Chronic Hyperglycaemia Induced Alterations of Hepatic Stellate Cells Differ from the Effect of TGFB1, and Point toward Metabolic Stress

Abstract

The deleterious effect of hyperglycemia on the biology of the liver is supported by clinical evidence. It can promote the development of fatty liver, liver fibrosis, even liver cancer as complication of diabetes mellitus. As liver fibrosis is the consequence of hepatic stellate cell (HSC) activation, the questions were addressed whether alterations induced by high glucose concentration are directly related to TGFB1 effect, or other mechanisms are activated. In order to obtain information on the response of HSC for high glucose, LX-2 cells (an immortalized human HSC cell lineage) were cultured in 15.3 mM glucose containing medium for 21 days. The effect of glucose was compared to that of TGFB1. Our data revealed that chronic exposure of high glucose concentration initiated profound alteration of LX-2 cells and the effect is different from those observed upon interaction with TGFB1. Whereas TGFB1 induced the production of extracellular matrix proteins, high glucose exposure resulted in decreased MMP2 activity, retardation of type I collagen in the endoplasmic reticulum, with decreased pS6 expression, pointing to development of endoplasmic stress and sequestration of p21^CIP1/WAF1 in the cytoplasm which can promote the proliferation of LX2 cells.

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Bacterial and ciliate biofilm community structure at different spatial levels of a salt lake meta-community

Abstract

Meta-communities are assembled along an ecological scale that determines local and regional diversity. Spatial patterns have been detected in planktonic bacterial communities at distances <20 m, but little is known about the occurrence of similar variation for other microbial groups and changes in microbial meta-community assembly at different levels of a meta-community. To examine this variation, the biofilm of eight saline ponds were used to investigate processes shaping diversity within ponds (β) and between ponds (δ). Bacterial and ciliate communities were assessed using ARISA and T-RFLP respectively, while diversity partitioning methods were used to examine the importance of taxonomic turnover and variation partitioning was used to distinguish spatial from environmental determinants. The results show that turnover is important for determining β- and δ-diversity of biofilms. Spatial factors are important drivers of bacterial β-diversity but were unimportant for ciliate β-diversity. Environmental variation was a strong determinant of bacterial and ciliate δ-diversity, suggesting sorting processes are important for assembling pond communities. Determinants of diversity in bacteria are not universal for ciliates, suggesting higher functional redundancy of bacteria or the greater niche breadth of ciliates may be important in discriminating assembly processes between the two organisms.

https://ift.tt/2w5KsRw

Assessment of Sep1virus interaction with stationary cultures by transcriptional and flow cytometry studies

ABSTRACT

The majority of phage infection studies are performed in bacteria that are growing exponentially, although in nature, phages usually interact also with non-replicating cells. These stationary-phase cells differ from exponential cells morphologically, physiologically and metabolically. The interaction of a Sep1virus with Staphylococcus epidermidis stationary and exponential phase cells was explored. Phage SEP1 efficiently infected both cell culture states, without the addition of any fresh nutrients to stationary cultures. Phage–host interactions, analysed by flow cytometry, showed stationary-phase cells response to phage immediately after SEP1 addition. Quantitative PCR experiments corroborate that phage genes are expressed within 5 min of contact with stationary phase cells. The increase of host RNA polymerase transcripts in stationary cells suggests that SEP1 infection leads to the upregulation of host machinery fundamental for completion of its lytic life cycle. SEP1 infection and replication process highlights its potential clinical interest targeting stationary phase cells.

https://ift.tt/2MqYMOz

Clinical and prognostic profile of Her2neu positive (non-luminal) intrinsic breast cancer subtype: comparison with Her2neu positive luminal breast cancers

Her2neu receptor is proto-oncogene which can be over-expressed in both luminal and non-luminal breast cancers. In the present study, we aimed to compare the prognostic and predictive factors like tumor grade, ...

https://ift.tt/2MqHp0c

Rifampicin resistance in new bacteriologically confirmed pulmonary tuberculosis patients in Cameroon: a cross-sectional survey

In Cameroon, tuberculosis (TB) cases are diagnosed and treated within a nationwide network of 248 diagnostic and treatment centres. In 2016, the centers notified a total of 175 multidrug-resistant (MDR-)TB cas...

https://ift.tt/2MKsM51

Successful nonsurgical therapy of a diabetic foot osteomyelitis in a patient with peripheral artery disease with almost complete radiological restoration

Diabetic foot ulcer (DFU) is a common complication in patients with diabetes mellitus (DM) and can consequently lead to soft tissue infection and osteomyelitis.

https://ift.tt/2MlWUql

Utilization of insecticide treated bed net and associated factors among households of Kola Diba town, North Gondar, Amhara region, Ethiopia

The primary aim of this study was to assess the utilization of an insecticide-treated bed net on the preceding night and associated factors among households of Kola Diba town in 2017.

https://ift.tt/2MIPhXZ

Determinants of hypothermia on neonates admitted to the intensive care unit of public hospitals of Central Zone, Tigray, Ethiopia 2017: unmatched case–control study

This study aims to identify determinants of hypothermia in neonates in neonatal intensive care unit of public hospitals of Central Zone Tigray, Ethiopia in 2017.

https://ift.tt/2vJnTCD

Prognostic and predictive biomarkers in nonmetastatic colorectal cancers

Future Oncology, Ahead of Print.


https://ift.tt/2BaDP6h

How PERK kinase conveys stress signals to nuclear factor-κB to mediate estrogen-induced apoptosis in breast cancer cells?

How PERK kinase conveys stress signals to nuclear factor-κB to mediate estrogen-induced apoptosis in breast cancer cells?

How PERK kinase conveys stress signals to nuclear factor-κB to mediate estrogen-induced apoptosis in breast cancer cells?, Published online: 13 August 2018; doi:10.1038/s41419-018-0516-y

How PERK kinase conveys stress signals to nuclear factor-κB to mediate estrogen-induced apoptosis in breast cancer cells?

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Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal [PublishAheadOfPrint]

Antiretroviral therapy (ART) does not cure HIV-1 infection due to the persistence of proviruses in long-lived resting T cells. Strategies targeting these latently infected cells will be necessary to eradicate HIV-1 in infected individuals. Protein kinase C (PKC) activation is an effective mechanism to reactivate latent proviruses, and allows for recognition and clearance of infected cells by the immune system. Several ingenol compounds, naturally occurring PKC agonists, have been described to have potent latency reversal activity. We sought to optimize this activity by synthesizing a library of novel ingenols via esterification of the C3 hydroxyl group of the ingenol core, which itself is inactive for latency reversal. Newly synthesized ingenol derivatives were evaluated for latency reversal activity, cellular activation and cytotoxicity alongside commercially available ingenols (ingenol-3,20-dibenzoate, ingenol 3-hexanoate and ingenol-3-angelate) in HIV latency cell lines and resting CD4⁺ T cells from aviremic participants. Among the synthetic ingenols that we produced, we identified several compounds that demonstrate high efficacy and represent promising leads as latency reversal agents for HIV-1 eradication.

https://ift.tt/2nBgxg1

In vitro Activities of the Benzoquinolizine Fluoroquinolone Levonadifloxacin (WCK 771) and Other Antimicrobial Agents Against Human Mycoplasmas and Ureaplasmas Including Isolates with Defined Resistance Mechanisms [PublishAheadOfPrint]

Levonadifloxacin (WCK 771) was evaluated against 68 type strains and clinical isolates of Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma pneumoniae and Ureaplasma species in comparison to moxifloxacin, levofloxacin, tetracycline and azithromycin or clindamycin. Levonadifloxacin MICs were ≤ 0.5 μg/ml for Mycoplasma genitalium. MIC_90s (μg/ml) were 1 (Mycoplasma hominis), 0.125 (Mycoplasma pneumoniae) and 2 (Ureaplasma spp). Levonadifloxacin merits further study for treating infections caused by these organisms.

https://ift.tt/2MJu9Rj

Disrupting Gram-negative bacterial outer membrane biosynthesis through inhibition of the lipopolysaccharide transporter MsbA [PublishAheadOfPrint]

There is a critical need for new antibacterial strategies to counter the growing problem of antibiotic resistance. In Gram-negative bacteria, the outer membrane (OM) provides a protective barrier against antibiotics and other environmental insults. The outer leaflet of the outer membrane is primarily composed of lipopolysaccharide (LPS). Outer membrane biogenesis presents many potentially compelling drug targets, as this pathway is absent in higher eukaryotes. Most proteins involved in LPS biosynthesis and transport are essential; however, few compounds have been identified that inhibit these proteins. The inner membrane ABC transporter MsbA carries out the first essential step in the trafficking of LPS to the outer membrane. We conducted a biochemical screen for inhibitors of MsbA, and identified a series of quinoline compounds that kill E. coli through inhibition of its ATPase and transport activity, with no loss of activity against clinical multidrug resistant strains. Identification of these selective inhibitors indicates that MsbA is a viable target for new antibiotics, and the compounds we identified serve as useful tools to further probe the LPS transport pathway in Gram-negative bacteria.

https://ift.tt/2nCsl1w

Encapsulated quinapyramine sulfate-loaded chitosan/mannitol nanoparticles: biocompatibility and targeting efficiency in rabbit model of trypanosomosis [PublishAheadOfPrint]

Quinapyramine sulfate (QS) produces trypanocidal effect against the parasite Trypanosoma evansi, but often poorly tolerated and causes serious local reactions in animals. The encapsulation of QS in chitosan/mannitol to provide the sustained release would improve both the therapeutic effect of QS and the quality of life of animals treated with this formulation. QS was encapsulated into nanoformulation prepared from chitosan, tripolyphosphate and mannitol nanomatrix (ChQS-NPs). ChQS-NPs were well-ordered in shape with nanoparticle size as determined by transmission electron microscopy and atomic force microscopy. Our research revealed a dose-dependent biosafety and DNA damage in mammalian cells treated with ChQS-NPs. ChQS-NPs were absolutely risk-free at effective as well as many times higher doses against T. evansi. ChQS-NPs were effective in rabbits as they killed the parasites, relieving the animals from the clinical symptoms of the disease. The extent of this protection was similar to that observed with the conventional drug at higher dosages (5 mg QS/Kg Bwt). ChQS-NPs are safe, non toxic and effective as compared to QS and offer a promising alternative to drug-delivery against trypanosomosis in animal models. ChQS-NPs may be useful for the treatment of trypanosomosis due to reduced dosages and frequency of administration.

https://ift.tt/2KVwZBe

Successful treatment of extensively drug-resistant Acinetobacter baumannii ventriculitis with intravenous plus intraventricular tigecycline- a case report [PublishAheadOfPrint]

A 70-year-old woman was adimittetd with subarachnoid haemorrhage. The patient underwent cerebral aneurysm embolization. On hospital day 14, the patient underwent a lumbar subarachnoid continuous drain insertion because of fever and enlarged ventricles were showed on the head computed tomography. On hospital day 19, the patient presented with remittent fever (peak at 39.1 °C) associated with altered mental status. Cerebro-Spinal Fluid (CSF) revealed white blood cell (WBC) count of 53484/mm3 (polymorphonucleocytes,75.4%; monocytes, 24.6 %), red blood cells (RBCs) were +++/HP, glucose was 1.26 mg/dL, and the total proteinwas 14.2 g/dL. The lumbar subarachnoid continunous drain was removed. The patient was started on meropenem 1g intravenous(IV) every 8 h and vancomycin 1g (IV ) every 12h. On hospital day 22, the patient's CSF culture showed that A. baumannii (polymyxin susceptibility was not tested) was susceptible only to tigecycline (MIC ≤1 μg/mL) and cefoperazone sulbatan. The same strain of A. baumannii was isolated from the sputum and blood. With permission, the antimicrobial therapy was changed to intravenous tigecycline (100mg first then 50 mg q12h) and cefoperazone sulbatan (3g q8h). Head computed tomography (CT) demonstrated enlarged ventricles compared with previous studies and an external ventricular drain (EVD) was inserted on hospital day 25. On hospital day 28, the blood culture was negative, however the same strain of A. baumannii was still isolated from the CSF. With permission, tigecycline 2mg intraventricular (IVT) every 12 h was started and lasted for 10 days. On hospital day 38, the patient's CSF culture was negative. On hospital day 104, the patient was discharged. Continued 3-month-follow-up showed no recurrence.

https://ift.tt/2MpQiY6

Treatment of Infections with OXA-48 producing Enterobacteriaceae [PublishAheadOfPrint]

Carbapenemase-producing Enterobacteriaceae (CPE) contribute significantly to the global public health threat of antimicrobial resistance. OXA-48, and its variants, are unique carbapenemases with low level hydrolytic activity toward carbapenems, but no intrinsic activity against expanded spectrum cephalosporins. bla_OXA-48 is usually located on a plasmid, but may also be integrated chromosomally, and these genes have progressively disseminated throughout Europe and the Middle East. Despite the inability of OXA-48-like carbapenemases to hydrolyse expanded spectrum cephalosporins, pooled isolates demonstrate high variable resistance to ceftazidime and cefepime, respectively, likely to represent high rates of extended-spectrum beta-lactamase (ESBL) co-production. In-vitro data from pooled studies suggests that avibactam is the most potent beta-lactamase inhibitor when combined with ceftazidime, cefepime, aztreonam, meropenem or imipenem. Resistance to novel avibactam combinations such as imipenem/avibactam or aztreonam/avibactam has not yet been reported in OXA-48 producers, although only few clinical isolates have been tested. Although combination therapy is thought to improve chances of clinical cure and survival in CPE infection, successful outcomes were seen in ~70% of patients with infections caused by OXA-48-producing Enterobacteriaceae treated with ceftazidime/avibactam monotherapy. A carbapenem in combination with either amikacin or colistin has achieved treatment success in a few case reports. Uncertainty remains over the best treatment options and strategies used to manage these infections. Newly available antibiotics such as ceftazidime/avibactam show promise, however recent reports of resistance are concerning. Newer choices of antimicrobial agents will likely be required to combat this problem.

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Nitazoxanide Inhibits Human Norovirus Replication and Synergizes with Ribavirin by Activation of Cellular Antiviral Response [PublishAheadOfPrint]

Norovirus is the main cause of viral gastroenteritis worldwide. Although norovirus gastroenteritis is self-limiting in immunocompetent individuals, chronic infections with debilitating and life-threatening complications occur in immunocompromised patients. Nitazoxanide (NTZ) has been empirically used in the clinic and demonstrated effectiveness against norovirus gastroenteritis. In this study we aimed at uncovering the antiviral potential and mechanisms of NTZ and its active metabolite, tizoxanide (TIZ) using a human norovirus (HuNV) replicon. NTZ and TIZ, collectively referred to as thiazolides (TZD) potently inhibited replication of HuNV and a norovirus surrogate feline calicivirus. Mechanistic studies revealed that TZD activated cellular antiviral response and stimulated the expression of a subset of interferon-stimulated genes (ISGs), particularly IRF-1 not only in Huh7-based HuNV replicon but also in naïve Huh7, Caco-2 and novel human intestinal organoids. Overexpression of exogenous IRF-1 inhibited HuNV replication; whereas knockdown of IRF-1 largely attenuated the antiviral activity of TZD, suggesting that IRF-1 mediated TZD inhibition of HuNV. By using a JAK inhibitor CP-690550 and STAT1 knockout approach, we found that TZD induced antiviral response independent of the classical Janus Kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Furthermore, TZD and ribavirin synergized to inhibit HuNV replication and completely depleted the replicons from host cells after long-term treatment. In summary, our results demonstrated that TZD combated HuNV replication through activation of cellular antiviral response, in particular inducing a prominent antiviral effector IRF-1. NTZ monotherapy or combination with ribavirin represented promising options for treating norovirus gastroenteritis, especially in immunocompromised patients.

https://ift.tt/2MGsLPy

Activity of aromathecins against African trypanosomes [PublishAheadOfPrint]

African sleeping sickness is responsible for thousands of deaths annually and new therapeutics are needed. This study evaluated aromathecins, experimental inhibitors of mammalian topoisomerase IB, against Trypanosoma brucei African trypanosomes. The compounds had selectively toxic antiparasitic potency, had in situ poisoning activity against the phylogenetically unique topoisomerase in these parasites, and a representative compound intercalated into DNA with micromolar affinity. DNA intercalation and topoisomerase poisoning may contribute to the antitrypanosomal activity of aromathecins.

https://ift.tt/2MkLS4C

C. albicans Zn Cluster Transcription Factors Tac1 and Znc1 are Activated by Farnesol to Up Regulate a Transcriptional Program Including the Multi-Drug Efflux Pump CDR1 [PublishAheadOfPrint]

Farnesol, a quorum-sensing molecule, inhibits C. albicans hyphal formation, affects its biofilm formation and dispersal, and impacts its stress response. Several aspects of farnesol's mechanism of action remain incompletely uncharacterized. Among these are a thorough accounting of the cellular receptors and transporters for farnesol. This work suggests these processes are linked through the Zn cluster transcription factors Tac1 and Znc1, and their induction of the multi-drug efflux pump Cdr1. Specifically, we have demonstrated that Tac1 and Znc1 are functionally activated by farnesol through a mechanism that mimics other means of hyperactivation of Zn cluster transcription factors. This is consistent with our observation that many genes acutely induced by farnesol are dependent on TAC1, ZNC1, or both. A related molecule, 1-dodecanol, invokes a similar TAC1/ZNC1 response, while several other proposed C. albicans quorum sensing molecules do not. Tac1 and Znc1 both bind to and up-regulate the CDR1 promoter in response to farnesol. Differences in inducer and DNA binding specificity lead to Tac1 and Znc1 having overlapping, but non-identical, regulons. Induction of genes by farnesol via Tac1 and Znc1 was inversely related to the level of CDR1 present in the cell, suggesting a model in which induction of CDR1 by Tac1 and Znc1 leads to an increase in farnesol efflux. Consistent with this premise, our results show that CDR1 expression, and its regulation by TAC1 and ZNC1, facilitates growth in the presence of high farnesol concentrations in C. albicans, and in certain strains of its close relative C. dubliniensis.

https://ift.tt/2nBg4KN

CAN WE IMPROVE STAVUDINE'S SAFETY PROFILE IN CHILDREN? PHARMACOKINETICS OF INTRACELLULAR STAVUDINE-TRIPHOSPHATE WITH REDUCED-DOSING [PublishAheadOfPrint]

Introduction Stavudine remains a useful replacement option for HIV+ children. WHO reduced the adult dose to 30mg twice-daily, which maintains efficacy and lowers mitochondrial toxicity. We explored intracellular stavudine-triphosphate levels in children receiving a reduced dose of 0.5-0.75mg/kg twice-daily to investigate whether a similar dose optimization can safely be made.

Methods A population pharmacokinetic model was developed to describe the pharmacokinetics of intracellular stavudine-triphosphate in 23 HIV+ children and 24 HIV+ adults who received stavudine at 0.5mg/kg and 20mg twice-daily for 7 days, respectively. Simulations were employed to optimise the paediatric dosing regimen to match exposures in adults receiving the current WHO-recommended dose of 30mg twice-daily.

Results A bi-phasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine-triphosphate. The use of allometric scaling with fat-free mass characterised well the pharmacokinetics in both adults and children, and no other significant effect could be detected. Simulations of 30mg twice-daily in adults predicted median (interquartile range) stavudine-triphosphate C_min and C_max values of 13 (10-19) and 45 (38-53)fmol/10⁶ cells, respectively. Targeting this exposure, simulations in HIV+ children were used to identify a suitable weight-band dosing approach (0.5-0.75mg/kg), which was predicted to achieve C_min and C_max of 13 (9-18) and 49 (40-58)fmol/10⁶ cells, respectively.

Conclusion Weight-band dosing using a stavudine dose of 0.5-0.75mg/kg is proposed and it shows comparable exposures to adults receiving the current WHO recommended dose of 30mg twice-daily. Our pharmacokinetic results suggest that the decreased stavudine dose in children >2years would have a reduced toxic effect while retaining antiretroviral efficacy.

https://ift.tt/2MNCXpa

Minocycline has no clear role in the treatment of Mycobacterium abscessus disease [PublishAheadOfPrint]

Mycobacterium abscessus (Mab) causes difficult-to-treat pulmonary disease (Mab-PD). After the initial intravenous treatment, minocycline is recommended in the oral continuation phase of treatment. We determined minimum inhibitory concentrations, synergy and time-kill kinetics of minocycline against Mab. With MICs of 8-512 mg/l, rapid emergence of tolerance in time-kill assays and no synergy with other drugs used to treat Mab-PD, minocycline appears ineffective against Mab. These in vitro data question its role as a Mab-PD treatment modality.

https://ift.tt/2nB5EL6

Loss of function mutations in epaR confer resistance to phage NPV1 infection in Enterococcus faecalis OG1RF [PublishAheadOfPrint]

Enterococcus faecalis is a Gram-positive opportunistic pathogen that inhabits the human gastrointestinal tract. Because of the high frequency of antibiotic resistance among Enterococcus clinical isolates, interest in using phage to treat enterococcal infections and to decolonize high-risk patients for antibiotic-resistant Enterococcus is rising. Bacteria can evolve phage resistance, but there is little published information on these mechanisms in E. faecalis. In this report, we identified genetic determinants of E. faecalis resistance to NPV1. We found that loss-of-function mutations in epaR confer NPV1 resistance by blocking phage adsorption. We attribute the inability of the phage to adsorb to the modification or loss of an extracellular polymer in strains with inactivated epaR. Phage-resistant epaR mutants exhibited increased daptomycin and osmotic stress susceptibilities. Our results demonstrate that in vitro spontaneous resistance to NPV1 comes at a cost in E. faecalis OG1RF.

https://ift.tt/2KPZMXu

Nontuberculous Mycobacterial Lung Diseases Caused by Mixed Infection with Mycobacterium avium complex and Mycobacterium abscessus complex [PublishAheadOfPrint]

Mycobacterium avium complex (MAC) and M. abscessus complex (MABC) comprise the two most important human pathogen groups causing nontuberculous mycobacterial lung disease (NTM-LD). However, there are limited data regarding NTM-LD caused by mixed NTM infections. This study aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-LD caused by mixed infection with these two major NTM pathogen groups. Seventy-one consecutive patients who had been diagnosed with NTM-LD caused by mixed infection with MAC (M. avium or M. intracellulare) and MABC (M. abscessus or M. massiliense) between January 2010 and December 2015 were identified. Nearly all patients (96%) had the nodular bronchiectatic form of NTM-LD. Mixed infection with MAC and M. massiliense (n = 47, 66%) was more common than mixed infection with MAC and M. abscessus (n = 24, 34%), and among the 43 (61%) patients who were treated for NTM-LD for more than 12 months, sputum culture conversion rates were significantly lower in patients infected with MAC and M. abscessus [25% (3/12)] compared with patients infected with MAC and M. massiliense [61% (19/31), P = 0.033]. Additionally, M. massiliense and M. abscessus showed marked differences in clarithromycin susceptibility (90% vs. 6%, P < 0.001). Of the 23 patients who successfully completed treatment, 11 (48%) redeveloped NTM lung disease, with mycobacterial genotyping results indicating that the majority of cases were due to reinfection. Precise identification of etiologic NTM organisms could help predict treatment outcomes in patients with NTM-LD due to mixed infections.

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Treatment of Pseudomonas aeruginosa biofilm present in endotracheal tubes by poly-L-Lysine. [PublishAheadOfPrint]

The endotracheal tube (ETT) is an essential interface between the patient and ventilator in mechanically-ventilated patients. However, a microbial biofilm is formed gradually on this tube and is associated with the development of ventilator-associated pneumonia. Bacteria present in the biofilm are more resistant to antibiotics and current medical practices do not make it possible to eliminate. P. aeruginosa is one of the leading pathogens that cause biofilm infections and ventilator-associated pneumonia. Poly-L-lysine (pLK) is a cationic polypeptide possessing antibacterial properties and mucolytic activity by compacting DNA. We explored here the anti-biofilm activity of pLK to treat P. aeruginosa biofilms on ETT, taking into consideration the necessary constraints for clinical translation in our experimental designs. First, we showed that pLK eradicate P. aeruginosa biofilm formed in vitro on 96-well microplates. We further demonstrated that pLK alters bacterial membrane integrity as revealed by scanning electron microscopy and eventually eradicate biofilm formed either by reference or clinical strains of P. aeruginosa biofilms generated in vitro on ETT. Second, we collected ETT from patients with P. aeruginosa ventilator-associated pneumonia. We observed that a single dose of pLK is able to immediately disrupt the biofilm structure and kills more than 90 % of bacteria present in biofilm. Additionally, we did not observe any lung tolerance issue when pLK solution was instilled into ETT of ventilated-pigs, an animal model particularly relevant to mimic invasive mechanical ventilation in humans. In conclusion, pLK appears as an innovative anti-biofilm molecule which could be applied in the ETT of mechanically-ventilated patients.

https://ift.tt/2nxU9Ei

Screening a Repurposing Library for Inhibitors of Multi-Drug Resistant Candida auris Identifies Ebselen as a Repositionable Candidate for Antifungal Drug Development [PublishAheadOfPrint]

Since its original isolation in 2009, Candida auris has spread across the globe as a causative agent of invasive candidiasis. C. auris is usually intrinsically resistant to fluconazole and can also be resistant to echinocandins and even amphotericin B. Thus, finding new treatment options against this emerging pathogen is urgent. To address this growing problem, we have performed a screen of the Prestwick Chemical Library, a repurposing library of 1,280 small molecules, consisting mostly of approved off-patent drugs, in search for those with activity against a multidrug resistant C. auris isolate. Our initial screen, using standardized susceptibility testing methodologies, identified nine miscellaneous compounds with no previous clinical indication as antifungals or antiseptics that displayed activity against C. auris. Confirmation and follow-up studies identified ebselen as the drug displaying the most potent activity, with 100% inhibition of growth detected at concentrations as low as 2.5 μM. We further evaluated the ability of ebselen to inhibit C. auris biofilm formation and examined the effects of combination therapy of ebselen with clinically used antifungals. We extended our studies to different C. auris strains with varying susceptibility patterns and also confirmed its antifungal activity against C. albicans and clinical isolates of multiple other Candida species. Furthermore, ebselen displays broad antifungal spectrum of action based on its activity against a variety of medically important fungi, including yeasts and molds. Overall our results indicate the promise of ebselen as a repositionable agent for the treatment of candidiasis and possibly other mycoses, and in particular for the treatment of infections refractory to conventional treatment with current antifungals.

https://ift.tt/2MF1DjM

Cyclic nucleotide specific phosphodiesterases as potential drug targets for anti-Leishmania therapy [PublishAheadOfPrint]

The available treatments for leishmaniasis are less than optimal due to inadequate efficacy, toxic side-effects and the emergence of resistant strains, clearly endorsing the urgent need for discovery and development of novel drug candidates. Ideally, these should act via an alternative mechanism-of-action to avoid cross-resistance with the current drugs. As cyclic nucleotide specific phosphodiesterases (PDEs) of L. major have been postulated as putative drug targets, a series of potential inhibitors of Leishmania PDEs was explored. Several displayed potent and selective in vitro activity against L. infantum intracellular amastigotes. One imidazole derivative, compound 35, was shown to reduce the parasite loads in vivo and dose-dependently increase the cellular cAMP level at just 2x and 5x the IC₅₀, indicating a correlation between antileishmanial activity and increased cellular cAMP. Docking studies and molecular dynamics simulations pointed to imidazole 35 exerting its activity through PDE inhibition. This study establishes for the first time that inhibition of cAMP PDEs can potentially be exploited for new antileishmanial chemotherapy.

https://ift.tt/2nBPNfB

Estimating Genetic Relatedness in Admixed Populations

Estimating genetic relatedness, and inbreeding coefficients is important to the fields of quantitative genetics, conservation, genome-wide association studies (GWAS), and population genetics. Traditional estimators of genetic relatedness assume an underlying model of population structure. Each individual is assigned to a population, depending on a priori assumptions about geographical location of sampling, proximity, or genetic similarity. But often, this population assignment is unknown and assumptions about assignment can lead to erroneous estimates of genetic relatedness. I develop a generalized method of estimating relatedness in admixed populations, to account for (1) multi-allelic genomic data, (2) including all nine Identity By Descent (IBD) states, and implement a maximum likelihood based estimator of pairwise genetic relatedness in structured populations, part of the software, InRelate. Replicated estimations of genetic relatedness between admixed full sib (FS), half sib (HS), first cousin (FC), parent-offspring (PO) and unrelated (UR) dyads in simulated and empirical data from the HGDP-CEPH panel shows considerably low bias and error while using InRelate, compared to several previously developed methods. I also propose a bootstrap scheme, and a series of Wald Tests to assign relatedness categories to pairs of individuals.

https://ift.tt/2KLsXex

Gender specific association between the use of complementary and alternative medicine (CAM) and alcohol consumption and injuries caused by drinking in the sixth Tromsø study

Alcohol is consumed almost worldwide and is the most widely used recreational drug in the world. Harmful use of alcohol is known to cause a large disease-, social- and economic burden on society. Only a few st...

https://ift.tt/2vIh6JD

An assessment of the use of complementary and alternative medicine by Korean people using an adapted version of the standardized international questionnaire (I-CAM-QK): a cross-sectional study of an internet survey

In Korea, there are two types of medical doctors: one practises conventional medicine (hereafter called a physician), and the other practises traditional medicine (hereafter called a Korean medical doctor). Th...

https://ift.tt/2OA408c

Rethinking gamma-secretase inhibitors for treatment of non-small cell lung cancer: Is Notch the target?

Lung cancer is the leading cause of cancer deaths among men and women. Gamma-secretase inhibitors, a class of small molecule compounds that target the Notch pathway, have been tested to treat non-small cell lung cancer (NSCLC) in pre-clinical and clinical trials. Although -secretase inhibitors elicit a response in some tumors as single agents and sensitize NSCLC to cytotoxic and targeted therapies, they have not yet been approved for NSCLC therapy. We discuss our recently published pre-clinical study using the -secretase inhibitor AL101, formerly BMS906024, on cell lines and PDX models of NSCLC, primarily lung adenocarcinoma. We propose that Notch pathway mutations may not be the most suitable biomarker for predicting NSCLC response to -secretase inhibitors. Gamma-secretases have over 100 known -secretase cleavage substrates. Many of the -secretase substrates are directly involved in carcinogenesis or tumor progression, and are ideal candidates to be the "on-target" biomarkers for -secretase inhibitors. We propose the need to systematically test the -secretase and other targets as potential biomarkers for sensitivity before continuing clinical trials. Now that we have entered the post-genome/transcriptome era, this goal is easily attainable. Discovery of the biomarker(s) that predict sensitivity to -secretase inhibitors would guide selection of the responder population that is most likely to benefit and move the compounds closer to approval for therapeutic use in NSCLC.

https://ift.tt/2KQHl51

Improved Survival Seen for Some with Pancreatic Cancer [News in Brief]

Results of two trials could prompt changes in clinical practice for patients with operable disease.

https://ift.tt/2Mih6dG

A digital RNA signature of Circulating Tumor Cells predicting early therapeutic response in localized and metastatic breast cancer [Research Articles]

The multiplicity of new therapies for breast cancer presents a challenge for treatment selection. We describe a 17-gene digital signature of breast circulating tumor cell (CTC)-derived transcripts enriched from blood, enabling high-sensitivity early monitoring of response. In a prospective cohort of localized breast cancer, an elevated CTC-Score after three cycles of neoadjuvant therapy is associated with residual disease at surgery (p=0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC-Score correlates with overall survival (p= 0.02), as does persistent CTC signal after four weeks of treatment (p=0.01). In the subset with estrogen receptor (ER)-positive disease, failure to suppress ER-signaling within CTCs after three weeks of endocrine therapy predicts early progression (p=0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of ESR1 mutations, pointing to diverse mechanisms of acquired endocrine drug resistance. Thus, CTC-derived digital RNA signatures enable noninvasive pharmacodynamic measurements to inform therapy in breast cancer.

https://ift.tt/2MGl2kw

Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1- profile in a TLR4-dependent manner

Paclitaxel (PCX) is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of PCX is based on microtubule stabilization inducing cell cycle arrest. Here, we use several tumor models to show that PCX not only induces tumor cell cycle arrest, but also promotes antitumor immunity. In vitro, PCX reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. PCX also modulated the tumor-associated macrophages (TAMs) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that PCX altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells e.g. macrophages (LysM-Cre+/-/TLR4fl/fl), the antitumor effect of PCX was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with PCX detected an enrichment of genes linked to the M1 macrophage activation profile (IFNy-stimulated macrophages). These findings indicate that PCX skews TAMs towards an immunocompetent profile via TLR4, which might contribute to the antitumor effect of PCX and provide a rationale for new combination regimens comprising PCX and immunotherapies as an anticancer treatment.

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Actin cytoskeleton remodeling drives breast cancer cell escape from natural killer-mediated cytotoxicity

Elucidation of the underlying molecular mechanisms of immune evasion in cancer is critical for the development of immunotherapies aimed to restore and stimulate effective antitumor immunity. Here we evaluate the role of the actin cytoskeleton in breast cancer cell resistance to cytotoxic NK cells. A significant fraction of breast cancer cells responded to NK cell attack via a surprisingly rapid and massive accumulation of F-actin near the immunological synapse, a process we termed 'actin response'. Live cell imaging provided direct evidence that the actin response is associated with tumor cell resistance to NK cell-mediated cell death. High-throughput imaging flow cytometry analyses showed that breast cancer cell lines highly resistant to NK cells were significantly enriched in actin response-competent cells as compared to susceptible cell lines. The actin response was not associated with a defect in NK cell activation but correlated with reduced intracellular levels of the cytotoxic protease Granzyme B and a lower rate of apoptosis in target cells. Inhibition of the actin response by knocking down CDC42 or N-WASP led to a significant increase in Granzyme B levels in target cells and was sufficient to convert resistant breast cancer cell lines into a highly susceptible phenotype. The actin response and its protective effects were fully recapitulated using donor-derived primary NK cells as effector cells. Together these findings establish the pivotal role of actin remodeling in breast cancer cell resistance to NK cell-mediated killing.

https://ift.tt/2P38WTU

Four Pros to Integrating EHR, Practice Management Software

MONDAY, Aug. 13, 2018 -- Consolidating electronic health records and practice management software allows practices to save time and money, make fewer mistakes, and reduce the risk of privacy breaches, according to an article published in Physicians...

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AAP Provides Safety Precautions to Prevent Drowning

MONDAY, Aug. 13, 2018 -- Drowning is the leading cause of unintentional injury-related death for children aged 1 to 4 years, with most drownings happening in home swimming pools, according to a report published by the American Academy of...

https://ift.tt/2P03xx7

Prenatal Tdap Vaccination Not Linked to Autism Risk

MONDAY, Aug. 13, 2018 -- Prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination is not associated with increased risk of autism spectrum disorder (ASD) in offspring, according to a study published online Aug. 13 in Pediatrics. Tracy A....

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Contents

https://ift.tt/2KRYAmz

Response:

We would like to thank our colleagues from Cleveland, Das Kunnathu et al,1 for their important study that evaluated the association between white mucosal patch (WMP) and gastric cancer in familial adenomatosis polyposis (FAP) patients and for their comments1 on our study.2

https://ift.tt/2P71k2U

EUS-guided biliary drainage versus ERCP for the primary treatment of malignant distal biliary obstruction: time for a large randomized study

We read with great interest the 2 randomized controlled studies1,2 comparing EUS-guided biliary drainage (EUS-BD) versus ERCP as primary treatment of distal malignant biliary obstruction. Despite different primary outcomes (adverse event rate for Bang et al1 and stent patency duration for Park et al,2) both studies concluded that EUS-BD and ERCP were comparable regarding both primary outcomes and secondary outcomes (ie, technical and clinical success). However, although EUS-BD is a promising technique, we believe that both studies were not sufficiently powered to support their conclusion.

https://ift.tt/2KQQ33e

Editors

https://ift.tt/2KSnp1P

Per-oral endoscopic myotomy in achalasia: Which way to go—anterior or posterior?

We read with great interest the article by Tan et al1 wherein the authors have compared the efficacy and safety of per-oral endoscopic myotomy (POEM) by an anterior versus a posterior approach. The authors concluded that POEM is equally safe and effective when performed by an anterior or a posterior approach. In addition, the incidence of gastroesophageal reflux disease (GERD) was equal in both groups (anterior, 26.7%; posterior, 33.3%).

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Focus on...

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Response:

We would like to thank Dr Kawakubo et al1 for the comments on our article.2 The sample size for this superiority randomized trial was performed for a 2-sided comparison at 80% power, type I error rate of 0.05, based on the primary outcome measure of adverse rates. Therefore, the null hypothesis (H0) was defined as there being no significant difference in adverse event rates between EUS-guided biliary drainage (EUS-BD) and ERCP, and the alternative hypothesis (H1) was defined as a significant difference in adverse event rates between the 2 treatment modalities, without the direction of the difference being specified.

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ASGE update

https://ift.tt/2KSnd2B

Role of warfarin as a predictor of recurrent bleeding after negative small-bowel capsule endoscopy

We read with interest the recent publication by Yung et al,1 who concluded that negative capsule endoscopy (CE) findings adequately demonstrate a subsequently low risk of rebleeding. This finding is important with regard to the treatment of patients with obscure GI bleeding (OGIB) and to risk stratification (Table 1, available online at www.giejournal.org).

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In upcoming issues...

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Worrisome endoscopic feature in the stomach of patients with familial adenomatous polyposis: the proximal white mucosal patch

Gastric adenocarcinoma (GC) is a recently reported cancer risk in Western patients with familial adenomatous polyposis (FAP).1,2 Most GCs in these FAP patients occur in an area of polyposis in the proximal gastric body or fundus.1 We previously demonstrated that Western FAP patients with GC were more likely than were non-GC FAP control patients to have high-risk endoscopic and histologic features, including a carpeting of proximal gastric polyposis, polypoid mounds of proximal polyps, large solitary polyps, and high-risk histologic features (pyloric gland adenoma, tubular adenoma, and fundic gland polyps with high-grade dysplasia).

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Information for readers

https://ift.tt/2KPErh0

Response:

We sincerely appreciate the comments and questions raised by Nabi et al1 regarding our article.2 On the basis of our findings, the short-term (follow-up duration, 9-21 months; mean, 15.5 months) treatment efficacy, manometry outcomes, and adverse events were comparable between the anterior and posterior myotomy groups.

https://ift.tt/2vGO7po

N-Linked Glycopeptide Identification Based on Open Mass Spectral Library Search

Confident characterization of intact glycopeptides is a challenging task in mass spectrometry-based glycoproteomics due to microheterogeneity of glycosylation, complexity of glycans, and insufficient fragmentation of peptide bones. Open mass spectral library search is a promising computational approach to peptide identification, but its potential in the identification of glycopeptides has not been fully explored. Here we present pMatchGlyco, a new spectral library search tool for intact N-linked glycopeptide identification using high-energy collisional dissociation (HCD) tandem mass spectrometry (MS/MS) data. In pMatchGlyco, MS/MS spectra of deglycopeptides are used to create spectral library, MS/MS spectra of glycopeptides are matched to the spectra in library in an open (precursor tolerant) manner and the glycans are inferred, and a false discovery rate is estimated for top-scored matches above a threshold. The efficiency and reliability of pMatchGlyco were demonstrated on a data set of mixture sample of six standard glycoproteins and a complex glycoprotein data set generated from human cancer cell line OVCAR3.

https://ift.tt/2OwJmFS

Improving accuracy of corneal power measurement with partial coherence interferometry after corneal refractive surgery using a multivariate polynomial approach

To improve accuracy of IOLMaster (Carl Zeiss, Jena, Germany) in corneal power measurement after myopic excimer corneal refractive surgery (MECRS) using multivariate polynomial analysis (MPA).

https://ift.tt/2P6QdXK

Eigenspace generalized sidelobe canceller combined with SNR dependent coherence factor for plane wave imaging

The eigenspace generalized sidelobe canceller (EGSC) beamformer combined with a signal-to-noise ratio (SNR) dependent coherence factor (CF) is suggested for coherent plane wave compounding (PW) imaging. Conven...

https://ift.tt/2KPEqcU

The Swiss Multiple Sclerosis Registry (SMSR): study protocol of a participatory, nationwide registry to promote epidemiological and patient-centered MS research

Multiple sclerosis (MS) is one of the most frequently observed neurological conditions in Switzerland, but data sources for country-wide epidemiological trend monitoring are lacking. Moreover, while clinical a...

https://ift.tt/2MJ5NqW

Electroclinical characteristics of seizures arising from the precuneus based on stereoelectroencephalography (SEEG)

Seizures arising from the precuneus are rare, and few studies have aimed at characterizing the clinical presentation of such seizures within the anatomic context of the frontoparietal circuits. We aimed to cha...

https://ift.tt/2Mp1QdS

Routine Screening for Urinary Incontinence in Women: Caution Advised

The Women's Preventive Services Initiative recommends that clinicians screen women of all ages for urinary incontinence annually and, if appropriate, refer them for further evaluation and treatment. This editorial discusses the recommendation and advises caution regarding widespread screening on the basis of limited, indirect evidence.

https://ift.tt/2KQ1qIP

Screening for Urinary Incontinence in Women: A Systematic Review for the Women's Preventive Services Initiative

Background:

Urinary incontinence is infrequently addressed during routine health care despite its high prevalence and adverse effects on health.

Purpose:

To evaluate whether screening for urinary incontinence in women not previously diagnosed improves outcomes (symptoms, quality of life, and function) and to evaluate the accuracy of screening methods and potential harms of screening.

Data Sources:

English-language searches of Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (1 January 1996 to 30 March 2018); ClinicalTrials.gov (April 2018); and reference lists of studies and reviews.

Study Selection:

Randomized trials, cohort studies, systematic reviews of studies that enrolled nonpregnant women without previously diagnosed urinary incontinence and compared clinical outcomes and adverse effects between women who were and were not screened, and diagnostic accuracy studies that reported performance measures of screening tests.

Data Extraction:

Dual extraction and quality assessment of individual studies.

Data Synthesis:

No studies evaluated the overall effectiveness or harms of screening. Seventeen studies evaluated the diagnostic accuracy of 18 screening questionnaires against a clinical diagnosis or results of diagnostic tests. Of these, 14 poor-quality studies were based in referral clinics, enrolled only symptomatic women, or had other limitations. One good-quality and 2 fair-quality studies (evaluating 4 methods) enrolled women not recruited on the basis of symptoms. Areas under the receiver-operating characteristic curve for stress, urge, and any type of incontinence in these studies were 0.79, 0.88, and 0.88 for the Michigan Incontinence Symptom Index; 0.85, 0.83, and 0.87 for the Bladder Control Self-Assessment Questionnaire; and 0.68, 0.82, and 0.75 for the Overactive Bladder Awareness Tool. The Incontinence Screening Questionnaire had a sensitivity of 66% and specificity of 80% for any type of incontinence.

Limitation:

Studies enrolled few participants, often from symptomatic referral populations; used various reference standards; and infrequently reported CIs.

Conclusion:

Evidence is insufficient on the overall effectiveness and harms of screening for urinary incontinence in women. Limited evidence in general populations suggests fairly high accuracy for some screening methods.

Primary Funding Source:

Health Resources and Services Administration.

https://ift.tt/2MEqMeq

Tumor Necrosis Factor Inhibitors and Cancer Relapse

https://ift.tt/2MoXUK8

Screening for Urinary Incontinence in Women: A Recommendation From the Women's Preventive Services Initiative

Description:

Recommendation on screening for urinary incontinence in women by the Women's Preventive Services Initiative (WPSI), a national coalition of women's health professional organizations and patient representatives. The WPSI's recommendations are intended to guide clinical practice and coverage of services for the Health Resources and Services Administration and other stakeholders. The target audience for this recommendation includes all clinicians providing preventive health care for women, particularly in primary care settings. This recommendation applies to women of all ages, as well as adolescents.

Methods:

The WPSI developed this recommendation after evaluating evidence regarding the benefits and harms of screening for urinary incontinence in women. The evaluation included a systematic review of the accuracy of screening instruments and the benefits and harms of treatments. Indirect evidence was used to link screening and health outcomes in the chain of evidence that might support screening in the absence of direct evidence. The WPSI also considered the effect of screening on symptom progression and avoidance of costly and complex treatments, as well as implementation factors.

Recommendation:

The WPSI recommends screening women for urinary incontinence annually. Screening ideally should assess whether women experience urinary incontinence and whether it affects their activities and quality of life. The WPSI recommends referring women for further evaluation and treatment if indicated.

https://ift.tt/2MLIKvt

Screening for Urinary Incontinence in Women: A Recommendation from the Women's Preventive Services Initiative

https://ift.tt/2MlpKal

Real-Time Use of Artificial Intelligence in Identification of Diminutive Polyps During Colonoscopy A Prospective Study

Background:

Computer-aided diagnosis (CAD) for colonoscopy may help endoscopists distinguish neoplastic polyps (adenomas) requiring resection from nonneoplastic polyps not requiring resection, potentially reducing cost.

Objective:

To evaluate the performance of real-time CAD with endocytoscopes (×520 ultramagnifying colonoscopes providing microvascular and cellular visualization of colorectal polyps after application of the narrow-band imaging [NBI] and methylene blue staining modes, respectively).

Design:

Single-group, open-label, prospective study. (UMIN [University hospital Medical Information Network] Clinical Trial Registry: UMIN000027360).

Setting:

University hospital.

Participants:

791 consecutive patients undergoing colonoscopy and 23 endoscopists.

Interventions:

Real-time use of CAD during colonoscopy.

Measurements:

CAD-predicted pathology (neoplastic or nonneoplastic) of detected diminutive polyps (≤5 mm) on the basis of real-time outputs compared with pathologic diagnosis of the resected specimen (gold standard). The primary end point was whether CAD with the stained mode produced a negative predictive value (NPV) of 90% or greater for identifying diminutive rectosigmoid adenomas, the threshold required to "diagnose-and-leave" nonneoplastic polyps. Best- and worst-case scenarios assumed that polyps lacking either CAD diagnosis or pathology were true- or false-positive or true- or false-negative, respectively.

Results:

Overall, 466 diminutive (including 250 rectosigmoid) polyps from 325 patients were assessed by CAD, with a pathologic prediction rate of 98.1% (457 of 466). The NPVs of CAD for diminutive rectosigmoid adenomas were 96.4% (95% CI, 91.8% to 98.8%) (best-case scenario) and 93.7% (CI, 88.3% to 97.1%) (worst-case scenario) with stained mode and 96.5% (CI, 92.1% to 98.9%) (best-case scenario) and 95.2% (CI, 90.3% to 98.0%) (worst-case scenario) with NBI.

Limitation:

Two thirds of the colonoscopies were conducted by experts who had each experienced more than 200 endocytoscopies; 186 polyps not assessed by CAD were excluded.

Conclusion:

Real-time CAD can achieve the performance level required for a diagnose-and-leave strategy for diminutive, nonneoplastic rectosigmoid polyps.

Primary Funding Source:

Japan Society for the Promotion of Science.

https://ift.tt/2MlpDLX

Treatment of Acute Intoxication From Inhaled 1,2-Difluoroethane

https://ift.tt/2KPjWB4

Tumor Necrosis Factor Inhibitors and Cancer Recurrence in Swedish Patients With Rheumatoid Arthritis A Nationwide Population-Based Cohort Study

Background:

Use of tumor necrosis factor inhibitors (TNFi) in patients with a history of cancer remains a clinical dilemma.

Objective:

To investigate whether TNFi treatment in rheumatoid arthritis (RA) is associated with increased risk for cancer recurrence.

Design:

Population-based cohort study based on linkage of nationwide registers.

Setting:

Sweden.

Participants:

Patients with RA who started TNFi treatment between 2001 and 2015, after being diagnosed with cancer, and matched patients with RA and a history of the same cancer who had never received biologics.

Measurements:

The primary outcome was the first recurrence of cancer. Adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs), taking into account time, cancer type, and whether the cancer was invasive or in situ (or tumor, node, metastasis [TNM] classification system stage in a subset of patients).

Results:

Among 467 patients who started TNFi treatment (mean time after cancer diagnosis, 7.9 years), 42 had cancer recurrences (9.0%; mean follow-up, 5.3 years); among 2164 matched patients with the same cancer history, 155 had recurrences (7.2%; mean follow-up, 4.3 years) (HR, 1.06 [95% CI, 0.73 to 1.54). Hazard ratios were close to 1 in analyses of patient subsets matched on cancer stage or with similar time from index cancer diagnosis to the start of TNFi treatment, as well as in unmatched analyses. Several CIs had upper limits close to 2.

Limitation:

The outcome algorithm was partly nonvalidated, and channeling bias was possible if patients with a better index cancer prognosis were more likely to receive TNFi.

Conclusion:

The findings suggest that TNFi treatment is not associated with increased risk for cancer recurrence in patients with RA, although meaningful risk increases could not be ruled out completely.

Primary Funding Source:

ALF (an agreement in Stockholm County Council concerning medical education and research in health and medical care), the Swedish Cancer Society, the Swedish Foundation for Strategic Research, and the Swedish Research Council.

https://ift.tt/2MqdHZl

Germs of thrones - spontaneous decolonization of Carbapenem-Resistant Enterobacteriaceae (CRE) and Vancomycin-Resistant Enterococci (VRE) in Western Europe: is this myth or reality?

In France, Carbapenem-Resistant Enterobacteriaceae (CRE) and Vancomycin-Resistant Enterococci (VRE) are considered as Extensively Drug-Resistant (XDR) bacteria. Their management requires reinforcement of hospi...

https://ift.tt/2B3wqFH

Leukotoxin and pyrogenic toxin Superantigen gene backgrounds in bloodstream and wound Staphylococcus aureus isolates from eastern region of China

The bicomponent leukotoxins and the pyrogenic toxin superantigens (PTSAgs) are important virulence factors of Staphylococcus aureus. It is necessary to survey the prevalence and expression of these toxin-encoding...

https://ift.tt/2OyMKjD

Undernutrition, intestinal parasitic infection and associated risk factors among selected primary school children in Bahir Dar, Ethiopia

Monitoring of undernutrition and parasitic infection are essential to design appropriate intervention strategies. The aim of this study was to assess the prevalence of undernutrition, intestinal parasitic infe...

https://ift.tt/2OAlfX4

Using Baidu index to nowcast hand-foot-mouth disease in China: a meta learning approach

Hand, foot, and mouth disease (HFMD) has been recognized as one of the leading infectious diseases among children in China, which causes hundreds of annual deaths since 2008. In China, the reports of monthly H...

https://ift.tt/2nAfkWf

CMV on surfaces in homes with young children: results of PCR and viral culture testing

Caring for young children is a known risk factor for cytomegalovirus (CMV) infection mainly through exposure to their saliva and urine. In a previous study, 36 CMV-seropositive children 2 mo. to 4 years old we...

https://ift.tt/2OAlb9M

Encapsulated Follicular Variant of Papillary Thyroid Carcinoma Arising in a Follicular Adenoma: a Diagnostic Dilemma

Abstract

Papillary thyroid carcinoma (PTC) arising within follicular adenoma is a rare histological subset of papillary carcinoma. A 24-year-old female (euthyroid and asymptomatic) presented with a solitary mass in the right lobe of thyroid for 2 years. Fine-needle aspiration cytology (FNAC) suggested features of hyperplasia of thyroid. Hemithyroidectomy was performed. Histopathological examination revealed two distinct areas and was reported as encapsulated variant of papillary carcinoma along with follicular adenoma. Papillary carcinoma was confirmed by positive immunohistochemistry for HBME-1. CT head and neck region ruled out metastasis and the patient was kept on follow-up. There have been reports of medullary and papillary carcinomas occurring together; however, there is a paucity of literature on co-existing follicular neoplasm and papillary carcinoma. We hereby report a rare case of follicular variant of papillary carcinoma arising within follicular adenoma of the thyroid.

https://ift.tt/2KRasoO

Lowering the starting age for colorectal cancer screening to 45 years: Who will come…and should they?

https://ift.tt/2OyatQP

Use of Augmented Reality and Virtual Reality Technologies in Endoscopic Training

https://ift.tt/2MnpEih

Combination therapy with vedolizumab and tofacitinib in a patient with ulcerative colitis and spondyloarthropathy

https://ift.tt/2MHHB8q

Successful Hemostasis of Bleeding from Biliary Varices

https://ift.tt/2MnOyP3

A Letter to the Editor regarding the Houston Consensus Conference on Testing for Helicobacter Pylori

https://ift.tt/2MHxTme

Spontaneous Seroclearance of Hepatitis B Surface Antigen and Risk of Hepatocellular Carcinoma

https://ift.tt/2MtBQ1m

https://ift.tt/2B6N9rw

Removing deep brain stimulation artifacts from the electroencephalogram: issues, recommendations and an open-source toolbox

During the past two decades, deep brain stimulation (DBS) has been recognized as an efficient therapy that alleviates the symptoms of various treatment-resistant movement disorders such as Parkinson's disease (PD), dystonia, and tremor (Lyons, 2011; Vidailhet et al., 2013; Aviles-Olmos et al., 2014; Fasano et al., 2014; Kalia et al., 2013; Larson, 2014). Recent reports suggest that DBS can also be effective for treating psychiatric disorders such as depression, obsessive-compulsive disorder, Tourette's syndrome (Holtzheimer and Mayberg, 2011) as well as dementia-related disorders and Alzheimer's disease (Laxton et al., 2013; Hescham et al., 2013).

https://ift.tt/2MlismZ

Tailored Healthcare: Two Perspectives on the Development and Use of Patient Profiles

Abstract

Calls for a more tailored approach to the management of cardiometabolic and musculoskeletal diseases have been increasing. Although tailored care is a centuries-old concept, it is still unclear how it should be best practised. The current paper introduces two phenotype-based Dutch approaches to support tailored care. One approach focuses on patients with type 2 diabetes, the other on patients undergoing total joint replacement. Using the patient profiling approach, both projects propose that care can be tailored by the assessment of biopsychosocial patient characteristics, stratification of patients into subgroups of patients with similar care needs, abilities, and preferences (so-called patient profiles) and tailoring of care in concordance with the common care preferences of these profiles. In this article, the advantages and disadvantages of the method are discussed to enable researchers or clinicians who want to extend the patient profiling approach to other patient populations to carefully evaluate these in relation to their project's focus and available resources.

Funding: Novo Nordisk B.V., the Netherlands Organisation for Scientific Research (NWO) (Grant 314-99-118) and Zimmer Biomet Inc.

https://ift.tt/2MnInKR

Evaluating the Impact and Benefits of Fluticasone Furoate/Vilanterol in Individuals with Asthma or COPD: A Mixed-Methods Analysis of Patient Experiences

Abstract

Introduction

This study evaluated patients' experiences with fluticasone furoate/vilanterol (FF/VI) combination therapy in UK patients with asthma or chronic obstructive pulmonary disease (COPD).

Methods

Participants aged ≥ 18 years, with self-reported, physician-diagnosed asthma or COPD (≥ 1 year) who had been receiving FF/VI (≥ 3 months) were recruited from UK primary care. This two-phase, mixed-methods study consisted of a semi-structured, telephone-interview phase (qualitative) and a self-completed online/paper-survey phase (quantitative).

Results

The telephone-interview phase included 50 individuals [asthma, n = 25; COPD, n = 25; mean age (SD) 56.7 years (13.3); 50% female]. Of these, 21 with asthma reported that their condition was stable/well controlled and 13 with COPD felt their condition was manageable. Most participants found FF/VI easy to use (asthma, 25; COPD, 23), easy to integrate into their daily routine (asthma, 25; COPD, 24), and able to control symptoms for ≥ 24 h (asthma, 14; COPD, 16). During the survey phase, 199 individuals were recruited [asthma, n = 100; COPD, n = 99; mean age (SD) 63.6 years (15.1); 59.3% female]. Most participants were satisfied/very satisfied with the efficacy of FF/VI in terms of all-day symptom relief (asthma, 84%; COPD, 75%) and found FF/VI easy/very easy to fit into their daily routine (asthma, 99%; COPD, 96%), easy/very easy to use (asthma, 97%; COPD, 92%), and convenient/very convenient to take as instructed (asthma, 95%; COPD, 93%). Significantly more individuals with asthma (87% versus 46%, P < 0.001) and numerically more individuals with COPD (84% versus 76%, P = 0.055) were satisfied/very satisfied with FF/VI compared with their most recent previous maintenance medication.

Conclusion

The majority of individuals in this study had confidence in FF/VI and were satisfied or very satisfied with various key attributes of the treatment.

Trial Registration

GSK study HO-15-15503/204888.

Funding

GSK.

https://ift.tt/2MMV7r6

Reconstruction options following pancreaticoduodenectomy after Roux-en-Y gastric bypass: a systematic review

Abstract

Background

Obesity is a risk factor for pancreatic cancer which may be treated with Roux-en-Y gastric bypass and represents an increasing morbidity. Post-RYGB anatomy poses considerable challenges for reconstruction after pancreaticoduodenectomy (PD), a growing problem encountered by surgeons. We characterize specific strategies used for post-PD reconstruction in the RYGB patient.

Methods

PubMed search was performed using MeSH terms "Gastric Bypass" and "Pancreaticoduodenectomy" between 2000 and 2018. Articles reporting cases of pancreaticoduodenectomy in post-RYGB patients were included and systematically reviewed for this study.

Results

Three case reports and five case series (25 patients) addressed PD after RYGB; we report one additional case. The typical post-gastric bypass PD patient is a woman in the sixth decade of life, presenting most commonly with pain (69.2%) and/or jaundice (53.8%), median 5 years after RYGB. Five post-PD reconstructive options are reported. Among these, the gastric remnant was resected in 18 cases (69.2%), with reconstruction of biliopancreatic drainage most commonly achieved using the distal jejunal segment of the pre-existing biliopancreatic limb (73.1%). Similarly, in the eight cases where the gastric remnant was spared (30.8%), drainage was most commonly performed using the distal jejunal segment of the biliopancreatic limb (50%). Among the 17 cases reporting follow-up data, median was 27 months.

Conclusion

Reconstruction options after PD in the post-RYGB patient focus on resection or preservation gastric remnant, as well as creation of new biliopancreatic limb. Insufficient data exists to make recommendations regarding the optimal reconstruction option, yet surgeons must prepare for the possible clinical challenge. PD reconstruction post-RYGB requires evaluation through prospective studies.

https://ift.tt/2MJcWYg

Safflower polysaccharide inhibits the development of tongue squamous cell carcinoma

Abstract

Background

Safflower polysaccharide (SPS) is one of the most important active components of safflower (Carthamus tinctorius L.), which has been confirmed to have the immune-regulatory function and antitumor effect. This study aimed to explore the effects of safflower polysaccharide (SPS) on tongue squamous cell carcinoma (TSCC).

Methods

HN-6 cells were treated with 5 μg/mL cisplatin and various concentrations of SPS (0, 0.02, 0.04, 0.08, 0.16, 0.32, 0.64, and 1.28 mg/mL), and cell proliferation was measured. After treatment with 5 μg/mL cisplatin and 0.64 mg/mL SPS, the induction of apoptosis and the protein and mRNA expression of Bax, Bcl-2, COX-2, and cleaved caspase-3 in HN-6 cells were quantified. In addition, HN-6 cells were implanted into mice to establish an in vivo tumor xenograft model. Animals were randomly assigned to three groups: SPS treatment, cisplatin treatment, and the model group (no treatment). The body weight, tumor volume, and tumor weight were measured, and the expression of the above molecules was determined.

Results

SPS treatment (0.02–0.64 mg/mL) for 24–72 h inhibited HN-6 cell proliferation. In addition, 0.64 mg/mL SFP markedly induced apoptosis in HN-6 cells and arrested the cell cycle at the G0/G1 phase. Compared with the control group, the expression of Bcl-2 and COX-2 was markedly reduced by SPS treatment, whereas the expression of Bax and cleaved caspase-3 was increased. Moreover, SPS significantly inhibited the growth of the tumor xenograft, with similar changes in the expression of Bcl-2, COX-2, Bax, and cleaved caspase-3 in the tumor xenograft to the in vitro analysis.

Conclusions

Our results indicated that SPS may inhibit TSCC development through regulation of Bcl-2, COX-2, Bax, and cleaved caspase-3 expression.

https://ift.tt/2MlhneV

Amendments and Corrections‘Information-theoretic optimality of observation-driven time series models for continuous responses’

Biometrika (2015) 102, pp. 325–43.

https://ift.tt/2P6RRZd

New SERVPRO First Responder Bowl to be played at Cotton Bowl Stadium

DALLAS — In a joint effort to honor the service and sacrifice of America's First Responders, the annual college football bowl game played at Cotton Bowl Stadium in Dallas, Texas has been renamed the SERVPRO First Responder Bowl. Kickoff for the newly christened SERVPRO First Responder Bowl is set for December 26 at 12:30 p.m. CT (1:30 p.m. ET) and will be televised by ESPN. The...

https://ift.tt/2OuHL3p

Is Point-of-Care Ultrasonography Effective for the Diagnosis of Urolithiasis?

The search strategy identified 627 unique abstracts, of which 26 were selected for full-text review. Nine studies were determined to meet the inclusion criteria (3 addressing accuracy only, 3 addressing prognostic value only, and 3 addressing both). One large study by Smith-Bindman et al2 was excluded from diagnostic accuracy assessment because of concern about risk of bias from a weak reference standard (ie, direct stone visualization or surgical removal determined by follow-up telephone call) and a large proportion of patients lost to follow-up (14.4%).

https://ift.tt/2MHs3Bk

What Is the Accuracy of Physical Examination, Imaging, and the LRINEC Score for the Diagnosis of Necrotizing Soft Tissue Infection?

Of 2,290 initial citations, the authors included 23 studies including 16 retrospective cohort studies, 2 prospective cohort studies, and 5 retrospective case-control studies. Pooled sensitivity values for physical examination findings ranged from 21.0% for hypotension to 46.0% for fever (Table). The sensitivity of CT presence of fascial edema, fascial enhancement, or fascial gas was significantly higher than the sensitivity of radiography (94.3% versus 48.9%). Finally, the sensitivity of LRINEC scores was poor, although the specificity for scores greater than or equal to 8 was very good (94.9%).

https://ift.tt/2MkKDT6

Relationship of Patent Ductus Arteriosus Size to Echocardiographic Markers of Shunt Volume

To define the technique of estimating ductal diameter (DD) that best correlates with echocardiographic markers of transductal shunt volume in preterm infants >7 days old with persistent patent ductus arteriosus (PDA).

https://ift.tt/2P5PRRe

A suppressive role of guanine nucleotide-binding protein subunit beta-4 inhibited by DNA methylation in the growth of anti-estrogen resistant breast cancer cells

Abstract

Background

Breast cancer is the most common malignancy in women worldwide. Although the endocrine therapy that targets estrogen receptor α (ERα) signaling has been well established as an effective adjuvant treatment for patients with ERα-positive breast cancers, long-term exposure may eventually lead to the development of acquired resistance to the anti-estrogen drugs, such as fulvestrant and tamoxifen. A better understanding of the mechanisms underlying antiestrogen resistance and identification of the key molecules involved may help in overcoming antiestrogen resistance in breast cancer.

Methods

The whole-genome gene expression and DNA methylation profilings were performed using fulvestrant-resistant cell line 182^R-6 and tamoxifen-resistant cell line TAM^R-1 as a model system. In addition, qRT-PCR and Western blot analysis were performed to determine the levels of mRNA and protein molecules. MTT, apoptosis and cell cycle analyses were performed to examine the effect of either guanine nucleotide-binding protein beta-4 (GNB4) overexpression or knockdown on cell proliferation, apoptosis and cell cycle.

Results

Among 9 candidate genes, GNB4 was identified and validated by qRT-PCR as a potential target silenced by DNA methylation via DNA methyltransferase 3B (DNMT3B). We generated stable 182^R-6 and TAM^R-1 cell lines that are constantly expressing GNB4 and determined the effect of the ectopic GNB4 on cell proliferation, cell cycle, and apoptosis of the antiestrogen-resistant cells in response to either fulvestrant or tamoxifen. Ectopic expression of GNB4 in two antiestrogen resistant cell lines significantly promoted cell growth and shortened cell cycle in the presence of either fulvestrant or tamoxifen. The ectopic GNB4 induced apoptosis in 182^R-6 cells, whereas it inhibited apoptosis in TAM^R-1 cells. Many regulators controlling cell cycle and apoptosis were aberrantly expressed in two resistant cell lines in response to the enforced GNB4 expression, which may contribute to GNB4-mediated biologic and/or pathologic processes. Furthermore, knockdown of GNB4 decreased growth of both antiestrogen resistant and sensitive breast cancer cells.

Conclusion

GNB4 is important for growth of breast cancer cells and a potential target for treatment.

https://ift.tt/2P0X0Ca

Two in, two out: Maintaining your marriage in EMS

Your partner at home can be your best resource in regard to your mental health

https://ift.tt/2B7wTXm

Correlation of serum levels and gene expression of tumor necrosis factor-α-induced protein-8 like-2 with Parkinson disease severity

Abstract

Different immune-mediated mechanisms involved in the pathogenesis of Parkinson disease (PD) as a neurodegenerative and inflammatory disease. According to our knowledge, there is no report evaluating Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2), a cytokine maintaining immune homeostasis, in PD. We analyzed the correlation of the serum levels and circulatory gene expression of TIPE2 with severity of PD. In this case-control study, 43 patients with PD and 40 healthy subjects were enrolled. The diagnosis of PD was performed byclinical diagnostic criteria of the UK Parkinson's Disease Society Brain Bank. The severity of PD was evaluated by modified Hoehn and Yahr (H and Y) scale. Serum levels and gene expression of TIPE2 were assessed by Elisa and real time PCR, respectively. The mean serum levels and gene expression of TIPE2 in patients with PD did not have significant difference compared to healthy subjects. Linear multiple regression analysis showed that increased serum levels of TIPE2 are positively related to age and severity of PD (P ≤ 0.0001). In addition, the gene expression of TIPE2 was found to be associated with age (P < 0.0001). Our study showed that the serum levels of TIPE2 and its gene expression might be important prognostic biomarkers of PD.

https://ift.tt/2B8Wf7g

Donepezil improves the cognitive impairment in a tree shrew model of Alzheimer’s disease induced by amyloid-β 1–40 via activating the BDNF/TrkB signal pathway

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder which can contribute to memory loss and cognitive damage in the elderly; moreover, evidence from clinical and animal studies demonstrated that AD always exhibit severe cognitive deficits. However, the effects of donepezil medications on cognition are controversial. Additionally, it is unclear whether donepezil can protect neurons to improve cognitive function through the brain-derived neurotropic factor (BDNF)/tyrosine receptor kinase B (TrkB) signalling pathway in the tree shrew (TS), which has a closer evolutionary relationship to primates than rodents. Here, we designed a study on an amyloid-β_1–40 (Aβ_1–40)-induced TS model of AD and investigated the molecular mechanism by which donepezil protects neurons and improves cognitive function through activating the BDNF/TrkB signalling pathway. The results showed that donepezil could rescue Aβ_1–40-induced spatial cognition deficits, and reverse Aβ_1–40-induced temporal horn along with ADC enlargement in the TS brain. Meanwhile, it suppressed Aβ_1–40-induced neuronal damage and loss of body weight. Intriguingly, donepezil could increase the choline acetyl transferase (ChAT) expression level and reduce the fibrillary acid protein (GFAP) expression level in the hippocampus and cortex of TS. Additionally, donepezil significantly upregulated the expression level of BDNF, as well as the phosphorylated level of TrkB. These results suggested that donepezil could protect neurocytes from senility and ameliorate learning and memory impairment in the TS model of AD, which appeared to be through regulating the cholinergic system and inhibiting the BDNF/TrkB-dependent signalling pathway. Moreover, the study underlines the potency of TS to be a novel animal model for research on AD, and it deserves intensive attention.

https://ift.tt/2P43IHJ

Hypoxemia in the ICU: prevalence, treatment, and outcome

Information is limited regarding the prevalence, management, and outcome of hypoxemia among intensive care unit (ICU) patients. We assessed the prevalence and severity of hypoxemia in ICU patients and analyzed...

https://ift.tt/2Ov97Xc

Video laryngoscopy versus direct laryngoscopy for first-attempt tracheal intubation in the general ward

Recent trials showed that video laryngoscopy (VL) did not yield higher first-attempt tracheal intubation success rate than direct laryngoscopy (DL) and was associated with higher rates of complications. Trache...

https://ift.tt/2vFGoru

Severe atypical pneumonia in critically ill patients: a retrospective multicenter study

Chlamydophila pneumoniae (CP) and Mycoplasma pneumoniae (MP) patients could require intensive care unit (ICU) admission for acute respiratory failure.

https://ift.tt/2OxBCmS

Current Status of Lymphadenectomy During Radical Nephroureterectomy for Upper Tract Urothelial Cancer—Yes, No or Maybe?

Abstract

While pelvic lymphadenectomy during radical cystectomy for bladder cancer is a well-established standard of care, the same does not hold true for upper tract urothelial carcinoma (UTUC). Indeed, a template-based lymphadenectomy is rarely, if ever, performed in conjunction with radical nephroureterectomy at most centres across the globe. While multiple studies have explored the staging and therapeutic role of lymphadenectomy in cases of UTUC, there remain large gaps in our understanding of the indications, extent and safety of this procedure as an adjunct to nephroureterectomy. This article elucidates the current knowledge on outcomes, benefits and complications of template-based lymphadenectomy during radical nephroureterectomy for UTUC. We also explore the current evidence-based guidelines on this controversial topic.

https://ift.tt/2B4K8Iw

CDC: EMS Administration of Naloxone Up From 2012 to 2016

MONDAY, Aug. 13, 2018 -- The rate of naloxone administrations by emergency medical services (EMS) providers increased 75 percent from 2012 to 2016, according to research published in the Aug. 10 issue of the U.S. Centers for Disease Control and...

https://ift.tt/2vHWktj

Bariatric Surgery Lowers Microvascular Disease Risk

MONDAY, Aug. 13, 2018 -- Bariatric surgery is tied to lower overall incidence of microvascular disease in patients with type 2 diabetes mellitus (T2DM), according to a study published online Aug. 7 in the Annals of Internal Medicine. Rebecca...

https://ift.tt/2MneKJp

Low-Energy Diet Induces Different Effects in Men, Women

MONDAY, Aug. 13, 2018 -- An eight-week low-energy diet (LED) induces different effects in men and women, according to a study published online Aug. 7 in Diabetes, Obesity and Metabolism. Pia Christensen, Ph.D., from the University of Copenhagen in...

https://ift.tt/2MM5pru

C. difficile Tied to Increased Graft Loss in Solid Organ Recipients

MONDAY, Aug. 13, 2018 -- For solid organ transplant (SOT) recipients, Clostridium difficile infection (CDI) is associated with increased graft loss, according to a study published in the July issue of the American Journal of Transplantation. Alexia...

https://ift.tt/2MlkfZe

Neurodevelopmental Anomalies, Birth Defects Linked to Zika ID'd

MONDAY, Aug. 13, 2018 -- Many children of mothers with evidence of confirmed or possible Zika virus infection during pregnancy do not undergo all recommended evaluations, according to a Vital Signs report published in the Aug. 10 issue of the U.S....

https://ift.tt/2MI9CN4

Eye Examination Can Help Detect Abuse in Children

MONDAY, Aug. 13, 2018 -- Eye examination is helpful for detecting abnormalities that could indicate abuse in children, according to a clinical report published in the August issue of Pediatrics. Cindy W. Christian, M.D., from the University of...

https://ift.tt/2OvJAgs

FDA Warns Against Long-Term Azithromycin Use for Some

MONDAY, Aug. 13, 2018 -- The U.S. Food and Drug Administration is warning patients with cancers of the blood or lymph nodes who undergo a donor stem cell transplant not to take azithromycin, as long-term use of the antibiotic has been associated...

https://ift.tt/2vHWkcN

Male Underwear Choice Affects Sperm Counts

MONDAY, Aug. 13, 2018 -- Men who wear boxers have higher sperm counts then men who wear tighter underwear, according to a study published Aug. 8 in Human Reproduction. Lidia Mínguez-Alarcón, Ph.D., M.P.H., from Harvard University in Boston, and...

https://ift.tt/2Ou8ddt

Sedation Level Doesn't Impact Delirium Risk After Hip Fx Repair

MONDAY, Aug. 13, 2018 -- For older patients undergoing hip fracture repair, the level of sedation does not impact delirium risk overall, according to a study published online Aug. 8 in JAMA Surgery. Frederick E. Sieber, M.D., from the Johns Hopkins...

https://ift.tt/2Mo6R6s

In Teens, Young Adults, High BMI May Hurt Cardiovascular Health

MONDAY, Aug. 13, 2018 -- Higher body mass index (BMI) is likely to cause worse cardiovascular health in youth, according to a study published online July 30 in Circulation. Kaitlin H. Wade, Ph.D., from the University of Bristol in the United...

https://ift.tt/2MG0KYc

Hornerin promotes tumor progression and is associated with poor prognosis in hepatocellular carcinoma

Abstract

Background

The function of hornerin (HRNR), a member of the S100 protein family, is poorly clarified in the development of human tumors. The role of HRNR in hepatocellular carcinoma (HCC) progression is investigated in the study.

Methods

The expression levels of HRNR were assessed in tumor samples from a cohort of 271 HCC patients. The effect of HRNR on proliferation, colony formation and invasion of tumor cells was examined. We further determined the role of HRNR in tumor growth in vivo by using xenograft HCC tumor models. The possible mechanism of the HRNR promotion of HCC progression was explored.

Results

We found that HRNR was overexpressed in HCC tissues. The high expression of HRNR in HCCs was significantly associated with vascular invasion, poor tumor differentiation, and advanced TNM stage. The disease-free survival (DFS) and overall survival (OS) of HCC patients with high HRNR expression were poorer than those in the low HRNR expression group. HRNR expression was an independent risk factor linked to both poor DFS (HR = 2.209, 95% CI = 1.627–2.998,P <  0.001) and OS (HR = 2.459,95% CI = 1.736–3.484, P <  0.001). In addition, the knockdown of HRNR by shRNAs significantly inhibited the proliferation, colony formation, migration and invasion of HCC tumor cells. HRNR silencing led to the decreased phosphorylation of AKT signaling. Notably, tumor growth was markedly inhibited by HRNR silencing in a xenograft model of HCC.

Conclusions

HRNR promotes tumor progression and is correlated with a poor HCC prognosis. HRNR may contribute to HCC progression via the regulation of the AKT pathway.

https://ift.tt/2KOmr6F

Case report: synovial sarcoma of the axilla with brachial plexus involvement

Abstract

Background

Synovial sarcoma is a rare soft tissue sarcoma which most commonly affects the extremities of young adults. Axilla involvement by this sarcoma is very rare especially with involvement of the brachial plexus. This combination adds to the challenge in approaching such tumors which might significantly affect survival and function.

Case presentation

Herein, we present a 48-year-old female patient who presented with an isolated painless lump in her right axilla. Initially, her workup, looking for possible breast cancer, included fine-needle aspiration (FNA) which did not provide the diagnosis. Core-needle biopsy, performed later, revealed monophasic synovial sarcoma. Her workup studies revealed no metastasis. Then, through extensile deltopectoral approach, the tumor was dissected out from within the brachial plexus. Ulnar nerve was sacrificed in order not to compromise the surgical margins which were confirmed tumor free by final pathology. The patient did not receive chemotherapy or radiation upon consultations with medical and radiation oncology teams. Her follow-up revealed no tumor recurrence with no restriction of her right shoulder motion.

Conclusion

Our case report represents a very rare occurrence of synovial sarcoma in the axilla with involvement of the brachial plexus. When clinical and radiological findings are suggestive of soft tissue sarcoma of the axilla, we recommend getting core-needle biopsy rather than fine-needle aspiration for earlier diagnosis. Early referral and multidisciplinary approach may contribute to better management.

https://ift.tt/2vG1SVd

Anti-Anginal Effectiveness and Tolerability of Trimetazidine Modified Release 80 Mg Once Daily in Stable Angina Patients in Real-World Practice

Abstract

Introduction

Trimetazidine (TMZ) was shown to reduce angina symptoms and increase the exercise capacity in stable angina (SA) patients. A new formulation allowing a once-daily (od) dosage could improve patients' satisfaction and adherence.

Methods

ODA was a 3-month, observational, multicenter, prospective Russian study in SA patients with persistent symptoms despite therapy. Angina attack frequency, short-acting nitrate (SAN) consumption, adherence to antianginal medications, and overall efficacy and tolerability of TMZ 80 mg od were assessed in a real-world setting.

Results

A total of 3066 patients were included (mean age 62.8, 48% male). After 3 months, TMZ 80 mg od treatment led to a significant (p < 0.001) decrease in angina attack frequency (from 4.7 ± 3.5 to 0.9 ± 1.3/week) and SAN use (from 4.5 ± 3.9 to 0.7 ± 1.3/week). Overall tolerability and effectiveness were rated as "very good" by the majority of physicians. Medication adherence improved significantly, with good adherence reported by 56% of patients (vs. 24% at baseline, p < 0.0001) and non-adherence by 3% (vs. 36% at baseline, p < 0.0001) at month 3. Patient satisfaction with TMZ od was 9.5 [on a scale of 1 to 10 (very satisfied)]. Patients reported improved physical activity: more patients reported no limitations (15% vs. 1% at baseline p < 0.01), slight limitation (46% vs. 5% at baseline, p < 0.001) or moderate limitation (30% vs. 23%, p < 0.01) and fewer patients reported substantial limitation (8% vs. 52% at baseline, p < 0.001) or very marked reduction (1% vs. 19% at baseline, p < 0.01) at month 3.

Conclusion

In this prospective, observational study, TMZ 80 mg od effectively reduced angina attacks and SAN consumption, improved physical activity and adherence and was well tolerated in chronic SA patients.

Trial Registration

ISRCTN registry Identifier, ISRCTN97780949.

Funding

Servier.

Plain Language Summary

Plain language summary available for this article.

https://ift.tt/2KObphV

Effectiveness and Tolerability of Micafungin in Chinese Patients with Invasive Fungal Infections: A Retrospective, Multicenter Study

Abstract

Introduction

Invasive fungal infections (IFIs) are a significant health problem in immunocompromised patients, resulting in substantial morbidity, mortality, and healthcare costs. Micafungin is a broad-spectrum echinocandin with activity against Candida and Aspergillus spp. This was a multicenter, non-comparative, retrospective observational study that evaluated the effectiveness and tolerability of intravenously administered micafungin for treating IFIs caused by Candida and Aspergillus spp.

Methods

Adult patients in China who had received at least one dose of intravenously administered micafungin were eligible. Retrospective data (May 2008–April 2015) were extracted from patients' medical files and recorded using electronic data capture. The primary endpoint was overall success rate (patients with complete or partial response). Subgroup analyses determined effectiveness according to diagnostic certainty, fungal species, type of IFI, duration of micafungin treatment, and daily dose of micafungin. Tolerability, including the incidence of adverse events (AEs), was also assessed.

Results

Overall, 2555 patients who received at least one dose of micafungin were identified. The mean duration of treatment and mean daily dose were 10.2 days and 133.0 mg, respectively. The overall success rate was 60.8%; this was significantly higher in patients who received treatment for at least 1 week (range 67.9–71.6% [mean 69.2%]) compared with less than 1 week (47.8%; P < 0.0001), and those who received 50–100 mg (65.7%) compared with other daily doses (range 42.9–60.1% [mean 59.0%]; P = 0.0011). Success rates in Candida- and Aspergillus-infected patients were similar (61.9% and 56.8%, respectively). AEs and adverse drug reactions were observed in 36.2% and 4.5% of patients, respectively. The majority of AEs were mild, while discontinuation due to AEs was low (2.3%).

Conclusion

Micafungin is effective and well tolerated for the treatment of patients with IFIs in China, as demonstrated in Candida- and Aspergillus-infected adults. Subgroup analyses highlighted the potential benefits of treating IFIs with micafungin for a minimum of 1 week.

Trial registration

ClinicalTrials.gov identifier NCT02678598.

Funding

Astellas Pharma Inc.

https://ift.tt/2Mlgcfp

Resuscitation education: What’s changed and what you need to know

The American Heart Association recently released a statement updating cardiac arrest resuscitation guidelines

https://ift.tt/2KO8AgG

What is a stroke?

A stroke is different from other conditions, as it essentially a term for the symptoms and not the cause

https://ift.tt/2MaFFsN

Resuscitation education: What’s changed and what you need to know

The American Heart Association recently released a statement updating cardiac arrest resuscitation guidelines

https://ift.tt/2w5foRX

Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071)

Abstract

Purpose

HER2-targeted therapy with trastuzumab and (CF/X) prolonged overall survival (OS) in metastatic HER2neu+ gastric carcinoma (GC). Lapatinib inhibits both EGFR and HER2neu. We investigated the efficacy and safety of lapatinib with epirubicin (E) + CF/X in GC according to HER2neu and EGFR status.

Methods

Tumors from chemotherapy-naïve patients were screened centrally by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Patients with EGFR and/or HER2neu expression or amplification were allocated to three strata based on EGFR/HER2neu status and were randomized to lapatinib (arm A) or placebo (arm B), with 6 cycles of ECF or ECX (investigator-selected). The primary endpoint was progression-free survival (PFS) in stratum 3.

Results

29 of 72 screened patients were randomized to strata 1 (HER2neu+: by FISH and IHC, n = 6), 2 (HER2neu−: by FISH/+ by IHC, n = 5) and 3 (HER2neu−/EGFR+, n = 18), of which 28 patients were eligible (14 per arm). Enrollment was curtailed after announcement of the negative LOGiC trial results. Median PFS was 8.0 versus 5.9 months (HR = 0.86, 95% CI 0.37–1.99) in the per protocol population, and 8.0 versus 6.3 months (HR = 0.85, 95% CI 0.30–2.46) for stratum 3, in the lapatinib versus placebo arm respectively. Median OS was 13.8 versus 10.1 months, respectively (HR = 0.90, 95% CI 0.35–2.27). There were no safety concerns.

Conclusions

Central EGFR and HER2neu stratification by IHC and FISH can be used for further pan-HER strategies. Lapatinib with ECF/X was well tolerated, but did not show clear activity in patients with metastatic GC.

https://ift.tt/2w7hAIB

In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia

Abstract

Purpose

Hyperbilirubinemia has been observed in patients treated with tyrosine kinase inhibitor (TKI) drugs. Therefore, it would be beneficial to understand whether there is a relationship between inhibition of uridine-5′-diphosphate glucuronosyltransferase (UGT) 1A1 activity and observed bilirubin elevations in TKI drug-treated patients. UGT1A1 is responsible for the glucuronidation of bilirubin which leads to its elimination in the bile.

Methods

To examine this question, an in vitro glucuronidation assay was developed to determine the inhibitory effect of TKI drugs employing human liver microsomes (HLM) with varying UGT1A1 activity. Utilizing β-estradiol as the UGT1A1 probe substrate, 20 TKI drugs were evaluated at concentrations that represent clinical plasma levels. Adverse event reports were searched to generate an empirical Bayes geometric mean (EGBM) score for clinical hyperbilirubinemia with the TKI drugs.

Results

Erlotinib, nilotinib, regorafenib, pazopanib, sorafenib and vemurafenib had IC₅₀ values that were lower than their clinical steady-state C_max concentrations. These TKI drugs had high incidences of hyperbilirubinemia and higher EBGM scores. The IC₅₀ values and C_max/IC₅₀ ratios correlated well with EBGM scores for hyperbilirubinemia (P < 0.005). For the TKI drugs with higher incidence of hyperbilirubinemia in Gilbert syndrome patients, who have reduced UGT1A1 activity, six of eight had smaller ratios in the low UGT1A1 activity microsomes than the wild-type microsomes for drugs, indicating greater sensitivity to the drugs in this phenotype.

Conclusions

These results suggest that in vitro UGT1A1 inhibition assays have the potential to predict clinical hyperbilirubinemia.

https://ift.tt/2nztzdS

Langerhans’ Cell Histiocytosis Masquerading as Metastatic Papillary Thyroid Cancer on F-18 FDG PET/CT: Diagnostic Dilemma Solved by PET/CT-Guided Biopsy

Abstract

We present a case of papillary thyroid cancer (post-thyroidectomy status) on regular treatment with suppressive Levothyroxine therapy. On follow-up at 6 months after radioactive iodine ablation for remnant thyroid tissue, her thyroglobulin, and anti-thyroglobulin levels were 0.06 ng/ml and 670 IU/ml, respectively. Low-dose whole-body I-131 scan was negative. To look for the cause of isolated increased anti-thyroglobulin level, a whole-body ¹⁸F-FDG PET/CT was done which revealed multiple FDG-avid lytic skeletal lesions suggestive of metastases. For confirmation of diagnosis, ¹⁸F-FDG PET/CT-guided metabolic biopsy was done, which revealed Langerhans' cell histiocytosis on histopathological examination.

https://ift.tt/2P71ebI

MKRN2 inhibits migration and invasion of non-small-cell lung cancer by negatively regulating the PI3K/Akt pathway

Abstract

Background

Makorin RING zinc finger-2 (MKRN2) belongs to the makorin RING zinc finger family and is a novel ubiquitin E3 ligase targeting the p65 subunit of NF-κB to negatively regulate inflammatory responses; however, the relationship between MKRN2 and tumorigenesis remains unclear. In this study, we clarified the role of MKRN2 in non-small cell lung cancer (NSCLC).

Methods

Tumor specimens collected from 261 NSCLC patients from 2013 to 2017 were retrieved from the Pathology Archive of the First Affiliated Hospital of China Medical University, and we performed assays to evaluate MKRN2 expression and to determine the impact of MKRN2 silencing and overexpression on NSCLC-cell migration and invasion.

Results

We demonstrated that MKRN2 expression was associated with lymph node metastasis, p-TNM stage, cancer-cell differentiation, and poor prognosis. By altering the expression of MKRN2 in selected cell lines, we found that MKRN2 inhibited cell migration and invasion through downregulation of the PI3K/Akt pathway.

Conclusions

These results suggested that MKRN2 inhibited NSCLC progression by reducing the metastatic potential of cancer cells. Our findings provide critical insight into the association of MKRN2 expression with favorable clinicopathological characteristics in NSCLC patients and suggested that MKRN2 plays a role in inhibiting NSCLC development.

https://ift.tt/2Mgy0IP

Dual effect of DLBCL-derived EXOs in lymphoma to improve DC vaccine efficacy in vitro while favor tumorgenesis in vivo

Abstract

Background

Exosomes derived from tumor cells (TEXs) are involved in both immune suppression, angiogenesis, metastasis and anticancer stimulatory, but the biological characteristics and role of diffuse large B cell lymphoma (DLBCL)-derived exosomes have been less investigated.

Methods

Exosomes (EXOs) were isolated from OCI-LY3, SU-DHL-16, and Raji cells and biological characteristics of EXOs were investigated using electron microscopy, flow cytometry analysis, and Western blot analysis. The protein expression of EXOs was determined by an antibody array. Next, the communication between EXOs and lymphoma cell, stromal cell, dendritic cells (DCs), and T cells was evaluated. Finally, effect of DLBCL TEXs on tumor growth in vivo was investigated.

Results

We demonstrated that EXOs derived from DLBCL cell lines displayed malignancy molecules such as c-Myc, Bcl-2, Mcl-1, CD19, and CD20. There was a different protein expression pattern between DLBCL TEXs and Burkitt lymphoma TEXs. DLBCL TEXs were easily captured by DCs and lymphoma cells, and mainly acted as an immunosuppressive mediator, evidenced by induction of apoptosis and upregulation of PD-1 in T cells. Furthermore, the TEXs stimulated not only cell proliferation, migration of stromal cells but also angiogenesis. As a result, the TEXs promoted tumor growth in vivo. On other hand, DLBCL TEXs did not induce apoptosis of DCs. After pulsed with the TEXs, DCs could stimulate clonal expansion of T cells, increase the secretion of IL-6 and TNFα, and decrease the production of immunosuppressive cytokine IL-4 and IL-10. The T cells from tumor bearing mice immunized by TEX were shown to possess superior antilymphoma potency relative to immunization of tumor lysates.

Conclusions

This study provides the framework for novel immunotherapies targeting TEXs in DLBCL.

https://ift.tt/2MHPNFz

SYT1-associated neurodevelopmental disorder: a case series

Abstract

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1^M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1^I368T and SYT1^N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1^D304G and SYT1^D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.

https://ift.tt/2w4AEXU

Motor and emotional behaviours elicited by electrical stimulation of the human cingulate cortex

Abstract

The cingulate cortex is a mosaic of different anatomical fields, whose functional characterization is still a matter of debate. In humans, one method that may provide useful insights on the role of the different cingulate regions, and to tackle the issue of the functional differences between its anterior, middle and posterior subsectors, is intracortical electrical stimulation. While previous reports showed that a variety of integrated behaviours could be elicited by stimulating the midcingulate cortex, little is known about the effects of the electrical stimulation of anterior and posterior cingulate regions. Moreover, the internal arrangement of different behaviours within the midcingulate cortex is still unknown. In the present study, we extended previous stimulation studies by retrospectively analysing all the clinical manifestations induced by intracerebral high frequency electrical stimulation (50 Hz, pulse width: 1 ms, 5 s, current intensity: average intensity of 2.7 ± 0.7 mA, biphasic) of the entire cingulate cortex in a cohort of 329 drug-resistant epileptic patients (1789 stimulation sites) undergoing stereo-electroencephalography for a presurgical evaluation. The large number of patients, on one hand, and the accurate multimodal image-based localization of stereo-electroencephalography electrodes, on the other hand, allowed us to assign specific functional properties to modern anatomical subdivisions of the cingulate cortex. Behavioural or subjective responses were elicited from the 32.3% of all cingulate sites, mainly located in the pregenual and midcingulate regions. We found clear functional differences between the pregenual part of the cingulate cortex, hosting the majority of emotional, interoceptive and autonomic responses, and the anterior midcingulate sector, controlling the majority of all complex motor behaviours. Particularly interesting was the 'actotopic' organization of the anterior midcingulate sector, arranged along the ventro-dorsal axis: (i) whole-body behaviours directed to the extra-personal space, such as getting-up impulses, were elicited ventrally, close to the corpus callosum; (ii) hand actions in the peripersonal space were evoked by the stimulation of the intermediate position; and (iii) body-directed actions were induced by the stimulation of the dorsal branch of the cingulate sulcus. The caudal part of the midcingulate cortex and the posterior cingulate cortex were, in contrast, poorly excitable, and mainly devoted to sensory modalities. In particular, the caudal part of the midcingulate cortex hosted the majority of vestibular responses, while posterior cingulate cortex was the principal recipient of visual effects. We will discuss our data in the light of current controversies on the role of the cingulate cortex in cognition and emotion.

https://ift.tt/2nwdhCC

Association of socioeconomic factors and the risk for unintentional injuries among children in Japan: a cross-sectional study

Objectives

While Japan has socioeconomic issues, such as income inequality, little is known about the association between socioeconomic factors and the risk of unintentional childhood injuries. The purpose of the study was to evaluate the influence of socioeconomic factors on the risk for unintentional injuries among preschool children in Japan.

Design

Cross-sectional study using data from a web-based questionnaire survey.

Setting

Japan (January 2015).

Participants

1000 households with preschool children under 6 years of age.

Outcome measures

Multivariate logistic regression was performed to analyse the influence of socioeconomic factors on the incidence of unintentional injuries.

Results

Overall, 976 households were eligible for the analysis, with 201 households reporting unintentional injuries. The incidence rates for unintentional injury were estimated to be constant across all strata constructed using combinations of socioeconomic factors. The multivariate logistic regression analysis showed no significant differences in socioeconomic factors between households that reported unintentional injuries and those that did not.

Conclusion

The findings of our study demonstrated that unintentional injuries among preschool children occurred at approximately fixed rates, independent of socioeconomic factors. Accordingly, prevention strategies for unintentional injuries that concern socioeconomic disadvantages should be avoided in Japan.

https://ift.tt/2w85Llc