Outcomes and morbidities of patients who survive haemoglobin Bart's hydrops fetalis syndrome: 20-year retrospective review.

Abstract:
INTRODUCTION
Haemoglobin Bart's hydrops fetalis syndrome was once considered a fatal condition. However, advances over the past two decades have enabled survival of affected patients. Data relating to their morbidities and outcomes will help medical specialists formulate a management plan and parental counselling.

METHODS
All babies with the syndrome who survived beyond the neonatal period and were subsequently managed long-term in eight public hospitals in Hong Kong from 1 January 1996 to 31 December 2015 were included. Patient and parent characteristics, antenatal care, reasons for continuation of pregnancy, intrauterine interventions, perinatal course, presence of congenital malformations, stem-cell transplantation details, and long-term neurodevelopmental outcomes were reviewed.

RESULTS
A total of nine patients were identified, of whom five were female and four male. The median follow-up duration was 7 years. All were Chinese and were homozygous for the Southeast Asian α-thalassaemia deletion. Five of the nine mothers received antenatal care at a public hospital and opted to continue the pregnancy after antenatal diagnosis and counselling. Despite intrauterine transfusions, all babies were born with respiratory depression and required intubation and mechanical ventilation during the neonatal period. Hypospadias was identified in all four male infants. Growth retardation, global developmental delay, and residual neurological deficits were noted in two-thirds of the patients. Haematopoietic stem-cell transplantation was performed in two patients, who became transfusion-independent.

CONCLUSIONS
Survival of patients with Bart's hydrops fetalis syndrome is possible but not without short- and long-term complications; local epidemiology is comparable to that documented for an international registry. Detailed antenatal counselling of parents with a non-judgemental attitude and cautious optimism are imperative.

Chan|W Yk|WY|
Leung|A Wk|AW|
Luk|C W|CW|
Li|R Ch|RC|
Ling|A Sc|AS|
Ha|S Y|SY|

Morbidity
Hydrops fetalis
Hong Kong
Alpha-thalassemia
Thalassemia


Iron Deficiency Anemia in Celiac Disease.

Abstract: The iron absorption process developsmainly in the proximal duodenum. This portion of the intestine is typically destroyed in celiac disease (CD), resulting in a reduction in absorption of iron and subsequent iron deficiency anemia (IDA). In fact, the most frequent extra-intestinal manifestation (EIM) of CD is IDA, with a prevalence between 12 and 82% (in relation with the various reports) in patients with new CD diagnosis. The primary treatment of CD is the gluten-free diet (GFD), which is associated with adequate management of IDA, if present. Iron replacement treatment historically has been based on oral products containing ferrous sulphate (FS). However, the absorption of FS is limited in patients with active CD and unpredictable in patients on a GFD. Furthermore, a poor tolerability of this kind of ferrous is particularly frequent in patients with CD or with other inflammatory bowel diseases. Normalization from anemic state typically occurs after at least 6 months of GFD, but the process can take up to 2 years for iron stores to replenish.

Iron deficiency Anemia
Celiac disease
iron absorption


No effects of a 6-week intervention with a glucagon-like peptide-1 receptor agonist on pancreatic volume and oedema in obese men without diabetes.

Abstract:
AIM
To investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans.

MATERIALS AND METHODS
We performed an open-label study in 14 obese men (age 38 ± 11 years, body mass index 32 ± 4 kg/m2 ) without diabetes. Subjects were examined at baseline, during titration (week 4) of liraglutide towards 3.0 mg/day, and 2 weeks after steady-state treatment (week 6) of a final dose of liraglutide. The primary endpoint was pancreatic volume determined by magnetic resonance imaging. Secondary endpoints included pancreatic oedema and cellularity, positron emission tomography-based [18 F]fluorothymidine (FLT) uptake (DNA synthesis) and plasma pancreatic enzymes.

RESULTS
Plasma amylase (+7 U/L [95% confidence intervals 3-11], P < .01) and lipase (+19 U/L [7-30], P < .01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm3 [-8-8], P = .96) and no change in pancreatic cellular infiltration was found (P = .22). During titration of liraglutide, FLT uptake in pancreatic tissue increased numerically (+0.08 [0.00-0.17], P = .0507).

CONCLUSIONS
Six weeks of treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes.

antiobesity drug clinical trial GLP-1 analogue


The observational study of delayed wound healing after tooth extraction in patients receiving oral bisphosphonate therapy.

Abstract:
INTRODUCTION
In this study, we investigated whether such a discontinuation of oral bisphosphonate (BP) for 3 months might influence the incidence of BP-related osteonecrosis of the jaw (BRONJ) and wound healing after tooth extraction in patients receiving oral BP therapy.

MATERIAL AND METHODS
There were a total of 434 teeth in 201 patients (18 males and 183 females). The patients were divided into two groups depending on whether or not they underwent a 3-month discontinuation of BP therapy (BP- and BP+) before tooth extraction. In this observational study investigated delayed wound healing after tooth extraction in patients receiving oral BP therapy.

RESULTS
In all cases of the BP- group, there were no BRONJ although there was delayed wound healing in two cases. However, in one case of the BP+ group, oral BP was continued because it was deemed high risk to discontinue treatment by the patient's physician. In this case, an intraoral fistula was still present with bone exposure at 120 weeks after extraction (BRONJ stage 1).

CONCLUSION
This study supports the idea of a drug holiday and encourages further clinical research on this topic of tooth extraction in patients receiving oral BP therapy.

Hasegawa|Takumi|T| Ri|Shinshou|S| Umeda|Masahiro|M| Komatsubara|Hideki|H| Kobayashi|Masaki|M| Shigeta|Takashi|T| Yoshitomi|Izumi|I| Ikeda|Hisazumi|H| Shibuya|Yasuyuki|Y| Asahina|Izumi|I| Komori|Takahide|T|

D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw

D050071:Bone Density Conservation Agents

Bisphosphonate related osteonecrosis of jaw


CRISPR FokI Dead Cas9 System: Principles and Applications in Genome Engineering.

Abstract: The identification of the robust clustered regularly interspersed short palindromic repeats (CRISPR) associated endonuclease (Cas9) system gene-editing tool has opened up a wide range of potential therapeutic applications that were restricted by more complex tools, including zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). Nevertheless, the high frequency of CRISPR system off-target activity still limits its applications, and, thus, advanced strategies for highly specific CRISPR/Cas9-mediated genome editing are continuously under development including CRISPR-FokI dead Cas9 (fdCas9). fdCas9 system is derived from linking a FokI endonuclease catalytic domain to an inactive Cas9 protein and requires a pair of guide sgRNAs that bind to the sense and antisense strands of the DNA in a protospacer adjacent motif (PAM)-out orientation, with a defined spacer sequence range around the target site. The dimerization of FokI domains generates DNA double-strand breaks, which activates the DNA repair machinery and results in genomic edit. So far, all the engineered fdCas9 variants have shown promising gene-editing activities in human cells when compared to other platforms. Herein, we review the advantages of all published variants of fdCas9 and their current applications in genome engineering.

Saifaldeen|Maryam|M|
Al-Ansari|Dana E|DE|0000-0003-3720-1570
Ramotar|Dindial|D|
Aouida|Mustapha|M|0000-0001-7945-5320

D015252:Deoxyribonucleases, Type II Site-Specific

CRISPR
dead Cas9
genome engineering
FokI endonuclease
spacer sequence
fdCas9 variants
FokI-dCas9
RNA-guided FokI nuclease
dual guide RNA


Chaos and unpredictability in evolution.

Abstract: The possibility of complicated dynamic behavior driven by nonlinear feedbacks in dynamical systems has revolutionized science in the latter part of the last century. Yet despite examples of complicated frequency dynamics, the possibility of long-term evolutionary chaos is rarely considered. The concept of "survival of the fittest" is central to much evolutionary thinking and embodies a perspective of evolution as a directional optimization process exhibiting simple, predictable dynamics. This perspective is adequate for simple scenarios, when frequency-independent selection acts on scalar phenotypes. However, in most organisms many phenotypic properties combine in complicated ways to determine ecological interactions, and hence frequency-dependent selection. Therefore, it is natural to consider models for evolutionary dynamics generated by frequency-dependent selection acting simultaneously on many different phenotypes. Here we show that complicated, chaotic dynamics of long-term evolutionary trajectories in phenotype space is very common in a large class of such models when the dimension of phenotype space is large, and when there are selective interactions between the phenotypic components. Our results suggest that the perspective of evolution as a process with simple, predictable dynamics covers only a small fragment of long-term evolution.

D000818:Animals
D019143:Evolution, Molecular
D008957:Models, Genetic
D017711:Nonlinear Dynamics

chaos
Adaptive dynamics
complex dynamics
high-dimensional phenotype space
logistic competition models


Effects of cardiopulmonary bypass on the disposition of cefazolin in patients undergoing cardiothoracic surgery.

Abstract: The aim of the study was to evaluate the disposition of plasma unbound cefazolin in patients undergoing cardiothoracic surgery with cardiopulmonary bypass (CPB). Adult patients undergoing cardiothoracic surgery with CPB were enrolled in the study. Cefazolin sodium was given intravenously before skin incision (1 g) and at the beginning of CPB (2 g). Thereafter, an additional dose (1 g) was given every 4 hours. Seven to ten blood samples were collected before and during surgery. Plasma total and unbound (ultrafiltrated) cefazolin concentrations were analyzed using an HPLC-UV method. Plasma protein binding was analyzed with the Langmuir model. Twenty-seven patients (aged 70 ± 12 years, body weight 62 ± 12 kg, mean ± SD) with GFR >30 mL min-1 completed the study. There was a significant (P < 0.001) increase in median plasma unbound fraction of cefazolin from 21% before skin incision to 45% during CPB (P < 0.001), which was accompanied by a significant (P < 0.001) reduction in median plasma albumin concentration from 36 to 27 g L-1. Plasma concentrations of unbound cefazolin exceeded the assumed target thresholds of 2 μg mL-1 in all samples and of 8 μg mL-1 in all but one of 199 samples. The increased plasma unbound fraction of cefazolin would be attributable to dilutional reduction of serum albumin at the beginning of CPB and to saturable plasma protein binding of cefazolin. These data reveal CPB may alter the plasma protein binding and possibly distribution of cefazolin. Further studies are warranted to reappraise the protocol of antimicrobial prophylaxis with cefazolin in patients undergoing surgery with CPB.

Asada|Mizuho|M| Nagata|Masashi|M|0000-0003-3169-7210 Mizuno|Tomohiro|T| Uchida|Tokujiro|T| Kurashima|Naoki|N| Takahashi|Hiromitsu|H| Makita|Koshi|K| Arai|Hirokuni|H| Echizen|Hirotoshi|H| Yasuhara|Masato|M|

cardiopulmonary bypass
cefazolin
plasma protein binding
unbound fraction
surgical site infection


Focal Unilateral Palatal Myoclonus Causing Objective Clicking Tinnitus without Uvula Elevation Diagnosed by Concurrent Auscultation.

Abstract: Palatal myoclonus generally entails a visible elevation of the palate and uvula and may be accompanied by myoclonus of other oropharyngeal muscles. A 55-year-old man presented with left ear clicking and hyperacusis. Examination showed arrhythmic left lateral soft palate contraction in the tensor veli palatini region without elevation of the uvula, which correlated with an audible click by auscultation with a stethoscope over the left ear. This is a rare case of focal, unilateral palatal myoclonus without visual uvula elevation with concurrent auscultation, demonstrating the importance of careful examination to detect focal myoclonic contractions.


The Impact of Vegan Diet in the Prevention and Treatment of Type 2 Diabetes: A Systematic Review.

Abstract: A protective effect of vegan diets on health outcomes has been observed in previous studies, but its impact on diabetes is still debated. The aim of this review is to assess the relationship between vegan diets and the risk for type 2 diabetes (T2D) along with its effect on glycemic control and diabetes-related complications. In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, Pubmed and Cochrane library databases were systematically searched for all relevant studies. Seven observational and eight randomized controlled (RCTs) studies were included. The methodological quality of studies was assessed using the National Institutes of Health quality assessment tool for observational cohort and cross-sectional studies and the Cochrane Risk of Bias Tool for RCTs. We found that a vegan diet is associated with lower T2D prevalence or incidence and in T2D patients decreases high glucose values and improves glucose homeostasis, as reported from the majority of included studies. This approach seems to be comparable to other recommended healthful eating models, but as it may have potential adverse effects associated with the long-term exclusion of some nutrients, appropriate nutritional planning and surveillance are recommended, particularly in specific groups of diabetic patients such as frail elderly, adolescents, and pregnant or breastfeeding women.

D016032:Randomized Controlled Trials as Topic

vegan diet
type 2 diabetes
insulin resistance
plant-based diet


Decreased angiogenic and increased apoptotic activities of bone microvascular endothelial cells in patients with glucocorticoid-induced osteonecrosis of the femoral head.

Abstract:
BACKGROUND
Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is closely associated with the dysfunction of the bone microvascular endothelial cells (BMECs). The present study investigated the angiogenic and apoptotic activity of the BMECs in glucocorticoid-induced ONFH.

METHODS
This study enrolled a total of 12 patients, six of whom were assigned to the ONFH group whereas the other six served as the control group. The ONFH group was composed of patients with glucocorticoid-induced ONFH while the control group had femoral neck fractures. BMECs were isolated from the subchondral region of the femoral head. Cell proliferation, cell viability, tube formation assay, Transwell assay, TUNEL assay, and Western blot analysis were performed.

RESULTS
BMECs of the two groups were successfully isolated and identified. No significant differences were noticed in BMECs proliferation between the two groups. However, compared to the control, cell viability, tube formation, and migration of BMECs were significantly decreased and the number of TUNEL positive cells was markedly increased in the ONFH group. In the ONFH group, it was also noted that the amount of Bax and cleaved-caspase3 was elevated while that of Bcl-2 was reduced.

CONCLUSION
The findings of our study revealed that BMECs obtained from the glucocorticoid-induced ONFH patients had decreased angiogenic and increased apoptotic activities, which could explain the pathogenesis and progression of glucocorticoid-induced ONFH.

Yu|Huachen|H| Liu|Pei|P| Zuo|Wei|W| Sun|Xiaowei|X| Liu|Hongzhi|H| Lu|Feifan|F| Guo|Wanshou|W| Zhang|Qidong|Q|

Bone microvascular endothelial cells
Osteonecrosis of the femoral head
Angiogenesis
Apoptosis
Glucocorticoids


Halofuginone promotes satellite cell activation and survival in muscular dystrophies.

Abstract: Halofuginone is a leading agent in preventing fibrosis and inflammation in various muscular dystrophies. We hypothesized that in addition to these actions, halofuginone directly promotes the cell-cycle events of satellite cells in the mdx and dysf(-/-) mouse models of early-onset Duchenne muscular dystrophy and late-onset dysferlinopathy, respectively. In both models, addition of halofuginone to freshly prepared single gastrocnemius myofibers derived from 6-week-old mice increased BrdU incorporation at as early as 18h of incubation, as well as phospho-histone H3 (PHH3) and MyoD protein expression in the attached satellite cells, while having no apparent effect on myofibers derived from wild-type mice. BrdU incorporation was abolished by an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated protein kinase, suggesting involvement of this pathway in mediating halofuginone's effects on cell-cycle events. In cultures of myofibers and myoblasts isolated from dysf(-/-) mice, halofuginone reduced Bax and induced Bcl2 expression levels and induced Akt phosphorylation in a time-dependent manner. Addition of an inhibitor of the phosphinositide-3-kinase/Akt pathway reversed the halofuginone-induced cell survival, suggesting this pathway's involvement in mediating halofuginone's effects on survival. Thus, in addition to its known role in inhibiting fibrosis and inflammation, halofuginone plays a direct role in satellite cell activity and survival in muscular dystrophies, regardless of the mutation. These actions are of the utmost importance for improving muscle pathology and function in muscular dystrophies.

Barzilai-Tutsch|Hila|H| Bodanovsky|Anna|A| Maimon|Hadar|H| Pines|Mark|M| Halevy|Orna|O|

D032496:Satellite Cells, Skeletal Muscle

Halofuginone
Satellite cell
Muscular dystrophy
Myofiber
Apoptosis
Cell cycle


Peste des Petits Ruminants Virus Surveillance in Domestic Small Ruminants, Mozambique (2015 and 2017).

Abstract: Peste des Petits Ruminants (PPR), a transboundary animal disease affecting mainly goats and sheep is caused by a morbillivirus and threatens food security and livelihoods as morbidity and mortality rates can reach 90%. There are no records of PPR in Mozambique, but the disease situation in Tanzania and the ability of PPR virus to rapidly spread across countries constitute a high risk for about 4.7 million goats and sheep in Mozambique. A total of 4,995 goats and sheep were sampled in several provinces during 2015 and 2017 to assess the status of PPR virus (PPRV) in Mozambique and to contribute to surveillance along the border with Tanzania. The sera were screened for anti-PPRV antibodies using a commercial PPR competition ELISA (c-ELISA) and the haemagglutinin based PPR blocking ELISA (HPPR-bELISA). The swabs were tested using one-step RT-PCR for detection of PPRV RNA. The overall percentage of animals with anti-PPRV antibodies by c-ELISA, was 0.46% [0.30-0.70]. However, all the sera positive on c-ELISA were confirmed to be negative by the HPPR-bELISA. Considering that all the swabs were negative for detection of PPRV, no clinical cases were observed during passive surveillance and active sampling, and no symptoms were reported, these results suggest that PPRV is not present in Mozambique.

Mapaco|Lourenço|L|
Monjane|Iolanda|I|
Fafetine|José|J|
Arone|Dercília|D|
Caron|Alexandre|A|
Chilundo|Abel|A|
Quembo|Carlos|C|
Carrilho|Maria Do Carmo|MDC|
Nhabomba|Virginia|V|
Zohari|Siamak|S|
Achá|Sara|S|

surveillance
small ruminants
Mozambique
PPR virus
antibody
RT-PCR


A study on liposomal encapsulation of a lipophilic prodrug of LHRH.

Abstract: This study aimed at evaluating whether derivatization of luteinizing hormone-releasing hormone (LHRH) peptide with an amphiphilic lipoamino acid moiety could allow, along with other technological and/or pharmacokinetic advantages, to improve its encapsulation in liposomes, potentially driving its further body distribution and cellular uptake. Experimental data confirmed that a lipophilic derivative of LHRH was efficiently incorporated in various liposomal systems, differing in lipid composition and surface charge, and obtained using different methods of production. Incubation of liposomes, loaded with a fluorescent derivative of the LHRH prodrug, with NCTC keratinocytes or Caco-2 cell cultures showed that the carriers can be rapidly internalized. Conversely, the internalization of the free prodrug occurred only at very high concentrations.

Pignatello|Rosario|R|
Musumeci|Teresa|T|
Graziano|Adriana C E|AC|
Lo Furno|Debora|D|
Varamini|Pegah|P|
Mansfeld|Friederike M|FM|
Cardile|Venera|V|
Toth|Istvan|I|

Amphiphilicity
lipoamino acids
LUVET liposomes
MLV liposomes
REV liposomes
cell uptake
fluorescence microscopy


Macro and small over micro: macromolecules and small molecules that regulate microRNAs.

Abstract: Given the correlation between the deregulation of specific miRNAs and disease onset, it is critical to identify miRNA regulators that effectively control miRNAs involved in the pathogenesis of target diseases. This review provides the latest update on oligonucleotide- and small-molecule-based miRNA regulators, and discusses assays developed to screen for small-molecule regulators.

Kang|Soowon|S| Im|Kyungtaek|K| Baek|Jihae|J| Yoon|Sungroh|S| Min|Hyeyoung|H|

D040761:Biomimetic Materials
D006801:Humans
D046911:Macromolecular Substances
D035683:MicroRNAs
D016376:Oligonucleotides, Antisense
D015203:Reproducibility of Results
D054852:Small Molecule Libraries
D013379:Substrate Specificity

small molecules
regulators
microRNAs
RNA
high-throughput screening


Tuning G-Quadruplex Nanostructures with Lipids. Towards Designing Hybrid Scaffolds for Oligonucleotide Delivery.

Abstract: Two G-quadruplex forming oligonucleotides [d(TG4T)4 and d(TG6T)4] were selected as two tetramolecular quadruplex nanostructures because of their demonstrated ability to be modified with hydrophobic molecules. This allowed us to synthesize two series of G-quadruplex conjugates that differed in the number of G-tetrads, as well as in the terminal position of the lipid modification. Both solution and solid-phase syntheses were carried out to yield the corresponding lipid oligonucleotide conjugates modified at their 3'- and 5'-termini, respectively. Biophysical studies confirmed that the presence of saturated alkyl chains with different lengths did not affect the G-quadruplex integrity, but increased the stability. Next, the G-quadruplex domain was added to an 18-mer antisense oligonucleotide. Gene silencing studies confirmed the ability of such G-rich oligonucleotides to facilitate the inhibition of target Renilla luciferase without showing signs of toxicity in tumor cell lines.

G-quadruplex
lipids
solid-phase
antisense oligonucleotides
luciferase
circular dichroism
gene delivery
gene transfection
nucleic acid conjugates
solution-phase


The degree of postural automaticity influences the prime movement and the anticipatory postural adjustments during standing in healthy young individuals.

Abstract: Less attention to a balance task reduces the center of foot pressure (COP) variability by automating the task. However, it is not fully understood how the degree of postural automaticity influences the voluntary movement and anticipatory postural adjustments. Eleven healthy young adults performed a bipedal, eyes closed standing task under the three conditions: Control (C, standing task), Single (S, standing + reaction tasks), and Dual (D, standing  +  reaction + mental tasks). The reaction task was flexing the right shoulder to an auditory stimulus, which causes counter-clockwise rotational torque, and the mental task was arithmetic task. The COP variance before the reaction task was reduced in the D condition compared to that in the C and S conditions. On average the onsets of the arm movement and the vertical torque (Tz, anticipatory clockwise rotational torque) were both delayed, and the maximal Tz slope (the rate at which the torque develops) became less steep in the D condition compared to those in the S condition. When these data in the D condition were expressed as a percentage of those in the S condition, the arm movement onset and the Tz slope were positively and negatively, respectively, correlated with the COP variance. By using the mental-task induced COP variance reduction as the indicator of postural automaticity, our data suggest that the balance task for those with more COP variance reduction is less cognitively demanding, leading to the shorter reaction time probably due to the attention shift from the automated balance task to the reaction task.

Anticipatory postural adjustments
Attention
Balance
Dual task


Regular insulin, rather than rapid-acting insulin, is a suitable choice for premeal bolus insulin in lean patients with type 2 diabetes mellitus.

Abstract: The aim of the present study was to compare the usefulness of premeal rapid-acting and regular insulin in type 2 diabetes patients. A total of 56 type 2 diabetic patients were investigated during hospitalization. Premeal rapid-acting insulin was applied instead of other medications. Premeal insulin was titrated to adjust premeal and bedtime blood glucose levels to 81-120 mg/dL. Premeal rapid-acting insulin was changed to regular insulin just before a meal at the same dosage if the postmeal blood glucose level was lower than the premeal blood glucose level. A total of 15 patients changed to regular insulin, and 41 patients continued rapid-acting insulin. The blood glucose level was comparable between these two groups. Body mass index was significantly lower in the patients using regular insulin. According to the multivariate logistic regression analysis, low body mass index was an independent variable accounting for the usefulness of regular insulin. Regular insulin, rather than rapid-acting insulin, is a suitable choice for premeal insulin in lean type 2 diabetic patients.

Kuroda|Akio|A| Kaneto|Hideaki|H| Kawashima|Satoshi|S| Sakamoto|Kenya|K| Takahara|Mitsuyoshi|M| Shiraiwa|Toshihiko|T| Yasuda|Tetsuyuki|T| Katakami|Naoto|N| Matsuoka|Taka-Aki|TA| Shimomura|Iichiro|I| Matsuhisa|Munehide|M|

Hypoglycemia
Insulin action
Insulin therapy


Skull-Stripping of Glioblastoma MRI Scans Using 3D Deep Learning.

Abstract: Skull-stripping is an essential pre-processing step in computational neuro-imaging directly impacting subsequent analyses. Existing skull-stripping methods have primarily targeted non-pathologicallyaffected brains. Accordingly, they may perform suboptimally when applied on brain Magnetic Resonance Imaging (MRI) scans that have clearly discernible pathologies, such as brain tumors. Furthermore, existing methods focus on using only T1-weighted MRI scans, even though multi-parametric MRI (mpMRI) scans are routinely acquired for patients with suspected brain tumors. Here we present a performance evaluation of publicly available implementations of established 3D Deep Learning architectures for semantic segmentation (namely DeepMedic, 3D U-Net, FCN), with a particular focus on identifying a skull-stripping approach that performs well on brain tumor scans, and also has a low computational footprint. We have identified a retrospective dataset of 1,796 mpMRI brain tumor scans, with corresponding manually-inspected and verified gold-standard brain tissue segmentations, acquired during standard clinical practice under varying acquisition protocols at the Hospital of the University of Pennsylvania. Our quantitative evaluation identified DeepMedic as the best performing method (Dice = 97.9, Hausdorf f 95 = 2.68). We release this pre-trained model through the Cancer Imaging Phenomics Toolkit (CaPTk) platform.

Thakur|Siddhesh P|SP|
Doshi|Jimit|J|
Pati|Sarthak|S|0000-0003-2243-8487
Ha|Sung Min|SM|
Sako|Chiharu|C|
Talbar|Sanjay|S|
Kulkarni|Uday|U|
Davatzikos|Christos|C|
Erus|Guray|G|
Bakas|Spyridon|S|0000-0001-8734-6482

Skull-stripping
Glioblastoma
Deep learning
Brain tumor
DeepMedic
U-Net
FCN
CaPTk
Brain extraction
GBM


How plants manage food reserves at night: quantitative models and open questions.

Abstract: In order to cope with night-time darkness, plants during the day allocate part of their photosynthate for storage, often as starch. This stored reserve is then degraded at night to sustain metabolism and growth. However, night-time starch degradation must be tightly controlled, as over-rapid turnover results in premature depletion of starch before dawn, leading to starvation. Recent experiments in Arabidopsis have shown that starch degradation proceeds at a constant rate during the night and is set such that starch reserves are exhausted almost precisely at dawn. Intriguingly, this pattern is robust with the degradation rate being adjusted to compensate for unexpected changes in the time of darkness onset. While a fundamental role for the circadian clock is well-established, the underlying mechanisms controlling starch degradation remain poorly characterized. Here, we discuss recent quantitative models that have been proposed to explain how plants can compute the appropriate starch degradation rate, a process that requires an effective arithmetic division calculation. We review experimental confirmation of the models, and describe aspects that require further investigation. Overall, the process of night-time starch degradation necessitates a fundamental metabolic role for the circadian clock and, more generally, highlights how cells process information in order to optimally manage their resources.

starch degradation
circadian clock
Arabidopsis thaliana
mathematical modeling
post-translational analog arithmetic


Preoperative pelvic floor physiotherapy improves continence after radical retropubic prostatectomy.

Abstract:
OBJECTIVES
Urinary incontinence is a predictable sequela of radical retropubic prostatectomy, and is most severe in the early postoperative phase. The present study aimed to evaluate the effect of a physiotherapist-guided pelvic floor muscle training program, commenced preoperatively, on the severity and duration of urinary continence after radical retropubic prostatectomy.

METHODS
A retrospective analysis of men undergoing radical retropubic prostatectomy by one high-volume surgeon (n = 284) was carried out. The intervention group received physiotherapist-guided pelvic floor muscle training from 4 weeks preoperatively (n = 152), whereas the control group was provided with verbal instruction on pelvic floor muscle exercise by the surgeon alone (n = 132). Postoperatively, all patients received physiotherapist-guided pelvic floor muscle training. The primary outcome measure was 24-h pad weight at 6 weeks and 3 months postoperatively. Secondary outcome measures were the percentage of patients experiencing severe urinary incontinence, and patient-reported time to one and zero pad usage daily.

RESULTS
At 6 weeks postoperatively, the 24-h pad weight was significantly lower (9 g vs 17 g, P < 0.001) for the intervention group, which also showed less severe urinary incontinence (24-h pad weight >50 g; 8/152 patients vs 33/132 patients, P < 0.01). There was no significant difference between groups in the 24-h pad weight at 3 months (P = 0.18). Patient-reported time to one and zero pad usage was significantly less for the intervention group (P < 0.05). Multivariate Cox regression showed that preoperative physiotherapist-guided pelvic floor muscle training reduced time to continence (1 pad usage daily) by 28% (P < 0.05).

CONCLUSIONS
A physiotherapist-guided pelvic floor muscle training program, commenced 4 weeks preoperatively, significantly reduces the duration and severity of early urinary incontinence after radical retropubic prostatectomy.

Patel|Manish I|MI|
Yao|Jinna|J|
Hirschhorn|Andrew D|AD|
Mungovan|Sean F|SF|

preoperative
pelvic floor
physiotherapy
incontinence
radical prostatectomy


Large-Area, Highly Sensitive SERS Substrates with Silver Nanowire Thin Films Coated by Microliter-Scale Solution Process.

Abstract: A microliter-scale solution process was used to fabricate large-area, uniform films of silver nanowires (AgNWs). These thin films with cross-AgNWs were deposited onto Au substrates by dragging the meniscus of a microliter drop of a coating solution trapped between two plates. The hot spot density was tuned by controlling simple experimental parameters, which changed the optical properties of the resulting films. The cross-AgNW films on the Au surface served as excellent substrates for surface-enhanced Raman spectroscopy, with substantial electromagnetic field enhancement and good reproducibility.

Silver nanowires
Thin film coating
Microliter-scale solution process
Surface-enhanced Raman spectroscopy


Hepatotoxicity in rats treated with dimethylformamide or toluene or both.

Abstract: The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione- S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of Nmethylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage.

Dimethylformamide
Toluene
Enzyme
Lipid peroxides
Cytochrome P-4502E1


Labour market affiliation among non-bullied colleagues at work units with reported bullying.

Abstract:
AIM
This study investigates if non-bullied employees in Work units (WUs) where bullying occur, are more prone to leave the WUs than employees in WUs with no bullying, and if the prevalence of workplace bullying had an impact on leaving the WUs. Leaving the workplace was defined by unemployment or change of workplace at follow-up.

METHODS
We had data from 8326 Danish public health invited employees from 302 WUs. Of these 3036 responded to a questionnaire on working conditions and health in 2007. WUs were classified into three categories of WUs: (1) no bullying (0% bullied), (2) moderate prevalence of bullying (< 10% bullied), and (3) high prevalence of bullying (≥ 10% bullied). Bullied respondents were used to classify the WUs and excluded in the analyses.

RESULTS
We found odds ratios (ORs) for unemployment 1 year later of 1.27 [95% CI 0.69-2.37] in WUs with moderate prevalence of bullying and 1.38 [95% CI 0.85-2.23] among employed in WUs with high prevalence of bullying, adjusted for size of WUs, age, sex, and job category. For turnover 1 year later the ORs were 1.27 [95% CI 0.78-2.15] and 1.46 [95% CI 0.99-2.15] in WUs with moderate and high prevalence of bullying, respectively.

CONCLUSION
We did not find that non-bullied employees leave the WUs with moderate and high prevalence of bullying more than employees in WUs with no bullying behaviour 1 year later. Leaving the workplace tended to be higher among employees in WUs with high prevalence of bullying compared to no and moderate bullying.

Non-bullied colleagues
Work units
Bullying
Unemployment
Turnover


Myrciaria dubia "camu camu" flour as a magnetoprotector in male mouse infertility.

Abstract: Possible adverse effects of extremely low frequency magnetic fields (ELF-MF) are linked to a decrease of antioxidant defenses and the production of free radicals. The increase of free radicals affects the mitochondrial functionality inducing apoptosis, which affects the phosphorylation and generation of key ATP in fertilization. Myrciaria dubia, known as "camu camu," is a fruit with high levels of ascorbic acid, which exerts an important antioxidant function in the prevention of premature cell damage. In this study, the effect of Myrciaria dubia flour on oxidative damage produced by ELF-MF (610 μT) was evaluated by detecting the activity of endogenous mitochondrial oxidoreductase enzymes in a complete sperm cycle of mice. We found that the MF caused a significant (P < 0.05) decrease in sperm quality, whereas the groups supplied with Myrciaria dubia flour (50 and 75 mg/kg of body mass) in ELF-MF exposure showed a significant recovery (P < 0.05) in parameters of viability, percentage of plasma membrane integrity and mitochondrial activity, and index of epidymal sperm. This suggests that Myrciaria dubia flour would have an antioxidant activity that counteracts the damaging effects of ELF-MF in spermatogenesis and could be used as a natural ELF-MF protector. Bioelectromagnetics. 40:91-103, 2019. © 2019 Bioelectromagnetics Society.

Myrciaria dubia
infertility
ELF-MF
mice
mitochondrial activity
spermatozoa


Inference on covariate effect types for treatment effectiveness in a randomized trial with a binary outcome.

Abstract:
BACKGROUND/AIMS
Some randomized clinical trials seek to establish covariate effect types that indicate whether a covariate is predictive and/or prognostic, in addition to endpoint evaluation. Here, for a case with a binary outcome, we propose that the covariate effect type should be assessed in terms of four types of potential responses: activated- (always-), inert- (never-), causative-, and preventive-responder.

METHODS
We introduce a new concept of covariate effect types differing from the commonly used "prediction" and "prognosis." We summarize the covariate effect types by inspecting the proportions of subjects in each response type in two subgroups of a covariate, and indicate whether the fractions are augmented, depleted, or neutral as one changes the level of the covariate. Although these proportions cannot generally be identified, we can derive the posterior distributions of the proportions by applying a recently developed Bayesian method. On the basis of the distributions, we would say that the covariate is "augmented-causative" if the difference between the proportions of causative-responders (who would respond if they received the treatment but would not if they did not) in two subgroups is positive, rather than that it is predictive. Similarly, we would say that the covariate is "neutral-activated" if the difference in the proportion of activated-responders (who would respond regardless of their randomized treatment assignment) is close to zero, rather than saying that the covariate is not prognostic. We further describe the relationship between our approach and standard subgroup analysis.

RESULTS
We applied our approach to data from a randomized clinical trial comparing nivolumab and docetaxel for subjects with advanced nonsquamous non-small-cell lung cancer; we assessed the covariate effect type of PD-L1 status, where PD-L1 is a ligand of the programmed death 1 (PD-1) receptor expressed by activated T cells. When the endpoint was the overall response rate, the posterior distributions for the differences between the proportions of subjects in response types in the PD-L1-positive and negative subgroups yielded an expected-a-posteriori estimate of 0.243 (95% credible interval (CI): 0.094, 0.374) for causative-responders and 0.014 (95% CI: -0.087, 0.125) for activated-responders. Thus, PD-L1 status was augmented-causative for nivolumab effectiveness, to an extent of 24.3%, and was neutral-activated.

CONCLUSION
Our approach characterizes the covariate effect types in terms of the response types, and to what extent. In a randomized clinical trial with a binary outcome, our approach is a potentially valuable addition to standard subgroup or regression analysis.

response type
Bayesian inference
causal inference
contingency table
potential outcome


Epidemiology of multiple myeloma in 17 Latin American countries: an update.

Abstract: The objective of this study was to describe incidence, mortality rates, and trends for multiple myeloma (MM) in Latin America (LA), contributing to better knowledge on the epidemiology of MM in this continent. Incidence data were extracted from the International Agency for Research on Cancer (IARC), for the period 1990-2007. Mortality data were obtained for 17 countries from the World Health Organization, for the period 1995-2013. Annual average percentage change (AAPC) and 95% confidence interval (95% CI) were calculated for incidence and mortality. The average incidence rate of MM was higher in Cali (Colombia). For the age-group over 60 years old, rates were 14.2 and 12.8 per 100,000 inhabitants for men and women, respectively. Increasing incidence trends were verified for Cali (Colombia). Mortality rates were higher among men; most countries presented increasing trends, and the highest increments were observed in Guatemala (12.5% [95% CI: 10.6; 14.5] in men; 8.8% [95% CI: 7.8; 9.8] in women), Ecuador (5.5% [95% CI: 5.0; 6.0] in men; 3.7 [95% CI: 3.1; 4.3] in women), Paraguay (2.9% [95% CI: 2.3; 3.5] in men; 3.2% [95% CI: 2.1; 4.3] in women), and Brazil (1.4% [95% CI: 1.3; 1.5] in men; 0.9% [95% CI: 0.8; 1.0] in women). Multiple myeloma presented heterogeneous incidence patterns in Cali (Colombia), Quito (Ecuador), and Costa Rica. Increasing mortality trends were verified for most Latin American countries and could be related to limited access to diagnosis and new therapies.

multiple myeloma
incidence
mortality
trend


Measurement error correction and sensitivity analysis in longitudinal dietary intervention studies using an external validation study.

Abstract: In lifestyle intervention trials, where the goal is to change a participant's weight or modify their eating behavior, self-reported diet is a longitudinal outcome variable that is subject to measurement error. We propose a statistical framework for correcting for measurement error in longitudinal self-reported dietary data by combining intervention data with auxiliary data from an external biomarker validation study where both self-reported and recovery biomarkers of dietary intake are available. In this setting, dietary intake measured without error in the intervention trial is missing data and multiple imputation is used to fill in the missing measurements. Since most validation studies are cross-sectional, they do not contain information on whether the nature of the measurement error changes over time or differs between treatment and control groups. We use sensitivity analyses to address the influence of these unverifiable assumptions involving the measurement error process and how they affect inferences regarding the effect of treatment. We apply our methods to self-reported sodium intake from the PREMIER study, a multi-component lifestyle intervention trial.

Siddique|Juned|J|0000-0002-1501-4152
Daniels|Michael J|MJ|
Carroll|Raymond J|RJ|
Raghunathan|Trivellore E|TE|
Stuart|Elizabeth A|EA|
Freedman|Laurence S|LS|

D000076206:Patient Generated Health Data

recovery biomarker
Multiple imputation
sodium intake
24-hour dietary recall


Phytochemical analysis and antimicrobial activity of some medicinal plants against selected pathogenic microorganisms.

Abstract: The aim of the present study is to investigate the antimicrobial potency of leaves from various extracts of Capparis zeylanica, Streblus asper and Tribulus terrestris were evaluated. In addition, this is the first report on MIC, MBC/MFC antimicrobial activities of above mentioned plants and also identify the phytochemical, functional groups by GC-MS and FT-IR respectively. Soxhlet extraction method was used for preparation of different extracts viz., aqueous, petroleum ether, ethyl acetate and methanol. The extracts were examined against Staphylococcus epidermidis, Enterococcus faecallis, Salmonella paratyphi, Shigella dysenteriae, Candida albicans and Mycobacterium tuberculosis by agar well diffusion method, and Minimum Inhibitory Concentratioon (MIC), Minimum Bactericidal/Fungicidal Concentration (MBC/MFC) values were determined through micro dilution method. Phytochemical analysis of compounds was carried out by GC-MS analysis and functional groups were identified by FT-IR. Based on the outcome of our results, Ethyl acetate extract Showed significant antimicrobial activity against the tested pathogens especially, for C. albicans (40 mm) followed by ethyl acetate of S. asper against S. paratyphi (38 mm). While, the least inhibition was observed with aqueous extract of T. terrestris against S. paratyphi (10 mm). The MIC ranged from 3.21 mg/ml to 50 mg/ml and MBC/MFC 6.25 mg/ml to 50 mg/ml was recorded. Ethyl acetate extracts of almost all samples showed better activity than other extracts in inhibition growth of pathogens. Phytochemical analysis exhibited the presence of Steroids, tannins and cardiac glycosides were found only in ethyl acetate extract of C. zeylanica. Functional group of leaf extract was confirmed by FT-IR spectrum and GC-MS analysis of the ethyl acetate extract revealed the presence of 20 compounds. The results revealed that ethyl acetate extract of C. zeylanica leaves has potential activity than the other extracts as well as standard drugs (Gentamycin and Ketocozole). Hence, this plant may be recommended for further studies in isolation of active compounds and related pharmacological activities.

D017550:Spectroscopy, Fourier Transform Infrared

Phytochemicals
Antimicrobial activity
Capparis zeylanica
MIC
MBC/MFC
GC-MS
FTIR


High Short-Term Blood Pressure Variability Predicts Long-Term Cardiovascular Mortality in Untreated Hypertensives But Not in Normotensives.

Abstract:
BACKGROUND
The prognostic value of the short-term blood pressure variability (BPV) from the 24-hour ambulatory blood pressure monitoring (ABPM) remains controversial. The present study aimed to investigate the long-term prognostic value of a high BPV in normotensive and hypertensive subjects from a community-based population.

METHODS
A cohort of 624 normotensive and 633 untreated hypertensive Taiwanese participants (overall 669 men, aged 30-79 years) with baseline ABPM and 20-year all-cause and cardiovascular mortality data was drawn from a community-based survey. BPV was assessed by the read-to-read average real variability of the 24-hour diastolic and systolic blood pressure (SBP) (ARVd and ARVs, respectively).

RESULTS
In Cox proportional hazards analysis, ARVd predicted cardiovascular mortality independently of office SBP (hazard ratios (HRs) and 95% confidence intervals (CIs) per 1 SD: 1.31 (1.10-1.55), respectively, bivariate analysis), 24-hour SBP (HR: 1.19, 95% CI: 1.00-1.43), and conventional risk factors (age, sex, smoking, total cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose, HR: 1.40, 95% CI: 1.18-1.67). In subjects with hypertension, a high vs. low ARVd (median: 8.8mm Hg) significantly predicted cardiovascular mortality (HR: 2.11, 95% CI: 1.23-3.62 and HR: 2.04, 95% CI: 1.19-3.51, respectively), when the conventional risk factors plus office SBP or 24-hour SBP were accounted for, respectively. Similar but less significant results were obtained with ARVs. A high ARVd or ARVs did not significantly predict cardiovascular mortality in the normotensive subjects.

CONCLUSIONS
A high short-term BPV is significantly predictive of long-term cardiovascular mortality in untreated hypertensive but not normotensive community-based subjects, independently of office or 24-hour SBP.

Hsu|Pai-Feng|PF|
Cheng|Hao-Min|HM|
Wu|Cheng-Hsueh|CH|
Sung|Shih-Hsien|SH|
Chuang|Shao-Yuan|SY|
Lakatta|Edward G|EG|
Yin|Frank C P|FC|
Chou|Pesus|P|
Chen|Chen-Huan|CH|

blood pressure variability
cardiovascular mortality
ambulatory blood pressure
hypertension.


Transport, Associated Handling Procedures and Behaviour of Calves Marketed through Chilean Auction Markets.

Abstract: In Chile, selling animals through livestock markets is common. At markets, stressful events like loading, unloading and travel are at least duplicated. We described procedures associated with transport of calves at 20 markets and evaluated compliance with Chilean law by performing a survey of drivers who transport calves from origin farms to markets (OM) and from markets to destination (MD). During loading and unloading, we evaluated handling by stockpersons, facilities, fitness for transport, and behavioural indicators of the calves through direct observation using protocols. A total of 80% of drivers claimed having the training required by law. The mean travel time was 1 h 31 min for OM and 1 h 44 min for MD journeys (overall range 5 min-40.5 h). Most drivers used bedding material and provided adequate space availability. A total of 99.2% of the observed calves were assessed as fit to transport; slipping, turning back, vocalizing and balking were frequent behaviours observed during loading and unloading. Prohibited practices like prodding and hitting using driving devices were still observed, mainly during loading. Compliance with the law during transport of calves was adhered to; however, the associated handling within markets was still inadequate, evidencing need for training in order to improve animal welfare.

Bravo|Viviana M|VM|
Knowles|Toby G|TG|0000-0002-3845-0942
Gallo|Carmen|C|

transport handling behaviour calves marketing welfare


Barriers and facilitators in the implementation of bio-psychosocial care at the primary healthcare level in South Kivu, Democratic Republic of Congo.

Abstract:
BACKGROUND
In the Democratic Republic of Congo (DRC), healthcare services are still focused on disease control and mortality reduction in specific groups. The need to broaden the scope from biomedical criteria to bio-psychosocial (BPS) dimensions has been increasingly recognized.

AIM
The objective of this study was to identify the barriers and facilitators to providing healthcare at the health centre (HC) level to enable BPS care.

SETTINGS
This qualitative study was conducted in six HCs (two urban and four rural) in South-Kivu (eastern DRC) which were selected based on their accessibility and their level of primary healthcare organization.

METHODS
Seven focus group discussions (FGDs) involving 29 healthcare workers were organized. A data synthesis matrix was created based on the Rainbow Model framework. We identified themes related to plausible barriers and facilitators for BPS approach.

RESULTS
Our study reports barriers common to a majority of HCs: misunderstanding of BPS care by healthcare workers, home visits mainly used for disease control, solidarity initiatives not locally promoted, new resources and financial incentives expected, accountability summed up in specific indicators reporting. Availability of care teams and accessibility to patient information were reported as facilitators to change.

CONCLUSION
This analysis highlighted major barriers that condition providers' mindset and healthcare provision at the primary care level in South-Kivu. Accessibility to the information regarding BPS status of individuals within the community, leadership of HC authorities, dynamics of HC teams and local social support initiatives should be considered in order to develop an effective BPS approach in this region.

Molima|Christian E N|CEN|
Karemere|Hermès|H|
Bisimwa|Ghislain|G|
Makali|Samuel|S|
Mwene-Batu|Pacifique|P|
Malembaka|Espoir B|EB|
Macq|Jean|J|

D015023:Democratic Republic of the Congo

barriers
bio-psychosocial
DRC
change
primary care
qualitative research


Expression of YAP1 and pSTAT3-S727 and their prognostic value in glioma.

Abstract:
AIMS
A growing research demonstrated that YAP1 played important roles in gliomagenesis. We explored the expression of YAP1 and STAT3, the relationship between them and the effect of YAP1, STAT3 on prognosis in glioma.

METHODS
Expression of YAP1, p-YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 in 141 cases of low-grade gliomas (LGG) and 74 cases of high-grade gliomas (HGG) of surgical specimens were measured by immunohistochemistry. Pearson's X2 test was used to determine the correlation between immunohistochemical expressions and clinicopathological parameters. Pearson's or Spearman correlation test was used to determine the association between these proteins expression. Survival analysis was used to investigate the effect of these proteins on prognosis.

RESULTS
High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in HGG compared with LGG (p=0.000). High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in 63.5%, 59.5%, 66.2% and 31.1% cases of HGG, respectively. YAP1 expression was associated to tumour location, Ki-67 and P53, STAT3 expression was related with Ki-67 and P53, and the expression of pSTAT3-S727 was associated with Ki-67. There was a significantly positive correlation between YAP1 and pSTAT3-S727 (p<0.0001; r=0.5663). Survival analysis revealed that patients with YAP1 and pSTAT3-S727 coexpression had worse overall survival (OS) and progression-free survival (PFS) (p<0.0001). Tumour grade, age, Ki-67 and YAP1 expression were independent prognostic factors for OS. In LGG group, both YAP1 and pSTAT3-S727 expressions were negative correlation with IDH1 mutation, YAP1 and pSTAT3-S727 coexpression showed worse OS and PFS of glioma patients.

CONCLUSION
Our research showed that YAP1 and STAT3 were significantly activated in HGG compared with LGG. YAP1 significantly correlated with pSTAT3-S727 in glioma, YAP1 and pSTAT3-S727 coexpression may serve as a reliable prognostic biomarker and therapeutic target for glioma.

D048868:Adaptor Proteins, Signal Transducing

brain neoplasms
carcinoma
genes
neoplasm


Delivery of Polymeric Nanoparticles to Target Vascular Diseases.

Abstract: Current advances in nanotechnology have paved the way for the early detection, prevention and treatment of various diseases such as vascular disorders and cancer. These advances have provided novel approaches or modalities of incorporating or adsorbing therapeutic, biosensor and targeting agents into/on nanoparticles. With significant progress, nanomedicine for vascular therapy has shown significant advantages over traditional medicine because of its ability to selectively target the disease site and reduce adverse side effects. Targeted delivery of nanoparticles to vascular endothelial cells or the vascular wall provides an effective and more efficient way for early detection and/or treatment of vascular diseases such as atherosclerosis, thrombosis and Cerebrovascular Amyloid Angiopathy (CAA). Clinical applications of biocompatible and biodegradable polymers in areas such as vascular graft, implantable drug delivery, stent devices and tissue engineering scaffolds have advanced the candidature of polymers as potential nano-carriers for vascular-targeted delivery of diagnostic agents and drugs. This review focuses on the basic aspects of the vasculature and its associated diseases and relates them to polymeric nanoparticle-based strategies for targeting therapeutic agents to diseased vascular site.

Polymeric nanoparticles
Vascular disease
Nanomedicine
Targeted delivery
Atherosclerosis
Thrombosis


Influence of Climate on Radial Growth of Black Pine on the Mountain Regions of Southwestern Turkey.

Abstract: In this study, we identified the most important climate factors affecting the radial growth of black pine at different elevations of the mountain regions of Southwestern Turkey (Sandıras Mountain, Muğla/Turkey). We used four black pine tree-ring chronologies, which represent upper and lower distribution limits of black pine forest on the South and North slopes of Sandıras Mountain. The relationships between tree-ring width and climate were identified using response function analysis. We performed hierarchical cluster analysis to classify the response functions into meaningful groups. Black pine trees in the mountain regions of Southwestern Turkey responded positively to a warmer temperature and high precipitation at the beginning of the growing season. As high summer temperatures exacerbated drought, radial growth was affected negatively. Hierarchical cluster analysis made clear that elevation differences, rather than aspect, was the main factor responsible for the formation of the clusters. Due to the mountainous terrain of the study area, the changing climatic conditions (air temperature and precipitation) affected the tree-ring widths differently depending on elevation.

radial growth
black pine
Southwestern Turkey
tree-ring
response function
dendroecology


Postinfectious inflammation in cerebrospinal fluid is associated with nonconvulsive seizures in subarachnoid hemorrhage patients.

Abstract:
PURPOSE
It was unclear how nonconvulsive seizures (NCS) occurred after subarachnoid hemorrhage (SAH). The aim of this prospective observational study was to determine the association between cerebrospinal fluid postinfectious inflammation and NCS in patients with SAH.

METHODS
Demographics and parameters were retrieved from pooled data of all SAH patients monitored by continuous electroencephalography (cEEG) in our Stroke-Intensive Care Unit (Stroke-ICU) over six years period. Patients were divided into two groups (NCS group and non-NCS group). According to clinical and cerebrospinal fluid (CSF) parameters, a logistic regression model was used to analyze the association between CSF inflammation and NCS.

RESULTS
The data of 143 SAH patients were analyzed (25 patients with NCS and 118 patients with non-NCS). Median age was 53 years (min - max: 19 years - 90 years). 4.8 % SAH patients were accompanied with NCS. Among these 25 NCS patients, only 2 (8%) had complete control of EEG discharges. After confounders correction, logistic regression analysis showed: SAH patients with older age [P = 0.003, OR = 1.193, 95 %CI (1.062-1.341)], intracranial infections [P = 0.000, OR = 171.939, 95 %CI (18.136-1630.064)] and higher increased modified Fisher Scale (mFS) [P = 0.003, OR = 8.884, 95 %CI (2.125-37.148)] were more likely to develop NCS; furthermore, a high level of CSF interleukin-6 (IL-6) was an independent risk factor for NCS [P = 0.000, OR = 1.015, 95 %CI (1.010-1.020)], with a threshold of 164.9 pg/mL (sensitivity = 0.84, specificity = 0.96). Compared with non-NCS patients, NCS patients were more likely to have poor Glasgow outcome scale (GOS) (1-3) at 3 months after discharge (88 %).

CONCLUSIONS
SAH patients with NCS were associated with poor neurological prognosis. With the increase of age and mFS, these patients were more likely to develop NCS. As an intracranial infective mark, a high level of CSF IL-6 was an independent risk factor for NCS. For brain protection of severe brain injury after SAH, we should focus on the increasingly important role of inflammatory response.

Tian|Fei|F| Liang|Jin|J| Liu|Gang|G| Zhang|Xue|X| Cai|Zengyan|Z| Huo|Hongzhi|H| Chai|Erqing|E|

Inflammation
Cerebrospinal fluid
Nonconvulsive seizures
Subarachnoid hemorrhage
Infection
Severe


On the metabolic interactions of (photo)respiration.

Abstract: Given that photorespiration is inextricably linked to the process of photosynthesis by virtue of sharing the common first enzyme Rubisco, the photorespiratory pathway has been less subject to study in isolation than many other metabolic pathways. That said, despite often being described to be linked to reactions of ammonia assimilation, C1 metabolism and respiratory metabolism, the precise molecular mechanisms governing these linkages in land plants remain partially obscure. The application of broad metabolite profiling on mutants with altered levels of metabolic enzymes has facilitated the identification of common and distinct metabolic responses among them. Here we provide an update of the recent findings from such studies, focusing particularly on the interplay between photorespiration and the metabolic reactions of mitochondrial respiration. In order to do so we evaluated (i) changes in organic acids following environmental perturbation of metabolism, (ii) changes in organic acid levels in a wide range of photorespiratory mutants, (iii) changes in levels of photorespiratory metabolites in transgenic tomato lines deficient in the expression of enzymes of the tricarboxylic acid cycle. In addition, we estimated the rates of photorespiration in a complete set of tricarboxylic acid cycle transgenic tomato lines. Finally, we discuss insight concerning the interaction between photorespiration and other pathways that has been attained following the development of (13)CO2-based flux profiling methods.

Obata|Toshihiro|T|
Florian|Alexandra|A|
Timm|Stefan|S|
Bauwe|Hermann|H|
Fernie|Alisdair R|AR|

photorespiration
respiration
tricarboxylic acid cycle.
GABA shunt
metabolic regulation
mitochondrial metabolism


Fibroepithelioma of Pinkus in continuity with nodular basal cell carcinoma: A rare presentation.

Abstract: Fibroepithelioma of Pinkus and nodular basal cell carcinoma (BCC) are different morphological variants of BCC. It is very rare to see both the variants together in a single lesion. Here we report a case of a 56-year-old female who presented with a nodule on the trunk, which on biopsy showed features of both nodular BCC and fibroepithelioma of Pinkus.

Dongre|Atul M|AM|
Khopkar|Uday S|US|
Kalyanpad|Yogesh N|YN|
Gole|Prachi V|PV|

fibroepithelioma of Pinkus
Basal cell carcinoma
basaloid cells


Strong Fermi Resonance Associated with Proton Motions Revealed by Vibrational Spectra of Asymmetric Proton-Bound Dimers.

Abstract: Infrared spectra for a series of asymmetric proton-bound dimers with protonated trimethylamine (TMA-H+ ) as the proton donor were recorded and analyzed. The frequency of the N-H+ stretching mode is expected to red shift as the proton affinity of proton acceptors increases. The observed band, however, shows a peculiar splitting of approximately 300 cm-1 with the intensity shifting pattern resembling a two-level system. Theoretical investigation reveals that the observed band splitting and its extraordinarily large gap of around 300 cm-1 is a result of strong coupling between the fundamental of the proton stretching mode and overtone states of the two proton bending modes, that is commonly known as Fermi resonance (FR). We also provide a general theoretical model to link the strong FR coupling to the quasi-two-level system. Since the model does not depend on the molecular specification of TMA-H+ , the strong coupling we observed is an intrinsic property associated with proton motions.

Fermi resonance
IR spectroscopy
ab initio calculations
anharmonic coupling
hydrogen bonds


Amblyomma yucumense n. sp. (Acari: Ixodidae), a Parasite of Wild Mammals in Southern Brazil.

Abstract: During 2013-2014, adult ticks were collected on the vegetation and subadult ticks were collected from small mammals [Didelphis aurita Wied-Neuwied, Sooretamys angouya (Fischer), Euryoryzomys russatus (Wagner), Akodon montensis Thomas, Oxymycterus judex Thomas] in an Atlantic rainforest reserve in southern Brazil. Analyses of the external morphology of the adult ticks revealed that they represent a new species, Amblyomma yucumense n. sp. Partial 16S rRNA sequences generated from males, females, and nymphs were identical to each other and closest (95% identity) to corresponding sequences of Amblyomma dubitatum Neumann. A. yucumense is morphologically and genetically closest related to A. dubitatum. Dorsally, male of these species can be separated by major longitudinal pale orange stripes associated with a pseudoscutum indicated by a pale stripe in A. yucumense, in contrast to pale creamy longitudinal stripes and absence of pseudoscutum in A. dubitatum. Ventrally, male coxal I spurs are separated by a space narrower than external spur width in A. yucumense, and wider than external spur width in A. dubitatum. Females of the two species can be separated by coxal I spurs, longer in A. yucumense than in A. dubitatum. In addition, the adult capitulum and ventral idiosoma of A. yucumense are generally dark brown colored, while A. dubitatum is yellowish or light brown colored. The nymph of A. yucumense differs from A. dubitatum by the scutal cervical groove length, slightly shorter in the former species. Currently, A. yucumense is restricted to southern Brazil.

Krawczak|Felipe S|FS|
Martins|Thiago F|TF|
Oliveira|Caroline S|CS|
Binder|Lina C|LC|
Costa|Francisco B|FB|
Nunes|Pablo H|PH|
Gregori|Fábio|F|
Labruna|Marcelo B|MB|

Amblyomma
Brazil
new species
description


Longitudinal Quantitation of Tooth Displacement in Chinese Adolescents with Normal Occlusion.

Abstract: This longitudinal study aims to analyze the different modes of the maxillary and mandibular tooth displacement in subjects, who were aged 12.5-17.5 years (150-210 months), with untreated normal (Class I) occlusion. Longitudinal lateral cephalograms for a set of 10 subjects (7 females and 3 males) at consecutive annual time points were selected and monitored. Data were analyzed on the basis of the superimpositions of serial tracings of lateral cephalograms on stable anterior cranial base, the anatomies of the maxillary and mandibular structures. The horizontal and vertical displacements of the first molar and incisor were assessed by t-test. The local and the secondary tooth displacements with growth contributed to the total horizontal and vertical displacements of the molars and incisors of the subjects. In the total tooth displacement, the horizontal growth of maxilla and mandible had the same contribution as the local tooth displacements. The vertical maxillary growth played a smaller role than the local drift, and mandibular remodeling went in a reverse direction with the local tooth drift. The first molars moved more forward than the incisors in the upper and lower arches. Both the upper and lower first molars showed forward tipping. The analysis of tooth displacement may be utilized in making orthodontic treatment plan, including anchorage or torque control.

superimposition
cephalometrics
growth evaluation
tooth movement


Numerical investigation of the influence of pattern topology on the mechanical behavior of PEGDA hydrogels.

Abstract:
Poly(ethylene glycol) diacrylate (PEGDA) hydrogels can be potentially used as scaffold material for tissue engineered heart valves (TEHVs) due to their good biocompatibility and biomechanical tunability. The photolithographic patterning technique is an effective approach to pattern PEGDA hydrogels to mimic the mechanical behavior of native biological tissues that are intrinsically anisotropic. The material properties of patterned PEGDA hydrogels largely depend on the pattern topology. In this paper, we adopt a newly proposed computational framework for fibrous biomaterials to numerically investigate the influence of pattern topology, including pattern ratio, orientation and waviness, on the mechanical behavior of patterned PEGDA hydrogels. The material parameters for the base hydrogel and the pattern stripes are directly calibrated from published experimental data. Several experimental observations reported in the literature are captured in the simulation, including the nonlinear relationship between pattern ratio and material linear modulus, and the decrease of material anisotropy when pattern ratio increases. We further numerically demonstrate that a three-region (toe-heel-linear) stress-strain relationship typically exhibited by biological tissues can be obtained by tuning the pattern waviness and the relative stiffness between the base hydrogel and pattern stripes. The numerical strategy and simulation results presented here can provide helpful guidance to optimize pattern design of PEGDA hydrogels toward the targeted material mechanical properties, therefore advance the development of TEHVs.

STATEMENT OF SIGNIFICANCE
Poly(ethylene glycol) diacrylate (PEGDA) hydrogels can be used as scaffold material for tissue engineered heart values (TEHVs) providing a promising alternative to generate suitable heart valve replacement method. The patterning of PEGDA hydrogels using photolithographic techniques creates materials that mimic the mechanical behavior of native heart valve tissues. However, targeted material properties are obtained via a trial-and-error process. Depending on experiments alone to explore the influence of pattern topology is expensive and time-consuming. We combine a newly proposed computational framework with published experimental data to numerically investigate the influence of pattern geometry on the mechanical behavior of patterned PEGDA hydrogels. The numerical strategy and simulation results presented here can provide guidance to optimize the design of PEGDA hydrogels with targeted material properties, therefore advance the development of TEHVs.

Pattern topology
PEGDA hydrogel
Embedded fiber approach


Do Patient Point of Entry and Medicaid Status Affect Quality Outcomes Following Total Knee Arthroplasty?

Abstract:
BACKGROUND
The effect of surgeon practice and patient care setting have not been studied in the Medicaid population undergoing total knee arthroplasty (TKA). This study aims to evaluate whether point of entry and Medicaid status affect outcomes following TKA.

METHODS
The electronic medical record at our urban, academic, tertiary care hospital system was retrospectively reviewed for all primary, unilateral TKA during January 2016 and January 2018. Outpatient visits within the 6-month preoperative period categorized TKA recipients as either Hospital Ambulatory Clinic Centers patients with Medicaid insurance or private office patients with non-Medicaid insurers.

RESULTS
There were 174 Medicaid patients and 317 non-Medicaid patients for 491 total patients. Medicaid patients were significantly younger (62.6 ± 1.6 vs 65.4 ± 1.1 years, P < .01), of "other' ethnicity (43.1% vs 25.6%, P < .01), and to be a current smoker (9.3% vs 6.6%, P = .02). There was no difference in gender, body mass index, and American Society of Anesthesiologists score. After controlling for patient factors, the Medicaid effect was insignificant for surgical time (exponentiated β 0.93, 95% confidence interval [CI] 0.86-1.01, P = .076) and facility discharge (odds ratio 1.58, 95% CI 0.71-3.51, P = .262). Medicaid status had a significant effect on length of stay (LOS) (rate ratio 1.21, 95% CI 1.02-1.43, P = .026).

CONCLUSION
Multivariable analysis controlling for patient factors demonstrated that Medicaid coverage had minimal effect on surgical time and facility discharge. Medicaid patients had significantly longer LOS by one-half day. These results indicate that comparable outcomes can be achieved for Medicaid patients following TKA provided that the surgeon and care setting are similar. However, increased care coordination and preoperative education may be necessary to normalize disparities in hospital LOS.

LEVEL OF EVIDENCE
III, retrospective observational analysis.

Feng|James E|JE|
Roof|Mackenzie A|MA|
Adnan|Mohamed|M|
Anoushiravani|Afshin A|AA|
Friedlander|Scott|S|
Lajam|Claudette M|CM|
Vigdorchik|Jonathan|J|
Slover|James D|JD|
Schwarzkopf|Ran|R|

D019645:Arthroplasty, Replacement, Knee
D006801:Humans
D007902:Length of Stay
D008484:Medicaid
D010351:Patient Discharge
D012189:Retrospective Studies
D014481:United States

Medicaid
outcomes
total knee arthroplasty
insurance type
primary payer


Pathophysiological Role of S-Nitrosylation and Transnitrosylation Depending on S-Nitrosoglutathione Levels Regulated by S-Nitrosoglutathione Reductase.

Abstract: Nitric oxide (NO) mediates various physiological and pathological processes, including cell proliferation, differentiation, and inflammation. Protein S-nitrosylation (SNO), a NO-mediated reversible protein modification, leads to changes in the activity and function of target proteins. Recent findings on protein-protein transnitrosylation reactions (transfer of an NO group from one protein to another) have unveiled the mechanism of NO modulation of specific signaling pathways. The intracellular level of S-nitrosoglutathione (GSNO), a major reactive NO species, is controlled by GSNO reductase (GSNOR), a major regulator of NO/SNO signaling. Increasing number of GSNOR-related studies have shown the important role that denitrosylation plays in cellular NO/SNO homeostasis and human pathophysiology. This review introduces recent evidence of GSNO-mediated NO/SNO signaling depending on GSNOR expression or activity. In addition, the applicability of GSNOR as a target for drug therapy will be discussed in this review.

S-nitrosylation
Transnitrosylation
Nitric Oxide
GSNO
GSNOR


Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265.

Abstract: Malaria is one of the most challenging human infectious diseases, and both prevention and control have been hindered by the development of Plasmodium falciparum resistance to existing therapies. Several new compounds with novel mechanisms are in clinical development for the treatment of malaria, including DSM265, an inhibitor of Plasmodium dihydroorotate dehydrogenase. To explore the mechanisms by which resistance might develop to DSM265 in the field, we selected for DSM265-resistant P. falciparum parasites in vitro. Any of five different amino acid changes led to reduced efficacy on the parasite and to decreased DSM265 binding to P. falciparum DHODH. The DSM265-resistant parasites retained full sensitivity to atovaquone. All but one of the observed mutations were in the DSM265 binding site, and the remaining C276F was in the adjacent flavin cofactor site. The C276F mutation was previously identified in a recrudescent parasite during a Phase IIa clinical study. We confirmed that this mutation (and the related C276Y) accounted for the full level of observed DSM265 resistance by regenerating the mutation using CRISPR/Cas9 genome editing. X-ray structure analysis of the C276F mutant enzyme showed that conformational changes of nearby residues were required to accommodate the larger F276 residue, which in turn led to a restriction in the size of the DSM265 binding pocket. These findings underscore the importance of developing DSM265 as part of a combination therapy with other agents for successful use against malaria.

D044925:Oxidoreductases Acting on CH-CH Group Donors

dihydroorotate dehydrogenase
Plasmodium
malaria
drug resistance
gene editing


Evaluating the process of online health information searching: a qualitative approach to exploring consumer perspectives.

Abstract:
BACKGROUND
The Internet is a common resource that patients and consumers use to access health-related information. Multiple practical, cultural, and socioeconomic factors influence why, when, and how people utilize this tool. Improving the delivery of health-related information necessitates a thorough understanding of users' searching-related needs, preferences, and experiences. Although a wide body of quantitative research examining search behavior exists, qualitative approaches have been under-utilized and provide unique perspectives that may prove useful in improving the delivery of health information over the Internet.

OBJECTIVE
We conducted this study to gain a deeper understanding of online health-searching behavior in order to inform future developments of personalizing information searching and content delivery.

METHODS
We completed three focus groups with adult residents of Olmsted County, Minnesota, which explored perceptions of online health information searching. Participants were recruited through flyers and classifieds advertisements posted throughout the community. We audio-recorded and transcribed all focus groups, and analyzed data using standard qualitative methods.

RESULTS
Almost all participants reported using the Internet to gather health information. They described a common experience of searching, filtering, and comparing results in order to obtain information relevant to their intended search target. Information saturation and fatigue were cited as main reasons for terminating searching. This information was often used as a resource to enhance their interactions with health care providers.

CONCLUSIONS
Many participants viewed the Internet as a valuable tool for finding health information in order to support their existing health care resources. Although the Internet is a preferred source of health information, challenges persist in streamlining the search process. Content providers should continue to develop new strategies and technologies aimed at accommodating diverse populations, vocabularies, and health information needs.

Internet
consumer health information
information seeking behavior
qualitative research


Recombinant human insulin-like growth factor binding protein 3 attenuates lipopolysaccharide-induced acute lung injury in mice.

Abstract: Acute lung injury (ALI) severely impairs gas exchange and results in high mortality. Insulin-like growth factor binding protein 3 (IGFBP-3) plays a crucial role in diverse lung diseases;however, the expression and function of IGFBP-3 in ALI remain unclear. In the present study, mice were injected with lipopolysaccharide to establish ALI, and IGF and IGFBP3 expression was measured using ELISA, western blotting, and immunohistochemical staining. Mice with ALI were then treated with recombinant human IGFBP-3 (rhIGFBP-3), and treatment was evaluated using survival analysis, histological staining analysis, and inflammatory cytokine expression in lung tissues and bronchoalveolar lavage fluid (BALF). The expression of NF-κB and VEGF was also measured using western blotting and ELISA in ALI mice. Our results demonstrated the upregulation of IGF expression in lung tissues and BALF of ALI mice, accompanied by downregulation of IGFBP-3. Administration of rhIGFBP-3 prolonged the survival time and attenuated LPS-induced lung injury. The expression of TNF-α, IL-6, IL-1β, and IFN-γ both in lung tissues and BALF decreased after rhIGFBP-3 treatment, whereas IL-10 expression increased. These results suggest that rhIGFBP-3 inhibits the expression of NF-κB and VEGF in lung tissues. Collectively, our study demonstrates a protective role of rhIGFBP-3 in ALI by regulation of lung inflammation.

Kang|Lili|L| Li|Xiaoying|X| Liu|Jianhong|J| Li|Yanfang|Y| Li|Sitao|S| Zhao|Cuifen|C|

Acute lung injury
IGFBP-3
NF-κB
VEGF
inflammation


Analysis of the relationship between geography and body color with the genetic diversity in the Echiura worm Urechis unicinctus based on the mitochondrial COI and D-loop sequences.

Abstract: Urechis unicinctus is the only Echiurini species distributed in Bohai Gulf of China. The wild populations of this species have sharply declined in China due to overfishing. Over 150 samples from Bohai Gulf were collected in the present study, which were classified into five populations according to their geographic areas and body colors. The genetic diversity and population structure of these populations were investigated by mitochondiral COI and D-loop sequences. The haplotype diversity of U. unicinctus based on COI and D-loop sequences were still high. In addition, the evolution rate of D-loop region could faster than the COI gene of U. unicinctus. Meanwhile, over 99% genetic diversity was contributed by different individuals within populations. Moreover, phylogenetic trees did not show clear geographic or color cluster. Our findings indicated that this species in Bohai Gulf of China should be treated as a whole population.

Zhang|Saisai|S| Li|Mo|M| Sun|Yang|Y| Shang|Hongxin|H| Wang|Lu|L| Yang|Tingting|T| Ma|Lin|L| Chen|Ying|Y| Zhang|Bin|B| Liu|Tong|T| Chen|Wenbo|W|

body color
genetic diversity
Echiura worm Urechis unicinctus
geographic population
mitochondrial sequence


PLK1 inhibition down-regulates polycomb group protein BMI1 via modulation of the miR-200c/141 cluster.

Abstract: The polycomb group protein BMI1 is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells. Its overexpression leads to increase in CSC fraction and therapy resistance in tumors. BMI1 functions via polycomb repressive complex 1 (PRC1)-mediated gene silencing and also via PRC1-independent transcriptional activities. At present, very little is known about the therapy reagents that can efficiently inhibit BMI1 expression, and the CSC phenotype. Here, we report that the polo-like kinase 1 (PLK1) regulates BMI1 expression, and that its inhibition can efficiently down-regulate BMI1 expression and PRC1 activity, and induce premature senescence in breast cancer cells. We also show that the exogenous BMI1 overexpression mitigates anti-oncogenic effects of PLK1 inhibition and overcomes senescence induction by PLK1 inhibitors. We further show that PLK1 inhibition down-regulates BMI1 by upregulating the miRNA-200c/141 cluster, which encodes miR-200c and miR-141, both of which are known to post-transcriptionally downregulate BMI1 expression. Thus, our data suggest that PLK1 inhibitors can be successfully used to inhibit growth of tumors in which PcG protein BMI1 is overexpressed or the PRC1 activity is deregulated.

Dimri|Manjari|M|
Cho|Joon-Ho|JH|
Kang|Mingu|M|
Dimri|Goberdhan P|GP|

D020133:Reverse Transcriptase Polymerase Chain Reaction

Polycomb
Breast Cancer
Cancer Biology
Cell Growth
Cellular Regulation
Cellular Senescence
Gene Regulation
microRNA (miRNA)


Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma.

Abstract:
OBJECTIVE
We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE.

MATERIALS AND METHODS
We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size-pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann-Whitney U-tests.

RESULTS
FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p<0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors.

CONCLUSION
FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor.

Isaka|Tetsuya|T| Yokose|Tomoyuki|T| Ito|Hiroyuki|H| Imamura|Naoko|N| Watanabe|Masato|M| Imai|Kentaro|K| Nishii|Teppei|T| Woo|Tetsukan|T| Yamada|Kouzo|K| Nakayama|Haruhiko|H| Masuda|Munetaka|M|

CT tumor size
Pathological tumor size
Frozen section examinations
Adenocarcinoma
Lepidic
Inflation method
Lung cancer


Patient-Derived Human Basal and Cutaneous Squamous Cell Carcinoma Tissues Display Apoptosis and Immunomodulation following Gas Plasma Exposure with a Certified Argon Jet.

Abstract: Reactive oxygen species (ROS) have been subject of increasing interest in the pathophysiology and therapy of cancers in recent years. In skin cancer, ROS are involved in UV-induced tumorigenesis and its targeted treatment via, e.g., photodynamic therapy. Another recent technology for topical ROS generation is cold physical plasma, a partially ionized gas expelling dozens of reactive species onto its treatment target. Gas plasma technology is accredited for its wound-healing abilities in Europe, and current clinical evidence suggests that it may have beneficial effects against actinic keratosis. Since the concept of hormesis dictates that low ROS levels perform signaling functions, while high ROS levels cause damage, we investigated herein the antitumor activity of gas plasma in non-melanoma skin cancer. In vitro, gas plasma exposure diminished the metabolic activity, preferentially in squamous cell carcinoma cell (SCC) lines compared to non-malignant HaCaT cells. In patient-derived basal cell carcinoma (BCC) and SCC samples treated with gas plasma ex vivo, increased apoptosis was found in both cancer types. Moreover, the immunomodulatory actions of gas plasma treatment were found affecting, e.g., the expression of CD86 and the number of regulatory T-cells. The supernatants of these ex vivo cultured tumors were quantitatively screened for cytokines, chemokines, and growth factors, identifying CCL5 and GM-CSF, molecules associated with skin cancer metastasis, to be markedly decreased. These findings suggest gas plasma treatment to be an interesting future technology for non-melanoma skin cancer topical therapy.

reactive oxygen species
ROS
skin cancer
cold physical plasma
cytokines
chemokines


Prognostic impact of an early marginal decline in forced vital capacity in idiopathic pulmonary fibrosis patients treated with pirfenidone.

Abstract:
BACKGROUND
Pirfenidone (PFD), an oral antifibrotic drug, is conditionally recommended for the treatment of idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the prognostic factors in IPF patients treated with PFD and clarify the clinical significance of marginal physiological changes after PFD therapy.

METHODS
We retrospectively reviewed 96 consecutive IPF patients treated with PFD. The physiological evaluation was performed at 3-6 months after PFD therapy, and the findings were classified into three groups based on the presence of a 5% change in %forced vital capacity (%FVC): improved, stable, and worsened. The clinical characteristics and prognostic outcomes were compared among groups, and the prognostic factors were evaluated by Cox proportional hazards analysis.

RESULTS
Of the 96 patients, 25 (26.0%) showed acute exacerbation (AE) and 40 (41.6%) died during the observation period (median, 17 months). Physiological responses could be evaluated in 80 patients and the findings were as follows: improved, 23%; stable, 36%; and worsened, 41%. Time to the first AE and the survival rate were significantly shorter and lower, respectively, in the worsened group than in the improved/stable group (P = 0.002, P < 0.001, respectively). The prognostic analysis revealed that low %FVC at baseline (hazard ratio [HR]: 0.973 [0.950-0.996]), use of supplemental oxygen (HR: 2.180 [1.041-4.622]), and a "worsened" status after PFD therapy (HR: 5.253 [2.541-11.400]) were significantly associated with a poor prognosis.

CONCLUSIONS
An early marginal decline in FVC may be important for survival outcomes in PFD-treated IPF patients.

Kono|Masato|M| Nakamura|Yutaro|Y| Enomoto|Noriyuki|N| Saito|Go|G| Koyanagi|Yu|Y| Miyashita|Koichi|K| Tsutsumi|Akari|A| Kobayashi|Takeshi|T| Yasui|Hideki|H| Hozumi|Hironao|H| Karayama|Masato|M| Suzuki|Yuzo|Y| Furuhashi|Kazuki|K| Miki|Yoshihiro|Y| Hashimoto|Dai|D| Fujisawa|Tomoyuki|T| Inui|Naoki|N| Suda|Takafumi|T| Nakamura|Hidenori|H|

Forced vital capacity
Idiopathic pulmonary fibrosis
Pirfenidone
Prognostic factor


Effectiveness of sulphonylureas in the therapy of diabetes mellitus type 2 patients: an observational cohort study.

Abstract:
BACKGROUND
We compared all-cause mortality, major macrovascular events (MACE) and diabetes-related hospitalizations in T2DM-incident patients newly treated with metformin (MET) versus sulphonylureas (SU) monotherapy and in T2DM-prevalent patients newly treated with MET+SU versus MET+DPP4-inhibitor combination therapy.

METHODS
We analysed anonymized data obtained from a German health fund. Patients were included when they had started MET versus SU therapy or MET+SU versus MET+DPP4 therapy between 01/07/2010 and 31/12/2011. Observation started with the first MET/SU prescription or the first prescription of the second agent of a MET+SU/MET+DPP4 combination therapy. Follow-up time lasted until the end of data availability (a minimum of 12 months), death or therapy discontinuation.

RESULTS
In total, 434,291 T2DM-prevalent and 35,661 T2DM-incident patients were identified. Of the identified T2DM-incident patients, 904/7,874 started SU/MET monotherapy, respectively, with a mean age of 70.1/61.4 years (54.6/50.3 % female; Charlson Comorbidity Index (CCI) 1.4/2.2; 933/7,350 observed SU/MET patient years). 4,157/1,793 SU+MET/DPP4+MET therapy starters had a mean age of 68.1/62.2 years (53.4/50.8 % female; CCI 2.8/2.6; 4,556/1,752 observed SU+MET/ DPP4+MET patient years). In a propensity score matched (PSM) comparison, the HRs (95 % CIs) associated with SU monotherapy compared to MET monotherapy exposure were 1.4 (0.9-2.3) for mortality, 1.4 (0.9-2.2) for MACE, 4.1 (1.5-10.9) for T2DM hospitalizations and 1.6 (1.2-2.3) for composite event risk. In a multivariable Cox regression model, SU monotherapy was associated with higher mortality (aHR 2.0; 1.5-2.6), higher MACE (aHR 1.3; 1.0-1.7) and higher T2DM hospitalizations (aHR 2.8; 1.8-4.4), which corresponded with a higher composite event risk (aHR 1.8; 1.5-2.1). No significant differences in event rates were observed in the PSM comparison between DPP4+MET/SU+MET combination therapy starters and in the multivariable Cox regression analysis.

CONCLUSIONS
Our results show that SU monotherapy may be associated with increased mortality, MACE and T2DM hospitalizations, compared to MET monotherapy. When considering SU therapy, the associated cardiovascular risk should also be taken into account.

Wilke|Thomas|T| Mueller|Sabrina|S| Groth|Antje|A| Berg|Bjoern|B| Hammar|Niklas|N| Tsai|Katherine|K| Fuchs|Andreas|A| Stephens|Stephanie|S| Maywald|Ulf|U|

Mortality risk for type 2 diabetes mellitus patients


Aldehyde dehydrogenase 2*2 knock-in mice show increased reactive oxygen species production in response to cisplatin treatment.

Abstract:
BACKGROUND
The aldehyde dehydrogenase (ALDH) enzyme family metabolizes and detoxifies both exogenous and endogenous aldehydes. Since chemotherapeutic agents, such as cisplatin, generate cytotoxic aldehydes and oxidative stress, and chemoresistant cancer cells express high levels of ALDH enzymes, we hypothesized that different ALDH expression within cells may show different chemosensitivity. ALDH2 has the lowest Km for acetaldehyde among ALDH isozymes and detoxifies acetaldehydes in addition to other reactive aldehydes, such as 4-hydroxy-nonenal, malondialdehyde and acrolein produced from lipid peroxidation by reactive oxygen species (ROS). Thus, cells with an ALDH2 variant may sensitize them to these ROS-inducing chemotherapy drugs.

METHODS
Here, we used wild type C57BL/6 mice and ALDH2*2 knock-in mutant mice and compared the basal level of ROS in different tissues. Then, we treated the mice with cisplatin, isolated cells from organs and fractionated them into lysates containing mitochondrial and cytosolic fractions, treated with cisplatin again in vitro, and compared the level of ROS generated.

RESULTS
We show that overall ROS production increases with cisplatin treatment in cells with ALDH2 mutation. The treatment of cisplatin in the wild type mice did not change the level of ROS compared to PBS treated controls. In contrast, ALDH2*2 knock-in mutant mice showed a significantly increased level of ROS compared to wild type mice in tongue, lung, kidney and brain tissues without any treatment. ALDH2*2 mutant mice showed 20% of the ALDH2 activity in the kidney compared to wild type mice. Treatment of ALDH2*2 mutant mice with cisplatin showed increased ROS levels in the mitochondrial fraction of kidney. In the cytosolic fraction, treatment of mutant mice with cisplatin increased ROS levels in lung and brain compared to PBS treated controls. Furthermore, ALDH2*2 mutant mice treated with cisplatin showed increased cytotoxicity in the kidney cells compared to PBS treated mutant controls.

CONCLUSIONS
These data indicate that deficiency in ALDH2 activity may contribute to increased cisplatin sensitivity and cytotoxicity by producing more ROS by the treatment. Based on these data, the amount of cisplatin used in patients may need to be adjusted based on their ALDH2 variant profile.

Kim|Jeewon|J| Chen|Che-Hong|CH| Yang|Jieying|J| Mochly-Rosen|Daria|D|

Aldehyde dehydrogenase
Cisplatin and Reactive Oxygen Species


High-resolution separation performance of poly(caprolactone)diol for challenging isomers of xylenes, phenols and anilines by capillary gas chromatography.

Abstract: Efficient separation of xylenes, phenols and anilines is a big issue in chemical and petroleum industries. This work presents the first example of employing poly (caprolactone) diol (PCL-Diol) as stationary phase for high-resolution gas chromatographic (GC) separations of these tough isomer mixtures. It showed medium polarity and stronger H-bonding basicity than H-bonding acidity. Impressively, PCL-Diol column exhibited extremely high resolving capability for the isomer mixtures of xylenes, cresols/xylenols, and toluidines/xylidines with good peak shapes. Moreover, it exhibited preferential retention for analytes of a linear alkyl chain, suggesting its shape fitting selectivity for specific analytes. In addition, its separation performance has good repeatability with RSD values on retention times below 0.01% for run to run (n=6), 0.67-0.80% for day to day (n=4) and 3.2-4.4% for column to column (n=4) repeatability, respectively. Furthermore, it was applied for the determination of isomer impurities in real samples, showing good potential for practical use. This work demonstrates the advantageous high-resolution separation performance for challenging isomers and shows its promising future of PCL-Diol-based materials in separation science.

Peng|Jianlin|J| Zhang|Yan|Y| Yang|Xiaohong|X| Qi|Meiling|M|

Poly(caprolactone)diol
Capillary gas chromatography
Stationary phase
Selectivity
Positional isomers


Endocrine therapy for advanced/metastatic breast cancer.

Abstract: First-line endocrine therapy by estrogen antagonism or suppression of estrogen achieves objective responses (ORs) and clinical benefit (CB) in around 30% and 50% of estrogen receptor-positive metastatic breast cancer patients, respectively. Aromatase inhibitors (AIs) are the most effective treatment in previously untreated postmenopausal women. Tamoxifen is an effective alternative. The optimal endocrine therapy on relapse remains uncertain. Tamoxifen and fulvestrant achieve CB in around 50% of patients and ORs of 10%. CB of exemestane after nonsteroidal AIs is 30% to 50% but ORs are rare. Targeted agents (eg, everolimus) plus endocrine therapy are likely to become increasingly important in overcoming endocrine resistance.

D000971:Antineoplastic Combined Chemotherapy Protocols

D020845:Selective Estrogen Receptor Modulators

Endocrine therapy
Advanced
Metastatic
Breast cancer
Endocrine resistance


Developing a conceptual framework for patient safety culture in emergency department: A review of the literature.

Abstract: Patient safety culture is a critical component of modern health care. However, the high-paced, unpredictable nature of the emergency department (ED) environment may impact adversely on it. The aim of this paper is to explore the concept of patient safety culture as it may apply to emergency health care, and to propose a conceptual framework that could form the basis for interventions designed to improve it. This is a systematic review of the literature. A search was undertaken of common electronic bibliographic databases using key words such as safety culture, safety climate, and Emergency Department. Articles were analysed for consistent themes with the aim to construct a conceptual framework. Ten articles met the inclusion criteria that specifically examined safety culture in the ED. Synthesis of the literature resulted in the emergence of three overarching themes of ED practice found to impact on safety culture in the ED. These were the dimensions of patient safety culture, the factors influencing it, and the interventions for improving it. A conceptual framework was constructed that identifies elements that significantly impact the patient safety culture in the ED. This framework may assist managers and researchers to take a comprehensive approach to build an effective safety culture in ED setting.

D003210:Concept Formation
D004636:Emergency Service, Hospital
D015279:Organizational Culture
D061214:Patient Safety
D017751:Safety Management

patient safety culture and patient safety