Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies.
Cerebellar degeneration-related protein 2 (CDR2) has been presumed to be the main antigen for the onconeural antibody Yo, which is strongly associated with ovarian cancer and paraneoplastic cerebellar degeneration (PCD). Recent data show that Yo antibodies also target the CDR2-like protein (CDR2L). We, therefore, examined the expression of CDR2 and CDR2L in ovarian cancer tissue from patients with and without Yo antibodies and from various other cancerous and normal human tissues. Ovarian cancer tissue and serum samples from 16 patients were included in the study (four with anti-Yo and PCD, two with anti-Yo without PCD, five with only CDR2L antibodies, and five without onconeural antibodies). Clinical data were available for all patients. The human tissues were examined by western blot and immunohistochemistry using rabbit CDR2 and CDR2L antibodies. Ovarian cancers from all 16 patients expressed CDR2 and CDR2L proteins. Both proteins were also present in normal and cancer tissue from mammary tissue, kidney, ovary, prostate, and testis. CDR2L is present in ovarian cancers from patients with and without Yo antibodies as was shown previously for CDR2. In addition, both CDR2 and CDR2L proteins are more widely expressed than previously thought, both in normal and cancerous tissues.


Determination of the Absolute Configuration of (-)-Hydroxynitrilaphos and Related Biosynthetic Questions.
The ongoing search for bioactive natural products has led to the development of new genome-based screening approaches to identify possible phosphonate producing microorganisms. From the identified phosphonate producers, several until now unknown phosphonic acid natural products were isolated, including (hydroxy)nitrilaphos (4 and 5) and (hydroxy)phosphonocystoximate (7 and 6). We present the synthesis of phosphonocystoximate via an aldoxime intermediate. Chlorination and coupling with methyl N-acetylcysteinate furnished 6 after global deprotection. The obtained experimental data confirm the previously assigned structure of the natural product. We were also able to determine the absolute configuration of (-)-hydroxynitrilaphos. Chiral resolution of diethyl cyanohydroxymethylphosphonate (24) with Noe's lactol furnished both enantiomers of 4. Conversion of (+)-24 to (R)-2-amino-1-hydroxyethylphosphonic acid by reduction of the cyano-group showed (-)-hydroxynitrilaphos ultimately to be S-configured. Further, we present a 13 C-isotope labeling strategy for 4 and 5 that will possibly solve the question of whether hydroxynitrilaphos is a biosynthetic intermediate or a downstream product of hydroxyphosphonocystoximate biosynthesis.


Novel RNA aptamers targeting gastrointestinal cancer biomarkers CEA, CA50 and CA72-4 with superior affinity and specificity.
Gastric cancer is the third most common cause of death from cancer in the world and it remains difficult to cure in Western countries, primarily because most patients present with advanced disease. Currently, CEA, CA50 and CA72-4 are commonly used as tumor markers for gastric cancer by immunoassays. However, the drawback and conundrum of immunoassay are the unceasing problem in standardization of quality of antibodies and time/effort for the intensive production. Therefore, there is an urgent need for the development of a standardized assay to detect gastric cancer at the early stage. Aptamers are DNA or RNA oligonucleotides with structural domain which recognize ligands such as proteins with superior affinity and specificity when compared to antibodies. In this study, SELEX (Systematic Evolution of Ligands by Exponential enrichment) technique was adopted to screen a random 30mer RNA library for aptamers targeting CEA, CA50 and CA72-4 respectively. Combined with high-throughput sequencing, we identified 6 aptamers which specifically target for these three biomarkers of gastrointestinal cancer. Intriguingly, the predicted secondary structures of RNA aptamers from each antigen showed significant structural similarity, suggesting the structural recognition between the aptamers and the antigens. Moreover, we determined the dissociation constants of all the aptamers to their corresponding antigens by fluorescence spectroscopy, which further demonstrated high affinities between the aptamers and the antigens. In addition, immunostaining of gastric adenocarcinoma cell line AGS using CEA Aptamer probe showed positive fluorescent signal which proves the potential of the aptamer as a detection tool for gastric cancer. Furthermore, substantially decreased cell viability and growth were observed when human colorectal cell line LS-174T was transfected with each individual aptamers. Taking together, these novel RNA aptamers targeting gastrointestinal cancer biomarker CEA, CA50 and CA72-4 will aid further development and standardization of clinical diagnostic method with better sensitivity and specificity, and potentially future therapeutics development of gastric cancer.


Micropropagation of Polygonum multiflorum THUNB and quantitative analysis of the anthraquinones emodin and physcion formed in in vitro propagated shoots and plants.
An efficient and rapid protocol for in vitro induction and complete plant regeneration of Polygonum multiflorum THUNB has been developed. Nodal explants were grown in vitro on Murashige and Skoog's (MS) basal medium containing different concentrations of alpha-naphthaleneacetic acid (NAA) and benzyladenine (BA). The nodal explants (97%) produced multiple shoots (4.7 shoots per explant) on MS basal medium supplemented with 0.2 mg/l NAA and 2.0 mg/l BA after 6 weeks of culture. Eighty-eight percent to 100% of the shoots (1.0 cm in length) elongated (about 3.02-4.28 cm) and rooted on MS basal medium supplemented with NAA or indole-3-butyric acid (IBA). All the rooted shoots were transferred to pots containing autoclaved soil, vermiculite, and peat moss (1 : 1 : 1). The plantlets were successfully acclimatized under greenhouse conditions with high humidity before transferring to the field. The anthraquinone contents were determined using HPLC. Analysis revealed that the contents of the major medicinal compounds-emodin and physcion in the 6 weeks old in vitro grown shoots and three month old in vitro propagated plants grown in greenhouse were higher than those of the marketed crude drug (processed underground or stem parts of P. multiflorum).


Potential novel markers in IBD and CRC diagnostics. Are MMP-19 and RAGE promising candidates?
Inflammatory bowel diseases and colorectal cancer are serious intestinal disorders with continuously increasing incidence. Many aspects of etiopathogenesis still remain unclear. There is an urgent need to improve early diagnostics and markers indicating the progression of the disease. The aim of our study was to analyze the expression of matrix metalloproteinase-19 (MMP-19), and the receptor for advanced glycation end-products (RAGE) in different cell subpopulations in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) compared to the tissue in the vicinity of pathological processes. Expression of both markers in epithelium, macrophages and vessels were evaluated in IBD and CRC groups. They were detected using immunohistochemistry in paraffin sections. There were significant differences between the expression of MMP-19 on macrophages and vessels among healthy and cancer tissues. In both, macrophages and vessels were significantly lower levels in cancer tissues. The expression of MMP-19 on vessels was also significantly different between peritumoral and cancer tissues (higher levels in peritumoral tissue). RAGE expression in macrophages was significantly different between healthy and cancer tissues and between peritumoral and cancer tissues. There was significantly lower expression in cancer tissues than in healthy and peritumoral tissues. Expression of RAGE in vessels was significantly different just in the comparison of healthy and peritumoral tissues (higher levels in healthy tissues). Both markers seem to be promising potential auxiliary markers in IBD and CRC diagnostics. They can also improve evaluation of disease progression.


Real-time imaging of drug-induced trapping of cellular topoisomerases and poly(ADP-ribose) polymerase 1 at the single-molecule level.
Topoisomerases (TOP1, TOP2α, and β) are nuclear enzymes crucial for virtually all aspects of DNA metabolisms. They also are the targets of important anti-tumor chemotherapeutics that act by trapping the otherwise reversible topoisomerase-DNA covalent complex intermediates (TOPccs) that are formed during their catalytic reactions, resulting in long-lived topoisomerase DNA-protein crosslinks (TOP-DPCs) that interfere with DNA transactions. The Poly(ADP-ribose) polymerase (PARP) family protein PARP1 is activated by DNA damage to recruit DNA repair proteins, and PARP inhibitors are another class of commonly used chemotherapeutics, which bind and trap PARP molecules on DNA. To date, the trapping of TOPccs and PARP by their respective inhibitors can only be measured by immune-biochemical methods in cells. Here, we developed an imaging-based approach enabling real-time monitoring of drug-induced trapping of TOPccs and PARP1 in live cells at the single-molecule level. Capitalizing on this approach, we calculated the fraction of self-fluorescence tag-labeled topoisomerases and PARP single-molecules that are trapped by their respective inhibitors in real time. This novel technique should help elucidate the molecular processes that repair TOPcc and PARP trapping and facilitate the development of novel topoisomerase and PARP inhibitor-based therapies.


Incidence Rates of Myomectomy-Related Mortality and Venous Thromboembolism in South Korea: A Population-Based Study.
Uterine leiomyomas are the most commonly observed pathologies, with an estimated prevalence of 4. 5-68.6%. We aimed to calculate myomectomy-related mortality and venous thromboembolism incidence rates in the Republic of Korea. The data of patients who underwent myomectomy (2009-2018) were obtained from the Health Insurance Review and Assessment Service-National Inpatient Sample. The mortality rate after myomectomy was calculated using the leiomyoma diagnostic codes and myomectomy procedure codes. The incidence rates of venous thromboembolism, deep vein thrombosis, and pulmonary embolism were calculated using their diagnostic codes, with concomitant use of an antithrombotic agent during the same period or within 90 days after myomectomy. The data of 23,549 women aged 15-55 years who underwent myomectomy were extracted. The myomectomy rate was 14.6 ± 0.1 per 10,000 patients. The average age was 39.39 ± 0.04 years. One patient who underwent myomectomy died; this patient did not have concomitant venous thromboembolism. The post-myomectomy mortality rate was 1.3 ± 0.8 per 10,000 patients. The incidence rates of venous thromboembolism, deep vein thrombosis, and pulmonary embolism after myomectomy were 5.7 ± 1.6 per 10,000 patients, 4.4 ± 1.4 per 10,000 patients, and 2.5 ± 1 per 10,000 patients, respectively. The conversion rate to hysterectomy was 2.9 ± 1.1 per 10,000 patients. The current mortality rate after myomectomy (0.013%) is substantially lower than that described in previous studies at the turn of the 20th century. The incidence of venous thromboembolism is also considerably lower than that in the general population worldwide.


Lipidomics Workflow for Analyzing Lipid Profiles Using Multiple Reaction Monitoring (MRM) in Liver Homogenate of Mice with Non-alcoholic Steatohepatitis (NASH).
Non-alcoholic steatohepatitis (NASH) is a condition characterized by inflammation and hepatic injury/fibrosis caused by the accumulation of ectopic fats in the liver. Recent advances in lipidomics have allowed the identification and characterization of lipid species and have revealed signature patterns of various diseases. Here, we describe a lipidomics workflow to assess the lipid profiles of liver homogenates taken from a NASH mouse model. The protocol described below was used to extract and analyze the metabolites from the livers of mice with NASH by liquid chromatography-mass spectrometry (LC-MS); however, it can be applied to other tissue homogenate samples. Using this method, over 1,000 species of lipids from five classes can be analyzed in a single run on the LC-MS. Also, partial elucidation of the identity of neutral lipid (triacylglycerides and diacylglycerides) aliphatic chains can be performed with this simple LC-MS setup. Key features Over 1,000 lipid species (sphingolipids, cholesteryl esters, neutral lipids, phospholipids, fatty acids) are analyzed in one run. Analysis of liver lipids in non-alcoholic steatohepatitis (NASH) mouse model. Normal-phase chromatography coupled to a triple quadrupole mass spectrometer.


An improved barnacle attachment inhibition assay.
The Balanus amphitrite attachment inhibition assay, developed by Rittschof et al. (1992), has been widely used for screening antifouling compounds. One shortcoming of this assay, however, is the low (often < 40%) attachment rate of cyprids, including in the controls that contain seawater only. In this study, trapping of cyprids at the air-water interface was found to be a main contributor to the low attachment rate. Procedures to eliminate the air-water interface were thus introduced. With the improved bioassay, a much higher cyprid attachment rate (>70%) was attained. To further illustrate the usefulness of the improved assay (ie eliminating the air-water interface), the effects of the length of cyprid storage and the effect of a reference biocide, tributyltin chloride, on the survival and attachment rate of the cyprids were examined. The length of cyprid storage was important, with newly molted cyprids, 3- to 9-day old cyprids and 12-day old cyprids having an attachment rate of 43%,>75% and 36%, respectively. The low attachment rate in the newly molted cyprids was due to a high percentage of cyprids that still swam at the end of exposure period, whereas the low attachment rate in the 12-day old cyprids was due to a high mortality rate. The cyprids showed an EC50 of 22 microg l(-1) for attachment inhibition and LC50 of 25 microg l(-1) for mortality. It is concluded that the air-water interface has an important confounding effect on cyprid attachment rate in the conventional B. amphitrite attachment assay. By eliminating the air-water interface more robust quantitative assay results were obtained.


Myocardial perfusion imaging parameters: IQ-SPECT and conventional SPET system comparison.
Technological advancement in hardware and software development in myocardial perfusion imaging (MPI) leads to the shortening of acquisition time and reduction of the radiation burden to patients. We compared semiquantitative perfusion results and functional parameters of the left ventricle between new dedicated cardiac system with astigmatic collimators called IQ-SPECT (Siemens Medical Solutions, USA) and conventional single photon emission tomography (SPET) system equipped with standard low energy high resolution collimators. A group of randomly selected 81 patients underwent consecutively the MPI procedure on IQ-SPECT and on conventional SPET systen, both without attenuation correction. The summed scores and the values of the functional parameters of the left ventricle: ejection fraction (EF), end-systolic and end-diastolic volumes (ESV, EDV) received from the automatic analysis software were compared and statistically analyzed. Our results showed that summed scores values were significantly higher for the IQ-SPECT system in comparison to the conventional one. Calculated EF were significantly lower for IQ-SPECT, whereas evaluated left ventricular volumes (LVV) were significantly higher for this system. In conclusion, we recorded significant differences in automatically calculated semiquantitative perfusion and functional parameters when compared uncorrected studies obtained by the IQ-SPECT with the conventional SPET system.


Understanding the domino reaction between 3-chloroindoles and methyl coumalate yielding carbazoles. A DFT study.
The molecular mechanism of the reaction between N-methyl-3-chloroindole and methyl coumalate yielding carbazole has been studied using DFT methods at the MPWB1K/6-311G(d,p) level in toluene. This reaction is a domino process that comprises three consecutive reactions: (i) a polar Diels-Alder (P-DA) reaction between indole and methyl coumalate yielding two stereoisomeric [2 + 4] cycloadducts (CAs); (ii) the elimination of HCl from these CAs affording two stereoisomeric intermediates; and (iii) the extrusion of CO2 in these intermediates, finally yielding the carbazole. This P-DA reaction proceeds in a completely regioselective and slightly exo selective fashion. In spite of the highly polar character of this P-DA reaction, it presents a high activation enthalpy of 21.8 kcal mol(-1) due to the loss of the aromatic character of the indole during the C-C bond formation. Thermodynamic calculations suggest that the P-DA reaction is the rate-determining step of this domino reaction; in addition, the initial HCl elimination in the formal [2 + 4] CAs is kinetically favoured over the extrusion of CO2. Although the P-DA reaction is kinetically and thermodynamically very unfavourable, the easier HCl and CO2 elimination from the [2 + 4] CAs together with the strong exergonic character of the CO2 extrusion makes the P-DA reaction irreversible. An ELF topological analysis of the bonding changes along the P-DA reaction supports a two-stage one-step mechanism. An analysis of the global DFT reactivity indices at the ground state of the reagents confirms the highly polar character of this P-DA reaction. Finally, the complete regioselectivity of the studied reactions can be explained using the Parr functions.


Clinical Characteristics and Treatment Patterns Among Patients Diagnosed With Cluster Headache in U.S. Healthcare Claims Data.
To characterize demographics, clinical characteristics, and treatment patterns of patients with cluster headache (CH). CH is an uncommon trigeminal autonomic cephalalgia with limited evidence-based treatment options. Patients suffer from extremely painful unilateral headache attacks and autonomic symptoms with episodic and chronic cycles. This retrospective analysis used insurance claims from Truven Health Analytics MarketScan® research databases from 2009 to 2014. Two cohorts were compared: CH patients (with ≥2 CH claims) were propensity score matched with 4 non-headache controls, all with continuous enrollment for 12 months before and after the date of first CH claim or matched period among controls. CH patients (N = 7589) were mainly male (57.4%) and 35-64 years old (73.2%), with significantly more claims for comorbid conditions vs controls (N = 30,341), including depressive disorders (19.8% vs 10.0%), sleep disturbances (19.7% vs 9.1%), anxiety disorders (19.2% vs 8.7%), and tobacco use disorders (12.8% vs 5.3%), with 2.5 times greater odds of suicidal ideation (all P < .0001). Odds of drug dependence were 3-fold greater among CH patients (OR = 2.8 [95% CI 2.3-3.4, P < .0001]). CH patients reported significantly greater use of prescription medications compared with controls; 25% of CH patients had >12 unique prescription drug claims. Most commonly prescribed drug classes for CH patients included: opiate agonists (41%), corticosteroids (34%), 5HT-1 agonists (32%), antidepressants (31%), NSAIDs (29%), anticonvulsants (28%), calcium antagonists (27%), and benzodiazepines (22%). Only 30.4% of CH patients received recognized CH treatments without opioids during the 12-month post-index period. These patients were less likely to visit emergency departments or need hospitalizations (26.8%) as compared to CH patients with no pharmacy claims for recognized CH treatments or opioids (33.6%; P < .0001). The burden of CH is associated with significant co-morbidity, including substance use disorders and suicidal ideation, and treatment patterns indicating low use of recognized CH treatments.


Prooxidant-antioxidant balance and malondialdehyde over time in adult rats after tubal sterilization and vasectomy.
Sterilization (tubal sterilization and vasectomy) is a widely applied contraceptive method worldwide. Although most studies have described sterilization as a safe method, there are reports of tubal ligation (TL) and vasectomy complications. The aim of this study was to evaluate the effects of TL and vasectomy on the serum oxidative stress, specifically prooxidant-antioxidant balance (PAB) and malondialdehyde (MDA) levels, over time. Male and female rats were classified into vasectomy, sham-vasectomy, TL, and sham-TL groups, respectively. The PAB and MDA levels were measured on days 15 and 45 and months 3 and 6 after the intervention. For female rats, blood sampling was performed during the diestrous phase and estradiol and progesterone were also measured. Serum PAB and MDA increased after TL (p<0.05). Vasectomy increased serum MDA remarkably after 45 days, 3 months, and 6 months (p<0.05). After vasectomy, serum PAB also increased although not significantly. Serum estradiol and progesterone decreased remarkably in the TL group compared to the sham group (p<0.05). Bilateral TL and vasectomy both increase the serum oxidative stress; however the imbalance after TL was very noticeable. As for the TL, the reduction of serum estrogen levels can be involved in this imbalance. Complications followed by TL or vasectomy could be due to increased levels of oxidants. Thus, prescribing antioxidants during and or after surgery may be a solution.


Asthma management: the challenge of equivalence.
Increasing prevalence and severity of asthma worldwide encourage the development of new antiasthmatic drugs, alternative treatment regimens and improved formulations of established drugs. Whereas the efficacy of new chemical entities (NCEs) is usually demonstrated by superiority over placebo or a subtherapeutic dose of the active drug, equivalence concepts have to be used in the following situations: the need to replace chlorofluorocarbon (CFC) propellants for inhalative asthma medications by suitable alternatives, and the need to demonstrate that an alternative treatment regimen is not clinically inferior to an established reference treatment. To cover both situations, the recent ICH guidance on biostatistics clearly distinguishes between two-sided equivalence trials and one-sided non-inferiority trials. In this context, non-inferiority always means "not inferior by a clinically relevant amount". After having confirmed non-inferiority, superiority of the alternative test treatment over the reference treatment can additionally be tested without the need to adjust the significance level. The definition of equivalence acceptance limits becomes crucial, particularly in studies conducted in the flat range of the dose-response curve of inhaled steroids. In order to assess the non-inferiority of steroid sparing add-on treatments we propose a one-sided test based on post-/pre-ratios which have substantially reduced coefficients of variation compared to the post-treatment values themselves. The non-inferiority acceptance limit of 0.90 - as opposed to 0.80 in bioequivalence assessment - reflects clinically irrelevant changes of lung function variables. The proposed methodology is illustrated by 2 examples from randomized, double-blind, parallel-group studies comparing inhaled steroid plus theophylline versus doubling the steroid dose in asthmatics who are symptomatic on low-dose inhaled steroid.


Anal cancer treated by fast neutron radiation.
Ten patients with anal cancer were treated with fast neutrons from the Medical Research Council Cyclotron at the Hammersmith Hospital. In all cases a temporary colostomy was established before treatment commenced. Three of the patients had advanced tumours that were extending into the pelvis; treatment for these patients was palliative and all died within 1 year. Four of the remaining 7 have normal anal function with no evidence of local recurrence of the tumour. Two others developed necrosis in the irradiated area and in another, the tumour recurred locally. The colostomy was re-established in 1 and the 2 others had abdominoperineal resections, after which wound healing was prolonged. A majority of the surviving patients have thus been able to avoid a permanent colostomy.


[Investigation on Qiantang medical school].
Qiantang medical school came into being during the late Ming Dynasty and the early Qing Dynasty, and lasted for 200 years until Guang Xu Reign in the late Qing Dynasty. Lu Zhiyi and Zhang Suichen were the early representative figures; Zhang Zhicong, Zhang Xiju and Gao Shizong were the mid-period representative figures; and Zhong Xuelu was the late representative figure. They respected consistently the classics and the ancients, cultivated new talents, studied medical literature with a trinity of teaching, studying the classics and practising medicine as its characteristic. Eventually, it developed under the specific background of time and geographical environment as the only academic medical school enbodying teaching, studying the classics, and medical practice as a whole with distinguished achievements.


Use of the zebrafish larvae as a model to study cigarette smoke condensate toxicity.
The smoking of tobacco continues to be the leading cause of premature death worldwide and is linked to the development of a number of serious illnesses including heart disease, respiratory diseases, stroke and cancer. Currently, cell line based toxicity assays are typically used to gain information on the general toxicity of cigarettes and other tobacco products. However, they provide little information regarding the complex disease-related changes that have been linked to smoking. The ethical concerns and high cost associated with mammalian studies have limited their widespread use for in vivo toxicological studies of tobacco. The zebrafish has emerged as a low-cost, high-throughput, in vivo model in the study of toxicology. In this study, smoke condensates from 2 reference cigarettes and 6 Canadian brands of cigarettes with different design features were assessed for acute, developmental, cardiac, and behavioural toxicity (neurotoxicity) in zebrafish larvae. By making use of this multifaceted approach we have developed an in vivo model with which to compare the toxicity profiles of smoke condensates from cigarettes with different design features. This model system may provide insights into the development of smoking related disease and could provide a cost-effective, high-throughput platform for the future evaluation of tobacco products.


Percolation of colloids with distinct interaction sites.
We generalize the Flory-Stockmayer theory of percolation to a model of associating (patchy) colloids, which consists of hard spherical particles, having on their surfaces f short-ranged-attractive sites of m different types. These sites can form bonds between particles and thus promote self-assembly. It is shown that the percolation threshold is given in terms of the eigenvalues of a m X m matrix, which describes the recursive relations for the number of bonded particles on the ith level of a cluster with no loops; percolation occurs when the largest of these eigenvalues equals unity. Expressions for the probability that a particle is not bonded to the giant cluster, for the average cluster size and the average size of a cluster to which a randomly chosen particle belongs, are also derived. Explicit results for these quantities are computed for the case f=3 and m=2 . We show how these structural properties are related to the thermodynamics of the associating system by regarding bond formation as a (equilibrium) chemical reaction. This solution of the percolation problem, combined with Wertheim's thermodynamic first-order perturbation theory, allows the investigation of the interplay between phase behavior and cluster formation for general models of patchy colloids.


Social support and self-care activities among the elderly patients with diabetes in Kelantan.
Diabetes is common among the elderly and can significantly affect their lives including the issues related with social support and diabetic self-care activities. The objective of this study was to examine the social support and self-care activities among the elderly patients with diabetes. A survey involving 200 patients was conducted from March 2013 to May 2013 in three hospitals in Kelantan. Data were obtained through self-administered questionnaires and clinical characteristics were acquired from the patients' records. The scores for social support (mean = 19.26; SD = 2.63) and self-care activities (mean = 14.83; SD = 4.92) were moderate. Higher social support was associated with high levels of glycated haemoglobin (HbA1c), fasting blood sugar (FBS) level, the duration of diabetes and a decrease in body mass index (BMI) (p<0.05). It was observed that the patients with low educational, Hb1Ac and FBS level, with other chronic diseases and who have had diabetes for some time had low self-care activities (p<0.05). There was a significant negative relationship between an increase in social support and decrease in self-care activity (p<0.05). Healthcare providers, family and friends have to strengthen their relationship with the elderly patients with diabetes to provide more social support and promote the compliance with diabetic self-care activities to improve clinical outcomes.


Improved cardiac anthropomorphic phantom.
An improved cardiac sonographic phantom is described that simulates the anatomy of the human heart for applications as a low cost quality assurance and training tool in echocardiography. The major new feature in the phantom is the development of a polyurethane sponge left ventricle, which mimics the myocardium during sonographic imaging while undergoing hydraulic pumping. The left ventricle, including prosthetic mechanical mitral and aortic valves, is housed in an optically transparent Lexan chamber or in a tissue mimicking polyurethane rubber torso. Additional new features include a port for transesophageal imaging, and an adjustable calibrated stroke volume on the piston pump, which can serve as a standard for echocardiographic stroke volume measurement. B-scans of the phantom show excellent image quality in all three standard echocardiographic views as well as in transesophageal scanning.


Question format shifts bias away from the emphasised response in tests of recognition memory.
The question asked to interrogate memory has potential to influence response bias at retrieval, yet has not been systematically investigated. According to framing effects in the field of eyewitness testimony, retrieval cueing effects in cognitive psychology and the acquiescence bias in questionnaire responding, the question should establish a confirmatory bias. Conversely, according to findings from the rewarded decision-making literature involving mixed incentives, the question should establish a disconfirmatory bias. Across three experiments (ns=90 [online], 29 [laboratory] and 29 [laboratory]) we demonstrate a disconfirmatory bias - "old?" decreased old responding. This bias is underpinned by a goal-driven mechanism wherein participants seek to maximise emphasised response accuracy at the expense of frequency. Moreover, we demonstrate that disconfirmatory biases can be generated without explicit reference to the goal state. We conclude that subtle aspects of the test environment influence retrieval to a greater extent than has been previously considered.


Superhydrophobic-Substrate-Assisted Construction of Free-Standing Microcavity-Patterned Conducting Polymer Films.
Patterned conducting polymer films with unique structures have promising prospects for application in various fields, such as actuation, water purification, sensing, and bioelectronics. However, their practical application is hindered because of the limitations of existing construction methods. Herein, a strategy is proposed for the superhydrophobic-substrate-assisted construction of free-standing 3D microcavity-patterned conducting polymer films (McPCPFs) at micrometer resolution. Easy-peeling and nondestructive transfer properties are achieved through electrochemical polymerization along the solid/liquid/gas triphase interface on micropillar-structured substrates. The effects of the wettability and geometrical parameters of the substrates on the construction of McPCPFs are systematically investigated in addition to the evolution of the epitaxial growth along the triphase interface at different polymerization times. The McPCPFs can be easily peeled from superhydrophobic surfaces using ethanol because of weak adhesion and nondestructively transferred to various substrates taking advantage of the capillarity. Furthermore, sensitive light-driven McPCPF locomotion on organic liquid surfaces is demonstrated. Ultimately, a facile strategy for the construction of free-standing 3D microstructure-patterned conducting polymer films is proposed, which can improve productivity and applicability of the films in different fields and expand the application scope of superwettable interfaces.


Closure of Universities Due to Coronavirus Disease 2019 (COVID-19): Impact on Education and Mental Health of Students and Academic Staff.
The novel coronavirus disease 2019 (COVID-19), originated in Wuhan city of China, has spread rapidly around the world, sending billions of people into lockdown. The World Health Organization (WHO) declared the coronavirus epidemic a pandemic. In light of rising concern about the current COVID-19 pandemic, a growing number of universities across the world have either postponed or canceled all campus events such as workshops, conferences, sports, and other activities. Universities are taking intensive measures to prevent and protect all students and staff members from the highly infectious disease. Faculty members are already in the process of transitioning to online teaching platforms. In this review, the author will highlight the potential impact of the terrible COVID-19 outbreak on the education and mental health of students and academic staff.


History, politics and vulnerability: explaining excess mortality in Scotland and Glasgow.
High levels of excess mortality (i.e. that not explained by deprivation) have been observed for Scotland compared with England & Wales, and especially for Glasgow in comparison with similar post-industrial cities such as Liverpool and Manchester. Many potential explanations have been suggested. Based on an assessment of these, the aim was to develop an understanding of the most likely underlying causes. Note that this paper distils a larger research report, with the aim of reaching wider audiences beyond Scotland, as the important lessons learnt are relevant to other populations. Review and dialectical synthesis of evidence. Forty hypotheses were examined, including those identified from a systematic review. The relevance of each was assessed by means of Bradford Hill's criteria for causality alongside-for hypotheses deemed causally linked to mortality-comparisons of exposures between Glasgow and Liverpool/Manchester, and between Scotland and the rest of Great Britain. Where gaps in the evidence base were identified, new research was undertaken. Causal chains of relevant hypotheses were created, each tested in terms of its ability to explain the many different aspects of excess mortality. The models were further tested with key informants from public health and other disciplines. In Glasgow's case, the city was made more vulnerable to important socioeconomic (deprivation, deindustrialisation) and political (detrimental economic and social policies) exposures, resulting in worse outcomes. This vulnerability was generated by a series of historical factors, processes and decisions: the lagged effects of historical overcrowding; post-war regional policy including the socially selective relocation of population to outside the city; more detrimental processes of urban change which impacted on living conditions; and differences in local government responses to UK government policy in the 1980s which both impacted in negative terms in Glasgow and also conferred protective effects on comparator cities. Further resulting protective factors were identified (e.g. greater 'social capital' in Liverpool) which placed Glasgow at a further relative disadvantage. Other contributory factors were highlighted, including the inadequate measurement of deprivation. A similar 'explanatory model' resulted for Scotland as a whole. This included: the components of the Glasgow model, given their impact on nationally measured outcomes; inadequate measurement of deprivation; the lagged effects of deprivation (in particular higher levels of overcrowding historically); and additional key vulnerabilities. The work has helped to further understanding of the underlying causes of Glasgow's and Scotland's high levels of excess mortality. The implications for policy include the need to address three issues simultaneously: to protect against key exposures (e.g. poverty) which impact detrimentally across all parts of the UK; to address the existing consequences of Glasgow's and Scotland's vulnerability; and to mitigate against the effects of future vulnerabilities which are likely to emerge from policy responses to contemporary problems which fail sufficiently to consider and to prevent long-term, unintended social consequences.


Markers for endothelial dysfunction, but not markers for oxidative stress correlate with classical risk factors and the severity of coronary artery disease. (A subgroup analysis from the Ludwigshafen Risk and Cardiovascular Health Study).
Endothelial dysfunction and oxidative stress are involved in atherogenesis. In the search for predictors of vascular disease markers for endothelial dysfunction and oxidative stress were analyzed. Of 208 consecutive patients 22% were controls (CO) without coronary artery disease (CAD), 52% presented with stable angina (SAP) and 26% had acute coronary syndromes (ACS). Nitric oxide (NO), thrombomodulin (TM), von Willebrand factor (vW), sVCAM-1, sICAM-1, sP-selectin, sE-selectin, sL-selectin and C-reactive protein (CRP) were determined as markers for endothelial dysfunction, glutathione (GSH), glutathione peroxidase (Gpx), myeloperoxidase (Mpx), lipid peroxides (Lpx), 8-isoprostane (Iso), superoxide dismutase (SOD), total antioxidant capacity (TAC) and homocysteine (Hc) as markers for oxidative stress. The increases of TM, vW, sVCAM-1, CRP, SOD and Mpx correlated with the CAD status in the order CO < SAP < ACS, whereas NO and sL-selectin were inversely correlated (p < 0.05, resp.). The other markers remained unchanged. For several markers a significant relationship to risk factors was detected. Markers for endothelial dysfunction rather than those for oxidative stress may serve as indicators for the presence and severity of CAD.


[P glycoprotein and multidrug resistance].
Drug resistance has been shown to be associated with the expression of P-glycoprotein (P-gp), the product of mdr-1 gene. One of the suggested mechanisms for the phenomenon called Multidrug Resistance (MDR) is related to the overexpression and amplification of the mdr-1 gene. The product of this gene is called P-gp and it has been considered as a potential marker for drug resistance. Transfection of the mdr-1 gene into drug-sensitive cells confers the role of mdr-1 gene in developing MDR phenotype. Structural analysis of homologous cDNA, responsible for production of transport proteins, from: MDR cell lines, bacteria and yeast, revealed high similarity. Molecular structure analysis indicate that P-gp has nucleotide binding sites. It has been established that P-gh has an internal ATP-ase activity, thus it can act as energy dependent transport protein. The expression of P-gp has been found in neoplastic and normal tissues (as adrenal glands, kidney, liver, pancreas, jejunum and large intestine), as well as in several cell lines which have been induced to become resistant to cytostatics. The aim of present study was to review the role of P-gp expression in laboratory and clinic.


New findings from the time trade-off for income approach to elicit willingness to pay for a quality adjusted life year.
In this paper we empirically investigate how to appropriately model utility of wealth and health. We use a recently proposed alternative approach to value willingness to pay (WTP) for health, making use of trade-offs between income and life years or quality of life, which we extend to allow for a more realistic multiplicative utility function over health and money. Moreover, we show how reference-dependency can be incorporated into this model and derive its predictions for WTP elicitation. We propose three experimental elicitation procedures and test these in a feasibility study, analysing the responses under different assumptions about the discount rate. Several interesting results are reported: first, the data are highly skewed, but if we trim the 5% lowest and highest values, we obtain plausible WTP estimates. Second, the results differ considerably between procedures, indicating that WTP estimates are sensitive to the assumed utility function. Third, respondents appear to be loss averse for both health and money, which is consistent with assumptions from prospect theory. Finally, our results also indicate that respondents are more willing to trade quality of life than life years.


The golgin GCC88 is required for efficient retrograde transport of cargo from the early endosomes to the trans-Golgi network.
Retrograde transport pathways from early/recycling endosomes to the trans-Golgi network (TGN) are poorly defined. We have investigated the role of TGN golgins in retrograde trafficking. Of the four TGN golgins, p230/golgin-245, golgin-97, GCC185, and GCC88, we show that GCC88 defines a retrograde transport pathway from early endosomes to the TGN. Depletion of GCC88 in HeLa cells by interference RNA resulted in a block in plasma membrane-TGN recycling of two cargo proteins, TGN38 and a CD8 mannose-6-phosphate receptor cytoplasmic tail fusion protein. In GCC88-depleted cells, cargo recycling was blocked in the early endosome. Depletion of GCC88 dramatically altered the TGN localization of the t-SNARE syntaxin 6, a syntaxin required for endosome to TGN transport. Furthermore, the transport block in GCC88-depleted cells was rescued by syntaxin 6 overexpression. Internalized Shiga toxin was efficiently transported from endosomes to the Golgi of GCC88-depleted cells, indicating that Shiga toxin and TGN38 are internalized by distinct retrograde transport pathways. These findings have identified an essential role for GCC88 in the localization of TGN fusion machinery for transport from early endosomes to the TGN, and they have allowed the identification of a retrograde pathway which differentially selects TGN38 and mannose-6-phosphate receptor from Shiga toxin.


The influence of perceived social support on medication adherence in first-episode psychosis.
Our study examines the unique influence of social and family support on adherence to medication in a sample of patients treated for first-episode psychosis (FEP). Social and family support using the Multidimensional Scale of Perceived Social Support and medication adherence (consensus of subjective and objective data) were evaluated on a monthly basis during a 6-month period in a sample of 82 FEP patients. The relation between social support and adherence was evaluated using correlational and linear regression analyses, controlling for other relevant variables. A longitudinal analysis using hierarchical linear models was conducted to model change in adherence over time. Monthly correlations between social support and adherence were significant at 4 of 7 time points during a 6-month period. There was a modest correlation between the percentage of months of good adherence and the average level of family support across the study period. The linear regression failed to demonstrate a significant relation between baseline social support and overall adherence during the entire study period. Change in social support over time was inversely associated with change in adherence. Our study emphasizes the concurrent influence of social (mostly family) support on adherence but this effect does not persist over time. Changes in the degree of social support may have a complex effect on changes in adherence.


Problems in the early recognition of hip dysplasia.
Ten children who had clinically stable hips at birth were radiographed at one month because they had factors predisposing to hip dislocation. In all cases one or both hips gave rise to a suspicion of dysplasia, though clinical abnormalities were slow to appear. Four of these hips subsequently dislocated. We believe that infants with late presentation of acetabular dysplasia and clinical abnormality belong to a different aetiological group from those with neonatal instability due to ligamentous laxity. The significance of this differentiation is that some infants presenting late have only recently dislocated, and the diagnosis has not necessarily been "missed" at neonatal examination.


Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia.
We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70. Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-func-tion with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological significance in pure AD-HSP and suggesting implications for the presumed function of spastin.


Pupillary responses to short-wavelength light are preserved in aging.
With aging, less blue light reaches the retina due to gradual yellowing of the lens. This could result in reduced activation of blue light-sensitive melanopsin-containing retinal ganglion cells, which mediate non-visual light responses (e.g., the pupillary light reflex, melatonin suppression, and circadian resetting). Herein, we tested the hypothesis that older individuals show greater impairment of pupillary responses to blue light relative to red light. Dose-response curves for pupillary constriction to 469-nm blue light and 631-nm red light were compared between young normal adults aged 21-30 years (n = 60) and older adults aged ≥50 years (normal, n = 54; mild cataract, n = 107; severe cataract, n = 18). Irrespective of wavelength, pupillary responses were reduced in older individuals and further attenuated by severe, but not mild, cataract. The reduction in pupillary responses was comparable in response to blue light and red light, suggesting that lens yellowing did not selectively reduce melanopsin-dependent light responses. Compensatory mechanisms likely occur in aging that ensure relative constancy of pupillary responses to blue light despite changes in lens transmission.


Abortion-related morbidity in six Latin American and Caribbean countries: findings of the WHO/HRP multi-country survey on abortion (MCS-A).
Abortion-related complications are a significant cause of morbidity and mortality among women in many Latin American and Caribbean (LAC) countries. The objective of this study was to characterise abortion-related complication severity, describe the management of these complications and report women's experiences with abortion care in selected countries of the Americas region. This is a cross-sectional study of 70 health facilities across six countries in the region. We collected data on women's characteristics including socio-demographics, obstetric history, clinical information, management procedures and using Audio Computer-Assisted Self-Interviewing (ACASI) survey the experience of abortion care. Descriptive bivariate analysis was performed for women's characteristics, management of complications and reported experiences of abortion care by severity of complications, organised in five hierarchical mutually exclusive categories based on indicators present at assessment. Generalised linear estimation models were used to assess the association between women's characteristics and severity of complications. We collected data on 7983 women with abortion-related complications. Complications were classified as mild (46.3%), moderate (49.5%), potentially life-threatening (3.1%), near-miss cases (1.1%) and deaths (0.2%). Being single, having a gestational age of ≥13 weeks and having expelled products of conception before arrival at the facility were significantly associated with experiencing severe maternal outcomes compared with mild complications.Management of abortion-related complications included both uterotonics and uterine evacuation for two-thirds of the women while one-third received uterine evacuation only. Surgical uterine evacuation was performed in 93.2% (7437/7983) of women, being vacuum aspiration the most common one (5007/7437, 67.4%).Of the 327 women who completed the ACASI survey, 16.5% reported having an induced abortion, 12.5% of the women stated that they were not given explanations regarding their care nor were able to ask questions during their examination and treatment with percentages increasing with the severity of morbidity. This is one of the first studies using a standardised methodology to measure severity of abortion-related complications and women's experiences with abortion care in LAC. Results aim to inform policies and programmes addressing sexual and reproductive rights and health in the region.


Effects of quantity and quality of dietary protein on the brain polysome profile in aged rats.
The purpose of this study was to determine whether the quantity and quality of dietary protein affected the polysome profile of the brain in aged rats. Two experiments were done on three groups of aged rats (30 wk) given the diets containing 20% casein, 5% casein, or 0% casein (experiment 1), and 20% casein, 20% gluten, or 20% gelatin (experiment 2) for 10 d. The aggregation in brain ribosomes declined with a decrease of quantity and quality of dietary protein except in the hippocampus. The RNA concentration (mg RNA/g protein) did not differ among the three groups varying the dietary protein in any brain regions. The results suggest that the higher quantity and quality of dietary protein improves the polysome profile in the brain of aged rats, and that the polysome profile is at least partly related to the mechanism by which the dietary protein affects brain protein synthesis in aged rats.


Relaxant effects of Azadirachta indica A. Juss var. siamensis Valeton flower extract on isolated rat ileum contractions and the mechanisms of action.
Azadirachta indica A. Juss var. siamensis Valeton or commonly known as Siamese neem is one of the most well-known plant in traditional Ayurvedic medicine. The aim of the present study was to investigate the relaxant effects of A. indica on isolated rat ileum contractions and its potential underlying mechanisms involved. The isometric contractions of ileum segments were investigated in organ baths for spontaneous activity and response to aqueous extract of Siamese neem flower (SNF). The spasmolytic action of the extract was also assessed on contraction induced by acetylcholine and high potassium. Our findings indicate that cumulative concentrations of SNF aqueous extract induced relaxant effect on spontaneous rat ileum contractions. The extract has also suppressed the cumulative concentration response curve for acetylcholine and pottasium ions-induced contraction. The presence and absence of propranol (antagonist of β-adrenergic receptor) and l-Name (antagonist of nitric oxide synthase) in SNF aqeous extract co-treatment demonstrated no significant different in term of contraction activity when compared to SNF extract treatment alone. The treatment of SNF extract caused a significant inhibition in tissue contraction stimulated by accumulation of calcium ions. Our results showed the relaxant effect of SNF aqueous extract on the isolated rat ileum. In short, the SNF aqueous extract exhibited an inhibitory effect on the spontaneous ileum contactions particularly on the contraction stimulated by acetylcholine and high potassium. The observed effect might acted through the modulation of calcium channels. This findings provide a pharmacological basis for the traditional use of SNF for the treatment of gastrointestinal spasms.


Asthma mortality in Sweden among children and adolescents during the period 1952-1972.
Asthma mortality in Sweden during the period of 1952-1972 in the age-group of 1-24 years, comprising a total of 183 cases, has been studied. As compared with the 1950's, there is a conspicuous increase in the number of deaths during the greater part of the sixties, reaching a maximum in 1967. Since then the mortality has shown a marked decrease. Further, a trend towards an averagely higher age at death has been ascertained in the latter part of the investigation period. The factors underlying the conspicuous variations in mortality rate were discussed. It was emphasized that the abuse of sympathomimetics in pressurized aerosols could not be accepted as the one and only cause. In all probability, the increase in the mortality during the 1960's can be attributed to a number of factors.


Unraveling the regulatory network of IncA/C plasmid mobilization: When genomic islands hijack conjugative elements.
Conjugative plasmids of the A/C incompatibility group (IncA/C) have become substantial players in the dissemination of multidrug resistance. These large conjugative plasmids are characterized by their broad host-range, extended spectrum of antimicrobials resistance, and prevalence in enteric bacteria recovered from both environmental and clinical settings. Until recently, relatively little was known about the basic biology of IncA/C plasmids, mostly because of the hindrance of multidrug resistance for molecular biology experiments. To circumvent this issue, we previously developed pVCR94ΔX, a convenient prototype that codes for a reduced set of antibiotic resistances. Using pVCR94ΔX, we then characterized the regulatory pathway governing IncA/C plasmid dissemination. We found that the expression of roughly 2 thirds of the genes encoded by this plasmid, including large operons involved in the conjugation process, depends on an FlhCD-like master activator called AcaCD. Beyond the mobility of IncA/C plasmids, AcaCD was also shown to play a key role in the mobilization of different classes of genomic islands (GIs) identified in various pathogenic bacteria. By doing so, IncA/C plasmids can have a considerable impact on bacterial genomes plasticity and evolution.


Improvement in activities of daily living and exercise tolerance in a patient with severe COVID-19 and femoral nerve palsy after Kaifukuki rehabilitation: a case report.
Yashiro T, Wada Y, Sugiyama M, Tateno H, Kasai F, Kawate N. Improvement in activities of daily living and exercise tolerance in a patient with severe COVID-19 and femoral nerve palsy after Kaifukuki rehabilitation: a case report. Jpn J Compr Rehabil Sci 2021; 12: 53-57. There have been many reports on rehabilitation techniques for patients with coronavirus disease 2019 (COVID-19). However, few have reported on the use of Kaifukuki rehabilitation for severe COVID-19 cases with complications of femoral nerve palsy after veno-venous extracorporeal membrane oxygenation (VV-ECMO) management. A male in his 50s who underwent VV-ECMO management during the course of his treatment for COVID-19 developed femoral nerve palsy due to iliopsoas hematoma. From day 120 after admission, he underwent Kaifukuki rehabilitation focusing on exercise therapy, activities of daily living (ADL) training, and respiratory rehabilitation to improve ADL and exercise tolerance. His respiratory function, functional independence measure scores, and 6-min walk test results improved. The patient was discharged on day 196. His recovery progressed without any further deterioration. Kaifukuki rehabilitation, focusing on respiratory rehabilitation, contributed to the improvement of ADL and exercise tolerance in a patient with severe COVID-19. In addition, attention should be paid to femoral nerve palsy after VV-ECMO.


Use of a Novel Abdominal Aortic and Junctional Tourniquet to Reduce or Eliminate Flow in the Brachial and Popliteal Arteries in Human Subjects.
Penetrating injuries of the proximal large arteries are a common cause of death on the battlefield due to rapid exsanguination. Applying an effective tourniquet to stop bleeding at the axillary and proximal femoral arteries (junctional sites) is difficult. Prior studies have shown that the Abdominal Aortic and Junctional Tourniquet (AAJT) effectively reduced blood flow in the common femoral artery with application of the device around the lower abdomen. Our objective was to determine the effectiveness of the AAJT to stop blood flow in the proximal femoral artery (PFA), and the axillary artery (AA). This was a prospective observational trial using human volunteers. The AAJT consists of a wedge-shaped bladder and integrated strap. The bladder has an integrated manometer, which is used to measure the pressure in the bladder. For the AA, the AAJT was placed over the axillary junction at the anterior axillary line with the strap placed across the contralateral shoulder. For the PFA, the AAJT bladder was placed over the right groin with the strap positioned across both femoral trochanters. Spectral Doppler measurements were taken of the PFA and AA at baseline and as the bladder was inflated. Collected data included pressure of the AAJT.


Diffusivity of whey protein and gum arabic in their coacervates.
Structural properties of whey protein (WP)/gum arabic (GA) coacervates were investigated by measuring the diffusivity of WP and GA in their coacervate phase as a function of pH by means of three different complementary techniques. The combination of these measurements revealed new insights into the structure of coacervates. Nuclear magnetic resonance (NMR) measured the self-diffusion coefficient of the GA in the coacervate phase prepared at various pH values. Fluorescence recovery after photobleaching (FRAP) was measured using a confocal scanning laser microscope. The WP and GA were covalently labeled with two different dyes. The time of fluorescence recovery, related to the inverse of the diffusion coefficient, was evaluated from the measurements, and the diffusivity of the WP and GA on a long time scale could be individually estimated at each pH value. Diffusing wave spectroscopy (DWS) combined with transmission measurement was carried out in the coacervate phase, and the diffusion coefficient, corresponding to the averaged diffusion of all particles that scattered in the system, was calculated as a function of pH. Independently of the technique used, the results showed that the diffusion of the WP and GA within the coacervate phase was reduced as compared to a diluted biopolymer mixture. NMR, DWS, and FRAP measurements gave similar results, indicating that the biopolymers moved the slowest in the coacervate matrix at pH 4.0-4.2. It is assumed that the diffusion of the WP and GA is reduced because of a higher electrostatic interaction between the biopolymers. Furthermore, FRAP results showed that in the coacervate phase WP molecules diffused 10 times faster than GA molecules. This result is very relevant because it shows that WP and GA move independently in the liquid coacervate phase. Finally, DWS measurements revealed that the coacervate phase rearranged with time, as evidenced by a decrease of the diffusion coefficient and a loss of the turbidity of the sample. A more homogeneous transparent coacervate phase was obtained after a few days/weeks. Faster rearrangement was obtained at pH 3.0 and 3.5 than at higher pH values.


Efficacy of Antiresorptive Drugs on Bone Mineral Density in Post-Menopausal Women With Early Breast Cancer Receiving Adjuvant Aromatase Inhibitors: A Systematic Review of Randomized Controlled Trials.
Cancer treatment-induced bone loss (CTIBL) is a frequent complication of breast cancer therapies affecting both disability and health-related quality of life (HRQoL). To date, there is still a lack of consensus about the most effective approach that would improve bone health and HRQoL. Therefore, the aim of this systematic review of randomized controlled trials (RCTs) was to summarize the evidence on the effects of antiresorptive drugs on CTIBL in patients with early breast cancer. PubMed, Scopus, and Web of Science databases were systematically searched up to April 30, 2021 to identify RCTs satisfying the following PICO model: P) Participants: postmenopausal women with early breast cancer receiving adjuvant aromatase inhibitors (AI), age >18 years; I) Intervention: antiresorptive drugs (i.e. bisphosphonates and/or denosumab); C) Comparator: any comparator; O) Outcome: bone mineral density (BMD) modifications. Moreover, a quality assessment was performed according to the Jadad scale. Out of the initial 2415 records, 21 papers (15 studies) were included in the data synthesis. According to the Jadad scale, 6 studies obtained a score of 5, 1 study obtained a score of 4, 13 studies obtained a score of 3, and 1 study with score 1. Although both bisphosphonates and denosumab showed to increase BMD, only denosumab showed significant advantages on fractures. Bone health management in patients with early breast cancer receiving adjuvant AIs remains challenging, and the optimal therapeutic approach is not standardized. Further studies are needed to investigate CTIBL, focusing on both the need for antiresorptive drugs and their duration based on individual patients' characteristics. https://www.crd.york.ac.uk/prospero, identifier CRD42021267107.


Climate change, human migration and health nexus: what do we know about public health implications on a global scale?
to address the nexus among climate change, migration, and health at global and Italian levels. narrative review. comprehensive, critical, and objective analysis of the current knowledge on the topic by searching online databases. evidence from the literature examining health issues associated with migration in the context of climate change. anthropogenic climate change has recently influenced the scale and patterns of human mobility, not only as a driver of migration, but also by interacting with and amplifying the effects of migration determinants, including health determinants. Despite research focusing on the distinct relationship between climate change and migration, as well as climate change and health, little attention has been paid to the nexus among climate change, migration, and health. Evidence available examining various health issues associated with migration in the context of climate change include changing patterns of infectious diseases and their risks, rising cases of malnutrition, trauma and injuries, changing patterns of noncommunicable diseases, impact on mental health. Inadequacy of access to health services due to the weakening and overstretching health systems also plays an important role. In a country like Italy, even if the immediate threats posed by climate change differ from one area to another, these threats are already exacerbating the country's existing infrastructure deficiencies, industrial pollution, and hydrogeological and seismic vulnerability. In addition, Italy has historically been a destination country of immigrant afflux through different migration routes. It is possible that the consequences of climate change in Sub-Saharan Africa will drive a growing number of people to cross the sea to reach Europe, specifically Italy. Conclusions: climate change, human migration, and health should be considered as an interconnected and complex issue. A shift to climate resilient health systems' is a useful precautionary measure as it aims to strengthen multiple aspects of national and sub-national health systems, regardless of the extent to which climate-related migration might occur.


The management of popliteal aneurysms.
Twenty-three patients with 34 popliteal aneurysms were treated between 1963 and 1974. Nearly half of the aneurysms were the site of thrombosis when they first presented, and of these nearly half required a major amputation. Surgical treatment of aneurysms in which the popliteal artery was patent was satisfactory; the only failure occurred when a Dacron graft became occluded after eight years. A small group of patients was observed for an average of one year, during which time the thrombus in one aneurysm embolized and one aneurysm became occluded, necessitating an amputation. The results of this series suggest that the prognosis for a limb with popliteal aneurysm depends on the patency of the popliteal artery at the time of the initial presentation, and lends support to the belief that popliteal arteries with aneurysms are best reconstructed before the onset of a serious complication.


Effect of cobalt alloying on the electrochemical performance of manganese oxide nanoparticles nucleated on multiwalled carbon nanotubes.
MnO is an electrically insulating material which limits its usefulness in lithium ion batteries. We demonstrate that the electrochemical performance of MnO can be greatly improved by using oxygen-functional groups created on the outer walls of multiwalled carbon nanotubes (MWCNTs) as nucleation sites for metal oxide nanoparticles. Based on the mass of the active material used in the preparation of electrodes, the composite conversion-reaction anode material Mn1-x Co x O/MWCNT with x = 0.2 exhibited the highest reversible specific capacity, 790 and 553 mAhg-1 at current densities of 40 and 1600 mAg-1, respectively. This is 3.1 times higher than that of MnO/MWCNT at a charge rate of 1600 mAg-1. Phase segregation in the [Formula: see text] nanoparticles was not observed for x ≤ 0.15. Capacity retention in x = 0, 0.2, and 1 electrodes showed that the corresponding specific capacities were stabilized at 478, 709 and 602 mAhg-1 respectively, after 55 cycles at a current density of 400 mAg-1. As both MnO and CoO exhibit similar theoretical capacities and MnO/MWCNT and CoO/MWCNT anodes both exhibit lower performance than Mn0.8Co0.2O/MWCNT, the improved performance of the [Formula: see text] alloy likely arises from beneficial synergistic interactions in the bimetallic system.


Onchocerca volvulus-neurotransmitter tyramine is a biomarker for river blindness.
Onchocerciasis, also known as "river blindness", is a neglected tropical disease infecting millions of people mainly in Africa and the Middle East but also in South America and Central America. Disease infectivity initiates from the filarial parasitic nematode Onchocerca volvulus, which is transmitted by the blackfly vector Simulium sp. carrying infectious third-stage larvae. Ivermectin has controlled transmission of microfilariae, with an African Program elimination target date of 2025. However, there is currently no point-of-care diagnostic that can distinguish the burden of infection--including active and/or past infection--and enable the elimination program to be effectively monitored. Here, we describe how liquid chromatography-MS-based urine metabolome analysis can be exploited for the identification of a unique biomarker, N-acetyltyramine-O,β-glucuronide (NATOG), a neurotransmitter-derived secretion metabolite from O. volvulus. The regulation of this tyramine neurotransmitter was found to be linked to patient disease infection, including the controversial antibiotic doxycycline treatment that has been shown to both sterilize and kill adult female worms. Further clues to its regulation have been elucidated through biosynthetic pathway determination within the nematode and its human host. Our results demonstrate that NATOG tracks O. volvulus metabolism in both worms and humans, and thus can be considered a host-specific biomarker for onchocerciasis progression. Liquid chromatography-MS-based urine metabolome analysis discovery of NATOG not only has broad implications for a noninvasive host-specific onchocerciasis diagnostic but provides a basis for the metabolome mining of other neglected tropical diseases for the discovery of distinct biomarkers and monitoring of disease progression.


Cardiovascular disease after renal transplantation.
Cardiovascular disease is a major hazard limiting the life expectancy of renal transplant recipients and the most frequent cause of late allograft loss. Patients with renal disease have usually been exposed for both traditional, and for them unique, risk factors over a prolonged period of time and may carry the burden of advanced atherosclerotic disease already at the time of transplantation. The observed survival benefit of transplantation is probably from elimination of the numerous uremia-related risk factors. However, immunosuppressive therapy and the chronic inflammatory state, together with genetic susceptibility and not infrequently impaired renal function, may bring about new potentially atherogenic conditions. Metabolic risk factors may jeopardize both patient and graft survival. Several observational studies provide evidence for the negative impact of preexisting metabolic abnormalities on long-term outcomes. Identification of modifiable cardiovascular risk factors may enable risk reduction also in renal transplant recipients. Results of ongoing intervention trials are awaited. The observed improvement of patient survival after renal transplantation during the past decade may reflect the increasing awareness and more optimal care of patients throughout the course of renal disease.


Spatially and temporally distinct patterns of expression for VPS10P domain receptors in human cerebral organoids.
Vacuolar protein sorting 10 protein (VPS10P) domain receptors are a unique class of intracellular sorting receptors that emerge as major risk factors associated with psychiatric and neurodegenerative diseases, including bipolar disorders, autism, schizophrenia, as well as Alzheimer's disease and frontotemporal dementia. Yet, the lack of suitable experimental models to study receptor functions in the human brain has hampered elucidation of receptor actions in brain disease. Here, we have adapted protocols using human cerebral organoids to the detailed characterization of VPS10P domain receptor expression during neural development and differentiation, including single-cell RNA sequencing. Our studies uncovered spatial and temporal patterns of expression unique to individual receptor species in the human brain. While SORL1 expression is abundant in stem cells and SORCS1 peaks in neural progenitors at onset of neurogenesis, SORT1 and SORCS2 show increasing expression with maturation of neuronal and non-neuronal cell types, arguing for distinct functions in development versus the adult brain. In neurons, subcellular localization also distinguishes between types of receptor species, either mainly localized to the cell soma (SORL1 and SORT1) or also to neuronal projections (SORCS1 and SORCS2), suggesting divergent functions in protein sorting between Golgi and the endo-lysosomal system or along axonal and dendritic tracks. Taken together, our findings provide an important resource on temporal, spatial, and subcellular patterns of VPS10P domain receptor expression in cerebral organoids for further elucidation of receptor (dys) functions causative of behavioral and cognitive defects of the human brain.


Empiric antibiotics for peripartum bacteremia: A chart review from a quaternary Canadian centre.
To evaluate the effectiveness of empiric antibiotic protocols for peripartum bacteremia at a quaternary institution by describing incidence, microbial epidemiology, clinical source of infection, susceptibility patterns, and maternal and neonatal outcomes. Retrospective chart review of peripartum patients with positive blood cultures between 2010 and 2018. The incidence of peripartum bacteremia was 0.3%. The most cultured organisms were Escherichia coli (51, 26.7%), Streptococcus spp. (52, 27.2%), and anaerobic spp. (35, 18.3%). Of the E. coli cases, 54.9% (28), 19.6% (10), and 19.6% (10) were resistant to ampicillin, first- and third-generation cephalosporins, respectively. Clinical sources of infection included intra-amniotic infection/endometritis (115, 67.6%), upper and/or lower urinary tract infection (23, 13.5%), and soft tissue infection (8, 4.7%). Appropriate empiric antibiotics were prescribed in 137 (83.0%) cases. There were 7 ICU admissions (4.2%), 18 pregnancy losses (9.9%), 9 neonatal deaths (5.5%), and 6 cases of neonatal bacteremia (3.7%). Peripartum bacteremia remains uncommon but associated with maternal morbidity and neonatal morbidity and mortality. Current empiric antimicrobial protocols at our site remain appropriate, but continuous monitoring of antimicrobial resistance patterns is critical given the presence of pathogens resistant to first-line antibiotics.


Stereocontrolled Synthesis of Resolvin D4.
The stereoselective synthesis of resolvin D4 (RvD4) was achieved using the Wittig reaction of the C1-C10 dienal with the known C11-C22 phosphonium salt. The ( S, E)-enantiomer ( S)-10, corresponding to the C1-C8 part, was synthesized in 95% ee by the asymmetric transfer hydrogenation reaction of the corresponding acetylenic ketone followed by Red-Al reduction. Sharpless epoxidation of this alcohol using Ti(O- i-Pr)4/l-(+)-DIPT as a catalyst produced anti epoxy alcohol with >99% ee as the sole product in 82% yield. A subsequent functional group manipulation, including removal of the PMB group, produced the alcohol, which upon Swern oxidation afforded anti 4-hydroxy-5-TBS-oxy enal via epoxide ring opening of the resulting aldehyde. The Horner-Wadsworth-Emmons reaction was used to add the C9-C10 enal part to this aldehyde, and the resulting dienal was subjected to the Wittig reaction with C11-C22 phosphonium salt to furnish the entire structure of RvD4. Conversion of the primary alcohol to the methyl ester and deprotection of the three TBS groups with TBAF afforded 5,17-dihydroxy-γ-lactone, which was hydrolyzed to RvD4. Additionally, anti-4,5-dihydroxydodecanoic acid, a model compound of RvD4, in CD3OD was observed to be stable at room temperature for several weeks, whereas 20% of the acid in CDCl3 was converted into the γ-lactone after 24 h at rt.


Superlubricity and Antiwear Properties of In Situ-Formed Ionic Liquids at Ceramic Interfaces Induced by Tribochemical Reactions.
Several ionic liquids (ILs) are formed in situ with monovalent metal salts and ethylene glycol (EG). The macroscale superlubricity and antiwear properties of the ILs were studied between ceramic materials. Superlow coefficients of friction of less than 0.01 could be obtained for all ILs at silicon nitride (Si3N4) interfaces induced by tribochemical reactions. Notably, the IL ([Li(EG)]PF6) formed with LiPF6 and EG exhibited the greatest superlubricity and antiwear properties. The results of film thickness calculations and surface analysis showed that the lubrication regime during the superlubricity period was the mixed lubrication, and a composite tribochemical layer (composed of phosphates, fluorides, silica (SiO2), and ammonia-containing compounds), hydration layer, and fluid film contributed to superlubricity and wear protection. It was found that the small size of metal cations was beneficial for alleviating wear, and PF6- anions exhibited the smallest friction and best antiwear performance at Si3N4 interfaces. This work studied the lubricity and antiwear properties of ILs with different cations and anions, enriching the range of alternative ILs for macroscale superlubricity and low wear, and is of importance to engineering applications.


Cognitive performance of community-dwelling oldest-old individuals with major depression: the Pietà study.
Individuals with late-life depression (LLD) may present cognitive symptoms. We sought to determine whether a brief cognitive battery (BCB) could identify cognitive and functional deficits in oldest-old individuals with LLD and a low level of education. We evaluated 639 community-dwelling individuals aged 75+ years in Caeté (MG), Brazil. We used the MINI and GDS-15 to diagnose major depression and evaluate its severity, respectively. The cognitive evaluation comprised the Mini-Mental State Examination (MMSE), BCB, clock-drawing test, category fluency test (animals) and Pfeffer's Functional Activities Questionnaire (FAQ). Fifty-four (11.6%) of the included individuals were diagnosed with LLD; on average, these participants were aged 81.0 ± 4.8 years and had 3.9 ± 3.4 years of schooling, and 77.8% of the subjects with LLD were female. Depressed individuals scored lower than subjects without dementia/depression on the MMSE overall (p < 0.001) and on several of the MMSE subscales, namely, time (p < 0.001) and spatial orientation (p = 0.021), attention/calculation (p = 0.019), and language (p = 0.004). Individuals with LLD performed worse on the incidental and (p = 0.011) immediate memory (p = 0.046) and learning tasks (p = 0.039) of the BCB. Individuals with LLD also performed worse on the category fluency test (p = 0.006), clock-drawing test (p = 0.011) and FAQ (p < 0.001). Depression severity was negatively correlated with incidental memory (ρ = -0.412; p = 0.003) and positively correlated with FAQ score (ρ = 0.308; p = 0.035). In the multiple regression analysis, only temporal orientation and FAQ score remained independently associated with LLD. Individuals with depression and a low level of education presented several cognitive and functional deficits. Depression severity was negatively correlated with incidental memory and functionality. Our findings serve as a description of the presence of cognitive dysfunction in individuals with LLD and suggest that these deficits may be identified based on the results of a BCB.


In vivo evaluation of (64)Cu-labeled magnetic nanoparticles as a dual-modality PET/MR imaging agent.
A novel nanoparticle-based dual-modality positron emission tomograph/magnetic resonance imaging (PET/MRI) contrast agent was developed. The probe consisted of a superparamagnetic iron oxide (SPIO) core coated with PEGylated phospholipids. The chelator 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to PEG termini to allow labeling with positron-emitting (64)Cu. Radiolabeling with (64)Cu at high yield and high purity was readily achieved. The (64)Cu-SPIO probes produced strong MR and PET signals and were stable in mouse serum for 24 h at 37 degrees C. Biodistribution and in vivo PET/CT imaging studies of the probes showed a circulation half-life of 143 min and high initial blood retention with moderate liver uptake, making them an attractive contrast agent for disease studies.


Transformation of Schizosaccharomyces pombe in a 96-Well Format.
This protocol describes chemical transformation of Schizosaccharomyces pombe with linear DNA in a 96-well format. This procedure has been successfully used for large-scale strain construction in fission yeast.


Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism.
Accumulated oncometabolites in the tumor microenvironment (TME) suppresses the metabolism, expansion, and function of T cells. Immunosuppressive TME also impeded Chimeric Antigen Receptor (CAR)-T cells mediated cytotoxicity since CAR-T cells had to adapt the in vivo metabolic characteristics with high levels of oncometabolites. We screened oncometabolites for the inhibition of glucose uptake in CD8 + T cells and found Kynurenine (Kyn) showed the strongest inhibiting effect on glucose uptake. In vitro experiments showed that 120 μM Kyn treatment in CD8 + T cells resulted in inhibiting the expansion of CD8 + T cells, decreasing the production of granzyme B and interferon-γ. CAR-T cells mediated cytotoxicity was also impaired by the high Kyn treatment from killing assay. We then explored the anti-tumor effect of Kynureninase (KYNU) modified CAR-T cells through catabolism o oncometabolites Kyn. KYNU over-expression (OE) CAR-T cells showed a superior killing effect against cancer cells even in the immunosuppressive TME with high Kyn levels. In vivo experiments confirmed KYNU-OE CAR-T cells showed an excellent anti-tumor effect in a TME with high Kyn levels since it improved the survival of mice bearing NALM6 cancer cells and NALM6-IDO1 cancer cells. The KYNU-modified CAR-T cells displayed distinct phenotypes related to the expansion, function, and memory differentiation status of CAR-T cells. This study explores an immunotherapy strategy for patients with alterations in Kyn metabolism. KYNU-OE CAR-T cells take advantage of Kyn catabolism to improve anti-tumor activity in the metabolic immunosuppressive TME with high Kyn.


Serum hyperviscosity syndrome associated with Ehrlichia canis infection in a dog.
A 10-year-old male Lhasa Apso was examined because of pyrexia, vomiting, weight loss, lethargy, and disorientation. The clinical and laboratory findings were supportive of a diagnosis of serum hyperviscosity syndrome associated with an Ehrlichia canis infection. After tetracycline therapy the serum hyperviscosity syndrome and E. canis infection were successfully resolved.


Proton-Coupled Electron Transfer Enables Tandem Radical Relay for Asymmetric Copper-Catalyzed Phosphinoylcyanation of Styrenes.
A tandem radical relay strategy was realized for the first Cu(I)-catalyzed enantioselective phosphinocyanation of styrenes. In this reaction, tBuOOSiMe3 generated in situ from tBuOOH serves as a radical initiator to trigger t-butoxy radical production upon oxidization of L*Cu(I) species via proton-coupled-electron transfer (PCET) pathway, which leads to sequential phosphinoyl radical and benzyl radical formations. The resultant β-cyanodiarylphosphine oxides could be easily converted to a series of chiral γ-amino phosphine ligands.


Apelin/APJ system: A novel promising target for neurodegenerative diseases.
Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are incurable diseases characterized by progressive loss of cognitive or motor function, which construct a serious threat to the life quality of aging populations and their life spans. Apelin is an endogenous ligand for the G protein-coupled receptor. Apelin is reported to be detected not only in the cardiovascular system but also in neurons of the central nervous system (CNS). In addition, alterations in the expression level of apelin appear to play a pivotal role in various physiological processes including loss of structure or function of neurons, inflammatory responses, oxidative stress, Ca2+ signaling, apoptosis, and autophagy. All of these processes are intimately related to the occurrence of neurodegenerative diseases. Recently, apelin is reported to improve cognitive impairment in PD by antioxidant and antiapoptotic properties. Hence, it is becoming increasingly appreciated that altering the level of apelin can change the course or dictate the outcome of neurodegenerative events such as AD, PD, and HD, suggesting that apelin could be a potential target for the treatment of neurodegenerative diseases possibly acting on a variety of signaling pathways such as suppression of inflammatory responses, inhibition of oxidative stress, reduction of Ca2+ signaling, induction of autophagy, and suppression of apoptosis.


Mycobacterium fortuitum infection interference with Mycobacterium bovis diagnostics: natural infection cases and a pilot experimental infection.
Mycobacterium fortuitum and at least 1 unidentified species of soil mycobacteria were isolated from lymph nodes from 4 of 5 African buffalo (Syncerus caffer) that had been culled because of positive test results using the Bovigam assay. The buffalo were part of a group of 16 free-ranging buffalo captured in the far north of the Kruger National Park (South Africa) assumed to be free of bovine tuberculosis. No Mycobacterium bovis was isolated. To investigate the possible cause of the apparent false-positive diagnosis, the Mycobacterium isolates were inoculated into 4 experimental cattle and their immune responses monitored over a 13-week period, using the gamma interferon assay. The immune reactivity was predominantly directed toward avian tuberculin purified protein derivative (PPD) and lasted for approximately 8 weeks. During that period 3 of 4 cattle yielded positive test results on 1 or 2 occasions. The immune responsiveness was boosted when the inoculations were repeated after 15 weeks, which led to 2 subsequent positive reactions in the experimental animal that did not react previously. Including an additional stimulatory antigen, sensitin prepared from M. fortuitum in the gamma interferon assay, showed that it was able to elicit a detectable gamma interferon response in all 4 experimentally inoculated cattle when applied in parallel with bovine and avian tuberculin PPD for the stimulation of blood samples. The implications of occasional cross-reactive responses in natural cases of infection with environmental mycobacteria in the diagnosis of bovine tuberculosis in African buffalo and cattle in South Africa are discussed.


Predictors of recurrence after total thyroidectomy plus neck dissection and radioactive iodine ablation for high-risk papillary thyroid carcinoma.
American Thyroid Association (ATA) proposed management guidelines for differentiated thyroid cancer, including a three-tiered risk stratification system for structural recurrence. This study aimed to compare the various 2015 ATA criteria for the strength of association with the recurrence of high-risk papillary thyroid carcinoma (PTC). This study included 545 consecutive patients who underwent total thyroidectomy plus neck dissection and radioactive iodine ablation (RAI) for previously untreated high-risk PTC. The association of recurrence-free survival (RFS) with clinicopathological factors was evaluated by univariate and multivariate Cox proportional hazard regression analyses. During a follow-up median period of 89 months, 90 (16.5%) patients had any-site recurrence. Of the high-risk factors, high stimulated thyroglobulin (sTg) level and >3-cm sized lymph nodes (LNs) were significantly associated with recurrence (all P < .005). Sex, tumor size, lymphovascular invasion, multifocality, number of positive LNs, extranodal extension, T and N classifications, and overall tumor-node-metastasis stage were also significantly associated with recurrence (all P < .05). In multivariate analyses, high sTg level [adjusted hazard ratio (HR) = 7.18] and N1b (adjusted HR = 3.27) were independent factors predictive of recurrence (all P ≤ .001). Postoperative high serum sTg level might be the most important predictor of PTC recurrence after total thyroidectomy plus neck dissection and RAI.


Contributions of Yale neuroscience to Donald O. Hebb's organization of behavior.
The neuropsychological concepts found in Donald Hebb's The Organization of Behavior have greatly influenced many aspects of neuroscience research over the last half century. Hebb's ideas arose from a rich tradition of research. An underappreciated contribution came from pioneering studies at Yale University. Here, we wish to reconsider these developments, placing particular emphasis on the roles of the neurophysiologists John Fulton, J.J. Dusser de Barenne, and Warren McCulloch and the psychologists Donald Marquis and Ernest Hilgard. These neuroscientists all contributed significantly to the intellectual climate that gave rise to Hebb's remarkable synthesis.


Inhibition of bacterial adhesion and salmonella infection in BALB/c mice by sialyloligosaccharides and their derivatives from chicken egg yolk.
The effects of an egg-yolk-derived sialyloligosaccharide (YDS), asialo-YDS, and a sialylglycopeptide of YDS (SGP) on bacterial adhesion to intestinal epithelial cells and on Salmonella infection in BALB/c mice were examined. YDS, its derivative asialo-YDS, and SGP strongly inhibited the binding of Salmonella enteritidis but not E. coli K-88 to a human epithelial cell line, Caco-2. In a Salmonella infection experiment using BALB/c mice, oral administration of these reagents effectively prevented the bacteria from proliferating in spleen, as well as preventing lethality. An experiment using radioactive SGP orally administered to mice revealed that the compound was absorbed from the intestine into blood and eliminated via urine within 8 h. However, these reagents did not influence the production of TNF-alpha or NO. in culture macrophages. The results suggest that they inhibit Salmonella infection not by activating macrophages but by inhibiting the entry of bacteria through the gut, suggesting that YDS and its derivatives are useful for preventing Salmonella infection when ingested continuously.


Psychometric Validation of the Parental Bonding Instrument in a U.K. Population-Based Sample: Role of Gender and Association With Mental Health in Mid-Late Life.
The factorial structure of the Parental Bonding Instrument (PBI) has been frequently studied in diverse samples but no study has examined its psychometric properties from large, population-based samples. In particular, important questions have not been addressed such as the measurement invariance properties across parental and offspring gender. We evaluated the PBI based on responses from a large, representative population-based sample, using an exploratory structural equation modeling method appropriate for categorical data. Analysis revealed a three-factor structure representing "care," "overprotection," and "autonomy" parenting styles. In terms of psychometric measurement validity, our results supported the complete invariance of the PBI ratings across sons and daughters for their mothers and fathers. The PBI ratings were also robust in relation to personality and mental health status. In terms of predictive value, paternal care showed a protective effect on mental health at age 43 in sons. The PBI is a sound instrument for capturing perceived parenting styles, and is predictive of mental health in middle adulthood.


In vitro antimalarial activity of Syzygium cumini fruit fraction.
Malaria is still one of the most severe public health problems worldwide. The development of treatment, prevention, and control of malaria is one of the substantial problems in the world. To investigate the in vitro antimalarial activity of Syzygium cumini methanol fruit fraction. Syzygium cumini L fruit powder was macerated with methanol (PA) and the extract obtained was fractionated using the liquid-liquid partition method with n-hexane, ethyl acetate, butanol, chloroform, methanol, and water solvents. In vitro antimalarial assay was conducted using the culture of Plasmodium falciparum 3D7 strain culture that had reached >5% growth and was examined for IC50 values using a 24-well microplate in duplicate. Each treatment and control well contained 1,080 μl of complete media. Well, number 1 was added with 120 μl fraction, and then the solution was diluted until it reached 0.01, 0.1, 1, 10, and 100 μg/ml the final concentration in the microtiter well. The control only contained complete media and infected erythrocytes without the addition of anti-malarial drugs. The microplate was incubated for 48 hours. After 48 hours, a thin blood smear was made fixed with methanol and stained with 20% Giemsa for 20 minutes to determine the IC50 value by plotting sample concentrations and percentage of parasitemia in Excel. The IC50 values of ethyl acetate fraction, n.hexane fraction, butanol fraction, and water fraction were 1.189, 76.996, 1,769, and 15.058 μg/ml, respectively. Whereases the IC50 values of C1 fraction (mix fraction from chloroform: methanol 100:0 and 90:10) and C4 fraction (mix fraction from chloroform: methanol 20:80, 10:90, and 0:100) were 100.126 and 1.015 μg/ml, respectively. The results showed that the IC50 value of ethyl acetate, butanol, and C4 fraction were lower than 10μg/ml and were considered as good activity (strong antimalarial activity). The ethyl acetate, butanol and C4 subfraction from S. cumini fruit have the potential to be developed as an antimalarial agent.


Current trends in medical ethics education.
The unprecedented progress in biomedical sciences and technology during the last few decades has resulted in great transformations in the concepts of health and disease, health systems and healthcare organization and practices. Those changes have been accompanied by the emergence of a broad range of ethical dilemmas that confront the health professionals more frequently in an increasing range of problems and situations. Health care that has been practiced for centuries on the basis of a direct doctor-patient relationship has been increasingly transformed to a more complex process integrating the health-team, the patient (healthcare seeker) and the community. Systematic review of the specialized literature revealed that Healthcare Ethics Education became a basic requirement for any training program for health professionals, and should cover the different stages of undergraduate, postgraduate and continuing education. Both theoretical foundations and practical skills are required for the appropriate ethical reasoning, ethical attitude and decision-making. There is growing evidence that physicians' professional and moral development is not determined by the formal curriculum of ethics, rather more, it is determined by the moral environment of the professional practice, the "hidden curriculum" which deserves serious consideration by medical educators.


Correlation signatures for a coherent three-photon scattering in waveguide quantum electrodynamics.
We study the correlation signatures of a coherent three-photon scattering process by computationally investigating scattering photon wavefunctions, correlation functions, and nonlinear conditional phases. It is shown that both the three-photon bound states and the hybrid states, which consist of two-photon bound states and one unbound photon, contribute to all the correlation signatures. All computational correlation signatures are in good agreement with a recent experiment, wherein a weak coherent photonic state propagates through a quantum nonlinear Rydberg medium [Liang et al., Science359, 783 (2018)SCIEAS0036-807510.1126/science.aao7293].


Feed efficiency and the liver proteome of fattening lambs are modified by feed restriction during the suckling period.
The present study was designed to describe the effects of early feed restriction of Merino lambs on feed efficiency during the fattening period by examining ruminal microbiota and fermentation parameters, gastrointestinal morphology, digestibility or liver proteome. In total, 24 male Merino lambs were randomly assigned to two experimental treatments (n=12 per treatment). Lambs of the first group (ad libitum (ADL)) were kept permanently with the dams, whereas the other 12 lambs (restricted (RES)) were milk restricted. When lambs reached a live BW (LBW) of 15 kg, all the animals were offered the same complete pelleted diet (35 g dry matter/kg LBW per day) until slaughter at a LBW of 27 kg. The RES lambs showed poorer feed efficiency during the fattening period when compared with the ADL group (feed to gain ratio, 3.69 v. 3.05, P<0.001). No differences were observed in ruminal microbiota, fermentation parameters or apparent digestibility. However, the proportion of the small intestine and the length of ileal villi were reduced in the RES lambs. In total, 26 spots/proteins were identified in the liver proteomic profile, with significant differences (P<0.05) between experimental treatments, suggesting a higher catabolism of proteins and a reduction in β-oxidation of fatty acids in RES lambs when compared with the ADL animals. In conclusion, early feed restriction of Merino lambs during the suckling period promotes long-term effects on the small intestine and the proteomic profile of the liver, which may influence the metabolic use of nutrients, thus negatively affecting feed efficiency during the fattening phase.


De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies.
Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%-6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders.