Agreement of the Resting Distal to Aortic Coronary Pressure With the Instantaneous Wave-Free Ratio

AbstractBackground

Recently, 2 randomized controlled trials showed that the instantaneous wave-free ratio (iFR), a resting coronary physiological index, is noninferior to fractional flow reserve for guiding revascularization. The resting distal to aortic coronary pressure (P_d/P_a) measured at rest is another adenosine-free index widely available in the cardiac catheterization laboratory; however, little is known about the agreement of P_d/P_a using iFR as a reference standard.

Objectives

The goal of this study was to investigate the agreement of P_d/P_a with iFR.

Methods

A total of 763 patients were prospectively enrolled from 12 institutions. iFR and P_d/P_a were measured under resting conditions. Using iFR ≤0.89 as a reference standard, the agreement of P_d/P_a and its best cutoff value were assessed.

Results

According to the independent core laboratory analysis, iFR and P_d/P_a were analyzable in 627 and 733 patients (82.2% vs. 96.1%; p < 0.001), respectively. The median iFR and P_d/P_a were 0.90 (interquartile range: 0.85 to 0.94) and 0.92 (interquartile range: 0.88 to 0.95), and the 2 indices were highly correlated (R² = 0.93; p < 0.001; iFR = 1.31 * P_d/P_a –0.31). According to the receiver-operating characteristic curve analysis, P_d/P_a showed excellent agreement (area under the curve: 0.98; 95% confidence interval: 0.97 to 0.99; p < 0.001) with a best cutoff value of P_d/P_a ≤0.91. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 93.0%, 91.4%, 94.4%, 93.3%, and 92.7%, respectively. These results were similar in patients with acute coronary syndrome and stable angina.

Conclusions

P_d/P_a was analyzable in a significantly higher number of patients than iFR. P_d/P_a showed excellent agreement with iFR, suggesting that it could be applied clinically in a similar fashion. (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology? [CONTRAST]; NCT02184117)

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JACC Instructions for Authors

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Similarity and Difference of Resting Distal to Aortic Coronary Pressure and Instantaneous Wave-Free Ratio

AbstractBackground

Instantaneous wave-free ratio (iFR) has been used in clinical practice to identify functionally significant stenosis and to guide treatment strategy. However, there are limited clinical data regarding another resting pressure-derived index, resting distal to aortic coronary pressure (Pd/Pa), and similarities and differences between resting Pd/Pa and iFR.

Objectives

The authors investigated the changes in resting Pd/Pa and iFR according to anatomic and hemodynamic stenosis severity and their prognostic implications.

Methods

From the 3V FFR-FRIENDS (Clinical Implication of 3-vessel Fractional Flow Reserve) and the IRIS-FFR (Study of the Natural History of FFR Guided Percutaneous Coronary Intervention) studies, 1,024 vessels (n = 435) with available pre-intervention resting Pd/Pa and iFR were used to explore the changes in resting physiological indices according to percent diameter stenosis. Among 115 patients who underwent ¹³N-ammonia positron emission tomography, the changes in those indices according to basal and hyperemic stenosis resistance and absolute hyperemic myocardial blood flow were compared. The association between physiological indices and the risk of 2-year major adverse cardiac events (MACE) (a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization) were analyzed among 375 deferred patients.

Results

There was a significant linear correlation between resting Pd/Pa and iFR (R = 0.970; p < 0.001, iFR = 1.370 x resting Pd/Pa – 0.370). Both resting Pd/Pa and iFR changed significantly according to percent diameter stenosis, basal and hyperemic stenosis resistance, and hyperemic absolute myocardial blood flow (all p values <0.001). Percent difference of iFR according to the increase in anatomic and hemodynamic severity was higher than that of resting Pd/Pa. Both resting Pd/Pa and iFR showed a significant association with the risk of 2-year MACE (resting Pd/Pa hazard ratio [per 0.10 increase]: 0.480; 95% confidence interval: 0.250 to 0.923; p = 0.027; iFR hazard ratio [per 0.1 increase]: 0.586; 95% confidence interval: 0.373 to 0.919; p = 0.020) in deferred patients. However, the difference between the upper- and lower-bound estimated MACE rates according to the approximate measurement variability of each index was significantly higher with resting Pd/Pa compared with iFR (resting Pd/Pa 3.85 ± 4.00% and iFR 3.27 ± 3.39%; p < 0.001).

Conclusions

Both resting Pd/Pa and iFR showed similar associations with anatomic and hemodynamic stenosis severity and the risk of MACE. However, iFR was more sensitive to the difference in stenosis severity and showed a lower maximum difference in estimated MACE risk influenced by the measurement variability compared with resting Pd/Pa. (Clinical Implication of 3-Vessel Fractional Flow Reserve [3V FFR-FRIENDS]; NCT01621438; and Study of the Natural History of FFR Guided Percutaneous Coronary Intervention [IRIS-FFR]; NCT01366404)

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Cardiovascular Medicine Amid Evolving Health Policy: Time to Train a Generation of Policy Leaders

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Agreement and Differences Among Resting Coronary Physiological Indices: Are All Things Equal?

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The Optimal Duration of Dual-Antiplatelet Therapy After Coronary Stenting: Shorter or Longer?

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The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis

AbstractBackground

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression.

Objectives

The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF).

Methods

The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores.

Results

This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance.

Conclusions

The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

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The Com-PLEC-sity of Atrial Fibrillation Genetics

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Cholesterol and Heart Failure: Is There an Important Connection?

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Biological Phenotypes of Heart Failure With Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) involves multiple pathophysiological mechanisms, which result in the heterogeneous phenotypes that are evident clinically, and which have potentially confounded previous HFpEF trials. A greater understanding of the in vivo human processes involved, and in particular, which are the causes and which are the downstream effects, may allow the syndrome of HFpEF to be distilled into distinct diagnoses based on the underlying biology. From this, specific interventions can follow, targeting individuals identified on the basis of their biological phenotype. This review describes the biological phenotypes of HFpEF and therapeutic interventions aimed at targeting these phenotypes.

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Renal Sympathetic Denervation Protects the Failing Heart Via Inhibition of Neprilysin Activity in the Kidney

AbstractBackground

Sustained sympathetic activation contributes to the progression of myocardial cell injury, cardiac fibrosis, and left ventricular (LV) dysfunction in heart failure (HF).

Objectives

This study investigated the effects of radiofrequency renal nerve denervation (RF-RDN) on the pathobiology of HF and the interaction between the renal sympathetic nerves and natriuretic peptide (NP) metabolism.

Methods

Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 45 min of coronary artery ligation and reperfusion for 12 weeks. At 4 weeks post-reperfusion, SHR and WKY underwent either bilateral RF-RDN or sham-RDN.

Results

Following RF-RDN in both strains, LV ejection fraction remained significantly above those levels in respective sham-RDN rats, and at the end of the 12-week study, rats in both strains had significantly reduced LV fibrosis and improved vascular function. RF-RDN therapy significantly improved vascular reactivity to endothelium-dependent and -independent vasodilators as well as vascular compliance in the setting of severe HF. Improvements in LV function were accompanied by significant elevations in circulating NP as compared to those associated with sham-RDN. Further investigation into the cause of increased circulating NP levels demonstrated that RF-RDN significantly inhibited renal neprilysin activity in SHR and WKY with HF. Likewise, chronic treatment with the beta₁ antagonist bisoprolol inhibited renal neprilysin activity and increased circulation NP levels in WKY with HF.

Conclusions

This study identifies a novel endogenous pathway by which the renal nerves participate in the degradation of cardioprotective NP. Furthermore, removal of the influence of the renal nerves on kidney function attenuates renal neprilysin activity, augments circulating NP levels, reduces myocardial fibrosis, and improves LV function in the setting of HF.

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Arterial Dissection as a Cause of Intracranial Stenosis in East Asians

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Neprilysin and Heart Failure: A "Sympathetic" Relationship?

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Reply: New Criteria for LVH Should Be Evaluated Against Age

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A Missense Variant in PLEC Increases Risk of Atrial Fibrillation

AbstractBackground

Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4.

Objectives

The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements.

Methods

The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals.

Results

The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 x 10^–18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 x 10^–10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive.

Conclusions

The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF.

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Reply: The Optimal Duration of Dual-Antiplatelet Therapy After Coronary Stenting: Shorter or Longer?

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Infantile Myofibroma of the Carotid Space Presenting as Horner Syndrome.

No abstract available

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Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review

Abstract

Purpose

Sex hormones play a role in bone density, cardiovascular health, and wellbeing throughout reproductive lifespan. Women with primary ovarian insufficiency (POI) have lower estrogen levels requiring hormone therapy (HT) to manage symptoms and to protect against adverse long-term health outcomes. Yet, the effectiveness of HT in preventing adverse outcomes has not been systematically assessed. We summarize the evidence regarding effects of HT on bone and cardiovascular health in women with POI.

Methods

A comprehensive search of the electronic databases MEDLINE, EMBASE, and Scopus was conducted by a medical reference librarian from database inception to January 2016. Randomized trials and observational cohort studies with an estrogen-based HT intervention in women with POI under the age of 40 were included. Reviewers worked independently and in duplicate to assess eligibility and risk of bias, and extract data of interest from each study.

Results

The search identified 1670 articles; 12 met inclusion criteria. Four randomized clinical trials and eight cohort studies at high risk of bias enrolled 806 women with POI. The most common HT formulations were transdermal estradiol and oral conjugated equine estrogen combined with medroxyprogesterone acetate. Bone mineral density was the most frequent outcome, with three out of eight studies showing HT associated increase benefits. Only one study reported effects on fractures or vasomotor symptoms and none on cardiovascular mortality. Results regarding lipid profiles were inconsistent.

Conclusions

Evidence supporting bone and cardiovascular benefits of HT in women with POI is limited by high risk of bias, reliance on surrogate outcomes, and heterogeneity of trials regarding the formulation, dose, route of administration, and regimen of HT. Further research addressing patient important outcomes such as fractures, stroke, and cardiovascular mortality are crucial to optimize benefits of this therapy.

http://ift.tt/2yta5yt

Heritability of Addison’s disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins

Abstract

Purpose

The pathophysiology behind autoimmune Addison's disease (AAD) is poorly understood, and the relative influence of genetic and environmental factors remains unclear. In this study, we examined the heritability of AAD and explored disease-associated autoimmune comorbidity among Swedish twins.

Methods

A population-based longitudinal cohort of 112,100 Swedish twins was used to calculate the heritability of AAD, and to explore co-occurrence of 10 organ-specific autoimmune disorders in twin pairs with AAD. Diagnoses were collected 1964–2012 through linkage to the Swedish National Patient Register. The Swedish Prescribed Drug Register was used for additional diagnostic precision. When available, biobank serum samples were used to ascertain the AAD diagnosis through identification of 21-hydroxylase autoantibodies.

Results

We identified 29 twins with AAD. Five out of nine (5/9) monozygotic pairs and zero out of fifteen (0/15) dizygotic pairs were concordant for AAD. The probandwise concordance for monozygotic twins was 0.71 (95% CI 0.40–0.90) and the heritability 0.97 (95% CI 0.88–99). Autoimmune disease patterns of monozygotic twin pairs affected by AAD displayed a higher degree of similarity than those of dizygotic twins, with an incidence rate ratio of 15 (95% CI 1.8–116) on the number of shared autoimmune diagnoses within pairs.

Conclusions

The heritability of AAD appears to be very high, emphasizing the need for further research on the genetic etiology of the disease. Monozygotic twin concordance for multiple autoimmune manifestations suggests strong genetic influence on disease specificity in organ-specific autoimmunity.

http://ift.tt/2gm5GXo

Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review

Abstract

Purpose

Sex hormones play a role in bone density, cardiovascular health, and wellbeing throughout reproductive lifespan. Women with primary ovarian insufficiency (POI) have lower estrogen levels requiring hormone therapy (HT) to manage symptoms and to protect against adverse long-term health outcomes. Yet, the effectiveness of HT in preventing adverse outcomes has not been systematically assessed. We summarize the evidence regarding effects of HT on bone and cardiovascular health in women with POI.

Methods

A comprehensive search of the electronic databases MEDLINE, EMBASE, and Scopus was conducted by a medical reference librarian from database inception to January 2016. Randomized trials and observational cohort studies with an estrogen-based HT intervention in women with POI under the age of 40 were included. Reviewers worked independently and in duplicate to assess eligibility and risk of bias, and extract data of interest from each study.

Results

The search identified 1670 articles; 12 met inclusion criteria. Four randomized clinical trials and eight cohort studies at high risk of bias enrolled 806 women with POI. The most common HT formulations were transdermal estradiol and oral conjugated equine estrogen combined with medroxyprogesterone acetate. Bone mineral density was the most frequent outcome, with three out of eight studies showing HT associated increase benefits. Only one study reported effects on fractures or vasomotor symptoms and none on cardiovascular mortality. Results regarding lipid profiles were inconsistent.

Conclusions

Evidence supporting bone and cardiovascular benefits of HT in women with POI is limited by high risk of bias, reliance on surrogate outcomes, and heterogeneity of trials regarding the formulation, dose, route of administration, and regimen of HT. Further research addressing patient important outcomes such as fractures, stroke, and cardiovascular mortality are crucial to optimize benefits of this therapy.

http://ift.tt/2yta5yt

Heritability of Addison’s disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins

Abstract

Purpose

The pathophysiology behind autoimmune Addison's disease (AAD) is poorly understood, and the relative influence of genetic and environmental factors remains unclear. In this study, we examined the heritability of AAD and explored disease-associated autoimmune comorbidity among Swedish twins.

Methods

A population-based longitudinal cohort of 112,100 Swedish twins was used to calculate the heritability of AAD, and to explore co-occurrence of 10 organ-specific autoimmune disorders in twin pairs with AAD. Diagnoses were collected 1964–2012 through linkage to the Swedish National Patient Register. The Swedish Prescribed Drug Register was used for additional diagnostic precision. When available, biobank serum samples were used to ascertain the AAD diagnosis through identification of 21-hydroxylase autoantibodies.

Results

We identified 29 twins with AAD. Five out of nine (5/9) monozygotic pairs and zero out of fifteen (0/15) dizygotic pairs were concordant for AAD. The probandwise concordance for monozygotic twins was 0.71 (95% CI 0.40–0.90) and the heritability 0.97 (95% CI 0.88–99). Autoimmune disease patterns of monozygotic twin pairs affected by AAD displayed a higher degree of similarity than those of dizygotic twins, with an incidence rate ratio of 15 (95% CI 1.8–116) on the number of shared autoimmune diagnoses within pairs.

Conclusions

The heritability of AAD appears to be very high, emphasizing the need for further research on the genetic etiology of the disease. Monozygotic twin concordance for multiple autoimmune manifestations suggests strong genetic influence on disease specificity in organ-specific autoimmunity.

http://ift.tt/2gm5GXo

Dynamics of rectal balloon implant shrinkage in prostate VMAT

Abstract

Purpose

To assess the effect of a shrinking rectal balloon implant (RBI) on the anorectal dose and complication risk during the course of moderately hypofractionated prostate radiotherapy.

Methods

In 15 patients with localized prostate cancer, an RBI was implanted. A weekly kilovolt cone-beam computed tomography (CBCT) scan was acquired to measure the dynamics of RBI volume and prostate–rectum separation. The absolute anorectal volume encompassed by the 2 Gy equieffective 75 Gy isodose (V_75Gy) was recalculated as well as the mean anorectal dose. The increase in estimated risk of grade 2–3 late rectal bleeding (LRB) between the start and end of treatment was predicted using nomograms. The observed acute and late toxicities were evaluated.

Results

A significant shrinkage of RBI volumes was observed, with an average volume of 70.4% of baseline at the end of the treatment. Although the prostate–rectum separation significantly decreased over time, it remained at least 1 cm. No significant increase in V_75Gy of the anorectum was observed, except in one patient whose RBI had completely deflated in the third week of treatment. No correlation between mean anorectal dose and balloon deflation was found. The increase in predicted LRB risk was not significant, except in the one patient whose RBI completely deflated. The observed toxicities confirmed these findings.

Conclusions

Despite significant decrease in RBI volume the high-dose rectal volume and the predicted LRB risk were unaffected due to a persistent spacing between the prostate and the anterior rectal wall.

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Acute Rupture of the Left Common Iliac Artery After Sigmoid Diverticulitis

Publication date: Available online 16 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Romina Frey, Vladimir Makaloski




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Increased Peak Wall Stress, but Not Maximum Diameter, Is Associated with Symptomatic Abdominal Aortic Aneurysm

Publication date: Available online 16 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Begoña Soto, Luis Vila, Jaime F. Dilmé, Jose R. Escudero, Sergi Bellmunt, Mercedes Camacho
ObjectiveMaximum diameter (MD) is the established rupture predictor for abdominal aortic aneurysm (AAA). However, biomechanical markers from finite element analysis (FEA) could be more accurate predictors for these patients. In this study, the association between peak wall stress (PWS) and MD with symptoms of AAA was evaluated.MethodsPatients diagnosed with infrarenal non-ruptured AAA at the centre between 2009 and 2015 were included. Clinical data, morphological variables (including MD), and the biomechanical variables PWS and diameter normalised PWS (dnPWS) in symptomatic (sAAA) and asymptomatic AAA patients (aAAA) were included.ResultsA total of 170 patients were analysed, 153 aAAA and 17 sAAA. MD was significantly greater in sAAA patients than in aAAA patients (70.4 mm, 95% CI 66.4–86.0 vs. 59.1 mm, 95% CI 53.7–67.8, respectively; p = .002). PWS was also significantly higher in the sAAA group (324.6 kPa, 95% CI 217.4–399.5 vs. 199.2 kPa, 95% CI 165.6–239.5; p < .01). No differences in MD were found in patients with an AAA ≥ 65 mm (43 aAAA and 14 sAAA); however, both PWS (327.4 kPa, 95% CI 239.0–473.3 vs. 229.4 kPa, 95% CI 210.0 to 289.4; p = .020) and dnPWS (4.3, 95% CI 3.17–4.67 vs. 3.03, 95% CI 2.8–3.49; p = .004) were higher in sAAA than in aAAA.ConclusionsThis study suggests that MD and the biomechanical parameters obtained by finite element analysis are greater in sAAA than in aAAA. However, considering patients with MD ≥ 65 mm alone, only PWS, and particularly dnPWS, were able to differentiate sAAA from aAAA.



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Effect of amount and duration of waste green tea powder on the growth performance, carcass characteristics, blood parameters, and lipid metabolites of growing broilers

Abstract

This study has evaluated the possible effect of waste powder of green tea (Camellia sinensis) in feed supplementation on the growth performance, carcass characteristics, blood parameters, and lipid metabolites of growing broilers (chicks) in both the amount and duration aspects of dietary additives during the finisher phases. In the experiment, growth performance, carcass characteristics, blood parameters, and lipid metabolites of broiler chicks have been fully recorded and explored. The diet of 271 day-old Ross 308 male broiler chicks has been supplemented with 0, 0.25, 0.50, 0.75, and 1.00% (w/w) green tea powder in addition to normal feeding additives. The experiment lasted for 21 and 42 days, respectively, for each value of the green tea supplement and for separate groups of animals. Broiler feed has been supplemented with different levels of green tea powder to assess the trial effect and potential beneficial dose on selected growth performance, carcass characteristics, and blood parameters of broiler chicks. Although there are almost no differences of broiler parameters and characteristics measured from one point of view of single treatment factor (amount or duration), against the control groups during the three trial periods, the overall effect of amount and duration of feeding green tea powder is positive on growth performance, carcass characteristics, blood parameters, and lipid metabolites of growing broilers, although there are nearly no differences in some broiler parameters and characteristics. However, there are a remarkable interactive effect of amount and duration of different feeding levels of green tea powder and obvious differences observed in all the parameters and characteristics of growing broilers. Especially, usage of feeding green tea powder largely decreased the abdominal fat content and some lipid metabolites, including VLDL cholesterol, LDL cholesterol, triglycerides, and AST of broiler chicks. While additional data are still needed to evaluate and analyze the optimum supplement feed doses, it can be concluded that dietary green tea is a positive feed supplementation to reduce abdominal fat and lipid metabolites and induce antioxidants.

http://ift.tt/2gJqdlB

DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile

Publication date: Available online 16 October 2017
Source:Clinical Immunology
Author(s): Waleed Al-Herz, Michel J. Massaad, Janet Chou, Luigi D. Notarangelo, Raif S. Geha
Defects in DNA Recombination due to mutations in RAG1/2 or DCLRE1C result in combined immunodeficiency (CID) with a range of disease severity. We present the clinical, immunologic and molecular characteristics of 21 patients with defects in RAG1, RAG2 or DCLRE1C, who accounted for 24% of combined immune deficiency cases in the Kuwait National Primary Immunodeficiency Disorders Registry. The distribution of the patients was as follow: 8 with RAG1 deficiency, 6 with RAG2 deficiency and 7 with DCLRE1C deficiency. Nine patients presented with SCID, 6 with OS, 2 with leaky SCID and 4 with CID and granuloma and/or autoimmunity (CID-G/AI). Eight patients [(7 SCID and 1 OS) (38%)] received hematopoietic stem cell transplant (HSCT). The median age of HSCT was 11.5months and the median time from diagnosis to HSCT was 6months. Fifty percent of the transplanted patients are alive while only 23% of the untransplanted ones are alive.



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Cosmetics, Vol. 4, Pages 40: Sea Buckthorn Oil—A Valuable Source for Cosmeceuticals

Cosmetics, Vol. 4, Pages 40: Sea Buckthorn Oil—A Valuable Source for Cosmeceuticals

Cosmetics doi: 10.3390/cosmetics4040040

Authors: Marijana Koskovac Snezana Cupara Mihailo Kipic Ana Barjaktarevic Olivera Milovanovic Ksenija Kojicic Marija Markovic

Sea buckthorn (Hippophae rhamnoides L., Elaeagnaceae.) is a thorny shrub that has small, yellow to dark orange, soft, juicy berries. Due to hydrophilic and lipophilic ingredients, berries have been used as food and medicine. Sea buckthorn (SB) oil derived from berries is a source of valuable ingredients for cosmeceuticals. The unique combination of SB oil ingredients, in qualitative and quantitative aspects, provides multiple benefits of SB oil for internal and external use. Externally, SB oil can be applied in both healthy and damaged skin (burns or skin damage of different etiology), as it has good wound healing properties. Due to the well-balanced content of fatty acids, carotenoids, and vitamins, SB oil may be incorporated in cosmeceuticals for dry, flaky, burned, irritated, or rapidly ageing skin. There have been more than 100 ingredients identified in SB oil, some of which are rare in the plant kingdom (e.g., the ratio of palmitoleic to γ-linolenic acid). This review discusses facts related to the origin and properties of SB oil that make it suitable for cosmeceutical formulation.

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Nicotinamide for prevention of nonmelanoma skin cancers: a change in practice?

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MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism

Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized.

http://ift.tt/2yt7lAZ

Cardiovascular manifestations of primary hyperparathyroidism: a narrative review

Data on cardiovascular disease in primary hyperparathyroidism (PHPT) are controversial; indeed, at present, cardiovascular involvement is not included among the criteria needed for parathyroidectomy. Aim of this narrative review is to analyze the available literature in an effort to better characterize cardiovascular involvement in PHPT. Due to physiological effects of both parathyroid hormone (PTH) and calcium on cardiomyocyte, cardiac conduction system, smooth vascular, endothelial and pancreatic beta cells, a number of data have been published regarding associations between symptomatic and mild PHPT with hypertension, arrhythmias, endothelial dysfunction (an early marker of atherosclerosis), glucose metabolism impairment and metabolic syndrome. However, the results, mainly derived from observational studies, are inconsistent. Furthermore, parathyroidectomy resulted in conflicting outcomes, which may be linked to several potential biases. In particular, differences in the methods utilized for excluding confounding co-existing cardiovascular risk factors together with differences in patient characteristics, with varying degrees of hypercalcemia, may have contributed to these discrepancies. The only meta-analysis carried out in PHPT patients, revealed a positive effect of parathyroidectomy on left ventricular mass index (a predictor of cardiovascular mortality) and more importantly, that the highest pre-operative PTH levels were associated with the greatest improvements. In normocalcemic PHPT, it has been demonstrated that cardiovascular risk factors are almost similar compared to hypercalcemic PHPT, thus strengthening the role of PTH in the cardiovascular involvement. Long-term longitudinal randomized trials are needed to determine the impact of parathyroidectomy on cardiovascular diseases and mortality in PHPT.

http://ift.tt/2yN29Jh

Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass

Objective

Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.

Methods

We studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.

Results

We found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.

Conclusion

An early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.

http://ift.tt/2yu6uAf

DIAGNOSIS OF ENDOCRINE DISEASE: Primary empty sella: a comprehensive review

Primary empty sella (PES) is characterized by the herniation of the subarachnoid space within the sella, which is often associated with variable degrees of flattening of the pituitary gland in patients without previous pituitary pathologies. PES pathogenetic mechanisms are not well known but seem to be due to a sellar diaphragm incompetence, associated to the occurrence of upper sellar or pituitary factors, as intracranial hypertension and change of pituitary volume. As PES represents in a majority of cases, a neuroradiological findings without any clinical implication, the occurrence of endocrine, neurological and opthalmological symptoms, due to the above describes anatomical alteration, which delineates from the so called PES syndrome. Headache, irregular menses, overweight/obesity and visual disturbances compose the typical picture of PES syndrome and can be the manifestation of an intracranial hypertension, often associated with PES. Although hyperprolactinemia and growth hormone deficit represent the most common endocrine abnormalities, PES syndrome is characterized by heterogeneity both in clinical manifestation and hormonal alterations and can sometime reach severe extremes, as occurrence of papilledema, cerebrospinal fluid rhinorrhea and worsening of visual acuity. Consequently, a multidisciplinary approach, with the integration of endocrine, neurologic and ophthalmologic expertise, is strongly advocated and recommended for a properly diagnosis, management, treatment and follow-up of PES syndrome and all of the related abnormalities.

http://ift.tt/2yMThTR

Inflammatory infiltrates in parathyroid tumors

Context

Inflammatory infiltrates are sometimes present in solid tumors and may be coupled to clinical behavior or etiology. Infectious viruses contribute to tumorigenesis in a significant fraction of human neoplasias.

Objective

Characterize inflammatory infiltrates and possible viral transcription in primary hyperparathyroidism.

Design

From the period 2007 to 2016, a total of 55 parathyroid tumors (51 adenomas and 4 hyperplasias) with prominent inflammatory infiltrates were identified from more than 2000 parathyroid tumors in the pathology archives, and investigated by immunohistochemistry for CD4, CD8, CD20 and CD45 and scored as +0, +1 or +2. Clinicopathological data were compared to 142 parathyroid adenomas without histological evidence of inflammation. Transcriptome sequencing was performed for 13 parathyroid tumors (four inflammatory, 9 non-inflammatory) to identify potential viral transcripts.

Results

Tumors had prominent germinal center-like nodular (+2) lymphocytic infiltrates consisting of T and B lymphocytes (31%) and/or diffuse (+1–2) infiltrates of predominantly CD8+ T lymphocytes (84%). In the majority of cases with adjacent normal parathyroid tissue, the normal rim was unaffected by the inflammatory infiltrates (96%). Presence of inflammatory infiltrates was associated with higher levels of serum-PTH (P = 0.007) and oxyphilic differentiation (P = 0.002). Co-existent autoimmune disease was observed in 27% of patients with inflammatory infiltrates, which in turn was associated with oxyphilic differentiation (P = 0.041). Additionally, prescription of anti-inflammatory drugs was associated with lower serum ionized calcium (P = 0.037).

Conclusions

No evidence of virus-like sequences in the parathyroid tumors could be found by transcriptome sequencing, suggesting that other factors may contribute to attract the immune system to the parathyroid tumor tissue.

http://ift.tt/2ytYor0

5 years later: irisin detection still an issue

http://ift.tt/2yN1Luj

Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer

Objective

Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer (FTC) over time have not been reported. Moreover, the prognostic effects of RAS and TERT promoter mutations in FTC have not been clearly elucidated. We investigated changes in the clinicopathological characteristics of patients with FTC over four decades, as well as the clinical significance of genetic mutations of FTC.

Design and methods

This retrospective study included 690 patients with FTC who underwent thyroidectomy between 1973 and 2015 at the Seoul National University Hospital. In 134 samples, genetic tests for N/H/KRAS and TERT promoter mutations and PAX8/PPAR rearrangement were performed.

Results

The age at diagnosis has increased (P < 0.001) in recent decades and extrathyroidal extension of the tumor has become less common (P = 0.033). Other clinicopathological characteristics and prognosis of FTC have not significantly changed. The prevalence of RAS mutations decreased (P = 0.042) over time, whereas that of TERT promoter mutations remained stable. RAS mutations were associated with distant metastasis and persistent disease, and TERT promoter mutations were associated with distant metastasis, advanced TNM stage, recurrence and disease-specific mortality. FTC patients with coexistent RAS and TERT promoter mutations showed a higher recurrence risk than those with only one mutation.

Conclusions

The age at diagnosis of FTC and the frequency of extrathyroidal extension have changed over four decades. Moreover, the prevalence of RAS mutations decreased. RAS and TERT promoter mutations may be associated with poor clinical outcomes in FTC, especially when the two mutations coexist.

http://ift.tt/2ytnJl2

The roles and applications of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours

Publication date: Available online 16 October 2017
Source:Autoimmunity Reviews
Author(s): Jing Wu, Xiaobo Li, Wuqi Song, Yong Fang, Li Yu, Siyuan Liu, Leonid P. Churilov, Fengmin Zhang
The existence of autoantibodies towards an individual's own proteins or nucleic acids has been established for more than 100years, and for a long period, these autoantibodies have been believed to be closely associated with autoimmune diseases. However, in recent years, researchers have become more interested in the role and application of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Over the past few decades, numerous epidemiological studies have shown that the risk of certain cancers is significantly altered (increased or decreased) in patients with autoimmune diseases, which suggests that autoantibodies may play either promoting or suppressing roles in cancer progression. The idea that autoantibodies are directly involved in tumour progression gains special support by the findings that some antibodies secreted by a variety of cancer cells can promote their proliferation and metastasis. Because the cancer cells generate cell antigenic changes (neoantigens), which trigger the immune system to produce autoantibodies, serum autoantibodies against tumour-associated antigens have been established as a novel type of cancer biomarkers and have been extensively studied in different types of cancer. The autoantibodies as biomarkers in cancer diagnosis are not only more sensitive and specific than antigens, but also could appear before clinical evidences of the tumours, thus disclosing them. The observations that cancer risk is lower in patients with some autoimmune diseases suggest that certain autoantibodies may be protective from certain cancers. Moreover, the presence of autoantibodies in healthy individuals implies that it could be safe to employ autoantibodies to treat cancer. Of note, an autoantibodies derived from lupus murine model received much attention due to their selective cytotoxicity for malignant tumour cell without harming normal ones. These studies showed the therapeutic value of autoantibodies in cancer. In this review, we revisited the pathological or protective role of autoantibodies in cancer progression, summarize the application of autoantibodies in cancer diagnosis and prognosis, and discuss the value of autoantibodies in cancer therapy. The studies established to date suggest that autoantibodies not only regulate cancer progression but also promise to be valuable instruments in oncological diagnosis and therapy.



http://ift.tt/2x0a0if

Le régime d’indemnisation par l’État des dommages résultant des vaccinations obligatoires et des vaccinations recommandées en Italie et en France : profils historiques, éthiques, médicaux, normatifs et jurisprudentiels

Publication date: Available online 16 October 2017
Source:Médecine & Droit
Author(s): Flavio Tovani, Nicola Luigi Bragazzi, Mariano Martini
La mise en place d'un régime obligatoire de vaccination permet de lutter contre des virus qui, dans le passé, ont fait des millions de victimes. Aussi, nombreuses sont les campagnes d'incitation promouvant la réalisation d'un tel acte, lequel participe de l'objectif de promotion du droit à la santé. En Italie, aux termes de l'article 32 de la Constitution, le droit à la santé constitue à la fois un « droit fondamental de l'individu » et un « intérêt de la collectivité » que les pouvoirs publics sont en charge de promouvoir. En France, le préambule de la Constitution de 1946 « garantit à tous, notamment à l'enfant, à la mère et aux vieux travailleurs, la protection de la santé ». La réalisation effective de ce droit trouve néanmoins une limite dans l'existence d'un risque d'effets indésirables, voire négatifs sur certaines personnes soumises à vaccination. En pratique peu fréquents, l'existence de risques liés à au régime des vaccinations obligatoires a amené législateurs et juges constitutionnels à la mise en place d'un système d'indemnisation au profit des victimes. Initialement portant exclusivement sur le régime des vaccinations obligatoires, ce mécanisme a été étendu aux victimes de vaccinations conseillées, participant d'une démarche de responsabilisation accrue des individus.The introduction of a compulsory vaccination regime makes it possible to fight against viruses and pathogens which in the past have caused millions of victims. Many incentive campaigns promote the realization of such an act, which is part of the objective of promoting the right to health. In Italy, under article 32 of the Constitution, the right to health is both a "fundamental right of the individual" and an "interest of the community" which the public authorities are responsible for promoting. In France, the preamble to the 1946 Constitution "guarantees the protection of health to all, including children, mothers and old workers". The actual realization of this right nevertheless has a limit in the existence of a risk of adverse or even negative effects on certain persons subjected to vaccination. In practice, infrequent, the existence of risks linked to the system of mandatory vaccinations has led legislators and constitutional judges to set up a system of compensation for the victims. Initially focusing exclusively on the system of mandatory vaccinations, this mechanism was extended to the victims of vaccinations advised, participating in a process of increased responsibility of individuals.



http://ift.tt/2zdSQ1l

Malignant PEComa

We report a metastasizing PEComa in a pregnant 41-year-old female who had initially presented at her dermatologist during the first trimester of pregnancy with a newly developed indolent, slowly growing dermatofibroma-like tumor on the back of the left thigh. During pregnancy and after parturition, the lesion considerably progressed in size (Fig.1); tumor excision was performed 14 months after initial presentation.

http://ift.tt/2ierLb2

Adiponectin circulating levels and 10-year (2002–2012) cardiovascular disease incidence: the ATTICA Study

Abstract

Purpose

Adiponectin is an adipokine with anti-inflammatory and cardiovascular-protective properties. Existing epidemiological evidence is conflicting on the exact relationship between adiponectin and long-term cardiovascular disease (CVD) risk. Our aim was to prospectively assess whether circulating adiponectin is associated with long-term incident CVD.

Methods

A population-based, prospective study in adults (>18 years) without previous CVD history (ATTICA study). Circulating total adiponectin levels were measured at baseline (2001–2002) in a sub-sample (n = 531; women/men: 222/309; age: 40 ± 11 years) of the ATTICA cohort and complete 10-year follow-up data were available in 366 of these participants (women/men: 154/212; age: 40 ± 12 years).

Results

After adjusting for multiple factors, including age, sex, body mass index, waist circumference, smoking, physical activity, Mediterranean diet adherence, hypertension, diabetes, and hypercholesterolemia, our logistic regression analysis indicates that an increase in circulating total adiponectin levels by 1 unit was associated with 36% lower CVD risk (relative risk [RR]: 0.64, 95% confidence interval [CI] 0.42–0.96; p = 0.03). Further adjusting for interleukin-6 plasma levels had no significant impact (RR: 0.60, 95% CI 0.38–0.94; p = 0.03), while additional adjustment for circulating C-reactive protein (CRP) modestly attenuated this association (RR: 0.63, 95% CI 0.40–0.99; p = 0.046).

Conclusions

In our study, elevated circulating total adiponectin levels were associated with lower 10-year CVD risk in adults without previous CVD, independently of other established CVD risk factors. This association appeared to be modestly attenuated by CRP, yet was not mediated by interleukin-6 which is the main endocrine/circulating pro-inflammatory cytokine.

http://ift.tt/2gn94RS

Adiponectin circulating levels and 10-year (2002–2012) cardiovascular disease incidence: the ATTICA Study

Abstract

Purpose

Adiponectin is an adipokine with anti-inflammatory and cardiovascular-protective properties. Existing epidemiological evidence is conflicting on the exact relationship between adiponectin and long-term cardiovascular disease (CVD) risk. Our aim was to prospectively assess whether circulating adiponectin is associated with long-term incident CVD.

Methods

A population-based, prospective study in adults (>18 years) without previous CVD history (ATTICA study). Circulating total adiponectin levels were measured at baseline (2001–2002) in a sub-sample (n = 531; women/men: 222/309; age: 40 ± 11 years) of the ATTICA cohort and complete 10-year follow-up data were available in 366 of these participants (women/men: 154/212; age: 40 ± 12 years).

Results

After adjusting for multiple factors, including age, sex, body mass index, waist circumference, smoking, physical activity, Mediterranean diet adherence, hypertension, diabetes, and hypercholesterolemia, our logistic regression analysis indicates that an increase in circulating total adiponectin levels by 1 unit was associated with 36% lower CVD risk (relative risk [RR]: 0.64, 95% confidence interval [CI] 0.42–0.96; p = 0.03). Further adjusting for interleukin-6 plasma levels had no significant impact (RR: 0.60, 95% CI 0.38–0.94; p = 0.03), while additional adjustment for circulating C-reactive protein (CRP) modestly attenuated this association (RR: 0.63, 95% CI 0.40–0.99; p = 0.046).

Conclusions

In our study, elevated circulating total adiponectin levels were associated with lower 10-year CVD risk in adults without previous CVD, independently of other established CVD risk factors. This association appeared to be modestly attenuated by CRP, yet was not mediated by interleukin-6 which is the main endocrine/circulating pro-inflammatory cytokine.

http://ift.tt/2gn94RS

Prevalence, antibiotic resistance, and MLST typing of Helicobacter pylori in Algiers, Algeria

Abstract

Background

Helicobacter pylori infection is common in Algeria, but there are few data on the characterization of isolated strains. The aim of this study was to update data on the prevalence of H. pylori in patients submitted to endoscopy, antibiotic resistance, and phylogeography of H. pylori strains isolated in Algiers.

Materials and Methods

This is a prospective study carried out between November 2015 and August 2016. The culture of H. pylori was performed on antral and fundic gastric biopsies of adult patients from 3 hospitals. A real-time PCR using the fluorescence resonance energy transfer (FRET) principle for the detection of H. pylori followed by a melting curve analysis for the detection of mutations associated with resistance to clarithromycin was applied. Differentiation between antral and fundic isolates of the same patient was also determined by RAPD, and an MLST typing was performed for characterization of the phylogeographic group of H. pylori.

Results

By real-time PCR, the prevalence of H. pylori infection among the 147 patients included was 57%. Culture was positive in only 29% of the cases. Twenty-seven percent of patients had received H. pylori eradication treatment. The primary and secondary resistance rates to clarithromycin were 23% and 36%, respectively, and to metronidazole, 45% and 71%, respectively. Only one isolate was resistant to levofloxacin, and no resistance to amoxicillin, tetracycline, and rifampicin was detected. A double population was present in 14 patients. The MLST analysis classified the 42 H. pylori strains from 38 patients in 2 haplotypes: hpEurope (33) and hpNEAfrica (9).

Conclusion

The prevalence of H. pylori remains high in Algeria but appears to be decreasing in recent years. High resistance to clarithromycin requires increased monitoring of the evolution of antibiotic resistance and adaptation of eradication therapy.

http://ift.tt/2xJoAiq

Immunological Profile of Solid Tumors Sample

Condition:   Solid Cancer
Intervention:   Other: immunohistochemistry assay
Sponsors:   Assistance Publique Hopitaux De Marseille;   Innate Pharma
Recruiting

http://ift.tt/2gdNhIy

Macintosh Laryngoscope Assisted Fiberoptic Intubation

Condition:   Difficult Intubation
Interventions:   Device: fiberoptic, airway;   Device: fiberoptic, Machintosh
Sponsor:   Mansoura University
Recruiting

http://ift.tt/2ykOisX

Simultaneous whole-body 18 F–PSMA-1007-PET/MRI with integrated high-resolution multiparametric imaging of the prostatic fossa for comprehensive oncological staging of patients with prostate cancer: a pilot study

Abstract

Introduction

The aim of the present study was to explore the clinical feasibility and reproducibility of a comprehensive whole-body ¹⁸F–PSMA-1007-PET/MRI protocol for imaging prostate cancer (PC) patients.

Methods

Eight patients with high-risk biopsy-proven PC underwent a whole-body PET/MRI (3 h p.i.) including a multi-parametric prostate MRI after ¹⁸F–PSMA-1007-PET/CT (1 h p.i.) which served as reference. Seven patients presented with non-treated PC, whereas one patient presented with biochemical recurrence. SUV_mean-quantification was performed using a 3D–isocontour volume-of-interest. Imaging data was consulted for TNM-staging and compared with histopathology. PC was confirmed in 4/7 patients additionally by histopathology after surgery. PET-artifacts, co-registration of pelvic PET/MRI and MRI-data were assessed (PI-RADS 2.0).

Results

The examinations were well accepted by patients and comprised 1 h. SUV_mean-values between PET/CT (1 h p.i.) and PET/MRI (3 h p.i.) were significantly correlated (p < 0.0001, respectively) and similar to literature of ¹⁸F–PSMA-1007-PET/CT 1 h vs 3 h p.i. The dominant intraprostatic lesion could be detected in all seven patients in both PET and MRI. T2c, T3a, T3b and T4 features were detected complimentarily by PET and MRI in five patients. PET/MRI demonstrated moderate photopenic PET-artifacts surrounding liver and kidneys representing high-contrast areas, no PET-artifacts were observed for PET/CT. Simultaneous PET-readout during prostate MRI achieved optimal co-registration results.

Conclusions

The presented ¹⁸F–PSMA-1007-PET/MRI protocol combines efficient whole-body assessment with high-resolution co-registered PET/MRI of the prostatic fossa for comprehensive oncological staging of patients with PC.

http://ift.tt/2xIFloX

Structure optimization of tetrahydropyridoindole-based aldose reductase inhibitors improved their efficacy and selectivity

Publication date: Available online 16 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Magdalena Majekova, Jana Ballekova, Marta Prnova, Milan Stefek
In our previous study, tetrahydropyridoindoles carboxymethylated in position 8 were identified as aldose reductase (ALR2) inhibitors with mild efficacy and selectivity yet with significant antioxidant activity. In the present study we proceeded with optimization of the tetrahydropyridoindole scaffold by shifting the carboxymethyl pharmacophore from position 8 to position 5, with the aim to improve the biological activity. Commercial databases were screened for the presence of tetrahydropyridoindoles carboxymethylated in position 5 and an experimental set of eight compounds was created. Mild inhibition characterized by IC50 in micromolar range was recorded for compound 8 with the isopropyl substituent at the piperidine nitrogen (position 2). This alkylated tertiary nitrogen is characterized by a rather high basicity (pKa ∼ 10.4) with complete protonization at physiological pH. On the other hand, ALR2 inhibition activity of the low basicity derivatives 3-7 with an acyl substituted nitrogen in position 2 (pKa ∼ -1 to -3) was characterized with IC50 values in low and medium nanomolar region. Docking into the binding site of human recombinant enzyme AKR1B1 performed for 3 revealed an interaction network responsible for the high affinity and selectivity. In ex vivo experiment, sorbitol accumulation in isolated rat eye lenses was significantly inhibited by 3 in the presence of high glucose, starting at a concentration as low as 0.1 μM. Moreover, in streptozotocin-induced diabetic rats, compound 3 administered intragastrically (i.g., 50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in red blood cells and the sciatic nerve. Molecular obesity indices predicted along with water solubility point an excellent "lead-likeness" of compound 3, with prospects of further structure optimizations.

Graphical abstract

http://ift.tt/2zck73X

Transoral endoscopic thyroidectomy via a vestibular approach: why and how?

Abstract

The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is a novel, scar-free surgical procedure that does not require visible incisions. Indications for TOETVA are as follows: predicted gland width on diagnostic imaging ≤10 cm; a thyroid volume outline of <45 mL or dominant nodule dimension of ≤50 mm; three or four Bethesda lesions; a primary papillary microcarcinoma without local or distant metastasis; and patient request for optimal esthetic results. Contraindications are as follows: patients unfit for general anesthesia; precedent radiation in the head, neck, upper mediastinum; antecedent neck surgery; recurrent goiter; a gland volume of >45 mL or main nodule diameter of >50 mm; and documentation of lymph node or distant metastases, tracheal/esophageal infiltration, preoperative laryngeal nerve palsy, hyperthyroidism, mediastinal goiter, or an oral abscess. Patients with poorly differentiated or un-differentiated cancer, dorsal extrathyroidal radius, and/or lateral neck metastasis are not suitable for TOETVA. Following the introduction of a robotic surgical system, enabling a three-dimensional surgical view and the use of articulating instruments, TOETVA became suitable for most differentiated thyroid cancers without evidence of extensive extrathyroidal invasion or lateral neck metastasis. The procedure is performed using a vestibular approach and three-port technique; a 10-mm port is used for the 30° endoscope, two 5-mm ports are used for the dissecting and coagulating instruments, and an 8-mm port is placed in the axillary fold during the robotic procedure to enhance fine countertraction of tissue for radical oncological dissection. TOETVA follows surgical planes and is probably the best scar-free approach to the thyroid, given the short distance between the gland and intraoral incisions.

http://ift.tt/2yriceh

Transoral endoscopic thyroidectomy via a vestibular approach: why and how?

Abstract

The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is a novel, scar-free surgical procedure that does not require visible incisions. Indications for TOETVA are as follows: predicted gland width on diagnostic imaging ≤10 cm; a thyroid volume outline of <45 mL or dominant nodule dimension of ≤50 mm; three or four Bethesda lesions; a primary papillary microcarcinoma without local or distant metastasis; and patient request for optimal esthetic results. Contraindications are as follows: patients unfit for general anesthesia; precedent radiation in the head, neck, upper mediastinum; antecedent neck surgery; recurrent goiter; a gland volume of >45 mL or main nodule diameter of >50 mm; and documentation of lymph node or distant metastases, tracheal/esophageal infiltration, preoperative laryngeal nerve palsy, hyperthyroidism, mediastinal goiter, or an oral abscess. Patients with poorly differentiated or un-differentiated cancer, dorsal extrathyroidal radius, and/or lateral neck metastasis are not suitable for TOETVA. Following the introduction of a robotic surgical system, enabling a three-dimensional surgical view and the use of articulating instruments, TOETVA became suitable for most differentiated thyroid cancers without evidence of extensive extrathyroidal invasion or lateral neck metastasis. The procedure is performed using a vestibular approach and three-port technique; a 10-mm port is used for the 30° endoscope, two 5-mm ports are used for the dissecting and coagulating instruments, and an 8-mm port is placed in the axillary fold during the robotic procedure to enhance fine countertraction of tissue for radical oncological dissection. TOETVA follows surgical planes and is probably the best scar-free approach to the thyroid, given the short distance between the gland and intraoral incisions.

http://ift.tt/2yriceh

Scholar : These new articles for Voice and Speech Review are available online

The online platform for Taylor & Francis Online content New for Voice and Speech Review and online now on Taylor & Francis Online: Original Articles Managing "Vocal Dose" and the acting voice: how much is too much? Chris Gaskill & Allison Hetzel Pages: 1-17 | DOI: 10.1080/23268263.2017.1389811 Browse this free access collection on: Communication, Media and Culture in Asia. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : These new articles for Archives and Manuscripts are available online

The online platform for Taylor & Francis Online content New for Archives and Manuscripts and online now on Taylor & Francis Online: Original Articles Small acts of resistance: teaching young and emerging artists sustainable preservation strategies for contemporary creative practice Lisa Cianci Pages: 1-21 | DOI: 10.1080/01576895.2017.1376286 Report Setting the Record Straight for the Rights of the Child Summit Joanne Evans Pages: 1-6 | DOI: 10.1080/01576895.2017.1373244 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Psychological effects of Helicobacter pylori-associated atrophic gastritis in patients under 50 years: A cross-sectional study

Abstract

Background

While gastrointestinal function is known to be closely related to psychological status, the influence of Helicobacter pylori-associated atrophic gastritis is currently unknown. We aimed to determine whether atrophic gastritis status or H. pylori infection is associated with psychological distress or depressed mood.

Materials and Methods

We performed a cross-sectional, observational study involving 975 Japanese individuals (503 females; mean age, 44 ± 8 years) who underwent a health checkup. Psychological distress was defined as a Kessler-6 Scale score ≥13 and depressive mood as a Center for Epidemiological Studies Depression Scale score ≥ 16. The odds ratios with 95% confidence intervals assessing the risk of psychological distress or depressive mood associated with H. pylori infection (H. pylori-specific immunoglobulin G levels >10 U/mL) and atrophic gastritis status (pepsinogen I levels < 70 μg/L and pepsinogen I/II ratio < 3) were calculated using multiple logistic analysis adjusting for several covariates.

Results

Individuals with atrophic gastritis had a significantly higher risk of experiencing psychological distress, with younger females (<50 years) displaying the highest risk for psychological distress and depressive mood regardless of H. pylori infection status. Among females aged <50 years, H. pylori-seropositive participants with atrophic gastritis (HP+AG+) showed the highest risk of psychological distress (OR, 16.4; 95% CI, 3.45-94.9) and depression (OR, 2.86; 95% CI, 1.31-6.05), using HP−AG− status as the reference.

Conclusions

Our findings support the results of previous animal studies regarding the psychological response to gastritis in humans. Further studies are needed to elucidate whether H. pylori eradication provides psychological benefits.

http://ift.tt/2xIsfZ6

Successful treatment of SAPHO syndrome with apremilast

Abstract

Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is a rare disease with inflammatory osteoarticular and skin involvement. The pathogenesis of SAPHO syndrome remains unclear, but evidence suggests it may be an autoinflammatory disease triggered upon exposure to infectious agents in genetically predisposed individuals. Induction of the IL-23/Th17 axis as well as neutrophil activation seem to play a key role, and therapies targeting these immunological pathways, including TNF-inhibitors, ustekinumab, secukinumab and the IL-1 inhibitor anakinra are potential treatment options that need further investigation. Here we report a case of a 24-year-old woman suffering from SAPHO syndrome who presented at our clinic with palmoplantar pustulosis and sternoclavicular joint involvement. Previous treatments with topical steroids and keratolytics combined with NSAIDs, intravenous methylprednisolone, methotrexate and salazopyrin had all failed to improve symptoms. Therapy with etanercept was not tolerated, and due to a previous demyelinating peripheral neuropathy, further treatment with TNF inhibitors was avoided. We initiated ustekinumab 45mg, which improved skin manifestations but not joint pain. Dose escalation to 90mg initially improved joint pain, but the dose had to be reduced to 45mg again due to increased infections. During subsequent 45mg ustekinumab treatment joint pain exacerbated so we switched to secukinumab, which improved skin and joint symptoms significantly but was associated with a pustular hypersensitivity reaction. Finally, we began treatment with apremilast, a pan-cytokine approach, resulting in stabilization of the skin and joint symptoms without side effects. To our knowledge, this is the first case report of apremilast as a treatment for SAPHO syndrome.

This article is protected by copyright. All rights reserved.

http://ift.tt/2gImo0b

Biochar as an adsorbent for inorganic nitrogen and phosphorus removal from water: a review

Abstract

Biochar is the solid product of biomass pyrolysis that can be used for carbon sequestration, soil amendment, and pollution remediation. The use of biochar as an adsorbent for the removal of water contaminants has elicited increasing interest due to the multifunctional properties of this material. The application of biochar in the adsorption of inorganic nutrients from eutrophic water has not been reviewed. This review focuses on recent research on the use of biochar for the adsorption of inorganic nitrogen (ammonium and nitrate) and phosphorus (phosphate) from water, especially for the main influence factors and mechanisms for nitrogen and phosphorus adsorption on biochar.

http://ift.tt/2yNtDP4

Recovery from sublethal damage and potentially lethal damage

Abstract

Purpose

In order to clarify the biological response of tumor cells to proton beam irradiation, sublethal damage recovery (SLDR) and potentially lethal damage recovery (PLDR) induced after proton beam irradiation at the center of a 10 cm spread-out Bragg peak (SOBP) were compared with those seen after X‑ray irradiation.

Methods

Cell survival was determined by a colony assay using EMT6 and human salivary gland tumor (HSG) cells. First, two doses of 4 Gy/GyE (Gray equivalents, GyE) were given at an interfraction interval of 0–6 h. Second, five fractions of 1.6 Gy/GyE were administered at interfraction intervals of 0–5 min. Third, a delayed-plating assay involving cells in plateau-phase cultures was conducted. The cells were plated in plastic dishes immediately or 2–24 h after being irradiated with 8 Gy/GyE of X‑rays or proton beams. Furthermore, we investigated the degree of protection from the effects of X‑rays or proton beams afforded by the radical scavenger dimethyl sulfoxide to estimate the contribution of the indirect effect of radiation.

Results

In both the first and second experiments, SLDR was more suppressed after proton beam irradiation than after X‑ray irradiation. In the third experiment, there was no difference in PLDR between the proton beam and X‑ray irradiation conditions. The degree of protection tended to be higher after X‑ray irradiation than after proton beam irradiation.

Conclusion

Compared with that seen after X‑ray irradiation, SLDR might take place to a lesser extent after proton beam irradiation at the center of a 10 cm SOBP, while the extent of PLDR does not differ significantly between these two conditions.

http://ift.tt/2gbClek

Assessment of GHG mitigation and CDM technology in urban transport sector of Chandigarh, India

Abstract

The increase in number of vehicles in metropolitan cities has resulted in increase of greenhouse gas (GHG) emissions in urban environment. In this study, emission load of GHGs (CO, N₂O, CO₂) from Chandigarh road transport sector has been estimated using Vehicular Air Pollution Inventory (VAPI) model, which uses emission factors prevalent in Indian cities. Contribution of 2-wheelers (2-w), 3-wheelers (3-w), cars, buses, and heavy commercial vehicles (HCVs) to CO, N₂O, CO₂, and total GHG emissions was calculated. Potential for GHG mitigation through clean development mechanism (CDM) in transport sector of Chandigarh under two scenarios, i.e., business as usual (BAU) and best estimate scenario (BES) using VAPI model, has been explored. A major contribution of GHG load (~ 50%) in Chandigarh was from four-wheelers until 2011; however, it shows a declining trend after 2011 until 2020. The estimated GHG emission from motor vehicles in Chandigarh has increased more than two times from 1065 Gg in 2005 to 2486 Gg by 2011 and is expected to increase to 4014 Gg by 2020 under BAU scenario. Under BES scenario, 30% of private transport has been transformed to public transport; GHG load was possibly reduced by 520 Gg. An increase of 173 Gg in GHGs load is projected from additional scenario (ADS) in Chandigarh city if all the diesel buses are transformed to CNG buses by 2020. Current study also offers potential for other cities to plan better GHG reduction strategies in transport sector to reduce their climate change impacts.

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Sensorimotor impairment of speech auditory feedback processing in aphasia

Publication date: 15 January 2018
Source:NeuroImage, Volume 165
Author(s): Roozbeh Behroozmand, Lorelei Phillip, Karim Johari, Leonardo Bonilha, Chris Rorden, Gregory Hickok, Julius Fridriksson
We investigated the brain network involved in speech sensorimotor processing by studying patients with post-stroke aphasia using an altered auditory feedback (AAF) paradigm. We combined lesion-symptom-mapping analysis and behavioral testing to examine the pervasiveness of speech sensorimotor deficits and their relationship with cortical damage. Sixteen participants with aphasia and sixteen neurologically intact individuals completed a speech task under AAF. The task involved producing speech vowel sounds under the real-time pitch-shifted auditory feedback alteration. This task provided an objective measure for each individual's ability to compensate for mismatch (error) in speech auditory feedback. Results indicated that compensatory speech responses to AAF were significantly diminished in participants with aphasia compared with control. We observed that within the aphasic group, subjects with lower scores on the speech repetition task exhibited greater degree of diminished responses. Lesion-symptom-mapping analysis revealed that the onset phase (50–150 ms) of diminished AAF responses were predicted by damage to auditory cortical regions within the superior and middle temporal gyrus, whereas the rising phase (150–250 ms) and the peak (250–350 ms) of diminished AAF responses were predicted with damage to the inferior frontal gyrus and supramarginal gyrus areas, respectively. These findings suggest that damage to the auditory, motor, and auditory-motor integration networks are associated with impaired sensorimotor function for speech error processing. We suggest that a sensorimotor integration network, as revealed by brain regions related to temporal specific components of AAF responses, is related to speech processing and specific aspects of speech impairment, notably repetition deficits, in individuals with aphasia.



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Long-read transcriptome data for improved gene prediction in Lentinula edodes

Publication date: December 2017
Source:Data in Brief, Volume 15
Author(s): Sin-Gi Park, Seung il Yoo, Dong Sung Ryu, Hyunsung Lee, Yong Ju Ahn, Hojin Ryu, Junsu Ko, Chang Pyo Hong
Lentinula edodes is one of the most popular edible mushrooms in the world and contains useful medicinal components such as lentinan. The whole-genome sequence of L. edodes has been determined with the objective of discovering candidate genes associated with agronomic traits, but experimental verification of gene models with correction of gene prediction errors is lacking. To improve the accuracy of gene prediction, we produced 12.6Gb of long-read transcriptome data of variable lengths using PacBio single-molecule real-time (SMRT) sequencing and generated 36,946 transcript clusters with an average length of 2.2kb. Evidence-driven gene prediction on the basis of long- and short-read RNA sequencing data was performed; a total of 16,610 protein-coding genes were predicted with error correction. Of the predicted genes, 42.2% were verified to be covered by full-length transcript clusters. The raw reads have been deposited in the NCBI SRA database under accession number PRJNA396788.



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Data on physicochemical properties of active films derived from plantain flour/PCL blends developed under reactive extrusion conditions

Publication date: December 2017
Source:Data in Brief, Volume 15
Author(s): Tomy J. Gutiérrez, Vera A. Alvarez
The data given below relates to the research paper entitled: "Eco-friendly films prepared from plantain flour/PCL blends under reactive extrusion conditions using zirconium octanoate as a catalyst", recently published by our research group [1]. This article provides information concerning the physicochemical properties of the above-mentioned film systems: thickness, density, opacity, moisture content and surface moisture.



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Emotion Dysregulation Moderates the Effect of Cognitive Behavior Therapy with Prolonged Exposure for Co-Occurring PTSD and Substance Use Disorders

Publication date: Available online 16 October 2017
Source:Journal of Anxiety Disorders
Author(s): Denise A. Hien, Teresa Lopez-Castro, Santiago Papini, Bernard Gorman, Lesia M. Ruglass
A goal of clinical trials is to identify unique baseline characteristics that can inform treatment planning. One such target is emotion dysregulation (ED), which contributes to the maintenance of co-occurring posttraumatic stress disorder (PTSD) and substance use disorder (SUD) and may be a potential moderator of treatment response. We examined the moderating impact of ED severity on treatment outcomes in an urban, socioeconomically disadvantaged, and racially/ethnically diverse sample with complex trauma and severe SUDs. Participants with co-occurring PTSD and SUD (PTSD+SUD) were randomized to Concurrent Treatment with Prolonged Exposure (COPE, n=39), Relapse Prevention Therapy (RPT, n=43), or an active monitoring control group (AMCG, n=28). Baseline ED severity moderated treatment outcomes such that high ED was associated with greater reduction in PTSD severity among those who received COPE relative to RPT and AMCG. In contrast, low ED was associated with greater reduction in substance use among those in RPT relative to COPE and AMCG. Implications for individualizing and optimizing treatment selection for PTSD+SUD are discussed.



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A biomimetic theranostic O2-meter for cancer targeted photodynamic therapy and phosphorescence imaging

Publication date: January 2018
Source:Biomaterials, Volume 151
Author(s): Shi-Ying Li, Bo-Ru Xie, Hong Cheng, Chu-Xin Li, Ming-Kang Zhang, Wen-Xiu Qiu, Wen-Long Liu, Xiao-Shuang Wang, Xian-Zheng Zhang
In this report, a biomimetic theranostic oxygen (O2)-meter (cancer cell membrane@Pt(II) porphyrinic-metal organic framework, designated as mPPt) was constructed for cancer targeted and phosphorescence image-guided photodynamic therapy (PDT). mPPt presents high photosensitizers (PSs) loading and evitable self-quenching behaviors for favorable biological O2 sensing and PDT. Besides, endowed by the surface functionalization of cancer cell membrane, the homotypic targeting and immune escape abilities of mPPt could dramatically enhance its cancer targeting ability. Importantly, the O2-dependent phosphorescence responsibility of mPPt could be employed to pre-evaluate the real time O2 level in situ and guide the PDT under light irradiation. A significant anticancer effect is observed after intravenous injection of mPPt and subsequent treatment with PDT with no obvious side effects. As a versatile platform for cell imaging, O2 fluctuation monitoring as well as PDT, this biomimetic O2-meter exhibits great potential for biological analysis and personalized cancer theranostics.

Graphical abstract

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Physical oncology: New targets for nanomedicine

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Alba Nicolas-Boluda, Amanda K.A. Silva, Sylvie Fournel, Florence Gazeau
Physical oncology is an emerging paradigm which recognizes tissue mechanics, per se, as an active modulator of tumorigenesis, treatment resistance and clinical outcome, mediated by mechanosignaling pathways, matrix remodeling and physical barriers to drugs. The tumor microenvironment displays abnormal physical properties in comparison to healthy tissue which contribute to cancer progression and resistance to current treatments. Physical aberrancies comprise the chaotic organization of tumor vasculature, an increased interstitial pressure, an increased solid stress, hypoxia, an abundant extracellular matrix and a progressive stiffening of solid tumors. The physical barriers in tumors are of critical importance, as tissue mechanics compromises drug delivery, reduces immune cell infiltration and promotes disease aggressiveness. All these physical hallmarks of cancer, although not fully understood, are inspiring new anticancer strategies aiming to target and normalize the physical anomalies of solid tumors, particularly in the field of nanomedicine. Here we summarize the recent paradigm shift of physical oncology and review some of the proposed strategies using nanomaterials to tackle the tumor microenvironment and its aberrant physical properties. Nanomedicine might harness the features of the tumor microenvironment in order to improve nanoparticle and drug delivery, or propose nano-agents that can be activated on demand to achieve a tailored spatio-temporal modulation of the tumor microenvironment, reduce tumor pressure and stiffness and alleviate the resistance to current treatments.



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Thrombin-activatable fluorescent peptide incorporated gold nanoparticles for dual optical/computed tomography thrombus imaging

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Sung-Pil Kwon, Sangmin Jeon, Sung-Hoon Lee, Hong Yeol Yoon, Ju Hee Ryu, Dayil Choi, Jeong-Yeon Kim, Jiwon Kim, Jae Hyung Park, Dong-Eog Kim, Ick Chan Kwon, Kwangmeyung Kim, Cheol-Hee Ahn
Thrombosis is an important pathophysiologic phenomenon in various cardiovascular diseases, which can lead to oxygen deprivation and infarction of tissues by generation of a thrombus. Thus, direct thrombus imaging can provide beneficial in diagnosis and therapy of thrombosis. Herein, we developed thrombin-activatable fluorescent peptide (TAP) incorporated silica-coated gold nanoparticles (TAP-SiO2@AuNPs) for direct imaging of thrombus by dual near-infrared fluorescence (NIRF) and micro-computed tomography (micro-CT) imaging, wherein TAP molecules were used as targeted thrombin-activatable peptide probes for thrombin-specific NIRF imaging. The freshly prepared TAP-SiO2@AuNPs had an average diameter of 39.8 ± 2.55 nm and they showed the quenched NIRF signal in aqueous condition, due to the excellent quenching effect of TAP molecules on the silica-gold nanoparticle surface. However, 30.31-fold higher NIRF intensity was rapidly recovered in the presence of thrombin in vitro, due to the thrombin-specific cleavage of quenched TAP molecules on the gold particle surface. Furthermore, TAP-SiO2@AuNPs were successfully accumulated in thrombus by their particle size-dependent capturing property, and they presented a potential X-ray absorption property in a dose-dependent manner. Finally, thrombotic lesion was clearly distinguished from peripheral tissues by dual NIRF/micro-CT imaging after intravenous injection of TAP-SiO2@AuNPs in the in situ thrombotic mouse model, simultaneously. This study showed that thrombin-activatable fluorescent peptide incorporated silica-coated gold nanoparticles can be potentially used as a dual imaging probe for direct thrombus imaging and therapy in clinical applications.



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Biomechanical regulation of drug sensitivity in an engineered model of human tumor

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): A. Marturano-Kruik, A. Villasante, K. Yaeger, S.R. Ambati, A. Chramiec, M.T. Raimondi, G. Vunjak-Novakovic
Predictive testing of anticancer drugs remains a challenge. Bioengineered systems, designed to mimic key aspects of the human tumor microenvironment, are now improving our understanding of cancer biology and facilitating clinical translation. We show that mechanical signals have major effects on cancer drug sensitivity, using a bioengineered model of human bone sarcoma. Ewing sarcoma (ES) cells were studied within a three-dimensional (3D) matrix in a bioreactor providing mechanical loadings. Mimicking bone-like mechanical signals within the 3D model, we rescued the ERK1/2-RUNX2 signaling pathways leading to drug resistance. By culturing patient-derived tumor cells in the model, we confirmed the effects of mechanical signals on cancer cell survival and drug sensitivity. Analyzing human microarray datasets, we showed that RUNX2 expression is linked to poor survival in ES patients. Mechanical loadings that activated signal transduction pathways promoted drug resistance, stressing the importance of introducing mechanobiological cues into preclinical tumor models for drug screening.



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Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Tian Tian, Hui-Xin Zhang, Chun-Peng He, Song Fan, Yan-Liang Zhu, Cui Qi, Ning-Ping Huang, Zhong-Dang Xiao, Zu-Hong Lu, Bakhos A. Tannous, Jun Gao
The safe and effective delivery of drugs is a major obstacle in the treatment of ischemic stroke. Exosomes hold great promise as an endogenous drug delivery nanosystem for the treatment of cerebral ischemia given their unique properties, including low immunogenicity, innate stability, high delivery efficiency, and ability to cross the blood-brain barrier (BBB). However, exosome insufficient targeting capability limits their clinical applications. In this study, the c(RGDyK) peptide has been conjugated to the exosome surface by an easy, rapid, and bio-orthogonal chemistry. In the transient middle cerebral artery occlusion (MCAO) mice model, The engineered c(RGDyK)-conjugated exosomes (cRGD-Exo) target the lesion region of the ischemic brain after intravenous administration. Furthermore, curcumin has been loaded onto the cRGD-Exo, and administration of these exosomes has resulted in a strong suppression of the inflammatory response and cellular apoptosis in the lesion region. The results suggest a targeting delivery vehicle for ischemic brain based on exosomes and provide a strategy for the rapid and large-scale production of functionalized exosomes.



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Editorial board

Publication date: December 2017
Source:Biomaterials, Volume 149





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Single-walled carbon nanotube: One specific inhibitor of cancer stem cells in osteosarcoma upon downregulation of the TGFβ1 signaling

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): Yanyan Miao, Haixia Zhang, Yubin Pan, Jian Ren, Miaoman Ye, Fangfang Xia, Rui Huang, Zhuoheng Lin, Shuai Jiang, Ya Zhang, Zhou Songyang, Yan Zhang
Cancer stem cells (CSCs) are believed to have a critical role in tumorigenesis, metastasis, therapeutic resistance or recurrence. Therefore, strategies designed to specifically target and eliminate CSCs have become one of the most promising and desirable ways for tumor treatment. Osteosarcoma stem cells (OSCs), the CSCs in osteosarcoma (OS), are critically associated with OS progression. Here, we show that single-walled carbon nanotubes (SWCNTs), including unmodified SWCNT (SWCNT-Raw) and SWCNT-COOH, have the ability to specifically inhibit the process of TGFβ1-induced OS cells dedifferentiation, prevent the stem cell phenotypes acquisition in OS cells and reduce the OSC viability under conditions which mimic the OS microenvironment. Concurrently, SWCNT treatment significantly down-regulates the expression of OSC markers in OS, and markedly reduces the tumor microvessel density and tumor growth. Furthermore, we found that SWCNT could suppress the TGFβ1-induced activation of TGFβ type I receptor and downstream signaling, which are key for the OSC formation and maintenance. Our results reveal an unexpected function of SWCNT in negative modulation of OSCs, and provide significant implications for the potential CSCs-targeted therapeutic applications of SWCNT.



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Nanolayered hybrid mediates synergistic co-delivery of ligand and ligation activator for inducing stem cell differentiation and tissue healing

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): Heemin Kang, Minkyu Kim, Qian Feng, Sien Lin, Kongchang Wei, Rui Li, Chan Ju Choi, Tae-Hyun Kim, Gang Li, Jae-Min Oh, Liming Bian
Cellular behaviors, such as differentiation, are regulated by complex ligation processes involving cell surface receptors, which can be activated by various divalent metal cations. The design of nanoparticle for co-delivery of ligand and ligation activator can offer a novel strategy to synergistically stimulate ligation processes in vivo. Here, we present a novel layered double hydroxide (LDH)-based nanohybrid (MgFe-Ado-LDH), composed of layered MgFe hydroxide nanocarriers sandwiching the adenosine cargo molecule, maintained through an electrostatic balance, to co-deliver the adenosine (Ado) ligand from the interlayer spacing and the Mg²⁺ ion (ligation activator) through the dissolution of the MgFe nanocarrier itself. Our findings demonstrate that the MgFe-Ado-LDH nanohybrid promoted osteogenic differentiation of stem cells through the synergistic activation of adenosine A2b receptor (A2bR) by the dual delivery of adenosine and Mg²⁺ ions, outperforming direct supplementation of adenosine alone. Furthermore, the injection of the MgFe-Ado-LDH nanohybrid and stem cells embedded within hydrogels promoted the healing of rat tibial bone defects through the rapid formation of fully integrated neo-bone tissue through the activation of A2bR. The newly formed bone tissue displayed the key features of native bone, including calcification, mature tissue morphology, and vascularization. This study demonstrates a novel and effective strategy of bifunctional nanocarrier-mediated delivery of ligand (cargo molecule) and activation of its ligation to receptor by the nanocarrier itself for synergistically inducing stem cell differentiation and tissue healing in vivo, thus offering novel design of biomaterials for regenerative medicine.

Graphical abstract

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Bimatoprost ophthalmic solution in facial vitiligo

Summary

Background

Vitiligo is one of the commonest pigmentary disorders characterized by destruction of melanocytes.

Aim

To evaluate the efficacy of topical bimatoprost ophthalmic solution in stable facial vitiligo.

Material and methods

Eight cases of stable facial vitiligo were treated with bimatoprost 0.03% ophthalmic solution once daily for 12 weeks. Photographic records were taken at 2 weeks follow-up along with dermoscopic (Polarized, 10×) evaluation.

Results

Four cases had excellent repigmentation, two cases had partial repigmentation and two cases had poor response.

Conclusion

Bimatoprost seems to be promising in treating stable vitiligo but large-scale studies are required.

http://ift.tt/2yrn8QR

A retrospective analysis of biochemical and haematological parameters in patients with eating disorders

Abstract

Background

The objective of the study was to determine whether levels of biochemical and haematological parameters in patients with eating disorders (EDs) varied from the general population. Whilst dietary restrictions can lead to nutritional deficiencies, specific abnormalities may be relevant to the diagnosis, pathogenesis and treatment of EDs.

Methods

With ethics approval and informed consent, a retrospective chart audit was conducted of 113 patients with EDs at a general practice in Brisbane, Australia. This was analysed first as a total group (TG) and then in 4 ED subgroups: Anorexia nervosa (AN), Bulimia nervosa (BN), ED Not Otherwise Specified (EDNOS), and AN/BN. Eighteen parameters were assessed at or near first presentation: cholesterol, folate, vitamin B12, magnesium, manganese, zinc, calcium, potassium, urate, sodium, albumin, phosphate, ferritin, vitamin D, white cell count, neutrophils, red cell count and platelets. Results were analysed using IBM SPSS 21 and Microsoft Excel 2013 by two-tailed, one-sample t-tests (TG and 4 subgroups) and chi-square tests (TG only) and compared to the population mean standards. Results for the TG and each subgroup individually were then compared with the known reference interval (RI).

Results

For the total sample, t-tests showed significant differences for all parameters (p < 0.05) except cholesterol. Most parameters gave results below population levels, but folate, phosphate, albumin, calcium and vitamin B12 were above. More patients than expected were below the RI for most parameters in the TG and subgroups.

Conclusions

At diagnosis, in patients with EDs, there are often significant differences in multiple haematological and biochemical parameters. Early identification of these abnormalities may provide additional avenues of ED treatment through supplementation and dietary guidance, and may be used to reinforce negative impacts on health caused by the ED to the patient, their family and their treatment team (general practitioner, dietitian and mental health professionals). Study data would support routine measurement of a full blood count and electrolytes, phosphate, magnesium, liver function tests, ferritin, vitamin B12, red cell folate, vitamin D, manganese and zinc for all patients at first presentation with an ED.

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