Atovaquone oral bioavailability enhancement using electrospraying technology

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Aditya Darade, Sulabha Pathak, Shobhona Sharma, Vandana Patravale
Atovaquone in combination with proguanil hydrochloride, marketed as Malarone® tablets by GlaxoSmithKline (GSK), is prescribed for the treatment of malaria. High dose and poor bioavailability are the main hurdles associated with atovaquone oral therapy. The present study reports development of atovaquone nanoparticles, using in house designed and fabricated electrospraying equipment, and the assessment of bioavailability and therapeutic efficacy of the nanoparticles after oral administration. Solid nanoparticles of atovaquone were successfully produced by electrospraying and were characterized for particle size and flow properties. Differential Scanning Calorimetry, X-ray Diffraction, Fourier Transform Infrared Spectroscopy studies were also carried out. Atovaquone nanoparticles along with proguanil hydrochloride and a suitable wetting agent were filled in size 2 hard gelatin capsules. The formulation was compared with Malarone® tablets (GSK) and Mepron® suspension (GSK) in terms of in vitro release profile and in vivo pharmacokinetic studies. It showed 2.9-fold and 1.8-fold improved bioavailability in rats compared to Malarone® tablets and Mepron® suspension respectively. Therapeutic efficacy of the formulation was determined using modified Peter's 4-day suppressive tests and clinical simulation studies using Plasmodium berghei ANKA infected Swiss mice and compared to Malarone®. The developed formulation showed a 128-fold dose reduction in the modified Peter's 4-day suppressive tests and 32-fold dose reduction in clinical simulation studies. Given that only one capsule a day of developed formulation is required to be administered orally compared to 4 Malarone® tablets once a day and that too at a significantly reduced dose, this nanoparticle formulation will definitely reduce the side-effects of the treatment and is also likely to increase patient compliance.

Graphical abstract

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Improvement in the water solubility of drugs with a solid dispersion system by spray drying and hot-melt extrusion with using the amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and d-mannitol

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Noriko Ogawa, Tomoki Hiramatsu, Ryohei Suzuki, Ryohei Okamoto, Kohei Shibagaki, Kosuke Fujita, Chisato Takahashi, Yoshiaki Kawashima, Hiromitsu Yamamoto
The aim of this study was to prepare and characterize solid dispersion particles with a novel amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, as a water-soluble carrier. Solid dispersion particles were prepared by hot-melt extrusion and spray drying. Indomethacin (IMC) was used as a model comprising drugs with low solubility in water and d-mannitol (MAN) was used as an excipient. The physicochemical properties of prepared particles were characterized by scanning electron microscopy, thermal analysis, powder X-ray diffraction (PXRD) analysis, FTIR spectra analysis, and drug release studies. Stability studies were also conducted under stress conditions at 40°C, 75% relative humidity. We found that dissolution behavior of the original drug crystal could be improved by solid dispersion with the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The PXRD pattern and thermal analysis indicated that the solid dispersion prepared with the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC was in an amorphous state. FTIR spectra analysis indicated that the interaction manner between the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC may differ with the preparation method and formulation of solid dispersions. Stability studies proved that the amorphous state of IMC in solid dispersion particles was preserved under stress conditions for more than two weeks.

Graphical abstract

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Peristomal psoriasis: an intriguing new subset of psoriasis

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Delusional infestation caused by pramipexole

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Efficacy of perilesional and intralesional triamcinolone acetonide injections in pemphigus vulgaris lesions of the scalp: an effective therapeutic option

Summary

The scalp is a common location for pemphigus vulgaris (PV), and scalp lesions may be resistant to standard treatment. Perilesional/intralesional triamcinolone acetonide (TA) injections have been used successfully to treat oropharyngeal and ocular involvement in PV. Data on the efficacy of perilesional and intralesional triamcinolone acetonide injections in scalp lesions in PV are lacking. We report two patients with immunopathologically and histopathologically confirmed PV and residual scalp lesions resistant to standard treatment, who were treated with perilesional and intralesional injections of TA 10 mg/mL. Clearance of scalp lesions was achieved after one after, respectively, one and two perilesional and intralesional injections. Perilesional and intralesional TA injections may serve as an effective and safe treatment for recalcitrant scalp lesions in pemphigus.

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First-line treatment in lymphomatoid papulosis: a retrospective multicentre study

Summary

Background

Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce.

Aim

To assess the daily clinical practice approach to LyP and the response to first-line treatments.

Methods

This was a retrospective study enrolling 252 patients with LyP.

Results

Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16–2.11). Overall median time to CR was 10 months (95% CI 6–13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9–13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10–36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96–4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84–33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality.

Conclusions

Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse.

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Self-reported minor infections in patients with hidradenitis suppurativa and healthy controls

Summary

Background

Patients with hidradenitis suppurativa (HS) often report opportunistic infections such as herpes and urinary tract infections.

Aim

To compare opportunistic infections in patients with HS against a group of healthy controls (HCs).

Methods

In total, 99 patients with HS and 109 HCs were recruited at random to this retrospective case–control study. We devised a questionnaire to explore the frequency of minor infections, general practitioner (GP) visits and sick days experienced during the past 6 months. Additionally, participants were asked if they felt unwell more often compared with their peers.

Results

Patients with HS felt unwell more often than did HCs (26.3% vs. 7.3%, P < 0.001). Although there was no difference between the groups in five of the seven diseases studied, patients with HS had a higher frequency of the common cold (P < 0.01) and genital herpes (P < 0.01). Number of pack-years of smoking did not affect risk of infections (Pearson correlation, P = 0.51). Subgroup analysis of nonsmokers found the same differences in frequency of minor infections, common cold and genital herpes between patients with HS and controls.

Conclusions

Patients with HS appear to experience more frequently symptoms compatible with minor infections in general, and the common cold and genital herpes specifically. This results in more GP visits and more sick days. Further research is needed to determine if this is caused by an immunological hyper-reactive state in these patients or a reduced threshold for minor infections.

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Eruptive melanocytic naevi secondary to azathioprine: case report and review of the literature

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Ultraviolet filters in hair-care products: a possible link with frontal fibrosing alopecia and lichen planopilaris

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Mapping the Landscape of Patient-Centric Activities Within Clinical Research

Publication date: Available online 9 October 2017
Source:Clinical Therapeutics
Author(s): Mary Jo Lamberti, Josephine Awatin
PurposeAlthough there has been more involvement by patients in the drug-development process, there are not a lot of published data that quantify patient-centric activities or that document these activities across a large scale. In order to examine the patient-centricity landscape and to quantify the adoption and implementation of these initiatives, the Tufts Center for the Study of Drug Development and the Drug Information Association collaborated on a research study. The study examined patient-centric activities implemented by pharmaceutical, biotechnology, and contract research organizations, as well as activities being piloted or in the planning stages.MethodsA global industry survey was conducted across pharmaceutical, biotechnology, and contract research organizations, assessing 25 patient-centric activities within clinical research. Some of these initiatives involve the use of social media to engage with patients, or the use of social listening to monitor study activity. Initiatives being implemented, planned, or piloted in addition to those not being considered were evaluated by respondents. Twenty-two unique companies responded to the survey, representing a mix of large, mid-sized, and small organizations.FindingsThe most widely adopted patient-centric initiatives, including activities both implemented and piloted across organizations, were patient advisory boards (17/22 companies), professional panels (16), lay-language clinical trial results summaries (13), assessment of the patient–organization landscape (10), and the use of home nursing networks (9).ImplicationsThe results of the study suggest that organizations have a varied approach to the adoption and implementation of patient-centric initiatives, with more activities occurring in the planning stages than are being piloted or implemented. Many factors affect implementation and adoption, including buy-in by senior management, organizational vision, resources, and level of investment.



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Impact of Penicillin Allergy on Time to First Dose of Antimicrobial Therapy and Clinical Outcomes

Publication date: Available online 9 October 2017
Source:Clinical Therapeutics
Author(s): Erin L. Conway, Ken Lin, John A. Sellick, Kari Kurtzhalts, James Carbo, Michael C. Ott, Kari A. Mergenhagen
PurposeThe objective of this study was to evaluate the impact of a listed penicillin allergy on the time to first dose of antibiotic in a Veterans Affairs hospital. Additional clinical outcomes of patients with penicillin allergies were compared with those of patients without a penicillin allergy.MethodsA retrospective chart review of veterans admitted through the emergency department with a diagnosis of pneumonia, urinary tract infection, bacteremia, and sepsis from January 2006 to December 2015 was conducted. The primary outcome was time to first dose of antibiotic treatment, defined as the time from when the patient presented to the emergency department to the medication administration time. Secondary outcomes included total antibiotic therapy duration and treatment outcomes, including mortality, length of stay, and 30-day readmission rate.FindingsA total of 403 patients were included in the final analysis; 57 patients (14.1%) had a listed penicillin allergy. The average age of the population was 75 years and 99% of the population was male. The mean time to first dose of antibiotic treatment for patients with a penicillin allergy was prolonged compared with those without a penicillin allergy (236.1 vs 186.6 minutes; P = 0.03), resulting in an approximately 50-minute delay. Penicillin-allergic patients were more likely to receive a carbapenem or fluoroquinolone antibiotic (P < 0.0001).ImplicationsPatients with a penicillin allergy had a prolonged time to first dose of antibiotic therapy. No significant differences were found in total antibiotic duration, length of stay, or 30-day readmission rate. The small sample size, older population, and single-center nature of this study may limit the generalizability of the present findings to other populations.



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miRNA Genetic Variants: as Potential Diagnostic Biomarkers For Oral Cancer

Publication date: Available online 10 October 2017
Source:Pathology - Research and Practice
Author(s): Divya Tandon, Jayant Dewangan, Sonal Srivastava, Vivek Kumar Garg, Srikanta Kumar Rath
MicroRNAs (miRNAs) comprise a novel class of small, non-coding endogenous RNAs that have a role in the plethora of regulatory activities by directing their target mRNAs for degradation or translational repression. Single nucleotide polymorphisms (SNPs) in miRNA genes can lead to alteration in mRNA expression, resulting in serious consequences. Detection of miRNA-polymorphisms can potentially improve diagnosis, treatment, prognosis in patients and has extreme implications in the fields of pharmacogenomics and personalization of medicine. The aim of this study is to investigate the association between miR-499 A/G and miR-149 C/T polymorphisms with susceptibility to development of Oral Squamous Cell Carcinoma (OSCC). 200 histopathologically diagnosed and confirmed samples from OSCC patients and 200 control samples from the general population were recruited for the study. All OSCC patients were graded based on their differentiation, and genetic analysis was performed by PCR-RFLP and sequencing. qRT-PCR was carried out to compare the expression of miR-499 and miR-149 in different grades of various stages of OSCC patients concerning to the controls. Further Immunohistochemistry (IHC) was performed to study the target gene of miR-499. The study shows a probable association of miR-499 A/G and miR-149 C/T with susceptibility of OSCC. Random sequencing analysis and Immunohistochemistry contribute to the result that miR-499 A/G increases the susceptibility of OSCC by targeting SOX-6. PCR- Restriction Fragment Length Polymorphism (RFLP) and multivariable logistic analysis revealed that there is a significant association between miR-149 CT+TT and CT and susceptibility of OSCC. Our study suggests that miR-499 A/G and miR-149 C/T polymorphisms may play crucial roles in susceptibility and development of OSCC in Indian population.



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DNMT1 is associated with cell cycle and DNA replication gene sets in diffuse large B-cell lymphoma

Publication date: Available online 9 October 2017
Source:Pathology - Research and Practice
Author(s): Suet Kee Loo, Suzina Sheikh Ab. Hamid, Mustaffa Musa, Kah Keng Wong
Dysregulation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) is associated with the pathogenesis of various types of cancer. It has been previously shown that DNMT1 is frequently expressed in diffuse large B-cell lymphoma (DLBCL), however its functions remain to be elucidated in the disease. In this study, we gene expression profiled (GEP) shDNMT1-treated germinal center B-cell-like DLBCL (GCB-DLBCL)-derived cell line (i.e. HT) compared with non-silencing shRNA (control shRNA)-treated HT cells. Independent gene set enrichment analysis (GSEA) performed using GEPs of shRNA-treated HT cells and primary GCB-DLBCL cases derived from two publicly-available datasets (i.e. GSE10846 and GSE31312) produced three separate lists of enriched gene sets for each gene sets collection from Molecular Signatures Database (MSigDB). Subsequent Venn analysis identified 268, 145 and six consensus gene sets from analyzing gene sets in C2 collection (curated gene sets), C5 sub-collection [gene sets from gene ontology (GO) biological process ontology] and Hallmark collection, respectively to be enriched in positive correlation with DNMT1 expression profiles in shRNA-treated HT cells, GSE10846 and GSE31312 datasets [false discovery rate (FDR)<0.05]. Cell cycle progression and DNA replication were among the significantly enriched biological processes (FDR<0.05). Expression of genes involved in the activation of cell cycle and DNA replication (e.g. CDK1, CCNA2, E2F2, PCNA, RFC5 and POLD3) were highly correlated (r>0.8) with DNMT1 expression and significantly downregulated (log fold-change <−1.35; p<0.05) following DNMT1 silencing in HT cells. These results suggest the involvement of DNMT1 in the activation of cell cycle and DNA replication in DLBCL cells.



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Combined Detection of Insulin-Like Growth Factor-Binding Protein 7 Promoter Methylation Improves the Diagnostic Efficacy of AFP in Hepatitis B Virus-associated Hepatocellular Carcinoma

Publication date: Available online 9 October 2017
Source:Pathology - Research and Practice
Author(s): Li-Ping Tao, Xiao-Peng Fan, Yu-Chen Fan, Jing Zhao, Shuai Gao, Kai Wang
This study quantitatively assessed serum insulin-like growth factor-binding protein 7 (IGFBP7) promoter methylation in hepatocellular carcinoma (HCC), and explored its clinical value. A total of 80 patients with hepatitis B virus-associated HCC, 35 patients with chronic hepatitis B (CHB), and 20 healthy controls (HC) were enrolled. MethyLight was used to quantitatively assess the methylation levels of serum IGFBP7 promoter. A logistic regression model was established for the combined evaluation of AFP and serum IGFBP7 promoter methylation. The results showed that mean methylation levels of serum IGFBP7 promoter were significantly higher in HCC (5.33%, interquartile range [IQR] 1.14–15.70%) patients than in individuals with CHB (1.54%, IQR 0.64–2.45%; P<0.01) and HC (0.63%, IQR 0.22–0.98%; P<0.01). In HCC subgroups, patients with vascular invasion, tumor size >3cm and advanced tumor node metastasis (TNM) showed higher methylation levels compared with the remaining groups (P<0.05). Compared with AFP alone, combined determination based on logistic regression analysis significantly improved the area under the receiver operating characteristic (ROC) curve (AUC) (0.759 vs 0.623, P<0.05). In addition, the Youden index was increased from 5.71%, 11.25% and 15.18%, when considering AFP alone at cut-off values of 20, 200, and 400ng/mL, respectively, to 45.71% with IGFBP7 promoter methylation taken into consideration (all P<0.05). These results suggested that combined quantitative measurement of serum IGFBP7 promoter methylation could enhance the diagnostic ability of AFP in distinguishing hepatitis B virus-associated HCC from CHB.



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PATHOBIOLOGY OF HER 2 POSITIVE SMALL INVASIVE (T1a,b) BREAST CANCER: A WOLF IN SHEEP'S CLOTHING

Publication date: Available online 9 October 2017
Source:Pathology - Research and Practice
Author(s): Joško Bezić, Ivana Šamija Projić, Petar Projić, Kristina Meljanac Salopek, Piero Marin Živković, Joško Božić, Snježana Tomić
Small invasive breast cancers (cancers with maximum diameter <1cm, T1a,b) become more prevalent form of breast cancer as a result of the introduction of breast cancer mammographic screening programs. Although associated with an excellent prognosis, T1a,b breast cancers are heterogeneous group of tumors with prognostically unfavorable subset of cases, primarily those with axillary lymph node metastases. To determine if the HER2 overexpression is associated with the prognostically unfavorable traditional clinicopathological features in this group of breast cancers, clinicopathological features (age, tumor size, histological type, histological grade, nodal status, hormone receptor status, proliferation index, lymphovascular invasion, ploidy) of 38 HER2 positive T1a,b cancers were compared with those of the control group consisting of 315 HER2 negative T1a,b cancers. The comparison of clinicopathological features was made using χ² and t-test. HER2 positive T1a,b breast cancers were significantly associated with higher tumor grades (p<0.001), negative hormone receptors (p=0.008), presence of lymphovascular invasion (p=0.025), high proliferation index (p<0.001), and abnormal DNA content (p=0.04). We also noticed the higher frequency of lymph node positive cases in the HER2 positive group of cancers (p=0.05). There were no differences in age, tumor size and histological type between investigated groups. Our group of HER2 positive T1a,b breast cancers was associated with many unfavorable traditional prognostic factors, demonstrating that this subtype of early breast cancer has an aggressive biological phenotype which may have potential benefit from adjuvant chemo and immunotherapy.



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The correlation between XIAP gene polymorphisms and esophageal squamous cell carcinoma susceptibility and prognosis in a Chinese population

Publication date: Available online 9 October 2017
Source:Pathology - Research and Practice
Author(s): Hai Peng, Li-Guo Wang, Xue-Zhi Wang, Ai-Jun Liu
ObjectiveThis study aims to explore the correlation between X-linked inhibitor of apoptosis protein (XIAP) gene polymorphisms (rs8371 and rs9856) with the susceptibility and prognosis of esophageal squamous cell carcinoma (ESCC), providing a potential treatment for ESCC.MethodA total of 170 ESCC patients (case group) and 191 healthy people (control group) were enrolled in our study. Genotyping was conducted on the basis of the ligase detection reaction (LDR). The expressions of XIAP polymorphisms were detected. The patients were followed up every three months until death or the last follow-up day. The overall survival (OS) and progression free survival (PFS) were recorded by Kaplan-Meier survival curve, and the relationship between XIAP gene polymorphism and risk and prognosis of ESCC was assessed by Cox multivariate analysis.ResultTT+CT genotype and T allele frequencies of XIAP rs8371 and rs9856 in the case group were significantly lower compared to those of the control group (all P<0.05), suggesting that TT+CT genotype of XIAP rs8371 and rs9856 was associated with ESCC susceptibility. XIAP rs8371 and rs9856 polymorphisms were associated with tumor node metastasis (TNM) staging, depth of invasion and lymph node metastasis. The OS and PFS of TT+CT genotype carriers of rs8371 were longer than those of CC genotype carriers. Smoking, alcohol, TNM staging, depth of invasion, and lymph node metastasis were significantly associated with the OS and PFS in ESCC patients. Higher TNM staging, depth of invasion, and presence of lymph node metastasis were independent risk factors, while XIAP rs8371 was an independent protective factor for the prognosis of ESCC patients.ConclusionThe present study demonstrates that XIAP rs8371 and rs9856 are associated with susceptibility to ESCC, and rs8371 polymorphisms might serve as an indicator for improved clinical efficacy and prognosis of ESCC patients.



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Comparative Assessment of three Methods to Analyze MGMT Methylation Status in a Series of 350 Gliomas and Gangliogliomas

Publication date: Available online 10 October 2017
Source:Pathology - Research and Practice
Author(s): Leiming Wang, Zhuo Li, Cuicui Liu, Li Chen, Li Liu, Zeliang Hu, Lihong Zhao, Dehong Lu, Lianghong Teng
MGMT promoter methylation is considered as a prognostic and predictive biomarker indicating response to chemotherapy and radiotherapy in glioblastoma. A number of different methods and platforms including pyrosequencing (PSQ), quantitative methylation-specific PCR (qMSP) and immunohistochemistry (IHC), methylation-sensitive high resolution melting (MS-HRM) and NGS (Next Generation Sequencing) have been used to detect MGMT promoter methylation in gliomas. However, controversy remains about the most appropriate method to use for analyzing MGMT status. The MGMT promoter methylation status of a total of 350 gliomas and gangliogliomas was examined using PSQ, qMSP and IHC in parallel. Using PSQ as a recommended standard method, the sensitivity, specificity, positive/negative predictive value and correlation with the other assays were calculated. Among 350 glioma- and ganglioglioma cases, the MGMT promoter tested positive for methylation in 53.1%, 55.4%, and 70.3% of the cases by PSQ, qMSP and IHC, respectively. The sensitivity and specificity of qMSP were 97.8% and 92.7%, respectively. Twelve cases that tested positive for methylation using qMSP were negative according to PSQ, and four cases that were negative according to qMSP tested positive according to PSQ. The concordance rate between PSQ and qMSP was 90.8%. The sensitivity and specificity of IHC for the detection of MGMT at the protein level were 84.4% and 45.7%, respectively. The concordance rate between PSQ and IHC was 30.8%.This study demonstrated that qMSP is an effective and rapid detection method for routine use in pathology laboratories for the identification of MGMT promoter methylation. A combination of IHC and qMSP assays can provide high sensitivity and specificity for the prediction of MGMT status. A few cases that tested negative with PSQ did harbor MGMT promoter methylation, as confirmed by qMSP and sequencing, and this subgroup of patients may benefit from temozolomide.



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Synergy between air pollution and urban meteorological changes through aerosol-radiation-diffusion feedback―A case study of Beijing in January 2013

Publication date: Available online 10 October 2017
Source:Atmospheric Environment
Author(s): Mizuo Kajino, Hiromasa Ueda, Zhiwei Han, Rei Kudo, Yayoi Inomata, Hidenori Kaku
The interactions of aerosol-radiation-stratification-turbulence-cloud processes during a severe haze event in Beijing in January 2013 were studied using a numerical model. For the clear days, solar radiation flux was reduced by approximately 15% and surface temperature was slightly decreased from 0 to 0.5 K throughout the day and night, except for a 1.4 K decrease around sunrise when fog was presented. The longwave radiation cooling was intensified by the fog or drizzle droplets near the top of the fog layer. Thus, in Beijing, both in the daytime and at night, the surface air temperature was decreased by air pollutants. In the presence of the low-level stratus and light precipitation, the modification of meteorology by aerosols was amplified and changed the wind speed and direction much more significantly compared to clear days. The non-linear effect (or positive feedback) of pollutant emission control on the surface air concentration was newly assessed―severe air pollution leads to the intensification of stable stratification near the surface at night and delays the evolution of the mixing layer, which in turn causes more severe air pollution. The non-linear effect was not significant for the current emission levels in the current case, approximately 10%. In another word, the mixing ratio of aerosols became higher by 10% due to their radiation effects.



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Involvement of mitochondrial pathway in environmental metal pollutant lead-induced apoptosis of chicken liver: perspectives from oxidative stress and energy metabolism

Abstract

This study aimed to investigate the possible mechanisms of environmental metal pollutant lead (Pb)-induced apoptosis in chicken. Forty 8-day-old healthy chickens were randomly assigned to two groups (n = 20/group) after raising standard commercial diet and drinking water for 1 week: including control group and Pb group ((CH₃COO)₂Pb 350 mg/L of drinking water); the chickens were given euthanasia and collected livers at 90 days. A significant increase of apoptosis rate were found in Pb group and Pb induced obvious ultrastructural changes of chicken liver. The mRNA levels of glycometabolism key enzymes were significantly lower in Pb group than those in controls. Higher levels of malondialdehyde (MDA) and nitric oxide (NO) were observed in Pb group; the activities of antioxidant enzymes and ATPases were significantly lower in Pb group than those in controls, while the inducible nitric oxide synthase (iNOS) activity was on the contrary. The mRNA and protein levels of pro-apoptotic genes were all lower in Pb group than those in controls. Altogether, Pb-induced mitochondrial swelling and nuclear chromatin condensation, oxidative stress, energy metabolism disorder, thereby lead to apoptosis via mitochondrial pathway in chicken liver, suggesting that Pb-induced mitochondrial pathway apoptosis plays an important role in the mechanisms of Pb cytotoxicity to chicken liver.

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Organ-on-chip models of cancer metastasis for future personalized medicine: From chip to the patient

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): D. Caballero, S. Kaushik, V.M. Correlo, J.M. Oliveira, R.L. Reis, S.C. Kundu
Most cancer patients do not die from the primary tumor but from its metastasis. Current in vitro and in vivo cancer models are incapable of satisfactorily predicting the outcome of various clinical treatments on patients. This is seen as a serious limitation and efforts are underway to develop a new generation of highly predictive cancer models with advanced capabilities. In this regard, organ-on-chip models of cancer metastasis emerge as powerful predictors of disease progression. They offer physiological-like conditions where the (hypothesized) mechanistic determinants of the disease can be assessed with ease. Combined with high-throughput characteristics, the employment of organ-on-chip technology would allow pharmaceutical companies and clinicians to test new therapeutic compounds and therapies. This will permit the screening of a large battery of new drugs in a fast and economic manner, to accelerate the diagnosis of the disease in the near future, and to test personalized treatments using cells from patients. In this review, we describe the latest advances in the field of organ-on-chip models of cancer metastasis and their integration with advanced imaging, screening and biosensing technologies for future precision medicine applications. We focus on their clinical applicability and market opportunities to drive us forward to the next generation of tumor models for improved cancer patient theranostics.



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Translating the role of osteogenic-angiogenic coupling in bone formation: Highly efficient chitosan-pDNA activated scaffolds can accelerate bone regeneration in critical-sized bone defects

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): Rosanne M. Raftery, Irene Mencía Castaño, Gang Chen, Brenton Cavanagh, Brian Quinn, Caroline M. Curtin, Sally Ann Cryan, Fergal J. O'Brien
The clinical translation of bioactive scaffolds for the treatment of large segmental bone defects has remained a challenge due to safety and efficacy concerns as well as prohibitive costs. The design of an implantable, biocompatible and resorbable device, which can fill the defect space, allow for cell infiltration, differentiation and neovascularisation, while also recapitulating the natural repair process and inducing cells to lay down new bone tissue, would alleviate the problems with existing treatments. We have developed a gene-activated scaffold platform using a bone-mimicking collagen hydroxyapatite scaffold loaded with chitosan nanoparticles carrying genes encoding osteogenic (BMP-2) and angiogenic (VEGF) proteins. With a single treatment, protein expression by mesenchymal stem cells (MSCs) seeded onto the scaffold is sustained for up to 28 days and is functional in inducing MSC osteogenesis. The in vivo safety and efficacy of this gene-activated scaffold platform was demonstrated resulting in the successful transfection of host cells, abrogating the requirement for multiple procedures to isolate cells or ex vivo cell culture. Furthermore, the level of bone formation at the exceptionally early time-point of 28 days was comparable to that achieved following recombinant BMP-2 protein delivery after 8 weeks in vivo, without the adverse side effects and at a fraction of the cost. This naturally derived cell-free gene-activated scaffold thus represents a new 'off-the-shelf' product capable of accelerating bone repair in critical-sized bone defects.



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Radiation, radionuclides and bacteria: An in-perspective review

Publication date: December 2017
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Arpit Shukla, Paritosh Parmar, Meenu Saraf
There has been a significant surge in consumption of radionuclides for various academic and commercial purposes. Correspondingly, there has been a considerable amount of generation of radioactive waste. Bacteria and archaea, being earliest inhabitants on earth serve as model microorganisms on earth. These microbes have consistently proven their mettle by surviving extreme environments, even extreme ionizing radiations. Their ability to accept and undergo stable genetic mutations have led to development of recombinant mutants that are been exploited for remediation of various pollutants such as; heavy metals, hydrocarbons and even radioactive waste (radwaste). Thus, microbes have repeatedly presented themselves to be prime candidates suitable for remediation of radwaste. It is interesting to study the behind-the-scenes interactions these microbes possess when observed in presence of radionuclides. The emphasis is on the indigenous bacteria isolated from radionuclide containing environments as well as the five fundamental interaction mechanisms that have been studied extensively, namely; bioaccumulation, biotransformation, biosorption, biosolubilisation and bioprecipitation. Application of microbes exhibiting such mechanisms in remediation of radioactive waste depends largely on the individual capability of the species. Challenges pertaining to its potential bioremediation activity is also been briefly discussed. This review provides an insight into the various mechanisms bacteria uses to tolerate, survive and carry out processes that could potentially lead the eco-friendly approach for removal of radionuclides.

Graphical abstract

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Examining temporal alterations in Social Anxiety Disorder and Posttraumatic Stress Disorder: The relation between autobiographical memory, future goals, and current self-views

Publication date: Available online 9 October 2017
Source:Journal of Anxiety Disorders
Author(s): Julie Krans, Manon Peeters, Gérard Näring, Adam D. Brown, June de Bree, Agnes van Minnen
The self is a multi-faceted and temporally dynamic construct reflecting representations and beliefs about identity in the past, present, and future. Clinical studies have shown that individuals with Posttraumatic Stress Disorder (PTSD) and Social Anxiety Disorder (SAD) exhibit alterations in self-related processing but these studies have focused primarily on memory. Few studies in PTSD and SAD have examined self-related processing for the present and future, and no studies have directly compared these processes across these two disorders. Individuals diagnosed with PTSD (n=21), SAD (n=21), and healthy controls (n=21) completed cognitive tasks related to the past, present, and future. Disorder congruent temporal alterations were found across both disorders. Further, regression analyses revealed that trauma-related memories were significantly predicted by future goals related to the trauma, whereas social anxiety-related recall was predicted by current socially anxious self-views. Thus, although self-related processing may be common in PTSD and SAD, those aspects of the self most strongly associated with disorder-congruent recall differ by disorder. Self-alterations may be modifiable and developing a better understanding of past, present, and future self-processing might aid in the development of interventions that target these process.



http://ift.tt/2g7DOGf

Coating of silicone with mannoside-PAMAM dendrimers to enhance formation of non-pathogenic Escherichia coli biofilms against colonization of uropathogens

Publication date: Available online 9 October 2017
Source:Acta Biomaterialia
Author(s): Zhiling Zhu, Fei Yu, Haoqing Chen, Jun Wang, Analette I. Lopez, Quan Chen, Siheng Li, Yuyu Long, Rabih O. Darouiche, Richard A. Hull, Lijuan Zhang, Chengzhi Cai
Bacterial interference using non-pathogenic Escherichia coli 83972 is a novel strategy for preventing catheter-associated urinary tract infection (CAUTI). Crucial to the success of this strategy is to establish a high coverage and stable biofilm of the non-pathogenic bacteria on the catheter surface. However, this non-pathogenic strain is sluggish to form biofilms on silicone as the most widely used material for urinary catheters. We have addressed this issue by modifying the silicone catheter surfaces with mannosides that promote the biofilm formation, but the stability of the non-pathogenic biofilms challenged by uropathogens over long-term remains a concern. Herein, we report our study on the stability of the non-pathogenic biofilms grown on propynylphenyl mannoside-modified silicone. The result shows that 94% non-pathogenic bacteria were retained on the modified silicone under >0.5 Pa shear stress. After being challenged by three multidrug-resistant uropathogenic isolates in artificial urine for 11 days, large amounts (>4 × 10⁶ CFU cm^-2) of the non-pathogenic bacteria remained on the surfaces. These non-pathogenic biofilms reduced the colonization of the uropathogens by >3.2-log.Statement of SignificanceIn bacterial interference, the non-pathogenic Escherichia coli strains are sluggish to form biofilms on the catheter surfaces, due to rapid removal by urine flow. We have demonstrated a solution to this bottleneck by pre-functionalization of mannosides on the silicone surfaces to promote E. coli biofilm formation. A pre-conjugated high affinity propynylphenyl mannoside ligand tethered to the nanometric amino-terminated poly(amido amine) (PAMAM) dendrimer is used for binding to a major E. coli adhesin FimH. It greatly improves the efficiency for the catheter modification, the non-pathogenic biofilm coverage, as well as the (long-term) stability for prevention of uropathogen infections.

Graphical abstract

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Proteomics of Periodontal Pocket

Abstract

Purpose of Review

This study aims to present and evaluate the findings of the literature referring to proteomic analysis of the periodontal pocket aimed to identify potential biomarkers for periodontal disease.

Recent Findings

A comprehensive examination of data from "shotgun" proteomic analysis has shown that a number of human proteins, previously not extensively investigated in the literature, have emerged as new candidates. Proteins relevant to various biological functions such as actin, profilin, hemoglobin, plastins, alpha-amylase, matrix metalloproteinases, keratins, histones, annexins, antimicrobial peptides including histatins, S-100A9, cathelicidin-related peptide-37 (LL-37), human neutrophil peptides (HNP)-1, -2, and -3, statherin, and cystatins are commonly identified in gingival crevicular fluid (GCF) by proteomic analysis and are upregulated in periodontal disease and therefore could serve as biomarkers.

Conclusions

Proteomic analysis has provided a new insight into the search for biomarkers of periodontal disease presence, progression, prognosis, and endpoints of treatment. Data derived should be validated by larger scale studies, including significant subject samples. These second-stage studies should focus on evaluating the importance of these proposed new biomarkers using standardized procedures.

http://ift.tt/2kBVYBt

Periodontal Abscess: a Review and the Role of Antimicrobial Therapy

Abstract

Purpose of Review

The aim was to summarize current knowledge about periodontal abscesses and describe recent research on antimicrobial treatment.

Recent Findings

For periodontal abscess treatment, antimicrobial therapy is implemented as an adjunct modality to subgingival debridement and/or abscess drainage. Among available systemic antimicrobial agents, amoxicillin (plus clavulanate), metronidazole, and azithromycin are often used with good clinical results. In our studies of patients with acute periodontal lesions, systemic administration of a new fluoroquinolone, sitafloxacin, yielded a significant improvement in clinical parameters, and was effective against subgingival bacteria, with no significant impact on the antimicrobial susceptibility of periodontal bacteria.

Summary

Plaque control during initial periodontal therapy or maintenance care is critical for the prevention and treatment of periodontal abscesses. In the case of acute periodontal abscesses, drainage is considered first. When drainage is not possible or insufficient, antimicrobial therapy should then be considered. Microbiological testing can contribute to the successful treatment.

http://ift.tt/2xsUiQN

Who Would Be Branded With Failure?.

Author: Stevenson, Lynne Warner MD

Page: 1359-1361

http://ift.tt/2zazMBz

Prolonged, Uninterrupted Sedentary Behavior and Glycemic Biomarkers Among US Hispanic/Latino Adults: The HCHS/SOL (Hispanic Community Health Study/Study of Latinos).

Author: Diaz, Keith M. PhD; Goldsmith, Jeff PhD; Greenlee, Heather ND, PhD; Strizich, Garrett MPH; Qi, Qibin PhD; Mossavar-Rahmani, Yasmin PhD; Vidot, Denise C. PhD; Buelna, Christina MA; Brintz, Carrie E. PhD; Elfassy, Tali PhD; Gallo, Linda C. PhD; Daviglus, Martha L. MD, PhD; Sotres-Alvarez, Daniela DrPH; Kaplan, Robert C. PhD

Page: 1362-1373

http://ift.tt/2xtULSX

Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency.

Author: van Veldhuisen, Dirk J. MD; Ponikowski, Piotr MD; van der Meer, Peter MD; Metra, Marco MD; Bohm, Michael MD; Doletsky, Artem MD; Voors, Adriaan A. MD; Macdougall, Iain C. MD; Anker, Stefan D. MD; Roubert, Bernard MSc; Zakin, Lorraine MD; Cohen-Solal, Alain MD; On Behalf of the EFFECT-HF Investigators

Page: 1374-1383

http://ift.tt/2zbelQY

"Pumping Iron" to Improve Exercise Performance in Heart Failure: New Data and New Guidelines.

Author: Katz, Stuart D. MD, MS

Page: 1384-1386

http://ift.tt/2xsTbk5

Outcomes Associated With Extraction Versus Capping and Abandoning Pacing and Defibrillator Leads.

Author: Pokorney, Sean D. MD, MBA; Mi, Xiaojuan PhD; Lewis, Robert K. MD, MBA, PhD; Greiner, Melissa MS; Epstein, Laurence M. MD; Carrillo, Roger G. MD, MBA; Zeitler, Emily P. MD, MHS; Al-Khatib, Sana M. MD, MHS; Hegland, Donald D. MD; Piccini, Jonathan P. MD, MHS

Page: 1387-1395

http://ift.tt/2zazOcF

Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury.

Author: Lacraz, Gregory P.A. MSc, PhD *; Junker, Jan Philipp MSc, PhD *; Gladka, Monika M. MSc, PhD; Molenaar, Bas MSc; Scholman, Koen T. MSc; Vigil-Garcia, Marta MSc; Versteeg, Danielle BS; de Ruiter, Hesther BS; Vermunt, Marit W. MSc, PhD; Creyghton, Menno P. MSc, PhD; Huibers, Manon M.H. MSc, PhD; de Jonge, Nicolaas MD; van Oudenaarden, Alexander MSc, PhD; van Rooij, Eva MSc, PhD

Page: 1396-1409

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Spatial Gene Profiling in the Ischemic Heart: Fibroblasts Put on Their SOX.

Author: Khalil, Hadi PhD; Maillet, Marjorie PhD; Molkentin, Jeffery D. PhD

Page: 1410-1411

http://ift.tt/2zb7Fm3

Interferon Regulatory Factor 4 Inhibits Neointima Formation by Engaging Kruppel-Like Factor 4 Signaling.

Author: Cheng, Wen-Lin MD *; She, Zhi-Gang MD, PhD *; Qin, Juan-Juan MD *; Guo, Jun-Hong PhD; Gong, Fu-Han MD; Zhang, Peng PhD; Fang, Chun PhD; Tian, Song BS; Zhu, Xue-Yong BS; Gong, Jun PhD; Wang, Zhi-Hua PhD; Huang, Zan PhD; Li, Hongliang MD, PhD

Page: 1412-1433

http://ift.tt/2xtKeHk

Wine and Cardiovascular Health: A Comprehensive Review.

Author: Haseeb, Sohaib BSc; Alexander, Bryce BSc; Baranchuk, Adrian MD

Page: 1434-1448

http://ift.tt/2zaPMUq

Scientists Correct a Pathogenic Gene Mutation in Human Embryos.

Author: Hampton, Tracy PhD

Page: 1449-1450

http://ift.tt/2xuowmr

Sedentary Behavior and Subclinical Cardiac Injury: Results From the Dallas Heart Study.

Author: Harrington, Josephine L. MD; Ayers, Colby MS; Berry, Jarett D. MD; Omland, Torbjorn MD, PhD; Pandey, Ambarish MD; Seliger, Stephen L. MD, MS; Ballantyne, Christie M. MD; Kulinski, Jacquelyn MD; deFilippi, Christopher R. MD; de Lemos, James A. MD

Page: 1451-1453

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Letter by Vos et al Regarding Article, "Primary Prevention With Statin Therapy in the Elderly: New Meta-Analyses From the Contemporary JUPITER and HOPE-3 Randomized Trials".

Author: Vos, Eddie MEng; Biron, Pierre MD; Rose, Colin P. MD, PhD

Page: 1454-1455

http://ift.tt/2xtQ0so

Letter by Kleipool et al Regarding Article, "Primary Prevention With Statin Therapy in the Elderly: New Meta-Analyses From the Contemporary JUPITER and HOPE-3 Randomized Trials".

Author: Kleipool, Emma E.F. MD; Peters, Mike J.L. MD, PhD; Muller, Majon MD, PhD

Page: 1456-1457

http://ift.tt/2zbRwge

On the interactions among zinc availability and responses to ozone stress in durum wheat seedlings

Abstract

Seedlings of durum wheat [Triticum turgidum subsp. durum (Desf.) Husn] were exposed to zinc nutrition and to ozone (O₃) in a factorial combination: adequate (+Zn treatment) or no Zn (−Zn) in the nutrient solution, followed by exposure to either ozone-free air (filtered air, FA) or to 150 nL L⁻¹ ozone (O₃) for 4 h. Although omitting Zn from the nutrient solution failed to impose a genuine Zn deficiency, −Zn*FA durum wheat seedlings showed a typical deficiency behaviour, i.e. Zn mobilisation from root to shoot. Such inter-organ Zn redistribution, however, did not occur in −Zn*O₃ plants. Exposure to each stress singly decreased the activity and the protein amount of foliar plasma membrane H⁺-ATPase, but not stress combination, which even increased the H⁺-ATPase expression with respect to control. In the −Zn*O₃ plants, moreover, the foliar activities of the plasma membrane-bound NAD(P)H-dependent superoxide synthase and of Cu,Zn-superoxide dismutase, and the transcripts abundance of the luminal binding protein and of the protein disulphide isomerase, were also stimulated. It is proposed that, even in the absence of actual Zn starvation, the perception of deficiency conditions could trigger changes in redox homoeostasis at the plasma membrane level, helpful in compensating an O₃-dependent oxidative damage.

http://ift.tt/2g66r6O

Using principal trabecular orientation to differentiate joint loading orientation in the 3rd metacarpal heads of humans and chimpanzees

Publication date: December 2017
Source:Journal of Human Evolution, Volume 113
Author(s): Meir M. Barak, Emma Sherratt, Daniel E. Lieberman
If Wolff's law is valid, then quantifying the three-dimensional architecture of trabecular bone, specifically 3D principal trabecular orientation (3D-PTO), can reveal joint loading direction among different taxa. This study measured the architecture of trabecular bone in the 3rd metacarpal head of humans and chimpanzees, and then tested their association with expected joint loading direction. We postulate that since chimpanzees, unlike humans, directly load their metacarpal bones during knuckle-walking, trabecular structure in the dorsal aspect of the 3rd metacarpal head will be significantly more organized and robust in chimpanzees. To test this hypothesis, we micro-CT scanned the 3rd metacarpal from 11 chimpanzees and 12 humans. Three 6 mm volumes of interest (VOI; palmar, center and dorsal) were selected and trabecular bone properties and 3D-PTO were measured. The results revealed many similarities between humans and chimpanzees: in both taxa the dorsal VOI demonstrated the lowest bone volume fraction (BV/TV), the most rod-like trabecular structure, the fewest and thinnest trabeculae, and low organization of the trabecular architecture (degree of anisotropy). Nevertheless, 3D-PTO in the dorsal VOI differed significantly between humans and chimpanzees. While 3D-PTO in humans was clustered together and aligned nearly along the bone long axis, in chimpanzees 3D-PTO was divided into two distinct groups and aligned with an angle toward either the medial or lateral orientations. Our results suggest that loading effects on trabecular bone properties such as BV/TV might be partially constrained by genetic factors. On the other hand, 3D-PTO is continually affected by active loading (i.e., modeling) and thus may serve as a useful tool to infer differences in joint loading directions.



http://ift.tt/2yceOnZ

Lessons from Yeast on How to Avoid Stress Eating

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Jean A. Smith, Amy S. Gladfelter
Cellular survival during periods of acute environmental stress is essential for single-celled organisms. Reporting in Nature Cell Biology, Saad et al. (2017) identify reversible aggregation of the metabolic enzyme pyruvate kinase under environmental stress and propose a method to protect and store proteins for immediate use post-stress.

Teaser

Cellular survival during periods of acute environmental stress is essential for single-celled organisms. Reporting in Nature Cell Biology, Saad et al. (2017) identify reversible aggregation of the metabolic enzyme pyruvate kinase under environmental stress and propose a method to protect and store proteins for immediate use post-stress.


http://ift.tt/2gpsD8U

Accessing the Phenotype Gap: Enabling Systematic Investigation of Paralog Functional Complexity with CRISPR

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Ben Ewen-Campen, Stephanie E. Mohr, Yanhui Hu, Norbert Perrimon
Single-gene knockout experiments can fail to reveal function in the context of redundancy, which is frequently observed among duplicated genes (paralogs) with overlapping functions. We discuss the complexity associated with studying paralogs and outline how recent advances in CRISPR will help address the "phenotype gap" and impact biomedical research.

Teaser

Single-gene knockout experiments can fail to reveal function in the context of redundancy, which is frequently observed among duplicated genes (paralogs) with overlapping functions. We discuss the complexity associated with studying paralogs and outline how recent advances in CRISPR will help address the "phenotype gap" and impact biomedical research.


http://ift.tt/2y4rm10

Microtubule Sliding within the Bridging Fiber Pushes Kinetochore Fibers Apart to Segregate Chromosomes

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Kruno Vukušić, Renata Buđa, Agneza Bosilj, Ana Milas, Nenad Pavin, Iva M. Tolić
During cell division, mitotic spindle microtubules segregate chromosomes by exerting forces on kinetochores. What forces drive chromosome segregation in anaphase remains a central question. The current model for anaphase in human cells includes shortening of kinetochore fibers and separation of spindle poles. Both processes require kinetochores to be linked with the poles. Here we show, by combining laser ablation, photoactivation, and theoretical modeling, that kinetochores can separate without any attachment to one spindle pole. This separation requires the bridging fiber, a microtubule bundle that connects sister kinetochore fibers. Bridging fiber microtubules in intact spindles slide apart with kinetochore fibers, indicating strong crosslinks between them. We conclude that sliding of microtubules within the bridging fibers drives pole separation and pushes kinetochore fibers poleward by the friction of passive crosslinks between these fibers. Thus, sliding within the bridging fiber works together with the shortening of kinetochore fibers to segregate chromosomes.

Graphical abstract

Teaser

The forces that drive chromosome segregation in mitosis in human cells remain poorly understood. Vukušić, Buđa et al. combine laser ablation, photoactivation, and theory to uncover a key role for bridging fibers, non-kinetochore microtubule bundles, in spindle pole separation. Forces from kinetochore and bridging fiber crosslinking contribute to chromosome segregation.


http://ift.tt/2gqkz7X

Germline Genome Protection on an Evolutionary Treadmill

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Yuh Chwen G. Lee, Mia T. Levine
Preservation of genome integrity is a conserved, essential function, yet genome defense machinery evolves rapidly. In this issue of Developmental Cell, Parhad et al. (2017) harness an evolution-guided approach to define the genetic determinants of genome defense and to reveal the molecular and cellular mechanisms shaped by adaptive evolution.

Teaser

Preservation of genome integrity is a conserved, essential function, yet genome defense machinery evolves rapidly. In this issue of Developmental Cell, Parhad et al. (2017) harness an evolution-guided approach to define the genetic determinants of genome defense and to reveal the molecular and cellular mechanisms shaped by adaptive evolution.


http://ift.tt/2gqqBW7

Fgf10-Hippo Epithelial-Mesenchymal Crosstalk Maintains and Recruits Lung Basal Stem Cells

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Thomas Volckaert, Tingting Yuan, Cho-Ming Chao, Harold Bell, Alina Sitaula, Luisa Szimmtenings, Elie El Agha, Diptiman Chanda, Susan Majka, Saverio Bellusci, Victor J. Thannickal, Reinhard Fässler, Stijn P. De Langhe
The lung harbors its basal stem/progenitor cells (BSCs) in the protected environment of the cartilaginous airways. After major lung injuries, BSCs are activated and recruited to sites of injury. Here, we show that during homeostasis, BSCs in cartilaginous airways maintain their stem cell state by downregulating the Hippo pathway (resulting in increased nuclear Yap), which generates a localized Fgf10-expressing stromal niche; in contrast, differentiated epithelial cells in non-cartilaginous airways maintain quiescence by activating the Hippo pathway and inhibiting Fgf10 expression in airway smooth muscle cells (ASMCs). However, upon injury, surviving differentiated epithelial cells spread to maintain barrier function and recruit integrin-linked kinase to adhesion sites, which leads to Merlin degradation, downregulation of the Hippo pathway, nuclear Yap translocation, and expression and secretion of Wnt7b. Epithelial-derived Wnt7b, then in turn, induces Fgf10 expression in ASMCs, which extends the BSC niche to promote regeneration.

Graphical abstract

Teaser

Volckaert et al. demonstrate a novel mode of stem cell regulation in which basal stem cells during homeostasis or differentiated airway epithelial cells after injury downregulate their Hippo signaling to generate their own localized Fgf10-expressing stromal niche, which maintains or amplifies the stem/progenitor cell population via Fgf10-Fgfr2b signaling.


http://ift.tt/2y4WOMP

Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Nadine Kirsch, Ling-Shih Chang, Stefan Koch, Andrey Glinka, Christine Dolde, Gabriele Colozza, Maria D.J. Benitez, Edward M. De Robertis, Christof Niehrs
Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/β-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.

Teaser

Kirsch et al. identify ANGPTL4 as an antagonist of the Wnt/β-catenin signaling pathway. ANGPTL4 binds syndecans to induce internalization and lysosomal degradation of the Wnt co-receptor LRP6, thereby inhibiting Wnt/β-catenin signaling. In Xenopus embryos, angptl4 is expressed in the Spemann organizer and antagonizes Wnt to promote notochord development.


http://ift.tt/2y4WFJh

A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Akhila Rajan, Benjamin E. Housden, Frederik Wirtz-Peitz, Laura Holderbaum, Norbert Perrimon
Adipocytes sense systemic nutrient status and systemically communicate this information by releasing adipokines. The mechanisms that couple nutritional state to adipokine release are unknown. Here, we investigated how Unpaired 2 (Upd2), a structural and functional ortholog of the primary human adipokine leptin, is released from Drosophila fat cells. We find that Golgi reassembly stacking protein (GRASP), an unconventional secretion pathway component, is required for Upd2 secretion. In nutrient-rich fat cells, GRASP clusters in close proximity to the apical side of lipid droplets (LDs). During nutrient deprivation, glucagon-mediated increase in calcium (Ca²⁺) levels, via calmodulin kinase II (CaMKII) phosphorylation, inhibits proximal GRASP localization to LDs. Using a heterologous cell system, we show that human leptin secretion is also regulated by Ca²⁺ and CaMKII. In summary, we describe a mechanism by which increased cytosolic Ca²⁺ negatively regulates adipokine secretion and have uncovered an evolutionarily conserved molecular link between intracellular Ca²⁺ levels and energy homeostasis.

Graphical abstract

Teaser

Rajan et al. identify a mechanism coupling nutrient status to adipocyte-mediated adipokine secretion involving glucagon-mediated calcium signaling and GRASP, an unconventional secretion protein. In fly fat cells, leptin ortholog Upd2 is associated with GRASP near lipid droplets, and, upon nutrient deprivation, increased calcium levels negatively regulate adipokine secretion via GRASP.


http://ift.tt/2grgcJT

Atrial myxomas causing severe left and right ventricular dysfunction

Aanchal Dixit, Prabhat Tewari, Rashmi Soori, Surendra Kumar Agarwal

Annals of Cardiac Anaesthesia 2017 20(4):450-452

Myxomas are the most common cardiac tumors, accounting for about 50% of benign primary cardiac tumors, with the majority located in the left atrium, and 80% of which originate in the interatrial septum. We report two cases with severe cachexia, neurological sequelae, and severe biventricle dysfunction secondary to atrial myxomas with marked early improvement after tumor excision.

http://ift.tt/2kC9ViX

Think beyond right bundle branch block in atrial septal defect

Monish S Raut, Arvind Verma, Arun Maheshwari, Ganesh Shivnani

Annals of Cardiac Anaesthesia 2017 20(4):475-476



http://ift.tt/2yUXst5

Congenital syndromes affecting heart and airway alike

Rajinder Singh Rawat

Annals of Cardiac Anaesthesia 2017 20(4):393-394



http://ift.tt/2yUrZqE

The use of intravenous hydroxocobalamin as a rescue in methylene blue-resistant vasoplegic syndrome in cardiac surgery

Yi Cai, Anwar Mack, Beth L Ladlie, Archer Kilbourne Martin

Annals of Cardiac Anaesthesia 2017 20(4):462-464

Vasoplegic syndrome is a well-recognized complication during cardiopulmonary bypass (CPB) and is associated with increased morbidity and mortality, especially when refractory to conventional vasoconstrictor therapy. This is the first reported case of vasoplegia on CPB unresponsive to methylene blue whereas responsive to hydroxocobalamin, which indicates that the effect of hydroxocobalamin outside of the nitric oxide system is significant or that the two drugs have a synergistic effect in one or multiple mechanisms.

http://ift.tt/2kE3Y5c

Low-dose intravenous ketamine for postcardiac surgery pain: Effect on opioid consumption and the incidence of chronic pain

Jennifer Cogan, Geneviève Lalumière, Grisell Vargas-Schaffer, Alain Deschamps, Zeynep Yegin

Annals of Cardiac Anaesthesia 2017 20(4):395-398

Background: Recent meta-analyses have concluded that low-dose intravenous ketamine infusions (LDKIs) during the postoperative period may help to decrease acute and chronic postoperative pain after major surgery. Aims: This study aims to evaluate the level of pain at least 3 months after surgery for patients treated with a postoperative LDKI versus patients who were not treated with a postoperative LDKI. Methods: Administrative and Ethics Board approval were obtained for this study. We performed a retrospective chart review for all patients receiving LDKI, and equal number of age-, sex-, and surgery-matched patients who did not receive LDKI. Low-dose ketamine was prepared using 100 mg of ketamine in 100 ml of normal saline and run between 50 and 200 mcg/kg/h. Results: We reviewed 115 patients with LDKI and 115 without LDKI. The average age was 63.1 years, 73% of the patients were men and sex was evenly distributed between LDKI and non-LDKI. The average duration of the ketamine infusions was 26.8 h with the average dose being 169.9 mg. At an average of 9 months after surgery, 42% of the ketamine group and 38% of the nonketamine group stated that they had had pain on discharge. Of these patients, 30% of the ketamine group and 26% of the nonketamine group still had pain at the time of the phone call. Women in both groups had more acute and chronic pain than men. Conclusion: These results show that LDKI does not promote a decrease in long-term postoperative pain.

http://ift.tt/2yUrP2w

An uncommon intraoperative implantable cardiac device complication and subsequent troubleshooting

Rekha Suthar, Omar Viswanath, S Howard Wittels, Gerald P Rosen

Annals of Cardiac Anaesthesia 2017 20(4):483-484



http://ift.tt/2kCMc24

An innovative technique to improve safety of volatile anesthetics suction from the cardiopulmonary bypass circuit

Francesco De Simone, Luigi Cassarà, Salvatore Sardo, Elena Scarparo, Omar Saleh, Caetano Nigro Neto, Alberto Zangrillo, Giovanni Landoni

Annals of Cardiac Anaesthesia 2017 20(4):399-402

Context: Myocardial injury during cardiac surgery on cardiopulmonary bypass (CPB) is a major determinant of morbidity and mortality. Preclinical and clinical evidence of dose- and time-related cardioprotective effects of volatile anesthetic drugs exist and their use during the whole surgery duration could improve perioperative cardiac protection. Even if administering volatile agents during CPB are relatively easy, technical problems, such as waste gas scavenging, may prevent safe and manageable administration of halogenated vapors during CPB. Aims: The aim of this study is to improve the safe administration of volatile anesthesia during CPB. Settings and Design: Tertiary teaching hospital. Subjects and Methods: We describe an original device that collects and disposes of any volatile anesthetic vapors present in the exit stream of the oxygenator, hence preventing its dispersal into the operating theatre environment and adaptively regulates pressure of oxygenator chamber in the CPB circuit. Results: We have so far applied a prototype of this device in more than 1300 adult cardiac surgery patients who received volatile anesthetics during the CPB phase. Conclusions: Widespread implementation of scavenging system like the one we designed may facilitate the perfusionist and the anesthesiologist in delivering these cardioprotective drugs with beneficial impact on patients' outcome without compromising on safety.

http://ift.tt/2kBPId0

Lutembacher syndrome: Dilemma of doing a tricuspid annuloplasty

AV Varsha, Gladdy George, Raj Sahajanandan

Annals of Cardiac Anaesthesia 2017 20(4):456-458

We discuss the case of a 24-year-old woman with Lutembacher syndrome and severe tricuspid regurgitation (TR) who underwent surgical closure of atrial septal defect and mitral valve replacement without tricuspid annuloplasty despite a severe TR and a large tricuspid annulus on preoperative echo. The pathophysiology of Lutembacher syndrome is discussed below. The utility of perioperative echocardiography in assessing the annular diameter, tenting area and coaptation depth and thus providing insights into the functioning of the tricuspid valve will also be emphasized.

http://ift.tt/2yT3hXK

Relationship between perioperative left atrial appendage doppler velocity estimates and new-onset atrial fibrillation in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass

Kunal Sarin, Sandeep Chauhan, Akshay K Bisoi, Poonam Malhotra Kapoor, Parag Gharde, Arindam Choudhury

Annals of Cardiac Anaesthesia 2017 20(4):403-407

Background: Literature search reveals that postoperative atrial fibrillation (POAF) occurs in 15%–40% of coronary artery bypass graft (CABG) patients. Although several risk models exist for predicting the development of POAF, few have studied left atrial appendage (LAA) velocity. We hypothesize that an association between LAA velocity and development of POAF exists. Design and Methods: Single institution university hospital prospective observational clinical study performed between May 2016 and November 2016 in 96 adult patients undergoing CABG surgery utilizing cardiopulmonary bypass (CPB). Transesophageal echocardiography was performed perioperatively to measure LAA velocity and left atrial (LA) size after anesthetic induction, post-CPB and during the postoperative period before extubation. Student's t-test was used for inter-group comparisons. Data are expressed as mean ± (standard deviation). The value of P < 0.05 was considered statistically significant. Results: A total of 95 patients (69 males and 26 females) completed the study and were included in the final analysis. Of these, 21 (22%) (15 males and 5 females) developed POAF. The patient group which developed POAF was compared with the group that did not develop POAF. On comparing mean age of patients in each group (59 years in patients with no POAF and 63.71 years in patients with POAF, P = 0.04). LA volume indexed in POAF group (34.13 ml/m2) compared with that in group with no POAF (34.82 ml/m2) resulted in P = 0.04. Mean LAA velocities (pre-CPB, post-CPB, postoperative Intensive Care Unit) in group with no POAF were 41.06, 56.33, and 60.44 cm/s, respectively, whereas in the other group with POAF the values were 39.68, 55.04, and 58.09 cm/s, respectively. No statistical significance was noted (P > 0.05). Comparison of comorbidities also did not yield any significant results (P > 0.05). Conclusions: Decreasing LAA velocity does not appear to independently predict the development of POAF in patients undergoing CABG surgery with the use of CPB. There is, however, a positive correlation of POAF with age and LA volume.

http://ift.tt/2kBPDWK

Perioperative management of a patient with glanzmann's thrombasthenia for mitral valve repair under cardiopulmonary bypass

Parimala Prasanna Simha, Prasanna Simha Mohan Rao, Deepak Arakalgud, Rakesh Rajashekharappa, Manjunath Narasimhaih

Annals of Cardiac Anaesthesia 2017 20(4):468-471

A 30-year-old male patient presented with Glanzmann's thrombasthenia and mitral valve prolapse. He was in acute decompensated congestive heart failure due to severe mitral and tricuspid regurgitation. After his cardiac failure had been stabilized, the patient was subjected to mitral and tricuspid valve repair. His transfusion requirements were guided by thrombelastography and his bleeding disorder was managed by infusing single donor plasmapheresed platelet transfusions in the perioperative period. The patient underwent surgery uneventfully.

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Comparison of the renoprotective effect of dexmedetomidine and dopamine in high-risk renal patients undergoing cardiac surgery: A double-blind randomized study

Rabie Soliman, Mohamed Hussien

Annals of Cardiac Anaesthesia 2017 20(4):408-415

Objective: The purpose of the current study was to compare the renoprotective effects of continuous infusion of dexmedetomidine and dopamine in high-risk renal patients undergoing cardiac surgery. Design: A double-blind randomized study. Setting: Cardiac Centers. Patients: One hundred and fifty patients with baseline serum creatinine level ≥1.4 mg/dl were scheduled for cardiac surgery with cardiopulmonary bypass. Intervention: The patients were classified into two groups (each = 75): Group Dex – the patients received a continuous infusion of dexmedetomidine 0.4 μg/kg/h without loading dose during the procedure and the first 24 postoperative hours and Group Dopa – the patients received a continuous infusion of dopamine 3 μg/kg/min during the procedure and the first 24 postoperative hours. Measurements: The monitors included serum creatinine, creatinine clearance, blood urea nitrogen, and urine output. Main Results: The creatinine levels and blood urea nitrogen decreased at days 1, 2, 3, 4, and 5 in Dex group and increased in patients of Dopa group (P < 0.05). The creatinine clearance increased at days 1, 2, 3, 4, and 5 in Dex group and decreased in patients of Dopa group (P < 0.05). The amount of urine output was too much higher in the Dex group than the Dopa group (P < 0.05). Conclusions: The continuous infusion of dexmedetomidine during cardiac surgery has a renoprotective effect and decreased the deterioration in the renal function in high-risk renal patients compared to the continuous infusion of dopamine.

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Bifid epiglottis: What perioperative physician should know about it?

Rupesh Yadav, Sohan Lal Solanki, Jeson R Doctor

Annals of Cardiac Anaesthesia 2017 20(4):479-480



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Does bilevel positive airway pressure improve outcome of acute respiratory failure after open-heart surgery?

Ahmed Said Elgebaly

Annals of Cardiac Anaesthesia 2017 20(4):416-421

Background: Respiratory failure is of concern in the postoperative period after cardiac surgeries. Invasive ventilation (intermittent positive pressure ventilation [IPPV]) carries the risks and complications of intubation and mechanical ventilation (MV). Aims: Noninvasive positive pressure ventilation (NIPPV) is an alternative method and as effective as IPPV in treating insufficiency of respiration with less complications and minimal effects on respiratory and hemodynamic parameters next to open-heart surgery. Design: This is a prospective, randomized and controlled study. Materials and Methods: Forty-four patients scheduled for cardiac surgery were divided into two equal groups: Group I (IPPV) and Group II (NIPPV). Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), oxygen saturation (SpO2), arterial blood gas, weaning time, reintubation, tracheotomy rate, MV time, postoperative hospital stay, and ventilator-associated pneumonia during the period of hospital stay were recorded. Results: There was statistically significant difference in HR between groups with higher in Group I at 30 and 60 min and at 12 and 24 h. According to MAP, it started to increase significantly at hypoxemia, 15 min, 30 min, 4 h, 12 h, and at 24 h which was higher in Group I also. RR, PaO2, and PaCO2showed significant higher in Group II at 15, 30, and 60 min and 4 h. According to pH, there was a significant difference between groups at 15, 30, and 60 min and at 4, 12, and 24 h postoperatively. SpO2showed higher significant values in Group I at 15 and 30 min and at 12 h postoperatively. Duration of postoperative supportive ventilation was higher in Group I than that of Group II with statistically significant difference. Complications were statistically insignificant between Group I and Group II. Conclusion: Our study showed superiority of invasive over noninvasive mode of ventilator support. However, NIPPV (bilevel positive airway pressure) was proved to be a safe method.

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Atmospheric pollution in cardiac operating rooms

Mukul Chandra Kapoor

Annals of Cardiac Anaesthesia 2017 20(4):391-392



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Comparison of dexmedetomidine and ketamine versus propofol and ketamine for procedural sedation in children undergoing minor cardiac procedures in cardiac catheterization laboratory

Vidya Sagar Joshi, Sandeep S Kollu, Ram Murti Sharma

Annals of Cardiac Anaesthesia 2017 20(4):422-426

Background: The ideal anaesthetic technique for management of paediatric patients scheduled to undergo cardiac catheterisation is still not standardised. Aim: To compare the effects of ketamine-propofol and ketamine-dexmedetomidine combinations on hemodynamic parameters and recovery time in paediatric patients undergoing minor procedures and cardiac catheterisation under sedation for various congenital heart diseases. Material and Methods: 60 children of either sex undergoing cardiac catheterisation were randomly assigned into two groups Dexmedetomidine-ketamine group (DK) and Propofol-ketamine (PK) of 30 patients each. All patients were premedicated with glycopyrrolate and midazolam (0.05mg/kg) intravenously 5-10 min before anaesthetic induction. Group 'DK'received dexmedetomidineiv infusion 1 μg/kg over 10 min + ketamine1mg/kg bolus, followed by iv infusion of dexmedetomidine 0.5μg/kg/hr and of ketamine1 mg/kg/hr. Group 'PK' received propofol 1mg/kg and ketamine 1mg/kg/hr for induction followed by iv infusion of propofol 100 μg/kg/hr and ketamine 1 mg/kg/hr for maintenance. Haemodynamic parameters and recovery time was recorded postoperatively. Statistical Analysis: Independent sample t test was used to compare the statistical significance of continuous variables of both the groups.Chi square test was used for numerical data like gender.Fischer exact test was applied for non parametric data like ketamine consumption. Results: We observed that heart rate in dexmedetomidine (DK) group was significantly lower during the initial 25 mins after induction compared to the propofol (PK) group. Recovery was prolonged in the DK group compared to the PK group (40.88 vs. 22.28 min). Even ketamine boluses consumption was higher in DK group. Conclusion: Use of dexmedetomidine-ketamine combination is a safe alternative, without any hemodynamic orrespiratory effects during the cardiac catheterization procedure but with some delayed recovery.

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Rhabdomyolysis and compartment syndrome in a bodybuilder undergoing minimally invasive cardiac surgery

Sebastian John Baxter, Madhusudan Rao Puchakayala, Vinayak N Bapat

Annals of Cardiac Anaesthesia 2017 20(4):453-455

Rhabdomyolysis is the result of skeletal muscle tissue injury and is characterized by elevated creatine kinase levels, muscle pain, and myoglobinuria. It is caused by crush injuries, hyperthermia, drugs, toxins, and abnormal metabolic states. This is often difficult to diagnose perioperatively and can result in renal failure and compartment syndrome if not promptly treated. We report a rare case of inadvertent rhabdomyolysis and compartment syndrome in a bodybuilder undergoing minimally invasive cardiac surgery. The presentation, differential diagnoses, and management are discussed. Hyperkalemia may be the first presenting sign. Early recognition and management are essential to prevent life-threatening complications.

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Evaluation of the effect of metformin and insulin in hyperglycemia treatment after coronary artery bypass surgery in nondiabetic patients

Kamran Ghods, Hossein Davari, Abbasali Ebrahimian

Annals of Cardiac Anaesthesia 2017 20(4):427-431

Introduction: Insulin therapy is the most commonly used treatment for controlling hyperglycemia after coronary artery bypass surgery in both diabetic and nondiabetic patients. Metformin has been indicated for critically ill patients as an alternate for the treatment of hyperglycemia. This study evaluated the effect of metformin and insulin in hyperglycemia treatment after coronary artery bypass surgery in nondiabetic patients. Settings and Design: This study was a clinical trial comprising nondiabetic patients who had undergone coronary artery bypass surgery. Patients were randomly divided into the insulin group and the metformin group. Methods: Patients in the insulin group received continuous infusion of insulin while those in the metformin group received 500 mg metformin tablets twice daily. All the patients were followed up for 3 days after stabilization of blood glucose levels. Statistical Analysis: Data were analyzed using Chi-square test and Mann–Whitney U-test. Results: This study included a total of 56 patients. During the study period, the mean blood glucose levels decreased from 225.24 to 112.36 mg/dl (↓112.88 mg/dl) in the insulin group and from 221.80 to 121.92 mg/dl in the metformin group (↓99.88 mg/dl). There was no significant difference in the blood glucose levels of the patients between the two groups at any measurement times (P > 0.05). Conclusion: Using 500 mg metformin twice daily is similar to using insulin in nondiabetic patients undergoing coronary artery bypass graft. Therefore, the use of metformin can be considered as a treatment strategy for controlling hyperglycemia in this group of patients.

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Two episodes of cardiac tamponade in the same patient from removing pacing wires and a pericardial drain: A case report

Rekha Suthar, Osman Nawazish Salaria, Carolina De La Cuesta, Omar Viswanath

Annals of Cardiac Anaesthesia 2017 20(4):459-461

A patient presented for an elective transcatheter aortic valve replacement with temporary transvenous pacing (TVP) wires placement per protocol. On postoperative day 1, the patient remained stable, so the wires were subsequently removed, after which the patient acutely decompensated, with transthoracic echocardiography revealing pericardial effusion. Emergent pericardiocentesis was performed, and a pericardial drain was placed. Three days later, the drain was removed; again, the patient acutely decompensated, requiring another emergent pericardiocentesis. Despite the relatively benign nature of TVP wires and pericardial drains, the possibility of cardiac tamponade should be kept in mind as a potential complication when they are being removed.

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Ischemic mitral regurgitation

Praveen Kerala Varma, Neethu Krishna, Reshmi Liza Jose, Ashish Narayan Madkaiker

Annals of Cardiac Anaesthesia 2017 20(4):432-439

Ischemic mitral regurgitation (IMR) is a frequent complication of left ventricular (LV) global or regional pathological remodeling due to chronic coronary artery disease. It is not a valve disease but represents the valvular consequences of increased tethering forces and reduced closing forces. IMR is defined as mitral regurgitation caused by chronic changes of LV structure and function due to ischemic heart disease and it worsens the prognosis. In this review, we discuss on etiology, pathophysiology, and mechanisms of IMR, its classification, evaluation, and therapeutic corrective methods of IMR.

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A case report of combined radical pericardiectomy and beating heart coronary artery bypass grafting in a patient with tubercular chronic constrictive pericarditis with coronary artery disease

Gauranga Majumdar, Surendra Kumar Agarwal, Shantanu Pande, Bipin Chandra, Prabhat Tewari

Annals of Cardiac Anaesthesia 2017 20(4):465-467

We here report a successful midterm outcome following combined off-pump radical pericardiectomy and coronary artery bypass surgery (CABG) in a 65-year-old male patient who was suffering from chronic constrictive calcified tubercular pericarditis with coronary artery disease. Simultaneous off-pump CABG and radical pericardiectomy for nonsurgical constrictive pericarditis is reported very rarely in English literature.

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Late-occurring nivolumab-induced cryptogenic organising pneumonia mimicking lung progression in a patient with metastatic non–small cell lung cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): Linda Mahjoubi, Anas Gazzah, Aurélien Marabelle, François Le Roy Ladurie, Olivier Lambotte, Caroline Caramella, Julien Adam, Benjamin Besse, Jean-Charles Soria




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A systematic review of economic evaluation in pancreatic ductal adenocarcinoma

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Claire Gérard, Philippe Fagnoni, Angélique Vienot, Christophe Borg, Samuel Limat, Franck Daval, François Calais, Julie Vardanega, Marine Jary, Virginie Nerich
ObjectivesThe economic evaluation (EE) of healthcare interventions has become a necessity. However, high quality needs to be ensured in order to achieve validated results and help making informed decisions. Thus, the objective of the present study was to systematically identify and review published pancreatic ductal adenocarcinoma-related EEs and to assess their quality.MethodsSystematic literature research was conducted in PubMed and Cochrane to identify published EEs between 2000 and 2015. The quality of each selected EE was assessed by two independent reviewers, using the Drummond's checklist.ResultsOur systematic review was based on 32 EEs and showed a wide variety of methodological approaches, including different perspectives, time horizon, and cost effectiveness analyses. Nearly two-thirds of EEs are full EEs (n = 21), and about one-third of EEs had a Drummond score ≥7, synonymous with 'high quality'. Close to 50% of full EEs had a Drummond score ≥7, whereas all of partial EEs had a Drummond score <7 (n = 11).ConclusionsOver the past 15 years, a lot of interest has been evinced over the EE of pancreatic ductal adenocarcinoma (PDAC) and its direct impact on therapeutic advances in PDAC. To provide a framework for health care decision-making, to facilitate transferability and to lend credibility to health EEs, their quality must be improved. For the last 4 years, a tendency towards a quality improvement of these studies has been observed, probably coupled with a context of rational decision-making in health care, a better and wider spread of recommendations and thus, medical practitioners' full endorsement.



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Accuracy of screening women at familial risk of breast cancer without a known gene mutation: Individual patient data meta-analysis

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): Xuan-Anh Phi, Nehmat Houssami, Maartje J. Hooning, Christopher C. Riedl, Martin O. Leach, Francesco Sardanelli, Ellen Warner, Isabelle Trop, Sepideh Saadatmand, Madeleine M.A. Tilanus-Linthorst, Thomas H. Helbich, Edwin R. van den Heuvel, Harry J. de Koning, Inge-Marie Obdeijn, Geertruida H. de Bock
IntroductionWomen with a strong family history of breast cancer (BC) and without a known gene mutation have an increased risk of developing BC. We aimed to investigate the accuracy of screening using annual mammography with or without magnetic resonance imaging (MRI) for these women outside the general population screening program.MethodsAn individual patient data (IPD) meta-analysis was conducted using IPD from six prospective screening trials that had included women at increased risk for BC: only women with a strong familial risk for BC and without a known gene mutation were included in this analysis. A generalised linear mixed model was applied to estimate and compare screening accuracy (sensitivity, specificity and predictive values) for annual mammography with or without MRI.ResultsThere were 2226 women (median age: 41 years, interquartile range 35–47) with 7478 woman-years of follow-up, with a BC rate of 12 (95% confidence interval 9.3–14) in 1000 woman-years. Mammography screening had a sensitivity of 55% (standard error of mean [SE] 7.0) and a specificity of 94% (SE 1.3). Screening with MRI alone had a sensitivity of 89% (SE 4.6) and a specificity of 83% (SE 2.8). Adding MRI to mammography increased sensitivity to 98% (SE 1.8, P < 0.01 compared to mammography alone) but lowered specificity to 79% (SE 2.7, P < 0.01 compared with mammography alone).ConclusionIn this population of women with strong familial BC risk but without a known gene mutation, in whom BC incidence was high both before and after age 50, adding MRI to mammography substantially increased screening sensitivity but also decreased its specificity.



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Assessing value in breast reconstruction - a systematic review of cost-effectiveness studies

Breast reconstruction is one of the most common procedures performed by plastic surgeons and is achieved through various choices in both technology and method. Cost-effectiveness analyses are increasingly important in assessing differences in value between treatment options, which is relevant in a world of confined resources. A thorough evaluation of the cost-effectiveness literature can assist surgeons and health systems evaluate high value care models.

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87th Annual Meeting of the American Thyroid Association October 18–22, 2017, Victoria, British Columbia, Canada

Angela M. Leung and Mingzhao Xing
2017 ATA Annual Meeting Co-Chairs.

 We are excited that the 87th annual meeting of the American Thyroid Association (ATA) is almost upon us! On behalf of the Program Committee, we look forward to welcoming attendees and their guests to the annual meeting that will be held October 18–22, 2017, at the Fairmont Empress and Victoria Conference Centre in Victoria, British Columbia, Canada. Over this past year, the committee, comprised of experts from all thyroid disciplines, has thoughtfully worked to put together a program featuring the latest advances in basic, translational, and clinical thyroidology. Read More….

The post 87th Annual Meeting of the American Thyroid Association October 18–22, 2017, Victoria, British Columbia, Canada appeared first on American Thyroid Association.

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Cardiac pathologic findings in three unusual cases of sudden cardiac death related to anorexiant drugs

Publication date: Available online 9 October 2017
Source:Human Pathology
Author(s): Ornella Leone, Valentina Agostini, Alberto Foà, Bruna Cerbelli, Cira Rosaria Tiziana di Gioia, Mariarosaria Aromatario, Costantino Ciallella, Joaquin Lucena, Giulia d'Amati
Amphetamine congeners can be prescribed as anorexiant drugs, despite their potential side effects, including cardiac toxicity. However, the morphologic features of cardiac damage related to protracted use of these compounds are unknown. We provide a detailed description of cardiac autopsy findings in three cases of sudden death associated with protracted use of high-doses of phendimetrazine and/or phenylpropanolamine or bupropion prescribed as anorexiants, in association with other compounds. The main cardiac findings were similar in all three cases: i) mild–moderate hypertrophy of the left ventricle and/or the septum; ii) myocardial non-ischemic scarring (mid-mural and/or sub-epicardial) appearing as discrete foci or with a band/like morphology; iii) mild–moderate intramural small vessel disease, in absence of significant epicardial coronary artery stenosis; iv) acute/recent inflammatory lesions consistent with toxic myocarditis. In summary, the detailed pathology examination of the heart in these three cases revealed myocardial lesions identical to those reported in catecholamine myocardial damage, in all their various stages of evolution. In presence of a clinical history of long-term intake of anorexiants of this category, it is most important at autopsy to recognize and correctly interpret the acute and chronic myocardial lesions of the type herein described, since they represent an anatomical substrate for arrhythmic death.



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Calf hemodialysate hypothesis: Nutritive value plus placebo effect

Publication date: November 2017
Source:Medical Hypotheses, Volume 109
Author(s): Sergei V. Jargin




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Reactions between methylglyoxal and its scavengers in-vivo appear to be catalyzed enzymatically

Publication date: Available online 9 October 2017
Source:Medical Hypotheses
Author(s): Benjamin Szwergold
Methylglyoxal (MGO) is an important contributor to the development of diabetic complications. In this paper I propose that MGO, not detoxified by the glyoxalase system, is removed from circulation by MGO-scavengers. Furthermore, since rates of reactions between MGO and its scavengers in-vitro are low, I propose that in-vivo these reactions are catalyzed enzymatically.



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M. biceps femoris - a wolf in sheep’s clothing: The downside of a lower limb injury prevention training

Publication date: Available online 9 October 2017
Source:Medical Hypotheses
Author(s): Thomas Ertelt, Thomas Gronwald
Both, hamstring and ACL injuries are amongst the most typical injuries, particularly in change of direction and high speed running sports. They're also difficult to treat. Therefore, in the past few years, sports medicine practitioners and exercise scientists have mainly been focusing on the de velopment and implementation of preventive programs in order to reduce the number of lower limb injuries, mainly by improving knee alignment. A number of studies have been able to prove the success of these training interventions, which are mainly addressing sensorimotor abilities and plyometric activities. The number of non‐contact hamstring injuries has nevertheless been on the rise, particularly in sports like soccer and football. Therefore, the purpose of the following article is to introduce the hypothesis that the above‐mentioned training interventions have a massive influence on the activation patterns on the targeted muscle group, and on the biceps femoris in particular. Muscle function and the resulting internal load are directly related to muscle architec ture at the insertion. Training induced adaptations in hamstring activation patterns can thus lead to an increased injury susceptibility. In this case, a simulation model that directly relates to an acute deceleration maneuver provides valuable insights into the function of the biceps femoris muscle, especially when the rate of activity and the muscle geometry at the insertion area are taken into consideration. We conclude that there needs to be a greater individualization of pre vention programs, especially in regards to anatomical requirements, in order to further reduce injury rates in elite sports. Moreover, it would also seem reasonable to apply a similar approach to aspects of chronic pain such as chronic non‐specific low back pain.



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Organizational downsizing and alcohol use: A national study of U.S. workers during the Great Recession

Publication date: February 2018
Source:Addictive Behaviors, Volume 77
Author(s): Michael R. Frone
Organizational downsizing, which represents the reduction of an organization's workforce, results in a stressful work environment for those who survive the downsizing. However, we know little about the association between surviving an organizational downsizing and employee alcohol use. This study explored the association between exposure to organizational downsizing and four dimensions of alcohol use during the Great Recession. Also explored were the moderating influences of length of recession exposure, state drinking culture, gender, age, education, family income, and financial demands. Data for this study came from a national telephone survey of U.S. workers that was conducted from December 2008 to April 2011 (N=2296). The results revealed that exposure to organizational downsizing was positively associated with usual frequency of drinking, number of drinks consumed per usual drinking occasion, and both the frequency of binge drinking and drinking to intoxication. Length of exposure to the recession moderated the association between organizational downsizing exposure and usual number of drinks consumed. The conditional effects revealed that this association became stronger as length of exposure to the recession increased. Furthermore, age moderated the associations between organizational downsizing exposure and the usual number of drinks consumed and the frequency of binge drinking and intoxication. The conditional effects revealed that these associations were positive and significant among young survivors (ages 40 or younger), but were nonsignificant among middle-aged survivors (over 40years of age). State drinking culture, gender, education, family income, and financial demands did not moderate the associations between organizational downsizing exposure and alcohol use.



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When the party continues: Impulsivity and the effect of employment on young adults' post-college alcohol use

Publication date: February 2018
Source:Addictive Behaviors, Volume 77
Author(s): I.M. Geisner, J. Koopmann, P. Bamberger, M. Wang, M.E. Larimer, I. Nahum-Shani, S. Bacharach
BackgroundThe transition from college to work is both an exciting and potentially high risk time for young adults. As students transition from academic settings to full-time employment, they must navigate new social demands, work demands, and adjust their drinking behaviors accordingly. Research has shown that there are both protective factors and risk factors associated with starting a new job when it comes to alcohol use, and individual differences can moderate these factors.Method1361 students were recruited from 4 geographically diverse universities and followed 1month pre- and 1month post-graduation. Drinking frequency, quantity, consequences, and impulsivity were assessed.ResultsFull-time employment was related to increased drinking quantity but not related to changes in other drinking outcomes. However, impulsivity moderated the relationship between employment and drinking. For those reporting higher levels of impulsivity at baseline, full-time employment was associated with an increase in drinking variables (quantity and frequency), whereas drinking was unaffected by full-time employment status among those reporting lower levels of impulsivity. Implications for future research are discussed.



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Smoking and drinking behaviors of military spouses: Findings from the Millennium Cohort Family Study

Publication date: February 2018
Source:Addictive Behaviors, Volume 77
Author(s): Daniel W. Trone, Teresa M. Powell, Lauren M. Bauer, Amber D. Seelig, Arthur V. Peterson, Alyson J. Littman, Emily C. Williams, Charles C. Maynard, Jonathan B. Bricker, Edward J. Boyko
Introduction: The associations between stressful military experiences and tobacco use and alcohol misuse among Service members are well documented. However, little is known about whether stressful military experiences are associated with tobacco use and alcohol misuse among military spouses. Methods: Using 9872 Service member–spouse dyads enrolled in the Millennium Cohort Family Study, we employed logistic regression to estimate the odds of self-reported cigarette smoking, risky drinking, and problem drinking among spouses by Service member deployment status, communication regarding deployment, and stress associated with military-related experiences, while adjusting for demographic, mental health, military experiences, and Service member military characteristics. Results: Current cigarette smoking, risky drinking, and problem drinking were reported by 17.2%, 36.3%, and 7.3% of military spouses, respectively. Current deployment was not found to be associated with spousal smoking or drinking behaviors. Communication about deployment experiences with spouses was associated with lower odds of smoking, but not with risky or problem drinking. Spouses bothered by communicated deployment experiences and those who reported feeling very stressed by a combat-related deployment or duty assignment had consistently higher odds of both risky and problem drinking. Conclusions: Our findings suggest that contextual characteristics about the deployment experience, as well as the perceived stress of those experiences, may be more impactful than the simple fact of Service member deployment itself. These results suggest that considering the impact of deployment experiences on military spouses reveals important dimensions of military community adaptation and risk.



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Testing weight motives and guilt/shame as mediators of the relationship between alcohol use and physical activity

Publication date: February 2018
Source:Addictive Behaviors, Volume 77
Author(s): Tonya Dodge, Paige Clarke
ObjectivesTest whether weight motives and guilt/shame mediate the positive relationship between physical activity and alcohol use among college-attending young adults.DesignA longitudinal design was employed.MethodYoung adults who were attending college (N=371) completed two self-administered questionnaires separated by approximately one month. Heavy episodic drinking was assessed at Time 1. Vigorous physical activity, moderate physical activity, weight motives, and guilt/shame were assessed at Time 2.ResultsResults are consistent with weight motives as a mediator of the positive relationship between heavy episodic drinking and vigorous physical activity. Results were inconsistent with guilt/shame as a mediator of this relationship. There was no statistically significant relationship between heavy episodic drinking and moderate physical activity.ConclusionsHeavy episodic drinking was related to vigorous but not to moderate physical activity in the subsequent 30-days. Furthermore, the results are consistent with weight motives as a mediator of the relationship between alcohol use and vigorous physical activity.



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E-cigarette use among treatment-seeking smokers: Moderation of abstinence by use frequency

Publication date: February 2018
Source:Addictive Behaviors, Volume 77
Author(s): Emily N. Subialka Nowariak, Rebecca K. Lien, Raymond G. Boyle, Michael S. Amato, Laura A. Beebe
IntroductionEmerging literature suggests that frequency of use of electronic cigarettes (e-cigarettes) may be an important moderating variable in the relationship between e-cigarette use and smoking cessation. However, few studies have focused specifically on treatment-seekers, a group that may differ in important ways from smokers in the general population. This study looks at the relationship between e-cigarette use frequency and abstinence among a sample of treatment-seeking tobacco users.MethodsSeven-month follow-up survey data from N=2760 treatment-seeking tobacco users who utilized statewide tobacco quitlines in three states were used to assess the relationship between 30-day point prevalence abstinence and e-cigarette use frequency at follow-up. E-cigarette use was examined in two ways. First, we looked at any use in the past 30days versus no use. Additionally, past 30-day e-cigarette use frequency was categorized into four groups: 0days, 1–5days – infrequent, 6–29days – intermediate, 30days – daily. Logistic regression models were constructed predicting 30-day point prevalence tobacco abstinence.ResultsBoth infrequent (AOR=0.35; CI=0.20–0.59) and intermediate (AOR=0.50; CI=0.32–0.80) past 30-day e-cigarette use were associated with lower rates of tobacco abstinence versus no past 30-day use. However, daily e-cigarette users (AOR=1.16; CI=0.71–1.70) had similar 30-day abstinence when compared to non-users.ConclusionsResults from this study of treatment-seekers support findings from studies of general population tobacco users that suggest frequency of e-cigarette use is an important moderating variable in the relationship between e-cigarette use and tobacco cessation. Future studies should employ more refined measures of e-cigarette use.



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