroidism is known to be associated with increased serum cholesterol. Since thyroid-stimulating hormone (TSH) exerts an inductor effect on cholesterol biosynthesis, we aimed to investigate the relationship between TSH mRNA and cholesterol metabolism in human adipose tissue (AT). Cross-sectionally, AT TSH-β (TSHB) mRNA was evaluated in 4 independent cohorts in association with serum total and LDL cholesterol, and AT lipidomics. Longitudinally, the effects of statins and of diet and exercise on AT TSHB mRNA were also examined. The bidirectional relationship between cholesterol and TSHB were studied in isolated human adipocytes. TSHB mRNA was consistently detected in AT from euthyroid subjects, and positively associated with serum total- and LDL-cholesterol, and with AT-specific cholesterol metabolism-associated lipids [arachidonoyl cholesteryl ester, C8-dihydroceramide, N-stearoyl-d-sphingosine, and GlcCer(18:0, 24:1)]. Reduction of cholesterol with statins and with diet and exercise interventions led to decreased TSHB mRNA in human AT, whereas excess cholesterol up-regulated TSHB mRNA in human adipocytes. In addition, recombinant human TSH α/β administration resulted in increased HMGCR mRNA levels in human adipocytes. In mice, subcutaneous AT Tshb expression levels correlated directly with circulating cholesterol levels. In summary, current results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human AT.—Moreno-Navarrete, J. M., Moreno, M., Ortega, F., Xifra, G., Hong, S., Asara, J. M., Serrano, J. C. E., Jové, M., Pissios, P., Blüher, M., Ricart, W., Portero-Otin, M., Fernández-Real, J. M. TSHB mRNA is linked to cholesterol metabolism in adipose tissue.
Deficiency of the cysteine protease inhibitor cystatin M/E (Cst6) in mice leads to disturbed epidermal cornification, impaired barrier function, and neonatal lethality. We report the rescue of the lethal skin phenotype of ichq (Cst6-deficient; Cst6–/–) mice by transgenic, epidermis-specific, reexpression of Cst6 under control of the human involucrin (INV) promoter. Rescued Tg(INV-Cst6)Cst6ichq/ichq mice survive the neonatal phase, but display severe eye pathology and alopecia after 4 mo. We observed keratitis and squamous metaplasia of the corneal epithelium, comparable to Cst6–/–Ctsl+/– mice, as we have reported in other studies. We found the INV promoter to be active in the hair follicle infundibulum; however, we did not observe Cst6 protein expression in the lower regions of the hair follicle in Tg(INV-Cst6)Cst6ichq/ichq mice. This result suggests that unrestricted activity of proteases is involved in disturbance of hair follicle biology, eventually leading to baldness. Using quenched activity-based probes, we identified mouse cathepsin B (CtsB), which is expressed in the lower regions of the hair follicle, as an additional target of mouse Cst6. These data suggest that Cst6 is necessary to control CtsB activity in hair follicle morphogenesis and highlight Cst6-controlled proteolytic pathways as targets for preventing hair loss.—Oortveld, M. A. W., van Vlijmen-Willems, I. M. J. J., Kersten, F. F. J., Cheng, T., Verdoes, M., van Erp, P. E. J., Verbeek, S., Reinheckel, T., Hendriks, W. J. A. J., Schalkwijk, J., Zeeuwen, P. L. J. M. Cathepsin B as a potential cystatin M/E target in the mouse hair follicle.
The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic system-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [i.e., maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor–positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPAE12.75 treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPAE12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPAE12.75 neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPAE12.75 treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress–induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPAE12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.—Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.
Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct–ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2–knockout (Mdr2–/–) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2–/– mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2–/– mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine N-acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells in vitro, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2–/– mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2–/– mice and patients with PSC compared with controls and decreased in Mdr2–/– mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2–/– ablates biliary proliferation, liver fibrosis, and angiogenesis. In vitro, overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.—Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.
Mitochondrial dysfunction causes renal tubular epithelial cell injury and promotes cell apoptosis and renal tubulointerstitial fibrosis (TIF) progression. TNF receptor-associated protein 1 (TRAP1) is a molecular chaperone protein that is localized in mitochondria. It plays an important role in cell apoptosis; however, its functional mechanism in TIF remains unclear. In this study, we observed the effects of TRAP1 in renal tubular epithelial cell mitochondria in mice with unilateral ureteral obstruction and its function in cell apoptosis and TIF. Results show that TRAP1 could protect the mitochondrial structure in renal tubular epithelial cells; maintain the levels of mitochondrial membrane potential, ATP, and mitochondrial DNA copy number; inhibit reactive oxygen species production; stabilize the expression of the mitochondrial inner membrane protein mitofilin; reduce renal tubular epithelial cell apoptosis; and inhibit TIF. These results provide new theoretical foundations for additional understanding of the antifibrotic mechanism of TRAP1 in the kidney.—Chen, J.-F., Wu, Q.-S., Xie, Y.-X., Si, B.-L., Yang, P.-P., Wang, W.-Y., Hua, Q., He, Q. TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria.
Maternal cigarette smoke, including prenatal nicotinic exposure (PNE), is responsible for sudden infant death syndrome (SIDS). The fatal events of SIDS are characterized by severe bradycardia and life-threatening apneas. Although activation of transient receptor potential vanilloid 1 (TRPV1) of superior laryngeal C fibers (SLCFs) could induce bradycardia and apnea and has been implicated in SIDS pathogenesis, how PNE affects the SLCF-mediated cardiorespiratory responses remains unexplored. Here, we tested the hypothesis that PNE would aggravate the SLCF-mediated apnea and bradycardia via up-regulating TRPV1 expression and excitation of laryngeal C neurons in the nodose/jugular (N/J) ganglia. To this end, we compared the following outcomes between control and PNE rat pups at postnatal days 11–14: 1) the cardiorespiratory responses to intralaryngeal application of capsaicin (10 µg/ml, 50 µl), a selective stimulant for TRPV1 receptors, in anesthetized preparation; 2) immunoreactivity and mRNA of TRPV1 receptors of laryngeal sensory C neurons in the N/J ganglia retrogradely traced by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; and 3) TRPV1 currents and electrophysiological characteristics of these neurons by using whole-cell patch-clamp technique in vitro. Our results showed that PNE markedly prolonged the apneic response and exacerbated the bradycardic response to intralaryngeal perfusion of capsaicin, which was associated with up-regulation of TRPV1 expression in laryngeal C neurons. In addition, PNE increased the TRPV1 currents, depressed the slow delayed rectifier potassium currents, and increased the resting membrane potential of these neurons. Our results suggest that PNE is capable of aggravating the SLCF-mediated apnea and bradycardia through TRPV1 sensitization and neuronal excitation, which may contribute to the pathogenesis of SIDS.—Gao, X., Zhao, L., Zhuang, J., Zang, N., Xu, F. Prenatal nicotinic exposure prolongs superior laryngeal C-fiber–mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation.
Novel biomaterials are of paramount importance for bone regrowth. In this study, we investigated human adipose stem cells (hASCs) for osteogenic, osteoconductivity, and osteoinductivity effects of an innovative collagen/hydroxylapatite hybrid scaffold. In hASCs that were grown on this scaffold, osteogenic genes were analyzed for their expression profiles, together with adhesion and extracellular matrix genes. In hASC integrins, basement membrane constituents and collagens were up-regulated, together with cell proliferation. In addition, expression of osteopontin and activated focal adhesion kinase was studied at the protein level. Our in vitro data indicate that hASCs, together with hybrid biomaterial, is an important model of study to investigate in vitro bone induction.—Mazzoni, E., D'Agostino, A., Manfrini, M., Maniero, S., Puozzo, A., Bassi, E., Marsico, S., Fortini, C., Trevisiol, L., Patergnani, S., Tognon, M. Human adipose stem cells induced to osteogenic differentiation by an innovative collagen/hydroxylapatite hybrid scaffold.
Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve–airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ~3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas β2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.—Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.
As the use of recreational drugs increases, the likelihood of an anesthesiologist perioperatively encountering patients using or addicted to these drugs will also increase.
Addicted patients may present for anesthetic care in a variety of circumstances in everyday elective surgeries or in acute or life-saving situations, such as emergency Cesarean delivery or trauma surgery. Therefore, it is important for anesthesiologists to know about the most common illicit drugs being used, their clinical presentation and side effects, and the anesthetic options that are beneficial or detrimental to these patients. The most frequently used illicit substances, apart from alcohol and tobacco, are cannabis, cocaine, heroin, prescription opioids, methamphetamine, and hallucinogens. When planning anesthetic care, it is important for anesthesiologists to understand the effects of these agents, including various drug interactions, to predict tolerance to some anesthetic agents, to recognize drug withdrawal signs and symptoms, and to be prepared to manage all these factors in the perioperative period.
For optimal patient care through the perioperative period, it is critical to obtain information about patient drug use and other associated treatment in order to construct an appropriate anesthetic plan, including specific considerations during surgery, emergence, and in the postanesthesia care unit.
JTE-052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD).
To evaluate the efficacy and safety of JTE-052 ointment in Japanese adult patients with AD.
Methods Patients with moderate-to-severe AD were randomised (2:2:2:2:1:1) to receive JTE-052 ointment at 0.25%, 0.5%, 1% or 3%, the vehicle ointment or 0.1% tacrolimus ointment (reference) twice daily for 4 weeks. The primary efficacy endpoint was the percent change in modified Eczema Area Severity Index (m-EASI) score from the baseline at the end of treatment (EOT). Secondary efficacy endpoints included change from baseline in the pruritus numeric rating scale (NRS) score.
A total of 327 patients were enrolled. At EOT, the least-squares mean percent change from baseline in m-EASI score for JTE-052 0.25%, 0.5%, 1%, 3% and the vehicle ointment was –41.7%, –57.1%, –54.9%, –72.9% and –12.2%, respectively. All JTE-052 groups showed significant reductions of m-EASI score versus the vehicle group (p <0.001 for all). In the tacrolimus group, the mean percent change in m-EASI score was –62.0%. JTE-052 groups also showed significant improvement in other parameters; notably, the pruritus NRS score was reduced as early as Day 1 night-time. JTE-052 ointment at doses up to 3% was safe and well tolerated.
Topical JTE-052 markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD with a favourable safety profile. The study results indicate that topical JTE-052 is a promising therapeutic option for AD.
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Past studies utilizing cognitive control tasks have noted that trials following errors are characterized by slowed reaction time. Despite the assumption long held by researchers that this slowing is compensatory (in the service of post-error performance recovery), studies consistently show that post-error trials are no more accurate than post-correct trials. As a result, it has recently been proposed that post-error slowing (PES) is merely part of an orienting response that serves no task-relevant cognitive control purpose. Frontal midline theta (FMθ) oscillations represent another potential compensatory mechanism serving cognitive control processes, yet past studies relying on ERPs have failed to find an association between FMθ and post-error accuracy. The present study investigated the potentially adaptive role of PES and FMθ oscillations during a flanker task using trial-by-trial comparisons. Results indicated that error-related FMθ oscillations signal the need for enhanced top-down cognitive control and that PES supports cognitive control by providing the added time needed to achieve greater confidence in judgment. Overall, findings provide convergent evidence that both error-related FMθ and PES predict performance recovery following errors.
Reactive cognitive control refers to a complementary set of cognitive operations by which individuals monitor for and detect the presence of goal-interfering conflict (i.e., conflict monitoring/evaluation) and, subsequently, initiate attention-focusing and response selection processes to bolster goal-directed action in the face of such conflict (regulative control). The purpose of the current study was to characterize the nature of conflict adaptation in both components of this dynamic process across sequences of trials and, more broadly, across time as participants complete a cognitive control task. Fifty-two young adults completed a standard arrow flanker task while behavioral and ERP data were recorded. Multilevel modeling of sequences of compatible and incompatible trials over time showed that, whereas response time data demonstrated a typical conflict adaptation effect throughout the task, N2 and frontal slow wave (FSW) indices of conflict monitoring and regulative control, respectively, demonstrated significant conflict adaptation only during the early part of the task. Moreover, although differential change in N2 and FSW over time suggested that conflict monitoring and regulative control were dissociable, a reciprocal relation between them was maintained throughout the task and was not present in a component theoretically unrelated to conflict adaptation (visual attention-related N1). Findings are discussed in terms of compensatory processes that help to maintain goal-directed performance even as control-related neural responses become fatigued.
To cope with the facility location problem, a method based on simulated annealing and "ZKW" algorithm is proposed in this article. The method is applied to some real cases, which aims to deploy video content server at appropriate nodes in an undirected graph to satisfy the requirements of the consumption nodes with the least cost. Simulated annealing can easily find the optimum with less reliance on the initial solution. "ZKW" algorithm can find the shortest path and calculate the least cost from the server node to consumption node quickly. The results of three kinds of cases illustrate the efficiency of our method, which can obtain the optimum within 90 s. A comparison with Dijkstra and Floyd algorithms shows that, by using "ZKW" algorithm, the method can have large iteration with limited time. Therefore, the proposed method is able to solve this video content server location problem.
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Based on a fractional subequation and the properties of the modified Riemann-Liouville fractional derivative, we propose a new analytical method named extended fractional -expansion method for seeking traveling wave solutions of fractional partial differential equations. To illustrate the effectiveness of the method, we discuss a space-time fractional Fokas equation, many types of exact analytical solutions are obtained, and the solutions include hyperbolic function and trigonometric and negative exponential solutions.
from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2wlJak6
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Purpose. Astaxanthin (AST) has a strong antioxidant cellular membrane chaperone protective effect. Recently, a water-soluble nanosized AST (nano-AST) form was produced, which is expected to improve the efficacy of oral intake effects. The purpose of this study was to examine whether oral nano-AST has therapeutic effects on UV-induced photokeratitis in mice. Methods. C57BL/6 mice were administered twice with either nano-AST, AST oil, lutein, or bilberry extracts 3 hours before and shortly before UV irradiation (dose: 400 mJ/cm2). The corneas were collected 24 hours after irradiation and stained with H&E and TUNEL. NF-κB, dihydroethidium (DHE), COX-2, p-IκB-α, TNFα, and CD45 expression were evaluated through immunohistochemistry, Western blot analysis, and qPCR. Results. Corneal epithelium was significantly thicker in mice orally administered with nano-AST than in the others (), with significantly less NF-κB nucleus translocation (), and significantly fewer TUNEL cells (). Weaker DHE signals were detected in the nano-AST group () relative to the others. Furthermore, reduced inflammation and decreased cell death in corneal tissue were observed in the nano-AST group, as indicated by a reduction in the expression of COX-2, p-IκB-α, TNFα, and CD45. Conclusions. Oral administration of nano-AST demonstrated a protective effect on UV-induced photokeratitis via antioxidative, anti-inflammatory, and antiapoptotic activity.
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The aim of the study is to investigate the relationship between physical activity as assessed by accelerometers and cognitive development across the human age ranges (from children and adolescents to adults). Additionally, this study seeks to explore whether physical activity contributes to cognitive development via modification of plasma insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor (BDNF). In the study, 500 preschool children (3.5–5.5 years old) are taking part in 6 triennial assessment waves over the span of 15 years. At each wave, participant measures included (a) 7-day physical activity monitoring using ActiGraph's GT3X accelerometers, (b) the evaluation of cognitive development, (c) anthropometric and physical fitness assessments, (d) plasma IGF-1 and BDNF concentrations, and (e) retrospective questionnaires. Linear regression models are used to examine the effect of physical activity on cognitive development; plasma IGF-1 and BDNF concentrations are considered as mediators into data analyses. The results of the study may help to inform future health interventions that utilize physical activity as a means to improve cognitive development in children, adolescents, and adults. Additionally, the study may assist in determining whether the putative effects occur via modification of plasma IGF-1 or BDNF concentrations.
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As an important complex problem, the temporal logic model checking problem is still far from being fully resolved under the circumstance of DNA computing, especially Computation Tree Logic (CTL), Interval Temporal Logic (ITL), and Projection Temporal Logic (PTL), because there is still a lack of approaches for DNA model checking. To address this challenge, a model checking method is proposed for checking the basic formulas in the above three temporal logic types with DNA molecules. First, one-type single-stranded DNA molecules are employed to encode the Finite State Automaton (FSA) model of the given basic formula so that a sticker automaton is obtained. On the other hand, other single-stranded DNA molecules are employed to encode the given system model so that the input strings of the sticker automaton are obtained. Next, a series of biochemical reactions are conducted between the above two types of single-stranded DNA molecules. It can then be decided whether the system satisfies the formula or not. As a result, we have developed a DNA-based approach for checking all the basic formulas of CTL, ITL, and PTL. The simulated results demonstrate the effectiveness of the new method.
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With layered milling flour technology, the efficiency of the nutrient distribution and hardness was demonstrated with the green and normal wheat separation milling. The results showed that the total content of amino acid in green wheat was 8.3%–13.0% higher compared to the common wheat. Comparing the main nutriments Se, Fe, and Ca between green wheat and common wheat, the results showed that different milling treatment methods are capable of separating the different wheat flour from endosperms, bran, and aleurone layers. Micro- and physicochemical characterization of different wheat flour and layers by means of microscopy techniques and images analysis provided relevant qualitative and quantitative information, which can be useful for the study of the microstructure of green and normal wheat products and also for its processing and utilization.
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Brain endocasts obtained from computed tomography (CT) are now widely used in the field of comparative neuroanatomy. They provide an overview of the morphology of the brain and associated tissues located in the cranial cavity. Through anatomical comparisons between species, insights on the senses, the behavior, and the lifestyle can be gained. Although there are many studies dealing with mammal and bird endocasts, those performed on the brain endocasts of squamates are comparatively rare, thus limiting our understanding of their morphological variability and interpretations. Here, we provide the first comparative study of snake brain endocasts in order to bring new information about the morphology of these structures. Additionally, we test if the snake brain endocast encompasses a phylogenetic and/or an ecological signal. For this purpose, the digital endocasts of 45 snake specimens, including a wide diversity in terms of phylogeny and ecology, were digitized using CT, and compared both qualitatively and quantitatively. Snake endocasts exhibit a great variability. The different methods performed from descriptive characters, linear measurements and the outline curves provided complementary information. All these methods have shown that the shape of the snake brain endocast contains, as in mammals and birds, a phylogenetic signal but also an ecological one. Although phylogenetically related taxa share several similarities between each other, the brain endocast morphology reflects some notable ecological trends: e.g. (i) fossorial species possess both reduced optic tectum and pituitary gland; (ii) both fossorial and marine species have cerebral hemispheres poorly developed laterally; (iii) cerebral hemispheres and optic tectum are more developed in arboreal and terrestrial species.
The ganglion pterygopalatinum has become a therapeutic target to treat various pain syndromes in recent years. It is located in the fossa pterygopalatina, and the fissura pterygomaxillaris is the main access to surgically approach this structure. Recently, the neuromodulation of the ganglion pterygopalatinum by microstimulator implantation has become the first therapeutic line in refractory cluster headache treatment. This invasive technique is performed transorally through the fissura pterygomaxillaris, and is limited by the size of the implantation device, which requires an opening of at least 2 mm. Therefore, extensive knowledge about the anatomy of the fissura pterygomaxillaris prior to surgery is necessary to predict the success of both the approach and intervention. Likewise, establishing a morphological typology of the different fissura pterygomaxillaris variations would be a valuable predictive tool in the clinical practice. In this work, an anatomical analysis was performed of the morphological characteristics of the 242 fissurae pterygomaxillares, which corresponded to 121 adult patients, 58 males and 63 females, aged between 18 and 87 years. For each subject, right and left fissures were studied with radiological computed tomography images. Aperture fissura pterygomaxillaris measurements were taken in an upper (Measure A), middle (Measure B) and lower craneo-caudal third (Measure C). Intra-subject differences were studied between the measurements taken of each patient's right and left fissures, and the inter-subject measures in which fissures were compared according to patients' age and gender. The obtained results showed no significant differences between each patient's right and left fissures in any three measurements taken. Intra-subject differences were not significant for gender or age. No statistically significant differences were found for the inter-subject measures between the measures of fissures according to patients' age. However, our data revealed that males' fissurae pterygomaxillares were significantly larger than those of females in all three measures. Having analysed fissures, a typological classification was made according to the morphological patterns found. A 2-mm limiting measure was considered, and Measures A, B and C of each fissure were classified depending on whether they had a value above or equal to 2 mm, or below 2 mm. With this classification criterion, four fissurae pterygomaxillares types were obtained. Type I and II fissure values (with a higher prevalence) were equal to or were greater than 2 mm in all three measures, or in two measures. Type III fissure values were only greater than or equal to 2 mm in Measure A, whereas all the Type IV fissure values were below 2 mm. Future studies are necessary to correlate the fissure types successfully proposed in the surgical ganglion pterygopalatinum approach.
The existing different modes of reproduction in monotremes, marsupials and placentals are the main source for our current understanding of the origin and evolution of the mammalian reproduction. The reproductive strategies and, in particular, the maturity states of the neonates differ remarkably between the three groups. Monotremes, for example, are the only extant mammals that lay eggs and incubate them for the last third of their embryonic development. In contrast, marsupials and placentals are viviparous and rely on intra-uterine development of the neonates via choriovitelline (mainly marsupials) and chorioallantoic (mainly placentals) placentae. The maturity of a newborn is closely linked to the parental care strategy once the neonate is born. The varying developmental degrees of neonates are the main focus of this study. Monotremes and marsupials produce highly altricial and nearly embryonic offspring. Placental mammals always give birth to more developed newborns with the widest range from altricial to precocial. The ability of a newborn to survive and grow in the environment it was born in depends highly on the degree of maturation of vital organs at the time of birth. Here, the anatomy of four neonates of the three major extant mammalian groups is compared. The basis for this study is histological and ultrastructural serial sections of a hatchling of Ornithorhynchus anatinus (Monotremata), and neonates of Monodelphis domestica (Marsupialia), Mesocricetus auratus (altricial Placentalia) and Macroscelides proboscideus (precocial Placentalia). Special attention was given to the developmental stages of the organs skin, lung, liver and kidney, which are considered crucial for the maintenance of vital functions. The state of the organs of newborn monotremes and marsupials are found to be able to support a minimum of vital functions outside the uterus. They are sufficient to survive, but without capacities for additional energetic challenges. The organs of the altricial placental neonate are further developed, able to support the maintenance of vital functions and short-term metabolic increase. The precocial placental newborn shows the most advanced state of organ development, to allow the maintenance of vital functions, stable thermoregulation and high energetic performance. The ancestral condition of a mammalian neonate is interpreted to be similar to the state of organ development found in the newborns of marsupials and monotremes. In comparison, the newborns of altricial and precocial placentals are derived from the ancestral state to a more mature developmental degree associated with advanced organ systems.
Metastasis is the commonest bone tumors. The commonest primary metastasis to the bone are the breast, lung, prostate, kidney, and thyroid. The bone is the third common site of metastatic disease, only the lung and the liver have higher metastatic rate than skeleton. We have no epidemiological studies conducted to evaluate the various aspects of skeletal metastasis like age, sex distribution, presentation, common sites of primary and associated secondary metastases, and investigation from Indian subcontinent. Here we are presenting the first epidemiological study of skeletal metastasis from our region. We have conducted a prospective descriptive study in the Departments of Orthopedics and Radiotherapy, Government Medical College, Kozhikode, during the period of 2007 to 2009. One hundred eleven patients were included in the study above the age of 30 years. Clinical examination and investigation were done on these patients. Skeletal metastasis commonly occurs in the fifth decade of life with modest male preponderance. In most of the cases, the primary site of malignancy was undetected at the time of presentation. Pain was the commonest presented complaint of the patient. The spine is the commonest site affected and the lung was the common site of primary metastasis. Most of the cases were detected by radiogram and confirmation was obtained by minimally invasive technique like FNAC or CNB.
To evaluate the color stability of novel bulk-fill composite resins.
Color measurements of a nanohybrid composite resin (Z550) and 3 bulk-fill composite resins (BLK, AFX, XTF; n = 45) were performed before polymerization. After polymerization, color measurements were repeated and specimens were immersed in distilled water or red wine, or coffee. Color change [CIEDE2000 (ΔE00)] was calculated after 24 h, 1 and 3 weeks. Data were analyzed with Kruskal-Wallis, Mann-Whitney U and Wilcoxon tests (α = 0.05).
Color changes observed after polymerization were significant for all groups. Color changes observed in distilled water for Z550 and AFX were significant. Color changes after stored in red wine and coffee were significant for all groups. Bulk-fill composite resin color change increased over time for all groups in red wine and coffee (P < .05).
Polymerization significantly changed the color of nanohybrid composite resin and bulk-fill composite resins. AFX had the highest color change in distilled water. The color of tested bulk-fill composite resins significantly changed after immersion in beverages and over time. Color change observed with the nanohybrid composite resin after 1 week was stable.
Clinicians should keep in mind that tested composite resins may change color when exposed to water and significantly change color immediately after they are polymerized. In addition, the color change continues over time should the patient is a coffee and/or red wine consumer.
