Socioeconomic risk moderates the association between caregiver cortisol levels and infant cortisol reactivity to emotion induction at 24 months

Abstract

Relations between maternal baseline cortisol and infant cortisol reactivity to an emotion induction procedure at child ages 7, 15, and 24 months were analyzed using data from the Family Life Project (N = 1,292). The emotion induction consisted of a series of standardized and validated tasks, including an arm restraint, toy removal, and mask presentation, intended to elicit responses of fear and frustration. Results revealed that at 7 and 15 months, maternal baseline cortisol was negatively related to child cortisol reactivity, such that children of mothers with lower cortisol exhibited steeper cortisol increases in response to the emotion induction. At 24 months, the association between mother and infant cortisol was moderated by socioeconomic risk, such that maternal baseline cortisol was associated with child cortisol reactivity only in dyads characterized by low socioeconomic risk. Furthermore, at 24 months, children of mothers with low baseline cortisol and low socioeconomic risk exhibited decreasing cortisol responses, whereas children of mothers with low baseline cortisol but high risk exhibited flat cortisol responses. Children in dyads characterized by high baseline maternal cortisol also exhibited flat cortisol responses regardless of socioeconomic risk. The role of caregiver physiology in the regulation of the child's stress response in the context of adversity is discussed.

https://ift.tt/2ISTI5c

Basic and Clinical Application of Adeno-Associated Virus–Mediated Genome Editing

Human Gene Therapy, Ahead of Print.


https://ift.tt/2TipoVu

INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma

Future Oncology, Ahead of Print.


https://ift.tt/2H8qEnt

5th Symposium on Primary Breast Cancer in Older Women

Future Oncology, Ahead of Print.


https://ift.tt/2tHS3EO

Erosive rheumatoid arthritis in a young patient with mirror hand

Mirror hand is a congenital anomaly characterised by duplication of the ulnar ray, resulting in polydactyly and functional disability of the hand. It can cause arthralgias and weakness in intrinsic muscles of the hand. We present a young woman who had a surgically corrected mirror hand and subsequently developed aggressive rheumatoid arthritis, which increased her limitations to a significant degree. Early diagnosis and treatment in such cases is very important to prevent long-term disability.

https://ift.tt/2GSGJOX

Multiorgan embolisation of a left ventricular thrombus

https://ift.tt/2NzMEJk

'Carpal tunnel syndrome and 'tennis elbow as prodromes for granulomatosis with polyangiitis (formerly Wegeners granulomatosis)

A 62-year-old man presented with excruciating joint pains, back stiffness and numbness of his hands and feet. Over the past 18 months, he had experienced similar episodes for which the diagnoses of bilateral carpal tunnel syndrome and lateral epicondylitis had been made. Physical examination revealed polyarticular arthritis affecting the shoulders, wrists and right knee. Palpable purpura overlying the calves and ankles was present. Laboratory tests showed markedly elevated erythrocyte sedimentation rate and C-reactive protein in the setting of negative blood and urine cultures. Rheumatoid factor and antinuclear antibodies were negative. Chest CT demonstrated bilateral pulmonary infiltrates. A punch biopsy of the rash showed leukocytoclastic vasculitis. Anti-proteinase-3 titers returned strongly positive. A diagnosis of granulomatosis with polyangiitis was made. Treatment with high-dose steroids, followed by rituximab resulted in normalisation of inflammatory markers with subsequent resolution of joint pains, rash and pulmonary infiltrates and improvement of neuropathic symptoms.

https://ift.tt/2GOB9go

Just one more rash?

https://ift.tt/2NEbvvC

Hydroxychloroquine-induced inverse psoriasis

A 65-year-old woman presented to our rheumatology clinic with pain and swelling of multiple joints of her hands. After a thorough evaluation, she was diagnosed with rheumatoid arthritis and was started on hydroxychloroquine therapy. A week later, she presented to our clinic with an acute condition and reported that after taking hydroxychloroquine for a few days she developed multiple rashes, most prominent at skin folds around her breasts, neck, axillae and buttocks. The rashes were characteristic of inverse psoriasis. Hydroxychloroquine was discontinued and the patient was started on methotrexate therapy that resulted in resolution of her rashes in a week.

https://ift.tt/2GS9n2y

Littres hernia

https://ift.tt/2NBqx4Y

Delayed diagnosis of postcardiac injury syndrome

Postcardiac injury syndrome (PCIS) is a rare condition that is considered to have a trauma-induced autoimmune mechanism triggered by damage to pericardial and/or pleural tissues. We report a case of PCIS accompanied by systemic oedema after thymectomy. A 73-year-old woman was referred to our hospital for dyspnoea and oedema, 9 months after thymectomy. Evaluation revealed the presence of pericardial effusion, pleural effusion and systemic oedema. Differential diagnosis included constrictive pericarditis (secondary to tuberculosis), serositis caused by collagen disease and malignancy. Detailed investigations led to the diagnosis of PCIS, which was successfully treated with prednisolone. This report focuses on the diagnostic approach to PCIS. Since it took time to make a final diagnosis in our patient, we analysed several past case reports and series to determine the cause of the delay in diagnosis.

https://ift.tt/2GTpCMN

Mandibular resorption and vocal cord paralysis: a catastrophic form of systemic sclerosis

Sudden respiratory distress in association with severe weight loss are unusual features of systemic sclerosis (SSc). We report the case of a 56-year-old Caucasian woman with a 9-year history of a diffuse form of SSc who presented with acute stridor due to vocal cord paralysis and required an emergency tracheostomy. She had sought medical attention only after 4 years of disease onset, presenting with a mask-like face, diffuse skin thickening, acro-osteolysis and severe interstitial lung disease. Even though skin tightness improved after immunosuppressive treatment, several spontaneous facial fractures and episodes of dysphagia and choking occurred in the years that followed. At the time of stridor, she was severely malnourished and a percutaneous endoscopic gastrostomy was required for feeding. Permanent vocal cord damage in combination with severe loco-regional bone resorption resulted in severe disability and impaired nutrition. We hereby highlight the features of SSc for which therapy remains challenging.

https://ift.tt/2NBFbJw

Neuroleptic malignant syndrome as part of an akinetic crisis associated with sepsis in a patient with Lewy body disease

A 65-year-old Japanese woman with Parkinson's disease, later diagnosed with Lewy body disease, presented with a 2-day history of systemic tremors. She also had fever without rigidity or creatine kinase (CK) elevation. She was diagnosed with sepsis caused by pyelonephritis with acute kidney injury and parkinsonism exacerbation. Although antibiotic and fluid therapy improved her pyuria and renal function, her fever and tremors persisted. On the fourth day, her symptoms worsened and resulted in cardiopulmonary arrest; however, quick resuscitation allowed the return of spontaneous circulation. Simultaneously, hyperthermia, altered consciousness, extrapyramidal symptoms, dysautonomia and CK elevation were noted. Thus, dantrolene administration was initiated with a tentative diagnosis of neuroleptic malignant syndrome (NMS). This caused her fever to subside, and her symptoms gradually improved. It was difficult to distinguish between parkinsonism exacerbation associated with sepsis and NMS. Physicians should consider NMS early on, even if the patient does not fulfil the diagnostic criteria.

https://ift.tt/2GPb6G9

Uncontrolled diabetes as a rare presenting cause of pituitary apoplexy

Pituitary apoplexy is a rare endocrine emergency. The extent to which hyperglycaemia is a contributory risk factor in the precipitation of pituitary apoplexy is not known. A 38-year-old man with poorly controlled diabetes presented to the emergency department with sudden onset of nausea and headache with drooping of his right eyelid for about 4 days. On physical examination, he had orthostatic hypotension, ptosis of the right eye, lateral and downward positioning of the eye and absent pupillary reflex. Visual field testing of the left eye revealed superolateral quadrantanopia. MRI of the brain showed pituitary macroadenoma with necrosis. Investigations showed hyperglycaemia, decreased T3, T4 with normal Thyroid stimulating hormone (TSH), low serum Leutinizing hormone (LH), Follicle stimulating hormone (FSH), testosterone and low normal serum prolactin levels. About 21% of non-functioning pituitary adenomas present with apoplexy as was seen in our patient. It is likely that his uncontrolled diabetes precipitated this episode of apoplexy as hyperosmolarity and dehydration, caused by hyperglycaemia can lead to changed pituitary microvascular environment increasing the risk of pituitary infarction.

https://ift.tt/2NyUdQs

Xanthoma and paraproteinaemia: a spot diagnosis

https://ift.tt/2GRuv9i

Monthly News Roundup - February 2019

Cablivi is First Approval for Rare Blood Clotting Disorder In February, the U.S. Food and Drug Administration (FDA) cleared Cablivi (caplacizumab-yhdp) injection from Ablynx, the first treatment approved in combination with plasma exchange and...

https://ift.tt/2EEf3uK

A comparative study of methods used to generate the arterial fiber structure in a clinically relevant numerical analysis

Abstract

The advanced constitutive material models of artery wall require the definition of the mean collagen fiber directions in the material configuration. There are several proposed methods, however it is unclear how much does the fiber structures obtained by these methods differ one from the other and how much this difference may affect the results of the structural analysis of a clinically relevant scenario. Therefore, in this paper we address this issue by presenting the results of the comparative study of our developed and currently state of the art fiber definition methods. In addition, we present the verification of our developed numerical model that incorporates the extended Holzapfel‐Gasser‐Ogden (HGO) constitutive material model and the generalized pre‐stressing algorithm (GPA).

In the case of the patient‐specific internal carotid artery (ICA), the percentage error of the mean fiber directions defined by different methods does not exceed 17.73 % (at least 0.05 %, at most 81.82 %), and has negligible effect on the stress levels, as the percentage error of the mean stress does not exceed 0.1 %. Both fiber definition methods produce comparable fiber structure, but our proposed method has an advantage, as it does not depend on method and software used to model the arterial wall mechanics.

https://ift.tt/2ElAhfF

Generality of Genomic Findings on Blood Pressure Traits and Its Usefulness in Precision Medicine in Diverse Populations: A Systematic Review

Remarkable findings from genome wide association studies (GWAS) on blood pressure (BP) traits have made new insights for developing precision medicine towards more effective screening measures. However, generality of GWAS findings in diverse populations is hampered by some technical limitations. There is no comprehensive study to evaluate source(s) of the non‐generality of GWAS results on BP traits, so to fill the gap, this systematic review study was carried out. Using MeSH terms, 1545 records were detected through searching in 5 databases and 49 relevant full‐text articles were included in our review. Overall, 749 unique variants were reported, of those, majority of variants have been detected in Europeans and were associated to systolic and diastolic blood pressure traits. Frequency of genetic variants with same position was low in European and Non‐European populations (n=38). However, more than 200 (>25%) single nucleotide polymorphism were found on same loci or linkage disequilibrium blocks (r²≥80%). Investigating for locus position and linkage disequilibrium of infrequent unique variants showed modest to high reproducibility of findings in Europeans that in some extent was generalizable in other populations. Beyond theoretical limitations, our study addressed other possible sources of non‐generality of GWAS findings for BP traits in same and different origins.

https://ift.tt/2C0OJcK

Telomeropathies: Aetiology, diagnosis, treatment and follow‐up. Ethical and legal considerations

Telomeropathies involve a wide variety of infrequent genetic diseases caused by mutations in the telomerase maintenance mechanism or the DNA damage response system (DDR). They are considered a family of rare diseases that often share causes, molecular mechanisms and symptoms. Generally, these diseases are not diagnosed until the symptoms are advanced, diminishing the survival time of patients. Although several related syndromes may still be unrecognized this work describes those that are known, highlighting that since they are rare diseases, physicians should be trained in their early diagnosis. The aetiology and diagnosis are discussed for each telomeropathy and the treatments when available, along with a new classification of this group of diseases. Ethical and legal issues related to this group of diseases are also considered.

This article is protected by copyright. All rights reserved.

https://ift.tt/2Ud3vUP

Activity and mRNA expression levels of selected cytochromes P450 in various sections of the human small intestine

Aims

To characterize mRNA expression levels (17 cytochromes P450) and activity (9 isoforms) of major cytochromes P450 expressed throughout the human small intestine.

Methods

Tissue samples were obtained from 9 deceased subjects and intestinal sections (n=10) were isolated for each subject. Relative mRNA expression levels were determined using quantitative real‐time PCR. Intestinal microsomes were prepared from 5 subsections: duodenum, jejunum (proximal and mid‐jejunum) and ileum (proximal and mid‐ileum) regions. In vitro incubations were performed with various cytochrome P450 probe substrates: bupropion (CYP2B6), repaglinide (CYP2C8), tolbutamide (CYP2C9), S‐mephenytoin (CYP2C19), bufuralol (CYP2D6), chlorzoxazone (CYP2E1), ebastine (CYP2J2), midazolam (CYP3A4/5) and lauric acid (CYP4A11). Metabolite formation was assessed using validated LC‐MS‐MS assays.

Results

Cytochrome P450 mRNA levels ranked as follows: CYP3A4>CYP2C9>CYP2C19>CYP2J2>CYP4F2. Cytochrome P450 mRNA transcripts showed different patterns in their relative expression from one region to the other but CYP3A4, CYP2C9, CYP2C19 and CYP2J2 displayed the highest levels of mRNA expression (>5%) in all intestinal sections. Cytochrome P450 activities were greater in proximal part of the small intestine with the jejunum showing the greatest drug‐metabolism activity. Spearman's correlation analyses indicated that cytochrome P450 mRNA expressions and corresponding cytochrome P450 activities in the human intestine were moderately associated for CYP2C19, CYP2D6 and CYP4A11 (r_s = 0.44‐0.56).

Conclusions

Our study provides new and additional information on the expression and activities of selected cytochromes P450 in various sections of the human small intestine.

https://ift.tt/2C1Jvxf

Cancers, Vol. 11, Pages 286: The Novel Role of SOX2 as an Early Predictor of Cancer Risk in Patients with Laryngeal Precancerous Lesions

Cancers, Vol. 11, Pages 286: The Novel Role of SOX2 as an Early Predictor of Cancer Risk in Patients with Laryngeal Precancerous Lesions

Cancers doi: 10.3390/cancers11030286

Authors: Rocío Granda-Díaz Sofía T. Menéndez Daniel Pedregal Mallo Francisco Hermida-Prado René Rodríguez Laura Suárez-Fernández Aitana Vallina Mario Sánchez-Canteli Aida Rodríguez M. Soledad Fernández-García Juan P. Rodrigo Juana M. García-Pedrero

The SOX2 gene located at 3q26 is frequently amplified and overexpressed in multiple cancers, including head and neck squamous cell carcinomas (HNSCC). The tumor-promoting activity and involvement of SOX2 in tumor progression has been extensively demonstrated, thereby emerging as a promising therapeutic target. However, the role of SOX2 in early stages of tumorigenesis and its possible contribution to malignant transformation remain unexplored. This study investigates for the first time SOX2 protein expression by immunohistochemistry and gene amplification by real-time PCR using a large series of 94 laryngeal precancerous lesions. Correlations with the histopathological classification and the risk of progression to invasive carcinoma were established. Nuclear SOX2 expression was frequently detected in 38 (40%) laryngeal dysplasias, whereas stromal cells and normal adjacent epithelia showed negative expression. SOX2 gene amplification was detected in 18 (33%) of 55 laryngeal dysplasias. Univariate Cox analysis showed that SOX2 gene amplification (p = 0.046) and protein expression (p < 0.001) but not histological grading (p = 0.432) were significantly associated with laryngeal cancer risk. In multivariate stepwise analysis including age, tobacco, histology, SOX2 gene amplification and SOX2 expression, SOX2 expression (HR = 3.531, 95% CI 1.144 to 10.904; p = 0.028) was the only significant independent predictor of laryngeal cancer development. These findings underscore the relevant role of SOX2 in early tumorigenesis and a novel clinical application of SOX2 expression as independent predictor of laryngeal cancer risk in patients with precancerous lesions beyond current WHO histological grading. Therefore, targeting SOX2 could lead to effective strategies for both cancer prevention and treatment.

https://ift.tt/2SzktLt

Three‐dimensional architecture of common benign and pre‐cancerous prostate epithelial lesions

Abstract

Aim

Many glandular lesions can mimic prostate cancer microscopically including atrophic glands, adenosis and prostate intraepithelial neoplasia. While the characteristic histopathological and immunohistochemical features of these lesions have been well established, little is known about their three‐dimensional architecture. Our objective was to evaluate the three‐dimensional organization of common prostate epithelial lesions.

Methods and results

Five hundred micron thick punches (n=42) were taken from radical prostatectomy specimens, and stained with antibodies targeting Keratin 8‐18 and Keratin 5 for identification of luminal and basal cells respectively. Tissue samples were optically cleared in benzyl alcohol: benzyl benzoate and imaged using a confocal laser scanning microscope. The three‐dimensional architecture of peripheral and transition zone glands was acinar, composed of interconnecting and blind‐ending saccular tubules. In simple atrophy, partial atrophy and post‐atrophic hyperplasia, the acinar structure was attenuated with branching blind‐ending tubules from parental tubular structures. Three‐dimensional imaging revealed a novel variant of prostate atrophy characterized by large Golgi‐like atrophic spaces parallel to the prostate surface, which were represented by thin, elongated tubular structures on HE slides. Adenosis on the other hand lacked acinar organization, so that it closely mimicked low‐grade prostate cancer. High‐grade prostate intraepithelial neoplasia displayed prominent papillary intra‐luminal protrusions but retained an acinar organization, whereas intraductal carcinoma predominantly consisted of cribriform proliferations with either spheroid, ellipsoid or complex interconnecting lumens.

Conclusions

While various prostate epithelial lesions might mimic malignancy on HE slides, their three‐dimensional architecture is acinar and clearly different from the tubular structure of prostate cancer, with adenosis as exception.

This article is protected by copyright. All rights reserved.

https://ift.tt/2T4EKxv

Annals of Neurology: Volume 85, Number 3, March 2019

A photomicrograph of a section through the cerebellum of a patient with mood, but not motor manifestations of Huntington's disease (HD), stained immunohistochemically for calbindin (brown) and counterstained with cresyl violet to show granule cells. Large, dark brown Purkinje cells are aligned along the border of the granule cell layer, and have healthy dendritic trees, while in cases with motor manifestations of HD, the Purkinje cells degenerate. See Singh‐Bains et al., pp. 396–405

https://ift.tt/2TqPllG

Issue Information

https://ift.tt/2ISAAnU

Correction

https://ift.tt/2TqDrrW

Effects of different processing methods on the antioxidant and immune stimulating abilities of garlic

Processing methods affect the health effects of garlic. Heat drying followed by fermentation improves the biological activities of garlic. Heating improves the levels of S‐Allylcysteine in garlic.

Abstract

In this study, we determined the antioxidant and immune stimulating abilities of a garlic product developed by freeze drying, heat drying, and solid‐state fermentation of heat‐dried garlic. Lactobacillus plantarum KCTC21004 and Leuconostoc mesenteroides KCTC13302 were used for the sample fermentation. The optimum conditions for fermentation were 50% (v/w) moisture, a fermentation time of 48 hr and a temperature of 37°C. Heat‐dried garlic samples fermented with L. plantarum KCTC21004 (HD21004) and L. mesenteroides KCTC13302 (HD13302) showed the highest flavonoid contents while heat‐dried garlic (HD) had the lowest flavonoid content. HD21004 contained the highest phenolic compounds, showed the highest antioxidant activity and demonstrated a strong immune stimulating effect while freeze‐dried garlic showed the lowest flavonoid and polyphenolic contents. Overall, the heat‐dried garlic samples (fermented and unfermented) contained about three times more S‐Allylcysteine (SAC) than the freeze‐dried samples (FD). The current study demonstrates that heat drying and subsequent fermentation of garlic with L. plantarum KCTC21004 can improve its therapeutic effects.

https://ift.tt/2H8WzV6

Rational design and in vitro characterization of novel dental implant and abutment surfaces for balancing clinical and biological needs

Abstract

Background

Long‐term success and patient satisfaction of dental implant systems can only be achieved by fulfilling clinical as well as biological needs related to maintenance, aesthetics, soft tissue sealing, and osseointegration, among others. Surface properties largely contribute to the biological and clinical performance of implants and abutments.

Purpose

To decipher the clinical and biological needs in implant dentistry. To address identified needs, next‐generation dental implant and abutment surfaces are designed and characterized in vitro.

Materials and Methods

Novel implant and abutment surface designs were produced and characterized using surface chemical analysis, surface topography analysis, scanning electron microscopy, contact‐angle measurements, and cell‐culture experiments.

Results

The novel anodized implant surface was gradually anodized, increasing the surface roughness, surface enlargement, and oxide‐layer thickness from platform to apex. The surface was phosphorus enriched, nonporous, and nanostructured at the collar, and showed micropores elsewhere. The novel anodized abutment surface was smooth, nanostructured, nonporous, and yellow. Pristine surfaces with high density of hydroxyl‐groups were protected during storage using a removable cell‐friendly layer that allowed dry packaging.

Conclusions

A novel anodized implant system was developed with surface chemistry, topography, nanostructure, color, and surface energy designed to balance the clinical and biological needs at every tissue level.

https://ift.tt/2H8eUkT

Quantitative in vitro comparison of the thrombogenicity of commercial dental implants

Abstract

Background

Dental implants often have surface modifications that alter surface topography and chemistry to improve osseointegration and thereby increase treatment predictability. Surface contact‐induced blood coagulation is associated with the onset of osseointegration.

Purpose

To quantitatively evaluate the thrombogenicity of two commercially available dental implants that have similar surface roughness but different surface chemistry.

Material and Methods

Two commercially available dental implants with anodized or sandblasted acid‐etched surfaces were evaluated for thrombogenic properties. Thrombogenicity was assessed by incubating implants for 1 hour in fresh, partially heparinized blood followed by hemocyte quantification, microscopic evaluation, and quantification of thrombogenic biomarkers.

Results

Fibrin coverage was significantly higher on the anodized surface compared with the sandblasted acid‐etched surface (P < 0.0001). Platelet and white blood cell attachment followed a similar pattern. The increased thrombogenicity was confirmed based on a significant increase in the levels of the coagulation cascade biomarkers, thrombin antithrombin complex, and β‐thromboglobulin (all P < 0.05).

Conclusion

Dental implants with comparable roughness but differing surface chemistry had differing extents of blood contact activation. These data suggest that surface chemistry from anodization augments implant thrombogenicity compared with that from sandblasting and acid‐etching, which could have implications for osseointegration.

https://ift.tt/2tGzHnM

On osseointegration in relation to implant surfaces

Abstract

Background

The understanding of mechanisms of osseointegration as well as applied knowledge about oral implant surfaces are of paramount importance for successful clinical results.

Purpose

The aim of the present article is to present an overview of osseointegration mechanisms and an introduction to surface innovations with relevance for osseointegration that will be published in the same supplement of Clinical Implant Dentistry and Related Research.

Materials and Methods

The present article is a narrative review of some osseointegration and implant surface‐related details.

Results and Conclusions

Osseointegration has a changed definition since it is realized today that oral implants are but foreign bodies and that this fact explains osseointegration as a protection mechanism of the tissues. Given adequate stability, bone tissue is formed around titanium implants to shield them from the tissues. Oral implant surfaces may be characterized by microroughness and nanoroughness, by surface chemical composition and by physical and mechanical parameters. An isotropic, moderately rough implant surface such as seen on the TiUnite device has displayed improved clinical results compared to previously used minimally rough or rough surfaces. However, there is a lack of clinical evidence supporting any particular type of nanoroughness pattern that, at best, is documented with results from animal studies. It is possible, but as yet unproven, that clinical results may be supported by a certain chemical composition of the implant surface. The same can be said with respect to hydrophilicity of implant surfaces; positive animal data may suggest some promise, but there is a lack of clinical evidence that hydrophilic implants result in improved clinical outcome of more hydrophobic surfaces. With respect to mechanical properties, it seems obvious that those must be encompassing the loading of oral implants, but we need more research on the mechanically ideal implant surface from a clinical aspect.

https://ift.tt/2H6B0o1

TGF‐β activity in acid bone lysate adsorbs to titanium surface

Abstract

Objectives

Osteoblasts lay down new bone on implant surfaces. The underlying cellular mechanism and the spatio‐temporal mode of action, however, remain unclear. It can be proposed that growth factors released upon acidification by osteoclasts adsorb to the implant surface and control the early stages of osseointegration.

Methods

To simulate bone lysis by osteoclasts, titanium discs were exposed to acid bone lysate (ABL) followed by vigorous washing and seeding of oral fibroblasts. The expression of TGF‐β target genes interleukin 11 (IL11) and NADPH oxidase 4 (NOX4) was evaluated by reverse transcriptase polymerase chain reaction and IL11 ELISA. TGF‐β signaling activation was assessed via Smad2/3 immunofluorescence. The impact of ABL on osteogenic differentiation was determined with murine ST2 mesenchymal stromal cells.

Results

We report here that ABL‐conditioned titanium discs, independent of turned or rough surface, increased the expression of IL11 and NOX4. This increase was blocked by the TGF‐β receptor 1 antagonist SB431542. Further support for the TGF‐β signaling activation came from the translocation of Smad2/3 into the nucleus of oral fibroblasts. Moreover, titanium discs exposed to ABL decreased alkaline phosphatase and osteopontin in ST2 cells.

Conclusions

These in vitro findings suggest that titanium can adsorb TGF‐β from ABLs. The data provide a strong impetus for studies on the protein adsorption on implant surfaces in vitro and in vivo, specifically for growth factors including bone‐derived TGF‐β during successful and failed osseointegration.

https://ift.tt/2tGzDEy

On osseointegration in relation to implant surfaces

Abstract

Background

The understanding of mechanisms of osseointegration as well as applied knowledge about oral implant surfaces are of paramount importance for successful clinical results.

Purpose

The aim of the present article is to present an overview of osseointegration mechanisms and an introduction to surface innovations with relevance for osseointegration that will be published in the same supplement of Clinical Implant Dentistry and Related Research.

Materials and Methods

The present article is a narrative review of some osseointegration and implant surface‐related details.

Results and Conclusions

Osseointegration has a changed definition since it is realized today that oral implants are but foreign bodies and that this fact explains osseointegration as a protection mechanism of the tissues. Given adequate stability, bone tissue is formed around titanium implants to shield them from the tissues. Oral implant surfaces may be characterized by microroughness and nanoroughness, by surface chemical composition and by physical and mechanical parameters. An isotropic, moderately rough implant surface such as seen on the TiUnite device has displayed improved clinical results compared to previously used minimally rough or rough surfaces. However, there is a lack of clinical evidence supporting any particular type of nanoroughness pattern that, at best, is documented with results from animal studies. It is possible, but as yet unproven, that clinical results may be supported by a certain chemical composition of the implant surface. The same can be said with respect to hydrophilicity of implant surfaces; positive animal data may suggest some promise, but there is a lack of clinical evidence that hydrophilic implants result in improved clinical outcome of more hydrophobic surfaces. With respect to mechanical properties, it seems obvious that those must be encompassing the loading of oral implants, but we need more research on the mechanically ideal implant surface from a clinical aspect.

https://ift.tt/2H8eJGf

A functional landscape of resistance to MEK1/2 and CDK4/6 inhibition in NRAS mutant melanoma

Combinatorial inhibition of MEK1/2 and CDK4/6 is currently undergoing clinical investigation in NRAS-mutant melanoma. To prospectively map the landscape of resistance to this investigational regimen, we utilized a series of gain- and loss-of-function forward genetic screens to identify modulators of resistance to clinical inhibitors of MEK1/2 and CDK4/6 alone and in combination. First, we identified NRAS-mutant melanoma cell lines that were dependent on NRAS for proliferation and sensitive to MEK1/2 and CDK4/6 combination treatment. We then employed a genome-scale ORF overexpression screen and a CRISPR knockout screen to identify modulators of resistance to each inhibitor alone or in combination. These orthogonal screening approaches revealed concordant means of achieving resistance to this therapeutic modality, including tyrosine kinases, RAF, RAS, AKT, and PIK3CA signaling. Activated KRAS was sufficient to cause resistance to combined MEK/CDK inhibition and to replace genetic depletion of oncogenic NRAS. In summary, our comprehensive functional genetic screening approach revealed modulation of resistance to the inhibition of MEK1/2, CDK4/6 or their combination in NRAS-mutant melanoma.

https://ift.tt/2EDQvSK

Label-free Raman spectroscopy reveals signatures of radiation resistance in the tumor microenvironment

Delay in the assessment of tumor response to radiation therapy continues to pose a major challenge to quality of life for patients with non-responsive tumors. Here we exploited label-free Raman spectroscopic mapping to elucidate radiation-induced biomolecular changes in tumors and uncovered latent microenvironmental differences between treatment-resistant and -sensitive tumors. We used isogenic radiation-resistant and -sensitive A549 human lung cancer cells human head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-47 and UM-SCC-22B, respectively) to grow tumor xenografts in athymic nude mice and demonstrated the molecular specificity and quantitative nature of Raman spectroscopic tissue assessments. Raman spectra obtained from untreated and treated tumors were subjected to chemometric analysis using multivariate curve resolution-alternating least squares (MCR-ALS) and support vector machine (SVM) to quantify biomolecular differences in the tumor microenvironment. The Raman measurements revealed significant and reliable differences in lipid and collagen content post-radiation in the tumor microenvironment, with consistently greater changes observed in the radiation-sensitive tumors. In addition to accurately evaluating tumor response to therapy, the combination of Raman spectral markers potentially offers a route to predicting response in untreated tumors prior to commencing treatment. Combined with its non-invasive nature, our findings provide a rationale for in vivo studies using Raman spectroscopy, with the ultimate goal of clinical translation for patient stratification and guiding adaptation of radiotherapy during the course of treatment.

https://ift.tt/2VnsAMI

Camber Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25 mg, 50 mg and 100 mg Due to the Detection of Trace Amounts of NMBA Impurity found in the Active Pharmaceutical Ingredient

Audience: Consumer, Health Professional, Pharmacy Camber Pharmaceuticals, Inc. is recalling 87 lots of Losartan Tablets USP 25 mg, 50 mg, and 100 mg to consumer level. This recall was prompted due to the detection of trace amounts of N-Nitroso...

https://ift.tt/2Ekx009

ATML1 activity is restricted to the outermost cells of the embryo through post-transcriptional repressions [RESEARCH ARTICLE]

Hiroyuki Iida, Ayaka Yoshida, and Shinobu Takada

Cell fate determination in plants relies on positional cues. To investigate the position-dependent gene regulation in plants, we focused on shoot epidermal cell specification, which occurs only in the outermost cells. ATML1, which encodes an HD-ZIP class IV transcription factor, is a positive regulator of shoot epidermal cell identity. Despite the presence of a weak ATML1 promoter activity in the inner cells, ATML1 protein was detected mostly in the outermost cells, which suggests that ATML1 accumulation is inhibited in the inner cells. ATML1 nuclear localization was reduced in the epidermis and there was a positive, albeit weak, correlation between the amount of ATML1 in the nuclei and the expression of a direct target of ATML1. Nuclear accumulation of ATML1 was more strongly inhibited in the inner cells than in the outermost cells. Domain deletion analyses revealed that the ZLZ-coding sequence was necessary and partially sufficient for the post-transcriptional repression of ATML1. Our results suggest that post-transcriptional repressions contribute to the restriction of master transcriptional regulator activity in specific cells to enable position-dependent cell differentiation.

https://ift.tt/2BVEczq

Let there be preLights: one year on [EDITORIAL]

James Briscoe and Katherine Brown



https://ift.tt/2UcX58b

USP22 controls multiple signaling pathways that are essential for vasculature formation in the mouse placenta [RESEARCH ARTICLE]

Evangelia Koutelou, Li Wang, Andria C. Schibler, Hsueh-Ping Chao, Xianghong Kuang, Kevin Lin, Yue Lu, Jianjun Shen, Collene R. Jeter, Andrew Salinger, Marenda Wilson, Yi Chun Chen, Boyko S. Atanassov, Dean G. Tang, and Sharon Y. R. Dent

USP22, a component of the SAGA complex, is overexpressed in highly aggressive cancers, but the normal functions of this deubiquitinase are not well defined. We determined that loss of USP22 in mice results in embryonic lethality due to defects in extra-embryonic placental tissues and failure to establish proper vascular interactions with the maternal circulatory system. These phenotypes arise from abnormal gene expression patterns that reflect defective kinase signaling, including TGFβ and several receptor tyrosine kinase pathways. USP22 deletion in endothelial cells and pericytes that are induced from embryonic stem cells also hinders these signaling cascades, with detrimental effects on cell survival and differentiation as well as on the ability to form vessels. Our findings provide new insights into the functions of USP22 during development that may offer clues to its role in disease states.

https://ift.tt/2BY3NYp

The HMG box transcription factors Sox1a and Sox1b specify a new class of glycinergic interneuron in the spinal cord of zebrafish embryos [RESEARCH ARTICLE]

Vanessa Gerber, Lixin Yang, Masanari Takamiya, Vanessa Ribes, Victor Gourain, Ravindra Peravali, Johannes Stegmaier, Ralf Mikut, Markus Reischl, Marco Ferg, Sepand Rastegar, and Uwe Strähle

Specification of neurons in the spinal cord relies on extrinsic and intrinsic signals, which in turn are interpreted by expression of transcription factors. V2 interneurons develop from the ventral aspects of the spinal cord. We report here a novel neuronal V2 subtype, named V2s, in zebrafish embryos. Formation of these neurons depends on the transcription factors sox1a and sox1b. They develop from common gata2a- and gata3-dependent precursors co-expressing markers of V2b and V2s interneurons. Chemical blockage of Notch signalling causes a decrease in V2s and an increase in V2b cells. Our results are consistent with the existence of at least two types of precursor arranged in a hierarchical manner in the V2 domain. V2s neurons grow long ipsilateral descending axonal projections with a short branch at the ventral midline. They acquire a glycinergic neurotransmitter type during the second day of development. Unilateral ablation of V2s interneurons causes a delay in touch-provoked escape behaviour, suggesting that V2s interneurons are involved in fast motor responses.

https://ift.tt/2UeEmsD

Gene-environment interaction impacts on heart development and embryo survival [RESEARCH ARTICLE]

Julie L. M. Moreau, Scott Kesteven, Ella M. M. A. Martin, Kin S. Lau, Michelle X. Yam, Victoria C. O'Reilly, Gonzalo del Monte-Nieto, Antonio Baldini, Michael P. Feneley, Anne M. Moon, Richard P. Harvey, Duncan B. Sparrow, Gavin Chapman, and Sally L. Dunwoodie

Congenital heart disease (CHD) is the most common type of birth defect. In recent years, research has focussed on identifying the genetic causes of CHD. However, only a minority of CHD cases can be attributed to single gene mutations. In addition, studies have identified different environmental stressors that promote CHD, but the additive effect of genetic susceptibility and environmental factors is poorly understood. In this context, we have investigated the effects of short-term gestational hypoxia on mouse embryos genetically predisposed to heart defects. Exposure of mouse embryos heterozygous for Tbx1 or Fgfr1/Fgfr2 to hypoxia in utero increased the incidence and severity of heart defects while Nkx2-5^+/– embryos died within 2 days of hypoxic exposure. We identified the molecular consequences of the interaction between Nkx2-5 and short-term gestational hypoxia, which suggest that reduced Nkx2-5 expression and a prolonged hypoxia-inducible factor 1α response together precipitate embryo death. Our study provides insight into the causes of embryo loss and variable penetrance of monogenic CHD, and raises the possibility that cases of foetal death and CHD in humans could be caused by similar gene-environment interactions.

https://ift.tt/2BYmHP0

Morphogenesis of neurons and glia within an epithelium [RESEARCH ARTICLE]

Isabel I. C. Low, Claire R. Williams, Megan K. Chong, Ian G. McLachlan, Bradley M. Wierbowski, Irina Kolotuev, and Maxwell G. Heiman

To sense the outside world, some neurons protrude across epithelia, the cellular barriers that line every surface of our bodies. To study the morphogenesis of such neurons, we examined the C. elegans amphid, in which dendrites protrude through a glial channel at the nose. During development, amphid dendrites extend by attaching to the nose via DYF-7, a type of protein typically found in epithelial apical ECM. Here, we show that amphid neurons and glia exhibit epithelial properties, including tight junctions and apical-basal polarity, and develop in a manner resembling other epithelia. We find that DYF-7 is a fibril-forming apical ECM component that promotes formation of the tube-shaped glial channel, reminiscent of roles for apical ECM in other narrow epithelial tubes. We also identify a requirement for FRM-2, a homolog of EPBL15/moe/Yurt that promotes epithelial integrity in other systems. Finally, we show that other environmentally exposed neurons share a requirement for DYF-7. Together, our results suggest that these neurons and glia can be viewed as part of an epithelium continuous with the skin, and are shaped by mechanisms shared with other epithelia.

https://ift.tt/2UhOSQc

Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain [REVIEW]

Kirsten Obernier and Arturo Alvarez-Buylla

In the adult rodent brain, neural stem cells (NSCs) persist in the ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ), which are specialized niches in which young neurons for the olfactory bulb (OB) and hippocampus, respectively, are generated. Recent studies have significantly modified earlier views on the mechanisms of NSC self-renewal and neurogenesis in the adult brain. Here, we discuss the molecular control, heterogeneity, regional specification and cell division modes of V-SVZ NSCs, and draw comparisons with NSCs in the SGZ. We highlight how V-SVZ NSCs are regulated by local signals from their immediate neighbors, as well as by neurotransmitters and factors that are secreted by distant neurons, the choroid plexus and vasculature. We also review recent advances in single cell RNA analyses that reveal the complexity of adult neurogenesis. These findings set the stage for a better understanding of adult neurogenesis, a process that one day may inspire new approaches to brain repair.

https://ift.tt/2C0eUA2

Nell2 regulates the contralateral-versus-ipsilateral visual projection as a domain-specific positional cue [RESEARCH ARTICLE]

Chizu Nakamoto, Elaine Durward, Masato Horie, and Masaru Nakamoto

In mammals with binocular vision, retinal ganglion cell (RGC) axons from each eye project to eye-specific domains in the contralateral and ipsilateral dorsal lateral geniculate nucleus (dLGN), underpinning disparity-based stereopsis. Although domain-specific axon guidance cues that discriminate contralateral and ipsilateral RGC axons have long been postulated as a key mechanism for development of the eye-specific retinogeniculate projection, the molecular nature of such cues has remained elusive. Here, we show that the extracellular glycoprotein Nell2 (neural epidermal growth factor-like-like 2) is expressed in the dorsomedial region of the dLGN, which ipsilateral RGC axons terminate in and contralateral axons avoid. In Nell2 mutant mice, contralateral RGC axons abnormally invaded the ipsilateral domain of the dLGN, and ipsilateral axons terminated in partially fragmented patches, forming a mosaic pattern of contralateral and ipsilateral axon-termination zones. In vitro, Nell2 exerted inhibitory effects on contralateral, but not ipsilateral, RGC axons. These results provide evidence that Nell2 acts as a domain-specific positional label in the dLGN that discriminates contralateral and ipsilateral RGC axons, and that it plays essential roles in the establishment of the eye-specific retinogeniculate projection.

https://ift.tt/2UeWHWy

Genetic interactions support an inhibitory relationship between bone morphogenetic protein 2 and netrin 1 during semicircular canal formation [RESEARCH ARTICLE]

Chan Ho Hwang, James Keller, Charles Renner, Sho Ohta, and Doris K. Wu

The semicircular canals of the mammalian inner ear are derived from epithelial pouches in which epithelial cells in the central region of each pouch undergo resorption, leaving behind the region at the rim to form a tube-shaped canal. Lack of proliferation at the rim and/or over-clearing of epithelial cells in the center of the pouch can obliterate canal formation. Otic-specific knockout of bone morphogenetic protein 2 (Bmp2) results in absence of all three semicircular canals; however, the common crus and ampullae housing the sensory tissue (crista) are intact. The lack of Bmp2 causes Ntn1 (which encodes netrin 1), which is required for canal resorption, to be ectopically expressed at the canal rim. Ectopic Ntn1 results in reduction of Dlx5 and Lmo4, which are required for rim formation. These phenotypes can be partially rescued by removing one allele of Ntn1 in the Bmp2 mutants, indicating that Bmp2 normally negatively regulates Ntn1 for canal formation. Additionally, non-resorption of the canal pouch in Ntn1^–/– mutants is partially rescued by removing one allele of Bmp2. Thus, reciprocal inhibition between Bmp2 and netrin 1 is involved in canal formation of the vestibule.

https://ift.tt/2C0eQAi

Postnatal liver functional maturation requires Cnot complex-mediated decay of mRNAs encoding cell cycle and immature liver genes [RESEARCH ARTICLE]

Toru Suzuki, Chisato Kikuguchi, Saori Nishijima, Takeshi Nagashima, Akinori Takahashi, Mariko Okada, and Tadashi Yamamoto

Liver development involves dramatic gene expression changes mediated by transcriptional and post-transcriptional control. Here, we show that the Cnot deadenylase complex plays a crucial role in liver functional maturation. The Cnot3 gene encodes an essential subunit of the Cnot complex. Mice lacking Cnot3 in liver have reduced body and liver masses, and they display anemia and severe liver damage. Histological analyses indicate that Cnot3-deficient (Cnot3^–/–) hepatocytes are irregular in size and morphology, resulting in formation of abnormal sinusoids. We observe hepatocyte death, increased abundance of mitotic and mononucleate hepatocytes, and inflammation. Cnot3^–/– livers show increased expression of immune response-related, cell cycle-regulating and immature liver genes, while many genes relevant to liver functions, such as oxidation-reduction, lipid metabolism and mitochondrial function, decrease, indicating impaired liver functional maturation. Highly expressed mRNAs possess elongated poly(A) tails and are stabilized in Cnot3^–/– livers, concomitant with an increase of the proteins they encode. In contrast, transcription of liver function-related mRNAs was lower in Cnot3^–/– livers. We detect efficient suppression of Cnot3 protein postnatally, demonstrating the crucial contribution of mRNA decay to postnatal liver functional maturation.

https://ift.tt/2U9Hgih

TOP1{alpha} regulates FLOWERING LOCUS C expression by coupling histone modification and transcription machinery [RESEARCH REPORT]

Peiqiao Zhong, Jiaojiao Li, Linjie Luo, Zhong Zhao, and Zhaoxia Tian

The key steps of transcription are coupled with the opening of the DNA helical structure and establishment of active chromatin to facilitate the movement of the transcription machinery. Type I topoisomerases cleave one DNA strand and relax the supercoiled structure of transcribed templates. How topoisomerase-mediated DNA topological changes promote transcription and establish a permissive histone modification for transcription elongation is largely unknown. Here, we show that TOPOISOMERASE 1α in plants regulates FLOWERING LOCUS C transcription by coupling histone modification and transcription machinery. We demonstrate that TOP1α directly interacts with the methyltransferase SDG8 to establish high levels of H3K36 methylation downstream of FLC transcription start sites and recruits RNA polymerase II to facilitate transcription elongation. Our results provide a mechanistic framework for TOP1α control of the main steps of early transcription and demonstrate how topoisomerases couple RNA polymerase II and permissive histone modifications to initiate transcription elongation.

https://ift.tt/2C0eObE

The OsJAZ1 degron modulates jasmonate signaling sensitivity during rice development [RESEARCH REPORT]

Jiaqi Tian, Lichun Cao, Xiaofei Chen, Mingjiao Chen, Peng Zhang, Liming Cao, Staffan Persson, Dabing Zhang, and Zheng Yuan

Jasmonates (JAs) are crucial to the coordination of plant stress responses and development. JA signaling depends on JASMONATE-ZIM DOMAIN (JAZ) proteins that are destroyed by the SCF^COI1-mediated 26S proteasome when the JAZ co-receptor COI1 binds active JA or the JA-mimicking phytotoxin coronatine (COR). JAZ degradation releases JAZ-interacting transcription factors that can execute stress and growth responses. The JAZ proteins typically contain Jas motifs that undergo conformational changes during JA signal transduction and that are important for the JAZ-COI1 interaction and JAZ protein degradation. However, how alterations in the Jas motif and, in particular, the JAZ degron part of the motif, influence protein stability and plant development have not been well explored. To clarify this issue, we performed bioassays and genetic experiments to uncover the function of the OsJAZ1 degron in rice JA signaling. We found that substitution or deletion of core segments of the degron altered the OsJAZ1-OsCOI1b interaction in a COR-dependent manner. We show that these altered interactions function as a regulator for JA signaling during flower and root development. Our study therefore expands our understanding of how the JAZ degron functions, and provides the means to change the sensitivity and specificity of JA signaling in rice.

https://ift.tt/2Uc3hwZ

Phase 1 Open-Label, Multicenter Study of First-in-Class ROR{gamma} Agonist LYC-55716: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

Purpose:Transcription factor retinoic acid receptor-related orphan receptor g (RORg) regulates type 17 effector T cell differentiation and function and is key to immune cell regulation. Synthetic RORg agonists modulate immune cell gene expression to increase effector T cell activity and decrease immune suppression. A Phase 1 study evaluated the safety and tolerability of LYC-55716, a first-in-class, oral, small-molecule RORg agonist in adults with relapsed/refractory metastatic cancer. Experimental Design: Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. Results: No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AEs) were primarily Grade 1-2 and included diarrhea (n=11), fatigue (n=7), anemia (n=4), decreased appetite (n=4), nausea (n=4). Grade 3 AEs were anemia (n=2), elevated gamma-glutamyl transferase (n=1), and hypophosphatemia (n=1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORg pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2-12 months (6 received >4 months of treatment). Conclusions: These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a Phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

https://ift.tt/2EE4XKm

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate <i>CBX2</i> in invasive breast carcinoma, Published online: 01 March 2019; doi:10.1038/s41416-019-0387-8

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma

https://ift.tt/2IJA0Zz

TIPSS for variceal bleeding in patients with idiopathic non‐cirrhotic portal hypertension: comparison with patients who have cirrhosis

Summary

Background

In patients with idiopathic non‐cirrhotic portal hypertension (INCPH), the usual recommended strategy for management of variceal bleeding is the same as that in cirrhosis. However, this policy has been challenged by the different natural history between INCPH and cirrhosis.

Aim

To compare outcomes after transjugular intrahepatic portosystemic shunt (TIPSS) between INCPH and cirrhotic patients admitted for variceal bleeding.

Methods

Between March 2001 and September 2015, 76 consecutive patients with biopsy‐proven INCPH undergoing TIPSS for variceal bleeding in a tertiary‐care centre were included. 76 patients with cirrhotic portal hypertension receiving TIPSS for variceal bleeding, and matched for age, sex, Child‐Pugh class, stent type and index year of TIPSS creation served as controls.

Results

Patients with INCPH, compared to those with cirrhosis, had significantly lower mortality (11% vs 36% at 5 years, adjusted HR, 0.37; 95% CI 0.15‐0.87, P = 0.022), overt hepatic encephalopathy (16% vs 33% at 5 years, adjusted HR, 0.35; 95% CI 0.16‐0.75, P = 0.007) and hepatic impairment, despite similar rates of further bleeding (33% vs 32% at 5 years, adjusted HR, 0.72; 95% CI 0.36‐1.44, P = 0.358), and shunt dysfunction (35% vs 36% at 5 years, adjusted HR, 0.84; 95% CI 0.41‐1.72, P = 0.627). These findings were consistent across different relevant subgroups.

Conclusions

Patients with INCPH treated with TIPSS for variceal bleeding had similar progression of portal hypertension (further bleeding and shunt dysfunction) but fewer complications of liver disease (overt hepatic encephalopathy and hepatic insufficiency) and lower mortality rate compared with cirrhotic patients with comparable liver function.

https://ift.tt/2H96VEc

Radionuclide Treatment Yields Responses in mCRPC [News in Brief]

Lutetium-177 PSMA-617 provides targeted delivery of radiation to metastatic castration-resistant prostate cancer.

https://ift.tt/2Vnr4Kw

An R Package for Bayesian Analysis of Multi-environment and Multi-trait Multi-environment Data for Genome-Gased Prediction

Evidence that genomic selection (GS) is a technology that is revolutionizing plant breeding continues to grow. However, it is very well documented that its success strongly depends on statistical models, which are used by GS to perform predictions of candidate genotypes that were not phenotyped. Because there is no universally better model for prediction and models for each type of response variable are needed (continuous, binary, ordinal, count, etc.), an active area of research aims to develop statistical models for the prediction of univariate and multivariate traits in GS. However, most of the models developed so far are for univariate and continuous (Gaussian) traits. Therefore, to overcome the lack of multivariate statistical models for genome-based prediction by improving the original version of the BMTME, we propose an improved Bayesian multi-trait and multi-environment (BMTME) R package for analyzing breeding data with multiple traits and multiple environments. We also introduce Bayesian multi-output regressor stacking (BMORS) functions that are considerably efficient in terms of computational resources. The package allows parameter estimation and evaluates the prediction performance of multi-trait and multi-environment data in a reliable, efficient and user-friendly way. We illustrate the use of the BMTME with real toy datasets to show all the facilities that the software offers the user. However, for large datasets, the BME() and BMTME() functions of the BMTME R package are very intense in terms of computing time; on the other hand, less intensive computing packages like the BMORS functions BMORS() and BMORS_Env() are also included in the R package.

https://ift.tt/2TneNIQ

A Novel Root-Knot Nematode Resistance QTL on Chromosome Vu01 in Cowpea

The root-knot nematode (RKN) species Meloidogyne incognita and M. javanica cause substantial root system damage and suppress yield of susceptible cowpea cultivars. The narrow-based genetic resistance conferred by the Rk gene, present in some commercial cultivars, is not effective against Rk-virulent populations found in several cowpea production areas. The dynamics of virulence within RKN populations require a broadening of the genetic base of resistance in elite cowpea cultivars. As part of this goal, F₁ and F₂ populations from the cross CB46-Null (susceptible) x FN-2-9-04 (resistant) were phenotyped for M. javanica induced root-galling (RG) and egg-mass production (EM) in controlled growth chamber and greenhouse infection assays. In addition, F_2:3 families of the same cross were phenotyped for RG on field sites infested with Rk-avirulent M. incognita and M. javanica. The response of F₁ to RG and EM indicated that resistance to RKN in FN-2-9-04 is partially dominant, as supported by the degree of dominance in the F₂ and F_2:3 populations. Two QTLs associated with both RG and EM resistance were detected on chromosomes Vu01 and Vu04. The QTL on Vu01 was most effective against aggressive M. javanica, whereas both QTLs were effective against avirulent M. incognita. Allelism tests with CB46 x FN-2-9-04 progeny indicated that these parents share the same RKN resistance locus on Vu04, but the strong, broad-based resistance in FN-2-9-04 is conferred by the additive effect of the novel resistance QTL on Vu01. This novel resistance in FN-2-9-04 is an important resource for broadening RKN resistance in elite cowpea cultivars.

https://ift.tt/2IEI8u6

Usefulness Criterion and Post-selection Parental Contributions in Multi-parental Crosses: Application to Polygenic Trait Introgression

Predicting the usefulness of crosses in terms of expected genetic gain and genetic diversity is of interest to secure performance in the progeny and to maintain long-term genetic gain in plant breeding. A wide range of crossing schemes are possible including large biparental crosses, backcrosses, four-way crosses, and synthetic populations. In silico progeny simulations together with genome-based prediction of quantitative traits can be used to guide mating decisions. However, the large number of multi-parental combinations can hinder the use of simulations in practice. Analytical solutions have been proposed recently to predict the distribution of a quantitative trait in the progeny of biparental crosses using information of recombination frequency and linkage disequilibrium between loci. Here, we extend this approach to obtain the progeny distribution of more complex crosses including two to four parents. Considering agronomic traits and parental genome contribution as jointly multivariate normally distributed traits, the usefulness criterion parental contribution (UCPC) enables to (i) evaluate the expected genetic gain for agronomic traits, and at the same time (ii) evaluate parental genome contributions to the selected fraction of progeny. We validate and illustrate UCPC in the context of multiple allele introgression from a donor into one or several elite recipients in maize (Zea mays L.). Recommendations regarding the interest of two-way, three-way, and backcrosses were derived depending on the donor performance. We believe that the computationally efficient UCPC approach can be useful for mate selection and allocation in many plant and animal breeding contexts.

https://ift.tt/2TnXwz8

Flu Vaccination During Pregnancy Does Not Cause Miscarriage

THURSDAY, Feb. 28, 2019 -- An influenza vaccine cannot cause a pregnant woman to miscarry, researchers say. The findings are based on an examination of the 2012-13, 2013-14, and 2014-15 flu seasons and were presented Wednesday to the U.S. Centers...

https://ift.tt/2Svblr3

Robotically Assisted Devices Not Approved for Cancer Surgery

THURSDAY, Feb. 28, 2019 -- The use of robotically assisted surgical devices for breast removal and other cancer-related surgeries is not approved by the U.S. Food and Drug Administration because there is no proof of its safety or effectiveness in...

https://ift.tt/2XnX9DU

Teens' Social Media Use Does Not Predict Later Depression

THURSDAY, Feb. 28, 2019 -- Social media use does not predict later depressive symptoms among adolescents or college undergraduates, according to a study recently published in Clinical Psychological Science. Taylor Heffer, from Brock University in...

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Mental Health Disorders Up After Head & Neck Cancer Diagnosis

THURSDAY, Feb. 28, 2019 -- In patients with head and neck cancer (HNC), the prevalence of mental health disorders (MHDs) is significantly higher after cancer diagnosis, according to a study published online Feb. 28 in JAMA Otolaryngology-Head &...

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FDA: Pulmonary Embolism Risk Up With Tofacitinib 10 mg for RA

THURSDAY, Feb. 28, 2019 -- A safety clinical trial has revealed that tofacitinib (Xeljanz, Xeljanz XR) 10 mg twice daily is associated with an increased risk for pulmonary embolism (PE) and death among patients with rheumatoid arthritis (RA), the...

https://ift.tt/2SvbhHP

Comment on “Predictive value of 18F-FDG PET/CT on survival in locally advanced rectal cancer after neoadjuvant chemoradiation”

L'articolo Comment on "Predictive value of 18F-FDG PET/CT on survival in locally advanced rectal cancer after neoadjuvant chemoradiation" sembra essere il primo su European Review.

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Evaluation of the antileukemic effects of neurokinin-1 receptor antagonists, aprepitant, and L-733,060, in chronic and acute myeloid leukemic cells

Neurokinin-1 receptor (NK1R) antagonists are known for their anxiolytic, antiemetic, anticancer, and anti-inflammatory effects. Aprepitant is used in vomiting and nausea, which are the most common side-effects of patients undergoing chemotherapy for cancer. L-733,060 has been shown to have anxiolytic and antidepressant effects in animal studies and anticancer effect in in-vitro studies. Previous anticancer activity studies with NK1R antagonists have reported that NK-1 antagonists have an antitumoral activity on gastric carcinoma, larynx carcinoma, retinoblastoma, hepatocarcinoma, glioma, neuroblastoma, and osteoblastoma cells. In this study, we have aimed to show and compare the antileukemic effects of aprepitant and L-733,060 on acute and chronic myeloid leukemic cells by using in-vitro experiments, such as WST-1, cell imaging, annexin-V binding, soft agar colony formation, and Hoescht staining. As a result, we have determined that both aprepitant and L-733,060 had strong antiproliferative effects on K562 and HL-60 cells. Moreover, the two drugs caused significant apoptosis and decreased colony forming depending on concentration increase. These findings suggested that NK1R antagonists exhibited antileukemic activities and may be considered to have a novel therapeutic potential for acute and chronic myeloid leukemia. Correspondence to Miriş Dikmen, PhD, Department of Pharmacology, Faculty of Pharmacy, Anadolu Universty, Eskisehir, Centrum TR-26470, Turkey Tel: +90 222 335 0580 x3748; fax: +90 222 335 0750; e-mail: mirisd@anadolu.edu.tr Received October 7, 2018 Accepted January 29, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2SCPrm0

Andrographolide sensitizes Hep-2 human laryngeal cancer cells to carboplatin-induced apoptosis by increasing reactive oxygen species levels

Andrographolide is a natural diterpenoid from Andrographis paniculata that has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. Carboplatin is the first-line chemotherapeutic agent for advanced laryngeal carcinoma. However, the clinical efficacy of carboplatin is limited by drug resistance and side effects. The aim of this study was to investigate whether andrographolide has a synergistic antitumor effect with carboplatin on human laryngeal cancer cells. Hep-2 cells were exposed to andrographolide with or without carboplatin. The effects of indicated therapies were examined using the Cell Counting Kit-8 assay, the colony-forming assay, the Hoechst 33342/PI double staining, and flow cytometry analysis. The molecular mechanism was assessed by reactive oxygen species (ROS) detection and western blot. At the sublethal concentration, andrographolide increased carboplatin sensitivity of Hep-2 cells by increasing carboplatin-induced apoptosis and inhibiting cell viability. Moreover, we found that andrographolide sensitized carboplatin mainly through the induction of ROS generation and apoptotic signaling. Taken together, these results indicate that andrographolide, along with carboplatin, synergistically inhibited cell proliferation and induced mitochondrial apoptosis of Hep-2 cells by increasing the intracellular ROS, regulating the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K/AKT) pathways, altering the BCL2/BAX ratio, and ultimately activating the cleavage of Caspase-3 and PARP. These results suggest that andrographolide sensitizes human laryngeal cancer cells to carboplatin-induced apoptosis by increasing ROS levels. *Wenjing Mao and Peijie He contributed equally to the writing of this article. Correspondence to Chunsheng Wei, PhD, Department of Otolaryngology-Head and Neck Surgery, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, No. 83, Fenyang Road, Shanghai 200031, China Tel/fax: +86 21 6437 7134; e-mail: weics2003@163.com Received October 2, 2018 Accepted February 7, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2Xvto4j

A randomized phase II study to determine the efficacy and tolerability of two doses of eribulin plus lapatinib in trastuzumab-pretreated patients with HER-2-positive metastatic breast cancer (E-VITA)

The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m2 (equivalent to 1.4 mg/m2 eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m2 (equivalent to 2.0 mg/m2 eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8–9.4] in the split-dose arm and 6.5 months (95% CI: 4.6–13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0–73.7) in the split-dose arm and 45.0% (95% CI: 23.2–66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1–90.8) and 75.0% (95% CI: 56.0–94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3–4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m2 day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted. Presented in part at the 2016 ESMO meeting, Copenhagen, 7–11 October 2016. Correspondence to Sibylle Loibl, MD, German Breast Group, Martin-Behaim-Strasse 12, 63263 Neu-Isenburg, Germany Tel: +49 610 274 800; fax: +49 610 2748 0440; e-mail: sibylle.loibl@gbg.de Received April 17, 2018 Accepted November 3, 2018 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2SCPo9O

Talazoparib has no clinically relevant effect on QTc interval in patients with advanced solid tumors

The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia's (QTcF) and Bazett's (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from −3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization. * Justin Hoffman and Jayeta Chakrabarti contributed equally to the writing of this article. Correspondence to Diane Wang, PhD, 10555 Science Center Drive, San Diego, CA 92130, USA Tel: +1 858 622 3000; fax: +1 858 678 8263; e-mail: diane.wang@pfizer.com Received December 13, 2018 Accepted February 2, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2Xvtlp9

Insights Into a “Negative” ICU Trial Derived From Gene Expression Profiling

Objectives: Randomized controlled trials in the ICU often fail to show differences in endpoints between groups. We sought to explore reasons for this at a molecular level by analyzing transcriptomic data from a recent negative trial. Our objectives were to determine if randomization successfully balanced transcriptomic features between groups, to assess transcriptomic heterogeneity among the study subjects included, and to determine if the study drug had any effect at the gene expression level. Design: Bioinformatics analysis of transcriptomic and clinical data collected in the course of a randomized controlled trial. Setting: Tertiary academic mixed medical-surgical ICU. Patients: Adult, critically ill patients expected to require invasive mechanical ventilation more than 48 hours. Interventions: Lactoferrin or placebo delivered enterally and via an oral swab for up to 28 days. Measurements and Main Results: We found no major imbalances in transcriptomic features between groups. Unsupervised analysis did not reveal distinct clusters among patients at the time of enrollment. There were marked differences in gene expression between early and later time points. Patients in the lactoferrin group showed changes in the expression of genes associated with immune pathways known to be associated with lactoferrin. Conclusions: In this clinical trial, transcriptomic data provided a useful complement to clinical data, suggesting that the reasons for the negative result were less likely related to the biological efficacy of the study drug, and may instead have been related to poor sensitivity of the clinical outcomes. In larger studies, transcriptomics may also prove useful in predicting response to treatment. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Funding for the Prevention of nosocomial infections in critically ill patients with lactoferrin (PREVAIL) study was provided by the Southeastern Ontario Academic Medical Association Innovation Fund and the John Hechte Memorial Foundation. Funding for the genomics sub-study was provided by the McLaughlin Center, University of Toronto, and the Garfield Kelly Fund, Queen's University. Ms. Hoekstra received funding and support for article research from Natural Sciences and Engineering Research Council of Canada (Undergraduate Student Research Award). Dr. Maslove disclosed off-label product use of lactoferrin of ICU. Dr. Muscedere's institution received funding from Lotte and John Hechte Memorial Foundation Grant and Southeastern Academic Medical Association Grant, and he received funding from Poly- Phor Pharma. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: david.maslove@queensu.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Anesthetic Implications of the New Guidelines for Button Battery Ingestion in Children

Button battery ingestions result in significant morbidity and mortality in children—before, during, and even after removal. The injuries created by a button battery lodged in the esophagus develop rapidly and can be severe. The current of the button battery, conducted through saliva and the tissue drives a highly alkaline caustic injury, leading to liquefactive tissue necrosis. In June 2018, new guidelines were released from the National Capital Poison Center, which include the use of preoperative protective, pH-neutralizing and viscous barrier interventions with honey and/or sucralfate administered within 12 h of ingestion. In addition, the use of postremoval irrigation of the esophagus with 50–150 mL 0.25% acetic acid is done in the operating room to help neutralize the site of tissue injury. Given that anesthesiologists play an important role in the management of esophageal foreign body removal, the entire specialty needs to be aware of the supporting data behind this and general perioperative considerations for management and potential complications of button battery ingestion. Accepted for publication December 13, 2018. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Debnath Chatterjee, MD, FAAP, Department of Anesthesiology, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 E 16th Ave, B090, Aurora, CO 80045. Address e-mail to debnath.chatterjee@childrenscolorado.org. © 2019 International Anesthesia Research Society

https://ift.tt/2VutOGd

Retrospective Analysis of Obstetric Intensive Care Unit Admissions Reveals Differences in Etiology for Admission Based on Mode of Conception

BACKGROUND: The use of in vitro fertilization is increasing. The incidence of adverse outcomes is greater for women who undergo in vitro fertilization, potentially leading to intensive care unit admission. This study aimed to assess the etiology and course of intensive care unit admission in women who underwent in vitro fertilization compared to those who did not, with specific focus on intensive care unit admission due to postpartum hemorrhage. METHODS: In this retrospective study, medical records of patients admitted to the intensive care unit during pregnancy or the peripartum period at 2 medical centers (2005–2016 at Mount Sinai Hospital, New York, NY, and 2005–2013 at Shaare Zedek Medical Center, Jerusalem, Israel) were analyzed. Demographic, past medical and obstetric history, and details regarding delivery and intensive care unit stay were collected, as was information regarding mode of conception (in vitro fertilization versus non–in vitro fertilization) for the current pregnancy. The primary outcome measure was difference in etiology of intensive care unit admission between in vitro fertilization and non–in vitro fertilization groups. Secondary outcome measures included differences in prepregnancy characteristics, incidence, severity, and management of postpartum hemorrhage, as well as incidence of other clinical major morbidity events and delivery-related complications. Multivariable logistic regression was performed to study the relationship between in vitro fertilization and the odds of having been admitted to the intensive care unit due to hemorrhage. RESULTS: During the study period, there were nearly 192,000 deliveries, with 428 pregnant and peripartum women admitted to the intensive care unit. Of the 409 cases analyzed, 60 had conceived following in vitro fertilization and 349 had conceived without in vitro fertilization. The non–in vitro fertilization group was more likely to have multiple medical comorbidities, and the in vitro fertilization group was more likely to have multiple gestations. The groups also differed in etiology of intensive care unit admission; more women in the in vitro fertilization group were admitted due to a pregnancy-related complication. Intensive care unit admission for postpartum hemorrhage was more frequent in the in vitro fertilization group (60.0% vs 43.1%, P = .014), with a 2-fold increase in the incidence of hemorrhagic shock. Logistic regression analysis revealed a 2-fold increase in the odds that intensive care unit admission was due to hemorrhage in women undergoing in vitro fertilization, a finding that was not statistically significant when multiple gestation was added to the model. CONCLUSIONS: Among patients admitted to the intensive care unit, patients with different modes of conception had dissimilar etiologies for intensive care unit admission with intensive care unit admission due to hemorrhage greater in those with in vitro fertilization. Higher rates of multiple gestation pregnancies may explain this difference. Differences in pregnancies conceived via in vitro fertilization versus without in vitro fertilization may affect the obstetric intensive care unit case mix. Accepted for publication January 2, 2019. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Diana N. Romano, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl, Box 1010 New York, NY 10029. Address e-mail to diana.romano@mountsinai.org. © 2019 International Anesthesia Research Society

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Real-Time Ultrasound Improves Accuracy of Caudal Block in Children

BACKGROUND: Caudal block, the most common regional anesthetic in children, is predominantly performed using palpation to determine placement. The efficacy of the palpation technique is unknown with respect to block success. While ultrasound has been suggested for use during caudal block, its use is infrequent. METHODS: A single-blinded prospective observational trial was performed evaluating provider success rate of caudal blocks placed by palpation alone. After needle insertion and partial local anesthetic injection, an ultrasound was performed to confirm correct location. RESULTS: A total of 109 caudal blocks were performed during the prospective observational study. Success rate for caudal blocks done by palpation alone was 78.9% as confirmed by ultrasound. In 21.1% of caudal blocks, the provider incorrectly judged the needle to be in the caudal space as confirmed with ultrasound. CONCLUSIONS: Real-time ultrasound visualization of local anesthetic injection provides reliable and immediate confirmation during caudal block in children. Accepted for publication January 8, 2019. Funding: Departmental. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). This work was presented in abstract form at the 43rd Annual Regional Anesthesiology and Acute Pain Medicine Meeting, New York, NY, April 21, 2018. Reprints will not be available from the authors. Address correspondence to Adam C. Adler, MD, MS, FAAP, FASE, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin St, Suite #A3300, Houston, TX 77030. Address e-mail to adam.adler@bcm.edu. © 2019 International Anesthesia Research Society

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Hypertonic Saline in Human Sepsis: A Systematic Review of Randomized Controlled Trials

The role of hypertonic saline in sepsis remains unclear because clinical data are limited and the balance between beneficial and adverse effects is not well defined. In this systematic literature review, we searched PubMed and Embase to identify all randomized controlled trials up until January 31, 2018 in which hypertonic saline solutions of any concentration were used in patients of all ages with sepsis and compared to a cohort of patients receiving an isotonic fluid. We identified 8 randomized controlled trials with 381 patients who had received hypertonic saline. Lower volumes of hypertonic saline than of isotonic solutions were needed to achieve the desired hemodynamic goals (standardized mean difference, −0.702; 95% CI, −1.066 to −0.337; P

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Dose–Response Study of 4 Weight-Based Phenylephrine Infusion Regimens for Preventing Hypotension During Cesarean Delivery Under Combined Spinal–Epidural Anesthesia

BACKGROUND: Prophylactic IV infusion of phenylephrine has been recommended to prevent hypotension during spinal anesthesia for cesarean delivery. However, the optimal infusion dose is unknown. This study aimed to determine the infusion dose of phenylephrine that would be effective in preventing hypotension in 50% (ED50) and 90% (ED90) of patients when administered as a prophylactic infusion at a fixed rate based on the individual body weight. METHODS: Eighty parturients scheduled for elective cesarean delivery were randomly allocated to receive IV infusion of prophylactic phenylephrine at 0.25, 0.375, 0.5, or 0.625 µg/kg/min (n = 20 per group) started immediately after intrathecal injection of 10 mg hyperbaric bupivacaine and 5 µg sufentanil using a combined spinal–epidural technique. An effective dose was defined by the occurrence of no hypotension (defined as a decrease in systolic blood pressure by ≥20% below baseline and to

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Road to Perioperative Medicine: A Perspective From China

With the development of anesthesiology, patient safety has been remarkably improved, but the postoperative mortality rate at 30 days is still as high as 0.56%–4%, and the morbidity is even higher. Three years ago, the Chinese Society of Anesthesiology proposed that the direction of the anesthesiology development should be changed to perioperative medicine in China. Anesthesiologists should pay more attention to the long-term outcome. In this article, we introduced what we have done, what the challenges are, and what we should do in the future with regard to the practice of perioperative medicine in China. Accepted for publication January 8, 2019 Funding: This study was partly supported by the National Natural Science Foundation of China (Grant No. 81842018). The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Lize Xiong, MD, PhD, Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China 710032. Address e-mail to mzkxlz@126.com. © 2019 International Anesthesia Research Society

https://ift.tt/2EFe25K

Customizable Curriculum to Enhance Resident Communication Skills

Communication remains challenging to teach and evaluate. We designed an online patient survey to assess anesthesia residents' communication skills from August 2014 to July 2015. In December 2014, we implemented a customized, simulation-based curriculum. We calculated an overall rating for each survey by averaging the ratings for the individual questions. Based on the Hodges–Lehmann 2-sample aligned rank-sum test, overall ratings, reported as the median (interquartile range) of residents' average overall ratings, differed significantly between the preintervention (3.86 [3.76–3.94]) and postintervention (3.91 [3.84–3.95]) periods (P = .025). Future studies should assess the intervention's effectiveness and generalizability. Accepted for publication January 16, 2019. Funding: This study was funded by the Department of Anesthesia, Critical Care and Pain Medicine at Beth Israel Deaconess Medical Center, Boston, MA. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to John D. Mitchell, MD, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, 1 Deaconess Rd, RB-470, Boston, MA 02215. Address e-mail to jdmitche@bidmc.harvard.edu. © 2019 International Anesthesia Research Society

https://ift.tt/2EFTxWJ

Proliferator-Activated Receptor-Gamma Coactivator-1α Haploinsufficiency Promotes Pain Chronification After Burn Injury

BACKGROUND: Tissue injuries such as surgery and trauma are usually accompanied by simultaneous development of acute pain, which typically resolves along with tissue healing. However, in many cases, acute pain does not resolve despite proper tissue repair; rather, it transitions to chronic pain. In this study, we examined whether proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondria biogenesis, is implicated in pain chronification after burn injury in mice. METHODS: We used PGC-1α+/+ and littermates PGC-1α+/− mice of both sex. Burn injury was induced on these mice. Hindpaw mechanical withdrawal thresholds and thermal withdrawal latency were examined. RESULTS: Hindpaw mechanical withdrawal thresholds and thermal withdrawal latencies were comparable at baseline between PGC-1α+/− and PGC-1α+/+ mice. After burn injury, both PGC-1α+/+ and PGC-1α+/− mice exhibited an initial dramatic decrease of withdrawal parameters at days 3 and 5 after injury. While PGC-1α+/+ mice fully recovered their withdrawal parameters to preinjury levels by days 11–14, PGC-1α+/− mice failed to recover those parameters during the same time frame, regardless of sex. Moreover, we found that PGC-1α+/− mice resolved tissue inflammation in a similar fashion to PGC-1α+/+ mice using a chemiluminescence-based reactive oxygen species imaging technique. CONCLUSIONS: Taken together, our data suggest that PGC-1α haploinsufficiency promotes pain chronification after burn injury. Accepted for publication January 16, 2019. J. Miao and X. Zhou contributed equally and share first authorship. The authors declare no conflicts of interest. Funding: J.M. is supported by R01DE02290 and R01DA039925. S.S. is supported by the Foundation of Anesthesia Education and Research, National Institute of General Medical Sciences R35-GM1286928, and research fund from the Department of Anesthesia, Critical Care and Pain Medicine at the Massachusetts General Hospital. Reprints will not be available from the authors. Address correspondence to Shiqian Shen, MD, Department of Anesthesia, Critical Care and Pain Medicine, Center for Translational Pain Research, Massachusetts General Hospital, Harvard Medical School, Jackson Bldg 458, 55 Fruit St, Boston, MA 02121. Address e-mail to sshen2@mgh.harvard.edu. © 2019 International Anesthesia Research Society

https://ift.tt/2EBUO0I

Core Topics in Preoperative Anaesthetic Assessment and Management

No abstract available

https://ift.tt/2EDTaff

Minocycline Relieves Depressive-Like Behaviors in Rats With Bone Cancer Pain by Inhibiting Microglia Activation in Hippocampus

BACKGROUND: Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain. METHODS: Bone cancer pain was induced by injection of Walker 256 mammary gland carcinoma cells into the tibia of rats. The effects of intracerebroventricular administration of microglia inhibitor minocycline were examined. RESULTS: Carcinoma intratibia injection caused comorbidity of mechanical allodynia and depressive-like behaviors in rats and activation of microglia in the hippocampus. Both mechanical allodynia and depressive-like behaviors were attenuated by minocycline. Enzyme-linked immunosorbent assay analysis showed that the enhanced expressions of M1 microglia marker (CD 86) and the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the hippocampus of cancer-bearing rats were decreased by minocycline. On the other hand, minocycline also increased the expressions of M2 microglia marker (MRC1) and anti-inflammatory cytokine interleukin-10. CONCLUSIONS: The results suggest that the activation of microglia in the hippocampus plays an important role in the development of pain and depressive-like behaviors in bone cancer condition. Accepted for publication January 3, 2019. The authors declare no conflicts of interest. Funding: Nature Science Foundation of Hunan Province (2018JJ3836 to S.Z.), National Nature Science Foundation of China (81300958 to S.Z.), and Nature Science Foundation of Hunan Province (S2016J504F2145 to Z.J.). Reprints will not be available from the authors. Address correspondence to Zongbin Song, MD, PhD, Department of Anesthesiology, Xiangya Hospital, Central S. University, Hunan, China. Address e-mail to songzb2001@163.com. © 2019 International Anesthesia Research Society

https://ift.tt/2VtxJCX

Gupta and Gelb’s Essentials of Neuroanesthesia and Neurointensive Care

No abstract available

https://ift.tt/2VtOFcM

Early Treatment With Metformin in a Mice Model of Complex Regional Pain Syndrome Reduces Pain and Edema

BACKGROUND: Metformin, an adenosine monophosphate (AMP)–activated protein kinase activator, as well as a common drug for type 2 diabetes, has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. The objective of this study is to determine if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of complex regional pain syndrome. METHODS: Mice were allocated into distal tibia fracture or nonfracture groups (n = 12 per group). The fracture was stabilized with intramedullary pinning and external casting for 21 days. Animals were then randomized into 4 groups (n = 6 per group): (1) fracture, metformin treated, (2) fracture, saline treated, (3) nonfracture, metformin treated, and (4) nonfracture, saline treated. Mice received daily intraperitoneal injections of metformin 200 mg/kg or saline between days 14 and 21. After cast removal, von Frey force withdrawal (every 3 days) and burrowing (every 7 days) were tested between 25 and 56 days. Paw width was measured for 14 days after cast removal. AMP-activated protein kinase downregulation at 4 weeks after tibia fracture in the dorsal root ganglia was examined by immunohistochemistry for changes in the AMP-activated protein kinase pathway. RESULTS: Metformin injections elevated von Frey thresholds (reduced mechanical allodynia) in complex regional pain syndrome mice versus saline-treated fracture mice between days 25 and 56 (difference of mean area under the curve, 42.5 g·d; 95% CI of the difference, 21.0–63.9; P

https://ift.tt/2ECCHIj

Suppression of Human Natural Killer Cells by Different Classes of Opioids

BACKGROUND: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized. METHODS: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester–labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction. RESULTS: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5]enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells. CONCLUSIONS: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not overserved after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with μ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by μ- and κ-receptor agonism and that suppression is similar with many clinically used opioids. Accepted for publication January 3, 2018. Funding: D.P.M. received funding from the Blaustein Pain Research Fund Grant and National Institutes of Health (NIH) Grant 5T32GM075774. N.M.H. receives funding from NIH Grant R01 HL124477. No copyrighted material from outside sources was used in preparation of this manuscript. This study has not been previously presented. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Dermot P. Maher, MD, MS, Johns Hopkins Blaustein Pain Treatment Center, Johns Hopkins University School of Medicine, 601 N Caroline St, Baltimore, MD 21205. Address e-mail to dmaher3@jhmi.edu. © 2019 International Anesthesia Research Society

https://ift.tt/2VsX1kC

Ultrasound-Guided Erector Spinae Plane Block in Patients Undergoing Open Epigastric Hernia Repair: A Prospective Randomized Controlled Study

BACKGROUND: Hernia repair is associated with considerable postoperative pain. We studied the analgesic efficacy of bilateral ultrasound-guided erector spinae plane block in patients undergoing open midline epigastric hernia repair (T6–T9). METHODS: Sixty patients 18–65 years of age were randomly allocated into 2 groups. Patients in the erector spinae plane block group received bilateral ultrasound-guided erector spinae plane block at the level of T7 transverse process using 20 mL of bupivacaine 0.25% on each side, while the control group received bilateral sham erector spinae plane block using 1 mL of normal saline. All patients underwent general anesthesia for surgery. Pain severity (visual analog scale), consumption of intraoperative fentanyl, time to first request of rescue analgesia, and postoperative pethidine consumption were recorded over the first 24 hours postoperatively. RESULTS: At 2 hours postoperatively, the visual analog scale pain score was significantly lower in the erector spinae plane block group compared to the control group (estimated main effect of 2.53; P

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In Response

No abstract available

https://ift.tt/2VpkByN

Association of Preoperative Frailty With Intraoperative Hemodynamic Instability and Postoperative Mortality

BACKGROUND: Frailty, a state of decreased physiological reserve, is strongly associated with perioperative mortality in older adults. However, the mechanism by which frailty is associated with mortality is not yet understood. Autonomic dysfunction in the form of decreased intraoperative hemodynamic variability has been shown to be associated with increased mortality. We aimed to see whether frail patients have less hemodynamic variability under anesthesia and whether variability mediates the relationship between frailty and 30-day mortality. METHODS: We performed a single-center retrospective study of 1223 patients ≥65 years of age undergoing surgery between July 2008 and December 2012. We used markers of frailty: age >70, preoperative body mass index 2.0 mg/dL. We modeled the outcome of 30-day mortality with number of frailty conditions adjusting for gender, length of surgery, American Society of Anesthesiologists class, and need for transfusion. Intraoperative hemodynamic variability was defined as the count of episodes of absolute change >15% in fractional mean arterial pressure (MAP) between consecutive 5-minute intervals. We evaluated the role of intraoperative hemodynamic variability as a mediator (modifier) of the relationship between frailty and mortality, checking for 3 conditions: (1) frailty must affect episodes of absolute change >15% in fractional MAP; (2) episodes of absolute change >15% in fractional MAP must affect 30-day mortality; and (3) mediation effect is significant. We used the product method, in which the mediation effect was estimated as the product of the first 2 relationships. Then we applied the percentile bootstrap method to obtain the 95% CI for the estimate of mediation effect. RESULTS: Number of frailty conditions and episodes of absolute change >15% in fractional MAP were inversely proportional. Presence of ≥4 frailty conditions was associated with >40% reduction of the number of episodes of absolute change >15% in fractional MAP. Regarding mortality, episodes of absolute change >15% in fractional MAP were protective. The addition of absolute change >15% in fractional MAP in the mortality model resulted in a decrease in the frailty odds ratio from 10.6 to 9.1 (4+ conditions), suggesting that episodes of absolute change >15% in fractional MAP are indeed a mediator. The mediation effect was modest; 5 episodes of absolute change >15% in fractional MAP was 5.2%, 6.4%, 6.9%, and 9.0% for frailty conditions from 1 to 4+, respectively. CONCLUSIONS: Frailty is associated with less intraoperative blood pressure variation, and the relationship of frailty with 30-day mortality is partially mediated by episodes of absolute change >15% in fractional MAP. This suggests that autonomic dysregulation may be a modest part of the mechanism behind the association between frailty and perioperative mortality. Our finding is consistent with recent literature, suggesting that an intact autonomic nervous system confers lower perioperative mortality. Accepted for publication January 16, 2019. Funding: This work was supported by National Institute on Aging (K23 AG17-015; S.G.D.), Optimizing Postoperative Cognition in the Elderly, (American Federation of Aging Beeson Scholar Program; S.G.D.), and the American Federation for Aging Research, Medical Student Training in Aging Research (L.A.J.). Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Stacie G. Deiner, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, c/o S Deiner, Box 1010, 1 Gustave L. Levy Pl, New York, NY 10029. Address e-mail to stacie.deiner@mssm.edu. © 2019 International Anesthesia Research Society

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