Impact of Helicobacter pylori on Alzheimer's disease: What do we know so far?

Abstract

Background

Helicobacter pylori has changed radically gastroenterologic world, offering a new concept in patients' management. Over time, more medical data gave rise to diverse distant, extragastric manifestations and interactions of the "new" discovered bacterium. Special interest appeared within the field of neurodegenerative diseases and particularly Alzheimer's disease, as the latter and Helicobacter pylori infection are associated with a large public health burden and Alzheimer's disease ranks as the leading cause of disability. However, the relationship between Helicobacter pylori infection and Alzheimer's disease remains uncertain.

Methods

We performed a narrative review regarding a possible connection between Helicobacter pylori and Alzheimer's disease. All accessible relevant (pre)clinical studies written in English were included. Both affected pathologies were briefly analyzed, and relevant studies are discussed, trying to focus on the possible pathogenetic role of this bacterium in Alzheimer's disease.

Results

Data stemming from both epidemiologic studies and animal experiments seem to be rather encouraging, tending to confirm the hypothesis that Helicobacter pylori infection might influence the course of Alzheimer's disease pleiotropically. Possible main mechanisms may include the bacterium's access to the brain via the oral-nasal-olfactory pathway or by circulating monocytes (infected with Helicobacter pylori due to defective autophagy) through disrupted blood-brain barrier, thereby possibly triggering neurodegeneration.

Conclusions

Current data suggest that Helicobacter pylori infection might influence the pathophysiology of Alzheimer's disease. However, further large-scale randomized controlled trials are mandatory to clarify a possible favorable effect of Helicobacter pylori eradication on Alzheimer's disease pathophysiology, before the recommendation of short-term and cost-effective therapeutic regimens against Helicobacter pylori-related Alzheimer's disease.

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Detection of Helicobacter pylori in stool samples of young children using real-time polymerase chain reaction

Abstract

Background

The aims of this study were to develop and validate a multiplex real-time polymerase chain reaction (q-PCR) assay of Helicobacter pylori in stool samples of healthy children. Additionally, we determined the prevalence of clarithromycin resistance and cagA gene in H. pylori-positive samples.

Materials and methods

Archived stool samples from 188 children aged 6-9 years and 272 samples of 92 infants aged 2-18 months were tested for H. pylori antigens using enzyme immunoassay (EIA). A multiplex q-PCR assay was designed to detect H. pylori 16S rRNA and urease and the human RNase P gene as an internal control. Kappa coefficient was calculated to assess the agreement between q-PCR and EIA.

Results

Laboratory validation of the q-PCR assay using quantitated H. pylori ATCC 43504 extracted DNA showed S-shaped amplification curves for all genes; the limit of detection was 1 CFU/reaction. No cross-reactivity with other bacterial pathogens was noted. Applying the multiplex q-PCR to DNA extracted from fecal samples showed clear amplification curves for urease gene, but not for 16S rRNA. The prevalence of H. pylori infection was 50% (95% CI 43%-57%) by q-PCR (urease cycle threshold <44) vs 59% (95% CI 52%-66%) by EIA. Kappa coefficient was .80 (P < .001) and .44 (P < .001) for children aged 6-9 years and 2-18 months, respectively. Sixteen samples were positive for cagA and three were positive for clarithromycin resistance mutation (A2143G) as confirmed by sequencing.

Conclusions

The developed q-PCR can be used as a cotechnique to enhance the accuracy of H. pylori detection in epidemiological studies and in clinical settings.

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Pharmacokinetic/pharmacodynamic analysis of adjunctive perampanel in subjects with partial-onset seizures

Objectives

Explore perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis.

Materials & methods

Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive perampanel in POS. Perampanel exposure was predicted for all subjects and adolescents. Population PK/PD analyses were performed using data from phase III studies to explore the relationship between perampanel exposure and 28-day average seizure frequency and responder probability.

Results

Pooled perampanel PK data from 1318 subjects were described by a one-compartment disposition model. In the absence of antiepileptic drugs (AEDs) affecting perampanel PK, estimated perampanel apparent clearance (CL/F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co-administration of carbamazepine and oxcarbazepine/phenytoin reduced perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered perampanel CL/F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK/PD data from 1748 subjects, percent reduction in 28-day average seizure frequency from baseline and responder probability increased with increasing perampanel exposure; concomitant CYP3A-inducing AEDs lowered perampanel exposure but did not impact the slope for responder probability.

Conclusions

These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.

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Prognosis of status epilepticus in elderly patients

Purpose

To evaluate the clinical features and prognosis of status epilepticus (SE) in patients above 70 years old.

Methods

Retrospective analysis of all patients ≥70 years old with SE registered prospectively during 4 years. Follow-up after discharge was performed.

Results

Ninety patients were evaluated. Acute symptomatic etiology was the most prevalent. The mean number of antiepileptic drugs (AEDs) used was 2.7 ± 1.2, and 21% of the patients required sedation. A poor outcome was considered when death (31.1%) or developing of new neurological impairment at discharge (32.2%) occurred. After multivariate analysis, four variables predicted a poor outcome: acute symptomatic etiology (OR: 6.320; 95% CI: 1.976-20.217; P = .002), focal motor SE type (OR: 9.089; 95% CI: 2.482-33.283; P = .001), level of consciousness (OR: 4.596; 95% CI: 1.903-11.098; P = .001), and SE duration >12 hours (OR: 3.763; 95% CI: 1.130-12.530; P = .031). Independent predictive factors of mortality were SE duration >12 hours (OR: 4.306; 95% CI: 1.044-17.757; P = .043), modified Status Epilepticus Severity Score (mSTESS) (OR: 2.216; 95% CI: 1.313-3.740; P = .003), and development of complications (OR: 3.334; 95% CI: 1.004-11.070, P = .049). Considering long-term mortality, age (HR 1.036; 95% CI 1.001-1.071; P = .044), a potentially fatal underlying cause (HR 2.609; 95% CI 1.497- 4.548; P = .001), and mSTESS score >4 (HR 1.485; 95% CI 1.158-1.903; P = .002) remained as predictive factors. There was no association between sedation and the number of AEDs used with outcome at discharge or long-term mortality (P > .05). Conclusions: SE above 70 years old has a high morbimortality. Prognosis is not related to treatment aggressiveness.

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Seizures, CSF neurofilament light and tau in patients with subarachnoid haemorrhage

Objectives

Patients with severe subarachnoid haemorrhage (SAH) often suffer from complications with delayed cerebral ischaemia (DCI) due to vasospasm that is difficult to identify by clinical examination. The purpose of this study was to monitor seizures and to measure cerebrospinal fluid (CSF) concentrations of neurofilament light (NFL) and tau, and to see whether they could be used for predicting preclinical DCI.

Methods

We prospectively studied 19 patients with aneurysmal SAH who underwent treatment with endovascular coiling. The patients were monitored with continuous EEG (cEEG) and received external ventricular drainage (EVD). CSF samples of neurofilament light (NLF) and total tau (T-tau) protein were collected at day 4 and day 10. Cox regression analysis was applied to evaluate whether seizures and protein biomarkers were associated with DCI and poor outcome.

Results

Seven patients developed DCI (37%), and 4 patients (21%) died within the first 2 months. Six patients (32%) had clinical seizures, and electrographic seizures were noted in one additional patient (4.5%). Increased tau ratio (proportion tau10/tau4) was significantly associated with DCI and hazard ratio [HR=1.33, 95% confidence interval (CI) 1.055-1.680. P = .016].

Conclusion

Acute symptomatic seizures are common in SAH, but their presence is not predictive of DCI. High values of the tau ratio in the CSF may be associated with development of DCI.

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Serial electrophysiology in Guillain-Barré syndrome: A retrospective cohort and case-by-case multicentre analysis

Objectives

To assess the usefulness of serial electrophysiology in Guillain-Barré syndrome (GBS) in a multicenter setting and the reasons for change in electrodiagnostic subtypes with serial studies.

Methods

We retrospectively analysed serial electrophysiology of 51 patients with GBS from 4 European centres. Proportions of subtypes were determined at each timing. Individual case analyses were also performed where diagnostic changes occurred with either criteria, to ascertain if changes were due to disease progression or criteria inadequacy.

Results

At first study, comparing old vs new criteria, acute inflammatory demyelinating polyneuropathy (AIDP) was diagnosed in 70.6% vs 51%, axonal GBS in 15.7% vs 39.2%, equivocal forms in 11.8% vs 7.8%. At second study, AIDP was diagnosed in 72.5% vs 52.9%, axonal GBS in 9.8% vs 33.3%, equivocal forms in 15.7% vs 11.7%. Subtype proportions were unchanged, indicating serial studies did not, in the cohort, alter diagnostic rates for each subtype irrespective of criteria used. Individual review of cases where subtype electrodiagnosis changed indicated suboptimal specificity for AIDP/sensitivity for axonal GBS as main cause of diagnostic shifts with old criteria, whereas disease progression explained most changes with new criteria (55.6% vs 81.8%; P = .039).

Conclusions

Serial electrophysiology is unhelpful in GBS. Repeat studies cannot represent the gold standard as electrodiagnosis may alter due to disease progression. Changes in electrodiagnosis relate more often to disease progression with new criteria but are more frequently due to suboptimal sensitivity/specificity with old criteria. A single electrophysiological study using the most accurate available criteria appears sufficient in GBS.

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Real-life clinical use of natalizumab and fingolimod in Austria

Objectives

To compare the efficacy of natalizumab or fingolimod in a nationwide observational cohort using prospectively collected data.

Materials and methods

We included all patients starting treatment with natalizumab or fingolimod documented in the Austrian MS Treatment Registry (AMSTR) from 2011 and staying on therapy for at least 24 months. We used propensity scores for several matching methods and as a covariate in multivariate models to correct for the bias of this non-randomized registry study.

Results

The study cohort includes 588 patients with RRMS. Ten patients did not produce a propensity score in the common support region, thus leaving 578 cases for final analyses, 332 in the fingolimod and 246 in the natalizumab group. Mean annualized relapse rates (ARR) during the 24 months observation period were 0.19 under fingolimod and 0.12 under natalizumab treatment (P = .005). No statistical significant differences were found analysing the log-transformed ARR, probability for experiencing a relapse, EDSS progression and EDSS regression. The hazard ratio for switching treatment from fingolimod comparing with natalizumab was 0.36 (95% CI: 0.247-0.523), P < .001.

Conclusions

The generalized linear model (GLM) for relapse count as Poisson distributed dependent variable and propensity score as covariate showed a statistically significant reduction for the mean relapse count in the natalizumab group compared with fingolimod. This effect was smaller in the analyses of log-transformed ARR with propensity score matching, loosing statistical significance although showing the same direction for the effect. We assume that the GLM was the more sensitive model analysing this question.

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IJMS, Vol. 18, Pages 2547: Nodule-Enriched GRETCHEN HAGEN 3 Enzymes Have Distinct Substrate Specificities and Are Important for Proper Soybean Nodule Development

IJMS, Vol. 18, Pages 2547: Nodule-Enriched GRETCHEN HAGEN 3 Enzymes Have Distinct Substrate Specificities and Are Important for Proper Soybean Nodule Development

International Journal of Molecular Sciences doi: 10.3390/ijms18122547

Authors: Suresh Damodaran Corey Westfall Brian Kisely Joseph Jez Senthil Subramanian

Legume root nodules develop as a result of a symbiotic relationship between the plant and nitrogen-fixing rhizobia bacteria in soil. Auxin activity is detected in different cell types at different stages of nodule development; as well as an enhanced sensitivity to auxin inhibits, which could affect nodule development. While some transport and signaling mechanisms that achieve precise spatiotemporal auxin output are known, the role of auxin metabolism during nodule development is unclear. Using a soybean root lateral organ transcriptome data set, we identified distinct nodule enrichment of three genes encoding auxin-deactivating GRETCHEN HAGEN 3 (GH3) indole-3-acetic acid (IAA) amido transferase enzymes: GmGH3-11/12, GmGH3-14 and GmGH3-15. In vitro enzymatic assays showed that each of these GH3 proteins preferred IAA and aspartate as acyl and amino acid substrates, respectively. GmGH3-15 showed a broad substrate preference, especially with different forms of auxin. Promoter:GUS expression analysis indicated that GmGH3-14 acts primarily in the root epidermis and the nodule primordium where as GmGH3-15 might act in the vasculature. Silencing the expression of these GH3 genes in soybean composite plants led to altered nodule numbers, maturity, and size. Our results indicate that these GH3s are needed for proper nodule maturation in soybean, but the precise mechanism by which they regulate nodule development remains to be explained.

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Termination of reentrant atrial tachycardia via optogenetic stimulation with optimized spatial targeting: insights from computational models

Abstract

Optogenetics has emerged as a potential alternative to electrotherapy for treating arrhythmia, but feasibility studies have been limited to ventricular defibrillation via epicardial light application. Here, we assess the efficacy of optogenetic atrial tachycardia (AT) termination in human hearts using a strategy that targets for illumination specific regions identified in an automated manner. In three patient-specific models reconstructed from late gadolinium-enhanced MRI scans, we simulated channelrhodopsin-2 (ChR2) expression via gene delivery. In all three models, we attempted to terminate reentrant AT (induced via rapid pacing) via optogenetic stimulation. We compared two strategies: (1) distributed illumination of the endocardium by multi-optrode grids (N_opt = 64, 128, 256) and (2) targeted illumination of the critical isthmus, which was identified via analysis of simulated activation patterns using an algorithm based on flow networks. The illuminated area and input power were smaller for the targeted approach (19–57.8 mm²; 0.6–1.8 W) compared to the sparsest distributed arrays (N_opt = 64; 124.9 ± 6.3 mm²; 3.9 ± 0.2 W). AT termination rates for distributed illumination were low, ranging from <5% for short pulses (1/10 ms-long) to ∼20% for longer stimuli (100/1000 ms). When we attempted to terminate the same AT episodes with targeted illumination, outcomes were similar for short pulses (1/10 ms-long: 0% success) but improved for longer stimuli (100 ms: 54% success; 1000 ms: 90% success). We conclude that simulations in patient-specific models show that light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT in atria light-sensitized via gene delivery. We show that targeted optogenetic stimulation based on analysis of AT morphology may be a reliable approach for defibrillation and requires less power than distributed illumination.

This article is protected by copyright. All rights reserved

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Functions of the multi-interacting protein KIDINS220/ARMS in cancer and other pathologies

Abstract

Development of an organ and subsequently the whole system from an embryo is a highly integrated process. Although there are evidence that different systems are interconnected during developmental stages, the molecular understanding of this relationship is either not known or only to a limited extent. Nervous system development, amongst all, is maybe the most crucial and complex process. It relies on the correct distribution of specific neuronal growth factors and hormones to the specific receptors. Among the plethora of proteins that are involved in downstream signalling of neuronal growth factors, we find the Kinase-D Interacting Substrate of 220 kDa (KIDINS220), also known as Ankyrin-rich Repeat Membrane Spanning (ARMS) protein. KIDINS220 has been shown to play a substantial role in the nervous system and vascular system development as well as in neuronal survival and differentiation. It serves as a downstream regulator for many important neuronal and vascular growth factors such as Vascular Endothelial Growth Factor (VEGF), the neurotrophin family, glutamate receptors and ephrin receptors. Moreover, activation and differentiation of B- and T-cells, as well as tumour cell proliferation has also shown to be related KIDINS220. This review comprehensively summarises the existing research data on this protein, with a particular interest in its role in cancer and in other pathologies. This article is protected by copyright. All rights reserved.

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Serial lipase for pancreatitis: not enough evidence

Background

Lipase is both a sensitive and specific marker for diagnosing pancreatitis. However, the benefit of serial lipase in both monitoring and defining prognosis remains undetermined. This systematic review was conducted to further evaluate this potential application. In addition, this review also looked into the benefits of serial lipase in the subgroup of traumatic pancreatitis.

Methods

PubMed, Cochrane Library and Google Scholar were systematically searched for related articles, between January 1995 and December 2015, according to Preferred Reporting Items for Systematic Reviews and Meta-analyses standards. Data was extracted and analysed by two authors.

Results

Seven studies were included in the final analysis: six retrospective and one prospective studies were identified. Five studies (all retrospective) concluded no benefits in serial lipase for prognostication, while two studies identified serial lipase as a beneficial prognostic factor for acute pancreatitis. Of the included studies, only two involved traumatic pancreatitis (both dedicated to the paediatric population).

Conclusion

The evidence supporting or opposing serial lipase as a prognostic factor for pancreatitis is weak and consists mainly of retrospective analyses. The only prospective data identified suggested benefits to serial lipase in prognosis. Further prospective studies evaluating the prognostic value of serial lipase in the adult population with both traumatic and non-traumatic pancreatitis are required given the paucity of available evidence.

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Correction to: Heavy metal and nutrient uptake in plants colonizing post-flotation copper tailings

Abstract

The correct presentation of Table 4 is shown in this paper.

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Phantom validation of quantitative Y-90 PET/CT-based dosimetry in liver radioembolization

Abstract

Background

PET/CT has recently been shown to be a viable alternative to traditional post-infusion imaging methods providing good quality images of ⁹⁰Y-laden microspheres after selective internal radiation therapy (SIRT). In the present paper, first we assessed the quantitative accuracy of ⁹⁰Y-PET using an anthropomorphic phantom provided with lungs, liver, spine, and a cylindrical homemade lesion located into the hepatic compartment. Then, we explored the accuracy of different computational approaches on dose calculation, including (I) direct Monte Carlo radiation transport using Raydose, (II) Kernel convolution using Philips Stratos, (III) local deposition algorithm, (IV) Monte Carlo technique (MCNP) considering a uniform activity distribution, and (V) MIRD (Medical Internal Radiation Dose) analytical approach. Finally, calculated absorbed doses were compared with those obtained performing measurements with LiF:Mg,Cu,P TLD chips in a liquid environment.

Results

Our results indicate that despite ⁹⁰Y-PET being likely to provide high-resolution images, the ⁹⁰Y low branch ratio, along with other image-degrading factors, may produce non-uniform activity maps, even in the presence of uniform activity. A systematic underestimation of the recovered activity, both for the tumor insert and for the liver background, was found. This is particularly true if no partial volume correction is applied through recovery coefficients. All dose algorithms performed well, the worst case scenario providing an agreement between absorbed dose evaluations within 20%. Average absorbed doses determined with the local deposition method are in excellent agreement with those obtained using the MIRD and the kernel-convolution dose calculation approach.

Finally, absorbed dose assessed with MC codes are in good agreement with those obtained using TLD in liquid solution, thus confirming the soundness of both calculation approaches. This is especially true for Raydose, which provided an absorbed dose value within 3% of the measured dose, well within the stated uncertainties.

Conclusions

Patient-specific dosimetry is possible even in a scenario with low true coincidences and high random fraction, as in ⁹⁰Y–PET imaging, granted that accurate absolute PET calibration is performed and acquisition times are sufficiently long. Despite Monte Carlo calculations seeming to outperform all dose estimation algorithms, our data provide a strong argument for encouraging the use of the local deposition algorithm for routine ⁹⁰Y dosimetry based on PET/CT imaging, due to its simplicity of implementation.

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Management of hereditary breast and ovarian cancer

Abstract

Hereditary breast and ovarian cancer (HBOC) syndrome represents 5−10% of all breast cancers. In Japan, the HBOC syndrome is frequently diagnosed in patients with breast cancer. Therefore, a treatment strategy combining a plan for existing breast cancer and for reduction of future breast and ovarian cancer risk is necessary. Breast cancer risk-reducing management involves three options—surveillance, chemoprevention, and risk-reducing mastectomy (RRM). RRM can prevent >90% of new breast cancers. Ovarian cancer risk management options are more limited, and risk-reduction salpingo-oophorectomy is the only option since there is no proven effective early detection method available. The local recurrence rate following breast-conserving surgery in BRCA1/2 mutation-associated breast cancer is not significantly higher than that in sporadic breast cancer. Furthermore, there is no difference in prognosis between surgical methods. Clinicians should inform patients that there are no data on long-term monitoring and fully discuss risks of re-developing breast cancer with patients when choosing the surgical method. In HBOC, BRCA1/2 mutations lead to failure of double-strand DNA break repair, with poly ADP-ribose polymerase (PARP) playing an important role in single-strand DNA nick repair. Use of PARP inhibitors in HBOC prevents DNA repair (synthetic lethality) leading to cell death. This review summarizes management of the HBOC syndrome based on recent evidence.

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A Ra dial Pi llar D evice (RAPID) for continuous and high-throughput separation of multi-sized particles

Abstract

Pillar-based microfluidic sorting devices are preferred for isolation of rare cells due to their simple designs and passive operation. Dead-end pillar filters can efficiently capture large rare cells, such as, circulating tumor cells (CTCs), nucleated red blood cells (NRBCs), CD4 cells in HIV patients, etc., but they get clogged easily. Cross flow filters are preferred for smaller rare particles (e.g. separating bacteria from blood), but they need additional buffer inlets and a large device footprint for efficient operation. We have designed a new microparticle separation device i.e. Ra dial Pi llar D evice (RAPID) that combines the advantages of dead-end and cross flow filters. RAPID can simultaneously isolate both large and small rare particles from a mixed population, while functioning for several hours without clogging. We have achieved simultaneous separation of 10 μ m and 2 μ m polystyrene particles from a mixture of 2 μ m, 7 μ m and 10 μ m particles. RAPID achieved average separation purity and recovery in excess of ∼90%. The throughput of our device (∼3ml/min) is 10 and 100 times higher compared to cross flow and dead-end filters respectively, thereby justifying the name RAPID.

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First practical synthesis of novel 1-phosphonylated pyrrolo[1,2-a]pyrazine derivatives

Abstract

We present a convenient synthetic approach to novel 1-phosphonylated pyrrolo[1,2-a]pyrazine derivatives based in efficient three-component reactions. According to this method, N-functionalized 2-formylpyrrole derivatives are used as bifunctional coupling reagents in the reaction with dialkyl phosphites and amines to access to the target compounds.

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A new cyclic telluride. Synthesis and reactions of 1,3,5,6,7,8-hexahydronaphtho[2,3-c]tellurophene

Abstract

Reaction of 6,7-bis(chloromethyl)-1,2,3,4-tetrahydronaphthalene with tellurium powder and potassium iodide in 2-butoxyethanol gave 2,2-diiodo-1,3,5,6,7,8-hexahydro-naphtho[2,3-c]tellurophene(1) as a red-orange solid in 40% yield. Reduction of 1 with hydrazine hydrate gave a pale yellow solid of 1,3,5,6,7,8-hexahydronaphtho[2,3-c]telluro-phene(2) in 80% yield. Chlorination, bromination of 2 and its reaction with benzyl bromide and N-bromosuccinimide were reported. 2,2-Bis(dimethyldithiocarbamato)-, 2,2-bis (diethyldithiocarbamato)- and 2,2-bis(piperidine-1-carbodithioate)-1,3,5,6,7,8-hexahydro-naphtho[2,3-c]tellurophene were prepared by the reaction of the corresponding sodium dithiocarbamate salt with 1. Mononuclear platinum complex (ie, [(C₁₂H₁₄Te)₂PtCl₂]) was obtained by the reaction of 2 with K₂PtCl₄. Reaction of 6,7-bis(chloromethyl)-1,2,3,4-tetrahydronaphthalene with KTeCN in DMSO solution gave 2,2-dihydroxo-1,3,5,6,7,8-hexahydronaphtho[2,3-c]tellurophene (11) as a white solid in 55% yield. All these new compounds were characterized by elemental analysis, IR, ¹H, and ¹³C NMR, and mass spectroscopic data.

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A DFT study of O2 and Cl2 adsorption onto Al12N12 fullerene-like nanocluster

Abstract

In this study, the adsorption and dissociation of chlorine and oxygen molecules on the surface of Al₁₂N₁₂ nanocluster have been investigated by density functional theory (DFT). Traditional B3LYP and dispersion-corrected (ωB97XD) functionals have been used to optimize the studied structures. One relaxed structure for adsorbed Cl₂ and two for adsorbed O₂ (denoted as P1 and P2 configurations) have been found. Both functionals showed strong chemisorption of O₂ compared to Cl₂ on nanocluster. The dispersion-corrected (ωB97XD) binding energies of Cl₂ and O₂ (P1 and P2) on Al₁₂N₁₂ are calculated to be −32.4 (−29.1 BSSE corrected), −60.6 (−47.0 BSSE corrected), and −217.8 (−191.4 BSSE corrected) kJ/mol, respectively. We can conclude that in the suitable configuration, the adsorption of O₂ associates with significant charge transfer as well as dissociation. The Gibbs free energies of all adsorptions were calculated and their values confirm exothermic spontaneous adsorption of both molecules on nanocluster.

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C-O and C-S coupling reaction of 1,2-di(pyrimidin-2-yl) disulfides with phenols/thiophenols promoted by copper(I) chloride

Abstract

An efficient protocol for C-O and C-S bonds formation by the cross-coupling reaction of 1,2-di(pyrimidin-2-yl) disulfides with phenols/thiophenols promoted by copper(I) chloride was established. It was discovered that variously substituted di(hetero)aryl disulfides and phenols were well tolerated. This strategy is the conversion of disulfides into hetero-aryl ethers and thioethers by a copper-promoted chemoselective C-S bond cleavage of disulfides.

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Alkylation of 9-substituted guanine derivatives with α,ω-dihaloalkanes

Abstract

Reactions of 9-substituted guanine derivatives with NaH/1,2-dibromoethane, 1,3-dibromopropane, or 1,4-dibromobutane at room temperature resulted in the isolation of tricyclic 1,N²-(1,2-ethano)guanine, 1,N²-(1,3-propano)guanine, or 1,N²-(1,4-butano)guanine products, respectively. O⁶-Haloalkyl and N1-haloalkyl products were obtained following the use of NaH/1,4-dibromobutane, higher α,ω-dibromoalkanes, or α-bromo-ω-fluoroalkanes. Raising the reaction temperature opened the synthetic way toward O⁶-guanine-alkylene-O⁶-guanine and N1-guanine-alkylene-O⁶-guanine symmetric and unsymmetric dimers. Protection of the substrate amine group to form N,N-dialkylformamidine provided the access to N1-guanine-alkylene-N1-guanine dimers.

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Effect of Xylan Sulfates on Coagulation of Human Blood Plasma

Sulfated derivatives of xylan (isolated from Bétula pubéscens wood) with average molecular weight ~34 kDa, sulfur content of 11.3-17.5%, a degree of substitution of 0.74-1.64 are anticoagulants of direct type of action. Antithrombin and antifactor Xa activities in three tested xylan samples did not differ and reached 30.8-31.8 and 13.5-14.3 U/mg, respectively.

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Pirfenidone-induced hyponatraemia: insight in mechanism, risk factor and management

Pirfenidone was approved in October 2014 in the USA for the treatment of idiopathic pulmonary fibrosis. Although not included in the adverse events published in the CAPACITY-1 and CAPACITY-2 or ASCEND trials, hyponatraemia was reported in supplementary data with rate of 3.4% in the active therapy arm versus 0.3% in the placebo arm. We performed a retrospective analysis of patients who were initiated on pirfenidone or nintedanib for the treatment of pulmonary fibrosis at our centre. Of the 52 patients who were started on pirfenidone, three (5.8%) developed severe hyponatraemia. Of the 29 patients who were started on nintedanib, none developed hyponatraemia. Laboratory data suggested syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by pirfenidone and the medication was discontinued. Hyponatraemia is a possible significant adverse effect of pirfenidone, able to induce SIADH in patients taking the medication.

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Puff laddy: a 5-year-old-boy with forehead swelling

Description

A 5-year-old boy presented with forehead swelling in the setting of a recent sinus infection. His initial symptoms were fever and nasal congestion for which he was prescribed a 10-day course of antibiotics, completed 3 days prior to admission. He subsequently developed unsteady gait, photophobia, headache, vomiting and progressive forehead swelling. He was noted to have central forehead oedema and tenderness without overlying erythaema (figure 1). There were no neurological or ophthalmological deficits. Magnetic Resonance Imaging (MRI)/Magnetic Resonance Venography (MRV) of the head demonstrated a 3.5x1.2x3.9 cm subgaleal abscess with communication to the frontal sinuses as well as osteomyelitis of the frontal bone (figure 2). The patient underwent surgical drainage of the abscess with evacuation of purulent fluid (figure 3). Culture from the procedure grew Streptococcus anginosus. He clinically improved following surgery and was transitioned home to complete a 21-day total course of antibiotics.

...

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Dying art of a history and physical: pulsatile tinnitus

Modern medicine often leaves the history and physical by the wayside. Physicians instead skip directly to diagnostic modalities like MRI and angiography. In this case report, we discuss a patient who presented with migraine symptoms. Auscultation revealed signs of pulsatile tinnitus. Further imaging concluded that it was secondary to a type I dural arteriovenous fistula. Thanks to a proper and thorough history and physical, the patient was streamlined into an accurate and efficient work-up leading to symptomatic relief and quality of life improvement. Imaging is a powerful adjunctive technique in modern medicine, but physicians must not rely on machines to diagnose their patients. If this trend continues, it will have a tremendous negative impact on the cost and calibre of healthcare. Our hope is that this case will spread awareness in the medical community, urging physicians to use the lost art of a history and physical.

http://ift.tt/2i9XXws

Rare and unusual case of perforated appendicitis in a Spigelian hernia

Background

Amyand hernia is a rare phenomenon, defined as an inguinal hernia containing the vermiform appendix. It is seen in less than 1% of inguinal hernias. Claudius Amyand first reported this interesting finding in 1735.

De Garengeot hernia: this is the clinical finding of the vermiform appendix within a femoral hernia sac; it occurs in less than 1% of all femoral hernias and is named after the French surgeon, Rene Jacques Croissant de Garengeot.

Unnamed: The clinical entity we describe in this case report is the last of the 'appendix in a hernia—yet to be eponymously named'. It is an interesting and intriguing clinical finding, yet without a referenced name it does not immediately come to mind as a potential differential diagnosis. Medical historians may well commence the search for the first description of the condition.

Case presentation

An 83-year-old woman was admitted to the...

http://ift.tt/2ibG5Bw

Fish hook injury: an easy removal using the string yank technique

Description

An embedded fish hook injury is a tough condition for clinical decision-making, as it needs to be determined whether to advance the hook or to pull it out. Patients or their friends usually attempt to remove a fish hook, causing more soft tissue trauma. There are many different sizes and types of fish hooks, and the four main techniques for their removal are (1) retrograde technique for barbless and superficially embedded hooks, (2) needle cover technique for large hooks with a single barb, (3) advance and cut technique for large fish hooks with potential additional trauma and (4) string yank technique for superficially embedded, small-sized to medium-sized fish hooks.1 The technique of removal should be selected based on the size and shape of a fish hook and the anatomical condition of the injury. Here, we report a useful technique for primary care physicians, accompanied by an instructional video given in the online...

http://ift.tt/2k3ZZyS

Paediatric Salter-Harris type IV injury of distal tibia with talus fracture

Fracture of talus with Salter-Harris injury of the distal end of tibia is a rare injury in paediatric age group. The authors report a case of a 13-year-old male child who sustained type IV Salter-Harris injury to the medial malleolus with coronal spilt along with spilt and depressed fracture of the neck of talus and fracture of the lateral process of talus with stable compression fracture of spine sustained due to fall from 6 meters height. CT scan delineated the morphology of fracture pattern and helped in preoperative planning. Talar articular fracture was reduced and fixed arthroscopically while distal tibial fracture was fixed under image intensifier. We observed favourable outcome following arthroscopic reduction at 4-year follow-up.

http://ift.tt/2ia7zY5

Lesion in the external auditory canal: an unusual site for basal cell carcinoma

Description

An 85-year-old woman presented to the ear, nose and throat clinic with a 2-week history of left-sided otorrhoea and pruritus of the ear. Examination of the left external auditory canal (EAC) revealed a polypoidal lesion and purulent discharge (figure 1). The tympanic membrane was intact. The suspicious lesion prompted imaging, including CT neck and thorax (figure 2). An ultrasound scan of the parotid and neck showed no metastatic disease. A biopsy was undertaken and histology demonstrated a basal cell carcinoma (BCC). The patient was managed with a staged procedure. Stage 1 consisted of a wide local excision of the BCC, with a 4 mm margin. Frozen section was not available; therefore, a second stage was needed to achieve clear margins using a sleeve resection. Fortunately, the disease was limited to the cartilaginous ear canal, hence did not require further resection or reconstruction. This management...

http://ift.tt/2k3ZMM6

Cancer-related microangiopathic haemolytic anaemia

Description

A 71-year-old woman with widely metastatic breast cancer to liver and bone marrow presented with 2 weeks of fatigue. Examination revealed a severely ill-appearing woman in moderate distress with icterus and jaundice. Laboratory investigations revealed profound anaemia (haemoglobin 5.2 g/dL) with appropriate reticulocyte response (14.4%) and a normal platelet count (207x 10⁹/L). Additional tests revealed a lactate dehydrogenase of 2997 IU/L (normal: 140–297 IU/L), negative direct Coombs antiglobulin, an undetectable haptoglobin level, elevated total bilirubin, newly elevated prothrombin time (19.7 s, normal: <14.1 s), elevated fibrin split products and D-dimer (14.36 µg/dL, normal: <0.53 µg/dL) but normal fibrinogen level (322 mg/dL, normal: 193–488 mg/dL). Peripheral blood smear revealed marked schistocytosis (figure 1) with normal platelet count. The patient was diagnosed with cancer-associated microangiopathic haemolytic anaemia1 2 with laboratory evidence of disseminated intravascular coagulation, and she passed away on comfort measures 24 hours after admission.

Figure 1

Arrows showing marked schistocytes.

...

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Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer

Abstract

Background

In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (2 cycles of cisplatin 50 mg/m2 in week 1 and 4 of RT, followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required prior to patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.

Patients and methods

A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n=395) and the United Kingdom (n=900), and for 1226/1295 (95%) matching review and original reports were available. 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the United Kingdom, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).

Results

In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).

Conclusion

Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved.This study is registered with ISRCTN (ISRCTN14387080, http://ift.tt/HkCGY7) and with ClinicalTrials.gov (NCT00411138).

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Pirfenidone-induced hyponatraemia: insight in mechanism, risk factor and management

Pirfenidone was approved in October 2014 in the USA for the treatment of idiopathic pulmonary fibrosis. Although not included in the adverse events published in the CAPACITY-1 and CAPACITY-2 or ASCEND trials, hyponatraemia was reported in supplementary data with rate of 3.4% in the active therapy arm versus 0.3% in the placebo arm. We performed a retrospective analysis of patients who were initiated on pirfenidone or nintedanib for the treatment of pulmonary fibrosis at our centre. Of the 52 patients who were started on pirfenidone, three (5.8%) developed severe hyponatraemia. Of the 29 patients who were started on nintedanib, none developed hyponatraemia. Laboratory data suggested syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by pirfenidone and the medication was discontinued. Hyponatraemia is a possible significant adverse effect of pirfenidone, able to induce SIADH in patients taking the medication.

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Puff laddy: a 5-year-old-boy with forehead swelling

Description

A 5-year-old boy presented with forehead swelling in the setting of a recent sinus infection. His initial symptoms were fever and nasal congestion for which he was prescribed a 10-day course of antibiotics, completed 3 days prior to admission. He subsequently developed unsteady gait, photophobia, headache, vomiting and progressive forehead swelling. He was noted to have central forehead oedema and tenderness without overlying erythaema (figure 1). There were no neurological or ophthalmological deficits. Magnetic Resonance Imaging (MRI)/Magnetic Resonance Venography (MRV) of the head demonstrated a 3.5x1.2x3.9 cm subgaleal abscess with communication to the frontal sinuses as well as osteomyelitis of the frontal bone (figure 2). The patient underwent surgical drainage of the abscess with evacuation of purulent fluid (figure 3). Culture from the procedure grew Streptococcus anginosus. He clinically improved following surgery and was transitioned home to complete a 21-day total course of antibiotics.

...

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Dying art of a history and physical: pulsatile tinnitus

Modern medicine often leaves the history and physical by the wayside. Physicians instead skip directly to diagnostic modalities like MRI and angiography. In this case report, we discuss a patient who presented with migraine symptoms. Auscultation revealed signs of pulsatile tinnitus. Further imaging concluded that it was secondary to a type I dural arteriovenous fistula. Thanks to a proper and thorough history and physical, the patient was streamlined into an accurate and efficient work-up leading to symptomatic relief and quality of life improvement. Imaging is a powerful adjunctive technique in modern medicine, but physicians must not rely on machines to diagnose their patients. If this trend continues, it will have a tremendous negative impact on the cost and calibre of healthcare. Our hope is that this case will spread awareness in the medical community, urging physicians to use the lost art of a history and physical.

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Rare and unusual case of perforated appendicitis in a Spigelian hernia

Background

Amyand hernia is a rare phenomenon, defined as an inguinal hernia containing the vermiform appendix. It is seen in less than 1% of inguinal hernias. Claudius Amyand first reported this interesting finding in 1735.

De Garengeot hernia: this is the clinical finding of the vermiform appendix within a femoral hernia sac; it occurs in less than 1% of all femoral hernias and is named after the French surgeon, Rene Jacques Croissant de Garengeot.

Unnamed: The clinical entity we describe in this case report is the last of the 'appendix in a hernia—yet to be eponymously named'. It is an interesting and intriguing clinical finding, yet without a referenced name it does not immediately come to mind as a potential differential diagnosis. Medical historians may well commence the search for the first description of the condition.

Case presentation

An 83-year-old woman was admitted to the...

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/2ibG5Bw
via IFTTT

Fish hook injury: an easy removal using the string yank technique

Description

An embedded fish hook injury is a tough condition for clinical decision-making, as it needs to be determined whether to advance the hook or to pull it out. Patients or their friends usually attempt to remove a fish hook, causing more soft tissue trauma. There are many different sizes and types of fish hooks, and the four main techniques for their removal are (1) retrograde technique for barbless and superficially embedded hooks, (2) needle cover technique for large hooks with a single barb, (3) advance and cut technique for large fish hooks with potential additional trauma and (4) string yank technique for superficially embedded, small-sized to medium-sized fish hooks.1 The technique of removal should be selected based on the size and shape of a fish hook and the anatomical condition of the injury. Here, we report a useful technique for primary care physicians, accompanied by an instructional video given in the online...

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/2k3ZZyS
via IFTTT

Paediatric Salter-Harris type IV injury of distal tibia with talus fracture

Fracture of talus with Salter-Harris injury of the distal end of tibia is a rare injury in paediatric age group. The authors report a case of a 13-year-old male child who sustained type IV Salter-Harris injury to the medial malleolus with coronal spilt along with spilt and depressed fracture of the neck of talus and fracture of the lateral process of talus with stable compression fracture of spine sustained due to fall from 6 meters height. CT scan delineated the morphology of fracture pattern and helped in preoperative planning. Talar articular fracture was reduced and fixed arthroscopically while distal tibial fracture was fixed under image intensifier. We observed favourable outcome following arthroscopic reduction at 4-year follow-up.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/2ia7zY5
via IFTTT

Cancer-related microangiopathic haemolytic anaemia

Description

A 71-year-old woman with widely metastatic breast cancer to liver and bone marrow presented with 2 weeks of fatigue. Examination revealed a severely ill-appearing woman in moderate distress with icterus and jaundice. Laboratory investigations revealed profound anaemia (haemoglobin 5.2 g/dL) with appropriate reticulocyte response (14.4%) and a normal platelet count (207x 10⁹/L). Additional tests revealed a lactate dehydrogenase of 2997 IU/L (normal: 140–297 IU/L), negative direct Coombs antiglobulin, an undetectable haptoglobin level, elevated total bilirubin, newly elevated prothrombin time (19.7 s, normal: <14.1 s), elevated fibrin split products and D-dimer (14.36 µg/dL, normal: <0.53 µg/dL) but normal fibrinogen level (322 mg/dL, normal: 193–488 mg/dL). Peripheral blood smear revealed marked schistocytosis (figure 1) with normal platelet count. The patient was diagnosed with cancer-associated microangiopathic haemolytic anaemia1 2 with laboratory evidence of disseminated intravascular coagulation, and she passed away on comfort measures 24 hours after admission.

Figure 1

Arrows showing marked schistocytes.

...

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Delayed presentation of iatrogenic bladder perforation

Description 

A 41-year-old lady presented to a district general hospital with a 24-hour history of abdominal pain, shoulder tip pain and anuria. No other symptoms were reported, and observations were stable. Her medical history included endometriosis, one normal vaginal delivery in 1998 and three caesarean sections dated 2003, 2010 and 2012. On examination, there was tenderness in the suprapubic region and left loin; the bladder was not palpable, and she did not elicit any signs of peritonitis. A Foley catheter was inserted. Urinalysis showed 4+ blood and 2+ ketones. She had raised inflammatory markers and a raised creatinine of 200 µmol/L.

The following day, creatinine had normalised, but there was no improvement in symptoms, despite antibiotics. A CT of her kidneys, ureters and bladder was reported as showing locules of free gas in the bladder consistent with recent catheterisation. There was free fluid in the pelvis, and a faecolith...

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Tuberculosis in Pap Samples with Emphasis on LBC: Caught Only When Thought

Despite being a commonly encountered infection, the clinical diagnosis of tuberculosis of the uterine cervix is elusive. Though a straightforward diagnosis on tissue sections, identification of typical features of tubercular infection on cervical Pap samples is challenging. In our experience, the infrequent pale staining collections of epithelioid cells are difficult to pick up on Pap stained smears, particularly LBC samples. In this series, 2 of the three samples were reported as atypical squamous cells of undetermined significance while 1 was reported as inflammatory at the initial diagnosis. Scattered Langhans' type giant cells may be seen as a subtle clue which should prompt the search for epithelioid cell granulomas. These cases may have a mass lesion clinically while no obvious signs of malignancy on the cervical samples.

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Cysticercosis and cytodiagnosis

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A comparison of results of empirical studies of supplementary search techniques and recommendations in review methodology handbooks: a methodological review

The purpose and contribution of supplementary search methods in systematic reviews is increasingly acknowledged. Numerous studies have demonstrated their potential in identifying studies or study data that wou...

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Rhabdomyolysis, lactic acidosis, and multiple organ failure during telbivudine treatment for hepatitis B: a case report and review of the literature

Telbivudine can cause severe side effects, including myositis, neuritis, rhabdomyolysis, and lactic acidosis. However, reported cases of telbivudine leading to multiple organ failure are rare. Here, we report ...

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Rhabdomyolysis, lactic acidosis, and multiple organ failure during telbivudine treatment for hepatitis B: a case report and review of the literature

Telbivudine can cause severe side effects, including myositis, neuritis, rhabdomyolysis, and lactic acidosis. However, reported cases of telbivudine leading to multiple organ failure are rare. Here, we report ...

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Mycotic pseudoaneurysm of a pulmonary artery branch caused by Cladosporium

We report the case of a 53-year-old male with a history of acute myelogenous leukemia, who suffered the rupturing of a right-sided pulmonary artery pseudoaneurysm combined with pneumonia. He underwent a right-sided lower lobectomy. The resected lung tissue demonstrated a mycotic pseudoaneurysm of a pulmonary artery branch together with a filamentous fungal infection. Pseudoaneurysms are caused by the breaching of all layers of a blood vessel wall. The extravasated blood is trapped by the surrounding extravascular tissue or clots. Cladosporium was detected during a polymerase chain reaction-based analysis followed by DNA sequencing of formalin-fixed paraffin-embedded lung tissue samples. Although previous cases of pulmonary artery pseudoaneurysms caused by fungal infections, e.g., Candida or Aspergillus sp., have been reported, to the best of our knowledge this is the first case to involve cladosporiosis.

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Analysis of the characteristics of cracked teeth and evaluation of pulp status according to periodontal probing depth

Abstract

Background

The purpose of this study was to analyze the characteristics of cracked teeth and to evaluate pulp status according to periodontal probing depth (PPD).

Methods

A total of 182 cracked teeth were included. The location and type of the cracked teeth, age and gender of the patients, restoration type, pulp status, PPD, and radiographic findings were analyzed.

Results

Mandibular second molars (25.3%) were the most frequently involved teeth, followed by mandibular first molars (22.5%), maxillary first molars (22.0%), and maxillary second molars (17.6%). The patient age was most frequently 50–59 years. Cracks occurred mainly in nonbonded restorations, such as gold (26.9%), and were usually found in intact teeth (37.9%). A total of 103 teeth (56.6%) had an initial PPD of less than 3 mm, while 40 (22.0%) had a PPD of 4–6 mm, and 39 (21.4%) had PPD of 7 mm or more. A total of 33 cracked teeth (18.1%) were diagnosed with pulp necrosis, 40 (22.0%) with irreversible pulpitis, and 97 (53.3%) with reversible pulpitis. The incidence of pulp necrosis was 31.8% among cracked teeth with a PPD of 4–6 mm, and 28.6% among those with a PPD of 7 mm or more.

Conclusions

Cracks occurred mainly in molar teeth, and were commonly found in intact teeth with no restoration. Patients with cracked teeth were most frequently aged 50–59 years. Cracked teeth showing a PPD of more than 4 mm were more likely to show pulp necrosis.

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The costs and benefits of water fluoridation in NZ

Abstract

Background

Implementing community water fluoridation involves costs, but these need to be considered against the likely benefits. We aimed to assess the cost-benefit and cost-effectiveness of water fluoridation in New Zealand (NZ) in terms of expenditure and quality-adjusted life years.

Methods

Based on published studies, we determined the risk reduction effects of fluoridation, we quantified its health benefits using standardised dental indexes, and we calculated financial savings from averted treatment. We analysed NZ water supplies to estimate the financial costs of fluoridation. We devised a method to represent dental caries experience in quality-adjusted life years.

Results

Over 20 years, the net discounted saving from adding fluoride to reticulated water supplies supplying populations over 500 would be NZ$1401 million, a nine times pay-off. Between 8800 and 13,700 quality-adjusted life years would be gained. While fluoridating reticulated water supplies for large communities is cost-effective, it is unlikely to be so with populations smaller than 500.

Conclusions

Community water fluoridation remains highly cost-effective for all but very small communities. The health benefits—while (on average) small per person—add up to a substantial reduction in the national disease burden across all ethnic and socioeconomic groups.

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Nickle(II) ions exacerbate bleomycin-induced pulmonary inflammation and fibrosis by activating the ROS/Akt signaling pathway

Abstract

Nickle (Ni) is a heavy metal found in particulate matter. We previously reported that Ni ions are strongly associated with high apoptosis rates and high expression of IL-1β in human bronchial epithelial cells following exposure to PM2.5; however, the effects of Ni ions on pulmonary fibrosis have not been fully elucidated. In the current study, we evaluated whether Ni ions can exacerbate bleomycin (BLM)-induced pulmonary fibrosis in a mouse model and illustrated the potential mechanism. Ni ions inhibited cell proliferation and induced apoptosis in A549 and MRC-5 cells. BLM-induced lung injury and fibrosis in mice were significantly enhanced by nickel treatment, and these findings were also supported by inflammatory cell accumulation in bronchoalveolar lavage fluid and elevated levels of pro-inflammatory cytokines in lung tissues. Ni ions also increased extracellular matrix protein levels, including those of type I collagen and MMP9 in mouse lung tissues and cell lines. Moreover, Ni ions promoted the phosphorylation of AKT in this mouse model. The effect of increased collagen levels and MMP9 expression was inhibited by blocking the AKT phosphorylation. Together, these findings suggest AKT activation as a critical contributor to this Ni-exacerbated pulmonary fibrotic process.

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Heterogeneous activation of peroxymonosulfate by hierarchical CuBi 2 O 4 to generate reactive oxygen species for refractory organic compounds degradation: morphology and surface chemistry derived reaction and its mechanism

Abstract

Activation of peroxymonosulfate (PMS) by a novel hierarchical CuBi₂O₄ generated reactive oxygen radical for degradation refractory organic compounds in aqueous solution, which would be controlled by the morphology and surface chemistry of solid catalyst. It's found that the activation ability of CuBi₂O₄ toward PMS was highly dependent on the morphology and surface hydroxyl group, as using rhodamine B (RhB) as the model compound. The spherical CuBi₂O₄, which possessed higher density of surface hydroxyl group, exhibited better catalytic activity in RhB degradation than scattered cluster CuBi₂O₄, and as-prepared CuBi₂O₄ could efficiently activated PMS to degrade RhB within a wide pH range as an absolute heterogeneous process. The emerging organic chemicals, including bisphenol A, 1H-benzotriazole, and carbamazepine, could also be effectively removed in this novel CuBi₂O₄/PMS. Furthermore, activation mechanism of PMS by as-prepared CuBi₂O₄ was proposed, the existence of surface hydroxyl group bonded with Cu(II), and inward electron transfer cycling reaction between Cu(II)/Cu(I) facilitated the effective activation of PMS to generate SO₄^·− and ·OH. In addition, the intermediates of RhB formed in this process were identified by silylation derivatation-GC-MS and LC-high-resolution MS/MS, and degradation pathway was proposed.

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Scutellarin alleviates lipopolysaccharide-induced cognitive deficits in the rat: Insights into underlying mechanisms

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Tourandokht Baluchnejadmojarad, Hossein Zeinali, Mehrdad Roghani
Inflammation is a common hallmark of neurodegenerative disorders. Systemic inflammation is usually associated with cognitive deficits. Scutellarin is a flavone with established antioxidant, anti-inflammatory, and neuroprotective effects. In this study, the effect of this flavone in prevention of lipopolysaccharide (LPS)-induced cognitive deficit was evaluated. LPS was i.p. injected at a dose of 500μg/kg/day and scutellarin was administered i.p. at doses of 5, 25, or 50mg/kg/day. Treatment of LPS-injected rats with scutellarin dose-dependently ameliorated deficits of spatial recognition memory in Y maze, discrimination index in novel object discrimination task, and retention and recall index in passive avoidance test. Additionally, scutellarin lowered hippocampal malondialdehyde (MDA) and potentiated antioxidant defense elements comprising superoxide dismutase (SOD), catalase, and glutathione (GSH) in addition to reduction of acetylcholinesterase (AChE) activity. Furthermore, scutellarin decreased hippocampal nuclear factor-kappaB (NF-κB), tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and elevated nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Inappropriate alterations of authophagy markers including beclin-1, LC3 II, mTOR, and P62 were also prevented in the presence of scutellarin. Our findings demonstrate that scutellarin alleviates LPS-induced cognitive disturbances, however, the precise mechanism remains still speculative.



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Characteristics of the trace elements and arsenic, iodine and bromine species in snow in east-central China

Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): Yunchuan Gao, Chao Yang, Jin Ma, Meixue Yin
Fifty-five snow samples were collected from 11 cities in east-central China. These sampling sites cover the areas with the most snowfall in 2014, there were only two snowfalls from June 2013 to May 2014 in east-central China. Twenty-three trace elements in the filtered snow samples were measured with inductively coupled plasma-mass spectrometry (ICP-MS). Statistical analysis of the results show that the total concentrations of elements in the samples from different cities are in the order of SJZ > LZ > XA > ZZ > GD > NJ > QD > JX > WH > HZ > LA, which are closely related to the levels of AQI, PM2.5 and PM10 in these cities, and their correlation coefficients are 0.93, 0.76 and 0.93. The concentration of elements in snow samples is highly correlated with air pollution and reflects the magnitude of the local atmospheric deposition. The concentrations of Fe, Al, Zn, Ba, and P are over 10.0 μg/L, the concentrations of Mn, Cu, Pb, As, Br and I are between 1.0 μg/L to 10.0 μg/L, the concentrations of V, Cr, Co, Ni, Se, Mo, Cd and Sb are less than 1.0 μg/L in snow samples in east-central China, and Rh, Pd, Pt, Hg were not detected. Iodine and bromine species in all samples and arsenic species (As(III), As(V), dimethylarsinic acid (DMA) and monomethyl arsenic (MMA)) in some samples were separated and measured successfully by HPLC-ICP-MS. The majority of arsenic in the snow samples is inorganic arsenic, and the concentration of As(III) (0.104–1.400 μg/L) is higher than that of As(V) (0.012–0.180 μg/L), while methyl arsenicals, such as DMA and MMA, were almost not detected. The concentration of I⁻ (Br⁻) is much higher than that of IO3⁻ (BrO3⁻). The mean concentration of soluble organic iodine (SOI) (1.64 μg/L) is higher than that of I⁻ (1.27 μg/L), however the concentration of Br⁻ (5.58 μg/L) is higher than that of soluble organic bromine (SOBr) (2.90 μg/L). The data presented here shows that SOI is the most abundant species and the majority of the total bromine is bromide in snow sampled at east-central China. Using Fe as the reference element to calculate the EFs, the enrichment factors of V, Cr, Co, Ni, Mn, Ba and P are between 12.3 and 82.8, and the enrichment factors of Cu, Pb, Mo, Zn, Cd, As, Sb, Br, I and Se are between 189.4 and 27667.9, indicating that these elements are contributed by artificial sources. Results of principal component analysis (PCA) on the elements showed that most of trace elements (e.g. V, Cr, Mn, Co, Ni, Cu, As, Mo, Sb, Se, Br, I, Ba and P)were from the combustion of fossil fuels, traffic and ocean sources and some other elements (e.g. Zn, Cd and Pb) were mainly originated from industrial activities.



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Variations of radon concentration in the atmosphere. Gamma dose rate

Publication date: February 2018
Source:Atmospheric Environment, Volume 174
Author(s): D.E. Tchorz-Trzeciakiewicz, A.T. Solecki
The purposes of research were following: observation and interpretation of variations of radon concentration in the atmosphere - vertical, seasonal, spatial and analysis of relation between average annual radon concentration and ground natural radiation and gamma dose rate. Moreover we wanted to check the occurrence of radon density currents and the possibility of radon accumulation at the foot of the spoil tip.The surveys were carried out in Okrzeszyn (SW Poland) in the area of the spoil tip formed during uranium mining that took place in 60's of 20th century. The measurements were carried out in 20 measurements points at three heights: 0.2 m, 1 m and 2 m a.g.l. using SSNTD LR-115. The survey lasted one year and detectors were exchanged at the beginning of every season. Uranium eU (ppm), thorium eTh (ppm) and potassium K (%) contents were measured using gamma ray spectrometer Exploranium RS-230, ambient gamma dose rate using radiometer RK-100.The average radon concentration on this area was 52.8 Bq m-3. The highest radon concentrations were noted during autumn and the lowest during winter. We observed vertical variations of radon concentration. Radon concentrations decreased with increase of height above ground level. The decrease of radon with increase of height a.g.l. had logarithmic character. Spatial variations of radon concentrations did not indicate the occurrence of radon density currents and accumulation of radon at the foot of the spoil tip.The analysis of relation between average radon concentrations and ground natural radiation (uranium and thorium content) or gamma dose rate revealed positive relation between those parameters. On the base of results mentioned above we suggested that gamma spectrometry measurements or even cheaper and simpler ambient gamma dose rate measurements can be a useful tool in determining radon prone areas. This should be confirmed by additional research.



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Efficacy and safety of the “Xingnao Kaiqiao” acupuncture technique via intradermal needling to treat postoperative gastrointestinal dysfunction of laparoscopic surgery: study protocol for a randomized controlled trial

Xingnao Kaiqiao acupuncture involves needling of the Neiguan (PC6), Renzhong (DU26), and Sanyinjiao (SP6) acupoints. The technique has a significant clinical effect in many neurologica...

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An integrated digital/clinical approach to smoking cessation in lung cancer screening: study protocol for a randomized controlled trial

Delivering effective tobacco dependence treatment that is feasible within lung cancer screening (LCS) programs is crucial for realizing the health benefits and cost savings of screening. Large-scale trials and...

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Sustained inflations versus UK standard inflations during initial resuscitation of prematurely born infants in the delivery room: a study protocol for a randomised controlled trial

Many infants born at less than 34 weeks of gestational age will require resuscitation in the delivery suite. Yet, different resuscitation techniques are specified in different national guidelines, likely refle...

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Editorial Board/Aims and Scope

Publication date: 15 December 2017
Source:Vaccine, Volume 35, Issue 50





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Dengue vaccine supplies under endemic and epidemic conditions in three dengue-endemic countries: Colombia, Thailand, and Vietnam

Publication date: 15 December 2017
Source:Vaccine, Volume 35, Issue 50
Author(s): Jung-Seok Lee, Jacqueline K. Lim, Duc Anh Dang, Thi Hien Anh Nguyen, Andrew Farlow
BackgroundDengue fever has been a major public health concern in Colombia, Thailand, and Vietnam. Unlike other infectious diseases, dengue vaccines had not been available for a long time, causing difficulties to control the disease. However, the first live attenuated, tetravalent dengue vaccine (CYD-TDV) became available in 2016 and has been already licensed in some dengue-endemic countries. Because several second-generation dengue vaccines are also in the pipeline, it is critical to understand the efficient allocation of dengue vaccines considering the geographical variation of the disease.MethodsThe Climate Risk Factor (CRF) index was created using the climate and non-climate factors in the three countries. A random-coefficient negative binomial model was chosen to validate the relationship between the CRF index and dengue incidence proxy. Given the statistical significance of the CRF index, high risk areas for dengue fever were identified at the 5 km by 5 km resolution and used to estimate vaccination coverage rates and the number of doses required for various types of vaccination scenarios by country.Results and conclusionsBased upon a three-dose scheme, the estimated number of vaccines required for routine vaccination targeting 9 years old ranged from 1 to 2.6 million doses across the countries during the first year of introduction. A one-off catch-up campaign targeting the age group of 10–17 year olds would require 8 to 18 million additional doses. Routine vaccination (with or without a catch-up campaign) covered 63%, 90%, and 91% of the targeted age group populations in Colombia, Thailand, and Vietnam respectively. Given that many dengue-endemic countries face limited resources and that the costs for mass vaccination campaigns may not be trivial, the findings of this study can guide the decision makers in the three countries regarding the efficient distribution of vaccines by identifying populations at high risk at 5 km by 5 km resolution.



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Effect of dendritic cell-cytokine-induced killer cells in patients with advanced colorectal cancer combined with first-line treatment

Abstract

Background

Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment.

Methods

A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression.

Results

Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non-DC-CIK group was 57.4 versus 33.6% (p = 0.022).

Conclusions

Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS.

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A guide to virtual reality da Vinci simulators

 A great article appeared from Julian et al. in IJMRCAS: A comparative analysis and guide to virtual reality robotic surgical simulators.  

AbstractBackground: Since the US Food and Drug Administration approved robotically assisted surgical devices for human surgery in 2000, the number of surgeries utilizing this innovative technology has risen. In 2015, approximately 650 000 robot‐assisted procedures were performed worldwide. Surgeons must be properly trained to safely transition to using such innovative technology. Multiple virtual reality robotic simulators are now commercially available for educational and training purposes. There is a need for comparative evaluations of these simulators to aid users in selecting an appropriate device for their purposes.Methods: We conducted a comparison of the design and capabilities of all dedicated simulators of the da Vinci robot – the da Vinci Skills Simulator (dVSS), dV‐Trainer (dVT), Robotic Skills Simulators (RoSS) and the RobotiX Mentor. This paper provides the base specifications of the hardware and software, with an emphasis on the training capabilities of each system.  

Results: Each simulator contains a large number of training exercises for skills development: dVSS n = 40, dVT n = 65, RoSS n = 52, RobotiX Mentor n = 31. All four offer 3D visual images but use different display technologies. The dVSS leverages the real robotic surgical console to provide visualization, hand controls and foot pedals. The dVT, RoSS and RobotiX Mentor created simulated versions of all of these control systems. Each includes systems management services that allow instructors to collect, export and analyze the scores of students using the simulators.Conclusions: This study provides comparative information on the four simulators' functional capabilities. Each device offers unique advantages and capabilities for training robotic surgeons. Each has been the subject of validation experiments, which have been published in the literature. But those do not provide specific details on the capabilities of the simulators, which are necessary for an understanding sufficient to select the one best suited for an organization's needs. This article provides comparative information to assist with that type of selection.

Jaksa L, Haidegger T, Galambos P, Kiss R. published another article recently: Tools for laparoscopic skill development – available trainers and simulators, in Orvosi Hetilap

Abstract
The laparoscopic minimally invasive surgical technique is widely employed on a global scale. However, the effcient and ethical teaching of this technique requires equipment for surgical simulation. These educational devices are present on the market in the form of box trainers and virtual reality simulators, or some combination of those. In this article, we present a systematic overview of commercially available surgical simulators describing the most important features of each product. Our overview elaborates on box trainers and virtual reality simulators, and also touches on surgical robotics simulators, together with operating room workflow simulators, for the sake of completeness. Apart from presenting educational tools, we evaluated the literature of laparoscopic surgical education and simulation, to provide a complete picture of the unfolding trends in this feld.

Read more here.

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2017 TERMIS - Americas; Conference & Exhibition; Charlotte, NC; December 3–6, 2017

Tissue Engineering Part A Dec 2017, Vol. 23, No. S1: S-1-S-159.


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Abstract Author Index; by abstract number

Tissue Engineering Part A Dec 2017, Vol. 23, No. S1: S-160-S-172.


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Development of a high-resolution infrared thermographic imaging method as a diagnostic tool for acute undifferentiated limp in young children

Abstract

Acute limp is a common presenting condition in the paediatric emergency department. There are a number of causes of acute limp that include traumatic injury, infection and malignancy. These causes in young children are not easily distinguished. In this pilot study, an infrared thermographic imaging technique to diagnose acute undifferentiated limp in young children was developed. Following required ethics approval, 30 children (mean age = 5.2 years, standard deviation = 3.3 years) were recruited. The exposed lower limbs of participants were imaged using a high-resolution thermal camera. Using predefined regions of interest (ROI), any skin surface temperature difference between the healthy and affected legs was statistically analysed, with the aim of identifying limp. In all examined ROIs, the median skin surface temperature for the affected limb was higher than that of the healthy limb. The small sample size recruited for each group, however, meant that the statistical tests of significant difference need to be interpreted in this context. Thermal imaging showed potential in helping with the diagnosis of acute limp in children. Repeating a similar study with a larger sample size will be beneficial to establish reproducibility of the results.

Graphical abstract

A young child with an acute undifferentiated limp undergoes thermal imaging and the follow on image analysis assists the limp diagnosis.

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Life course evolution of body size and breast cancer survival in the E3N cohort

Abstract

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty, and early adulthood and body size trajectories from childhood to adulthood.

Self-assessed body size at age 8, at puberty, at age 20-25, and at age 35-40 and trajectories of body size of 4 662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models.

Four trajectories of body size were identified (T1 "moderate increase", T2 "stable/low increase", T3 "increase at puberty", T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 versus T2=1.27; 95% CI=1.01-1.60), and an increased risk of second invasive cancer event (HR T1 versus T2=1.25; 95% CI=1.06-1.47). Silhouettes at various ages were not associated with survival.

Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death. This article is protected by copyright. All rights reserved.

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Examining tRNA 3-ends in Escherichia coli: A teamwork between CCA-adding enzyme, RNase T and RNase R [Article]

tRNA maturation and quality control are crucial for proper functioning of these transcripts in translation. In several organisms, defective tRNAs were shown to be tagged by poly(A) or CCACCA tails and subsequently degraded by 3'-exonucleases. In a deep sequencing analysis of tRNA 3'-ends, we detected the CCACCA tag also in Escherichia coli. However, this tag closely resembles several 3'-trailers of tRNA precursors targeted for maturation and not for degradation. Here, we investigate the ability of two important exonucleases, RNase R and RNase T, to distinguish tRNA precursors with native 3' trailer from tRNAs with CCACCA tag. Our results show that the degrading enzyme RNase R breaks down both tRNAs primed for degradation as well as precursor transcripts, indicating that it is a rather non-specific RNase. RNase T, a main processing exonuclease involved in trimming of 3'-trailers, is very inefficient in converting the CCACCA-tagged tRNA into a mature transcript. Hence, while both RNases compete for trailer-containing tRNA precursors, the inability of RNase T to process CCACCA tails ensures that defective tRNAs cannot re-enter the functional tRNA pool, representing a safeguard to avoid detrimental effects of tRNAs with erroneous integrity on protein synthesis. Furthermore, these data indicate that the RNase T-mediated end turnover of the CCA sequence represents a means to deliver a tRNA to a repeated quality control performed by the CCA-adding enzyme. Hence, originally described as a futile side reaction, the tRNA end turnover seems to fulfil an important function in the maintenance of the tRNA pool in the cell.

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Safety and Pharmacokinetics of the Aminomethylcycline Antibiotic Omadacycline Administered to Healthy Subjects in Oral Multiple Dose Regimens [PublishAheadOfPrint]

Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines, but structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300 mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose, but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on Day 5 was ~50% higher than on Day 1. Omadacycline plasma concentrations on Day 1 of 450-mg dosing were similar to those on Day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.

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The ABC of biofilm drug tolerance: The MerR-like regulator BrlR is an activator of ABC transport systems, with PA1874-77 contributing to the tolerance by Pseudomonas aeruginosa biofilms to tobramycin [PublishAheadOfPrint]

A hallmark of biofilms is their tolerance to killing by antimicrobial agents. In P. aeruginosa, biofilm drug tolerance requires the c-di-GMP responsive, MerR transcriptional regulator BrlR. However, the mechanism by which BrlR mediates biofilm drug tolerance has not been elucidated. Here, we demonstrate that BrlR activates the expression of at least 7 ABC transport systems, including PA1874-77, with ChIP and DNA binding assays confirming BrlR binding to the promoter region of PA1874-77. Insertional inactivation of the 7 ABC transport systems rendered P. aeruginosa PAO1 biofilms susceptible to tobramycin or norfloxacin. Susceptibility was linked to drug accumulation, with BrlR contributing to norfloxacin accumulation in a manner dependent on multidrug efflux pumps and the ABC transport system PA1874-77. Inactivation of the respective ABC transport system furthermore eliminated the recalcitrance of biofilms to killing by tobramycin but not norfloxacin, indicating that drug accumulation is not linked to biofilm drug tolerance. Our findings indicate for the first time that BrlR, a MerR-type transcriptional activator, activates genes encoding several ABC transport systems, in addition to multiple multi-drug efflux pump genes. Moreover, our data confirm a BrlR target contributing to drug tolerance, likely countering the prevailing dogma that biofilm tolerance arises from a multiplicity of factors.

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Azithromycin Pharmacodynamics against 'Persistent Haemophilus influenza in Chronic Obstructive Pulmonary Disease [PublishAheadOfPrint]

The pharmacodynamic profile of azithromycin against persistent strains of non-typeable H. influenzae (NTHi) from COPD patients was characterized. Azithromycin displayed differential concentration-dependent activity (R² >0.98): pharmacodynamic response was attenuated comparing the 'first' vs. 'last' strain of NTHi which persisted in the airway of the same patient for 819 days (EC₅₀ increased >50 times: 0.0821 mg/L vs. 4.23). In the Hollow Fiber Infection Model NTHi viability was maintained throughout simulated Zithromax Z-pak regimens over 10 days.

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Increasing antimicrobial resistance in non-typhoidal Salmonella in Australia, 1979 - 2015 [PublishAheadOfPrint]

Australia has high and increasing rates of salmonellosis. To date, the serovar distribution and associated antimicrobial resistance (AMR) patterns of non-typhoidal Salmonella enterica (NTS) in Australia have not been assessed. Such information provides critical knowledge about AMR in the food chain, and informs decisions about public health. We reviewed longitudinal data on NTS in two Australian states over a thirty-seven-year period, between 1979 and 2015, and antimicrobial resistance since 1984. Overall, 17% of isolates were non-susceptible to at least one antimicrobial, 4.9% were non-susceptible to ciprofloxacin, and 0.6% were non-susceptible to cefotaxime. In total, 2.5% of isolates were from invasive infections, with no significant difference in AMR profiles between invasive and non-invasive isolates. Most isolates with clinically relevant AMR profiles were associated with travel, particularly to South East Asia, with multiple 'incursions' of virulent and resistant clones into Australia. Our findings represent the largest longitudinal surveillance system for NTS in Australia and provide valuable public health knowledge on the trends and distribution of AMR in NTS. Ongoing surveillance is critical to identify local emergence of resistant isolates.

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A simple in vitro assay to evaluate the incorporation efficiency of ribonucleotide analog 5' -triphosphates into RNA by human mitochondrial DNA-dependent RNA polymerase [PublishAheadOfPrint]

There is a growing body of evidence suggesting that some ribonucleoside/ribonucleotide analogs may be incorporated into mitochondrial RNA by human mitochondrial DNA-dependent RNA polymerase (POLRMT) and disrupt mitochondrial RNA synthesis. An assessment of incorporation efficiency of a ribonucleotide analog 5' -triphosphate by POLRMT may be used to evaluate potential mitochondrial toxicity of the analog early in the development process. In this report, we provide a simple method to prepare active recombinant POLRMT. A robust in vitro nonradioactive primer extension assay was developed to assay the incorporation efficiency of ribonucleotide analog 5' -triphosphates. Our results showed that many ribonucleotide analogs, including some antiviral compounds currently in various pre-clinical or clinical development stages, can be incorporated into newly synthesized RNA by POLRMT, and that the incorporation of some of them can lead to chain termination. The discrimination values (D values) of ribonucleotide analog 5' -triphosphates over natural ribonucleotide triphosphates (rNTPs) were measured to evaluate the incorporation efficiency of the ribonucleotide analog 5' -triphosphates by POLRMT. Discrimination values of natural rNTPs in the condition of misincorporation by POLRMT were used as a reference to evaluate the potential mitochondrial toxicity of ribonucleotide analogs. We proposed the following criteria for potential mitochondrial toxicity of ribonucleotide analogs based on D values: a safe compound (D > 10⁵); a potentially toxic compound (10⁵ > D > 10⁴); and a toxic compound (D < 10⁴). This report provides a simple screening method that should assist investigators in designing ribonucleoside-based drugs having lower mitochondrial toxicity.

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Efficacy of novel anti-staphylococcal ectolysin P128 in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia [PublishAheadOfPrint]

Staphylococcus aureus (S.aureus) causes systemic infections with high morbidity and mortality and emergence of drug resistance strains are a rapidly growing clinical concerns. Novel therapeutic agents are required to tackle S.aureus infections. P128 is a bacteriophage-derived chimeric ectolysin with potent and rapid bactericidal activity on S. aureus. In the current study, efficacy of P128 was evaluated in a newly-developed rat model of S. aureus bacteremia. Prior to in vivo testing, P128 was shown to be stable in whole blood by incubation in rat blood for up to 6 hrs and testing of its bactericidal activity against MRSA isolate USA 300. Rats succumbed to intravenous challenge with 10⁹ CFU of S. aureus USA300 resulting in 80 to 100% mortality by day 14. Evaluation of the bacterial load in various organs at 96 hours post-infection revealed high bacterial counts in the kidney, and this correlated with the presence of renal abscesses. Treatment of infected animals with P128 either by intravenous bolus administration via tail vein or by one-hour infusion via jugular vein 2 hours post-infection, resulted in dose-dependent survival of rats. P128 treatment also resulted in very few or no abscesses in the kidneys. These data show that P128 is stable in the physiological milieu and that intravenous treatment with P128 is highly effective in rescuing rats from S. aureus bacteremia. P128 can be a novel therapeutic option for treatment of S.aureus systemic infections.

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On the antibacterial and sterilizing effect of benzylpenicillin in tuberculosis [PublishAheadOfPrint]

The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis (Mtb). Here, we found that >64 mg/L of static benzylpenicillin concentrations killed 1.16-1.43 log₁₀ CFU/mL below starting inoculum of extracellular and intracellular Mtb over 7 days. When we added the β-lactamase-inhibitor avibactam, benzylpenicillin maximal kill (E_max) of either extracellular log-phase growth Mtb was 6.80±0.45 log₁₀ CFU/mL at an EC₅₀ of 15.11±5.2.32 mg/L, while for intracellular Mtb was 2.42±0.14 log₁₀ CFU/mL at an EC₅₀ of 6.70±0.56 mg/L. The median penicillin (plus avibactam) MIC against South African clinical Mtb strains (80% either multi- or extensively drug-resistant) was 2 mg/L. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow fiber model of tuberculosis (HFS-TB). The percentage time above MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase growth Mtb was 1.44 log₁₀ CFU/mL/day, while 3.28 log₁₀ CFU/mL of intracellular Mtb was killed over 3 weeks. In an 8 week HFS-TB study of non-replicating persistent Mtb, penicillin-avibactam alone versus the drug combination of isoniazid, rifampin, and pyrazinamide, both killed >7.0 log₁₀ CFU/mL. Monte Carlo simulations of 10,000 pre-term infants with disseminated disease identified an optimal dose of 10,000 U/kg/hr, while for pregnant women or non-pregnant adults with pulmonary tuberculosis optima dose was 25,000 U/kg/hr, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.

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Preconditioned Augmented Lagrangian formulation for nearly incompressible cardiac mechanics

Summary

Computational modeling of the heart is a subject of substantial medical and scientific interest, which may contribute to increase the understanding of several phenomena associated with cardiac physiological and pathological states. Modeling the mechanics of the heart have led to considerable insights, but it still represents a complex and a demanding computational problem, especially in a strongly coupled electromechanical setting. Passive cardiac tissue is commonly modeled as hyperelastic, and is characterized by quasi-incompressible, orthotropic and non-linear material behavior. These factors are known to be very challenging for the numerical solution of the model. The near-incompressibility is known to cause numerical issues such as the well known locking phenomenon and ill-conditioning of the stiffness matrix. In this work, the Augmented Lagrangian method (ALG) is used to handle the nearly incompressible condition. This approach can potentially improve computational performance by reducing the condition number of the stiffness matrix and thereby improving the convergence of iterative solvers. We also improve the performance of iterative solvers by the use of an algebraic multigrid preconditioner. Numerical results of the ALG method combined with a preconditioned iterative solver for a cardiac mechanics benchmark suite are presented to show its improved performance. This article is protected by copyright. All rights reserved.

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Cell-Autonomous Metabolic Reprogramming in Hypoxia

Publication date: Available online 27 November 2017
Source:Trends in Cell Biology
Author(s): Luana Schito, Sergio Rey
Molecular oxygen (O2) is a universal electron acceptor that enables ATP synthesis through mitochondrial respiration in all metazoans. Consequently, hypoxia (low O2) has arisen as an organizing principle for cellular evolution, metabolism, and (patho)biology, eliciting a remarkable panoply of metabolic adaptations that trigger transcriptional, translational, post-translational, and epigenetic responses to determine cellular fitness. In this review we summarize current and emerging cell-autonomous molecular mechanisms that induce hypoxic metabolic reprogramming in health and disease.



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