Application of disaccharides alone and in combination,for the improvement of stability and particle properties of spray-freeze dried IgG

Purpose: Spray-freeze drying (SFD) is a recently applied method to develop pharmaceutical powders. This study aimed to analyze the competence of Trehalose, Mannitol, Lactose, and Sorbitol instability and aerosolization of Immunoglobulin G (IgG) via SFD.

Methods: Induced soluble aggregates were quantified at 0 and 3?months, and 45?°C using size-exclusion chromatography. Conformation and thermogravimetric assessments were done by Fourier transform infrared spectroscopy and differential scanning calorimetry. Laser light scattering was performed to determine the particle sizes. Aerodynamic features were characterized by twin stage impinger and scanning electron microscopy.

Results: Although sugars/polyols preferably stabilized IgG following the process, storage stabilization was achieved in Trehalose, Trehalose-Lactose, Lactose, and Trehalose-Mannitol-based powders with soluble aggregates <5%. The conformation of antibody was preserved with β sheet content from 66.28% to 76.37%. Particle sizes ranged from 5.23 to 8.12?µm. Mannitol exhibited the best aerodynamic behavior, fine particle fraction (FPF: 70%) but high degree of protein aggregation during storage.

Conclusions: SFD could favorably stabilize antibody using Trehalose and its combination with Lactose and Mannitol, and also, Lactose alone. Sorbitol disturbed IgG powder recovery. Incorporation of other types of excipient is required for efficient respiratory delivery of IgG molecules.     

Potential roles of chromium on inflammatory biomarkers in diabetes: A Systematic

Diabetes, as a low‐grade chronic inflammatory disease, causes disruption in proper function of immune and metabolic system. Chromium is an important element required for normal lipid and glucose metabolism. Chromium deficiency is correlated with elevation in cardiometabolic risk, which results from increased inflammation. This systematic review was conducted to discover the potential roles of chromium on inflammatory biomarkers. Eligible studies were all in vitro, animal and human studies published in English‐language journals from inception until October 2018. PubMed, Scopus, Embase, ProQuest and Google Scholar databases were searched to fined interventional studies from the effects of chromium on inflammatory biomarkers such as tumour necrosis factor a (TNF‐a), C‐reactive protein (CRP), interleukins, monocyte chemoattractant protein–1 (MCP‐1), intercellular adhesion molecule‐1 (ICAM‐1) and adipocytokines in hyperglycaemia and diabetes. Out of 647 articles found in the search, only 14 articles were eligible for analysis, three in vitro studies, eight animal studies and three human studies. Twelve of the 14 studies included in this review, chromium significantly decreased inflammatory factors. The findings of this review indicate, based on in vitro and in vivo studies, that chromium might have potential anti‐inflammatory properties, but some of the studies did not show anti‐inflammatory effects for chromium (two studies). There are only three studies in humans with controversial results. Therefore, more consistent randomized double‐blind controlled trials are needed to reach relevant clinical recommendations, as well as to determine the precise mechanism, of chromium on inflammation in diabetes.     

The Burden of Stroke in Kurdistan Province,Iran From 2011 to 2017

ObjectivesThe aim of this study was to calculate the burden of stroke in Kurdistan Province, Iran between 2011 and 2017.MethodsIncidence data extracted from the hospital information system of Kurdistan Province and death data extracted from the system of registration and classification of causes of death were used in a cross-sectional study. The World Health Organization method was used to calculate disability-adjusted life years (DALYs).ResultsThe burden of stroke increased from 2453.44 DALYs in 2011 to 5269.68 in 2017, the years of life lost increased from 2381.57 in 2011 to 5109.68 in 2017, and the years of healthy life lost due to disability increased from 71.87 in 2011 to 159.99 in 2017. The DALYs of ischaemic stroke exceeded those of haemorrhagic stroke. The burden of disease, new cases, and deaths doubled during the study period. The age-standardised incidence rate of ischaemic stroke and haemorrhagic stroke in 2017 was 21.72 and 20.72 per 100 000 population, respectively.ConclusionsThe burden of stroke is increasing in Kurdistan Province. Since health services in Iran are based on treatment, steps are needed to revise the current treatment services for stroke and to improve the quality of services. Policy-makers and managers of the health system need to plan to reduce the known risk factors for stroke in the community. In addition to preventive interventions, efficient and up-to-date interventions are recommended for the rapid diagnosis and treatment of stroke patients in hospitals. Along with therapeutic interventions, preventive interventions can help reduce the stroke burden.     

Monitoring Information-Seeking Patterns and Obesity Prevalence in Africa With Internet Search Data: Observational Study

BackgroundThe prevalence of chronic conditions such as obesity, hypertension, and diabetes is increasing in African countries. Many chronic diseases have been linked to risk factors such as poor diet and physical inactivity. Data for these behavioral risk factors are usually obtained from surveys, which can be delayed by years. Behavioral data from digital sources, including social media and search engines, could be used for timely monitoring of behavioral risk factors.ObjectiveThe objective of our study was to propose the use of digital data from internet sources for monitoring changes in behavioral risk factors in Africa.MethodsWe obtained the adjusted volume of search queries submitted to Google for 108 terms related to diet, exercise, and disease from 2010 to 2016. We also obtained the obesity and overweight prevalence for 52 African countries from the World Health Organization (WHO) for the same period. Machine learning algorithms (ie, random forest, support vector machine, Bayes generalized linear model, gradient boosting, and an ensemble of the individual methods) were used to identify search terms and patterns that correlate with changes in obesity and overweight prevalence across Africa. Out-of-sample predictions were used to assess and validate the model performance.ResultsThe study included 52 African countries. In 2016, the WHO reported an overweight prevalence ranging from 20.9% (95% credible interval [CI] 17.1%-25.0%) to 66.8% (95% CI 62.4%-71.0%) and an obesity prevalence ranging from 4.5% (95% CI 2.9%-6.5%) to 32.5% (95% CI 27.2%-38.1%) in Africa. The highest obesity and overweight prevalence were noted in the northern and southern regions. Google searches for diet-, exercise-, and obesity-related terms explained 97.3% (root-mean-square error [RMSE] 1.15) of the variation in obesity prevalence across all 52 countries. Similarly, the search data explained 96.6% (RMSE 2.26) of the variation in the overweight prevalence. The search terms yoga, exercise, and gym were most correlated with changes in obesity and overweight prevalence in countries with the highest prevalence.ConclusionsInformation-seeking patterns for diet- and exercise-related terms could indicate changes in attitudes toward and engagement in risk factors or healthy behaviors. These trends could capture population changes in risk factor prevalence, inform digital and physical interventions, and supplement official data from surveys.     

A comprehensive non‐invasive framework for automated evaluation of acute renal transplant rejection using DCE‐MRI

The objective was to develop a novel and automated comprehensive framework for the non‐invasive identification and classification of kidney non‐rejection and acute rejection transplants using 2D dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI). The proposed approach consists of four steps. First, kidney objects are segmented from the surrounding structures with a geometric deformable model. Second, a non‐rigid registration approach is employed to account for any local kidney deformation. In the third step, the cortex of the kidney is extracted in order to determine dynamic agent delivery, since it is the cortex that is primarily affected by the perfusion deficits that underlie the pathophysiology of acute rejection. Finally, we use an analytical function‐based model to fit the dynamic contrast agent kinetic curves in order to determine possible rejection candidates. Five features that map the data from the original data space to the feature space are chosen with a k‐nearest‐neighbor (KNN) classifier to distinguish between acute rejection and non‐rejection transplants. Our study includes 50 transplant patients divided into two groups: 27 patients with stable kidney function and the remainder with impaired kidney function. All of the patients underwent DCE‐MRI, while the patients in the impaired group also underwent ultrasound‐guided fine needle biopsy. We extracted the kidney objects and the renal cortex from DCE‐MRI for accurate medical evaluation with an accuracy of 0.97 ± 0.02 and 0.90 ± 0.03, respectively, using the Dice similarity metric. In a cohort of 50 participants, our framework classified all cases correctly (100%) as rejection or non‐rejection transplant candidates, which is comparable to the gold standard of biopsy but without the associated deleterious side‐effects. Both the 95% confidence interval (CI) statistic and the receiver operating characteristic (ROC) analysis document the ability to separate rejection and non‐rejection groups. The average plateau (AP) signal magnitude and the gamma‐variate model functional parameter α have the best individual discriminating characteristics. Copyright © 2013 John Wiley & Sons, Ltd.     

Soy,Soy Isoflavones,and Protein Intake in Relation to Mortality from All Causes,Cancers, and Cardiovascular Diseases: A Systematic Review and Dose–Response Meta-Analysis of Prospective Cohort Studies

ObjectiveWe conducted a systematic review and dose–response meta-analysis of prospective studies to summarize findings on the associations between intakes of soy, soy isoflavones, and soy protein and risk of mortality from all causes, cancers, and cardiovascular diseases.MethodsOnline databases were systematically searched to identify relevant articles published earlier than May 2018. We applied restricted cubic splines using random-effects analysis to assess dose–response associations. Between-study heterogeneity was assessed by I² value and Cochrane Q test. Potential publication bias was assessed by visual inspection of funnel plots and Begg regression test.ResultsIn total, 23 prospective studies with an overall sample size of 330,826 participants were included in the current systematic review and the meta-analysis. Soy/soy products consumption was inversely associated with deaths from cancers (pooled relative risk 0.88, 95% CI 0.79 to 0.99; P=0.03; I²=47.1%, 95% CI 0.0% to 75.4%) and cardiovascular diseases (pooled effect size: 0.85, 95% CI 0.72 to 0.99; P=0.04; I²=50.0%, 95% CI 0.0% to 77.6%). Such significant associations were also observed for all-cause mortality in some subgroups of the included studies, particularly those with higher quality. In addition, higher intake of soy was associated with decreased risk of mortality from gastric, colorectal, and lung cancers as well as ischemic cardiovascular diseases. Participants in the highest category of dietary soy isoflavones intake had a 10% lower risk of all-cause mortality compared with those in the lowest category. We also found that a 10-mg/day increase in intake of soy isoflavones was associated with 7% and 9% decreased risk of mortality from all cancers and also breast cancer respectively. Furthermore, a 12% reduction in breast cancer death was indicated for each 5-g/day increase in consumption of soy protein. However, intake of soy protein was not significantly associated with all-cause and cardiovascular diseases mortality.ConclusionsSoy and its isoflavones may favorably influence risk of mortality. In addition, soy protein intake was associated with a decreased risk in the mortality of breast cancer. Our findings may support the current recommendations to increase intake of soy for greater longevity.     

Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells

We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca alkaloids such as Vincristine (VCR), Vinblastine (VBL) and Vinorelbine (VNR). Additionally, BV6 acts in concert with DOX or VCR to suppress long-term clonogenic growth. While BV6 causes rapid downregulation of cellular IAP (cIAP)1 protein and nuclear factor-kappaB (NF-κB) activation, DOX/BV6- or VCR/BV6-induced apoptosis occurs independently of NF-κB or TNFα signaling, since overexpression of dominant-negative IκBα superrepressor or the Tumor Necrosis Factor (TNF)α-blocking antibody Enbrel fail to block cell death. Mechanistic studies reveal that Receptor-interacting protein (RIP)1 is required for DOX/BV6-, but not for VCR/BV6-induced apoptosis, since transient or stable knockdown of RIP1 or the pharmacological RIP1 inhibitor necrostatin-1 significantly reduce apoptosis. By comparison, VCR/BV6-mediated apoptosis critically depends on the mitochondrial pathway. VCR/BV6 cotreatment causes phosphorylation of BCL-2 during mitotic arrest, enhanced activation of BAX and BAK and loss of mitochondrial membrane potential (MMP). Additionally, overexpression of BCL-2 profoundly suppresses VCR/BV6-induced apoptosis. Thus, BV6 sensitizes NB cells to chemotherapy-induced apoptosis via distinct initial signaling mechanisms depending on the chemotherapeutic drug. These findings provide novel mechanistic insights into Smac mimetic-mediated chemosensitization of NB.     

Clinical aspects of infertile 47,XYY patients: a retrospective study

47,XYY syndrome is a sex chromosomal anomaly in men, which may be associated with infertility and has an incidence of 0.1% of male births. The clinical and paraclinical characteristics of men suffering from this anomaly have not been fully described. In this retrospective study, we present 37 cases of 47,XYY infertile men with sperm counts varying from normal to azoospermia, referred to the Genetics Laboratory at the Royan Institute, Iran. Thirteen individuals were mosaic and 24 non-mosaics. Non-mosaic patients were classified as azoospermic (nine cases) and normospermic/oligozoospermic men (15 cases). Two of the non-mosaic and three mosaic patients had secondary infertility. In addition, 13 of them underwent IUI, IVF or ICSI, and in seven cases, there was a biochemical pregnancy. The remaining 14 patients did not have ART. The 47,XYY syndrome is relatively unusual and can be missed clinically because of the lack of symptoms and of diverse phenotypes. Diagnosis of this aneuploidy can provide valuable data for counselling and early management of the patients who undergo fertility evaluation.