Microplastic and mesoplastic pollution in farmland soils in suburbs of Shanghai, China.

Abstract: Microplastics are emerging pollutants which have been extensively detected in water environments. However, little is known about microplastic pollution in soil environments. In this study, we investigated microplastics and mesoplastics in farmland soils from twenty vegetable fields around the suburbs of Shanghai. In each site, three duplicate soil samples were collected from shallow (0-3 cm) and deep soils (3-6 cm), respectively. Microplastics (sizes of 20 μm - 5 mm) and mesoplastics (5 mm - 2 cm) were detected using methods of density extraction, 30% H2O2 digestion and micro-fourier transform infrared spectroscopy. The abundance of microplastics was 78.00 ± 12.91 and 62.50 ± 12.97 items kg-1 in shallow and deep soils, respectively. While, mesoplastics were found with abundance of 6.75 ± 1.51 and 3.25 ± 1.04 items kg-1 in shallow and deep soils. Among these micro(meso)plastics, 48.79% and 59.81% were in size of <1 mm in shallow and deep soils. The main morphotypes of microplastics included fiber, fragment and film, mostly in color of black or transparent. Moreover, we found that topsoil contained higher concentrations and larger sizes of micro(meso)plastics than deep soil. In addition, the vast majority of micro(meso)plastics were polypropylene (50.51%) and polyethylene (43.43%). This study reveals occurrence and characteristics of microplastic pollution in typical farmland soils. It provides important data for subsequent research on microplatics in the terrestrial ecosystem.

Liu|Mengting|M| Lu|Shibo|S| Song|Yang|Y| Lei|Lili|L| Hu|Jiani|J| Lv|Weiwei|W| Zhou|Wenzong|W| Cao|Chengjin|C| Shi|Huahong|H| Yang|Xiaofeng|X| He|Defu|D|

D017550:Spectroscopy, Fourier Transform Infrared

Microplastics
Mesoplastics
Farmland
Soils
Terrestrial ecosystem


Cysteamine revisited: repair of arginine to cysteine mutations.

Abstract: Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.

Gallego-Villar|L|L|
Hannibal|Luciana|L|
Häberle|J|J|
Thöny|B|B|
Ben-Omran|T|T|
Nasrallah|G K|GK|
Dewik|Al-N|AN|
Kruger|W D|WD|
Blom|H J|HJ|

Cysteamine
Aminothiols
Cysteine residue modification
Repair Arg to Cys mutations


High-content phenotypic and pathway profiling to advance drug discovery in diseases of unmet need.

Abstract: Conventional thinking in modern drug discovery postulates that the design of highly selective molecules which act on a single disease-associated target will yield safer and more effective drugs. However, high clinical attrition rates and the lack of progress in developing new effective treatments for many important diseases of unmet therapeutic need challenge this hypothesis. This assumption also impinges upon the efficiency of target agnostic phenotypic drug discovery strategies, where early target deconvolution is seen as a critical step to progress phenotypic hits. In this review we provide an overview of how emerging phenotypic and pathway-profiling technologies integrate to deconvolute the mechanism-of-action of phenotypic hits. We propose that such in-depth mechanistic profiling may support more efficient phenotypic drug discovery strategies that are designed to more appropriately address complex heterogeneous diseases of unmet need.

Hughes|Rebecca E|RE|
Elliott|Richard J R|RJR|
Dawson|John C|JC|
Carragher|Neil O|NO|

esophageal cancer
glioblastoma
high-content imaging
machine learning
network pharmacology
structural similarity


Bahamaolide A from the marine-derived Streptomyces sp. CNQ343 inhibits isocitrate lyase in Candida albicans.

Abstract: Bahamaolide A, a new macrocyclic lactone isolated from the culture of marine actinomycete Streptomyces sp. CNQ343, was evaluated for its inhibitory activity toward isocitrate lyase (ICL) from Candida albicans. These studies led to the identification of bahamaolide A as a potent ICL inhibitor with IC50 value of 11.82 μM. The growth phenotype of ICL deletion mutants and quantitative RT-PCR analyses indicated that this compound inhibits the ICL mRNA expression in C. albicans under C2-carbon-utilizing conditions. The present data highlight the potential for bahamaolide A treatment of C. albicans infections via inhibition of ICL activity.

Lee|So-Hyoung|SH| Moon|Kyuho|K| Kim|Heegyu|H| Shin|Jongheon|J| Oh|Dong-Chan|DC| Oh|Ki-Bong|KB|

Bahamaolide A
Streptomyces sp.
Isocitrate lyase
Candida albicans
Marine actinomycete


Feasibility of spinal stereotactic body radiotherapy in Elekta Unity® MR-Linac.

Abstract: The Elekta Unity MR-Linac (MRL) is expected to benefit spine stereotactic body radiotherapy (SBRT) due to the improved soft tissue contrast available with onboard MR imaging. However, the irradiation geometry and beam configuration of the MRL deviates from the conventional linear accelerator (Linac). The purpose of the study was to investigate the feasibility of spine SBRT on the MRL. Treatment plans were generated for lumbar and thoracic spines. Target and spinal cord doses were measured with two cylindrical ion chambers inserted into an anthropomorphic spine phantom. Our study indicated that the Monaco treatment planning system (TPS) could generate clinical treatment plans for the MRL that were of comparable quality to the RayStation TPS with a conventional Linac. For both Linacs the planned dose within the gross tumor volume agreed with measurements within ±3%. For the spinal cord, while the measured doses from the TrueBeam were 1.8% higher for the lumbar spine plan and 6.9% higher for thoracic spine plan, the measured doses from MRL were 0.6% lower for the lumbar spine plan and 3.9% higher for the thoracic spine plan. In conclusion, the feasibility of spine SBRT in Elekta Unity MRL has been demonstrated, however, more effort is needed for such as optimizing the online plan adaptation method.

Han|Eun Young|EY|
Aima|Manik|M|
Hughes|Neil|N|
Briere|Tina M|TM|
Yeboa|Debra N|DN|
Castillo|Pam|P|
Wang|Jihong|J|
Yang|Jinzhong|J|
Vedam|Sastry|S|


Sand bedding as a reservoir for Lactococcus garvieae dissemination in dairy farms.

Abstract: Lactococcus garvieae is now recognized as a species with clinical significance for human and veterinary medicine. The aim of this study was to evaluate the presence of this pathogen in sand bedding and milk samples. Two farms in Minnesota with problems of clinical and subclinical mastitis due to streptococci-like organisms were selected. Twenty-four Lactococcus garvieae isolates from sand bedding and 18 isolates from quarter milk were comparatively studied using a genotypic approach. RAPD (random amplification of polymorphic DNA) PCR and REP (repetitive element palindromic) PCR experiments highlighted a similar electrophoretic profile. When genes belonging to the core genome of L. garvieae were tested through a MLRT (multilocus restriction typing), we again observed that all L. garvieae isolates coming from sand bedding and milk shared a common profile, distinguishable from previously studied representative L. garvieae strains. These data indicate that the L. garvieae isolated from sand bedding and milk originated from a few strains adapted to persist in the same habitat. This supports the hypothesis that sand bedding can represent a reservoir of L. garvieae strains and be a potential vehicle for their dissemination in dairy farms.

Eraclio|Giovanni|G|
Ricci|Giovanni|G|
Moroni|Paolo|P|
Santisteban|Carlos|C|
Plumed-Ferrer|Carme|C|
Bennett|James|J|
Fortina|Maria Grazia|MG|

D019105:Random Amplified Polymorphic DNA Technique

sand bedding
milk
MLRT
dissémination environnementale
environmental dissemination
lait
litière de sable
molecular typing
typage moléculaire


Effects of dried natto diet on the transcript levels of the peroxisome proliferator-activated receptor-γ, coactivator-1α and -1β, and nuclear receptor corepressor 1 genes in laying hens.

Abstract: The effects of natto, a fermented soybean food, on transcript levels of hen peroxisome proliferator-activated receptor-γ (PPARG), PPARG coactivator-1α and -1β (PPARGC1A and PPARGC1B), and nuclear receptor corepressor 1 (NCOR1) were investigated using real-time polymerase chain reaction in white leghorn (Julia strain) hens. Twenty-one- and 34-week-old hens were fed a basic or 3% dried natto-supplemented diet for 8 weeks. In the 21- and 34-week-old hens fed the natto-supplemented diet, hepatic PPARGC1B and NCOR1 transcript levels and adipose and hepatic PPARG transcript levels were significantly lower, respectively, than those in the control group. Furthermore, 34- and 42-week-old hens were fed a basic diet supplemented with 3% of the protein/fiber-enriched fraction (PFB) or 0.6% of the fat-enriched fraction (FAT) of natto, respectively, for 8 weeks. Adipose PPARG transcript levels were higher in the FAT diet group and significantly lower in the PFB diet group than in the control group. However, both FAT and PFB diet groups showed significantly lower hepatic PPARG transcript levels than did the control group. These results suggest that dried natto influences the transcript levels of PPARG, PPARGC1B, and NCOR1, and the FAT and PFB of natto influence the adipose and hepatic PPARG transcript levels in hens.

D000824:Animal Nutritional Physiological Phenomena

D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha


Patient Characteristics and Treatment Patterns among Medicare Beneficiaries Initiating PCSK9 Inhibitor Therapy.

Abstract:
PURPOSE
There is limited real-world evidence around use of proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) among US older adults. This study examined baseline characteristics of fee-for-service (FFS) Medicare beneficiaries newly initiating PCSK9i therapy during the period immediately following market availability.

METHODS
This cross-sectional study used Medicare claims (2013-2016) to identify 5051 FFS Medicare beneficiaries who filled ≥ 1 PCSK9i prescription between August 2015 and December 2016. We analyzed patient demographics, clinical characteristics, and baseline healthcare expenditures in the 12-month period prior to PCSK9i initiation, for these beneficiaries.

RESULTS
Most beneficiaries initiating PCSK9i were female (57%), < 75 years of age (61%), white (89%), and lived in metropolitan areas (83%). At baseline, these PCSK9i initiators had 6 chronic conditions on average, with conditions such as hyperlipidemia, hypertension, and ischemic heart disease being most prevalent. Approximately 88% had a diagnosis of atherosclerotic cardiovascular disease (ASCVD), and 14% experienced acute cardiovascular events during the 12-month baseline period. Use of any statin and/or ezetimibe ranged from 54 to 76% in the 6-month and 24-month baseline period. Their total annual Medicare expenditures averaged US$17,552, of which most were attributable to ambulatory care and prescription use, in the 12-month baseline period.

CONCLUSION
High burden of cardiovascular conditions and prescription expenditures at baseline were common among FFS beneficiaries initiating PCSK9i therapy. These findings suggest that physicians prescribe PCSK9i to elderly patients at high risk for adverse cardiovascular events. Considering the evolving treatment landscape, PCSK9i utilization might increase in Medicare.

Feng|Xue|X|
Berklein|Flora|F|
Rane|Pallavi B|PB|
Habib|Mohdhar|M|
Lin|Pei-Jung|PJ|

Medicare beneficiaries
PCSK9i
ASCVD
LDL-C
Lipid-lowering therapy


Children Placed In Out-of-Home Care as Midlife Adults: Are They Still Disadvantaged or Have They Caught Up With Their Peers?

Abstract: International research has consistently reported that children placed in out-of-home care (OHC) have poor outcomes in young adulthood. Yet, little is known about their outcomes in midlife. Using prospective data from a cohort of more than 14,000 Swedes born in 1953, of which nearly 9% have been placed in OHC, this study examines whether there is developmental continuity or discontinuity of disadvantage reaching into middle age in OHC children, compared to same-aged peers. Outcome profiles, here conceptualized as combinations of adverse outcomes related to education, economic hardship, unemployment, and mental health problems, were assessed in 1992-2008 (ages 39-55). Results indicate that having had experience of OHC was associated with 2-fold elevated odds of ending up in the most disadvantaged outcome profile, controlling for observed confounding factors. These findings suggest that experience of OHC is a strong marker for disadvantaged outcomes also in midlife.

Brännström|Lars|L|
Vinnerljung|Bo|B|
Forsman|Hilma|H|
Almquist|Ylva B|YB|

child welfare
cohort study
foster care
longitudinal research


A Strangulated Amyand's hernia:The first case report in Syria.

Abstract: Amyand's hernia is a rare case of inguinal hernia where the hernia sac contains the appendix, and depending on the condition of the appendix, this type is classified into under types where the appendix can be normal, inflamed, or even perforated. Accordingly, the patient's condition can be good or bad. In our case, we have a 13-year-old child who suffers from abdominal pain and discomfort. He is referred to the emergency department with this complaint. By clinical and radiological examination, the presence of an inguinal hernia containing the appendix was found. Based on that, we performed emergency and investigative surgery in order to determine the condition of the appendix and whether there is suffocation or not. It was found by surgical opening that the hernia was incarcerated and this required excision of the appendix and repair of the hernia.

Alibrahim|Hidar|H| Albattour|Mouhammad|M| Swed|Sarya|S| Sawaf|Bisher|B|


Has the COVID 19 Virus Changed Adherence to Hand Washing among Healthcare Workers?

Abstract: The aim of the study was to assess adherence to hand washing by healthcare workers (HCWs) and its variations over time in hospital wards. We wanted to check whether the pandemic had changed the behavior of HCWs. The study was conducted between 1 January 2015, and 31 December 2020. The HCWs were observed to assess their compliance with the Five Moments for Hand Hygiene. We described the percentage of adherence to World Health Organization (WHO) guidelines stratified per year, per specialty areas, per different types of HCWs. We also observed the use of gloves. Descriptive data were reported as frequencies and percentages. We observed 13,494 hand hygiene opportunities. The majority of observations concerned nurses who were confirmed as the category most frequently involved with patients. Hospital's global adherence to WHO guidelines did not change in the last six years. During the pandemic, the rate of adherence to the procedure increased significantly only in Intensive Care Unit (ICU). In 2020, the use of gloves increased in pre-patient contact. The hand-washing permanent monitoring confirmed that it is very difficult to obtain the respect of correct hand hygiene in all opportunities, despite the ongoing pandemic and the fear of contagion.

Ragusa|Rosalia|R|0000-0002-0964-3438
Marranzano|Marina|M|
Lombardo|Alessandro|A|
Quattrocchi|Rosalba|R|
Bellia|Maria Alessandra|MA|
Lupo|Lorenzo|L|

COVID 19
adherence to hand washing
hand hygiene
hand-washing permanent monitoring
HCWs behavior
guideline adherence
health promotion positive actions


How Far is the Spanish Snack Sector from Meeting the Acrylamide Regulation 2017/2158?

Abstract: In 2017, the European Commission published Regulation 2017/2158 establishing mitigation measures and benchmark levels to reduce acrylamide in foods. Acrylamide was determined in seventy potato crisp samples commercialized in Spain. The aim was to update knowledge about the global situation in the snack sector and evaluate the effectiveness of mitigation strategies applied, especially since the publication of the Regulation. Results were compared with data previously published in 2004, 2008, and 2014, assessing the evolution over recent years. Average acrylamide content in 2019 (664 µg/kg, range 89-1930 μg/kg) was 55.3% lower compared to 2004, 10.3% lower compared to 2008 and practically similar to results from 2014. Results support the effectiveness of mitigation measures implemented by Spanish potato crisp manufacturers. However, 27% of samples exhibited concentrations above the benchmark level established in the Regulation (750 μg/kg), which suggests that efforts to reduce acrylamide formation in this sector must be continued. Besides the variability seen between samples, acrylamide significantly correlated with the color parameter a*, which enables discrimination of whether potato crisps contain above or below benchmark content. The calculated margin of exposure for carcinogenicity was below the safety limit, which should be considered from a public health point of view.

Mesias|Marta|M|
Nouali|Aouatif|A|
Delgado-Andrade|Cristina|C|
Morales|Francisco J|FJ|

acrylamide
potato crisps
exposure
consumers
dietary intake


Self-assembled PEG-b-PDPA-b-PGEM copolymer nanoparticles as protein antigen delivery vehicles to dendritic cells: preparation, characterization and cellular uptake.

Abstract: Antigen uptake by dendritic cells (DCs) is a key step for initiating antigen-specific T cell immunity. In the present study, novel synthetic polymeric nanoparticles were prepared as antigen delivery vehicles to improve the antigen uptake by DCs. Well-defined cationic and acid-responsive copolymers, monomethoxy poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate)-block-poly(2-(guanidyl) ethyl methacrylate) (mPEG-b-PDPA-b-PGEM, PEDG) were synthesized by reversible addition-fragmentation chain transfer polymerization of 2-(diisopropylamino)ethyl methacrylate) and N-(tert-butoxycarbonyl) amino ethyl methacrylate monomers, followed by deprotection of tert-butyl protective groups and guanidinylation of obtained primary amines. 1H NMR, 13C NMR and GPC results indicated the successful synthesis of well-defined PEDG copolymers. PEDG copolymers could self-assemble into nanoparticles in aqueous solution, which were of cationic surface charges and showed acid-triggered disassembly contributed by PGEM and PDPA moieties, respectively. Significantly, PEDG nanoparticles could effectively condense with negatively charged model antigen ovalbumin (OVA) to form OVA/PEDG nanoparticle formulations with no influence on its secondary and tertiary structures demonstrating by far-UV circular dichroism and UV-vis spectra. In vitro antigen cellular uptake by bone marrow DCs (BMDCs) indicated using PEDG nanoparticles as antigen delivery vehicles could significantly improve the antigen uptake efficiency of OVA compared with free OVA or the commercialized Alum adjuvant. Moreover, as the surface cationic charges of OVA/PEDG nanoparticle formulations reduced, the uptake efficiency decreased correspondingly. Collectively, our work suggests that guanidinylated, cationic and acid-responsive PEDG nanoparticles represent a new kind of promising antigen delivery vehicle to DCs and hold great potential to serve as immunoadjuvants in the development of vaccines.

Li|Pan|P| Zhou|Junhui|J| Huang|Pingsheng|P| Zhang|Chuangnian|C| Wang|Weiwei|W| Li|Chen|C| Kong|Deling|D|

nanoparticles
antigen delivery
dendritic cells
guanidyl
synthetic copolymer


Changes in sleep timing and subjective sleep quality during the COVID-19 lockdown in Italy and Belgium: age, gender and working status as modulating factors.

Abstract: Italy and Belgium have been among the first western countries to face the Coronavirus disease 2019 (COVID-19) emergency, imposing a total lockdown over the entire national territories. These limitations have proven effective in slowing down the spread of the infection. However, the benefits obtained in public health have come with huge costs in terms of social, economic, and psychological well-being. In the current study, we aimed to investigate how the period of home confinement affected self-reported sleep characteristics in Italians and Belgians, with special regard to sleep timing and subjective quality. Using an online survey we collected data from 2272 participants, 1622 Italians (Mage = 34.1 ± 13.6 years, 1171 F), and 650 Belgian (Mage = 43.0 ± 16.8 years, 509 F). Participants reported their sleep pattern (eg, bedtime, risetime) and perceived sleep quality during and, retrospectively, before the lockdown. During the lockdown, sleep timing was significantly delayed, time spent in bed increased, and sleep quality was markedly impaired in both Italians and Belgians. The most vulnerable individuals appeared to be women, subjects experiencing a more negative mood, and those perceiving the pandemic situation as highly stressful. However, the two samples differed in the subgroups most affected by the changes, possibly because of the different welfare systems of the two countries. In fact, in the Italian sample sleep quality and timing underwent significant modifications especially in unemployed participants, whereas in the Belgian sample this category was the one who suffered less from the restrictions. Considering that the novel coronavirus has spread across the whole globe, involving countries with different types of health and welfare systems, understanding which policy measures have the most effective protective role on physical and mental health is of primary importance.

Cellini|Nicola|N|
Conte|Francesca|F|
De Rosa|Oreste|O|
Giganti|Fiorenza|F|
Malloggi|Serena|S|
Reyt|Mathilde|M|
Guillemin|Camille|C|
Schmidt|Christina|C|
Muto|Vincenzo|V|
Ficca|Gianluca|G|

D007319:Sleep Initiation and Maintenance Disorders

Sleep
COVID-19
Working status
Home confinement
Circadian rhythms


Hepatitis C virus cascade of care in the general population, in people with diabetes, and in substance use disorder patients.

Abstract:
BACKGROUND
The aim was to evaluate the hepatitis C virus (HCV) cascade of care in the general population (GP) and in two high-risk populations: patients with diabetes mellitus (DM) and substance users (AS) in treatment in Reggio Emilia Province, Italy.

METHODS
A population-based cross-sectional study was conducted that included 534,476 residents of the Reggio Emilia Province, of whom 32,800 were DM patients and 2726 AS patients. Age-adjusted prevalence was calculated using the direct method of adjustment based on the age-specific structure of EU population.

RESULTS
The prevalence of HCV testing was 11.5%, 13.8%, and 47.8% in GP, DM, and AS patients respectively, while HCV prevalence was 6.5/1000, 12.6/1000, and 167/1000, respectively. The prevalence of HCV RNA positivity was 4.4/1000, 8.7/1000, and 114/1000 in the three populations, respectively. The rates of HCV RNA-positive individuals not linked to care were 27.9%, 27.3%, and 26% in GP, DM, and AS patients, respectively, while the rates of those cured or cleared were 70.9%, 71%, and 69.9%, respectively. The prevalence of HCV testing was higher for females of reproductive age than for males the same age: 218.4/1000 vs. 74.0/1000, respectively. While more foreigners than Italians underwent the HCV test and were HCV positive, fewer foreigners than Italians received HCV treatment and were cured.

CONCLUSIONS
The low HCV testing and linkage to care rates remain an important gap in the HCV cascade of care in Northern Italy. The prevalence of cured/cleared residents remains lower among foreigners than among Italians.

Hepatitis C virus
Cascade of care
Diabetes mellitus
Linkage to care
Addiction
Hepatocellular carcinoma


Understanding the molecular mechanisms and role of autophagy in obesity.

Abstract: Vital for growth, proliferation, subsistence, and thermogenesis, autophagy is the biological cascade, which confers defence against aging and various pathologies. Current research has demonstrated de novo activity of autophagy in stimulation of biological events. There exists a significant association between autophagy activation and obesity, encompassing expansion of adipocytes which facilitates β cell activity. The main objective of the manuscript is to enumerate intrinsic role of autophagy in obesity and associated complications. The peer review articles published till date were searched using medical databases like PubMed and MEDLINE for research, primarily in English language. Obesity is characterized by adipocytic hypertrophy and hyperplasia, which leads to imbalance of lipid absorption, free fatty acid release, and mitochondrial activity. Detailed evaluation of obesity progression is necessary for its treatment and related comorbidities. Data collected in regard to etiological sustaining of obesity, has revealed hypothesized energy misbalance and neuro-humoral dysfunction, which is stimulated by autophagy. Autophagy regulates chief salvaging events for protein clustering, excessive triglycerides, and impaired mitochondria which is accompanied by oxidative and genotoxic stress in mammals. Autophagy is a homeostatic event, which regulates biological process by eliminating lethal cells and reprocessing physiological constituents, comprising of proteins and fat. Unquestionably, autophagy impairment is involved in metabolic syndromes, like obesity. According to an individual's metabolic outline, autophagy activation is essential for metabolism and activity of the adipose tissue and to retard metabolic syndrome i.e. obesity. The manuscript summarizes the perception of current knowledge on autophagy stimulation and its effect on the obesity.

Autophagy
Obesity
Metabolic syndrome
Cardiac autophagy
Insulin resistance


Chronic illness in the workplace: stigma, identity threat and strain.

Abstract: Chronic illness affects a large and growing number of workers in the United States and globally. Stigmatization (devaluation) at work based on chronic illness may be stressful for individuals and therefore may lead to negative psychological consequences (i.e. strains). In order to better understand stressful experiences of stigma for workers with chronic illnesses, a model of stigma-related identity threat (perceptions that one is at risk of being treated negatively at work because of chronic illness) was tested on a sample of 203 working adults with chronic illnesses. The following variables related to workers' perceptions of chronic illness-related identity threat: workers' boundary flexibility (flexibility in managing their work and life), their meta-perceptions of devaluation (perceptions of others' devaluation of them based on illness) and their job self-efficacy (feelings of confidence related to performing their job). In turn, perceptions of identity threat related to both feelings of psychological strain and (lower levels of) perceived work ability. Surprisingly, neither stigma centrality (how fundamental illness is to one's identity) nor supervisor support related to workers' identity threat perceptions.

McGonagle|Alyssa K|AK|
Barnes-Farrell|Janet L|JL|

chronic illness
stigma
identity threat
strain
stress


Captivity influences immune responses, stress endocrinology, and organ size in house sparrows (Passer domesticus).

Abstract: Studies using wild animals in laboratory-based research require bringing wild-captured organisms into a novel setting, which can have long-lasting impacts on physiology and behavior. In several species, captivity stimulates stress hormone production and can alter immune function. Despite this, there is little consensus on how captivity influences stress hormone regulation, or if captivity-induced changes in stress hormone production and regulation mediate changes in immune function. In this study, we investigate the influence of captivity on the physiology of a wild bird commonly-used in laboratory-based research, the house sparrow (Passer domesticus). We tested how captivity influences stress endocrinology, immune responses, and organ mass, and also investigated if the production or regulation of corticosterone, the main stress hormone in birds, correlated with changes in immunity. We found that baseline corticosterone concentrations and maximum capacity of the adrenals to secrete corticosterone increase following captivity and remain elevated after 9weeks of captivity. A measure of innate immune function, the bactericidal ability of plasma, also increased with time spent in captivity. Wound healing was also influenced by time spent in captivity, with birds taking almost 2days longer to heal if they were wounded after 3weeks in captivity when compared with birds that were wounded immediately upon capture. Additionally, captivity caused notable reductions in spleen and liver mass. Together, these results imply that captivity can have long-lasting effects on house sparrow corticosterone release and immune function, and suggest that even after 9weeks house sparrows do not acclimate physiologically to life in captivity.

Love|Ashley C|AC|
Lovern|Matthew B|MB|
DuRant|Sarah E|SE|

Captivity
House sparrow
Immune function
Corticosterone
HPA axis


Loss-of-function polymorphism in IL6R reduces risk of JAK2V617F somatic mutation and myeloproliferative neoplasm: A Mendelian randomization study.

Abstract:
Background
Whether inflammation is independently associated with development of JAK2V617F mutation and myeloproliferative neoplasm is not clear. We tested the hypothesis that a loss-of-function polymorphism in IL6R (marked by rs4537545) reduces risk of JAK2V617F mutation and myeloproliferative neoplasm in a Mendelian randomization study.

Methods
We genotyped 107,969 Danes from the Copenhagen General Population Study for the IL6R rs4537545 genotype, where the T-allele is associated with impaired interleukin-6 receptor signaling and reduced inflammation. JAK2V617F was examined in a subset of 49,143 individuals. We investigated the association between IL6R rs4537545 and risk of JAK2V617F using logistic regression and myeloproliferative neoplasm using Cox regression.

Findings
36,871 were non-carriers, 52,500 heterozygotes, and 18,598 homozygotes for the T-allele of the IL6R rs4537545 genotype. Among 107,969 individuals, 352 were diagnosed with myeloproliferative neoplasm, and among 49,143 individuals, 62 were JAK2V617F-positive (of these 62 individuals, 46 had myeloproliferative neoplasm diagnosed). Compared to non-carriers, age- and sex-adjusted odds ratios for risk of JAK2V617F were 0·55(95%CI:0·32-0·94) in heterozygotes, 0·51(0·24-1·12) in homozygotes, 0·54(0·33-0·89) in carriers, and 0·66(0·45-0·96) per T-allele. Compared to non-carriers, age- and sex-adjusted hazard ratios for risk of myeloproliferative neoplasm were 0·82(95% CI: 0·65-1·02) in heterozygotes, 0·65(0·47-0·91) in homozygotes, 0·77(0·63-0·96) in carriers, and 0·81(0·70-0·94) per T-allele. Associations were primarily observed for polycythaemia vera and myelofibrosis, and for JAK2V617F-positive myeloproliferative neoplasm.

Interpretation
A loss-of-function polymorphism in IL6R reduces risk of JAK2V617F mutation and myeloproliferative neoplasm. This finding supports inflammation as an independent risk factor for JAK2V617F mutation and myeloproliferative neoplasm and indicates that therapeutics designed to block interleukin-6 receptor signaling might prevent or retard progression of myeloproliferative neoplasm.

Funding
Karen Elise Jensen Foundation.

Pedersen|Kasper Mønsted|KM|
Çolak|Yunus|Y|
Ellervik|Christina|C|
Hasselbalch|Hans Carl|HC|
Bojesen|Stig Egil|SE|
Nordestgaard|Børge Grønne|BG|

Myeloproliferative neoplasm
Mendelian randomization
Myelofibrosis
Drug target
Essential thrombocythemia
Polycythemia vera


Cognitive-behavioral therapy for irritable bowel syndrome: a meta-analysis.

Abstract:
OBJECTIVE
To establish whether cognitive behavioral therapy (CBT) improves the bowel symptoms, quality of life (QOL) and psychological states of irritable bowel syndrome (IBS) patients.

METHODS
Randomized controlled trials (RCTs) of CBT for adult patients with IBS were searched by using PubMed, Scopus and Web of Science. The standardized mean difference (SMD) with 95% confidence intervals (CIs) of the evidence-based outcome measures of the IBS bowel symptoms, QOL and psychological states at post-treatment and follow-up was calculated. Prespecified subgroup analysis was performed.

RESULTS
Eighteen RCTs satisfied our inclusion criteria. In the subgroup analyses, CBT was more effective in reducing IBS bowel symptoms, QOL and psychological states than waiting list controls at the end of the intervention and short-term follow-up. When compared with controls of basic support and medical treatment, the effect sizes were found to favor CBT for the improvement of IBS bowel symptoms at post-treatment and short-term follow-up, but CBT was not superior to controls in improving QOL and psychological states. When comparing CBT with other psychological controls, the effect sizes were almost non-significant.

CONCLUSIONS
For IBS patients, CBT was superior to waiting list, basic support or medical treatment at the end of treatment but not superior to other psychological treatments. The meta-analysis might be limited by the heterogeneities and small sample sizes of the included studies.

Li|Li|L| Xiong|Lishou|L| Zhang|Shenghong|S| Yu|Qiao|Q| Chen|Minhu|M|

D015928:Cognitive Behavioral Therapy
D006801:Humans
D043183:Irritable Bowel Syndrome
D011788:Quality of Life

Irritable bowel syndrome
Meta-analysis
Cognitive behavioral therapy


Proposing standardised geographical indicators of physical access to emergency obstetric and newborn care in low-income and middle-income countries.

Abstract: Emergency obstetric and newborn care (EmONC) can be life-saving in managing well-known complications during childbirth. However, suboptimal availability, accessibility, quality and utilisation of EmONC services hampered meeting Millennium Development Goal target 5A. Evaluation and modelling tools of health system performance and future potential can help countries to optimise their strategies towards reaching Sustainable Development Goal (SDG) 3: ensure healthy lives and promote well-being for all at all ages. The standard set of indicators for monitoring EmONC has been found useful for assessing quality and utilisation but does not account for travel time required to physically access health services. The increased use of geographical information systems, availability of free geographical modelling tools such as AccessMod and the quality of geographical data provide opportunities to complement the existing EmONC indicators by adding geographically explicit measurements. This paper proposes three additional EmONC indicators to the standard set for monitoring EmONC; two consider physical accessibility and a third addresses referral time from basic to comprehensive EmONC services. We provide examples to illustrate how the AccessMod tool can be used to measure these indicators, analyse service utilisation and propose options for the scaling-up of EmONC services. The additional indicators and analysis methods can supplement traditional EmONC assessments by informing approaches to improve timely access to achieve Universal Health Coverage and reach SDG 3.

Ebener|Steeve|S|
Stenberg|Karin|K|
Brun|Michel|M|
Monet|Jean-Pierre|JP|
Ray|Nicolas|N|
Sobel|Howard Lawrence|HL|
Roos|Nathalie|N|
Gault|Patrick|P|
Morrissey Conlon|Claudia|C|
Bailey|Patsy|P|
Moran|Allisyn C|AC|
Ouedraogo|Leopold|L|
Kitong|Jacqueline F|JF|
Ko|Eunyoung|E|
Sanon|Djenaba|D|
Jega|Farouk M|FM|
Azogu|Olajumoke|O|
Ouedraogo|Boureima|B|
Osakwe|Chidude|C|
Chimwemwe Chanza|Harriet|H|
Steffen|Mona|M|
Ben Hamadi|Imed|I|
Tib|Hayat|H|
Haj Asaad|Ahmed|A|
Tan Torres|Tessa|T|

physical accessibility
emergency obstetric and newborn care
sustainable development goals
universal health coverage


Dispersive solid-liquid phase microextraction based on nanomagnetic Preyssler heteropolyacid: A novel method for the preconcentration of nortriptyline.

Abstract: In this study, a new, simple, rapid, and efficient method combined with ultraviolet visible spectrophotometry and high-performance liquid chromatography analysis was developed for the extraction and determination of nortriptyline. The tendency of the Preyssler tungsten heteropolyacid, H14 [NaP5 W30 O110 ], immobilized on the surface of mesoporous nanomagnetite to adsorb the drug from the solution has been investigated. This method involves the use of an appropriate mixture of nanosorbent that was homogenized in disperser solvent (1.0 mL, ethanol). At first, the mixture containing the nanomagnetic sorbent and disperser solvent was injected into the aqueous sample, and a cloudy solution was formed. Subsequently, separation of the two phases was carried out using a magnet. In the second stage, analyte was desorbed from the sorbent by methanol as the optimal desorption solvent using sonication method. The elution solvent containing enriched analyte was introduced to the instruments for further analysis. Optimization of experimental conditions with respect to the extraction efficiency was investigated. The method was linear in the range of 25-5000, while the detection limit (LOD = 3SB /m) was 7.9 ng/mL and the limit of quantification (LOQ = 10SB /m) was 26.4 ng/mL. The relative standard deviation was 4.66%. The method was successfully applied to human hair samples.

Preyssler heteropolyacids
Nortriptyline
Nanomagnetite
Dispersive solid-liquid microextraction


TP53 Abnormalities and MMR Preservation in 5 Cases of Proliferating Trichilemmal Tumours.

Abstract: Proliferating trichilemmal tumours (PTT) are defined by a benign squamous cell proliferation inside a trichilemmal cystic (TC) cavity. A possible explanation of this proliferative phenomenon within the cyst may be molecular alterations in genes associated to cell proliferation, which can be induced by ultraviolet radiation. Among other genes, alterations on TP53 and DNA mismatch repair proteins (MMR) may be involved in the cellular proliferation observed in PTT. Based on this assumption, but also taking into account the close relationship between the sebaceous ducts and the external root sheath where TC develop, a MMR, a p53 expression assessment and a TP53 study were performed in a series of 5 PTT cases, including a giant one. We failed to demonstrate a MMR disorder on studied PTT, but we agree with previous results suggesting increased p53 expression in these tumours, particularly in proliferative areas. TP53 alteration was confirmed with FISH technique, demonstrating TP53 deletion in most cells.


Evaluating the Acceptability, Feasibility, and Outcomes of Two Methods Involving Patients With Disability in Developing Clinical Guidelines: Crossover Pilot Study.

Abstract:
BACKGROUND
Engaging patients and the public in clinical practice guideline (CPG) development is believed to contribute significantly to guideline quality, but the advantages of the various co-design strategies have not been empirically compared, making it difficult to choose one strategy over another.

OBJECTIVE
This pilot study aims to document the acceptability, feasibility, and outcomes of 2 methods of involving patients in outlining CPG.

METHODS
A single-blind crossover pragmatic study was performed with patients with traumatic brain injury. The patients experimented with 2 alternative methods of producing clinical practice recommendations (ie, a discussion group and a wiki). The participants rated the acceptability of the 2 methods, and feasibility was assessed using indicators, such as the number of participants who completed the 2 methods and the number of support interventions required. Experts, blinded to the method, independently rated the participants' outcome recommendations for clarity, accuracy, appropriateness, and usefulness.

RESULTS
We recruited 20 participants, and 16 completed the study. The acceptability of the 2 methods showed little variation, with qualitative comments expressing a slight preference for the social nature of focus groups. Thus, both methods of involving patients in CPG development appeared feasible, and the experts' opinions of the adapted recommendations were both positive, although the recommendations produced through focus groups were deemed more relevant to support clinical practice.

CONCLUSIONS
Our results confirm the acceptability and feasibility of focus groups and wikis to allow patients with traumatic brain injury to participate in clinical practice guideline production. This study contributes to the scientific literature by suggesting that the 2 methods were acceptable, feasible, and produced positive outcomes.

TRIAL REGISTRATION
ClinicalTrials.gov NCT02023138; https://clinicaltrials.gov/ct2/show/NCT02023138.

patient
clinical practice
clinical practice guidelines
traumatic
traumatic brain injuries
brain injury
participation
patient participation


A procedure for deriving wind turbine noise limits by taking into account annoyance.

Abstract: With the increasing installation of wind farms, the attention of citizens towards wind turbine noise (WTN) has grown. Differently from some national legislations, the scientific community has promptly responded, increasing the studies and the social surveys in order to better understand the cause of disturbance and the indicators that relate to it. At first, the paper underlines the importance of low WTN levels for indirect health effects such as sleep disturbance and annoyance. The importance to consider noise annoyance in legislation is also discussed, as WTN is more disturbing than other most common noise sources. Then, conversion curves for equally highly annoyed are introduced considering the annoyance perceived by population in relation with the type of source. Finally, a specific limit value of 43 dB(A) for WTN is derived and suggested, comparable with British and Danish standards.

Wind turbine noise
Noise limits
Noise annoyance
Dose-effect
Exposure-response relationship
Road traffic noise


Maintaining plasma quality and safety in the state of ongoing epidemic - The role of pathogen reduction.

Abstract: In the field of transfusion medicine, many pathogen reduction techniques (PRTs) are currently available, including those based on photochemical (PI) and photodynamic inactivation (PDI). This is particularly important in the face of emerging viral pathogens that may pose a threat to blood recipients, as in the case of the COVID-19 pandemic. However, PRTs have some limitations, primarily related to their adverse effects on coagulation factors, which should be considered before their intended use. A comprehensive search of PubMed, Wiley Online Library and Science Direct databases was conducted to identify original papers. As a result, ten studies evaluating fresh plasma and frozen-thawed plasma treated with different PI/ PDI methods and evaluating concentrations of coagulation factors and natural anticoagulants both before and after photochemical treatment were included in the review. The use of PI and PDI is associated with a significant decrease in the activity of all analysed coagulation factors, while the recovery of natural anticoagulants remains at a satisfactory level, variable for individual inactivation methods. In addition, the published evidence reviewed above does not unequivocally favour the implementation of PI/PDI either before freezing or after thawing as plasma products obtained with these two approaches seem to satisfy the existing quality criteria. Based on current evidence, if implemented responsibly and in accordance with the current guidelines, both PI and PDI can ensure satisfactory plasma quality and improve its safety.

Wasiluk|Tomasz|T| Rogowska|Anna|A| Boczkowska-Radziwon|Barbara|B| Zebrowska|Agnieszka|A| Bolkun|Lukasz|L| Piszcz|Jaroslaw|J| Radziwon|Piotr|P|


Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

Abstract:
OBJECTIVE
Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture.

APPROACH AND RESULTS
In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1β, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs.

CONCLUSIONS
CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies.

Starke|Robert M|RM|
Thompson|John W|JW|
Ali|Muhammad S|MS|
Pascale|Crissey L|CL|
Martinez Lege|Alejandra|A|
Ding|Dale|D|
Chalouhi|Nohra|N|
Hasan|David M|DM|
Jabbour|Pascal|P|
Owens|Gary K|GK|
Toborek|Michal|M|
Hare|Joshua M|JM|
Dumont|Aaron S|AS|

D000098:Acetophenones
D017542:Aneurysm, Ruptured
D000818:Animals
D000975:Antioxidants
D002478:Cells, Cultured
D002536:Cerebral Arteries
D000073865:Cigarette Smoking
D004108:Dilatation, Pathologic
D004195:Disease Models, Animal
D002532:Intracranial Aneurysm
D000090062:Kruppel-Like Factor 4
D008297:Male
D018345:Mice, Knockout
D009131:Muscle, Smooth, Vascular
D032389:Myocytes, Smooth Muscle
D000074624:NADPH Oxidase 1
D019255:NADPH Oxidases
D018384:Oxidative Stress
D010641:Phenotype
D017207:Rats, Sprague-Dawley
D015398:Signal Transduction
D012906:Smoke
D066253:Vascular Remodeling

smoke
aneurysm
oxygen
rupture
atherosclerosis
subarachnoid hemorrhage


Review of policies to increase fruit and vegetable consumption and physical activity in 49 low- and middle-income countries.

Abstract:
BACKGROUND
Inadequate physical activity (PA) and consumption of fruits and vegetables (FV) are known risk factors for non-communicable diseases (NCDs). Consequently, the World Health Organization (WHO) encourages the development of policies to increase PA and FV consumption. We reviewed available policies between 2004 and 2013 to increase FV consumption and PA from a convenience sample of 49 LMICs.

METHOD
Information on national policies were obtained from government ministries involved with the formulation of nutrition and PA policies, WHO databases and from PubMed and Scopus.

RESULTS
Of the 49 countries, 57% had policies to increase FV consumption, and 76% had policies to promote PA. Policy reviews indicated strategies that focus on schools, communities, the general public, the environment, the economy, mass media and WHO recommendations. Of the 28 countries with FV policies, 18% had formulated policies that met the WHO recommendations for daily intake of FV. Likewise, of the 37 countries with PA policies, 24% had policies that promoted the WHO recommendations for daily PA.

CONCLUSION
Greater progress has been made in developing policies to increase PA compared to policies to increase FV consumption in low- and middle-income countries. However, most countries are still lagging behind in developing policies to meet the WHO recommendations.

Darfour-Oduro|S A|SA|
Andrade|J E|JE|
Grigsby-Toussaint|D S|DS|

fruits
low- and middle-income countries
non-communicable diseases
WHO recommendations
behavioral health policies
nutrition policies
physical activity policies
school-based policies
vegetables policies


Q-Finder: An Algorithm for Credible Subgroup Discovery in Clinical Data Analysis - An Application to the International Diabetes Management Practice Study.

Abstract: Addressing the heterogeneity of both the outcome of a disease and the treatment response to an intervention is a mandatory pathway for regulatory approval of medicines. In randomized clinical trials (RCTs), confirmatory subgroup analyses focus on the assessment of drugs in predefined subgroups, while exploratory ones allow a posteriori the identification of subsets of patients who respond differently. Within the latter area, subgroup discovery (SD) data mining approach is widely used-particularly in precision medicine-to evaluate treatment effect across different groups of patients from various data sources (be it from clinical trials or real-world data). However, both the limited consideration by standard SD algorithms of recommended criteria to define credible subgroups and the lack of statistical power of the findings after correcting for multiple testing hinder the generation of hypothesis and their acceptance by healthcare authorities and practitioners. In this paper, we present the Q-Finder algorithm that aims to generate statistically credible subgroups to answer clinical questions, such as finding drivers of natural disease progression or treatment response. It combines an exhaustive search with a cascade of filters based on metrics assessing key credibility criteria, including relative risk reduction assessment, adjustment on confounding factors, individual feature's contribution to the subgroup's effect, interaction tests for assessing between-subgroup treatment effect interactions and tests adjustment (multiple testing). This allows Q-Finder to directly target and assess subgroups on recommended credibility criteria. The top-k credible subgroups are then selected, while accounting for subgroups' diversity and, possibly, clinical relevance. Those subgroups are tested on independent data to assess their consistency across databases, while preserving statistical power by limiting the number of tests. To illustrate this algorithm, we applied it on the database of the International Diabetes Management Practice Study (IDMPS) to better understand the drivers of improved glycemic control and rate of episodes of hypoglycemia in type 2 diabetics patients. We compared Q-Finder with state-of-the-art approaches from both Subgroup Identification and Knowledge Discovery in Databases literature. The results demonstrate its ability to identify and support a short list of highly credible and diverse data-driven subgroups for both prognostic and predictive tasks.

Esnault|Cyril|C| Gadonna|May-Line|ML| Queyrel|Maxence|M| Templier|Alexandre|A| Zucker|Jean-Daniel|JD|

subgroup discovery
credibility criteria
IDMPS
exploratory subgroup analysis
hypothesis generation
precision medicine
predictive factor
prognostic factor


Controlled drug release with surface-capped mesoporous silica nanoparticles and its label-free in situ Raman monitoring.

Abstract: Mesoporous silica nanoparticles (MSNs) have drawn attention as efficient nanocarriers for drug delivery systems owing to their unique physiochemical properties. However, systemically controlling the kinetics of drug release from the nanocarriers and in situ monitoring of the drug release are still challenging. Here, we report surface-capped MSNs used for controlled drug release and demonstrate label-free in situ Raman monitoring of released drugs based on the molecule-specific spectral fingerprints. By capping the surface of MSNs with amine moieties, gold nanoparticles, and albumin, we achieved high loading efficiencies (up to 97%) of doxorubicin and precisely controlled drug release stimulated by changing pH value. Moreover, we monitored in real-time drug release profile and visualized cellular distribution of the delivered drug at nanoscale based on its intrinsic Raman peak. Finally, we evaluated drug responses in cancer cells and normal cells to investigate whether capped-dMSNs exhibit selective drug release. Our findings would be beneficial for designing smart drug carriers and directly monitoring the release behavior of drugs in actual cellular environments.

Lee|Seungki|S|
Kwon|Jung A|JA|
Park|Keon Hee|KH|
Jin|Chang Min|CM|
Joo|Ji Bong|JB|
Choi|Inhee|I|

Mesoporous silica nanoparticles
Drug delivery
Controlled release
Raman mapping
Raman spectroscopy


Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α Upregulation in PTEN Negative Prostate Cancer Cells.

Abstract: The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid-a broad acting inhibitor of dicarboxylic acid carriers-strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone.

Weber|Anja|A|
Klocker|Helmut|H|
Oberacher|Herbert|H|
Gnaiger|Erich|E|
Neuwirt|Hannes|H|
Sampson|Natalie|N|0000-0001-9326-8177
Eder|Iris E|IE|

D051795:Hypoxia-Inducible Factor 1, alpha Subunit

succinate
prostate cancer
Na+-dicarboxylate transporter
acidic tumor microenvironment
mitochondria
oxidative phosphorylation


Anti-Mycobacterium tuberculosis activity of essential oil and 6,7-dehydroroyleanone isolated from leaves of Tetradenia riparia (Hochst.) Codd (Lamiaceae).

Abstract:
BACKGROUND
The global resurgence of tuberculosis (TB) and the development of drug resistance, as multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis isolates, are a threat to TB control and have created a need for new and more effective anti-TB drugs.

AIM
The current study evaluated the in vitro cytotoxicity and activity of Tetradenia riparia essential oil (TrEO) and 6,7-dehydroroyleanone pure compound against M. tuberculosis H37Rv and susceptible and resistant clinical isolates.

METHODS
The in vitro activities of TrEO and 6,7-dehydroroyleanone were determined by Resazurin Microtiter Assay Plate (REMA). The cytotoxicity was evaluated in murine peritoneal macrophages by Alamar Blue assay. The cytotoxic effects were expressed as median concentration cytotoxicity (CC50) and the selectivity index (SI) was calculated.

RESULTS
TrEO and 6,7-dehydroroyleanone showed activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) 62.5 µg/ml and 31.2 µg/ml, respectively. Both of them exhibited activities against resistant and susceptible M. tuberculosis clinical isolates with MIC values between 31.2 and 62.5 µg/ml. Cytotoxicity assays showed SI 1.9 and 7.9 for TrEO and 6,7-dehydroroyleanone, respectively.

CONCLUSION
These results revealed that TrEO isolated from leaves of T. riparia and the pure compound 6,7-dehydroroyleanone display good activity against M. tuberculosis clinical isolates, including MDR isolates, with low cytotoxicity to murine macrophages. The 6,7-dehydroroyleanone compound is a potential candidate for anti-TB drug.

Baldin|Vanessa Pietrowski|VP|
Scodro|Regiane Bertin de Lima|RBL|
Lopes-Ortiz|Mariana Aparecida|MA|
de Almeida|Aryadne Larissa|AL|
Gazim|Zilda Cristiani|ZC|
Ferarrese|Letícia|L|
Faiões|Viviane Dos Santos|VDS|
Torres-Santos|Eduardo Caio|EC|
Pires|Claudia Terencio Agostinho|CTA|
Caleffi-Ferracioli|Katiany Rizzieri|KR|
Siqueira|Vera Lucia Dias|VLD|
Cortez|Diógenes Aparício Garcia|DAG|
Cardoso|Rosilene Fressatti|RF|

D045784:Abietanes
D000818:Animals
D000995:Antitubercular Agents
D002478:Cells, Cultured
D019686:Lamiaceae
D017737:Macrophages, Peritoneal
D051379:Mice
D008826:Microbial Sensitivity Tests
D009169:Mycobacterium tuberculosis
D009822:Oils, Volatile
D010936:Plant Extracts
D018515:Plant Leaves
D010938:Plant Oils

Essential oil
Tetradenia riparia
Mycobacterium tuberculosis
Cytotoxicity
Antimycobacterial activity


Efficient synthesis and biological evaluation of new benzopyran-annulated pyrano[2,3-c]pyrazole derivatives.

Abstract: A one-pot method has been described to synthesize benzopyran-annulated pyrano[2,3-c]pyrazoles, effectively by combining O-alkenyloxy/alkynyloxy-acetophenones with various pyrazolones in triethylammonium acetate (TEAA) under microwave irradiation. While combination of O-allyloxy- or O-prenyloxy-acetophenones with pyrazolones occurred efficiently, that of O-propargyloxy-acetophenones was found effective in the presence of ZnO catalyst, via a domino Knoevenagel-hetero-Diels-Alder (DKHDA) reaction. Aminobenzopyran frameworks were also synthesized, after nitro-containing products were reduced in tandem with iron(II) in an acidic medium. The in vitro antiproliferative activity of these compounds was measured and discussed against gram-positive, gram-negative and M. tuberculosis bacteria, fungi, and various representative human solid tumor cell lines, in addition to their ferric reducing antioxidant capability.

Labana|Balvantsingh M|BM|
Brahmbhatt|Gaurangkumar C|GC|
Sutariya|Tushar R|TR|
Parmar|Narsidas J|NJ|
Padrón|José M|JM|
Kant|Rajni|R|
Gupta|Vivek K|VK|

Pyrano[2,3-c]pyrazole
Antiproliferative activity
Benzopyran
DKHDA reaction
Ketone-based DKHDA substrates


Linoleic Acid is a Diabetes-relevant Stimulator of Retinal Inflammation in Human Retinal Muller Cells and Microvascular Endothelial Cells.

Abstract:
OBJECTIVE
To determine the effect of oleic acid and linoleic acid on the production and secretion of specific diabetic retinopathy- (DR-) related cytokines: vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and interleukin-8 (IL-8) by human retinal glial cells, retinal endothelial cells, and retinal pigment epithelial cells. These expression profiles will be compared to those obtained by treatment of the same cell types with elevated D-glucose, a diabetes-relevant stimulus often used in retinal cell culture experiments.

METHODS
Primary cultures of human retinal Müller cells, astrocytes, and microvascular endothelial cells (RMEC) and a human retinal pigment epithelial cell line (ARPE-19) were treated with oleic acid, linoleic acid, elevated D-glucose, or L-glucose as an osmotic control. VEGF, IL-6, and IL-8 concentrations in conditioned media were determined by colorimetric ELISA and normalized to total cellular protein.

RESULTS
In the conditioned medium of human Müller cells, linoleic and oleic acid increased VEGF production by 6.4-fold and 9.9-fold, respectively. Linoleic acid also significantly increased IL-6 by 2.9-fold and IL-8 by 5.7-fold. L-glucose and D-glucose both increased VEGF by 3.1-fold in Müller cell conditioned medium. Linoleic acid increased IL-8 concentrations by 56% in human RMEC conditioned medium. Human retinal astrocytes and ARPE-19 were unaffected by all stimuli.

CONCLUSIONS
Linoleic and oleic acid induce inflammatory mediators believed to be involved in the pathogenesis of diabetic retinopathy (DR). In culture, the free fatty acid insults, particularly linoleic acid, significantly increased cytokine production by Müller cells. In summary, these data identified Müller cells as the primary producer of these inflammatory mediators when treated with unsaturated fatty acids. This study also demonstrates that elevated glucose is an inadequate stimulus for assessing the production of inflammatory mediators. Therefore this study provides a novel in vitro model system of the dyslipidemia-induced inflammation occurring in DR.

Capozzi|Megan E|ME|
McCollum|Gary W|GW|
Cousins|David B|DB|
Penn|John S|JS|

Linoleic acid
Oleic acid
Vascular endothelial growth factor
Interleukin-6
Interleukin-8
Diabetic retinopathy


Skin characteristics after fractional photothermolysis.

Abstract:
BACKGROUND
Fractional photothermolysis makes thousands of minute areas called microthermal treatment zones on the skin surface and transmits thermal injury to facilitate heat shock protein formation around the dermis. Potential side effects include acneiform eruption, herpes simplex virus outbreak, erythema, and post-inflammatory hyperpigmentation.

OBJECTIVE
To investigate and compare the changes in the skin of Asian patients after two different fractional photothermolysis systems (FPS) on a split face.

METHODS
A half-split face study was performed with 10,600 nm carbon dioxide FPS on the left and 1,550 nm erbium-doped FPS on the right side of the face. Only one session of laser irradiation and several biophysical measurements were done.

RESULTS
Although both FPS proved to be effective in treating acne scar and wrinkle patients, a slightly higher satisfaction rating was seen with the 10,600 nm FPS treatment. Both types of FPS showed a significant increase in transepidermal water loss which decreased gradually after treatment and returned to pre-treatment level after 1 week. A decreased reviscometer score was sustained for a longer period in wrinkle areas treated with 10,600 nm FPS.

CONCLUSION
Even though the changes in skin varied according to different FPS wave-length, adverse outcomes, such as increased erythema and TEWL were entirely subdued within 3 months of treatment.

Oh|Byung Ho|BH|
Hwang|Young Ji|YJ|
Lee|Yang Won|YW|
Choe|Yong Beom|YB|
Ahn|Kyu Joong|KJ|

Fractional photothermolysis
Acne scar
Wrinkle


Optical sampling depth in the spatial frequency domain.

Abstract: We present a Monte Carlo (MC) method to determine depth-dependent probability distributions of photon visitation and detection for optical reflectance measurements performed in the spatial frequency domain (SFD). These distributions are formed using an MC simulation for radiative transport that utilizes a photon packet weighting procedure consistent with the two-dimensional spatial Fourier transform of the radiative transport equation. This method enables the development of quantitative metrics for SFD optical sampling depth in layered tissue and its dependence on both tissue optical properties and spatial frequency. We validate the computed depth-dependent probability distributions using SFD measurements in a layered phantom system with a highly scattering top layer of variable thickness supported by a highly absorbing base layer. We utilize our method to establish the spatial frequency-dependent optical sampling depth for a number of tissue types and also provide a general tool to determine such depths for tissues of arbitrary optical properties.

Hayakawa|Carole K|CK|
Karrobi|Kavon|K|
Pera|Vivian|V|
Roblyer|Darren|D|
Venugopalan|Vasan|V|

spatial frequency domain
Monte Carlo simulation
diffuse optical spectroscopy
diffuse optics
photon migration


A Novel Approach to New-Onset Hemiplegic Shoulder Pain With Decreased Range of Motion Using Targeted Diagnostic Nerve Blocks: The ViVe Algorithm.

Abstract: Introduction: Hemiplegic shoulder pain (HSP) is the most common pain disorder after stroke with incidence estimates of 30-70% and associated with reductions in function, interference with rehabilitation, and a reduced quality of life. Onset may occur as soon as a week after stroke in 17% of patients. Management of HSP represents a complex treatment pathway with a lack of evidence to support one treatment. The pain has heterogeneous causes. In the acute setting, decreased range of motion in the shoulder can be due to early-onset spasticity, capsular pattern stiffness, glenohumeral pathology, or complex regional pain syndrome (CRPS). As contracture can form in up to 50% of patients after stroke, effective management of the painful shoulder and upper limb with decreased range of motion requires assessment of each possible contributor for effective treatment. The anesthetic diagnostic nerve block (DNB) is known to differentiate spasticity from contracture and other disorders of immobility and can be useful in determining an appropriate treatment pathway. Objective: To create a diagnostic algorithm to differentiate between the causes of HSP in the stiff, painful shoulder in the subacute setting using diagnostic techniques including the Budapest Criteria for CRPS and DNB for spasticity and pain generators. Results: Examination of each joint in the upper extremity with HSP may differentiate each diagnosis with the use of an algorithm. Pain and stiffness isolated to the shoulder may be differentiated as primary shoulder pathology; sensory suprascapular DNB or intra-articular/subacromial injection can assist in differentiating adhesive capsulitis, arthritis, or rotator cuff injury. CRPS may affect the shoulder, elbow, wrist, and hand and can be evaluated with the Budapest Criteria. Spasticity can be differentiated with the use of motor DNB. A combination of these disorders may cause HSP, and the proposed treatment algorithm may offer assistance in selecting a systematic treatment pathway.

Fitterer|John W|JW|
Picelli|Alessandro|A|
Winston|Paul|P|

stroke
rehabilitation
complex regional pain syndromes
bursitis
muscle spasticity


Exploring interactions between force, repetition and posture on intervertebral disc height loss and bulging in isolated porcine cervical functional spinal units from sub-acute-failure magnitudes of cyclic compressive loading.

Abstract: Most in vitro studies are limited in the ability to partition intervertebral disc (IVD) height loss from total specimen height loss since the net changes in the actuator position of the materials testing system simply reflect net changes to functional spinal units (FSUs) used for testing. Three levels of peak compressive force, three cycle rates and two dynamic postural conditions were examined using a full-factorial design. Cyclic compressive force was applied using a time-varying waveform with synchronous flexion/extension for 5000 cycles. Surface scans from the anterior aspect of the IVD were recorded in a neutral and flexed posture before and after the cyclic loading protocol using a 3D laser scanner to characterise changes in IVD height loss and bulging. A significant three-way interaction (p=0.0092) between the magnitude of peak compressive force, cycle rate and degree of postural deviation was observed in cycle-varying specimen height loss data. A significant main effect of peak compressive force (p=0.0003) was also observed in IVD height loss calculated from the surface profiles of the IVD. The relative contribution of IVD height loss (measured on the anterior surface) to total specimen height loss across experimental conditions varied considerably, ranging from 19% to 58%. Postural deviation was the only factor that significantly affected the magnitude of peak AF bulge (p=0.0016). This investigation provides evidence that total specimen height loss is not an accurate depiction of cycle-varying changes in the IVD across a range of in vivo scenarios that were replicated with in vitro testing.

Intervertebral disc
Height loss
Bulging
Laser scanner
Annulus fibrosus


The effect of levodopa-carbidopa intestinal gel infusion long-term therapy on motor complications in advanced Parkinson's disease: a multicenter Romanian experience.

Abstract: Chronic treatment with oral levodopa is associated with an increased frequency of motor complications in the late stages of Parkinson's disease (PD). Continuous administration of levodopa-carbidopa intestinal gel (LCIG-Duodopa(®), Abbott Laboratories), which has been available in Romania since 2009, represents an option for treating patients with advanced PD. Our primary objective was to report changes in motor complications after initiation of LCIG therapy. The secondary objectives were as follows: to determine the impact of LCIG therapy on the daily levodopa dose variation before/and after LCIG, to collect patient self-assessments of quality of life (QoL), and to study the overall tolerability and safety of LCIG administration. A retrospective analysis (2009-2013) of LCIG therapy and the experience in nine neurology centers in Romania was performed. The impact of LCIG therapy was evaluated by analyzing changes in motor fluctuations, dyskinesia and the patients' QoL after initiating therapy. The safety of LCIG therapy was estimated by noting agent-related adverse events (AEs) and medical device-related AEs. In the 113 patients included, we observed a significant improvement in PD symptoms after initiation of LCIG therapy. The "on" period increased, with a mean value of 6.14 h, and the dyskinesia period was reduced, with a mean value of 29.4 %. The quantified non-motor symptoms subsided. The patients exhibited significant improvements in QoL scores. There were few AEs and few cases of LCIG therapy discontinuation. LCIG is an important and available therapeutic option for managing patients with advanced PD.

Levodopa–carbidopa intestinal gel (LCIG)


Epidemiology And Outcomes Of Radiator Burns At A High Throughput Burns Centre.

Abstract: Indoor radiator burns can cause significant morbidity and mortality, especially in vulnerable patients. However, the epidemiology and clinical outcomes are poorly characterized. A retrospective study of all radiator burns referred to a tertiary regional burns centre between 2013-2019 was conducted. Four hundred and forty-seven patients (median age 25.6 years, male:female ratio 1.4:1) were referred; 109 (24%) admitted, 201 (45%) managed in outpatients and 137 (31%) managed locally. The incidence of burns leading to referral was 0.65/100,000/year, but increased annually. Contact burns consisted of 99.6%. Age distribution was bimodal: <5 years (43%), >65 years (27%), although all ages were affected. Median TBSA was 0.75% (0.1-11.5%), but 79% had injuries <2%. Childhood burns were predominantly superficial dermal grab injuries, usually manageable as outpatients. Elderly patients had larger burns usually secondary to falls or impaired sensorium, and were more likely to die (p<0.05). Burns due to impaired sensorium were deeper and more likely to require surgery (p<0.05). Sixty-three (14%) patients required surgery. Thirty-day mortality was 1.1%. Age was the only significant predictor of mortality. This study quantifies the epidemiology and outcomes of a growing problem. It identifies at risk populations (extremes of age), and important features of the clinical assessment.

Brewer|Cc F|CF|
Mabvuure|N T|NT|
Pinto-Lopes|R|R|
El-Muttardi|N|N|

epidemiology
radiator
burn
contact burn
central heating


Providing prostate cancer survivorship care in Japan: Implications from the USA care model.

Abstract: Despite an increasing number of prostate cancer survivors in Japan, the current delivery of prostate cancer survivorship care is insufficient and lacks a multidisciplinary approach. We carried out a study to characterize prostate cancer survivorship care in Japan, examine the Japanese workforce available to deliver survivorship care, introduce a conceptual framework for survivorship and identify opportunities to improve Japanese survivorship care. We systematically searched PubMed for prostate cancer survivorship care studies, including those from Japan. We also searched the internet for prostate cancer guidelines relevant to survivorship care. We found 392 articles, of which 71 were relevant, read in detail and reported here. In Japan, survivorship care is mostly provided by urologists. Primary care as a specialty does not exist in Japan, and there are no independent nurse practitioners or physician assistants to assist with survivorship care. Japanese quality of life studies characterize the long-term effects of prostate cancer treatment, but routine use of patient-reported outcomes is not common in Japan. In the USA, in light of a growing comprehensive awareness of challenges facing survivors and their providers, the American Cancer Society prostate cancer survivorship care guidelines serve as a tool for optimizing the management of long-term treatment effects and coordination of care. In order to deliver high-quality survivorship care in Japan, urologists need to establish collaborations with other disciplines within the delivery system. A multidisciplinary guideline for prostate cancer survivorship care in Japan appears warranted.

Osawa|Takahiro|T|
Wittmann|Daniela|D|
Jimbo|Masahito|M|
Keller|Evan T|ET|
Namiki|Shunichi|S|
Abe|Takashige|T|
Shinohara|Nobuo|N|
Skolarus|Ted A|TA|

prostate cancer
survivorship care
cancer survivor
workforce
quality of life


Prevalence and Phylogenetic Analysis of Microsporidium Enterocytozoon bieneusi in Diarrheal Patients.

Abstract: Enterocytozoon bieneusi can cause severe diarrhea in children and adults. However, in China, there are scant studies on E. bieneusi in diarrheal children and adults, with the exception of prevalence and genotyping data in a small number of cities including Hubei, Shanghai, and Heilongjiang. In this study, 196 fecal samples (n = 132 in Chongqing, n = 44 in Shandong, n = 20 in Hubei) were collected, including 91 from children and 105 from adults. Through microscopic examination, 19 positive samples (11 from children and 8 from adults) were detected. Using PCR examination, the internal transcriptional spacer (ITS) region was utilized by nested PCR to detect and characterize E. bieneusi. Twenty positive samples were detected, including 14 from children (≤11 years of age) and 6 from adults. According to the sequence analysis of ITS data, one known zoonotic (D) and seven novel (CQH5-11) genotypes were identified. This is the first molecular epidemiological study of E. bieneusi in diarrheal patients in different regions of China. Therefore, this study can provide useful information for the molecular epidemiology and control of E. bieneusi infection in humans in the future.

Zang|Manman|M| Li|Jinjin|J| Tang|Chun|C| Ding|Songtao|S| Huang|Wei|W| Qin|Qizhong|Q| Liu|Handeng|H|

Enterocytozoon bieneusi
patient
genotype
microscopic examination
phylogeny


Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents.

Abstract:
Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B-cell lymphoma-2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control.

IMPLICATIONS FOR PRACTICE
Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for TLS in patients with tumors characterized by rapid growth, high tumor burden, and/or high sensitivity to treatment. In this review, prevention strategies and management of patients with CLL who develop TLS are described.

Cheson|Bruce D|BD|
Heitner Enschede|Sari|S|
Cerri|Elisa|E|
Desai|Monali|M|
Potluri|Jalaja|J|
Lamanna|Nicole|N|
Tam|Constantine|C|

D019086:Bridged Bicyclo Compounds, Heterocyclic

D015451:Leukemia, Lymphocytic, Chronic, B-Cell

Tumor lysis syndrome
Chronic lymphocytic leukemia
Hematologic malignancies
Targeted cancer agents


The negative effect of unloading exceeds the bone-sparing effect of alkaline supplementation: a bed rest study.

Abstract:
Potassium bicarbonate was administrated to an already alkaline diet in seven male subjects during a 21-day bed rest study and was able to decrease bed rest induced increased calcium excretion but failed to prevent bed rest-induced bone resorption.

INTRODUCTION
Supplementation with alkali salts appears to positively influence calcium and bone metabolism and, thus, could be a countermeasure for population groups with an increased risk for bone loss. However, the extent to which alkalization counteracts acid-induced bone resorption or whether it merely has a calcium and bone maintenance effect is still not completely understood. In the present study, we hypothesized that additional alkalization to an already alkaline diet can further counteract bed rest-induced bone loss.

METHODS
Seven healthy male subjects completed two parts of a crossover designed 21-day bed rest study: bed rest only (control) and bed rest supplemented with 90 mmol potassium bicarbonate (KHCO3) daily.

RESULTS
KHCO3supplementation during bed rest resulted in a more alkaline status compared to the control intervention, demonstrated by the increase in pH and buffer capacity level (pH p = 0.023, HCO3p = 0.02, ABE p = 0.03). Urinary calcium excretion was decreased during KHCO3 supplementation (control 6.05 ± 2.74 mmol/24 h; KHCO3 4.87 ± 2.21 mmol/24 h, p = 0.03); whereas, bone formation was not affected by additional alkalization (bAP p = 0.58; PINP p = 0.60). Bone resorption marker UCTX tended to be lower during alkaline supplementation (UCTX p = 0.16).

CONCLUSIONS
The more alkaline acid-base status, achieved by KHCO3 supplementation, reduced renal calcium excretion during bed rest, but was not able to prevent immobilization-induced bone resorption. However, advantages of alkaline salts on bone metabolism may occur under acidic metabolic conditions or with respect to the positive effect of reduced calcium excretion within a longer time frame.

TRIAL REGISTRATION
Trial number: NCT01509456.

Bed rest
Potassium bicarbonate
Calcium excretion
Bone metabolism


Co-Circulation of Phleboviruses and Leishmania Parasites in Sand Flies from a Single Site in Italy Monitored between 2017 and 2020.

Abstract: Sand flies transmit Leishmania infantum, which is responsible for causing leishmaniasis, as well as many phleboviruses, including the human pathogenic Toscana virus. We screened sand flies collected from a single site between 2017 and 2020 for the presence of both phleboviruses and Leishmania. The sand flies were sampled with attractive carbon dioxide traps and CDC light traps between May and October. We collected more than 50,000 sand flies; 2826 were identified at the species level as Phlebotomus perfiliewi (98%) or Phlebotomus perniciosus (2%). A total of 16,789 sand flies were tested in 355 pools, and phleboviruses were found in 61 pools (6 Toscana virus positive pools, 2 Corfou virus positive pools, 42 Fermo virus positive pools, and 7 Ponticelli virus positive pools, and 4 unidentified phlebovirus positive pools). Leishmania was found in 75 pools and both microorganisms were detected in 16 pools. We isolated nine phleboviruses from another 2960 sand flies (five Ponticelli viruses and for Fermo viruses), not tested for Leishmania; the complete genome of a Fermo virus isolate was sequenced. The simultaneous detection in space and time of the Fermo virus and L. infantum is evidence that supports the co-circulation of both microorganisms in the same location and partial overlap of their cycles. A detailed characterization of the epidemiology of these microorganisms will support measures to limit their transmission.

sand fly
leishmania infantum
toscana virus
phlebotomus perfiliewi
phlebotomus perniciosus
corfou virus
fermo virus
phlebovirus
ponticelli I virus
ponticelli II virus
ponticelli III virus


Refashioned lamb tissue as an animal model for training complex techniques of laryngotracheal stenosis surgery.

Abstract: Open reconstructive upper airway surgery for laryngotracheal stenosis (LTS), whether for subglottic or tracheal stenosis, constitutes a group of complex approaches. LTS requiring open reconstruction is overall rare and primarily performed at tertiary centres. This poses an obvious challenge for the acquisition and maintenance of surgical skills for this group of complex approaches. In this context, animal models provide a unique opportunity for open reconstructive airway surgery training. Such models ought to take into consideration ethical aspects, be easily available and easy to maintain, and have similar macroscopic anatomical features to the human laryngotracheal frame. Here, we provide a brief surgical guide for the use of refashioned lamb tissue as a training model for surgery of adult and pediatric reconstructive airway surgery. The techniques of laryngotracheal reconstruction, partial cricotracheal resection, tracheal resection with end-to-end anastomosis, and slide tracheoplasty are presented. Proper training in open LTS surgery is challenging, time consuming and its complexity further lengthens the learning curve. The lamb larynx and trachea model is an effective model for practising various airway reclaiming surgeries.

Animal model
Airway surgery
Tracheal stenosis
Subglottic stenosis


The siRNAsome: A Cation-Free and Versatile Nanostructure for siRNA and Drug Co-delivery.

Abstract: Nanoparticles show great potential for drug delivery. However, suitable nanostructures capable of loading a range of drugs together with the co-delivery of siRNAs, which avoid the problem of cation-associated cytotoxicity, are lacking. Herein, we report an small interfering RNA (siRNA)-based vesicle (siRNAsome), which consists of a hydrophilic siRNA shell, a thermal- and intracellular-reduction-sensitive hydrophobic median layer, and an empty aqueous interior that meets this need. The siRNAsome can serve as a versatile nanostructure to load drug agents with divergent chemical properties, therapeutic proteins as well as co-delivering immobilized siRNAs without transfection agents. Importantly, the inherent thermal/reduction-responsiveness enables controlled drug loading and release. When siRNAsomes are loaded with the hydrophilic drug doxorubicin hydrochloride and anti-P-glycoprotein siRNA, synergistic therapeutic activity is achieved in multidrug resistant cancer cells and a tumor model.

Zheng|Meng|M|0000-0003-2932-1062 Jiang|Tong|T| Yang|Wen|W| Zou|Yan|Y| Wu|Haigang|H| Liu|Xiuhua|X| Zhu|Fengping|F| Qian|Rongjun|R| Ling|Daishun|D| McDonald|Kerrie|K| Shi|Jinjun|J| Shi|Bingyang|B|0000-0002-1043-3163

D004354:Drug Screening Assays, Antitumor

D057927:Hydrophobic and Hydrophilic Interactions

nanostructures
siRNA
co-delivery
vesicles
synergistic therapy


Functional Limitations and Gender Differences: Neighborhood Effects.

Abstract: Rates of functional limitations are consistently higher for women than for men, but it is not clear why. While some studies have examined individual risk factors, others have turned to broader social characteristics. We examined the effects of both individual and neighborhood characteristics associated with the functional limitations of older men and women. Multilevel structural equation models were developed using data from a random digit dial sample of 5,688 adults aged 50 to 74 years living in New Jersey. We found that greater numbers of fast-food restaurants, storefronts, and supermarkets was associated with more functional limitations of women, while greater numbers of fast-food restaurants was the only neighborhood characteristic associated with more functional limitations of men. Functional limitations of women, but not men, are affected by multiple neighborhood characteristics. This research reveals that specific neighborhood contextual characteristics, not just poverty, are associated with the health of community-dwelling adults.

functional limitations
gender
neighborhood
multilevel structural equation modeling


A Prospective Cohort Study on the Effects of Geriatric Rehabilitation Following Acute Exacerbations of COPD.

Abstract:
OBJECTIVES
Older patients with chronic obstructive pulmonary disease (COPD), hospitalized for an acute exacerbation, often do not receive recommended post-acute pulmonary rehabilitation. This underuse might be related to the impaired clinical and functional status of these patients, who are more likely to present with frailty, comorbidities, and disability. Having developed and implemented a geriatric rehabilitation program for these patients (GR_COPD), the primary aim of this study was to investigate the effectiveness of this program.

DESIGN AND INTERVENTION
A prospective cohort study with a 3-month follow-up period. Patients who declined the GR_COPD program were considered as controls.

SETTING AND PARTICIPANTS
The study was conducted at the pulmonary department of 2 hospitals. Patients were eligible when hospitalized as a result of an acute exacerbation of COPD and indicated for the GR_COPD program based on standardized criteria.

METHODS
Primary outcome was defined as change in disease-specific health status measured with the clinical COPD questionnaire (CCQ), secondary outcome as the exacerbation rate ratio during follow-up. To balance potential confounders between the intervention and control group, propensity score-based weighted linear regression analyses were performed.

RESULTS
Of the 158 included patients [78 (49.4%) male, mean age 70.8 (±8.1) years, mean forced expiratory volume in 1 second: 35.5 (±12.8) as % of predicted], 78 received the GR_COPD program. The results of the CCQ showed a significant and clinically relevant treatment effect of -0.56 points [95% confidence interval (CI) -0.89, -0.23; P = .001). Patients in the control group had 2.77 times more exacerbations compared with the intervention group (95% CI 2.13, 3.58; P < .001).

CONCLUSIONS/IMPLICATIONS
This study shows a clinically relevant effect of the GR_COPD program on disease-specific health status and exacerbation rate. Implementation of the program for older patients with severe COPD hospitalized for an acute exacerbation is recommended.

van Dam van Isselt|Eléonore F|EF|
van Eijk|Monica|M|
van Geloven|Nan|N|
Groenewegen-Sipkema|Karin H|KH|
van den Berg|Jan-Willem K|JK|
Nieuwenhuys|Cécile M A|CMA|
Chavannes|Niels H|NH|
Achterberg|Wilco P|WP|

D029424:Pulmonary Disease, Chronic Obstructive

Geriatric rehabilitation
COPD
health status
post-acute PR
propensity score


Linoleic acid salt with ultrapure soft water as an antibacterial combination against dermato-pathogenic Staphylococcus spp.

Abstract:
AIMS
Skin colonization of Staphylococcus spp. critically affects the severity of dermatitis in humans and animals. We examined different types of fatty acid salts for their antibacterial activity against Staphylococcus spp. when used in ultrapure soft water (UPSW). We also evaluated their therapeutic effect on a spontaneous canine model of dermatitis.

METHODS AND RESULTS
UPSW, in which Ca(++) and Mg(++) were replaced with Na(+) , was generated using a water softener with cation-exchange resin. Staphylococcus aureus (Staph. aureus), Staphylococcus intermedius (Staph. intermedius), and Staphylococcus pseudintermedius (Staph. pseudintermedius) were incubated with various fatty acid salts in distilled water (DW) or UPSW and the number of bacteria was counted. Among the fatty acids, oleic acid salt and linoleic acid (LA) salt reduced the number of these bacteria. Also, UPSW enhanced the antibacterial effect of LA on Staph. spp. In spontaneously developed itchy dermatitis in companion dogs, shampoo treatment with liquid soap containing 10% LA in UPSW improved skin conditions.

CONCLUSIONS
LA salt showed antibacterial activity against Staph. spp. Treatment with soap containing LA with UPSW reduced clinical conditions in dogs with dermatitis.

SIGNIFICANCE AND IMPACT OF THE STUDY
Because colonization of Staph. spp. on the skin exacerbates dermatitis, the use of LA-containing soap in UPSW may reduce unpleasant clinical symptoms of the skin.

Jang|H|H| Makita|Y|Y| Jung|K|K| Ishizaka|S|S| Karasawa|K|K| Oida|K|K| Takai|M|M| Matsuda|H|H| Tanaka|A|A|

linoleic acid salt
ultrapure soft water
skin
Staphylococcus spp.
dermatitis


Evaluation of effects of a preoperative 2-hour fast with glutamine and carbohydrate rich drink on insulin resistance in maxillofacial surgery.

Abstract:
INTRODUCTION
The aim of this prospective, randomized, single-blinded study was to compare the effects of preoperative fast for clear fluids on insulin resistance and hemodynamic stability on patient undergoing maxillofacial surgery.

METHOD
In this study 20 patients undergoing maxillofacial surgery were randomized into four groups i.e. - group I patients with standard 08 h fasting before anesthesia, group-II patients were given 400 ml and 200 ml of water 08 h and 2 h respectively before anesthesia, group III patients were given 400 ml water with 50 gms of glucose and 40 gm of glutamine 08 h before anesthesia and 200 ml water with 25 gms of glucose and 10 gm of glutamine 2 h before anesthesia, group IV patients were given 400 ml water with 50 gms of glucose 08 h before anesthesia and 200 ml water with 25 gms of glucose 2 h before anesthesia. Blood samples were collected pre-operatively and post-operatively.

RESULTS
Overall results suggest that Post-operative insulin resistance was greater in control patients (2.0 [0.3]) compared with the other 3 groups (placebo = 1.8 [0.9]); glutamine = (1.8 [0.6]); carbohydrate = (1.9 [0.6]).

DISCUSSION
This study shows that shortening of pre-operative fasting time for clear fluids until 2- h prior to anesthesia may induce a favorable environment for the post-operative course. In conclusion, Glutamine with carbohydrate drink can be used safely in surgical patients.

Singh|Manpreet|M| Chaudhary|Manoj|M| Vashistha|Arpit|A| Kaur|Gagandeep|G|

Glutamine
Insulin resistance
Clear fluids
Pre-operative fast


TOS-sing aside the glycolytic role of HK2/hexokinase-II to activate autophagy.

Abstract: Hexokinase is the first enzyme in the glycolytic pathway catalyzing the reaction in which glucose is phosphorylated into glucose-6-phosphate. Mammals possess 4 isoforms of hexokinase; HK2 (hexokinase 2) is the predominant form in insulin-sensitive tissues such as adipocytes, as well as skeletal and cardiac muscle. In addition to its function in glucose metabolism, HK2 is associated with cardiomyocyte protection against mitochondrial-mediated apoptotic cell death; whether or not HK2 played a role in cardioprotective autophagy was yet to be discovered. However, in a recent study highlighted by a punctum in this issue of Autophagy, Roberts et al. addressed this possibility, uncovering a direct link between HK2, TORC1, and autophagy regulation.

hexokinase-II
autophagy
cardiomyocytes
MTORC1
TOR signaling motif


Effect of H2O2 on the treatment of NO and NO2 using a Mg-Al oxide slurry.

Abstract: We examined the effect of H2O2 on the removal of NO and NO2 by treatment with a Mg-Al oxide slurry. The removal of NO2 and dissolution of NOx species in an aqueous solution increased with increasing concentrations of H2O2. NO2 was reduced to NO2(-) by HOO(-) derived from H2O2. The contribution of Mg-Al oxide decreased with increasing H2O2 concentration. The addition of H2O2 to the Mg-Al oxide slurry promoted the removal of NO owing to the oxidation of NO to NO3(-) by H2O2. However, the contribution of Mg-Al oxide decreased with increasing H2O2 concentration.

D017607:Aluminum Compounds
D006861:Hydrogen Peroxide
D017616:Magnesium Compounds
D009569:Nitric Oxide
D009585:Nitrogen Dioxide
D010084:Oxidation-Reduction

Effect
Treatment
NO
H(2)O(2)
Mg–Al oxide slurry
NO(2)


Propofol infusion syndrome in refractory status epilepticus.

Abstract:
BACKGROUND AND PURPOSE
Propofol is used for treating refractory status epilepticus, which has high rate of mortality. Propofol infusion syndrome is a rare but often fatal syndrome, characterized by lactic acidosis, lipidemia, and cardiac failure, associated with propofol infusion over prolonged periods of time. We investigated the clinical factors that characterize propofol infusion syndrome to know the risk of them in refractory status epilepticus.

METHODS
This retrospective observation study was conducted in Samsung medical center from Jan. 2005 to Dec. 2009. Thirty two patients (19 males, 13 females, aged between 16 and 64 years), with refractory status epilepsy were included. Their clinical findings and treatment outcomes were evaluated retrospectively. We divided our patients into established status epilepticus (ESE) and refractory status epilepticus (RSE). And then the patients with RSE was further subdivided into propofol treatment group (RSE-P) and the other anesthetics treatment group (RSE-O). We analyzed the clinical characteristics by comparison of the groups.

RESULTS
There were significant differences of hypotension and lipid change between ESE and RSE (p<0.05). However, there was no significant difference between RSE-P and RSE-O groups. The hospital days were longer in RSE than in ESE (p=0.012) and treatment outcome was also worse in RSE than in ESE (p=0.007) but there were no significant differences of hospital stays and treatment outcome between RSE-P and RSE-O.

CONCLUSIONS
RSE is very critical disease with high mortality, which may show as many clinical changes as propofol infusion syndrome. Therefore propofol infusion syndrome might be considered as one of the clinical manifestations of RSE.

Hwang|Woo Sub|WS|
Gwak|Hye Min|HM|
Seo|Dae-Won|DW|

Propofol infusion syndrome
Status Epilepticus
Anesthetics


Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death.

Abstract: Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years led to the remarkable conclusion that these two calpain isoforms exhibit opposite functions in the brain. Calpain-1 activation is required for certain forms of synaptic plasticity and corresponding types of learning and memory, while calpain-2 activation limits the extent of plasticity and learning. Calpain-1 is neuroprotective both during postnatal development and in adulthood, while calpain-2 is neurodegenerative. Several key protein targets participating in these opposite functions have been identified and linked to known pathways involved in synaptic plasticity and neuroprotection/neurodegeneration. We have proposed the hypothesis that the existence of different PDZ (PSD-95, DLG and ZO-1) binding domains in the C-terminal of calpain-1 and calpain-2 is responsible for their association with different signaling pathways and thereby their different functions. Results with calpain-2 knock-out mice or with mice treated with a selective calpain-2 inhibitor indicate that calpain-2 is a potential therapeutic target in various forms of neurodegeneration, including traumatic brain injury and repeated concussions.

Wang|Yubin|Y|0000-0002-8836-9632 Liu|Yan|Y| Bi|Xiaoning|X| Baudry|Michel|M|

learning
neurodegeneration
signaling pathways
hippocampus