Elabela-APJ axis contributes to embryonic development and prevents pre-eclampsia in pregnancy

http://ift.tt/2CVMqpA

Prevalence of cardiovascular disease risk factors among students of a tertiary institution in Ghana

Abstract

Cardiovascular diseases (CVDs) are listed as one of the main causes of mortality and morbidity by the World Health Organization. The World Heart Federation lists overweight/obesity, blood lipid profile, and blood pressure as some of the modifiable risk factors to developing CVDs. This study sought to determine the prevalence of some of these modifiable risk factors among University of Ghana students. One hundred and twenty students were sampled for the study. Lipid profile parameters such as high-density lipoprotein (HDL), total cholesterol (TC), and total triglycerides (TG) were measured using the Vitros 5-IFS chemistry analyzer (NY, USA). The Friedewald's equation was used to determine low-density lipoprotein (LDL) levels. Anthropometric indices such as height and weight were measured following standard protocols. Body mass index (BMI) was calculated in kg/m² using the height and weight measurements. The students were then categorized into underweight, normal, overweight, and obese according to their BMI. Blood pressure measurements were also taken. The mean age of the students was 30.04 ± 7.99 years. A total of 4.2%, 30%, and 67.5% had TG, TC, and LDL, respectively, above normal recommended ranges. Low HDL levels were observed in 32.5% of the students. About 45% had high systolic blood pressure and 32.5% with high diastolic blood pressure. In all, the risk factors studied contributed to about 95% of the variance in explaining the risk of developing CVDs. The study concludes that the cardiovascular risk factors assessed are prevalent among the students and therefore steps must be taken to address the increase in prevalence.

This study investigates the prevalence of the modifiable risk factors of cardiovascular diseases. The cardiovascular risk factors assessed explained 95% of the variance in the risk of developing cardiovascular diseases.

http://ift.tt/2Dn576I

Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

http://ift.tt/2EAJbV7

Therapists experiences with a new treatment combining physical exercise and dietary therapy (the PED-t) for eating disorders: an interview study in a randomised controlled trial at the Norwegian School of Sport Sciences

Objectives

The aim of the current study is to explore how therapists running a guided physical exercise and dietary therapy programme (PED-t) experience their contribution to the treatment of patients with bulimia nervosa and binge eating disorder.

Methods

Ten therapists running the PED-t were semistructurally interviewed and the transcribed interviews were analysed using a systematic text condensation approach.

Setting

The study was run within the context of a randomised controlled trial at the Norwegian School of Sport Sciences.

Results

The therapists experienced their knowledge about physical exercise and nutrition as important and useful, and that they could share their knowledge with the patients in different ways and with confidence in their own role. They also believed that their knowledge could serve as tools for the patients' post-treatment recovery and management of their daily lives. Moreover, the therapists put much effort in adjusting their teaching to fit each individual participant. Finally, they reported their personal qualities as important to build trust and therapeutic alliance.

Conclusions

The terms 'clinical confidence' and 'alliance' may stand out as the overarching 'metacategories' covering the experiences revealed in this study. The clinical implication is that new groups of professionals may have an important role in the treatment of eating disorders.

Trial registration number

NCTO2079935; Results.

http://ift.tt/2Dn1Y6U

Views and experiences of seeking information and help for vitiligo: a qualitative study of written accounts

Objectives

Vitiligo is a relatively common autoimmune condition causing loss of skin pigment. Around 1 in 100 people in the UK develop vitiligo. It can have a significant impact on quality of life for many of those affected. How people access information and help for vitiligo may influence how they manage such impact. We aimed to explore people's views and experiences of seeking health information and help for vitiligo.

Design

Qualitative analysis of free-text responses to four open-ended questions in an online survey.

Setting

Online survey conducted in the UK between February and March 2016.

Participants

A survey link was emailed to 675 members of The Vitiligo Society, a UK-based charity providing information and support for people with vitiligo. One hundred and sixty-one members responded to the survey (24%).

Results

Many participants wrote extensive free text, often reporting frustration with help-seeking. They perceived general practitioners (GP) as their primary source of advice but felt that GPs had low awareness of available treatments. Where GPs appeared sympathetic or signposted towards further information this was appreciated, even where people felt their GP had not seemed knowledgeable. Many felt that vitiligo was dismissed by health professionals including GPs and dermatologists as 'cosmetic', which upset those who experienced substantial impact. Participants expressed concerns about the credibility of online information on vitiligo and the need for reliable, detailed information, as well as a desire for support with managing its psychosocial impact.

Conclusions

Information and help-seeking needs of people with vitiligo currently appear to be poorly met, even among members of The Vitiligo Society, who are likely to have received more information than others. People with vitiligo would welcome greater health professional awareness of available vitiligo treatments. Acknowledging the psychosocial impacts of vitiligo and signposting towards credible information are also welcomed.

http://ift.tt/2CT5LrG

Seasonal variations in tuberculosis diagnosis among HIV-positive individuals in Southern Africa: analysis of cohort studies at antiretroviral treatment programmes

Objectives

Seasonal variations in tuberculosis diagnoses have been attributed to seasonal climatic changes and indoor crowding during colder winter months. We investigated trends in pulmonary tuberculosis (PTB) diagnosis at antiretroviral therapy (ART) programmes in Southern Africa.

Setting

Five ART programmes participating in the International Epidemiology Database to Evaluate AIDS in South Africa, Zambia and Zimbabwe.

Participants

We analysed data of 331 634 HIV-positive adults (>15 years), who initiated ART between January 2004 and December 2014.

Primary outcome measure

We calculated aggregated averages in monthly counts of PTB diagnoses and ART initiations. To account for time trends, we compared deviations of monthly event counts to yearly averages, and calculated correlation coefficients. We used multivariable regressions to assess associations between deviations of monthly ART initiation and PTB diagnosis counts from yearly averages, adjusted for monthly air temperatures and geographical latitude. As controls, we used Kaposi sarcoma and extrapulmonary tuberculosis (EPTB) diagnoses.

Results

All programmes showed monthly variations in PTB diagnoses that paralleled fluctuations in ART initiations, with recurrent patterns across 2004–2014. The strongest drops in PTB diagnoses occurred in December, followed by April–May in Zimbabwe and South Africa. This corresponded to holiday seasons, when clinical activities are reduced. We observed little monthly variation in ART initiations and PTB diagnoses in Zambia. Correlation coefficients supported parallel trends in ART initiations and PTB diagnoses (correlation coefficient: 0.28, 95% CI 0.21 to 0.35, P<0.001). Monthly temperatures and latitude did not substantially change regression coefficients between ART initiations and PTB diagnoses. Trends in Kaposi sarcoma and EPTB diagnoses similarly followed changes in ART initiations throughout the year.

Conclusions

Monthly variations in PTB diagnosis at ART programmes in Southern Africa likely occurred regardless of seasonal variations in temperatures or latitude and reflected fluctuations in clinical activities and changes in health-seeking behaviour throughout the year, rather than climatic factors.

http://ift.tt/2DnAFcG

Development and validation of an instrument for measuring the burden of medicine on functioning and well-being: the Medication-Related Burden Quality of Life (MRB-QoL) tool

Objective

Medication-related burden (MRB) is a negative experience with medicine, which may impact on psychological, social, physical and financial well-being of an individual. This study describes the development and initial validation of an instrument specifically designed to measure MRB on functioning and well-being—the Medication-Related Burden Quality of Life (MRB-QoL) tool.

Methods

An initial pool of 76-items for MRB-QoL was generated. The link to MRB-QoL survey was sent to a sample of consumers living with at least one chronic medical condition and taking ≥3 prescription medicines on a regular basis. Exploratory factor analysis (EFA) was used to determine the underlining factor structure. Internal consistency (Cronbach's α) and construct validity were examined. The latter was examined through correlation with Medication Regimen Complexity Index (MRCI), Drug Burden Index (DBI) and Charlson's Comorbidity Index (CCI).

Results

367 consumers completed the survey (51.2% male). EFA resulted in a 31-item, five-factor solution explaining 72% of the total variance. The five subscales were labelled as 'Routine and Regimen Complexity' (11 items), 'Psychological Burden' (six items), 'Functional and Role Limitation' (seven items), 'Therapeutic Relationship' (three items) and 'Social Burden' (four items). All subscales showed good internal consistency (Cronbach's α 0.87 to 0.95). Discriminant validity of MRB-QoL was demonstrated via its correlations with MRCI (Spearman's r –0.16 to 0.08), DBI (r 0.12 to 0.28) and CCI (r –0.23 to –0.15). Correlation between DBI and 'Functional and Role Limitation' subscale (r 0.36) indicated some evidence of convergent validity. Patients with polypharmacy, multiple morbidity and DBI >0 had higher median scores of MRB-QoL providing evidence for known group validity.

Conclusions

The MRB-QoL V.1 has good construct validity and internal consistency. The MRB-QoL may be a useful humanistic measure for evaluating the impact of pharmaceutical care interventions on patients' quality of life. Future research is warranted to further examine additional psychometric properties of MRB-QoL V.1 and its utility in patient care.

http://ift.tt/2CV3hc2

Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy

Summary

Objective

Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1^−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1^−/− mice, thereby increasing risk of respiratory failure and sudden death (SD).

Methods

Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1^+/+, Kcna1^+/−, and Kcna1^−/− littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1^−/− mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46, and P48-56, respectively. Saturated arterial O₂ (SaO₂) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh.

Results

Kcna1^−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume, and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1^−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1^−/− mice approached SD. MCh-induced seizures experienced by a subset of younger Kcna1^−/− mice triggered death. Respiratory parameters of these younger Kcna1^−/−mice resembled older near-SD Kcna1^−/− mice. Kcna1 gene and protein were not expressed in Kcna1^+/+ and Kcna1^+/− lungs, and MCh-mediated airway smooth muscle contractions exhibited similar half-maximal effective concentration( EC₅₀) in isolated Kcna1^+/+ and Kcna1^−/− trachea.

Significance

The Kcna1^−/− model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.

http://ift.tt/2CSyJrx

Oak flour as a replacement of wheat and corn flour to improve biscuit antioxidant activity

Abstract

Due to the high antioxidant activity of oak fruits, the partial substitution effects of wheat flour (WF) or corn flour (CF) with oak flour (OF) have been investigated. WF or CF was replaced by OF at levels of 0%, 15%, 30%, and 45% in the biscuit formulations to prevent the spontaneous oxidation of lipids, and the characteristics, including peroxide value, antioxidant activity, and sensory properties, were evaluated during 28 days storage. According to the results obtained, biscuit samples with higher OF percentage had higher antioxidant activity and less peroxide value. In terms of sensory evaluation, no adverse effect was observed in the samples containing OF. Therefore, it could be introduced as a good natural source of antioxidant compounds for use in food formulations.

Biscuit samples with higher oak flour percentage had higher antioxidant activity and less peroxide value. Consumption of oak fruit (as a food waste, because of not consuming as a food source in the most country) increasing nutrition value in food industry, specially in bakery industry. Oak fruit could be introduced as a good natural source of antioxidant compounds for use in food formulations.

http://ift.tt/2AS5pPW

Determination of some quality properties of “hamsi kaygana” prepared with different additives

Abstract

This study was aimed to determine the changes of the local anchovy meal which is known as hamsi kaygana in Turkey during cold storage at +4°C ± 1°C. Physicochemical (pH, TVB-N, TMA-N, and TBA) shelf life analyses were carried out for hamsi kaygana samples. It was confirmed that the pH values obtained from research groups were within the limit values of the literature. No statistically significant difference was observed (p > .05) between control, stinging nettle, and rosemary groups that were within all created product groups on 12th day of storage, and the observed difference was only present in cumin group (p < .05). Upon examining TVB-N (Total Volatile Basic Nitrogen) values on 12th day of storage, we saw the lowest TVB-N value (17.01 ± 0.21 mg/100 g) was at stinging nettle group. However; it was found out that highest TVB-N value belonged to cumin group with the value of 19.38 ± 0.42 mg/100 g. It was found that 12th day TBA (Thiobarbituric Acid) values of all other groups except control group did not exceed limit values. Among TMA-N (Trimethylamine Nitrogen) values of all groups on 12th storage period, the lowest value belonged to cumin group samples. While the highest TMA-N value was found as 14.70 ± 0.30 in control group samples. Therefore, the results showed us that using dried herb and spices in hamsi kaygana production and the storage of the products have an influence on shelf life.

This study aimed to determine the effect of dried stinging nettle, rosemary and cumin on the meat quality and shelf life of hamsi kaygana, a traditional food in the Black Sea Region of Turkey. The study groups consist of the control group, stinging nettle, rosemary and cumin. The effects of dried herb and spices on shelf life and quality of cooked hamsi kaygana which is stored in refrigerator conditions (4°C ± 1°C). At the end of the storage period, the pH value showed an increase in all groups compared to the initial value and was determined to be 6.30 ± 0.01, 6.32 ± 0.04, 6.32 ± 0.00 and 6.31 ± 0.02 for groups control, stinging nettle, rosemary and cumin respectively. It was found out that pH values obtained from the groups were within limit values of the literature. On the last day of the storage, the cumin group had the highest TVB- N value of 19.38 ± 0.42 mg/100. According to the TVB-N analysis results obtained on the final day of storage, it was seen that all groups remained within acceptable limits. As a result of the study, other groups apart from the control group did not exceed the threshold values for TBA on 12th day. It was found that the rosemary group had the lowest TBA value (5.85 ± 0.37 mg·MDA/kg) on the 12th day of storage of all groups. TMA-N value of stinging nettle group at the beginning was measured as 2.90 ± 0.17, it was found that this value was approximately seven times more (13.50 ± 0.30) than the value at the beginning on 12th day. It was seen that the value measured exceeded the spoilage value of TMA-N. First TMA-N value of the group containing rosemary was found to be 3.30 ± 0.00 mg/100 g before storage. On the 8th day of storage, a TMA-N value was found as 9.90 ± 0.30 mg/100 g which is a rapid increase with three times more than the first value. The TMA- N values increased in all groups and the highest increase was observed in the control group (14.70 ± 0.30 mg/100 g) on the 12th day of storage. The lowest TMA- N value (12.90 ± 0.30 mg/100 g) was obtained in the cumin group at the end of the storage day. It was found that the cumin used in the production is much more effective than the stinging nettle (13.50 ± 0.30 mg/100 g) and rosemary (14.40 ± 0.00 mg/100 g) in terms of product shelf life. According to results obtained, the effects of dried herbs and spices which are used in the production of hamsi kaygana on the storage of products were examined. As a result of the study conducted, the importance of the alternative consumable food product, which is obtained from anchovy which has a high potential of consumption in our country, pointed out.

http://ift.tt/2D70Xmv

Effects of pretreatment during drying on the antioxidant properties and color of selected tomato varieties

Abstract

Drying is essential in lowering the water activity and increasing the shelf stability of perishables. Thus, this study investigated the effect of pretreatment on the retention of the antioxidant properties and color of four tomato varieties; that is, Anna F1, Kilele, Prostar F1, and Riogrande during drying. Prepared quarters were treated by spraying with 0.5% sodium metabisulfate, 0.5% calcium chloride, and distilled water. The quarters were oven dried at 50°C, 60°C, and 70°C to 13% moisture content. Lycopene, β carotene, total phenolics, color, and moisture content were determined in both the fresh and dried samples. Initial moisture content among the four varieties did not differ significantly and ranged between 94.2 and 94.6%. Results showed that the main effects were significant (p < .05) on all measurable variables. Significantly (p < .05) higher retention levels in lycopene, β carotene, total phenolics, and lightness was observed in chemically pretreated samples compared to the control during drying.

This study investigated the effect of pretreatment on the retention of the antioxidant properties and color of four tomato varieties. Prepared tomato quarters were treated by spraying with sodium metabisulfate and calcium chloride and distilled water. The quarters were oven dried and lycopene, β carotene, total phenolics, color, and moisture content were determined in both the fresh and dried samples.

http://ift.tt/2ATh8xY

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Abstract

Objective

To assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimer's disease.

Methods

Immunoassays were used to measure cerebrospinal fluid neurogranin in 114 participants including healthy controls (n = 27), biomarker-proven amnestic Alzheimer's disease (n = 68), and the atypical visual variant of Alzheimer's (n = 19) according to international criteria. CSF total-tau, Aβ42, and neurofilament light concentrations were investigated using commercially available assays. All affected individuals had T1-weighted volumetric MR images available for analysis of whole and regional brain volumes. Associations between neurogranin, brain volumes, total-tau, Aβ42, and neurofilament light were assessed.

Results

Median cerebrospinal fluid neurogranin concentrations were higher in typical and atypical Alzheimer's compared to controls (P < 0.001 and P = 0.005). Both neurogranin and total-tau concentrations, but not neurofilament light and Aβ42, were higher in typical Alzheimer's compared to atypical patients (P = 0.004 and P = 0.03). There were significant differences in the left hippocampus and right and left superior parietal lobules in atypical patients, which were larger (P = 0.03) and smaller (P = 0.001 and P < 0.001), respectively, compared to typical patients. We found no evidence of associations between neurogranin and brain volumes but a strong association with total-tau (P < 0.001) and a weaker association with neurofilament light (P = 0.005).

Interpretation

These results show significant differences in neurogranin and total-tau between typical and atypical patients, which may relate to factors other than disease topography. The differential relationships between neurogranin, total-tau and neurofilament light in the Alzheimer's variants, provide evidence for mechanistically distinct and coupled markers of neurodegeneration.

http://ift.tt/2mkgXXe

Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

http://ift.tt/2EAJbV7

Evaluation of the eighth American Joint Committee on Cancer staging system for malignant melanoma of the skin

Future Oncology, Ahead of Print.


http://ift.tt/2qVZOc1

Bioinformatic analysis of PFN2 dysregulation and its prognostic value in head and neck squamous carcinoma

Future Oncology, Ahead of Print.


http://ift.tt/2mubE8i

Identification of CDK2 as a novel target in treatment of prostate cancer

Future Oncology, Ahead of Print.


http://ift.tt/2r0upFo

Generalized nonmotor (absence) seizures—What do absence, generalized, and nonmotor mean?

Summary

Objective

Clinical absences are now classified as "generalized nonmotor (absence) seizures" by the International League Against Epilepsy (ILAE). The aim of this paper is to critically review the concept of absences and to put the accompanying focal and motor symptoms into the context of the emerging pathophysiological knowledge.

Methods

For this narrative review we performed an extensive literature search on the term "absence," and analyzed the plethora of symptoms observed in clinical absences.

Results

Arising from the localization and the involved cortical networks, motor symptoms may include bilateral mild eyelid fluttering and mild myoclonic jerks of extremities. These motor symptoms may also occur unilaterally, analogous to a focal motor seizure with Jacksonian march. Furthermore, electroencephalography (EEG) abnormalities may exhibit initial frontal focal spikes and consistent asymmetries. Electroclinical characteristics support the cortical focus theory of absence seizures. Simultaneous EEG/functional magnetic resonance imaging (fMRI) measurements document cortical deactivation and thalamic activation. Cortical deactivation is related to slow waves and disturbances of consciousness of varying degrees. Motor symptoms correspond to the spike component of the 3/s spike-and-wave-discharges. Thalamic activation can be interpreted as a response to overcome cortical deactivation. Furthermore, arousal reaction during drowsiness or sleep triggers spikes in an abnormally excitable cortex. An initial disturbance in arousal mechanisms ("dyshormia") might be responsible for the start of this abnormal sequence.

Significance

The classification as "generalized nonfocal and nonmotor (absence) seizure" does not covey the complex semiology of a patient's clinical events.

http://ift.tt/2CSoqDR

Abstract from the Chinese Journal of Hypertension

The Relationship Between Blood Pressure Variability and Circadian Rhythm in Normal Normotensives

http://ift.tt/2Ezx4rm

Abstract from the Chinese Journal of Hypertension

The Status of the Use of Antihypertensive Agents in Hypertensive Patients in the Community

http://ift.tt/2Fto1cN

The New ACC/AHA Hypertension Guidelines for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults

The long-awaited American College of Cardiology/American Heart Assoc iation (ACC/AHA) hypertension guidelines¹ were released on 13 November 2017 at the American Heart Association (AHA) annual meeting in Anaheim, CA, USA, with simultaneous publication in the journals Hypertension and the Journal of the American College of Cardiology (JACC). This guideline is the first one released since the National Heart Lung and Blood Institute (NHLBI) transferred responsibility for hypertension guideline development to these organizations; the last official NHLBI hypertension guideline, JNC 7², was published 14 years ago. Though the JNC 8 committee was disbanded after nearly 5 years of deliberation, the JNC 8 report³ was, however, published 4 years ago by a subgroup of the original committee.

http://ift.tt/2EzkgkV

The Year in Clinical Hypertension From Other Pages

The year 2017 has been another year dominated by clinical research in hypertension by multiple publications issuing from the Systolic Pressure Intervention Trial (SPRINT) trial. There have also been numerous advances in our understanding of both basic mechanisms in hypertension and the epidemiology and population science in the field of high blood pressure (BP). And, caveat emptor, others in the field might have chosen only some or none of these and could have been more impressed by other publications.

http://ift.tt/2Fw4vMz

Noncoding RNAs in Cardiovascular Disease: Pathological Relevance and Emerging Role as Biomarkers and Therapeutics

Abstract

Noncoding RNAs (ncRNA) include a diverse range of functional RNA species—microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) being most studied in pathophysiology. Cardiovascular morbidity is associated with differential expression of myriad miRNAs; miR-21, miR-155, miR-126, miR-146a/b, miR-143/145, miR-223, and miR-221 are the top 9 most reported miRNAs in hypertension and atherosclerotic disease. A single miRNA may have hundreds of messenger RNA targets, which makes a full appreciation of the physiologic ramifications of such broad-ranging effects a challenge. miR-21 is the most prominent ncRNA associated with hypertension and atherosclerotic disease due to its role as a "mechano-miR", responding to arterial shear stresses. "Immuno-miRs", such as miR-155 and miR-223, affect cardiovascular disease (CVD) via regulation of hematopoietic cell differentiation, chemotaxis, and activation in response to many pro-atherogenic stimuli. "Myo-miRs", such as miR-1 and miR-133, affect cardiac muscle plasticity and remodeling in response to mechanical overload. This in-depth review analyzes observational and experimental reports of ncRNAs in CVD, including future applications of ncRNA-based strategies in diagnosis, prediction (e.g., survival and response to small molecule therapy), and biologic therapy.

http://ift.tt/2EABVbP

Microvascular Adaptations to Exercise: Protective Effect of PGC-1 Alpha

Abstract

BACKGROUND

Sedentary behavior and obesity are major risk factors for cardiovascular disease. Regular physical activity has independent protective effects on the cardiovascular system, but the mechanisms responsible remain elusive. Recent studies suggest that the protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) participates in the response to exercise training. We hypothesized that the arterioles of athletes maintain dilation to flow despite combined inhibition of multiple vasodilators, but loss of PGC-1α renders these vessels susceptible to inhibition of a single vasodilator pathway. In addition, arterioles from overweight and obese individuals will display an an exercise-like phenotype when PGC-1α is activated.

METHODS

Isolated arterioles from exercise-trained (ET) and from mildly overweight or obese subjects (body mass index >25) were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the absence and presence of compounds that inhibit various endothelium-dependent vasodilators.

RESULTS

Microvessels of ET subjects displayed robust dilation that could not be inhibited through targeting the combination of nitric oxide, prostaglandins, and hydrogen peroxide, but were inhibited via interference with membrane hyperpolarization. Loss of PGC-1α (siRNA) in the microcirculation of ET subjects eliminates this vasodilatory robustness rendering vessels susceptible to blockade of H₂O₂ alone. Pharmacological activation of PGC-1α with alpha-lipoic acid in isolated microvessels from sedentary, overweight, and obese subjects increases arteriolar resistance to vasodilator blockade and protects against acute increases in intraluminal pressure.

CONCLUSIONS

These findings suggest that the microvascular adaptations to exercise training, and the exercise-induced protection against acute vascular stress in overweight/obese subjects, are mediated by PGC-1α.

http://ift.tt/2FtnRSJ

The Reproducibility of Racial Differences in Ambulatory Blood Pressure Phenotypes and Measurements; Methodological Issues

Dear editor, I was interested to read the paper by Husain A and colleagues published in the Am J Hypertens 2017 October.¹ The purpose of the authors was to evaluate the reproducibility of differences in ambulatory blood pressure (BP) monitoring phenotypes and other parameters (sustained hypertension, masked hypertension, nocturnal hypertension, and nondipping) between African Americans and Whites. A total of 420 participants untreated for hypertension attended 2 research visits 1 week apart during which traditional office BP averages and ambulatory BP monitoring session averages were determined. They computed percent agreement in ambulatory BP monitoring phenotypes across the 2 visits stratified by race and associated kappa statistics with 95% confidence intervals. Agreement was quantified using the kappa statistic, its 95% confidence interval and P value. Kappa statistics were calculated based on the agreement between the binary outcomes of whether or not a subject had a particular phenotype between sessions.

http://ift.tt/2EBzupv

B-Type Natriuretic Peptide and Ventricular Dysfunction in the Prediction of Cardiovascular Events and Death in Hypertension

Abstract

BACKGROUND

The prevalence and morbidity of hypertension continues to grow globally and improved methods of stratifying risk and identifying organ damage earlier are required. Methods such as echocardiography and population-based risk scores are suggested by guidelines as approaches to aid in risk stratification. However, biomarkers such as natriuretic peptides may help provide such an approach.

METHODS

We analyzed data from the screening to prevent heart failure cohort including participants with hypertension with and without a history of a cardiovascular (CV) event at baseline. We investigated the ability of ventricular dysfunction on echocardiography at baseline and of B-type natriuretic peptide (BNP) levels in predicting future major adverse CV events (MACE) and death. We also investigated the use of Systematic COronary Risk Evaluation (SCORE) to predict these events in the uncomplicated cohort.

RESULTS

In total, 572 patients (427 with uncomplicated hypertension) were included. Thirty-three patients had MACE or died during follow up. In a univariate analysis, BNP was predictive of MACE and death in all groups. Ventricular dysfunction was not predictive of MACE and death in any group. Both BNP and SCORE had predictive value in this category. However, the magnitude and strength of the continuous association between BNP and events is higher and BNP adds significantly to the predictive value of SCORE as determined by likelihood ratios. The net reclassification improvement for BNP compared to stage B heart failure was 0.20.

CONCLUSION

This study demonstrates that in patients with hypertension, BNP is superior to ventricular dysfunction on echocardiography in the prediction of risk of MACE and death in a community-based cohort of patients with complicated and uncomplicated hypertension.

http://ift.tt/2EB0WU2

Molecular Genetics of Salt-Sensitivity and Hypertension: Role of Renal Epithelial Sodium Channel Genes

Essential hypertension (EH) is a complex trait determined by endogenous mechanisms—genetic factors and physiological systems—and environmental exposures. Nowadays, EH is a major public health problem due to its high prevalence and concomitant increase in the risk for several cardiovascular diseases.¹

http://ift.tt/2FtlkYz

Resequencing Epithelial Sodium Channel Genes Identifies Rare Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study

Abstract

BACKGROUND

A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with blood pressure (BP) salt-sensitivity.

METHODS

The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1,906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Three ENaC genes (SCNN1A, SCNN1B, and SCNN1G) were resequenced using capillary-based sequencing methods. Traditional burden tests were utilized to examine association between rare variants and BP salt-sensitivity. Associations of low-frequency and common variants were tested using single-marker analyses.

RESULTS

Carriers of SCNN1A rare variants had a 0.52 [95% confidence interval (CI): 0.32–0.85] decreased odds of BP salt-sensitivity compared with noncarriers. Neither SCNN1B nor SCNN1G associated with salt-sensitivity of BP in rare variant analyses (P = 0.65 and 0.48, respectively). In single-marker analyses, 3 independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914, associated with salt-sensitivity after Bonferroni correction (P = 4.4 × 10^–4, 1.1 × 10^–8, and 1.3 × 10^–3). Each copy of the minor allele of rs4764586 was associated with a 1.36-fold (95% CI: 1.23–1.52) increased odds of salt-sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold (95% CI: 0.55–0.84) and 0.69-fold (95% CI: 0.54–0.86) decreased odds of salt-sensitivity, respectively.

CONCLUSIONS

This study demonstrated for the first time a relationship between rare variants in the ENaC pathway and BP salt-sensitivity. Future replication and functional studies are needed to confirm the findings in this study.

CLINICAL TRIAL REGISTRY

Trial Number NCT00721721

http://ift.tt/2Ezkng4

ECG Voltage in Relation to Peripheral and Central Ambulatory Blood Pressure

Abstract

BACKGROUND

The heart ejects in the central elastic arteries. No previous study in workers described the diurnal profile of central blood pressure (BP) or addressed the question whether electrocardiogram (ECG) indexes are more closely associated with central than peripheral BP.

METHODS

In 177 men (mean age, 29.1 years), we compared the associations of ECG indexes with brachial and central ambulatory BP, measured over 24 hours by the validated oscillometric Mobil-O-Graph 24h PWA monitor.

RESULTS

From wakefulness to sleep, as documented by diaries, systolic/diastolic BP decreased by 11.7/13.1 mm Hg peripherally and 9.3/13.6 mm Hg centrally, whereas central pulse pressure (PP) increased by 4.3 mm Hg (P < 0.0001). Over 24 hours and the awake and asleep periods, the peripheral-minus-central differences in systolic/diastolic BPs averaged 11.8/–1.6, 12.7/–1.8, and 10.3/–1.2 mm Hg, respectively (P < 0.0001). Cornell voltage and index averaged 1.18 mV and 114.8 mV·ms. Per 1-SD increment in systolic/diastolic BP, the Cornell voltages were 0.104/0.086 mV and 0.082/0.105 mV higher in relation to brachial 24-hour and asleep BP and 0.088/0.90 mV and 0.087/0.107 mV higher in relation to central BP. The corresponding estimates for the Cornell indexes were 9.6/8.6 and 8.2/10.5 mV·ms peripherally and 8.6/8.9 and 8.8/10.7 mV·ms centrally. The regression slopes (P ≥ 0.067) and correlation coefficients (P ≥ 0.088) were similar for brachial and central BP. Associations of ECG measurements with awake BP and PP were not significant.

CONCLUSIONS

Peripheral and central BPs run in parallel throughout the day and are similarly associated with the Cornell voltage and index.

http://ift.tt/2FtnEPr

Short-Term High-Salt Diet Increases Corin Level to Regulate the Salt–Water Balance in Humans and Rodents

Abstract

BACKGROUND

Dietary sodium and potassium affect the fluctuation in blood pressure (BP) and renal function. Corin, with its enzymatic activity to convert pro-atrial natriuretic peptide (pro-ANP) to biologically active ANP, regulates BP, cardiac, and renal functions. We investigated whether corin expression responds to a high-salt (HS) diet to regulate salt and water balance.

METHODS

Forty-two volunteers followed 3 sequential diets for 7 days each: a low-salt (LS) diet (3.0 g/day NaCl), a HS diet (18.0 g/day NaCl), followed by an HS diet with K⁺ supplementation (HS + K⁺) (18.0 g/day NaCl and 4.5 g/day KCl).

RESULTS

Corin level was higher with the HS diet than the LS and HS + K⁺ diets and was positively correlated with systolic BP (SBP) and 24-hour urinary Na⁺ and microalbumin (U-mALB) excretion. In rodents, serum and renal levels of corin were transiently increased with the HS diet and were decreased if the HS diet was continued for up to 7 days. HS loading increased SBP, 24-hour urinary Na⁺, U-mALB excretion, and the expression of proprotein convertase subtilisin/kexin-6 (PCSK6), a corin activator. Knockdown of PCSK6 or corin in high salt-treated M1-cortical collecting duct (M1-CCD) cells increased the expression of aquaporin 2 (AQP2) and β-epithelial Na⁺ channel (β-ENaC).

CONCLUSIONS

Short-term HS may induce the PCSK6–corin–ANP–AQP2/β-ENaC pathway in the kidney. Enhanced serum corin level in humans and rodents is positively correlated with HS-induced SBP and 24-hour urinary Na⁺ and U-mALB excretion, which suggests that corin is involved in the salt-water balance in response to HS intake.

CLINICAL TRIALS REGISTRATION

Public Trials Registry Number NCT02915315

http://ift.tt/2Ezx0YE

Renin–Angiotensin–Aldosterone System Parameters as Biomarker in Heart Failure Patients With Preserved Ejection Fraction: Focus on Angiotensinogen

Aging of the population has a strong impact on the prevalence of heart failure (HF). Given our aging population, the number of patients with HF is expected to increase rapidly over the next decades.¹ The clinical syndrome of HF consists of 2 largely distinct phenotypes, readily discerned by echocardiographic determination of the left ventricular ejection fraction (EF). While pharmacological inhibition of the renin–angiotensin–aldosterone system (RAAS) improves survival in patients with HF with reduced EF (left ventricular EF <50%; HFrEF), such therapy has little or no effect in patients with HF with preserved EF (left ventricular EF >50%; HFpEF).² This may not be too surprising in view of the marginal RAAS parameter alterations in HFpEF vs. HFrEF.³ Indeed, in HFrEF, plasma renin activity is a strong predictor of mortality, even in patients taking renin-affecting drugs like RAAS inhibitors and β-adrenergic antagonists.⁴ Yet, neither renin nor aldosterone associates with diastolic dysfunction, a well-known characteristic of HFpEF.⁵ Nevertheless, both angiotensin II and aldosterone are established contributors to left ventricular hypertrophy and cardiac fibrosis, 2 important determinants of diastolic dysfunction.

http://ift.tt/2FtlcZ5

Concomitant Hypertension and Diabetes: Role of Aortic Stiffness and Glycemic Management

Even with adequate glycemic and blood pressure (BP) control, treated type 2 diabetic hypertensive subjects (DHS) maintain a consistently elevated overall and cardiovascular (CV) risk.^1–4 Increasing evidence shows that when overall and CV mortality rates are calculated exclusively from the hemodynamic factors that affect BP, these parameters do not differ significantly from those of non-DHS.⁵ Evaluation of the interaction term (hypertensive with or without diabetes * hemodynamic factors) indicates that the impact of BP hemodynamic variables is similar in both groups. Consequently, BP hemodynamic factors alone cannot explain the difference in mortality rates between DHS and non-DHS. The paper by Yashkin et al,⁶ in this issue shows that intensive drug therapy in DHS patients is associated with an increased risk of congestive heart failure, myocardial infarction, and stroke/transient ischemic attack, but a reduction in the risk of mortality. The risk for these CV events and death is decreased significantly by adherence to diabetes management guidelines. The possible signification of these considerations for DHS is the subject of the present commentary.

http://ift.tt/2EyJPCy

Angiotensinergic Innervation of the Human Right Atrium: Implications for Cardiac Reflexes

Abstract

BACKGROUND

The right atrium is densely innervated and provides sensory input to important cardiocirculatory reflexes controlling cardiac output and blood pressure. Its angiotensin (Ang) II-expressing innervation may release Ang II as a neuropeptide cotransmitter to modulate reflexes but has not yet been characterized.

METHODS

Intraoperative surgical biopsies from human right atria (n = 7) were immunocytologically stained for Ang II, tyrosine hydroxylase (TH), and synaptophysin (SYN). Tissue angiotensins were extracted and quantified by radioimmunoassay.

RESULTS

Angiotensinergic fibers were frequent in epicardial nerves and around vessels with variable TH co-localization (none to >50%/bundle). Fibers were also widely distributed between cardiomyocytes and in the endocardium where they were typically nonvaricose, TH/SYN-negative and usually accompanied by varicose catecholaminergic fibers. In the endocardium, some showed large varicosities and were partially TH or SYN-positive. A few endocardial regions showed scattered nonvaricose Ang fibers ending directly between endothelial cells. Occasional clusters of thin varicose terminals co-localizing SYN or TH were located underneath, or protruded into, the endothelium. Endocardial density of Ang and TH-positive fibers was 30–300 vs. 200–450/mm². Atrial Ang II, III, and I concentrations were 67, 16, and 5 fmol/g (median) while Ang IV and V were mostly undetectable.

CONCLUSIONS

The human right atrium harbors an abundant angiotensinergic innervation and a novel potential source of atrial Ang II. Most peripheral fibers were noncatecholaminergic afferents or preterminal vagal efferents and a minority was presumably sympathetic. Neuronal Ang II release from these fibers may modulate cardiac and circulatory reflexes independently from plasma and tissue Ang II sources.

http://ift.tt/2EyJOP0

The Effect of Head and Neck Radiotherapy on Blood Pressure and Orthostatic Hypotension in Patients With Head and Neck Tumors

Abstract

BACKGROUND

Radiotherapy (RT) plays a key role in the management of head and neck cancer (HNC), especially in locally advanced disease. Patients undergoing head and neck RT, especially elderly ones, are suffering from low and labile blood pressure (BP) during the treatment. They complain of weakness and fatigue and are prone to recurrent falls. The aim of this study was to characterize BP changes during RT period.

METHODS

Patients with HNC, receiving radiation to the neck, were recruited from Sheba medical center RT unit. Office BP, orthostatic measurements, 24-hour ambulatory BP monitoring, body weight, and metabolic parameters were measured at baseline after 30 days and after 90 days from beginning of therapy.

RESULTS

Nineteen patients (17 males), 64 ± 12 years old were recruited. Nine hypertensive patients continued their antihypertensive treatment during the study. Office systolic BP and diastolic BP decreased significantly after 30 days (128 ± 4/80 ± 3 to 122 ± 3/74 ± 3 mm Hg; P < 0.05). Average 24-hour BP values after 30 days of RT decreased from 130 ± 3/76 ± 2 to 123 ± 3/71 ± 2 mm Hg; P < 0.05. A similar trend was observed for day and night BP levels. Decrease in office and ambulatory BP was sustained for several months after RT completion. No orthostasis was observed during the study period. Patient lost weight significantly during the study period. However, BP changes were independent of weight loss.

CONCLUSION

There is a significant and sustained BP reduction after head and neck RT, without orthostatic changes. Clinicians should be aware of this phenomenon and consider treatment adaption accordingly.

http://ift.tt/2FtkYkH

Systemic Angiotensinogen Concentrations Are Independently Associated With Left Ventricular Diastolic Function in a Community Sample

Abstract

BACKGROUND

Left ventricular (LV) diastolic dysfunction characterizes heart failure with a preserved ejection fraction. Although it is recognized that the renin–angiotensin–aldosterone system (RAAS) decreases LV diastolic function, whether systemic angiotensinogen (AGT) contributes to these effects is uncertain. Hence, the aim was to determine the relationship between systemic AGT concentrations and LV diastolic function.

METHODS

LV diastolic function was determined from the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (average e') and from the ratio of early transmitral blood flow velocity (E) to average e' (E/e') in 445 Black African participants from a community sample.

RESULTS

In multivariate regression models with adjustments for age, sex, waist circumference diabetes mellitus, alcohol and tobacco use, hypertension treatment, systolic blood pressure (BP), and relative wall thickness, the square root of serum AGT concentrations was independently associated with E/e' (partial r (95% confidence interval [CI]) = 0.11 (0.02–0.21), P = 0.04), but not with average e' (partial r (95% CI) = −0.06 (−0.15 to 0.04), P = 0.25). There was no association between plasma renin concentrations and markers of diastolic function (all P > 0.05).

CONCLUSION

Circulating AGT concentrations are associated with LV diastolic function beyond BP and other confounders in an African population. Hence, through circulating AGT, the systemic RAAS may play an important role in contributing to LV diastolic function in Black Africans.

http://ift.tt/2EBrHYv

Base-Resolution Analysis of DNA Methylation Patterns Downstream of Dnmt3a in Mouse Naive B Cells

The DNA methyltransferase, Dnmt3a, is dynamically regulated throughout mammalian B cell development and upon activation by antigenic stimulation. Dnmt3a inactivation in hematopoietic stem cells has been shown to drive B cell-related malignancies, including chronic lymphocytic leukemia (CLL), and associates with specific DNA methylation patterns in transformed cells. However, while it is clear that inactivation of Dnmt3a in hematopoietic stem cells has profound functional impacts, the consequences of Dnmt3a inactivation in cells of the B lineage are unclear. To assess whether loss of Dnmt3a at the earliest stages of B cell development lead to DNA methylation defects that might impair function, we selectively inactivated Dnmt3a early in mouse B cell development and then utilized Whole Genome Bisulfite Sequencing to generate base-resolution profiles of Dnmt3a^+/+ and Dnmt3a^-/- naïve splenic B cells. Overall, we find that global methylation patterns are largely consistent between Dnmt3a^+/+ and Dnmt3a^-/-naïve B cells, indicating a minimal functional impact of DNMT3A in mature B cells. However, loss of Dnmt3a induced 449 focal DNA methylation changes, dominated by loss-of-methylation events. Regions found to be hypomethylated in Dnmt3a^-/- naïve splenic B cells were enriched in gene bodies of transcripts expressed in B cells, a fraction of which are implicated in B cell-related disease. Overall, the results from this study suggest that factors other than Dnmt3a are the major drivers for methylome maintenance in B cell development.

http://ift.tt/2qWYbKV

Genomic Understanding of an Infectious Brain Disease from the Desert

Rhinocladiella mackenziei accounts for the majority of fungal brain infections in the Middle East and is restricted to the arid climate zone between Saudi Arabia and Pakistan. Neurotropic dissemination caused by this fungus has been reported in immunocompromised, but also immunocompetent individuals. If untreated, the infection is fatal. Outside of humans, the environmental niche of R. mackenziei is unknown, and the fungus has been only cultured from brain biopsies. In this paper we describe the whole genome re-sequencing of two Rhinocladiella mackenziei strains from patients in Saudi Arabia and Qatar. We assessed intra-species variation and genetic signatures to uncover the genomic basis of the pathogenesis and potential niche adaptations. We found that the duplicated genes (paralogs) are more susceptible to accumulate significant mutations. Comparative genomics with other filamentous ascomycetes revealed a diverse arsenal of genes likely engaged in pathogenicity, such as the degradation of aromatic compounds and iron acquisition. In addition, intracellular accumulation of trehalose and choline suggest possible adaptations to the conditions of arid climate region. Specifically protein family contractions were found, including short-chain dehydrogenase/reductase SDR, the cytochrome P450 (E-class) and the G-protein beta WD-40 repeat. Gene composition and metabolic potential indicate extremotolerance and hydrocarbon assimilation, suggesting a possible environmental habitat of oil-polluted desert soil.

http://ift.tt/2mtlU0I

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy, Published online: 11 January 2018; doi:10.1038/bjc.2017.410

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

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RNF126 as a biomarker of a poor prognosis in invasive breast cancer and CHK1 inhibitor efficacy in breast cancer cells

Purpose: 1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. Experimental Design: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays. Results: RNF126 protein expression was elevated in BC tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHK1 transcript expression. Critically, a strong correlation between RNF126 and CHK1 proteins was identified in BC tissue and cell lines. The inhibition of CHK1 induced a greater cell killing and a higher level of replication stress in BC cells expressing RNF126 compared to RNF126 depleted cells. Conclusions: RNF126 protein is highly expressed in invasive BC tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive BC and is considered a potential biomarker of a cancer's responsiveness to CHK1 inhibitors. CHK1 inhibition targets BC cells expressing higher levels of RNF126 by enhancing replication stress.

http://ift.tt/2D3cHph

Evaluation of overall response rate and progression-free survival as potential surrogate endpoints for overall survival in immunotherapy trials

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria based objective response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Experimental Design: Thirteen randomized, multicenter, active control trials containing immunotherapeutic agents submitted to FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS and OS were evaluated at individual and trial-levels. Patient-level responder analysis was performed for PFS and OS. Results: The coefficient of determination (R2) measured the strength of associations, where values near 1 imply surrogacy and values close to zero suggest no association. At the trial-level, associations between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 - 0.1, and individual level correlations were approximately 0.6. HRs of PFS and OS for responders versus non-responders were 0.129 (95% CI: 0.11, 0.15) and 0.118 (95% CI: 0.11, 0.13), respectively. Conclusions: While responders exhibited longer survival and PFS than non-responders, the trial-level and individual level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations.

http://ift.tt/2mk2ESp

Gut Bacteria Shape Response to Checkpoint Inhibitor Therapy [News in Depth]

Microbiome composition one factor in determining efficacy of anti–PD-1 drugs, studies show.

http://ift.tt/2mlmsVq

Clinical Considerations of the Role of Palbociclib in the Management of Advanced Breast Cancer Patients With and Without Visceral Metastases

Abstract

Background

This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor−positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases.

Patients and methods

Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement.

Results

Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to endocrine therapy in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35 − 0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR, 0.53; 95% CI, 0.36 − 0.77. In patients naive to endocrine therapy in the advanced disease setting, mPFS was 19.3 months with palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR, 0.63; 95% CI, 0.47 − 0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR, 0.50; 95% CI, 0.36 − 0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC.

Conclusions

Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy.

Clinical trial registration

NCT01942135, NCT01740427

http://ift.tt/2mn6J8e

Watson for Oncology and breast cancer treatment recommendations: agreement with an expert multidisciplinary tumor board

Abstract

Background

Breast cancer oncologists are challenged to personalize care with rapidly changing scientific evidence, drug approvals, and treatment guidelines. Artificial intelligence (AI) clinical decision-support systems (CDSSs) have the potential to help address this challenge. We report here the results of examining the level of agreement (concordance) between treatment recommendations made by the AI CDSS Watson for Oncology (WFO) and a multidisciplinary tumor board for breast cancer.

Patients and methods

Treatment recommendations were provided for 638 breast cancers between 2014 and 2016 at the Manipal Comprehensive Cancer Center, Bengaluru, India. WFO provided treatment recommendations for the identical cases in 2016. A blinded second review was carried out by the center's tumor board in 2016 for all cases in which there was not agreement, to account for treatments and guidelines not available before 2016. Treatment recommendations were considered concordant if the tumor board recommendations were designated 'recommended' or 'for consideration' by WFO.

Results

Treatment concordance between WFO and the multidisciplinary tumor board occurred in 93% of breast cancer cases. Subgroup analysis found that patients with stage I or IV disease were less likely to be concordant than patients with stage II or III disease. Increasing age was found to have a major impact on concordance. Concordance declined significantly (P ≤ 0.02; P < 0.001) in all age groups compared with patients <45 years of age, except for the age group 55–64 years. Receptor status was not found to affect concordance.

Conclusion

Treatment recommendations made by WFO and the tumor board were highly concordant for breast cancer cases examined. Breast cancer stage and patient age had significant influence on concordance, while receptor status alone did not. This study demonstrates that the AI clinical decision-support system WFO may be a helpful tool for breast cancer treatment decision making, especially at centers where expert breast cancer resources are limited.

http://ift.tt/2D39Tsf

Clinical and Radiographic Predictors of Intracerebral Hemorrhage Outcome

Background: Intracerebral hemorrhage (ICH) represents 10-15% of all stroke cases in the US annually. Fewer than 40% of these patients ever reach long-term functional independence, and mortality rate is roughly 40% at 1 month. Due to the high morbidity and mortality rates after ICH, early detection of high-risk patients would be beneficial in directing the management course and goals of care. This review aims to discuss relevant clinical and radiographic characteristics that can serve as predictors of poor prognosis and examine their efficacy in predicting patient outcomes after ICH. Summary: A literature review was conducted on various clinical and radiographic factors. They were examined for their predictive value in relation to ICH outcome. Studies that focused on each of these factors were included, and their results analyzed for trends with regard to incidence, patient outcome, and mortality rate. Key Message: In this review, we examined clinical and radiographic characteristics that have been found to be significantly associated to a varying degree with poor outcome. Clinical and radiographic predictors of poor patient outcome are invaluable when it comes to identifying high-risk patients and triaging accordingly as well as guiding decision-making.
Intervent Neurol 2018;7:118-136

http://ift.tt/2D6eV7C

Estimating the scale of chronic hepatitis B virus infection among migrants in EU/EEA countries

Chronic hepatitis B (CHB) related morbidity and mortality can be reduced through risk group screening, linkage to care and anti-viral treatment. This study estimates the number of CHB cases among foreign-born ...

http://ift.tt/2mktvh2

Visceral adipose tissue and carotid intima-media thickness in HIV-infected patients undergoing cART: a prospective cohort study

Combined antiretroviral therapy (cART) in HIV-infected patients has been associated with lipodystrophy, metabolic abnormalities, and an increased risk of cardiovascular disease. Ultrasound measures of carotid ...

http://ift.tt/2D0zoL1

Persistent mammalian orthoreovirus, coxsackievirus and adenovirus co-infection in a child with a primary immunodeficiency detected by metagenomic sequencing: a case report

We report a rare case of Mammalian orthoreovirus (MRV) infection in a child with a primary immunodeficiency (PID). Infections with Mammalian orthoreovirus are very rare and probably of zoonotic origin. Only a few...

http://ift.tt/2mkpvNN

Modeling Radiation Effects of Ultrasoft X Rays on the Basis of Amorphous Track Structure

Radiation Research, Volume 189, Issue 1, Page 32-43, January 2018.


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R. J. Michael Fry, MD; 1925–2017

Radiation Research, Volume 189, Issue 1, Page 1-4, January 2018.


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Radiation- and Age-Associated Changes in Peripheral Blood Dendritic Cell Populations among Aging Atomic Bomb Survivors in Japan

Radiation Research, Volume 189, Issue 1, Page 84-94, January 2018.


http://ift.tt/2D26aeC

Improved Total-Body Irradiation Survival by Delivery of Two Radiation Mitigators that Target Distinct Cell Death Pathways

Radiation Research, Volume 189, Issue 1, Page 68-83, January 2018.


http://ift.tt/2mhLd4W

Second-order Kinetics of DTPA and Plutonium in Rat Plasma

Radiation Research, Volume 189, Issue 1, Page 64-67, January 2018.


http://ift.tt/2D31SDB

Rescue Effect Inherited in Colony Formation Assays Affects Radiation Response

Radiation Research, Volume 189, Issue 1, Page 44-52, January 2018.


http://ift.tt/2mmduaC

Gilbert W. Beebe Symposium on 30 Years after the Chernobyl Accident: Current and Future Studies on Radiation Health Effects

Radiation Research, Volume 189, Issue 1, Page 5-18, January 2018.


http://ift.tt/2D6L1Qk

Effects of 1H + 16O Charged Particle Irradiation on Short-Term Memory and Hippocampal Physiology in a Murine Model

Radiation Research, Volume 189, Issue 1, Page 53-63, January 2018.


http://ift.tt/2mjG1gS

Activation of the TRPV1 Thermoreceptor Induced by Modulated or Unmodulated 1800 MHz Radiofrequency Field Exposure

Radiation Research, Volume 189, Issue 1, Page 95-103, January 2018.


http://ift.tt/2D0YR71

Super-Resolution Nanoscopy Imaging Applied to DNA Double-Strand Breaks

Radiation Research, Volume 189, Issue 1, Page 19-31, January 2018.


http://ift.tt/2mo0SzU

A Microdosimetric-Kinetic Model of Cell Killing by Irradiation from Permanently Incorporated Radionuclides

Radiation Research, Volume 189, Issue 1, Page 104-116, January 2018.


http://ift.tt/2mmBkD7

Exam 1: Patient Characteristics Associated With Quality of Colonoscopy Preparation: A Systematic Review and Meta-analysis

http://ift.tt/2D2ZgWl

Patient satisfaction with hospital care and nurses in England: an observational study

Objectives

To inform healthcare workforce policy decisions by showing how patient perceptions of hospital care are associated with confidence in nurses and doctors, nurse staffing levels and hospital work environments.

Design

Cross-sectional surveys of 66 348 hospital patients and 2963 inpatient nurses.

Setting

Patients surveyed were discharged in 2010 from 161 National Health Service (NHS) trusts in England. Inpatient nurses were surveyed in 2010 in a sample of 46 hospitals in 31 of the same 161 trusts.

Participants

The 2010 NHS Survey of Inpatients obtained information from 50% of all patients discharged between June and August. The 2010 RN4CAST England Nurse Survey gathered information from inpatient medical and surgical nurses.

Main outcome measures

Patient ratings of their hospital care, their confidence in nurses and doctors and other indicators of their satisfaction. Missed nursing care was treated as both an outcome measure and explanatory factor.

Results

Patients' perceptions of care are significantly eroded by lack of confidence in either nurses or doctors, and by increases in missed nursing care. The average number of types of missed care was negatively related to six of the eight outcomes—ORs ranged from 0.78 (95% CI 0.68 to 0.90) for excellent care ratings to 0.86 (95% CI 0.77 to 0.95) for medications completely explained—positively associated with higher patient-to-nurse ratios (b=0.15, 95% CI 0.10 to 0.19), and negatively associated with better work environments (b=–0.26, 95% CI –0.48 to –0.04).

Conclusions

Patients' perceptions of hospital care are strongly associated with missed nursing care, which in turn is related to poor professional nurse (RN) staffing and poor hospital work environments. Improving RN staffing in NHS hospitals holds promise for enhancing patient satisfaction.

http://ift.tt/2Dl4wT0

What are the sources of stress and distress for general practitioners working in England? A qualitative study

Objectives

This paper reports the sources of stress and distress experienced by general practitioners (GP) as part of a wider study exploring the barriers and facilitators to help-seeking for mental illness and burnout among this medical population.

Design

Qualitative study using in-depth interviews with 47 GP participants. The interviews were audio-recorded, transcribed, anonymised and imported into NVivo V.11 to facilitate data management. Data were analysed using a thematic analysis employing the constant comparative method.

Setting

England.

Participants

A purposive sample of GP participants who self-identified as: (1) currently living with mental distress, (2) returning to work following treatment, (3) off sick or retired early as a result of mental distress or (4) without experience of mental distress. Interviews were conducted face-to-face or over the telephone.

Results

The key sources of stress/distress related to: (1) emotion work—the work invested and required in managing and responding to the psychosocial component of GPs' work, and dealing with abusive or confrontational patients; (2) practice culture—practice dynamics and collegial conflict, bullying, isolation and lack of support; (3) work role and demands—fear of making mistakes, complaints and inquests, revalidation, appraisal, inspections and financial worries.

Conclusion

In addition to addressing escalating workloads through the provision of increased resources, addressing unhealthy practice cultures is paramount. Collegial support, a willingness to talk about vulnerability and illness, and having open channels of communication enable GPs to feel less isolated and better able to cope with the emotional and clinical demands of their work. Doctors, including GPs, are not invulnerable to the clinical and emotional demands of their work nor the effects of divisive work cultures—culture change and access to informal and formal support is therefore crucial in enabling GPs to do their job effectively and to stay well.

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Protocadherin8 Promotes Invasion and Metastasis via Laminin Subunit γ2 in Gastric Cancer

Abstract

Growing evidence suggests that protocadherins (PCDHs) play crucial roles in pathogenesis and progression of cancers including gastric cancer (GC). Protocadherin8 (PCDH8) was previously reported to be involved in metastasis of GC, but functional studies yielded inconsistent results and the molecular mechanism remained unknown. This study aimed to explore the clinical relevance, function and molecular mechanism of PCDH8 in GC. Data from the GEPIA and Kaplan-Meier plotter databases showed that high expression of PCDH8 was significantly correlated with poorer prognosis in GC. Ectopic expression of PCDH8 in GC cells promoted invasion and migration in vitro and metastasis in vivo, and knockdown of PCDH8 inhibited invasion and migration in vitro. RNA sequencing followed by Gene Set Enrichment Analysis found a remarkable enrichment in the extracellular matrix receptor interaction pathway, with the expression of laminin subunit γ2 (LAMC2) being significantly increased in the PCDH8-overexpressing group. High expression of LAMC2 was significantly correlated to poor prognosis in GC in GEPIA database. Up-regulation of LAMC2 following PCDH8 overexpression was further confirmed by immunohistochemistry in liver metastatic lesions of nude mice. To our knowledge, this is the first report of the metastasis-enhancing property and molecular mechanism through up-regulation of LAMC2 of PCDH8 in cancer. High expression of PCDH8 could be used as a biomarker for poor prognosis in clinical practice.

This article is protected by copyright. All rights reserved.

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Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation

Abstract

Although hereditary kidney cancer syndrome accounts for around five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, U.S.A. and the first kidney cancer associated gene, VHL was identified through kindred analysis of von Hippel-Lindau syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms how an alteration of each kidney cancer associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer.

This article is protected by copyright. All rights reserved.

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Colonic perforation due to GI histoplasmosis in an immunocompetent host mimicking Crohn's disease

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The presence of small and diminutive proximal hyperplastic polyps is associated with higher rates of synchronous advanced neoplasia compared with patients without serrated lesions

The association of proximal small and diminutive hyperplastic polyps (HPs) with synchronous neoplasia (AN) is not well defined. However, sessile serrated polyps, even when small, are known to portend synchronous neoplastic risk. Currently, when proximal small hyperplastic polyps are detected, the USMTF does not recommend a change in surveillance interval. We aimed to compare the rates of synchronous AN in a screening colonoscopy cohort of patients with small and then diminutive proximal HPs in comparison, first to a cohort absent any serrated or proximal hyperplastic polyps, and then in comparison with a cohort with small proximal sessile serrated polyps (SSPs).

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No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

http://ift.tt/2mtedHY

EEG synchronization measures predict epilepsy-related BOLD-fMRI fluctuations better than commonly used univariate metrics

Because of their complementary properties, the simultaneous acquisition of the electroencephalogram (EEG) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been actively pursued. This is particularly important in the field of epilepsy, motivated by the need to map epileptic activity, as accurately as possible, in the brain of patients with drug-resistant focal epilepsy undergoing pre-surgical evaluation (Hoffmann et al., 2000; Ives et al., 1993; Lemieux et al., 2001; LeVan and Gotman, 2009; Salek-Haddadi et al., 2006).

http://ift.tt/2AS5m6V

Epileptiform and periodic EEG activities induced by rapid sevoflurane anaesthesia induction

Sevoflurane is a fluorinated inhalated anaesthetic introduced into clinical practice in the 1990's. It is now widely used in both adults and children because of its rapid onset and short-lasting activity, pleasant odour and non-pungency (Eger 1994; Lerman et al., 1994). A rapid increase in the inspiratory concentration of sevoflurane, however, has been demonstrated to be associated with a transient hyperdynamic reaction in adult patients during controlled mild hypocapneic hyperventilation (Vakkuri et al., 1999).

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Hepatosplenic T-cell Lymphoma: A Review of Clinicopathologic Features, Pathogenesis and Prognostic Factors

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and clinically aggressive type of T-cell lymphoma that arises most often in adolescents and young adults. Patients with HSTCL commonly present with B-symptoms and cytopenias which may suggest a diagnosis of acute leukemia initially. Patients present with extranodal disease involving the spleen, liver and bone marrow; lymphadenopathy is usually absent. The lymphoma cells can show a spectrum of cell sizes and are of T-cell lineage, often negative for CD4 and CD8 and positive for T-cell receptor γδ or, less often, αβ.

http://ift.tt/2ASjX22

Chinese Cervicocephalic artery dissection study (CCADS): rationale and protocol for a multicenter prospective cohort study

Cervicocephalic artery dissection (CAD) is an important etiology of stroke in the youth. Findings from recent studies suggest it a "group of disease entities" with different underlying etiologies, presentation...

http://ift.tt/2D3z79P

Hand Preference and Cognitive, Motor, and Behavioral Functioning in 10-Year-Old Extremely Preterm Children

The association of hand preference (left, mixed, and right) with cognitive, academic, motor, and behavioral function was evaluated in 864 extremely preterm children at 10 years of age. Left-handed and right-handed children performed similarly but mixed-handed children had greater odds of functional deficits across domains than right-handed children.

http://ift.tt/2qVXj9u

Deficit of Fat Free Mass in Very Preterm Infants at Discharge is Associated with Neurological Impairment at Age 2 Years

Preterm infants have a deficit of fat-free mass accretion during hospitalization. This study suggests that z score of fat-free mass at discharge is associated with neurologic outcome (P = .003) at 2 years of age, independent of sex, gestational age, and birth weight z score. Interventions to promote quality of growth should be considered.

http://ift.tt/2mt9tBX

An Ounce of Prevention May Be Worth Many Pounds of Cure

Studies in animals and humans have shown that transient inflammation (infectious and noninfectious) predisposes children to developing long-term functional gastrointestinal disorders (FGIDs).1-4 Acute gastroenteritis of bacterial,1,2 viral,2 and parasitic5 origin is a known risk factor for irritable bowel syndrome and functional dyspepsia. Henoch–Schönlein purpura3 and cow's milk protein allergy4,6 (CMA) also are associated with an increased risk of FGIDs in children. In 2011, Saps et al compared a cohort of 52 school-age children diagnosed with CMA as infants with their healthy siblings and used age-appropriate validated questionnaires (Questionnaire of Pediatric Gastrointestinal Symptoms) to diagnose FGIDs per the Rome III criteria.

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Oral Granular Cell Tumor Mimicking a Giant Sialolith in a Child

A 12-year-old girl was referred to us complaining of asymptomatic swellings at the left oral floor lasting 12 months. No relation with meals was reported, and extraoral evaluation was normal. Intraoral examination showed a white yellowish well-defined elongated swelling of approximately 1 cm in size at the floor of the mouth in relation to lower left canine to first molar region (Figure).

http://ift.tt/2qVQPrd

Pilot Clinical Trial of High-Flow Oxygen Therapy in Children with Asthma in the Emergency Service

To assess the efficacy of high-flow nasal cannula (HFNC) oxygen therapy and safety in children with asthma and moderate respiratory failure in the emergency department (ED).

http://ift.tt/2mtEMwv

A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network

A 5-year-old boy presented to the Undiagnosed Diseases Network (UDN) with a history of global developmental delay, postnatal microcephaly, hypotonia, jerking movements concerning for seizures, minimal speech, severe gastroesophageal reflux disease, dysmorphic features, and partial agenesis of the corpus callosum on brain magnetic resonance imaging.

http://ift.tt/2r0IiU3

Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018

Anemia is a frequent complication during the later stages of chronic kidney disease. When present, it may cause symptoms such as fatigue and shortness of breath. The pathogenesis of anemia in chronic kidney disease is complex, but a central feature is a relative deficit of erythropoietin. New information has elucidated the critical role of the hypoxia-sensing system in mediating erythropoietin synthesis and release. Iron deficiency is a second important factor in the anemia of chronic kidney disease.

http://ift.tt/2EyxMVX

Evaluation of Kidney Donors: Core Curriculum 2018

Nearly 100,000 patients are waiting for a kidney transplant, yet each year only 11,000 undergo transplantation with a deceased donor kidney. Annual death rates among waitlist registrants range from 5% to 15%; many die before receiving a transplant. Not surprisingly, registrants turn to family and friends to become living kidney donors on their behalf. Living kidney donor selection practices aim to quantify lifetime risk for kidney failure based on a candidate's predonation demographic and health characteristics.

http://ift.tt/2FuJq5s

Quiz: Understanding acid-base issues in EMS

How well do you know the conditions associated with pH imbalances?

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BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology

Abstract

BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early β-amyloid pathology. The longitudinal approach allowed to assess the kinetics of individual plaques and associated presynaptic pathology, before and throughout treatment. BACE1 inhibition could not halt but slow down progressive β-amyloid deposition and associated synaptic pathology. Notably, the data revealed that the initial process of plaque formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. This finding of particular susceptibility of plaque formation has profound implications to achieve optimal therapeutic efficacy for the prospective treatment of AD.

http://ift.tt/2D67tJk

Reanalysis of Chinese Treponema pallidum samples: all Chinese samples cluster with SS14-like group of syphilis-causing treponemes

Treponema pallidum subsp. pallidum (TPA) is the causative agent of syphilis. Genetic analyses of TPA reference strains and human clinical isolates have revealed two genetically distinct groups of syphilis-causing...

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Human echinostomiasis: a case report

Echinostomiasis is a food-borne infection caused by an intestinal trematodes belonging to the family Echinostomatidae. They infect the gastrointestinal tract of humans. Patients are usually asymptomatic. Howev...

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The impact of obesity on outcomes for patients undergoing mastectomy using the ACS-NSQIP data set

Abstract

Purpose

According to the World Health Organization (WHO), 34.7% of females in the United States are obese (BMI ≥ 30) in 2014, compared to 32.5% in 2010. The previous research has demonstrated high BMI as an independent risk factor for surgical complications after breast surgery. As more patients become obese, we sought to examine whether increasing obesity had an effect on outcomes of women who underwent a unilateral mastectomy without breast reconstruction.

Methods

The study reviewed the 2007–2012 ACS-NSQIP database and identified all patients who underwent a unilateral mastectomy without reconstruction. Patients were then categorized and compared according to the World Health Organization obesity classification. Data were analyzed for minor complications (e.g., UTI and SSI) and major complications (e.g., renal failure, sepsis, deep vein thrombosis, return to operating room [RTOR], and cardiac arrest).

Results

A total of 7207 women were identified. Median BMI was 27.3 kg/m². From the cohort, 453 patients (6.29%) had a major complication and 173 patients (2.40%) had a minor complication. 53 (0.74%) had bleeding complications, 148 (2.05%) had a surgical site infection (SSI), 352 (4.88%) RTOR, and 7 (0.01%) died within 30 days. Major complications (p = 0.005) and minor complications (p < 0.001) significantly increased as BMI increased. SSI and RTOR had increasing trends, but were not statistically significant.

Conclusions

This study characterizes the risk of complications in women undergoing unilateral mastectomies and shows that increasing obesity is associated with major and minor postoperative complications. Our finding highlights the need for personalized preoperative risk assessment and counseling of obese patients.

http://ift.tt/2D5XvbN

Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer

Abstract

Background

The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients.

Methods

Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations.

Results

The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55–37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50–45.0, P = 0.176).

Conclusions

Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

http://ift.tt/2mlvHoD

Automated Measurement of Cryptococcal Species Polysaccharide Capsule and Cell Body

This technique describes an automated batch image processor designed to measure polysaccharide capsule and body radii. While initially designed for Cryptococcus neoformans capsule measurements the automated image processor can also be applied to other contrast based detection of circular objects.

http://ift.tt/2qZqPeG

Spotlight: Braun Ambulances 'built for life' to protect, serve responders

Braun Industries prides itself on producing safe, quality ambulances for those who serve

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Certitude Delivery System by Edwards Lifesciences: Class I Recall - Mold Overflow Defect Which May Obstruct Blood Flow

Audience: Risk Manager, Cardiology, Surgery Model/Item Numbers: 9600CT20A, 9600CT23A, 9600CT26A, 9600CT29A, 9600SDS20A, 9600SDS23A, 9600SDS26A, 9600SDS29A [Posted 01/11/2018] ISSUE: Edwards LifeSciences is recalling its Certitude Delivery System...

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Prescription Opioid Cough and Cold Medicines: Drug Safety Communication - FDA Requires Labeling Changes

Audience: Family Practice, Pediatrics [Posted 01/11/2018] ISSUE: FDA is requiring safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone to limit the use of these products to adults 18 years and older...

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Observation and Analysis of Blinking Surface-enhanced Raman Scattering

This protocol describes the analysis of blinking surface-enhanced Raman scattering due to the random walk of a single molecule on a silver surface using power laws.

http://ift.tt/2EzLis2

Certitude Delivery System by Edwards Lifesciences: Class I Recall - Mold Overflow Defect Which May Obstruct Blood Flow

Audience: Risk Manager, Cardiology, Surgery Model/Item Numbers: 9600CT20A, 9600CT23A, 9600CT26A, 9600CT29A, 9600SDS20A, 9600SDS23A, 9600SDS26A, 9600SDS29A [Posted 01/11/2018] ISSUE: Edwards LifeSciences is recalling its Certitude Delivery System...

http://ift.tt/2D1bX4d

Prescription Opioid Cough and Cold Medicines: Drug Safety Communication - FDA Requires Labeling Changes

Audience: Family Practice, Pediatrics [Posted 01/11/2018] ISSUE: FDA is requiring safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone to limit the use of these products to adults 18 years and older...

http://ift.tt/2mkXcPj

Discovering Middle Ear Anatomy by Transcanal Endoscopic Ear Surgery: A Dissection Manual

The aim of this article is to describe the methodology of exclusively endoscopic cadaveric middle ear dissection. Moreover, we aim to provide a comprehensive guide to endoscopic middle ear anatomy.

http://ift.tt/2muCHQT

Analysis of DNA modifications in aging research

Abstract

As geroscience research extends into the role of epigenetics in aging and age-related disease, researchers are being confronted with unfamiliar molecular techniques and data analysis methods that can be difficult to integrate into their work. In this review, we focus on the analysis of DNA modifications, namely cytosine methylation and hydroxymethylation, through next-generation sequencing methods. While older techniques for modification analysis performed relative quantitation across regions of the genome or examined average genome levels, these analyses lack the desired specificity, rigor, and genomic coverage to firmly establish the nature of genomic methylation patterns and their response to aging. With recent methodological advances, such as whole genome bisulfite sequencing (WGBS), bisulfite oligonucleotide capture sequencing (BOCS), and bisulfite amplicon sequencing (BSAS), cytosine modifications can now be readily analyzed with base-specific, absolute quantitation at both cytosine-guanine dinucleotide (CG) and non-CG sites throughout the genome or within specific regions of interest by next-generation sequencing. Additional advances, such as oxidative bisulfite conversion to differentiate methylation from hydroxymethylation and analysis of limited input/single-cells, have great promise for continuing to expand epigenomic capabilities. This review provides a background on DNA modifications, the current state-of-the-art for sequencing methods, bioinformatics tools for converting these large data sets into biological insights, and perspectives on future directions for the field.

http://ift.tt/2ASPMIo

The Benefits of Singing and Strolling

We've heard of whistling while you work, but what about singing while you walk? Preliminary findings from a recent study (Harrison et al, 2017) suggest that those with mild to moderate Parkinson's  disease may see improvement (i.e., less variability) in their gait if they sing a little tune while they stroll along. While previous research has demonstrated the benefit of "external rhythmic auditory stimuli" has on gait in those with Parkinson's, this is the first to use a self-mediated approach.

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Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway

The aim of the present study was to investigate the effects of mangiferin on gastric carcinoma cells and to determine the possible mechanisms underlying such effects. The MTT assay was performed to evaluate the antiproliferative effect of mangiferin. Following treatment, apoptosis rates of SGC-7901 were established by flow cytometry and laser confocal microscopy, and western blot analysis was used to detect the expression of apoptosis-related proteins. The MTT assay showed that mangiferin inhibited the proliferation of SGC-7901 and BCG-823 cells in a dose-dependent and time-dependent manner. After SGC-7901 cells were exposed to mangiferin for 24, 48 and 72 h, the half-maximal inhibitory concentration values were 16.00, 8.63 and 4.79 µmol/l, respectively. SGC-7901 cell apoptosis induced by mangiferin was observed by Annexin V/PI doubling staining and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive staining. We found a significant decrease in Bcl-2, Bcl-xL and Mcl-1 expression and a significant increase in Bax, Bad and cleaved caspase-3 and caspase-9 expression in SGC-7901 cells by mangiferin treatment. Moreover, mangiferin significantly decreased the levels of p-PI3K, p-Akt and p-mTOR, but had no effects on those of PI3K, Akt and mTOR in epidermal growth factor-treated SGC-7901 cells. Interestingly, the proapoptotic effect of mangiferin on SGC-7901 cells was partially blocked by the Akt activator SC79, whereas LY294002 significantly increased mangiferin-induced apoptosis and growth inhibition. Taken together, our findings indicate that mangiferin effectively inhibits cell growth and induces apoptosis of gastric cancer cells through inhibiting the PI3K/Akt pathways with relative safety, and may be used as a novel chemotherapeutic agent against gastric cancer.

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The role of the globular heads of the C1q receptor in paclitaxel-induced human ovarian cancer cells apoptosis by a mitochondria-dependent pathway

As a mitochondrial membrane protein, globular C1q receptor (gC1qR) can mediate a variety of biological responses. Our study aims to investigate the role of gC1qR in paclitaxel-induced apoptosis of human ovarian cancer cells and to elucidate its potential molecular mechanism. The level of gC1qR was examined using real-time PCR and western blot analyses. Human ovarian cancer cells viability, migration, and proliferation were detected using the water-soluble tetrazolium salt (WST-1) assay, the transwell assay, and 3H-thymidine incorporation into DNA (3H-TdR) assay, respectively. Apoptosis in cells was assessed using flow cytometric analysis. The intracellular reactive oxygen species was estimated by the fluorescence of H2DCFDA and the mitochondrial membrane potential was tested using a JC-1 probe. The expression of the gC1qR gene decreased significantly in human ovarian cancer tissues relative to the surrounding non-neoplastic ovarian tissues. Cells treated with paclitaxel showed increased gC1qR gene expression, cell apoptosis, and mitochondria dysfunction, and the effects on these cells could be abrogated by the addition of gC1qR small-interfering RNA or α-lipoic acid that was used to protect the mitochondria function. In summary, these data support a mechanism that gC1qR-induced mitochondria dysfunction was involved in the paclitaxel-mediated apoptosis of ovarian cancer cells.

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Thioridazine upregulates programmed cell death 4 to induce apoptosis in nasopharyngeal carcinoma through the PI3K/Akt signalling pathway

Thioridazine (THZ) has been identified as a potential regulator of tumour progression, and programmed cell death 4 (PDCD4) has been reported as a novel tumour suppressor. This study aimed to investigate the link between PDCD4 and THZ in the regulation of nasopharyngeal cancer (NPC) cell proliferation. The effect of THZ on NPC cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Then, the involvement of apoptosis and cell cycle in the THZ-mediated regulation of cell viability was assessed by flow cytometry. Related mRNAs and proteins were subsequently examined by real-time PCR and western blot, respectively. After transfection with the PDCD4-siRNA, pGC-FU-GFP-PDCD4 vector and phosphoinositide 3-kinase (PI3K) inhibitor Ly294002, we investigated the antagonistic effects of THZ and PDCD4 on NPC-related protein expression. MTT assays showed that THZ treatment suppressed cell viability. THZ-treated cells were arrested at the G1/G0 phase and showed a significantly increased apoptotic fraction. Furthermore, PDCD4-siRNA antagonized THZ treatment and promoted NPC cell proliferation. Western blot analysis showed that PDCD4 overexpression or PI3K inhibition by LY294002 significantly reduced the expression of phospho-PI3K, phospho-Akt, phospho-mammalian target of rapamycin and phospho-p70s6k, but not their total protein levels. In conclusion, our findings show that THZ and PDCD4 exert antagonistic effects on NPC cell proliferation, probably through the PI3K/Akt pathway. Moreover, these results provide an insight into the mechanism by which THZ targets PDCD4 in NPC cell lines and suggest that the ectopic expression of PDCD4 is a potential therapeutic strategy.

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Efficacy and safety of apatinib as second-line therapy for advanced gastric cancer: a single-center observational study

Apatinib has been proven to be effective and safe among patients in the third-line treatment of advanced gastric cancer in phase II and III trials. We aimed to evaluate its efficacy and safety in second-line practice, and to explore the factors associated with efficacy. Between April 2015 and May 2017, a total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of gastroesophageal junction were enrolled and followed up retrospectively after failing the first line of systemic therapy. The median progression-free survival was 4.43 months (95% confidence interval: 1.63–7.22) and the median overall survival was 9.11 months (95% confidence interval: 8.22–9.99). Two patients achieved a partial response and 14 patients achieved stable disease. The disease control rate was 69.6% and the objective response rate was 8.7%. The most common adverse events over grade 3 were hypertension (8.7%) and thrombocytopenia (8.7%). No treatment-related death was documented during the drug administration. Apatinib is an effective regimen for the second-line treatment of advanced gastric and gastroesophageal cancer with manageable toxicity.

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Metformin and melatonin inhibit DMBA-induced mammary tumorigenesis in rats fed a high-fat diet

The data from in-vitro and in-vivo studies show that both peroral antidiabetic metformin (MF) and pineal hormone melatonin (MT) inhibit the growth of many cancers, including breast cancer. However, most in-vivo studies used standard-type diet with low fat content. Therefore, in this study, we evaluated the chemopreventive effect of MF and MT in an in-vivo model of breast cancer in rats on a high-fat diet (10% of total fat). Mammary carcinogenesis was induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Chemoprevention with MF (administered in a diet, 0.2%) and MT (administered in tap water, 20 mg/l) was induced 20 days before the carcinogen administration through the termination of the experiment (14 weeks after carcinogen administration). Tumor growth parameters were analyzed together with histopathological examination and immunohistochemical detection of KI67 (proliferation marker), caspase-3, BAX, BCL-2 (apoptosis markers), and CD24 and CD44 (cancer stem cell markers) in mammary tumor samples. The combination of chemopreventive agents decreased tumor incidence by 29%. Cumulative tumor volume was lower in all groups treated with chemoprevention. Histopathology did not show significant changes in high-grade/low-grade tumor ratio. Immunohistochemistry showed increased expression of BAX in the combination group, and caspase-3 expression increased in both MT and combination groups. MT, and particularly the MF and MT combination, inhibited DMBA-induced mammary tumor growth in rats by apoptosis stimulation in cancer cells. Our results indicate that MT supplements in patients treated with MF may have a considerable effect on the incidence of breast cancer.

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