AHNS Series: Do you know your guidelines? Guideline recommendations for head and neck cancer of unknown primary site

Abstract

This article reviews the clinical practice guidelines for head and neck oncology focusing on the management of head and neck cancers of unknown primary (CUP). The primary purpose of this series is to raise awareness of the current guidelines in head and neck oncology by reviewing the recommendations and the evidence supporting such recommendations, particularly those published by the National Comprehensive Cancer Network (NCCN). We review the importance of a thorough history and physical examination, the impact of the American Joint Committee on Cancer (AJCC) eighth edition changes and the importance of immunohistochemistry, the timing and type of imaging, the role of panendoscopy and tonsillectomy (palatine and lingual), and the role of surgery, radiation, and chemotherapy in the primary management of these tumors.

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Clinical diagnosis and treatment outcomes for parapharyngeal space schwannomas: A single-institution review of 21 cases

Abstract

Background

Because the incidence of schwannoma arising from the parapharyngeal space (PPS) is very low, no studies have analyzed extirpation methods and postoperative neurological complications exclusively in PPS schwannomas.

Methods

The preoperative diagnosis and clinical outcomes of surgical treatment in 21 patients with PPS schwannoma who underwent surgery were investigated.

Results

Neurological deficit of the involved nerve developed in all patients regardless of the extirpation method used. However, the incidence of first bite syndrome in sympathetic chain schwannoma was significantly lower after intracapsular enucleation (40%) than after total resection (100%; P = .045). Furthermore, the incidence of postoperative complications unrelated to the involved nerve was lower after intracapsular enucleation (0%) than after total resection (42.9%; P = .055).

Conclusion

Although postoperative neurological deficit of the involved nerve was unavoidable in PPS schwannoma, intracapsular enucleation could be beneficial by reducing its severity and the incidence of complications unrelated to the involved nerve.

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Bacterial Diversity in Traditional Doogh in Comparison to Industrial Doogh

Abstract

Forty-four samples of traditional Doogh and yoghurt were collected from 13 regions of 4 provinces in west of Iran (13 area) and analyzed using molecular methods including PCR, denaturing gradient gel electrophoresis (DGGE) of 16S rDNA, and sequencing. Moreover, collected samples as well as samples from industrially Doogh were analyzed with quantitative real-time PCR (RT-PCR). Analyzed 16S rRNA gene sequences of Doogh samples could be allocated to the presence of Lactobacillus spp. The typical yoghurt starter culture bacteria included four different Lactobacillus species with possible probiotic properties, L. acidophilus, L. helveticus, L. kefiranofaciens, and L. amylovorus. DGGE of traditional Doogh and yoghurt and RT-PCR of traditional Doogh and yoghurt and also industrial Doogh samples demonstrated that traditional Doogh and yoghurt show a higher abundance of total bacteria and lactobacilli and a higher bacterial diversity, respectively. Considering diversity and higher probiotic bacteria content in traditional Doogh, consumers' healthiness in tribes and villages could be promoted with these indigenous products.

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AHNS Series: Do you know your guidelines? Guideline recommendations for head and neck cancer of unknown primary site

Abstract

This article reviews the clinical practice guidelines for head and neck oncology focusing on the management of head and neck cancers of unknown primary (CUP). The primary purpose of this series is to raise awareness of the current guidelines in head and neck oncology by reviewing the recommendations and the evidence supporting such recommendations, particularly those published by the National Comprehensive Cancer Network (NCCN). We review the importance of a thorough history and physical examination, the impact of the American Joint Committee on Cancer (AJCC) eighth edition changes and the importance of immunohistochemistry, the timing and type of imaging, the role of panendoscopy and tonsillectomy (palatine and lingual), and the role of surgery, radiation, and chemotherapy in the primary management of these tumors.

http://ift.tt/2zn3nf0

Clinical diagnosis and treatment outcomes for parapharyngeal space schwannomas: A single-institution review of 21 cases

Abstract

Background

Because the incidence of schwannoma arising from the parapharyngeal space (PPS) is very low, no studies have analyzed extirpation methods and postoperative neurological complications exclusively in PPS schwannomas.

Methods

The preoperative diagnosis and clinical outcomes of surgical treatment in 21 patients with PPS schwannoma who underwent surgery were investigated.

Results

Neurological deficit of the involved nerve developed in all patients regardless of the extirpation method used. However, the incidence of first bite syndrome in sympathetic chain schwannoma was significantly lower after intracapsular enucleation (40%) than after total resection (100%; P = .045). Furthermore, the incidence of postoperative complications unrelated to the involved nerve was lower after intracapsular enucleation (0%) than after total resection (42.9%; P = .055).

Conclusion

Although postoperative neurological deficit of the involved nerve was unavoidable in PPS schwannoma, intracapsular enucleation could be beneficial by reducing its severity and the incidence of complications unrelated to the involved nerve.

http://ift.tt/2mNnBIL

Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay

Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.

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Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly

Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome phenotype (JS30), elucidates the genetic heterogeneity of Joubert syndrome, and expands the gene list for ciliopathies.

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Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.

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MED13L loss-of-function variants in two patients with syndromic Pierre Robin sequence

We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L–related disorders are a possible differential diagnosis for syndromic PRS.

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FGFR1 disruption identified by whole genome sequencing in a male with a complex chromosomal rearrangement and hypogonadotropic hypogonadism

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Discordant fetal phenotype of hypophosphatasia in two siblings

Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.

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Less common underlying genetic diagnoses found in a cohort of 139 individuals surgically corrected for craniosynostosis

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Response to: “In reply to: ‘Mast Cell Disorders in Ehlers–Danlos Syndrome’ (Jaime Vengoechea, Department of Human Genetics, Emory University)”

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Tarsal-carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation

We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum.

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Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16–18, 2017, Dallas, Texas

Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10° or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). "Congenital" scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is evidence that both conditions are etiologically related. A 2-day conference entitled "Genomic Approaches to Understanding and Treating Scoliosis" was held at Scottish Rite Hospital for Children in Dallas, Texas, to synergize research in this field. This first combined, multidisciplinary conference featured international scoliosis researchers in basic and clinical sciences. A major outcome of the conference advancing scoliosis research was the proposal and subsequent vote in favor of merging the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) and International Consortium for Scoliosis Genetics (ICSG) into a single entity called International Consortium for Spinal Genetics, Development, and Disease (ICSGDD). The ICSGDD is proposed to meet annually as a forum to synergize multidisciplinary spine deformity research.

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Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities

The diagnosis of intellectual disability/developmental delay (ID/DD) benefits from the clinical application of target/exome sequencing. The yield in Mendelian diseases varies from 25% to 68%. The aim of the present study was to identify the genetic causes of 33 ID/DD patients using target/exome sequencing. Recent studies have demonstrated that reanalyzing undiagnosed exomes could yield additional diagnosis. Therefore, in addition to the normal data analysis, in this study, re-evaluation was performed prior to manuscript preparation after updating OMIM annotations, calling copy number variations (CNVs) and reviewing the current literature. Molecular diagnosis was obtained for 19/33 patients in the first round of analysis. Notably, five patients were diagnosed during the re-evaluation of the geno/phenotypic data. This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re-evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next-generation sequencing (NGS), periodical re-evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re-contacting patients.

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Maternal inheritance of BDNF deletion, with phenotype of obesity and developmental delay in mother and child

Childhood obesity is a significant world health problem. Understanding the genetic and environmental factors contributing to the development of obesity in childhood is important for the rational design of strategies for obesity prevention and treatment. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth and development of the central nervous system, there is also an evidence that BDNF plays a role in regulation of appetite. Disruption of the expression of this gene in a child has been previously reported to result in a phenotype of severe obesity, hyperphagia, impaired cognitive function, and hyperactivity. We report a mother and child, both with micro-deletions encompassing the BDNF gene locus, who both have obesity and developmental delay, although without hyperactivity. This report highlights the maternal inheritance of a rare genetic cause of childhood obesity.

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B1 artifact reduction in abdominal DCE-MRI using kT-points: First clinical assessment of dynamic RF shimming at 3T

Background

The excitation inhomogeneity artifact occurring at 3T in the abdomen can lead to dramatic loss of signal and contrast, thereby hampering diagnosis.

Purpose

To assess excitation homogeneity and image quality achieved by nonselective prototypical k_T-points pulses, compared to tailored static RF shimming, in clinical routine on a commercial dual-transmit scanner.

Study Type

Retrospective study with Institutional Review Board approval; informed consent was waived.

Population

Fifty consecutive patients referred for liver MRI at a single hospital.

Field Strength/Sequence

3D breath-hold dynamic contrast-enhanced (DCE) MRI at 3T.

Assessment

Flip angle homogeneity was estimated via numerical simulation based on measured static and RF field maps. In all, 20 of the 50 patients underwent DCE-MRI while a pulse designer was present. The effect of RF shimming and k_T-point pulses could be compared by repeating the acquisition with each transmit scheme before injection and in the late phase. Signal homogeneity, T₁ contrast, enhancement quality, structure details, and global image quality were assessed on a 4-level scale (0 to 3) by two radiologists.

Statistical tests

Means were compared using Wilcoxon signed-rank tests.

Results

Normalized root mean square flip angle error was significantly reduced with k_T-points compared to static RF shimming (8.5% ± 1.5% [mean ± standard deviation, SD] vs. 20.4% ± 9.8%; P < 0.0001). The worst case (heavy ascites) led to 13.0% (k_T-points) vs. 54.9% (RF shimming). Global image quality was significantly higher for k_T-points (2.3 ± 0.5 vs. 1.9 ± 0.6; P = 0.008). One subject's examination was judged unusable with RF shimming by one reader, none with k_T-points. 85% of k_T-points acquisitions were graded at least 2/3, and only 55% for static RF shimming.

Data Conclusion

K_T-points reduce excitation inhomogeneity quantitatively and qualitatively, especially in patients with ascites and prone to B₁ shading.

Level of Evidence: 1

Technical Efficacy: Stage 1

J. Magn. Reson. Imaging 2017.

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Comparison of quantitative regional ventilation-weighted fourier decomposition MRI with dynamic fluorinated gas washout MRI and lung function testing in COPD patients

Background

Ventilation-weighted Fourier decomposition-MRI (FD-MRI) has matured as a reliable technique for quantitative measures of regional lung ventilation in recent years, but has yet not been validated in COPD patients.

Purpose/Hypothesis

To compare regional fractional lung ventilation obtained by ventilation-weighted FD-MRI with dynamic fluorinated gas washout MRI (¹⁹F-MRI) and lung function test parameters.

Study Type

Prospective study.

Population

Twenty-seven patients with chronic obstructive pulmonary disease (COPD, median age 61 [54–67] years) were included.

Field Strength/Sequence

For FD-MRI and for ¹⁹F-MRI a spoiled gradient echo sequence was used at 1.5T.

Assessment

FD-MRI coronal slices were acquired in free breathing. Dynamic ¹⁹F-MRI was performed after inhalation of 25–30 L of a mixture of 79% fluorinated gas (C₃F₈) and 21% oxygen via a closed face mask tubing using a dedicated coil tuned to 59.9 MHz. ¹⁹F washout times in numbers of breaths (¹⁹F-n_breaths) as well as fractional ventilation maps for both methods (FD-FV, ¹⁹F-FV) were calculated. Slices were matched using a landmark driven algorithm, and only corresponding slices with an overlap of >90% were coregistered for evaluation.

Statistical Tests

The obtained parameters were correlated with each other using Spearman's correlation coefficient (r).

Results

FD-FV strongly correlated with ¹⁹F-n_breaths on a global (r = –0.72, P < 0.0001) as well as on a lobar level and with lung function test parameters (FD-FV vs. FEV1, r = 0.76, P < 0.0001). There was a small systematic overestimation of FD-FV compared to ¹⁹F-FV (mean difference –0.03 (95% confidence interval [CI]: –0.097; –0.045).

Data Conclusion

Regional ventilation-weighted Fourier decomposition-MRI is a promising noninvasive, radiation-free tool for quantification of regional ventilation in COPD patients.

Level of Evidence: 2

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2017.

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Extracellular volume with bolus-only technique in amyloidosis patients: Diagnostic accuracy, correlation with other clinical cardiac measures, and ability to track changes in amyloid load over time

Background

Extracellular volume (ECV) by T₁ mapping requires the contrast agent distribution to be at equilibrium. This can be achieved either definitively with a primed contrast infusion (infusion ECV), or sufficiently with a delay postbolus (bolus-only ECV). For large ECV, the bolus-only approach measures higher than the infusion ECV, causing some uncertainty in diseases such as amyloidosis.

Purpose

To characterize the relationship between the bolus-only and current gold-standard infusion ECV in patients with amyloidosis.

Study Type

Bolus-only and infusion ECV were prospectively measured.

Population

In all, 186 subjects with systemic amyloidosis attending our clinic and 23 subjects with systemic amyloidosis who were participating in an open-label, two-part, dose-escalation, phase 1 trial.

Field Strength

Avanto 1.5T, Siemens Medical Solutions, Erlangen, Germany.

Assessment

Bolus-only and infusion ECV were measured in all subjects using shortened modified Look–Locker inversion recovery (ShMOLLI) T₁ mapping sequence.

Statistical Tests

Pearson correlation coefficient (r); Bland–Altman; receiver operating characteristic (ROC) curve analysis. Linear regression model with a fractional polynomial transformation.

Results

The difference between the bolus-only and infusion myocardial ECV increased as the average of the two measures increased, with the bolus-ECV measuring higher. For an average ECV of 0.4, the difference was 0.013. The 95% limits of agreement for the two methods, after adjustment for the bias, were ±0.056. However, cardiac diagnostic accuracy was comparable (bolus-only vs. infusion ECV area under the curve [AUC] = 0.839 vs. 0.836), as were correlations with other clinical cardiac measures, and, in the trial patients, the ability to track changes in the liver/spleen with therapy.

Data Conclusion

In amyloidosis, with large ECVs, the bolus-only technique reads higher than the infusion technique, but clinical performance by any measure is the same. Given the work-flow advantages, these data suggest that the bolus-only approach might be acceptable for amyloidosis, and might support its use as a surrogate endpoint in future clinical trials.

Level of Evidence: 1

Technical Efficacy: Stage 4

J. Magn. Reson. Imaging 2017.

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Issue Information

No abstract is available for this article.

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Endoplasmic reticulum in health and disease: the 12th International Calreticulin Workshop, Delphi, Greece

Abstract

Starting from 1994, every 2 years, an international workshop is organized focused on calreticulin and other endoplasmic reticulum chaperones. In 2017, the workshop took place at Delphi Greece. Participants from North and South America, Europe, Asia and Australia presented their recent data and discussed them extensively with their colleagues. Presentations dealt with structural aspects of calreticulin and calnexin, the role of Ca²⁺ in cellular signalling and in autophagy, the endoplasmic reticulum stress and the unfolded protein response, the role of calreticulin in immune responses. Several presentations focused on the role of calreticulin and other ER chaperones in a variety of disease states, including haemophilia, obesity, diabetes, Sjogren's syndrome, Chagas diseases, multiple sclerosis, amyotrophic lateral sclerosis, neurological malignancies (especially glioblastoma), haematological malignancies (especially essential thrombocythemia and myelofibrosis), lung adenocarcinoma, renal pathology with emphasis in fibrosis and drug toxicity. In addition, the role of calreticulin and calnexin in growth and wound healing was discussed, as well as the possible use of extracellular calreticulin as a marker for certain diseases. It was agreed that the 13th International Calreticulin Workshop will be organized in 2019 in Montreal, Quebec, Canada.

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Dihydromyricetin enhances glucose uptake by inhibition of MEK/ERK pathway and consequent down-regulation of phosphorylation of PPARγ in 3T3-L1 cells

Abstract

Accumulating evidence suggests that inhibition of mitogen-activated protein kinase signalling can reduce phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at serine 273, which mitigates obesity-associated insulin resistance and might be a promising treatment for type 2 diabetes. Dihydromyricetin (DHM) is a flavonoid that has many beneficial pharmacological properties. In this study, mouse fibroblast 3T3-L1 cells were used to investigate whether DHM alleviates insulin resistance by inhibiting PPARγ phosphorylation at serine 273 via the MEK/ERK pathway. 3T3-L1 pre-adipocytes were differentiated, and the effects of DHM on adipogenesis and glucose uptake in the resulting adipocytes were examined. DHM was found to dose dependently increase glucose uptake and decrease adipogenesis. Insulin resistance was then induced in adipocytes using dexamethasone, and DHM was shown to dose and time dependently promote glucose uptake in the dexamethasone-treated adipocytes. DHM also inhibited phosphorylation of PPARγ and ERK. Inhibition of PPARγ activity with GW9662 potently blocked DHM-induced glucose uptake and adiponectin secretion. Interestingly, DHM showed similar effects to PD98059, an inhibitor of the MEK/ERK pathway. DHM acted synergistically with PD98059 to improve glucose uptake and adiponectin secretion in dexamethasone-treated adipocytes. In conclusion, our findings indicate that DHM improves glucose uptake in adipocytes by inhibiting ERK-induced phosphorylation of PPARγ at serine 273.

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Table of Contents

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Editorial Board

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Prevalence of type I sensitization to alpha-gal in forest service employees and hunters: Is the blood type an overlooked risk factor in epidemiological studies of the α-Gal syndrome?

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Table of Contents

http://ift.tt/2iAJBCe

Editorial Board

http://ift.tt/2AZ93Z7

Prevalence of type I sensitization to alpha-gal in forest service employees and hunters: Is the blood type an overlooked risk factor in epidemiological studies of the α-Gal syndrome?

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Efficiently processing deterministic approximate aggregation query on massive data

Abstract

In actual applications, aggregation is an important operation to return statistical characterizations of subset of the data set. On massive data, approximate aggregation often is preferable for its better timeliness and responsiveness. This paper focuses on deterministic approximate aggregation to return running aggregate within progressive deterministic error interval. The existing methods either return approximate results with fixed accuracy, or return online approximate aggregate with probabilistic confidence interval, or incur a high I/O cost on massive data. This paper proposes LDA algorithm to compute deterministic approximate aggregate on massive data efficiently. LDA utilizes selection attribute lattice of hierarchical structure to distribute tuples and obtain a horizontal partitioning of the table. In each partition, each selection attribute is kept in column file and each ranking attribute is transposed to bit-slices. Given the selection condition, only relevant partitions are involved to compute the running aggregate. The compact storage scheme based on Z-order space filling curve is proposed to reduce the management cost of the partitions. An error reduction method is devised to reduce the error interval when computing running aggregate. The extensive experimental results on synthetic and real data sets show that LDA has a significant performance advantage over the existing algorithms.

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Neurological Complications of HIV Infection

Abstract

Purpose of Review

HIV-associated neurocognitive disorders (HAND) are common in patients with HIV disease, even during suppressive combination antiretroviral therapy (cART). This review article addresses the pathogenesis of HAND, focusing on important findings from the last 5 years.

Recent Findings

While HIV-associated dementia is now rare in settings with cART availability, mild forms of HAND are increasing in prevalence. Biomarkers of cellular injury, such as neurofilament light chain and neopterin, can detect early stages of neuroinflammation associated with HIV infection and are increased even in asymptomatic individuals with chronic HIV infection. Several recent studies form a growing body of evidence that HIV can infect and replicate in monocytes and that blocking monocyte activity can potentially improve neurological outcomes in HIV. Early cART may also prevent HAND.

Summary

Understanding the multifactorial causes of CNS infection and inflammation is critical to devising treatment and preventive strategies for HAND.

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A diuretic-sparing strategy to facilitate deactivation of vasopressin secretion

Click here to view the Review Symposium article by Dr. W. F. Clark et al.

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ABBV-085, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors

Conditions:   Advanced Solid Tumors;   Undifferentiated Pleomorphic Sarcoma;   Squamous Cell Carcinoma of the Head and Neck;   Carcinoma of the Breast
Intervention:   Drug: ABBV-085
Sponsor:   AbbVie
Recruiting

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Cohort profile: the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) in Olmsted County, Minnesota (USA)

Purpose

This cohort study was established to investigate the effects of unilateral and bilateral oophorectomy on the ageing processes in women.

Participants

We used the records-linkage system of the Rochester Epidemiology Project (REP, http://ift.tt/11Ne11B) to identify 570 women who underwent unilateral oophorectomy and 1653 women who underwent bilateral oophorectomy in Olmsted County, Minnesota from 1988 through 2007 (20 years). Each woman was matched by age (±1 year) to a population-based referent woman who had not undergone any oophorectomy (570 referent women) or bilateral oophorectomy (1653 referent women). These four cohorts are being followed to assess morbidity and mortality and to study imaging and biological markers related to ageing.

Findings to date

An extensive medical record abstraction using the REP has been completed for each woman to obtain demographic, reproductive and adult life characteristics and extensive clinical information about the surgical procedure and subsequent oestrogen replacement therapy (or other sex steroid therapy). The cohorts have been used to date to study the accumulation of multiple chronic conditions following bilateral oophorectomy in women with or without chronic conditions at the time of the oophorectomy (or index date). From the cohorts, we have also derived a sample of 128 pairs of women for a case–control study linking adverse childhood or adult experiences to the risk of bilateral oophorectomy.

Future plans

We hypothesise that the abrupt hormonal changes caused by bilateral oophorectomy in younger women have a major effect on the ageing processes across the full body. Therefore, we plan to investigate the risk of a wide range of chronic conditions following bilateral oophorectomy. Specific studies are underway for kidney diseases, psychiatric diseases and neurological diseases. In addition, we plan to invite a subsample of women from the bilateral oophorectomy cohort to participate in an in-person study involving brain imaging and the collection of biomarkers.

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Relationship between socioeconomic status and HIV infection: findings from a survey in the Free State and Western Cape Provinces of South Africa

Background

Studies have shown a mixed association between socioeconomic status (SES) and prevalent HIV infection across and within settings in sub-Saharan Africa. In general, the relationship between years of formal education and HIV infection changed from a positive to a negative association with maturity of the HIV epidemic. Our objective was to determine the association between SES and HIV in women of reproductive age in the Free State (FSP) and Western Cape Provinces (WCP) of South Africa (SA).

Study design

Cross-sectional.

Setting

SA.

Methods

We conducted secondary analysis on 1906 women of reproductive age from a 2007 to 2008 survey that evaluated effectiveness of Prevention of Mother-to-Child HIV Transmission Programmes. SES was measured by household wealth quintiles, years of formal education and employment status. Our analysis principally used logistic regression for survey data.

Results

There was a significant negative trend between prevalent HIV infection and wealth quintile in WCP (P<0.001) and FSP (P=0.025). In adjusted analysis, every additional year of formal education was associated with a 10% (adjusted OR (aOR) 0.90 (95% CI 0.85 to 0.96)) significant reduction in risk of prevalent HIV infection in WCP but no significant association was observed in FSP (aOR 0.99; 95% CI 0.89 to 1.11). There was no significant association between employment and prevalent HIV in each province: (aOR 1.54; 95% CI 0.84 to 2.84) in WCP and (aOR 0.96; 95% CI 0.71 to 1.30) in FSP.

Conclusion

The association between HIV infection and SES differed by province and by measure of SES and underscores the disproportionately higher burden of prevalent HIV infection among poorer and lowly educated women. Our findings suggest the need for re-evaluation of whether current HIV prevention efforts meet needs of the least educated (in WCP) and the poorest women (both WCP and FSP), and point to the need to investigate additional or tailored strategies for these women.

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Patient and practice characteristics predicting attendance and completion at a specialist weight management service in the UK: a cross-sectional study

Objective

To determine the association between patient and referring practice characteristics and attendance and completion at a specialist health service weight management service (WMS).

Design

Cross-sectional study.

Setting

Regional specialist WMS located in the West of Scotland.

Participants

9677 adults with obesity referred between 2012 and 2014; 3250 attending service and 2252 completing.

Primary and secondary outcome measures

Primary outcome measure was attendance at the WMS; secondary outcome was completion, defined as attending four or more sessions.

Analysis

Multilevel binary logistic regression models constructed to determine the association between patient and practice characteristics and attendance and completion.

Results

Approximately one-third of the 9677 obese adults referred attended at least one session (n=3250, 33.6%); only 2252 (23%) completed by attending four or more sessions. Practice referrals ranged from 1 to 257. Patient-level characteristics were strongest predictors of attendance; odds of attendance increased with age (OR 4.14, 95% CI 3.27 to 5.26 for adults aged 65+ compared with those aged 18–24), body mass index (BMI) category (OR 1.83, 95% CI 1.56 to 2.15 for BMI 45+ compared with BMI 30–35) and increasing affluence (OR 1.96, 95% CI 1.17 to 3.28). Practice-level characteristics most strongly associated with attendance were being a non-training practice, having a larger list size and not being located in the most deprived areas.

Conclusions

There was wide variation in referral rates across general practice, suggesting that there is still much to do to improve engagement with weight management by primary care practitioners. The high attrition rate from referral to attendance and from attendance to completion suggests ongoing barriers for patients, particularly those from the most socioeconomically deprived areas. Patient and practice-level characteristics can help us understand the observed variation in attendance at specialist WMS following general practitioner (GP) referral and the underlying explanations for these differences merit further investigation.

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Classroom Promotion of Oral Language (CPOL): protocol for a cluster randomised controlled trial of a school-based intervention to improve childrens literacy outcomes at grade 3, oral language and mental health

Introduction

Oral language and literacy competence are major influences on children's developmental pathways and life success. Children who do not develop the necessary language and literacy skills in the early years of school then go on to face long-term difficulties. Improving teacher effectiveness may be a critical step in lifting oral language and literacy outcomes. The Classroom Promotion of Oral Language trial aims to determine whether a specifically designed teacher professional learning programme focusing on promoting oral language can lead to improved teacher knowledge and practice, and advance outcomes in oral language and literacy for early years school children, compared with usual practice.

Methods and analysis

This is a two-arm cluster multisite randomised controlled trial conducted within Catholic and Government primary schools across Victoria, Australia. The intervention comprises 4 days of face-to-face professional learning for teachers and ongoing implementation support via a specific worker. The primary outcome is reading ability of the students at grade 3, and the secondary outcomes are teacher knowledge and practice, student mental health, reading comprehension and language ability at grade 1; and literacy, writing and numeracy at grade 3. Economic evaluation will compare the incremental costs of the intervention to the measured primary and secondary outcomes.

Ethics and dissemination

This trial was approved by the Monash University Human Research Ethics Committee #CF13/2634-2013001403 and later transferred to the University of Melbourne #1545540. The investigators (including Government and Catholic partners) will communicate trial results to stakeholders, collaborators and participating schools and teachers via appropriate presentations and publications.

Trial registration number

ISRCTN77681972; Pre-results.

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Sensitivity analysis for mistakenly adjusting for mediators in estimating total effect in observational studies

Objectives

In observational studies, epidemiologists often attempt to estimate the total effect of an exposure on an outcome of interest. However, when the underlying diagram is unknown and limited knowledge is available, dissecting bias performances is essential to estimating the total effect of an exposure on an outcome when mistakenly adjusting for mediators under logistic regression. Through simulation, we focused on six causal diagrams concerning different roles of mediators. Sensitivity analysis was conducted to assess the bias performances of varying across exposure-mediator effects and mediator-outcome effects when adjusting for the mediator.

Setting

Based on the causal relationships in the real world, we compared the biases of varying across the effects of exposure-mediator with those of varying across the effects of mediator-outcome when adjusting for the mediator. The magnitude of the bias was defined by the difference between the estimated effect (using logistic regression) and the total effect of the exposure on the outcome.

Results

In four scenarios (a single mediator, two series mediators, two independent parallel mediators or two correlated parallel mediators), the biases of varying across the effects of exposure-mediator were greater than those of varying across the effects of mediator-outcome when adjusting for the mediator. In contrast, in two other scenarios (a single mediator or two independent parallel mediators in the presence of unobserved confounders), the biases of varying across the effects of exposure-mediator were less than those of varying across the effects of mediator-outcome when adjusting for the mediator.

Conclusions

The biases were more sensitive to the variation of effects of exposure-mediator than the effects of mediator-outcome when adjusting for the mediator in the absence of unobserved confounders, while the biases were more sensitive to the variation of effects of mediator-outcome than those of exposure-mediator in the presence of an unobserved confounder.

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Protocol: a cluster randomised control trial study exploring stigmatisation and recovery-based perspectives regarding mental illness and substance use problems among primary healthcare providers across Toronto, Ontario

Introduction

Primary care settings are often the first and only point of contact for persons with mental health and/or substance use problems. However, staff experience and training in this area are often limited. These factors as well as a multitude of other components such as structural and systemic stigma experienced by staff can lead to clients being stigmatised, leading to poorer outcomes. By developing a comprehensive intervention for primary care staff working at community health centres (CHCs) aimed at reducing stigma towards people with mental health and substance use problems (MHSUP), we sought to test an innovative and contact-based intervention consisting of staff training, raising awareness, a recovery-focused art programme and an analysis of internal policies and procedures. All of these components can inform and support staff so they can provide better care for people who are experiencing MHSUP. CHC staff members and clients will be included in this project as active participants.

Methods and analysis

This mixed-methods project will consist of repeated surveys of staff and clients, as well as in-depth, semistructured interviews with a sample of clients and staff. A cluster randomised control trial design will test the effectiveness of an antistigma intervention for CHCs in Toronto, Canada. Six CHCs—three receiving the intervention and three controls—will be included in the study. Using a variety of measures, including the Opening Minds Scale for Health Care Providers (OMS-HC), Mental Illness: Clinicians Attitudes (MICA) Scale, Modified Bogardus Social Distance Scale, Perceived Devaluation-Discrimination Scale, Discrimination Experience subscale of the Internalized Stigma of Mental Illness (ISMI) Scale and the Recovery Assessment Scale (RAS), we hope to gain a thorough understanding of staff members' attitudes and beliefs and clients' perceptions of staff beliefs and behaviours. In-depth interviews will reveal important themes related to clients' experiences of stigma both within and outside the healthcare setting.

Ethics and dissemination

If demonstrated to be successful, this intervention can be used as a model for future initiatives aimed at reducing MHSUP-related stigma among healthcare providers in an organisational context. Adapting this work in other settings is a key strategic goal of this project. The project will also advance knowledge about stigma reduction and the experience of encountering stigma within a healthcare setting.

Trial registration

NCT03043417; Post-results.

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Functional visual fields: a cross-sectional UK study to determine which visual field paradigms best reflect difficulty with mobility function

Objectives

To develop an appropriate method of assessing visual field (VF) loss which reflects its functional consequences, this study aims to determine which method(s) of assessing VF best reflect mobility difficulty.

Setting

This cross-sectional observational study took place within a single primary care setting. Participants attended a single session at a University Eye Clinic, Cambridge, UK, with data collected by a single researcher (HS), a qualified optometrist.

Participants

50 adult participants with peripheral field impairment were recruited for this study. Individuals with conditions not primarily affecting peripheral visual function, such as macular degeneration, were excluded from the study.

Primary and secondary outcome measures

Participants undertook three custom and one standard binocular VF tests assessing VF to 60°, and also integrated monocular threshold 24–2 visual fields (IVF). Primary VF outcomes were average mean threshold, percentage of stimuli seen and VF area. VF outcomes were compared with self-reported mobility function assessed with the Independent Mobility Questionnaire, and time taken and patient acceptability were also considered. Receiver operating characteristic (ROC) curves determined which tests best predicted difficulty with mobility tasks.

Results

Greater VF loss was associated with greater self-reported mobility difficulty with all field paradigms (R²0.38–0.48, all P<0.001). All four binocular tests were better than the IVF at predicting difficulty with at least three mobility tasks in ROC analysis. Mean duration of the tests ranged from 1 min 26 s (±9 s) for kinetic assessment to 9 min 23 s (±24 s) for IVF.

Conclusions

The binocular VF tests extending to 60° eccentricity all relate similarly to self-reported mobility function, and slightly better than integrated monocular VFs. A kinetic assessment of VF area is quicker than and as effective at predicting mobility function as static threshold assessment.

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Data quality and 30-day survival for out-of-hospital cardiac arrest in the UK out-of-hospital cardiac arrest registry: a data linkage study

Objectives

The Out-of-Hospital Cardiac Arrest Outcomes (OHCAO) project aims to understand the epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) across the UK. This data linkage study is a subproject of OHCAO. The aim was to establish the feasibility of linking OHCAO data to National Health Service (NHS) patient demographic data and Office for National Statistics (ONS) date of death data held on the NHS Personal Demographics Service (PDS) database to improve OHCAO demographic data quality and enable analysis of 30-day survival from OHCA.

Design and setting

Data were collected from 1 January 2014 to 31 December 2014 as part of a prospective, observational study of OHCA attended by 10 English NHS Ambulance Services. 28 729 OHCA cases had resuscitation attempted by Emergency Medical Services and were included in the study. Data linkage was carried out using a data linkage service provided by NHS Digital, a national provider of health-related data. To assess data linkage feasibility a random sample of 3120 cases was selected. The sample was securely transferred to NHS Digital to be matched using OHCAO patient demographic data to return previously missing demographic data and provide ONS date of death data.

Results

A total of 2513 (80.5%) OHCAO cases were matched to patients in the NHS PDS database. Using the linkage process, missing demographic data were retrieved for 1636 (72.7%) out of 2249 OHCAO cases that had previously incomplete demographic data. Returned ONS date of death data allowed analysis of 30-day survival status. The results showed a 30-day survival rate of 9.3%, reducing unknown survival status from 46.1% to 8.5%.

Conclusions

In this sample, data linkage between the OHCAO registry and NHS PDS database was shown to be feasible, improving demographic data quality and allowing analysis of 30-day survival status.

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Role of PI3K in myocardial ischaemic preconditioning: mapping pro-survival cascades at the trigger phase and at reperfusion

Abstract

The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro-survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K-Akt, its negative regulator PTEN and other pro-survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3β and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3β was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K-dependent during the IPC phase. In conclusion, PI3K-Akt plays a major role in IPC-induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K-independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade.

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Psoas Muscle Area as a Prognostic Factor for Survival in Patients with an Asymptomatic Infrarenal Abdominal Aortic Aneurysm: A Retrospective Cohort Study

Publication date: Available online 20 November 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Reza Indrakusuma, Jendé L. Zijlmans, Hamid Jalalzadeh, R. Nils Planken, Ron Balm, Mark J.W. Koelemay
ObjectivesLoss of muscle mass has been associated with poor survival in several surgical patient populations, including those with an abdominal aortic aneurysm (AAA). We wanted to replicate these findings and assesse the association between psoas muscle area (PMA) and survival in patients with an asymptomatic AAA.MethodsPatients with an asymptomatic infrarenal AAA who underwent computed tomography (CT) scanning between January 1, 2007, and December 31, 2013, were included in this single-centre retrospective cohort study. PMA was measured with thresholding on an axial image at the centre level of the third lumbar vertebra. The lowest tertile of PMA in all patients was used as a cutoff value for a low PMA. Then, in separate analyses for conservatively and surgically managed patients, survival was estimated with the Kaplan–Meier method. Differences in survival between patients with and without a low PMA were tested with the log-rank test.ResultsOf 228 patients, 104 were managed conservatively and 124 underwent AAA repair. Seventy-seven patients (62%) had an endovascular repair. In these 228 patients, the median PMA was 16.83 cm², while the cutoff value for low PMA was 14.56 cm². Patients who were managed conservatively were more often classified as having low PMA (45/104, 43%, vs. 31/124, 25%; p = .004) and were significantly older (mean 73.44 ± 9.05 years vs. 69.03 ± 7.46 years; p < .001). Low PMA was not associated with survival, either in patients managed conservatively, or in those who underwent AAA repair (p = .512 and p = .311, respectively).ConclusionsThe association between low PMA and poor survival could not be replicated; in this study, low PMA was not associated with survival in patients with an asymptomatic AAA. Further research is recommended before PMA can be used for pre-operative risk stratification.



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“Economies of Experience”—Disambiguation of Degraded Stimuli Leads to a Decreased Dispersion of Eye-Movement Patterns

Abstract

We demonstrate "economies of experience" in eye-movement patterns—that is, optimization of eye-movement patterns aimed at more efficient and less costly visual processing, similar to the priming-induced formation of sparser cortical representations or reduced reaction times. Participants looked at Mooney-type, degraded stimuli that were difficult to recognize without prior experience, but easily recognizable after exposure to their undegraded versions. As predicted, eye-movement dispersion, velocity, and the number of fixations decreased with each stimulus presentation. Further analyses showed that this effect was contingent on recognition, and the selection of information from the stimulus could be informed by the identity of the presented object. Finally, our study demonstrates that after exposure to the undegraded version of the stimulus, eye-movement patterns associated with its degraded and undegraded versions become more similar. This suggests that eye-movement patterns can evolve to facilitate the optimal processing of a given stimulus via experience-driven perceptual learning.

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Context Effects and Spoken Word Recognition of Chinese: An Eye-Tracking Study

Abstract

This study examined the time-course of context effects on spoken word recognition during Chinese sentence processing. We recruited 60 native Mandarin listeners to participate in an eye-tracking experiment. In this eye-tracking experiment, listeners were told to listen to a sentence carefully, which ended with a Chinese homophone, and look at different visual probes (Chinese characters or different line-drawing pictures) presented concurrently on the computer screen naturally. Different types of context and probe types were manipulated in the experiment. The results showed that (1) preceding sentence context had an early effect on spoken word recognition processes and (2) phonological information of the distracters had only a negligible effect on the spoken word recognition processes. Finally, the patterns of eye-tracking results seemed to favor an interactive approach in spoken word recognition.

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Evaluating the mechanism and therapeutic potential of PTC-028, a novel inhibitor of BMI-1 function in ovarian cancer

BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathological significance of BMI-1, small molecule inhibitors against BMI1 are recently being developed. In the current study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by post-translational modification We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays whereas normal cells remain unaffected. Mechanistically, hyper-phosphorylation mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis. In vivo, orally administered PTC-028, as a single agent exhibits significant antitumor activity comparable to the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian cancer, where treatment options are limited.

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Comparative oncology evaluation of intravenous recombinant oncolytic Vesicular Stomatitis Virus therapy in spontaneous canine cancer

Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single shot systemic therapy with a VSV-IFNβ-NIS, a novel recombinant oncolytic Vesicular stomatitis virus (VSV), can induce curative remission in tumor bearing mice. Clinical translation of VSV-IFNβ-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models. Dogs spontaneously develop cancer with comparable etiology, clinical progression and response to therapy as human malignancies. A comparative oncology study was carried out to investigate feasibility and tolerability of intravenous oncolytic VSV-IFNβ-NIS therapy in pet dogs with spontaneous cancer. Nine dogs with various malignancies were treated with a single intravenous dose of VSV-IFNβ-NIS. Two dogs with high-grade peripheral T-cell lymphoma had rapid but transient remission of disseminated disease and transient hepatotoxicity that resolved spontaneously. There was no shedding of infectious virus. Correlative pharmacokinetic studies revealed elevated levels of VSV RNA in blood in dogs with measurable disease remission. This is the first evaluation of intravenous oncolytic virus therapy for spontaneous canine cancer, demonstrating that VSV-IFNβ-NIS is well-tolerated and safe in dogs with advanced or metastatic disease. This approach has informed clinical translation, including dose and target indication selection, leading to a clinical investigation of intravenous VSV-IFNβ-NIS therapy, and provided preliminary evidence of clinical efficacy, and potential biomarkers that correlate with therapeutic response.

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Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance.

Acquired resistance to cetuximab, an antibody that targets the epidermal growth factor receptor (EGFR), impacts clinical benefit in head and neck, and colorectal cancers (CRC). One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab resistance substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 Å resolution of the necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, pre-existing cavity in the necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that necitumumab binds to most cetuximab- and panitumumab-resistance EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together these data suggest that necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Further, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due mutations mapping to the antigen epitope.

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Treatment of Richter’s Syndrome

Opinion statement

Based on the available literature, mostly derived from retrospective or non-randomized phase I or II studies, it is difficult to define an optimized treatment approach for patients developing Richter's syndrome (RS). Early recognition of chronic lymphocytic leukemia (CLL) patients presenting clinical features suspected for a transformation is useful to avoid exposing them to multiple lines of therapy that, being targeted to CLL progression, have poor efficacy against RS. Because of the low specificity (~ 50–60%) of clinical signs of RS (such as rapid and discordant bulky localized lymphadenopathies, elevated LDH levels, emergent physical deterioration, and/or fever in the absence of infection), a ¹⁸FDG PET/CT and a biopsy are recommended to confirm RS. A ¹⁸FDG PET/CT showing low uptake is helpful to rule out RS and avoid unnecessary risks and costs of performing a biopsy. A ¹⁸FDG PET/CT showing a high uptake is not diagnostic of RS but may help in the choice of the site where the biopsy is to be performed. In the setting of the diffuse large B-cell lymphoma (DLBCL) variant of RS, the definition of a clonal relationship between RS and the underlying CLL may guide the choice of treatment. If a clonal relationship is confirmed (the most common situation), rituximab-CHOP-like treatment does not guarantee long-lasting remissions, and should be used as induction therapy followed by consolidation with a stem cell transplant in physically fit patients. If the CLL and RS are clonally unrelated (the less common situation), the management should be that of a de novo DLBCL. In the setting of the rare Hodgkin lymphoma variant of RS, which is usually clonally unrelated to the CLL, ABVD with or without radiotherapy may be curative of the aggressive lymphoma.

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Genes Integral to the Reproductive Function of Male Reproductive Tissues Drive Heterogeneity in Evolutionary Rates in Japanese Quail

Early comparative genomics studies originally uncovered a non-intuitive pattern - genes involved in reproduction appeared to evolve more rapidly than other classes of genes.  Currently, however, the emerging consensus is that genes encoding reproductive proteins evolve under variable selective pressures, producing more heterogeneous divergence patterns than previously appreciated.  We investigate a facet of that heterogeneity and explore the factors that drive male reproductive tissue-based heterogeneity in evolutionary rates.  In Japanese quail (Coturnix japonica), genes with enriched expression in the testis evolve much more rapidly than those enriched in the foam gland, a novel gland that secretes an airy foam males transfer to females during mating.  We compared molecular evolutionary patterns among 1) genes with induced expression in breeding versus wintering conditions for both tissues and 2) genes that encode foam proteins versus those with varying degrees of expression specificity in the foam gland.  We report two major findings.  First, genes up-regulated in breeding condition testis evolve exceptionally rapidly, while those induced in breeding condition foam glands evolve slowly.  These differences hold even after correcting for horomonally-dependent gene expression and chromosomal location.  Second, genes encoding foam proteins are extremely conserved in terms of gene identity and sequence.  Together, these finding suggest that genes involved in the reproductive function of each tissue drive the marked rate heterogeneity.

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A Single Residue Mutation in the G{alpha}q Subunit of the G Protein Complex Causes Blindness in Drosophila

Heterotrimeric G proteins play central roles in many signaling pathways, including the phototransduction cascade in animals. However, the degree of involvement of the G protein subunit Gα_q is not clear since animals with strong loss of function mutations previously reported remain responsive to light stimuli. We recovered a new allele of Gα_q in Drosophila that abolishes light response in a conventional ERG assay, and reduces sensitivity in whole-cell recordings of dissociated cells by at least 5 orders of magnitude. In addition, mutant eyes demonstrate a rapid rate of degeneration in the presence of light. Our new allele is likely the strongest hypomorph described to date. Interestingly, the mutant protein is produced in the eyes but carries a single amino acid change of a conserved hydrophobic residue that has been assigned to the interface of interaction between Gα_q and its downstream effector PLC. Our study thus uncovered possibly the first point mutation that specifically affects this interaction in vivo.

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Genome-Wide Mapping of Decay Factor-mRNA Interactions in Yeast Identifies Nutrient Responsive Transcripts as Targets of the Deadenylase Ccr4

The Ccr4-Not complex is a major regulator of stress responses that controls gene expression at multiple levels, from transcription to mRNA decay. Ccr4, a core subunit of the complex, is the main cytoplasmic deadenylase in Saccharomyces cerevisiae, however its mRNA targets have not been mapped on a genome-wide scale. Here we describe a genome-wide approach, RNA immunoprecipitation-high throughput sequencing (RIP-seq), to identify the RNAs bound to Ccr4, and two proteins that associate with it, Dhh1 and Puf5. All three proteins were preferentially bound to lowly abundant mRNAs, most often at the 3' end of the transcript. Furthermore, Ccr4, Dhh1 and Puf5 are recruited to mRNAs that are targeted by other RNA-binding proteins that promote decay, mRNA transport and inhibit translation.  Although Ccr4-Not regulates mRNA transcription and decay, Ccr4 recruitment to mRNAs correlates better with decay rates, suggesting it imparts greater control over transcript abundance through decay.  Ccr4-enriched mRNAs are refractory to control by the other deadenylase complex in yeast, Pan2/3, suggesting a division of labor between these deadenylation complexes. Finally, Ccr4 and Dhh1 associate with mRNAs whose abundance increases during nutrient starvation and those that fluctuate during metabolic and oxygen consumption cycles, which explains the known genetic connections between these factors and nutrient utilization and stress pathways.

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Clinicopathologic Predictive Factors of Cervical Lymph Node Metastasis in Differentiated Thyroid Cancer

Publication date: Available online 20 November 2017
Source:Acta Otorrinolaringológica Española
Author(s): Ronghao Sun, Hua Zhang, Kun Liu, Jinchuan Fan, Guojun Li, Xicheng Song, Chao Li
BackgroundCervical lymph node metastasis (LNM) has been proven to be a predictor for locoregional recurrence in differentiated thyroid carcinoma (DTC). Clinicopathological features could be effective predictive factors for central and lateral LNM of DTC, and provide references to surgeons for cervical neck dissection.MethodsRetrospective analysis of clinicopathological data was performed on 420 patients who underwent initial surgery from 2010 to 2015.ResultsThe incidence of central and lateral LNM was calculated. Of 420 patients, 247 (58.8%) exhibited central LNM, and 185 (44.1%) exhibited lateral LNM. There were 29 (6.9%) cases confirmed to have skip metastasis. Univariate and multivariate analysis revealed that tumour location, tumour size, multifocality, capsular invasion, affected lobes, and age were independent predictors of central LNM. Tumour location, capsular invasion, affected lobes, and tumour size were independent predictors of lateral LNM.ConclusionsOur findings suggest that tumour location, affected lobes, capsular invasion, age, tumour size and multifocality may be taken as predictive factors for cervical LNM of DTC. Meticulous perioperative evaluation of cervical LNM and prophylactic cervical lymph node dissection that aims to remove the occult lymph nodes may be an option for DTC with risk factors.



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Generation of complement molecular complex C5b-9 (C5b-9) in response to poly-traumatic hemorrhagic shock and evaluation of C5 cleavage inhibitors in non-human primates

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): R. Madelaine Paredes, Sarah Reyna, Philip Vernon, Douglas K. Tadaki, Jurandir J. Dallelucca, Forest Sheppard
Severe trauma initiates a systemic inflammatory cascade and that involves early activation of complement and cleavage of C5 into C5a (anaphylatoxin) and C5b (C5b-9 membrane attack complex). We examined activation of C5 in non-human primate (NHP) models of hemorrhagic shock.Blood plasma concentrations of C5b-9 were significantly increased in NHPs in response to hemorrhage alone and were further increased with the addition of tissue trauma. The onset of increased C5 cleavage was accelerated in NHPs that experienced decompensated poly-traumatic hemorrhagic shock. Next, to identify an effective inhibitor of NHP C5 cleavage in vitro, as a first step in the development of a potential therapy, three inhibitors of human C5 cleavage and hemolysis were tested in vitro. NHP C5 cleavage and complement-mediated hemolysis were successfully inhibited by pre-treatment of serum samples with a small, inhibitory peptide RA101348. Commercially-available C5 inhibitory antibodies were found to exhibit species-specific efficacy in vitro. Quidel's A217 antibody demonstrated dose-dependent inhibition of C5 cleavage and hemolysis in NHP samples, whereas LGM-Eculizumab only inhibited complement-mediated hemolysis in human samples.This study shows that complement activation in NHPs following experimental poly-traumatic hemorrhagic shock is consistent with clinical reports, and that cleavage of C5 and complement-mediated hemolysis can be effectively inhibited in vitro using a small peptide inhibitor. Taken together, these findings offer a clinically-relevant vehicle and a potential strategy for treatment of hemorrhagic shock with poly-traumatic injury.



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Limax extract ameliorates cigarette smoke-induced chronic obstructive pulmonary disease in mice

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Xue Liang, Jian Wang, Ruijuan Guan, Li Zhao, Defu Li, Zhen Long, Qian Yang, Jingyi Xu, Ziyi Wang, Jinkui Xie, Wenju Lu
Chronic obstructive pulmonary disease (COPD) is a chronic, progressive and lethal lung disease with few treatments. Limax, a mollusk with lung, has been widely used to control phlegm and cough in China, yet whether Limax has a positive effect on COPD is unknown. This study investigated the effects of water-soluble extract from Limax on COPD development and the underlying mechanisms. The results showed that Limax extract improved lung function, relieved emphysema and suppressed the inflammation in the lungs of CS-challenged mice, as evidenced by diminished release of IL-6, KC, TNF-α, IFN-γ, Muc5AC, IL-17 and diminished mRNA expression of Muc5B. Moreover, Limax extract also inhibited phosphorylation of P38 and ERK and increased the expression of PPARγ. More interestingly, Limax extract (0.1μg/ml) inhibited CSE-induced release of IL-6 in vitro, which was substantially abrogated by heat treatment, and filtrate obtained from the deproteinized Limax extract with the 100KD ultrafiltration membrane, inhibited the secretion of IL-6. Taken together, these results suggest that, Limax extract prevents COPD development via inhibition of inflammation and mucus production, thus has a potential preventive and therapeutic application in COPD.



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Lipopolysaccharide (LPS)-mediated priming of toll-like receptor 4 enhances oxidant-induced prostaglandin E2 biosynthesis in primary murine macrophages

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Yan Zhang, Orisa J. Igwe
Agonists and pseudo-agonists for toll-like receptor 4 (TLR4) are common in our environment. Thus, human exposure to these agents may result in "priming or sensitization" of TLR4. A body of evidence suggests that LPS-mediated sensitization of TLR4 can increase the magnitude of responses to exogenous agents in multiple tissues. We have previously shown that reactive oxygen and nitrogen species (RONS) stimulate TLR4. There is no evidence that LPS-primed TLR4 can influence the magnitude of responses to oxidants from either endogenous or exogenous sources. In the present study, we directly tested the hypothesis that LPS-primed TLR4 will sensitize primary murine peritoneal macrophages (pM) to oxidant-mediated prostaglandin E2 (PGE2) production. We used potassium peroxychromate (PPC) and potassium peroxynitrite (PPN) as direct in vitro sources of exogenous RONS. Our results showed that a direct treatment with PPC or PPN alone as sources of exogenous oxidants had a limited effect on PGE2 biosynthesis. In contrast, pM sensitized by prior incubation with LPS-EK, a TLR4-specific agonist, followed by oxidant stimulation exhibited increased transcriptional and translational expression of cyclooxygenase-2 (COX-2) with enhanced PGE2 biosynthesis/production only in pM derived from TLR4-WT mice but not in TLR4-KO mice. Thus, we have shown a critical role for LPS-primed TLR4 in oxidant-induced inflammatory phenotypes that have the potential to initiate, propagate and maintain many human diseases.



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Broncho-Vaxom in pediatric recurrent respiratory tract infections: A systematic review and meta-analysis

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Ju Yin, Baoping Xu, Xiantao Zeng, Kunling Shen
ObjectivesAssess the efficacy and safety of Broncho-Vaxom in pediatric recurrent respiratory tract infections (RRTIs).MethodsPublished randomized controlled trials (RCTs) of Broncho-Vaxom for pediatric RRTI were searched using PubMed, Embase, Cochrane Library, CBM, CNKI, WanFang Data, and VIP databases up to January 2017. Risk of bias was evaluated in accordance to the guidelines of the Cochrane collaboration and the level of evidence was graded according to the GRADE.Results53 RCTs involving 4851 pediatric patients were included in this meta-analysis. It showed that Broncho-Vaxom was positively correlated with a reduction in the frequency of respiratory infection [MD=−2.33, 95% CI (−2.75, −1.90), P<0.00001] compared to the control group. The Broncho-Vaxom group was more effective than control groups in relation to the duration of antibiotics course, infections, fever, cough, and wheezing, increasing serum immunoglobulin levels (IgG, IgA or IgM), and T-lymphocytes subtype (CD3+, CD4+, or CD8+). However, Broncho-Vaxom had higher adverse event rates [RR=1.39, 95% CI (1.02, 1.88), P=0.04]; these were not serious and did not influence the treatment course.ConclusionBroncho-Vaxom shows a good efficacy for pediatric RRTIs on the basis of routine therapy (e.g. anti-infection and antiviral therapy). However, the level of evidence was low and more international multicenter clinical trials are needed to explore the efficacy and safety of Broncho-Vaxom.



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Effects of Intrathecal Injection of the Conditioned Medium from Bone Marrow Stromal Cells on Spinal Cord Injury in Rats

Journal of Neurotrauma , Vol. 0, No. 0.


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Repeated Exposure to Experimental Pain Differentiates Combat Traumatic Brain Injury with and without Post-Traumatic Stress Disorder

Journal of Neurotrauma , Vol. 0, No. 0.


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Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation?

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Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma

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Inactivation of miR-100 combined with arsenic treatment enhances the malignant transformation of BEAS-2B cells via stimulating epithelial -mesenchymal transition

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Mycobacterium genavense infections in non-HIV immunocompromised hosts: a systematic review

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Impact of fluoroquinolone prophylaxis on documented infections in patients with febrile neutropenia

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The PREVENT study to evaluate the effectiveness and acceptability of a community-based intervention to prevent childhood tuberculosis in Lesotho: study protocol for a cluster randomized controlled trial

Effective, evidence-based interventions to prevent childhood tuberculosis (TB) in high TB/HIV-burden, resource-limited settings are urgently needed. There is limited implementation of evidence-based contact ma...

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Three-dimensional printing modeling: application in maxillofacial and hand fractures and resident training

Abstract

Background

Imaging techniques in reconstructive surgery are of great assistance not only in diagnosis but also in preoperative planning; however, they are often limited to interpreting three-dimensional structures on flat surfaces. Three-dimensional (3D) printing has made it possible to overcome these limitations by allowing the creation of customized 3D anatomical models. We set out to create 3D printed models to demonstrate its application in maxillofacial and hand fractures and resident training.

Methods

Ten patients with hand and craniofacial fractures of different types were studied. Computed tomography was performed; the image files were processed digitally, and 3D models were subsequently printed. The quality and accuracy of the obtained models were rigorously evaluated, and the models were then used by plastic surgery teachers and residents in the preoperative planning.

Results

The comparative measurements confirmed that the models are at real scale with a 1:1 ratio; the pre-cast osteosynthesis plates were perfectly matched to the patient's anatomy intraoperatively, and the lengths of the pre-selected screws were accurate. The anesthetic surgical time was reduced by 20%. Teachers and residents were satisfied with the use of models for clinical discussions of patients and for preoperative planning and the advantages of manipulating physical models were highlighted.

Conclusions

We have created low-cost, good quality, reliable, and accurate 3D printed models for the preoperative planning of reconstructive surgeries of maxillofacial and hand fractures, reducing the operative times and providing a new academic teaching tool in the training of residents of plastic surgery.

Level of Evidence: Level IV, therapeutic study.

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Combination antibiotic exposure selectively alters the development of vancomycin intermediate resistance in Staphylococcus aureus [PublishAheadOfPrint]

Invasive methicillin-resistant Staphylococcus aureus (MRSA) treated with vancomycin (VAN) is associated with reduced VAN susceptibility and treatment failure. VAN combination therapy is one strategy to improve response, but comprehensive assessments of combinations to prevent resistance are limited. This study identifies optimal combinations to prevent the emergence of VAN-intermediate Staphylococcus aureus (VISA). Two standard MRSA and two heterogeneous VISA (hVISA) strains were exposed for 28 days in vitro to VAN alone, VAN with cefazolin (CFZ), fosfomycin (FOF), gentamicin (GEN), meropenem (MEM), rifampin (RIF), piperacillin-tazobactam (TZP) or trimethoprim-sulfamethoxazole (SXT). In addition to VAN susceptibility testing, cell wall thickness (CWT), carotenoid content, and membrane fluidity were determined for Mu3. VAN plus any β-lactam limited the VAN MIC increase to 1-4 mg/L throughout the 28-day exposure, with CFZ and TZP as the most effective agents (VAN MIC=1-2 mg/L). Similar MIC trends occurred with the lipo-/glyco-peptide agents daptomycin and telavancin, where β-lactam combinations with VAN prevented MIC increases to these agents as well. Combinations with non β-lactams were ineffective in preventing VAN MIC increases with VAN MICs of 4-16 mg/L emerging during weeks 2-4 of treatment. VAN plus β-lactam decreased CWT significantly whereas VAN plus other antibiotics significantly increased the CWT. No correlation was observed between carotenoid content or membrane fluidity and antibiotic exposure. Only the combination exposures of VAN plus β-lactam suppress the development of VISA. Rational selection of VAN plus β-lactam should be further explored as a long-term combination treatment of MRSA infections due to their ability to suppress VAN resistance.

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Fluconazole Resistant Candida auris is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses [PublishAheadOfPrint]

Candida auris is a newly identified species causing invasive candidemia and candidiasis, and has broad multidrug resistance (MDR) not observed for other pathogenic Candida species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity against C. albicans, and is an attractive candidate to treat MDR fungi since antimicrobial peptides induce minimal drug resistance. We investigated the susceptibility of C. auris to Hst 5 and neutrophils, two first-line innate defenses in the human host. The majority of C. auris clinical isolates, including fluconazole resistant strains, were highly sensitive to Hst 5 with 55-90% of cells being killed using 7.5 μM Hst 5. Hst 5 was translocated to the cytosol and vacuole in C. auris cells, which are requirements for Hst 5 killing of C. albicans. The inverse relationship between fluconazole resistance and Hst 5 killing suggests different cellular targets for Hst 5 than for fluconazole. C. auris showed higher tolerance to oxidative stress compared to C. albicans, and higher survival within neutrophils which correlated with resistance to oxidative stress in vitro. Thus, ROS resistance is likely one, though not the only, important factor in neutrophil killing of C. auris. Hst 5 has a broad and potent candidacidal activity to effectively combat MDR C. auris strains.

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Pharmacokinetics and Safety of Omadacycline in Subjects With Impaired Renal Function [PublishAheadOfPrint]

Many antibiotics require dosing adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad-spectrum of bacterial pathogens, including resistant strains. Data from completed phase 3 acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) studies showed intravenous (IV) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of IV (100 mg) omadacycline was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). IV administration of omadacycline produced a similar plasma concentration-time profile in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar PK parameters were observed when omadacycline was administered IV after or before dialysis. The mean AUC_0-inf was 10.30 h·μg/mL when administered after dialysis, 10.20 h·μg/mL before dialysis, and 9.76 h·μg/mL in healthy subjects. The mean C_max in ESRD subjects was 1.88 μg/mL when administered after dialysis and 2.33 μg/mL when administered before dialysis, and in healthy subjects was 1.92 μg/mL. The 100-mg IV dose of omadacycline was generally safe and well-tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.

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The comparative in vitro activity of relebactam, imipenem and the combination of the two, plus six comparator antimicrobial agents against 432 strains of anaerobic organisms including imipenem-resistant strains. [PublishAheadOfPrint]

Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms but alone it has no anti-anaerobic activity, with most anaerobes having MICs ≥32 μg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.

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High-dose daptomycin is effective as an antibiotic-lock therapy in a rabbit model of Staphylococcus epidermidis catheter-related infection [PublishAheadOfPrint]

Long-term catheter-related bloodstream infections (CRBSI) involving coagulase-negative Staphylococci are associated with poor patient outcomes, increased hospitalization and high treatment costs. The use of vancomycin-lock therapy has been an important step forward to treat these biofilms although failures appear in 20% of patients. In this study, we report that a high dose of daptomycin-lock therapy may offer a therapeutic advantage for these CRBSI in just 24 h of treatment.

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In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, Against Carbapenem-Non-Susceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014-2016 [PublishAheadOfPrint]

The in vitro activity of the investigational siderophore cephalosporin, cefiderocol (formerly S-649266), was determined against a 2014-2016, 52-country, worldwide collection of clinical isolates of carbapenem-non-susceptible Enterobacteriaceae (n=1,022), multidrug-resistant (MDR) Acinetobacter baumannii (n=368), MDR Pseudomonas aeruginosa (n=262), Stenotrophomonas maltophilia (n=217), and Burkholderia cepacia (n=4) using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB), prepared following the recently approved (2017), but not yet published, CLSI protocol, was used to test cefiderocol; all other antimicrobial agents were tested using CAMHB. The concentration of cefiderocol inhibiting 90% of isolates of carbapenem-non-susceptible Enterobacteriaceae (MIC₉₀) was 4 μg/ml; cefiderocol MICs ranged from 0.004 to 32 μg/ml and 97.0% (991/1,022) of isolates demonstrated cefiderocol MICs ≤4 μg/ml. The MIC₉₀s for cefiderocol for MDR A. baumannii, MDR P. aeruginosa, and S. maltophilia were 8, 1, and 0.25 μg/ml, respectively, with 89.7% (330/368), 99.2% (260/262), and 100% (217/217) of isolates demonstrating cefiderocol MICs ≤4 μg/ml. Cefiderocol MICs for B. cepacia ranged from 0.004-8 μg/ml. We conclude that cefiderocol demonstrated potent in vitro activity against a 2014-2016, worldwide collection of clinical isolates of carbapenem non-susceptible Enterobacteriaceae, MDR A. baumannii, MDR P. aeruginosa, S. maltophilia, and B. cepacia as 96.2% of all (1,801/1,873) isolates tested had cefiderocol MICs ≤4 μg/ml.

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Evaluation of the in vitro activity of ceftaroline and comparators against S. pneumoniae isolates from U.S. hospitals: Results from 7 years of the AWARE Surveillance Program (2010-2016) [PublishAheadOfPrint]

We evaluated trends in Streptococcus pneumoniae antimicrobial susceptibility in United States hospitals in the 2010--2016 period. A total of 8,768 clinical isolates from 47 medical centers were tested for susceptibility by broth microdilution methods. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) rates decreased from 25.7/12.4% (MDR/XDR) in 2010 to 17.7%/3.6% in 2016. Susceptibility to most comparator antimicrobial agents increased, whereas susceptibility to ceftaroline, levofloxacin, linezolid, and tigecycline remained stable. Ceftaroline retained potent activity against S. pneumoniae (>99.9%) with no marked variations.

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Characterization of Plasmodium Atg3-Atg8 interaction inhibitors identifies novel alternative mechanisms of action in Toxoplasma gondii [PublishAheadOfPrint]

Protozoan parasites, including the apicomplexan pathogens Plasmodium falciparum (malaria) and Toxoplasma gondii (toxoplasmosis) infect millions of people world-wide and represent a major human disease burden. Despite their prevalence, therapeutic strategies to treat these infections remain limited and are threatened by the emergence of drug resistance, highlighting the need for the identification of novel drug targets. Recently, homologues of the core autophagy proteins, including Atg8 and Atg3, were identified in many protozoan parasites. Importantly, components of the Atg8 conjugation system that facilitate the lipidation of Atg8 are required for both canonical and parasite-specific functions, and are essential for parasite viability. Structural characterization of the P. falciparum Atg3-Atg8 interaction has led to the identification of compounds that block this interaction. Additionally, many of these compounds inhibit P. falciparum growth in vitro, demonstrating the viability of this pathway as a drug target. Given the essential role of the Atg8 lipidation pathway in Toxoplasma, we sought to determine whether three PfAtg3-Atg8 interaction inhibitors identified in the Medicines for Malaria Venture Malaria Box exerted a similar inhibitory effect in Toxoplasma. While all three inhibitors blocked Toxoplasma replication in vitro at sub-micromolar concentrations, they did not inhibit TgAtg8 lipidation. Rather, high concentrations of two of these compounds induced TgAtg8 lipidation and fragmentation of the parasite mitochondrion, similar to the effects seen following starvation and monensin-induced autophagy. Additionally, we report that one of the PfAtg3-Atg8 interaction inhibitors induces Toxoplasma egress, and provide evidence that this is mediated by an increase in intracellular calcium in response to drug treatment.

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Dissemination of multidrug-resistant Proteus mirabilis clones carrying a novel integron-borne blaIMP-1 in a tertiary hospital [PublishAheadOfPrint]

This study aimed to characterize multi-drug resistant P. mirabilis clones carrying a novel class 1 integron-borne bla_IMP-1. In1359 was inserted into a large conjugative plasmid that also carried bla_CTX-M-2. The production of carbapenemases in Enterobacteriaceae that are intrinsically resistant to polymyxins and tigecycline is very worrisome, representing a serious challenge to clinicians and infection control teams.

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A Simplified Derivative of Human Defensin 5 with Potent Efficiency against Multidrug-resistant Acinetobacter baumannii [PublishAheadOfPrint]

The increasing incidence of multidrug-resistant Acinetobacter baumannii (MDRAb) infections worldwide has necessitated the development of novel antibiotics. Human defensin 5 (HD5) is an endogenous peptide with a complex architecture and antibacterial activity against MDRAb. In the present study, we attempted to simplify the structure of HD5 by removing disulfide bonds. We found that the Cys2-4 bond was most indispensable for HD5 to inactivate MDRAb, although the antibacterial activity of the derivative was significantly attenuated. We then replaced the non-cationic and non-hydrophobic residues with electropositive Arg to increase the antibacterial activity of HD5 derivative that contains a Cys2-4 bond, obtaining another derivative termed HD5d5. The in vitro antibacterial assay and Irradiation-Wound-Infection animal experiment both showed that HD5d5 was much more effective than HD5 at eliminating MDRAb. Further investigations revealed that HD5d5 efficiently bound to outer membrane lipid A and penetrated membranes, leading to bacterial collapse and peptide translocation. Compared with HD5, more HD5d5 molecules were located in the cytoplasm of MDRAb, and HD5d5 was more efficient at reducing the activities of superoxide dismutase and catalase, causing the accumulation of reactive oxygen species that are detrimental to microbes. Additionally, HD5 failed to suppress the pathogenic outer membrane protein A of Acinetobacter baumannii (AbOmpA) at concentrations up to 50 μg/ml, whereas HD5d5 strongly bound to AbOmpA and exhibited a dramatic toxin-neutralizing ability, thus expanding the repertoire of drugs that is available to treat MRDAb infections.

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KKL-35 exhibits potent antibiotic activity against Legionella species independently of trans-translation inhibition [PublishAheadOfPrint]

Trans-translation is a ribosome rescue system that is ubiquitous in bacteria. Small molecules defining a new family of oxadiazole compounds that inhibit trans-translation have been found to have broad-spectrum antibiotic activity. We sought to determine the activity of KKL-35, a potent member of the oxadiazole family, against the human pathogen Legionella pneumophila and other related species that can also cause Legionnaires disease (LD). Consistent with the essential nature of trans-translation in L. pneumophila, KKL-35 inhibits growth of all tested strains at sub-micromolar concentrations. KKL-35 is also active against other LD-causing Legionella species. KKL-35 remains equally active against L. pneumophila mutants that have evolved resistance to macrolides. KKL-35 inhibits multiplication of L. pneumophila in human macrophages at several stages of infection. No resistant mutants could be obtained, even during extended and chronic exposure. Surprisingly, KKL-35 is not synergistic with other ribosome-targeting antibiotics and does not induce the filamentation phenotype observed in cells defective for trans-translation. Importantly, KKL-35 remains active against L. pneumophila mutants expressing an alternate ribosome-rescue system and lacking tmRNA, the essential component of trans-translation. These results indicate that the antibiotic activity of KKL-35 is not related to the specific inhibition of trans-translation and its mode of action remains to be identified. In conclusion, KKL-35 is an effective antibacterial agent against the intracellular pathogen L. pneumophila and with no detectable resistance. However, further studies are needed to better understand its mechanism of action and to assess further the potential of oxadiazoles in treatment.

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Antimicrobial octapeptin C4 analogues active against Cryptococcus species [PublishAheadOfPrint]

Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with minimum inhibitory concentration of 1.56 μg/mL. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed MIC 1.56-3.13 μg/mL while 20 clinical isolates of C. neoformans var. gattii had MIC 0.78-12.5 μg/mL. In each case MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogens sensitivity to octapeptin C4 while degree of melanisation had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents.

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