Proposal for development of a guideline in maintaining quality cancer care during and post-covid-19 in an upper middle-income country with universal health coverage.
During periods of high community transmission of COVID-19, the public hospitals in Malaysia, an upper middle-income country, have been forced to scale down elective surgeries, prioritize cancer treatments based on treatment benefits, and postpone non-emergency imaging procedures. These inevitably led to disruptions in cancer care delivery within the public health care system. This study aims to explore the facilitators and barriers faced by healthcare providers and cancer survivors in cancer care, and to co-design a guideline to maintain the delivery of cancer care amid the disaster situations. In-depth interviews (IDIs) will be conducted with Malaysian healthcare providers and cancer survivors and findings will be analysed thematically. The insights will be used in a subsequent phase to co-design a guideline to maintain the delivery of quality cancer care in Malaysia via a three-round modified Delphi survey with a broad range of cancer stakeholders. Findings derived from IDIs and existing literature will be included for rating across three rounds by the expert panel. Feedback provided will be refined until consensus on the best practises for cancer care continuity during crises is achieved. The output of the present study is not only expected to ensure the continuity of delivery of high-quality cancer care in Malaysia during the ongoing pandemic but also to be adapted during unforeseen crises in the near future. Collaborative work between policy makers, public health physicians, members of the multidisciplinary oncology team as well as cancer survivors is vital in developing an evidenced- based contingency plan for maintaining access to cancer care.


Mixtures, metabolites, ionic liquids: a new measure to evaluate similarity between complex chemical systems.
This communication deals with the scientific problem of evaluating the similarity between two chemical systems, each described by a finite discrete set of elements/members, which are in turn p-dimensional vectors of chemical/biological descriptors. A variant of the Hausdorff measure, called Hausdorff-like similarity (Hs), is proposed aimed at taking into account information on all the elements present in the compared sets, information that is usually lost by the other measures.


Positron emission tomography of 5-HT transporter sites in the baboon brain with [11C]McN5652.
[11C]McN5652 is a new radioligand specific for 5-hydroxytryptamine (5-HT; serotonin) transporters. In this study we used [11C]McN5652 to image the 5-HT transporter sites in baboon brain by positron emission tomography (PET). Dynamic PET studies were performed in three Papio anubis baboons. The animals were injected intravenously first with 11C-labeled (+)-McN5652([11C](+)McN5652), then with pharmacologically inactive enantiomer 11C-labeled (-)-McN5652 ([11C](-)McN5652); two animals received a third study with [11C](+)McN5652 after pretreatment with the specific 5-HT uptake site inhibitor fluoxetine (5 mg/kg). Initial uptake into the brain was similar for both [11C](+)McN5652 and [11C](-)McN5652. At later times (45-120 min after injection), only [11C](+)McN5652 showed a distribution characteristic for 5-HT uptake sites. In contrast, in studies with [11C](-)McN5652 and in those with [11C](+)McN5652 after 5-HT uptake site blockade with fluoxetine, 11C radioactivity concentrations were significantly lower and the distribution pattern was relatively even. The differences between [11C](+)-and (-)McN5652 were calculated for the time interval 95-125 min postinjection and used to estimate specific binding. Specific binding correlated well (r = 0.95, p < 0.001) with the known density of 5-HT uptake sites in human brain. These results indicate that [11C](+)McN5652 is suitable for PET imaging of 5-HT uptake sites in primate brain.


Patterns of adverse childhood experiences among Chinese preschool parents and the intergenerational transmission of risk to offspring behavioural problems: moderating by coparenting quality.
Background: Although intergenerational transmission of ACEs among parents and their offspring have been extensively studied in the West, few studies have been conducted in China on preschool children and their parents, and explore the protective fact for the intergeneration transmission. Objective: Using latent class analysis and moderation model, this study examined the associations between patterns of adverse childhood experiences of Chinese preschool parents and behavioural problems in their children and whether coparenting quality plays a protective role in this relationship. Method: A retrospective study was conducted on 3091 parent-child dyads from 11 kindergartens in the northern, central, and southern Anhui provinces in China. Online questionnaires were used to collect the data. Parents reported adverse childhood experiences (ACEs) and provided information on their children's behavioural problems and perceived coparenting quality. Latent class analysis and a moderating model were used to examine the associations between patterns of adverse childhood experiences of Chinese preschool parents and behavioural problems in their children, and the moderating role of coparenting quality. Results: Four classes were identified: a high ACEs group, a violent victimisation group, a child abuse and physical neglect group, and a low ACEs group. Increasing levels of co-parenting quality were associated with reduced parent-reported child behaviour problems for all classes, and that potentially buffering effect was significantly stronger for the low ACEs class than for children whose parents in high ACEs class. Conclusions: Exposure to high ACEs increases the risk of developing behavioural problems in offspring, and coparenting quality may serve as a protective mechanism for intergenerational transmission. Future research should develop and implement interventions to support disadvantaged, at-risk parents and promote coparenting quality.


An Immersive Motor Protocol for Frailty Rehabilitation.
Frailty is a pre-clinical condition that worsens physical health and quality of life. One of the most frequent symptoms of frailty is an increased risk of falling. In order to reduce this risk, we propose an innovative virtual reality motor rehabilitation program based on an immersive tool. All exercises will take place in the CAVE, a four-screen room with a stationary bike. The protocol will include two types of exercises for the improvement of balance: "Positive Bike" and "Avoid the Rocks." We will choose evaluation scales related to the functional aspects and subjective perception of balance. Our aim is to prove that our innovative motor rehabilitation protocol is as effective as or more effective than classical rehabilitation.


Hit discovery and hit-to-lead approaches.
Hit discovery technologies range from traditional high-throughput screening to affinity selection of large libraries, fragment-based techniques and computer-aided de novo design, many of which have been extensively reviewed. Development of quality leads using hit confirmation and hit-to-lead approaches present their own challenges, depending on the hit discovery method used to identify the initial hits. In this paper, we summarize common industry practices adopted to tackle hit-to-lead challenges and review how the advantages and drawbacks of different hit discovery techniques could affect the various issues hit-to-lead groups face.


Direct and indirect stimulations of cyclic AMP formation in human brain.
1. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation, by use of an [3H]-adenine prelabelling assay, was measured in fragments of human cerebral cortex, taken in the course of various neurosurgical procedures. 2. Large accumulations of [3H]-cyclic AMP due to isoprenaline, noradrenaline and adenosine and small effects due to forskolin were observed. Histamine, 5-hydroxytryptamine (5-HT) and the excitatory amino acids glutamate and quisqualate were ineffective. 3. The response to noradrenaline consisted of two components; a direct beta-adrenoceptor response and an enhancement mediated by an alpha-adrenoceptor which appears to be similar to that in rat cerebral cortex. 4. The response to isoprenaline was also potentiated by histamine H1 receptor stimulation but the direct effect of 2-chloroadenosine was not altered by histamine, 5-HT or quisqualate. 5. It is concluded that some, but not all, of the indirect modulations of cyclic AMP formation previously observed in experimental animal brain exist in human cerebral cortex.


The occurrence of 2-hydroxyisovaleric acid in patients with lactic acidosis and ketoacidosis.
Examination of urine samples by capillary column gas chromatography and mass spectrometry showed the presence of 2-hydroxyisovaleric acid together with trace amounts of the three branched-chain 2-keto acids in five patients with lactic and ketoacidosis. None of these compounds was detected in urine from healthy controls.


Angioplasty of an asymptomatic total occlusion of the left subclavian artery to provide access for coronary angiography and intervention: a case report.
Reports and follow-up of angioplasty and stenting of asymptomatic totally occluded subclavian arteries are limited. We present a case of unstable angina and arterial occlusion of all four extremities treated with subclavian angioplasty and stenting with subsequent coronary angiography and percutaneous coronary intervention. Twelve-month follow-up is also provided.


The sensitivity of radionuclide and thermodilution techniques to detect cardiac dysfunction in the baboon model during prolonged anaesthesia.
This study was undertaken to evaluate the fluctuations of cardiac parameters in a baboon model during pentobarbitone anaesthesia which will serve as a baseline control for shock studies. Thermodilution and radionuclide methods were used to determine cardiac parameters. Radionuclide studies were repeated without any cardiac catheters to assess the effect of these on cardiac performance. The results represent baseline fluctuations in cardiac parameters against which cardiac dysfunction can be diagnosed in shock studies. The results also indicate that cardiac catheterisation does not affect cardiac performance significantly.


A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity.
Cellular asymmetry is critical for the development of multicellular organisms. Here we show that homologues of proteins necessary for asymmetric cell division in Caenorhabditis elegans associate with each other in mammalian cells and tissues. mPAR-3 and mPAR-6 exhibit similar expression patterns and subcellular distributions in the CNS and associate through their PDZ (PSD-95/Dlg/ZO-1) domains. mPAR-6 binds to Cdc42/Rac1 GTPases, and mPAR-3 and mPAR-6 bind independently to atypical protein kinase C (aPKC) isoforms. In vitro, mPAR-3 acts as a substrate and an inhibitor of aPKC. We conclude that mPAR-3 and mPAR-6 have a scaffolding function, coordinating the activities of several signalling proteins that are implicated in mammalian cell polarity.


Axillary vein thrombosis in a healthy donor following platelet apheresis.
Platelet donation is a common and usually safe procedure accounting for almost half of the platelets donated in the UK. We describe a previously healthy female donor who developed an axillary vein thrombosis following an apheresis platelet donation.


Mechanism of potentiation of antitumor activity of 5-fluorouracil by guanine ribonucleotides against adenocarcinoma 755.
The effect of various guanine ribonucleotides on the antitumor activity of 5-fluorouracil (FUra) was investigated by its action on adenocarcinoma 755. 5'-GDP and 5'-GMP were both equally effective in potentiating the antitumor activity of FUra without increasing toxicity. 5'-GTP and 5'-IMP also potentiated the activity but not as much as 5'-GMP. 2'-GMP and 3'-GMP did not enhance the antitumor activity. In contrast, cGMP antagonized the effects of FUra. The incorporation of 3H-labeled FUra into RNA or DNA showed there was no obvious association between the incorporation and antitumor activity after any treatment with guanine ribonucleotides. The combination of FUra and 5'-GMP produced the greatest inhibition of RNA synthesis. The combination of FUra and 2'-GMP had no effect on RNA synthesis. The inhibition of RNA synthesis may be the result of decreased pyrimidine pool size and increased incorporation of FUra into RNA. Potentiation of the antitumor activity of FUra by 5'-GMP was reversed by the injection of cytidine. Moreover, the combination of 5-fluorocytidine (FCyd) and 5'-GMP showed greater antitumor activity than FCyd alone. These results indicate that a decreased CTP pool potentiates the antitumor activity of FUra. Thus, 5'-GMP or 5'-GDP strongly enhanced the antitumor activity of FUra, and the potentiation resulted from the inhibition of RNA synthesis caused by reduction of the CTP and UTP pool sizes and increased incorporation of FUra into RNA.


Gestational exposures to organophosphorus insecticides: From acute poisoning to developmental neurotoxicity.
For over three-quarters of a century, organophosphorus (OP) insecticides have been ubiquitously used in agricultural, residential, and commercial settings and in public health programs to mitigate insect-borne diseases. Their broad-spectrum insecticidal effectiveness is accounted for by the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that catalyzes acetylcholine (ACh) hydrolysis, in the nervous system of insects. However, because AChE is evolutionarily conserved, OP insecticides are also toxic to mammals, including humans, and acute OP intoxication remains a major public health concern in countries where OP insecticide usage is poorly regulated. Environmental exposures to OP levels that are generally too low to cause marked inhibition of AChE and to trigger acute signs of intoxication, on the other hand, represent an insidious public health issue worldwide. Gestational exposures to OP insecticides are particularly concerning because of the exquisite sensitivity of the developing brain to these insecticides. The present article overviews and discusses: (i) the health effects and therapeutic management of acute OP poisoning during pregnancy, (ii) epidemiological studies examining associations between environmental OP exposures during gestation and health outcomes of offspring, (iii) preclinical evidence that OP insecticides are developmental neurotoxicants, and (iv) potential mechanisms underlying the developmental neurotoxicity of OP insecticides. Understanding how gestational exposures to different levels of OP insecticides affect pregnancy and childhood development is critical to guiding implementation of preventive measures and direct research aimed at identifying effective therapeutic interventions that can limit the negative impact of these exposures on public health.


Molecular identification and characterization of Anaplasma platys and Ehrlichia canis in dogs in Mexico.
The tick-borne pathogens Ehrlichia canis and Anaplasma platys are the causative agents of canine monocytic ehrlichiosis (CME) and canine cyclic thrombocytopenia (CCT). Although molecular evidence of E. canis has been shown, phylogenetic analysis of this pathogen has not been performed and A. platys has not been identified in Mexico, where the tick vector Rhipicephalus sanguineus sensu lato (s.l.) is common. The aim of this research was to screen, identify and characterize E. canis and A. platys by PCR and phylogenetic analysis in dogs from La Comarca Lagunera, a region formed by three municipalities, Torreon, Gomez-Palacio and Lerdo, in the Northern states of Coahuila and Durango, Mexico. Blood samples and five engorged R. sanguineus s.l. ticks per animal were collected from 43 females and 57 male dogs presented to veterinary clinics or lived in the dog shelter from La Comarca Lagunera. All the sampled dogs were apparently healthy and PCR for Anaplasma 16S rRNA, Ehrlichia 16S rRNA, and E. canis trp36 were performed. PCR products were sequenced and used for phylogenetic analysis. PCR products were successfully amplified in 31% of the samples using primers for Anaplasma 16S rRNA, while 10% and 4% amplified products using primers for Ehrlichia 16S rRNA and E. canis trp36 respectively. Subsequent sequencing and phylogenetic analyses of these products showed that three samples corresponded to A. platys and four to E. canis. Based on the analysis of trp36 we confirmed that the E. canis strains isolated from Mexico belong to a conservative clade of E. canis and are closely related to strains from USA. In conclusion, this is the first molecular identification of A. platys and the first molecular characterization and phylogenetic study of both A. platys and E. canis in dogs in Mexico.


NDRG2 is expressed on enteric glia and altered in conditions of inflammation and oxygen glucose deprivation/reoxygenation.
Enteric glial cells are more abundant than neurons in the enteric nervous system. Accumulating evidence has demonstrated that enteric glial cells share many properties with astrocytes and play pivotal roles in intestinal diseases. NDRG2 is specifically expressed in astrocytes and is involved in various diseases in the central nervous system. However, no studies have demonstrated the expression of NDRG2 in enteric glial cells. We performed immunostaining of adult mouse tissue, human colon sections, and primary enteric glial cells and the results showed that NDRG2 was widely expressed in enteric glial cells. Meanwhile, our results showed that NDRG2 was upregulated after treatment with pro-inflammatory cytokines and exposure to oxygen glucose deprivation/reoxygenation, indicating that NDRG2 might be involved in these conditions. Moreover, we determined that NDRG2 translocated to the nucleus after treatment with pro-inflammatory cytokines but not after exposure to oxygen glucose deprivation/reoxygenation. This study is the first to show the expression and distribution of NDRG2 in the enteric glia. Our results indicate that NDRG2 might be involved in the pathogenesis of enteric inflammation and ischemia/reperfusion injury. This study shows that NDRG2 might be a molecular target for enteric nervous system diseases.


Inhibition of aryl hydrocarbon receptor-dependent transcription by resveratrol or kaempferol is independent of estrogen receptor α expression in human breast cancer cells.
Resveratrol and kaempferol are natural chemopreventative agents that are also aryl hydrocarbon receptor (AHR) antagonists and estrogen receptor (ER) agonists. In this study we evaluated the role of ERα in resveratrol- and kaempferol-mediated inhibition of AHR-dependent transcription. Kaempferol or resveratrol inhibited dioxin-induced cytochrome P450 1A1 (CYP1A1) and CYP1B1 expression levels and recruitment of AHR, ERα and co-activators to CYP1A1 and CYP1B1. Both phytochemicals induced the expression and recruitment of ERα to gene amplified in breast cancer 1 (GREB1). RNAi-mediated knockdown of ERα in T-47D cells did not affect the inhibitory action of either phytochemical on AHR activity. Both compounds also inhibited AHR-dependent transcription in ERα-negative MDA-MB-231 and BT-549 breast cancer cells. These data show that ERα does not contribute to the AHR-inhibitory activities of resveratrol and kaempferol.


Preclinical pharmacokinetics-related pharmacological effects of orally administered polysaccharides from traditional Chinese medicines: A review.
Polysaccharides (TCMPs) derived from traditional Chinese medicines (TCMs), such as Ganoderma lucidum, Astragalus membranaceus, Lycium barbarum, and Panax ginseng, are considered to be the main active constituents in TCMs. However, the significant pharmacological effects of orally administered TCMPs do not align well with their poor pharmacokinetics. This article aims to review the literature published mainly from 2010 to 2022, focusing on the relationship between pharmacokinetics and pharmacological effects. It has been found that unabsorbed TCMPs can exert local pharmacological effects in the gut, including anti-inflammation, anti-oxidation, regulation of intestinal flora, modulation of intestinal immunity, and maintenance of intestinal barrier integrity. Unabsorbed TCMPs can also produce systemic pharmacological effects, such as anti-tumor activity and immune system modulation, by regulating intestinal flora and immunity. Conversely, some TCMPs can be absorbed and distributed to various tissues, especially the liver, where they exhibit tissue-protecting effects against inflammation and oxidative stress-induced damage and improve glucose and lipid metabolism. In future studies, it is important to improve quality control and experimental design. Furthermore, research on enhancing the oral bioavailability of TCMPs, exploring the activity of TCMP metabolites, investigating pharmacokinetic interactions between TCMPs and oral drugs, and developing oral drug delivery systems using TCMPs holds great significance.


An homologous radioimmunoassay for coho salmon (Oncorhynchus kisutch) vitellogenin, with general applicability to other Pacific salmonids.
This paper describes an homologous radioimmunoassay for coho salmon vitellogenin that demonstrates parallel cross-reactivity for plasma vitellogenin of all Pacific salmonids tested (chinook, chum, coho, pink, and sockeye salmon, and cutthroat and rainbow trout), but not for Atlantic salmon or two nonsalmonids: common carp and sablefish. Plasma vitellogenin levels were high in ovulatory female Pacific salmonids (micrograms/ml to mg/ml range), but were mostly nondetectable in spermiating males of the same species.


The direct measurement of plasma colloid osmotic pressure is superior to colloid osmotic pressure derived from albumin or total protein.
Plasma colloid osmotic pressure (COP) has been calculated from both serum albumin concentration and plasma total protein concentration. These values have been compared to those measured directly using a membrane-transducer oncometer in a group of normal subjects, in a group of critically-ill patients with a variety of primary diagnoses and in a group of hypovolaemic patients before and after plasma volume replacement with 6% hydroxyethyl starch solution. In the normal samples, COP calculated from albumin (COPalb) underestimated the measured COP (COPm) by mean of 2.0 mmHg (p less than 0.002), with correlation coefficient r = 0.39(n/s). Similarly, the COPalb underestimated COPm by a mean of 5.7 mmHg (p less than 0.001) in the critically ill patient group; r = 0.38 (p less than 0.02). Furthermore, in the patients receiving plasma volume replacement serum albumin concentration fell by 13.1% (p less than 0.001) whilst COPm increased by 11.5% (p less than 0.002). In the normal subjects COP calculated from total protein concentration (COPtp) underestimated the COPm by 1.5 mmHg (p less than 0.02) with r = 0.65 (p less than 0.01). Conversely, in the patient samples, mean COPtp overestimated COPm by 3.5 mmHg (p less than 0.001) with r = 0.73 (p less than 0.002). We conclude that COPalb is an inadequate estimate of COPm particularly in patients where its use may have important clinical consequences. COPtp provides a reasonable estimate of COPm in normal subjects but in patients samples, where albumin: globulin ratio is low COPtp overestimates substantially in many cases. We advocate the direct measurement of COP in critically-ill patients.


Failed distal ulna resections.
Twenty patients with complaints of pain and limitation of activities for more than 1 year after ulnar head resection (Darrach) were studied. Their ages ranged from 18 to 60 years (mean, 38 years). The initial indications for operation were posttraumatic derangement in 18 patients, radial growth anomaly in 1, and a lesion of the ulna in 1. Follow-up ranged from 29 to 135 months (mean, 61 months). The patients had an average of 2.2 additional operations, with up to seven procedures per patient. Radiographs were compared with those from an equal number of successful Darrach resections chosen randomly, and no significant differences were noted. All 20 patients continue to have difficulties despite several years of treatment. The Darrach resection can result in serious disability, especially in the younger patient and the patient with lax ligaments. Reoperation on these patients is rarely successful.


Descriptive analysis of kinematics and kinetics of catchers throwing to second base from their knees.
In order to decrease the amount of time that it takes the catcher to throw the ball, a catcher may chose to throw from the knees. Upper extremity kinematics may play a significant role in the kinetics about the elbow observed in catchers throwing from the knees. If relationships between kinematics and kinetics exist then the development of training and coaching instruction may help in reduced upper extremity injury risk. Twenty-two baseball and softball catchers (14.36±3.86years; 165.11±17.54cm; 65.67±20.60kg) volunteered. The catchers exhibited a less trunk rotation (5.6±16.2°), greater elbow flexion (87.9±21.4°) and decreased humeral elevation (71.1±12.3°) at the event of maximum shoulder external rotation as compared to what has previously reported in catchers. These variables are important, as they have previously been established as potential injury risk factors in pitchers, however it is not yet clear the role these variables play in catchers' risk of injury. A positive relationship between elbow varus torque during the deceleration phase and elbow flexion at MIR was observed (r=0.609; p=0.003). Throwing from the knees reduces a catcher's ability to utilize the proximal kinetic chain and this may help to explain why their kinematics and kinetics differ from what has previously been presented in the literature.


Activation of tumor-specific T cells by dendritic cells expressing the NY-ESO-1 antigen after transfection with the cationic lipophosphoramide KLN5.
Genetic modification of human monocyte-derived dendritic cells (DC) with cDNA sequences encoding tumor-associated antigens (TAA) is a promising strategy for cancer immunotherapy. The present study aimed to develop a nonviral gene transfer method based on the use of the cationic lipophosphoramide reagent, KLN-5, as an alternative to the commonly used viral vectors. First, the efficiency of KLN5 for gene transfection into DC was investigated using the green fluorescent protein (GFP) reporter gene. The highest transfection efficiency/cell viability ratio was determined by flow cytometry. Next, DC were transfected with a plasmid encoding NY-ESO-1, a TAA expressed in numerous cancers, according to the transfection protocol previously established with the GFP reporter. Transfected DC were then co-cultured with a CD8+ NY-ESO-1 specific HLA-A*02.01 T cell clone to control their ability to correctly process and present the corresponding epitope in the HLA-A*02.01 context. Finally, T cell activation was assessed via flow cytometry-based detection of interferon-gamma production. An optimal KLN5/plasmid DNA ratio allowing both significant transgene expression and high viability of DC could be determined. Under the established experimental conditions, antigen processing and presentation of the immunodominant (SLLMWITQC(157-165)) epitope in the HLA-A*0201 context was demonstrated by activation of the NY-ESO-1-specific CD8+ T cell clone. KLN5-based gene transfection into DC allows the efficient induction of TAA presentation and may thus represent a novel attractive nonviral approach for cancer vaccination.


[Results of experimental studies of 51chromium-albumin kinetics following intravenous administration of Hylase "Dessau"].
Experiments on the effect of Hylase on albumin kinetics were carried out by means of 51chromium-labelled albumin on 52 wistar rats. Most of the examined tissues showed a faster exchange between blood and extravascular space by help of Hylase. That was recognized from advanced peaks of activity, their higher absolute values, and partly from the faster decrease of activity in organs and tissues. This effect did not depend on the structure of capillaries, it was observed also in bradytrophic tissues (cartilage).


Shift of functional cerebral asymmetry during the menstrual cycle.
This study investigated whether for females, who are said to be less strongly lateralized for cognitive functions than men, hemispheric superiority might depend on the phase of the menstrual cycle. The results show that while asymmetry in lexical decisions did not change throughout the menstrual cycle, asymmetry in face perception decreased linearly from a large right hemisphere superiority during menstruation to a small left hemisphere superiority during the premenstrual phase. This is seen as being relevant not only for the discussion of sex differences in cerebral asymmetry but also for the concept of cerebral organization in general.


"Towards Re-Inventing Psychohistory": Predicting the Popularity of Tomorrow's News from Yesterday's Twitter and News Feeds.
Rapid advances in machine learning combined with wide availability of online social media have created considerable research activity in predicting what might be the news of tomorrow based on an analysis of the past. In this work, we present a deep learning forecasting framework which is capable to predict tomorrow's news topics on Twitter and news feeds based on yesterday's content and topic-interaction features. The proposed framework starts by generating topics from words using word embeddings and K-means clustering. Then temporal topic-networks are constructed where two topics are linked if the same user has worked on both topics. Structural and dynamic metrics calculated from networks along with content features and past activity, are used as input of a long short-term memory (LSTM) model, which predicts the number of mentions of a specific topic on the subsequent day. Utilizing dependencies among topics, our experiments on two Twitter datasets and the HuffPost news dataset demonstrate that selecting a topic's historical local neighbors in the topic-network as extra features greatly improves the prediction accuracy and outperforms existing baselines.


Accumulation of pericardial fat correlates with left ventricular diastolic dysfunction in patients with normal ejection fraction.
Left ventricular diastolic dysfunction (LVDD) plays an important role in heart failure with normal left ventricular ejection fraction (LVEF). Obesity is one of the major comorbid conditions of LVDD. Pericardial fat (PF) is an ectopic fat depot with possible paracrine or mechanical effects on the coronary circulation and myocardial function. We measured PF volume on 64 slice computed tomography and analyzed echocardiographic parameters to confirm LVDD in 229 consecutive patients suspected of coronary artery disease with LVEF of more than 50% and no symptomatic heart failure (59% men, 67±12 years). LVDD was defined as the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e') >10. PF volume correlated significantly with E/e' (r=0.21, p<0.01), left ventricular mass index (r=0.23, p<0.001), and left atrial diameter (r=0.32, p<0.001). The mean PF volume was significantly greater in patients with LVDD (184±61cm(3), n=141) than in those without LVDD (154±58, n=88, p<0.001). Multivariate logistic regression analysis indicated that PF volume correlated significantly with the presence of LVDD (odds ratio: 2.00 per 100cm(3) increase in PF volume, p=0.02) independent of age, gender, abdominal obesity, hypertension, and diabetes. PF volumes are significantly associated with LVDD, independent of other factors such as hypertension or diabetes. PF may be implicated in the pathogenesis of LVDD in patients with normal LVEF.


Hull early walking aid for rehabilitation of transtibial amputees--randomized controlled trial (HEART).
To compare articulated and nonarticulated early walking aids (EWAs) for clinical and quality-of-life outcomes in transtibial amputees. Patients undergoing lower limb amputation in a tertiary-care vascular surgical unit were screened over a 4-year period. Recruited patients were randomized to receive articulated amputee mobility aid (AMA) or nonarticulated pneumatic postamputation mobility aid (PPAMA) during early rehabilitation. Primary (10-meter walking velocity) and secondary clinical (number and duration of physiotherapy treatments during EWA/prosthesis use) and quality-of-life (SF-36) outcome measures were recorded at five standardized assessment visits. Inter-group and intra-group analyses were performed. Two hundred seventy-two patients were screened and 29 transtibial amputees (median age, 56 years) were recruited (14/treatment arm). No significant difference was seen in demographics and comorbidities at baseline. Inter-group analysis: Median 10-meter walking velocity was significantly (Mann-Whitney, P = .020) faster in the PPAMA group (0.245 m/s, interquartile range [IQR] 0.218-0.402 m/s) compared with the AMA group (0.165 m/s; IQR, 0.118-0.265 m/s) at visit 1. However, there was no difference between the groups at any other visit. Similarly, the number of treatments using EWA was significantly (P = .045) lower in the PPAMA group (5.0; IQR, 3.5-8.0) compared with the AMA group (6.0; IQR, 6.0-10.5). No difference was observed between the groups in duration of physiotherapy or SF-36 domain and summary scores. Intra-group analysis: Both treatment groups showed significant improvement in 10-meter walking velocity (Friedman test; AMA P = .001; PPAMA P = .007); however, other clinical outcomes did not show any statistically significant improvement. Only physical function domain of SF-36 demonstrated significant improvement (Friedman test; AMA P = .037; PPAMA P = .029). There is no difference in clinical and QOL outcomes between articulated and nonarticulated EWAs in rehabilitation of transtibial amputees.


COVID-19 vaccination-related attendance at a pediatric emergency department in Singapore among 12- to 18-year old adolescents.
Singapore was one of the first countries to begin COVID-19 vaccination with the BNT162b2 vaccine for adolescents aged 12-18 years. This study evaluates the incidence of COVID-19 vaccine related attendances to a Pediatric Emergency Department (PED) to understand post-vaccination health behaviors among adolescents. This was a retrospective review of electronic medical records over a 4 month period, from the start of the adolescent vaccination drive to when more than 85% of this group had been fully vaccinated. The incidence of COVID-19 vaccination-related presentations to our PED was 3.1% over 4 months (291 of 9387 PED attendances), with a peak daily incidence of 15.4% (14 of 91 attendances). Presentations were characterized by severity into: severe (3.4%), moderate (7.9%) or mild (88.7%) based on predefined criteria. The most common presenting complaints were chest pain (58.8%), dyspnea (28.2%) and palpitations (22.6%). Hospitalization was required in only 6.2% of attendances. Patients with moderate-severe presentations were 0.7 years older (p = 0.030), more likely to have underlying drug allergies (p = 0.048) and had higher rates of hospitalization (p < 0.005) compared to mild presentations. Despite concerns of cardiac inflammation, chest pain related attendances were less likely to be severe (p < 0.005) with reduced hospitalization need (p = 0.043) compared to other presentations. Investigations beyond clinical assessment comprised 91% of attendances, but abnormalities were only found in 6.4% cases. Our study supports current evidence that COVID-19 vaccination is safe amongst adolescents. We highlight the health behaviors among adolescents post-vaccination, which is partly driven by media reports on vaccine side effects and an element of anxiety. While most of the presentations were mild, these can have implications on health resource utilization, particularly in an ongoing pandemic. As healthcare workers, we have an ongoing role to ensure accurate information on vaccine safety is communicated effectively to the public.


In vitro culture of erythrocytic stages, including gametocytes of Plasmodium berghei (NK 65 strain) using candle jar method and a newly designed continuous medium flow apparatus.
Three methods have been described for cultivation of erythrocytic stages, specially gametocytes of P. berghei NK65 strain, (1) by using vial candle jar where the cultures were subcultured by addition of fresh erythrocytes, (2) a newly designed simple and compact continuous medium flow apparatus, where medium was continuously perfused but fresh erythrocytes were not added and (3) where the subcultures were also done using simple and compact continuous medium flow apparatus for comparison. The maximum percentage of parasitized erythrocytes obtained by these methods was 24.3, 27.1 and 26.4% respectively. Parasites in vials could survive for more than 10 days with 3 to 4 subcultures with maximum 1.96% gametocytaemia. However, the gametocytaemia in continuous medium flow apparatus, where subcultures were not made reached 2.2% compared to that of 2.7% in this apparatus where subcultures were done. The asexual as well as sexual stages of this parasite survived for about 16-18 days in compact continuous medium flow apparatus, where at least 7 subcultures were done.


International multi-center real world implementation trial to increase out-of-hospital cardiac arrest survival with a dispatcher-assisted cardio-pulmonary resuscitation package (Pan-Asian resuscitation outcomes study phase 2).
Dispatcher-assisted CPR (DA-CPR) has the potential to deliver early bystander CPR (BCPR) and improve out-of-hospital cardiac arrest (OHCA) survival. This study in the Asia-Pacific evaluated the impact of a DA-CPR program on BCPR rates and survival. This was a three-arm, prospective, multi-national, population-based, community-level, implementation trial. Cases between January 2009 and June 2018 from the Pan-Asian Resuscitation Outcomes Study were included. Sites either implemented a comprehensive (with quality improvement tool) or a basic DA-CPR package, or served as controls. Primary outcome was survival-to-discharge/30th day post-arrest. Secondary outcomes were BCPR and favorable neurological outcome. A before-after comparison was made within each country; this before-after change was then compared across the three groups using logistic regression. 170,687 cases were analyzed. Before-after comparison showed that survival to discharge was higher in the 'implementation' period in all three groups: comprehensive odds ratio (OR) 1.09, 95% confidence interval (CI; [1.0-1.19]); basic OR 1.14, 95% CI (1.08-1.2); and control OR 1.25, 95% CI (1.02-1.53). Comparing between groups, the comprehensive group had significantly higher change in BCPR (comprehensive vs control ratio of OR 1.86, 95% CI [1.66-2.09]; basic vs control ratio of OR 0.94, 95% CI [0.85-1.05]; and comprehensive vs basic ratio of OR 1.97, 95% CI [1.87-2.08]) and survival with favorable neurological outcome (comprehensive vs basic ratio of OR 1.2, 95% CI [1.04-1.39]). We evaluated the impact of a DA-CPR program across heterogeneous EMS systems and demonstrated that a comprehensive DA-CPR program had the most impact on BCPR and favorable neurological outcome.


[Dissociation and reassociation of poliovirus. I. Effect of urea on the virion].
Poliovirus is dissociated by urea in the presence of mercaptoethanol or dithiothreitol into RNA and protein(s). Differences exist in the sensitivity of poliovirus type I, II or III toward these agents. The decrease in infectivity titer of the virion is in the range of 10(9). After appropriate dissociation no infectious virions are found in urea-treated poliovirus concentrates. The released viral RNA is infectious. Its infectivity (1 times 10(6) PFU/mug RNA) is comparable to that of phenol extracted RNA. Therefore, urea dissociation is a fast and reliable method for the preparation of infectious poliovirus RNA even at the microliter scale. The dissociation of poliovirus is dependent upon the concentration, temperature and pH. The decrease in virion infectivity is time dependent. It is preceded by a lag phase of different lengths for poliovirus type I, II or III. During the lag phase the virion undergoes configurational changes without losing infectivity. From the observed hyperchromic effect is it obvious that the secondary structure of the RNA inside the virion breaks down, giving rise to expanded forms of poliovirus particles. After the lag phase the RNA is released and the empty capsid dissociated into the appropriate polypeptides.


Estimating the burden of disease and the economic cost attributable to chikungunya, Colombia, 2014.
Chikungunya (CHIK) virus disease is expected to be a considerable cause of disability and economic burden in Latin America given its chronic sequelae, particularly its chronic inflammatory rheumatism. There have been no previous studies assessing CHIK costs and disability in Latin America. We calculated incidence rates for CHIK during the 2014 outbreak in Colombia using epidemiological data provided by the Colombian National Institute of Health, using demographic data from the National Administrative Department of Statistics. The burden of disease was estimated through disability adjusted life years (DALYs) lost and the costs were estimated based on the national recommendations for CHIK acute and chronic phase attention. There were a total of 106 592 cases, with incidence rates ranging from 0 to 1837.3 cases/100 000 population in different departments. An estimate was made of total DALYs lost of 40.44 to 45.14 lost/100 000 population. The 2014 outbreak estimated costs were at least US$73.6 million. Our estimates raise concerns about the effects of continued CHIK spread in Colombia and other Latin-American countries. The lack of transmission control for this disease and potential for spread means that there will be significant acute and chronic disability and related costs in the short and long term for Latin American health care systems.


The emergence of collective foraging in the arboreal Gnamptogenys menadensis (Hymenoptera: Formicidae).
Gnamptogenys menadensis is an arboreal nester that forages opportunistically almost exclusively on vegetation, sometimes recruiting others to participate in prey retrieval. The three-dimensional characteristics of vegetation suggest that functions describing recruitment decision thresholds or the pattern of recruitment in arboreal species may differ from those predicted by optimal foraging theory. To examine the effects of prey abundance and distance on the recruitment dynamics of G. menadensis, we baited nests with one termite, five termites or a number of termites between 20 and 40 either near to or far from the entrance and observed the ensuing behaviors. G. menadensis recruited others when encountering multiple termites regardless of the termite pile's distance from the nest, although a few individuals remained at the site and defended the resource. The pattern of arrivals at the site indicates that the majority and sometimes all arrivals were recruited from the branch trails. In combination, these results suggest that the architecture of the foraging habitat, which limits available return routes to the nest and thus increases encounter probabilities with potential recruits, shaped the process of information transfer and generated a collective pattern of foraging and prey retrieval.


Kinetin Riboside and Its ProTides Activate the Parkinson's Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization.
Since loss of function mutations of PINK1 lead to early onset Parkinson's disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.


Identification of a novel actin binding site within the Dp71 dystrophin isoform.
The Dp71 dystrophin isoform has recently been shown to localize to actin filament bundles in early myogenesis. We have identified an actin binding motif within Dp71 that is not found in other dystrophin isoforms. Actin overlay assays and transfection of COS-7 cells with fusion proteins of wild type and mutated Flag epitope-tagged Dp71 demonstrate that this motif is necessary and sufficient to direct localization of Dp71 to actin stress fibers. Furthermore, this localization is independent of alternative splicing which alters the C-terminus of the protein. The identification of an actin binding site suggests Dp71 may function to anchor membrane receptors to the cytoskeleton.


Coronary ostial stenosis.
From January 1970 to December 1986, 2.7% (228/8509) of all patients having coronary artery bypass grafting had atherosclerotic coronary ostial stenosis of 50% or more. There were 126 males (55%) and 102 females (45%) with mean ages of 60.2 +/- 9.0 and 59.2 +/- 10.2 years (P = NS), respectively. The left ostium was involved in 176 (77.2%) patients, the right in 41 (18.0%) and both in 11 (4.8%). Isolated ostial stenosis (no associated coronary disease of 50% or more) was present in 38/228 (17%) with females predominating (29/38, 76%). Isolated ostial stenosis occurred more frequently on the right (10/41, 25%) than on the left (18/176, 16%). Associated coronary disease occurred in a single vessel in 42 patients, in two vessels in 72 and in three vessels in 76 resulting in a mean of 2.0 diseased vessels per patient. If patients with isolated ostial stenosis are excluded there were 2.3 diseased arteries per patient. There were 687 grafts performed in these patients, an average of 2.3 grafts per patient. One month surgical mortality was 4.8% (11/228), but has been 2% (2/104) in the last 4 years. Nine of 27 late deaths were noncardiac with a mean follow-up of 49 +/- 44 months. Ostial stenosis is hemodynamically equivalent to left main disease when the left ostium is involved. Symptomatic ostial lesions, whether right or left, require operative therapy.


Mediastinal irradiation and valvular heart disease.
Anticancer therapy has the potential to cause unwanted cardiovascular side effects. Utilization of radiation therapy to treat tumors near the heart can result in radiation-induced valvular heart disease among other cardiovascular pathologies. The aim of this review is to describe the epidemiology, pathophysiology, risk prediction, non-invasive imaging modalities and management of radiation-induced valvular heart disease with a focus on pre-operative risk assessment and contemporary treatment options.


Evolution of the phenotype of craniosynostosis with dental anomalies syndrome and report of IL11RA variant population frequencies in a Crouzon-like autosomal recessive syndrome.
In 2011, biallelic loss-of-function variants in the interleukin receptor 11 alpha gene IL11RA were found to be associated with a Crouzon-like craniosynostosis syndrome with associated dental anomalies (CRSDA). Since then, a total of 41 similar patients have been reported with IL11RA variants. We report two adult brothers diagnosed with Crouzon syndrome as children, in which the clinical diagnosis of CRSDA was made on reevaluation. Laboratory testing detected biallelic IL11RA variants, c.916_924dup (p.Thr306_Ser308dup) and c.781C > T (p.Arg261Cys), both of which have now been reported in other families. Protein modeling and conservation analysis show that these two mutation sites cluster together near a WSXWS motif that likely plays a significant role in regulating IL11RA protein function. Population analysis from gnomAD shows that Non-Finnish Europeans (similar to ethnicity of this family), have an allele frequency for p.Thr306_Ser308dup of 0.014% and p.Arg261Cys of 0.008%. We found other ethnicities have functional IL11RA missense variants at higher frequencies. With this report, we provide a summary of the clinical findings including details of middle ear anomalies associated with conductive hearing loss. We also provide data supporting the populations at risk for this condition to increase recognition and diagnosis of this rare autosomal recessive craniosynostosis syndrome.


The influence of pelvicalyceal system anatomy on minimally invasive treatments of patients with renal calculi.
Nephrolithiasis has a multifactorial etiology, wherein, besides metabolic factors, the anatomy of the pelvicalyceal system might play a role. Using 3D-reconstructions of CT-urography (CT-U), we studied the morphometric properties of pelvicalyceal anatomy affecting kidney stone formation and compared those with existing literature on their effect on minimally invasive treatment techniques for renal calculi. CT-U's were made between 01-01-2017 and 30-09-2018. Patients were chronologically included in two groups: a nephrolithiasis group when ≥ 1 calculus was present on the CT-U and a control group of patients with both the absence of calculi on the CT-U and no medical history of urolithiasis. Patients with a medical history of diseases leading to higher risks on urolithiasis were excluded. In the nephrolithiasis group affected kidneys were measured. In the control group, left and right kidneys were alternately measured. Twenty kidneys were measured in both groups. Mean calyceopelvic tract width was significantly larger in the lower segments of affected kidneys (3.9 vs. 2.7 mm). No significant differences between the groups were found in number of calyces, infundibular length, infundibular width, calyceopelvic angle, upper-lower angle and diameters of the pelvis. Transversal calyceal orientation in hours was significantly smaller in the upper and lower segments of the nephrolithiasis group (7.69 vs. 8.52 and 8.08 vs. 9.09 h), corresponding with more dorsally located calyces in stone-forming kidneys. Pelvicalyceal anatomy differs between stone-forming and non-stone-forming kidneys. Understanding the pelvicalyceal system and etiology of stone formation can improve development of endourological techniques.


A pilot randomized clinical trial of biomedical link with mental health in art therapy intervention programs for alcohol use disorder: Changes in NK cells, addiction biomarkers, electroencephalography, and MMPI-2 profiles.
Alcohol intake is a major risk factor for various diseases. Elucidating alcohol use disorder (AUD) is important in preventing diseases and promoting health. We aimed to investigate the effect of art therapy on emotional (Minnesota Multiphasic Personality Inventory-2 [MMPI-2]) and physical (natural killer [NK] cell count, expression of stress-associated proteins [SAP], and electroencephalography) changes in patients with AUD. Participants were randomly divided into two groups (n = 35), with the experimental group undergoing art therapy involving weekly 60-min group therapy sessions for 10 weeks. Statistical analysis was performed using Ranked ANCOVA and Wilcoxon's signed rank test. Western blotting was performed to analyze serum SAP levels. We observed an association between psychological mechanisms and stress proteins. There was an increased number of NK cells in the experimental group after the program. Moreover, compared with the control group, the experimental group showed significant changes in SAP expression. Further, the experimental group showed a positive change in the MMPI-2 profile, as well as a decrease in depression, anxiety, impulsivity, and alcohol dependence. Continuous psychological support could be applied as a stress-control program for preventing stress recurrence and post-discharge relapse. Our findings strengthen the link between biomedical science and mental health in rehabilitation treatment for AUD.


Machine learning enables completely automatic tuning of a quantum device faster than human experts.
Variability is a problem for the scalability of semiconductor quantum devices. The parameter space is large, and the operating range is small. Our statistical tuning algorithm searches for specific electron transport features in gate-defined quantum dot devices with a gate voltage space of up to eight dimensions. Starting from the full range of each gate voltage, our machine learning algorithm can tune each device to optimal performance in a median time of under 70 minutes. This performance surpassed our best human benchmark (although both human and machine performance can be improved). The algorithm is approximately 180 times faster than an automated random search of the parameter space, and is suitable for different material systems and device architectures. Our results yield a quantitative measurement of device variability, from one device to another and after thermal cycling. Our machine learning algorithm can be extended to higher dimensions and other technologies.


Protein kinase C modulation of queuine uptake in cultured human fibroblasts.
Protein kinase C modulates the activity of a highly specific uptake mechanism for queuine in cultured human fibroblasts. Activators of protein kinase C induce an increased uptake rate for the radiolabeled analog of queuine, rQT3. The protein kinase C inhibitors, H-7, staurosporine and sphingosine all induced a dramatic decrease in the uptake rate of rQT3. This suggests that protein kinase C is tied to efficient cellular uptake of queuine. Uptake is prerequisite to the modification of transfer RNA with queuine. Perturbation of queuine-modified transfer RNA levels has been associated with neoplastic transformation, differentiation and growth control.


Isolation of high-molecular-weight nucleic acids for copy number analysis using high-performance liquid chromatography.
The Nucleogen DEAE 4000-10 high-performance liquid chromatography (HPLC) column was shown to isolate tRNA, rRNA, and DNA from crude cell lysates in the presence of a denaturant. Chromosomal DNA and plasmid DNA coeluted and retention was independent of size. An HPLC technique for plasmid copy number determination was then developed, verified, and optimized. The assay was successfully applied to a recombinant yeast system. Similar results were obtained earlier for recombinant Escherichia coli. The copy number can be calculated from the ratio of plasmid DNA to rRNA, then calculated to a per-cell basis using literature and measured constants. Chromosomal DNA coeluted with plasmid DNA and so was removed prior to analysis. For recombinant systems were the rRNA content is not constant, the plasmid area along with cell concentration can be used to calculate plasmid copy number. Nucleic acids' responses were linear, and plasmid copy number results using peak ratios had a low percent standard deviation. Errors increased when the absolute plasmid area was used to calculate plasmid copy number.


Analysis of the Effect of Intraocular Lens Implantation on Retinal Nerve and Postoperative Nursing Outcome Based on Ultrasound Imaging.
Traumatic cataract is a common complication of ocular contusion. Caused by various forms of trauma, the course and prognosis of traumatic cataract are also different. Intraocular lens (IOL) implantation is the most effective treatment at the present time and can provide good visual quality and near, medium, and far vision. In this study, an adaptive medical ultrasound image denoising algorithm was constructed based on the biological vision mechanism and was applied to observe IOL implantation and postoperative care of 30 patients with traumatic cataract. Results showed that eyesight could be restored to the original healthy state after IOL implantation, and eyesight was close to normal 3 months after surgery. The corresponding noise pixel block of the noise reduction algorithm was obviously the lowest. A total of 30 patients (9 patients with contusion, 13 patients with intraocular foreign body, and 8 patients with perforation) were treated with aspheric and multifocal IOL to achieve the expected outcome. The noise reduction algorithm constructed in this study effectively reduced the speckle noise of ultrasound images, improved the clarity of ultrasound images, and achieved the effective observation of medical nursing outcome after traumatic cataract IOL implantation. After IOL implantation, the retinal nerves of patients with traumatic cataract were affected to different degrees.


The prominent absence of Alfred Russel Wallace at the Darwin anniversaries in Germany in 1909, 1959 and 2009.
It is well known that the contribution of Alfred Russell Wallace (1823-1913) to the development of the "Darwinian" principle of natural selection has often been neglected. Here we focus on how the three anniversaries to celebrate the origin of the Darwin-Wallace theory in Germany in 1909, in 1959 in the divided country, as well as in 2009, have represented Charles Robert Darwin's and Alfred Russell Wallace's contributions. We have analyzed books and proceedings volumes related to these anniversaries, and the main result is that Wallace was almost always ignored, or only mentioned in passing. In 1909, Ernst Haeckel gave a talk in Jena, later published under the title The worldview of Darwin and Lamarck (Das Weltbild von Darwin und Lamarck), but not as the Darwin-Wallace concept. Haeckel mentions Wallace only once. In two important proceedings volumes from the 1959 anniversaries, Wallace was ignored. The only fair treatment of Wallace is given in another book, a collection of documents edited by Gerhard Heberer, for which the author selected nine key documents and reprinted excerpts (1959). Three of them were articles by Wallace, including the Sarawak- and Ternate-papers of 1855 and 1858, respectively. An analysis of the dominant themes during the celebrations of 2009 shows that none of the six topics had much to do with Wallace and his work. Thus, the tendency to exclude Alfred Russell Wallace is an international phenomenon, and largely attributable to the "Darwin industry".


Morphometric MRI as a diagnostic biomarker of frontotemporal dementia: A systematic review to determine clinical applicability.
Frontotemporal dementia (FTD) is difficult to diagnose, due to its heterogeneous nature and overlap in symptoms with primary psychiatric disorders. Brain MRI for atrophy is a key biomarker but lacks sensitivity in the early stage. Morphometric MRI-based measures and machine learning techniques are a promising tool to improve diagnostic accuracy. Our aim was to review the current state of the literature using morphometric MRI to classify FTD and assess its applicability for clinical practice. A search was completed using Pubmed and PsychInfo of studies which conducted a classification of subjects with FTD from non-FTD (controls or another disorder) using morphometric MRI metrics on an individual level, using single or combined approaches. 28 relevant articles were included and systematically reviewed following PRISMA guidelines. The studies were categorized based on the type of FTD subjects included and the group(s) against which they were classified. Studies varied considerably in subject selection, MRI methodology, and classification approach, and results are highly heterogeneous. Overall many studies indicate good diagnostic accuracy, with higher performance when differentiating FTD from controls (highest result was accuracy of 100%) than other dementias (highest result was AUC of 0.874). Very few machine learning algorithms have been tested in prospective replication. In conclusion, morphometric MRI with machine learning shows potential as an early diagnostic biomarker of FTD, however studies which use rigorous methodology and validate findings in an independent real-life cohort are necessary before this method can be recommended for use clinically.


How effective are clinical pathways with and without online peer-review? An analysis of bone metastases pathway in a large, integrated National Cancer Institute-Designated Comprehensive Cancer Center Network.
Clinical pathways are an important tool used to manage the quality in health care by standardizing processes. This study evaluated the impact of the implementation of a peer-reviewed clinical pathway in a large, integrated National Cancer Institute-Designated Comprehensive Cancer Center Network. In 2003, we implemented a clinical pathway for the management of bone metastases with palliative radiation therapy. In 2009, we required the entry of management decisions into an online tool that records pathway choices. The pathway specified 1 or 5 fractions for symptomatic bone metastases with the option of 10-14 fractions for certain clinical situations. The data were obtained from 13 integrated sites (3 central academic, 10 community locations) from 2003 through 2010. In this study, 7905 sites were treated with 64% of courses delivered in community practice and 36% in academic locations. Academic practices were more likely than community practices to treat with 1-5 fractions (63% vs. 23%; p < 0.0001). The number of delivered fractions decreased gradually from 2003 to 2010 for both academic and community practices (p < 0.0001); however, greater numbers of fractions were selected more often in community practices (p < 0.0001). Using multivariate logistic regression, we found that a significantly greater selection of 1-5 fractions developed after implementation online pathway monitoring (2009) with an odds ratio of 1.2 (confidence interval, 1.1-1.4) for community and 1.3 (confidence interval, 1.1-1.6) for academic practices. The mean number of fractions also decreased after online peer review from 6.3 to 6.0 for academic (p = 0.07) and 9.4 to 9.0 for community practices (p < 0.0001). This is one of the first studies to examine the efficacy of a clinical pathway for radiation oncology in an integrated cancer network. Clinical pathway implementation appears to be effective in changing patterns of care, particularly with online clinical peer review as a valuable aid to encourage adherence to evidence-based practice.


Environmental impacts of three Asian dust events in the northern China and the northwestern Pacific in spring 2021.
In March 2021, China experienced three dust events (Dust-1, 2, 3), especially the first of which was reported as the strongest one in recent ten years. Their environmental impacts have received great attention, demanding comprehensive study to assess such impacts quantitatively. Multiple advanced measurement methods, including satellite, ground-based lidar, online aerosol speciation instrument, and biogeochemical Argo float, were applied to examine and compare the transport paths, optical and chemical properties, and impacts of these three dust events on urban air quality and marine ecosystem. The results showed that Dust-1 exhibited the largest impacts on urban area, increasing PM10 concentration in Beijing, Shuozhou, and Shijiazhuang up to 7525, 3819, and 2992 μg m-3, respectively. However, due to fast movement of the Mongolian low-pressure cyclone, the duration of northwest wind over the land was quite short (e.g., only 10 h in Beijing), which prevented the transport of dust plume to the northwestern Pacific, resulting in limited impact on the ocean. Dust-2 and Dust-3, though weaker in intensity, were transported directly to the sea, and led to a substantial increase in chlorophyll-a concentration (up to near 3 times) in the northwestern Pacific, comparing to climatological value. This indicates that the impacts of dust events on ocean was not necessarily and positively correlated to their impacts on land. Based on the analyses of land-ocean-space integrated observational data and synoptic systems, this study examined how marine ecosystem responded to three significant Asian dust events in spring 2021 and quantitatively assessed the overall impacts of mega dust storms both on land and ocean, which could also provide an interdisciplinary research methodology for future research on strong aerosol emission events such as wildfire and volcanic eruption.


Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator.
Tumor-associated macrophages (TAM) promote malignant progression, yet the repertoire of oncogenic factors secreted by TAM has not been clearly defined. We sought to analyze which EGFR- and STAT3-activating factors are secreted by monocytes/macrophages exposed to tumor cell-secreted factors. Following exposure of primary human monocytes and macrophages to supernatants of a variety of tumor cell lines, we have analyzed transcript and secreted protein levels of EGFR family ligands and of STAT3 activators. To validate our findings, we have analyzed TAM infiltration levels, systemic and local protein levels as well as clinical data of primary breast cancer patients. Primary human monocytes and macrophages respond to tumor cell-derived factors by secreting EGFR- and STAT3-activating ligands, thus inducing two important oncogenic pathways in carcinoma cells. Tumor cell-secreted factors trigger two stereotype secretory profiles in peripheral blood monocytes and differentiated macrophages: monocytes secrete epiregulin (EREG) and oncostatin-M (OSM), while macrophages secrete heparin-binding EGF-like growth factor (HB-EGF) and OSM. HB-EGF and OSM cooperatively induce tumor cell chemotaxis. HB-EGF and OSM are co-expressed by TAM in breast carcinoma patients, and plasma levels of both ligands correlate strongly. Elevated HB-EGF levels accompany TAM infiltration, tumor growth and dissemination in patients with invasive disease. Our work identifies systemic markers for TAM involvement in cancer progression, with the potential to be developed into molecular targets in cancer therapy.


The effects of rotator cuff tear on shoulder proprioception.
To evaluate the effects of rotator cuff tear (RCT) and its severity on shoulder proprioception. We studied 132 consecutive patients (67 M-65 F; mean age ± SD, 66.03 ± 9.04; range, 43-78) who underwent arthroscopic rotator cuff repair. Tear size was determined intra-operatively. The control group included 82 subjects (38 M-44 F; mean age ± SD, 65.87 ± 8.06; range, 41-75) with no RCT. All participants, wearing an eye mask, were submitted to the evaluation of the joint position sense (JPS) at 30°, 60°, 90°, 120°, and 150° of shoulder forward flexion during the sitting position, using a digital inclinometer securely attached to the subject's arm using hook-and-loop straps. The passive placement and active replacement method was used; the order of the tested angles was randomly selected. The entire test was repeated three times. The error score, by averaging the three trials, was measured as the absolute difference between the target angle and the observed angle. Statistics were performed. The intraclass correlation coefficient for all degrees of flexion movement measured was > 0.90, exhibiting a very high correlation. We found significant differences between cases and controls regarding the results of joint position sense error at all measurements (p < 0.05). According to RCT size, we found significant differences between groups at 30° (F = 27.27, p < 0.001), 90° (F = 5.37, p = 0.006), 120° (F = 10.76, p < 0.001), and 150° (F = 30.93, p < 0.001) of shoulder flexion; in details, patients with massive RCT showed greater absolute error value than those with both small and large RCT at 30°, 90°, 120°, and 150° of shoulder flexion (p < 0.05). RCT provokes an alteration of shoulder proprioception, evaluated as the loss of joint position sense, and the impairment is related to tear severity.


Differences in structural parameters in patients with open-angle glaucoma, high myopia and both diseases concurrently. A pilot study.
To evaluate the differences in structural parameters in patients with open-angle glaucoma (OAG), high myopia (M), and both diseases (OAG-M) concurrently. 42 subjects with OAG (n = 14), M (n = 14) and OAG-M (n = 14) were included in a prospective pilot study. Mean peripapillary retinal nerve fiber layer (RNFL) thickness, RNFL in superior, temporal, inferior, nasal quadrants, macular ganglion cell complex (GCC) and its' layers, vessel density (VD) of optic nerve head (ONH) and macula were evaluated. The OAG-M group showed significantly lowest thickness of mean peripapillary RNFL 89 (49-103) μm (p = 0.021), temporal quadrant 64.5 (51-109) μm (p = 0.001) and inferior quadrant 107 (64-124) μm (p = 0.025). The macular RNFL was thinnest in the OAG-M group (p <0.001). Macular VD in inferior quadrant was lowest in OAG-M group at superficial capillary plexus 45.92 (40.39-51.72) % (p = 0.014) and choriocapillaris 51.62 (49.87-56.63) % (p = 0.035). The lowest ONH VD of temporal quadrant was found in the OAG-M group 52.15 (35.73-59.53) % (p = 0.001) in the superficial capillary plexus. Similarly, the lowest VD of inferior quadrant was found in OAG-M group in the choriocapillaris 54.42 (46.31-64.64) % (p<0.001). The M group showed the least thinning in the peripapillary RNFL thickness in the temporal quadrant and macular RNFL compared to other two groups. The highest macular VD in the inferior quadrant was in the M group in the superficial capillary plexus, deep capillary plexus and choriocapillaris. The M group showed highest VD in the temporal quadrant and in total VD of ONH at the superficial capillary plexus and in total VD of ONH at the deep capillary plexus. The observed decrease in peripapillary RNFL thickness of the temporal quadrant, macular RNFL thickness, the decrease of macular VD at the inferior quadrant and decrease in VD of the ONH temporal quadrant in deep capillary plexus could be beneficial for diagnosing glaucoma in high myopia.


Established and novel circulating neuroendocrine tumor biomarkers for diagnostic, predictive and prognostic use.
The management of neuroendocrine tumors (NETs) represents a clinical challenge due to heterogeneity of their clinical behaviour, molecular biology and response to treatment. Over the years, several circulating biomarkers have been developed for the early diagnosis and follow-up of NETs. The specific secretory products of tumors associated with a secretory syndrome (functioning tumors) may be used as diagnostic and/or prognostic biomarkers while the most common non-specific circulating biomarkers, that may be increased in both functioning and non-functioning tumors, are chromogranin A and the neuron specific enolase. However, the diagnostic accuracy as well as the prognostic and predictive value of these biomarkers are limited and novel techniques of multianalyte analysis of regulators of tumor biology have been developed. The NETest has been most extensively studied and proved to be useful in NET diagnosis, early detection of post-operative recurrence and prediction of response to treatment but further investigation establishing higher level of evidence is required for implementation in clinical practice.


Resolution and segmentation of hyperspectral biomedical images by multivariate curve resolution-alternating least squares.
MCR-ALS is a resolution method that has been applied in many different fields, such as process analysis, environmental data and, recently, hyperspectral image analysis. In this context, the algorithm provides the distribution maps and the pure spectra of the image constituents from the sole information in the raw image measurement. Based on the distribution maps and spectra obtained, additional information can be easily derived, such as identification of constituents when libraries are available or quantitation within the image, expressed as constituent signal contribution. This work summarizes first the protocol followed for the resolution on two examples of kidney calculi, taken as representations of images with major and minor compounds, respectively. Image segmentation allows separating regions of images according to their pixel similarity and is also relevant in the biomedical field to differentiate healthy from non-healthy regions in tissues or to identify sample regions with distinct properties. Information on pixel similarity is enclosed not only in pixel spectra, but also in other smaller pixel representations, such as PCA scores. In this paper, we propose the use of MCR scores (concentration profiles) for segmentation purposes. K-means results obtained from different pixel representations of the data set are compared. The main advantages of the use of MCR scores are the interpretability of the class centroids and the compound-wise selection and preprocessing of the input information in the segmentation scheme.


Mitochondriotropic antioxidant based on caffeic acid AntiOxCIN4 activates Nrf2-dependent antioxidant defenses and quality control mechanisms to antagonize oxidative stress-induced cell damage.
Mitochondria are key organelles involved in cellular survival, differentiation, and death induction. In this regard, mitochondrial morphology and/or function alterations are involved in stress-induced adaptive pathways, priming mitochondria for mitophagy or apoptosis induction. We have previously shown that the mitochondriotropic antioxidant AntiOxCIN4 (100 μM; 48 h) presented significant cytoprotective effect without affecting the viability of human hepatoma-derived (HepG2) cells. Moreover, AntiOxCIN4 (12.5 μM; 72 h) caused a mild increase of reactive oxygen species (ROS) levels without toxicity to primary human skin fibroblasts (PHSF). As Nrf2 is a master regulator of the oxidative stress response inducing antioxidant-encoding gene expression, we hypothesized that AntiOxCIN4 could increase the resistance of human hepatoma-derived HepG2 to oxidative stress by Nrf2-dependent mechanisms, in a process mediated by mitochondrial ROS (mtROS). Here we showed that after an initial decrease in oxygen consumption paralleled by a moderate increase in superoxide anion levels, AntiOxCIN4 led to a time-dependent Nrf2 translocation to the nucleus. This was followed later by a 1.5-fold increase in basal respiration and a 1.2-fold increase in extracellular acidification. AntiOxCIN4 treatment enhanced mitochondrial quality by triggering the clearance of defective organelles by autophagy and/or mitophagy, coupled with increased mitochondrial biogenesis. AntiOxCIN4 also up-regulated the cellular antioxidant defense system. AntiOxCIN4 seems to have the ability to maintain hepatocyte redox homeostasis, regulating the electrophilic/nucleophilic tone, and preserve cellular physiological functions. The obtained data open a new avenue to explore the effects of AntiOxCIN4 in the context of preserving hepatic mitochondrial function in disorders, such as NASH/NAFLD and type II diabetes.


Analysis of bacterial biotin-proteins.
The biotin-protein populations in several bacterial strains were analyzed by solubilization of [3H]biotin-labeled cells with sodium dodecylsulfate followed by electrophoresis on polyacrylamide gels containing the detergent. A variety of patterns of biotin-labeled polypeptide chains was seen, ranging from a single biotin-protein in Escherichia coli, corresponding to the biotin carboxyl carrier protein component of acetyl-CoA carboxylase, to multiple species in Enterobacter aerogenes, Pseudomonas citronellolis, Bacillus cereus, Propionibacterium shermanii, Lactobacillus plantarum, and Mycobacterium phlei, which probably represent subunits of multiple biotin-dependent enzymes present in these organisms. In the case of Pseudomonas citronellolis two major biotin-containing polypeptides with approximate molecular weights of 65 000 and 25 000 were shown to correspond to the biotin carboxyl carrier components of pyruvate carboxylase and acetyl-CoA carboxylase, respectively. Thus in the case of Pseudomonas citronellolis two different biotin-dependent enzymes in the same cell do not share common biotin carboxyl carrier subunits.


Age-dependent neuronal and synaptic degeneration in mice transgenic for the C terminus of the amyloid precursor protein.
The molecular basis for the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature in Alzheimer's disease (AD) is incompletely understood. We have proposed that one molecule common to these abnormal processes is a fragment of the Alzheimer amyloid precursor protein (APP) comprising the C-terminal 100 amino acids of this molecule (APP-C100). We tested this hypothesis by creating transgenic mice expressing APP-C100 in the brain. We report here that aging (18-28 month) APP-C100 transgenic mice exhibit profound degeneration of neurons and synapses in Ammon's horn and the dentate gyrus of the hippocampal formation. Of the 106 transgenic mice between 8 and 28 months of age that were examined, all of those older than 18 months displayed severe hippocampal degeneration. The numerous degenerating axonal profiles contained increased numbers of neurofilaments, whorls of membrane, and accumulations of debris resembling secondary lysosomes near the cell body. The dendrites of degenerating granule and pyramidal cells contained disorganized, wavy microtubules. Cerebral blood vessels had thickened refractile basal laminae, and microglia laden with debris lay adjacent to larger venous vessels. Mice transgenic for Flag-APP-C100 (in which the hydrophilic Flag tag was fused to the N terminus of APP-C100) showed a similar degree of neurodegeneration in the hippocampal formation as early as 12 months of age. The 45 control mice displayed only occasional necrotic cells and no extensive cell degeneration in the same brain regions. These findings show that APP-C100 is capable of causing some of the neuropathological features of AD.


Treatment outcomes of mucosal melanoma of the head and neck: Analysis of 190 cases from a single institution.
To analyze the treatment outcomes and prognostic factors of mucosal melanoma of the head and neck (MMHN) from a single institution. From December 1989 to November 2018, 190 patients diagnosed with MMHN were included. Survival analysis was performed using the Kaplan-Meier method for univariate analysis with a log-rank test for significance and Cox regression for multivariate analysis. With a median follow-up time of 43.5 months, 126 (68.5%) patients died. The median DSS was 35 months. The 3- and 5-year disease-specific survival (DSS) rates were 48.1% and 33.7%, respectively. The median overall survival (OS) was 34 months. The 3- and 5-year OS rates were 47.0% and 32.9%, respectively. In univariate analysis, the T3 stage, received surgery, R0 resection, and combined therapy (surgery+biotherapy/biochemotherapy) were significantly associated with better survival. Multivariable Cox regression analysis revealed that the T4 stage (HR = 1.692; 95% CI, 1.175-2.438; p = .005) and the N1 stage (HR = 1.600; 95% CI, 1.023-2.504; p = .039) were strong prognostic factors for poor survival, and that combined therapy (surgery+biotherapy/biochemotherapy) was a strong prognostic factor for better survival outcome (HR = 0.563; 95% CI, 0.354-0.896; p = .015). The prognosis of MMHN remains poor. Systemic treatment is warranted to reduce MMHN progression. Surgery combined with biotherapy may improve survival.


Development and validation of chemical kindling in adult zebrafish: A simple and improved chronic model for screening of antiepileptic agents.
Zebrafish has emerged as a potential animal model of acute convulsion for early screening of antiepileptic agents. There is a need for alternative chronic zebrafish models of epilepsy with more correlation to the clinical condition. Adult zebrafish were repeatedly exposed to subeffective concentrations of pentylenetetrazole (PTZ), until appearance to tonic-clonic seizures, considered as kindled. Valproic acid (VPA) exposure was given during kindling and in kindled fish in 2 different groups. The neurotransmitters level and expression of the genes associated with kindling were studied in the fish brain. There was an increase in seizure severity score at 1.25 mM concentration of PTZ, and 66.66 % of fish achieved kindling after 22 days' exposure. A marked increase in c-fos, crebbpa and crebbpbexpression, and glutamate/GABA level was observed in the brain of kindled fish. VPA inhibited the induction of PTZ-mediated kindling and reduced seizure severity in kindled fish. In contrast to an existing adult zebrafish kindling method, the present protocol is of longer duration, with more similarity to clinical epilepsy. Moreover, the induction of kindling involves a simple non-invasive technique without the use of anesthesia. The protocol can be used for evaluation of both antiepileptic and antiepileptogenic agents. Repeated exposure of 1.25 mM PTZ induced kindling in zebrafish, altering the brain neurotransmitter levels and gene expression. Inhibition of kindling induction and decrease in seizures in normal and kindled fish, respectively by VPA validated application of the model for preclinical testing of agents against epilepsy.


The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer.
Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein--a finding that correlates with increased numbers of autophagosomes--and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of "autophagy addiction" because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer.


Correction: Postnatal Anthropometric and Body Composition Profiles in Infants with Intrauterine Growth Restriction Identified by Prenatal Doppler.
[This corrects the article DOI: 10.1371/journal.pone.0150152.].


Pharmacist's Comprehensive Geriatric Assessment: Introduction and Evaluation at Elderly Patient Admission.
The role of the clinical pharmacist within the healthcare system remains unclear. Our objective was to describe a pharmacist's comprehensive geriatric assessment (pCGA) at admission of elderly patients and to assess its relevance in terms of medication compliance and pharmacist interventions (PIs). We conducted a prospective interventional study over 29 months in a 34-bed medical/rehabilitation geriatric ward in a French geriatric hospital. At admission, patients received pharmaceutical care through a consistent three-step process: (1) pharmacists met with the patient to undertake cognitive screening and assess their medication adherence (using the Girerd score) and medication history; (2) medication reconciliation was conducted at admission to detect intentional and unintentional discrepancies in treatment; and (3) clinical medication review was carried out throughout the patient's stay. The pharmacist conveyed proposed interventions to optimise treatment to the physician through the electronic health record. The number and type of PIs and their rate of implementation were recorded. In total, 539 patients aged >65 years were included; their mean age was 84 years. Cognitive screening showed that 45% of patients were confused at admission. Medication adherence assessment indicated that 50.2% had adherence problems. Medication reconciliation at admission detected discrepancies in 48%, with a mean of 1.09 unintended discrepancies per patient. Patients were taking an average of 7 ± 3 drugs. In total, 828 PIs were reported to physicians; 520 were accepted and implemented (62.8% acceptance rate). This approach helps to avoid medication errors and enables the suggestion of relevant PIs, which were implemented by physicians in two-thirds of cases.


Association between dementia and discharge status in patients hospitalized with pneumonia.
Pneumonia is the most common cause of death in patients with dementia, but the outcomes of patients with dementia hospitalized with pneumonia are poorly understood. We sought to illuminate the association between dementia and in-hospital mortality and discharge status in patients hospitalized with pneumonia. We used the Diagnosis Procedure Combination database, a national inpatient database in Japan, to identify retrospectively patients aged ≥60 years admitted to hospital with pneumonia during the study period of May 1, 2010 to March 31, 2014. We recorded their sex, age, body mass index, severity of pneumonia and comorbidities (including dementia). The outcomes were in-hospital mortality and discharge home. Multivariable Cox regression analysis was performed to analyze factors influencing discharge home. We identified 470,829 patients hospitalized with pneumonia; 45,031 were recorded as having dementia (9.6%). In-hospital mortality was 13.1% and 13.4% in patients with and without dementia, respectively (P = 0.63). The proportions of patients discharged home were 52.9% and 71.3% in patients with and without dementia, respectively (P < 0.001). The adjusted hazard ratio for discharge home for patients with dementia was 0.68 (95% confidence interval, 0.67-0.69; P < 0.001). In-hospital mortality from pneumonia did not differ significantly between patients with and without dementia; however, those with dementia were less likely to be discharged home.


Molecular mechanisms for the variation of mitochondrial gene content and gene arrangement among chigger mites of the genus Leptotrombidium (Acari: Acariformes).
The gene content of a mitochondrial (mt) genome, i.e., 37 genes and a large noncoding region (LNR), is usually conserved in Metazoa. The arrangement of these genes and the LNR is generally conserved at low taxonomic levels but varies substantially at high levels. We report here a variation in mt gene content and gene arrangement among chigger mites of the genus Leptotrombidium. We found previously that the mt genome of Leptotrombidium pallidum has an extra gene for large-subunit rRNA (rrnL), a pseudo-gene for small-subunit rRNA (PrrnS), and three extra LNRs, additional to the 37 genes and an LNR typical of Metazoa. Further, the arrangement of mt genes of L. pallidum differs drastically from that of the hypothetical ancestor of the arthropods. To find to what extent the novel gene content and gene arrangement occurred in Leptotrombidium, we sequenced the entire or partial mt genomes of three other species, L. akamushi, L. deliense, and L. fletcheri. These three species share the arrangement of all genes with L. pallidum, except trnQ (for tRNA-glutamine). Unlike L. pallidum, however, these three species do not have extra rrnL or PrrnS and have only one extra LNR. By comparison between Leptotrombidium species and the ancestor of the arthropods, we propose that (1) the type of mt genome present in L. pallidum evolved from the type present in the other three Leptotrombidium species, and (2) three molecular mechanisms were involved in the evolution of mt gene content and gene arrangement in Leptotrombidium species.


Carnosine and its (S)-Trolox™ derivative protect animals against oxidative stress.
The novel synthetic derivative of carnosine, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-β-alanyl-L-histidine (S-Trolox™-Carnosine, STC) increases the resistance of rats to experimental acute hypobaric hypoxia (AHH) thus protecting brain from the oxidative damage. This effect is accompanied by better preservation of the acquired skills in Morris water maze possibly by increasing efficiency of the brain antioxidant system. In addition, STC caused an increase in life span of both male and female fruit fly Drosophila melanogaster whereas carnosine increased life span only in male fruit flies. The results indicate that development of the drug based on STC could be beneficial in neurology and gerontology.


The role of depression in the association between physiotherapy frequency and duration and outcomes after hip fracture surgery: secondary analysis of the physiotherapy hip fracture sprint audit.
It is not known whether the association between the frequency and duration of physiotherapy and patient outcomes varies for those with and without depression. This study aims to evaluate whether the associations between the frequency and duration of physiotherapy after hip fracture surgery and discharge home, surviving at 30 days post-admission, and being readmitted 30 days post discharge vary by depression diagnosis. Data were from 5005 adults aged 60 and over included in the UK Physiotherapy Hip Fracture Sprint Audit who had undergone surgery for a nonpathological first hip fracture. Logistic regression models were used to estimate the unadjusted and adjusted odds ratios and their 95% confidence intervals for the associations between physiotherapy frequency and duration and outcomes. Physiotherapy frequency and duration were comparable between patients with and without depression (42.1% and 44.6%). The average adjusted odds for a 30-min increase in physiotherapy duration for those with and without depression for discharge home were 1.05 (95% CI 0.85-1.29) vs 1.16 (95% CI 1.05-1.28, interaction p = 0.36), for 30-day survival were 1.26 (95% CI 1.06-1.50) vs 1.11 (95% CI 1.05-1.17, interaction p = 0.45) and for readmission were 0.89 (95% CI 0.81-0.98) vs 0.97 (95% CI 0.93-1.00, interaction p = 0.09). None of the interaction tests reached formal significance, but the readmission models were close (p = 0.09). Results suggest physiotherapy duration may be negatively associated with readmission in those with depression but not those without depression, while no clear difference in the other outcomes was noted.


Demonstration of leapfrogging for implementing nonlinear model predictive control on a heat exchanger.
This work reveals the applicability of a relatively new optimization technique, Leapfrogging, for both nonlinear regression modeling and a methodology for nonlinear model-predictive control. Both are relatively simple, yet effective. The application on a nonlinear, pilot-scale, shell-and-tube heat exchanger reveals practicability of the techniques.


Hematopoietic Jagged1 is a fetal liver niche factor required for functional maturation and engraftment of fetal hematopoietic stem cells.
Notch signaling is essential for the emergence of definitive hematopoietic stem cells (HSCs) in the embryo and their development in the fetal liver niche. However, how Notch signaling is activated and which fetal liver cell type provides the ligand for receptor activation in HSCs is unknown. Here we provide evidence that endothelial Jagged1 (Jag1) has a critical early role in fetal liver vascular development but is not required for hematopoietic function during fetal HSC expansion. We demonstrate that Jag1 is expressed in many hematopoietic cells in the fetal liver, including HSCs, and that its expression is lost in adult bone marrow HSCs. Deletion of hematopoietic Jag1 does not affect fetal liver development; however, Jag1-deficient fetal liver HSCs exhibit a significant transplantation defect. Bulk and single-cell transcriptomic analysis of HSCs during peak expansion in the fetal liver indicates that loss of hematopoietic Jag1 leads to the downregulation of critical hematopoietic factors such as GATA2, Mllt3, and HoxA7, but does not perturb Notch receptor expression. Ex vivo activation of Notch signaling in Jag1-deficient fetal HSCs partially rescues the functional defect in a transplant setting. These findings indicate a new fetal-specific niche that is based on juxtracrine hematopoietic Notch signaling and reveal Jag1 as a fetal-specific niche factor essential for HSC function.


De novo expression of CD44 variants in sporadic and hereditary gastric cancer.
CD44 is the major ubiquitously expressed cell surface receptor for hyaluronate. The CD44 gene encodes several protein isoforms due to extensive alternative splicing and post-translational modifications. Some of these CD44 variable isoforms have been foreseen as key players in malignant transformation and their expression is highly restricted and highly specific, unlike the canonical CD44 standard isoform. In this study, we aimed at dissecting the mRNA splicing pattern of CD44 in normal stomach and gastric cancer (GC) cell lines (n=9) using cloning and quantitative mRNA amplification assays. Moreover, we assessed the RNA levels and protein expression pattern of relevant splicing forms in distinct premalignant and malignant gastric lesions (sporadic (n=43) and hereditary (n=3) forms) using real-time RT-PCR and immunohistochemistry. We also explored the association of CD44 and E-cadherin expression by immunohistochemistry, as E-cadherin has a pivotal functional role in GC. We established the pattern of CD44 variant forms in normal stomach and gastric malignancy. We observed that although exon v6-containing isoforms were rarely expressed in normal gastric mucosa, they became increasingly expressed both in gastric premalignant (hyperplastic polyps, complete and incomplete intestinal metaplasia, low- and high-grade dysplasia) and malignant lesions (cell lines derived from GCs, primary sporadic GCs and hereditary diffuse GCs (HDGCs)). Moreover, we verified that whenever E-cadherin expression was absent, exon v6-containing CD44 isoforms were overexpressed. The lack of expression of CD44 isoforms containing exon v6 in the surface and foveolar epithelia of normal stomach and, its de novo expression in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach, pinpoint CD44 v6-containing isoforms as potential biomarkers for early transformation of the gastric mucosa. Further, our results raise the hypothesis of using CD44v6 as a marker of early invasive intramucosal carcinoma in HDGC CDH1 mutation carriers that lack CDH1 expression in their tumors.


S100A4 is expressed in human odontoblasts and odontoblast-like cells.
The calcium-binding protein S100A4 has been found in fibroblasts in many tissues. It has been well studied in the regulating process of inflammation and tumor metastasis. However, as a calcium regulating protein, its expression in the dental pulp has not yet been elucidated. The aim of this study was to investigate the in situ expression of S100A4 in dental pulp tissue. Five intact and three carious human teeth were collected and sectioned. Hematoxylin and eosin (HE) staining was used to locate areas reflecting the characteristics of the tooth. Based on this initial evaluation, the slides adjacent to these areas were immunohistochemically stained with S100A4 and dentin sialophosphoprotein (DSPP) antibodies. In both the crown and root, S100A4 staining was observed in the odontoblast layer and in odontoblast-like cells, but not in other pulp cells. In contrast, DSPP was expressed in most cells of the dental pulp. S100A4 is expressed in the odontoblast layer and in odontoblast-like cells in mature human pulp tissue. This protein can be used as a marker to differentiate these two kinds of cells from pulp cells.


Qualitative and quantitative metals liberation assessment for characterization of various waste printed circuit boards for recycling.
Metals liberation and composition are decisive attributes in characterization of e-waste for metal recycling. Though end-of-life printed circuit board (PCB) is an integral part of e-waste as secondary resource reservoir, yet no standardized procedure exists for metals liberation and dissolution for its characterization. Thus, the paper aims at assessment of metals liberation upon comminution employing scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDS) followed by comparative assessment of the existing United States Environmental Protection Agency (USEPA) digestion procedures, viz., USEPA 3050B, USEPA 3051A, and USEPA 3052, in effective dissolution of metals from comminuted particles of waste PCBs of computer, laptop, mobile phone, and television. Effect of comminution and digestion conditions was assessed to have significant role in metal liberation and dissolution from PCBs. The SEM-EDS analysis demonstrated partial release of metals from the silica matrix of PCBs. The USEPA digestion methods showed statistically significant (P < 0.05) difference with greater dissolution of metals complexed to PCB matrix by the USEPA 3052 method owing to use of strong acid like hydrofluoric acid. Base metals like Cu and Zn and toxic metals such as Pb and Cd were present in abundance in PCBs and in general exceeded the total threshold limit concentration (TTLC). The maximum contents of Cu (20.13 ± 0.04 wt.%) and Zn (1.89 ± 0.05 wt.%) in laptop PCBs, Pb (2.26 ± 0.08 wt.%) in TV PCBs, and Cd (0.0812 ± 0.0008 wt.%) in computer PCBs were observed.


Usefulness of linkage disequilibrium of KM-19 and XV-2c DNA probes for genetic counselling in a high-risk CF family.
A French couple with an individual risk of carrying the cystic fibrosis (CF) mutation of 1/2 sought genetic counselling. From the DNA haplotypes generated by XV-2c and KM-19 RFLPs, it could be deduced that only one subject was a carrier, lowering the risk of having a CF baby from 1/16 to 1/200. The strong linkage disequilibrium between these RFLPs and the CF allele observed in France reduced the risk to 1/1600.