Children's use of moral behavior in selective trust: discrimination versus learning.
Does valence play a role in children's sensitivity to and use of moral information in the service of selective learning? In the present experiment, we explored this question by presenting 3- to 5-year-old children with informants who behaved in ways consistent or inconsistent with sociomoral norms, such as helping a peer retrieve a toy or deliberately tearing a peer's artwork. "Good" versus "bad" informants were contrasted with putatively neutral-behaving informants. In an effort to specify the role that moral information plays in guiding children's selective trust, we measured children's ability to discriminate the informants as well as their willingness to learn from them. We found that children were significantly more likely to discriminate negatively behaving agents from neutral ones than they were to discriminate positively behaving agents from neutral ones. In contrast, children did not differ in the degree to which they used negative versus positive moral information in their selective learning; both types of information were used to guide trust across domains of knowledge. Results are discussed in terms of the positive-negative asymmetry observed and the different forms that a negativity bias might take.


[Participation of bdellovibrios in sewage self-purification processes].
The participation of bacterial parasites belonging to the genus Bdellovibrio in the processes of sewage self-purification was studied in refineries of Pushchino. The lytic activity of Bdellovibrio resulting in a decrease of the number of heterotrophic Gram-negative bacteria and E. coli in sewage was found to depend on the temperature factor influencing the intensity of interaction between the parasite and the host bacterium. The maximal p/h (parasite/host) index was found at the water temperature of 26 degrees C and the minimal one at 19 degrees C. Sewage purified at 26 degrees C and transferred to a precipitation tank contained 800 cells of E. coli in 1 ml while that purified at 19 degrees C contained 4000 cells in 1 ml. The number of interacting organisms varied in sewage which was typical of the "parasite-host" relations. Therefore, Bdellovibrio should be involved in the self-purification of sewage from the intestinal microflora at 26 degrees C; to a lesser extent, at 23.5 degrees C; and not at all, at 19 degrees C.


The benefits and implementation challenges of the first state-wide comprehensive medication for addictions program in a unified jail and prison setting.
The prevalence of opioid use disorders among people who are incarcerated is high. People who are released from incarceration are at increased risk for overdose. The current study details the first year of implementation of a state-wide medications for addiction treatment (MAT) program in a unified jail and prison setting at the Rhode Island Department of Corrections in Cranston, Rhode Island. We conducted 40 semi-structured, qualitative interviews with people who were incarcerated and concurrently enrolled in the MAT program. Analysis employed a general, inductive approach in NVivo 12. We found that a majority of participants discussed program benefits such as reduced withdrawal symptoms, decreased prevalence of illicit drug use in the facility, improved general environment at the RIDOC, and increased post-release intentions to continue MAT. Suggested areas of improvement include reducing delays to first dose, increasing access to other recovery services in combination with MAT, improving staff training on stigma, and earlier access to medical discharge planning information prior to release. Our findings suggest that correctional MAT programs are acceptable to targeted populations and are a feasible intervention that may be transferable to other states.


Procalcitonin-guided antibiotic therapy in critically ill adults: a meta-analysis.
As a novel biomarker of inflammation, procalcitonin (PCT) has proven useful to guide antibiotic therapy in intensive care unit (ICU). However, there are controversial on mortality. The aim of this study was to evaluate the utility of PCT-guided antibiotic therapy in critically ill adults and determine whether studies are sufficient. A systematic search in PubMed, Embase and Cochrane was performed. We included only randomized controlled trials which compared the safety and efficacy between PCT-guided or standard antibiotic therapy groups in ICU adults. Trial sequential analysis and GARDE approach were performed. Fifteen studies met our criteria for inclusion finally, with a cumulative number of 5486 ICU patients. There was no difference in 28-day mortality between two compared groups (P = 0.626), but significant decreases were observed in the duration of antibiotic therapy for the first episode of infection (P < 0.001) and length of hospitalization (P = 0.049). No significant deference was found in secondary endpoints except total duration of antibiotic therapy (P < 0.001). TSA revealed that the pooled sample sizes of 28-day mortality and the duration of antibiotic therapy for the first episode of infection exceeded the estimated required information size, but not the length of hospitalization. PCT-guided therapy is a better and safer algorithm to be applied into ICU patients, which appears no effect on 28-day mortality while performing preferable utility in reducing the duration of antibiotic therapy for the first episode of infection. More studies on these endpoints were not recommended.


A question of balance: prioritizing public health responses to harm from gambling.
To provide an overview on the nature and importance of public health approaches to the global expansion of commercial gambling. Three key areas of public health activity are examined: harm minimization, health promotion and the political determinants for change. The rapid proliferation of gambling experienced in many countries is driven by the commercial development of new products orientated around continuous and rapid mass consumption. This is particularly the case with ongoing refinements to electronic gambling machines and the development of new gambling technologies using the internet and mobile telephones. So far responses to negative impacts have, on the whole, focused upon individualized treatment interventions. A public health approach to gambling offers a broad range of strategies to tackle the wider implications of gambling expansion: harm reduction provides evidence-based strategies for managing identifiable harm; health promotion focuses upon communities building their capacity, knowledge and resilience with regard to the attractions of gambling, and action on the political determinants sets out to increase the accountability and reduce the conflicts of interest that influence government resolve in managing their gambling environments. In this new environment of mass consumption, efforts in developing treatment responses to problem gambling need to be balanced with, at least, equal efforts in developing public health responses. With the expansion of commercial gambling occurring globally, international agencies could play a critical role in supporting public health initiatives.


Metabolism of secoisolariciresinol-diglycoside the dietary precursor to the intestinally derived lignan enterolactone in humans.
Secoisolariciresinol-diglycoside (SDG), a natural dietary lignan of flaxseeds now available in dietary supplements, is converted by intestinal bacteria to the mammalian lignans enterodiol and enterolactone. High levels of these lignans in blood and urine are associated with reduced risk of many chronic diseases. Our objective was to determine the bioavailability and pharmacokinetics of SDG in purified flaxseed extracts under dose-ranging and steady-state conditions, and to examine whether differences in secoisolariciresinol-diglycoside purity influence bioavailability. Pharmacokinetic studies were performed on healthy postmenopausal women after oral intake of 25, 50, 75, 86 and 172 mg of secoisolariciresinol-diglycoside. Extracts differing in secoisolariciresinol-diglycoside purity were compared, and steady-state lignan concentrations measured after daily intake for one week. Blood and urine samples were collected at timed intervals and secoisolariciresinol, enterodiol and enterolactone concentrations measured by mass spectrometry. Secoisolariciresinol-diglycoside was efficiently hydrolyzed and converted to secoisolariciresinol. Serum concentrations increased rapidly after oral intake, peaking after 5-7 h and disappearing with a plasma elimination half-life of 4.8 h. Maximum serum concentrations of the biologically active metabolites, enterodiol and enterolactone were attained after 12-24 h and 24-36 h, respectively, and the half-lives were 9.4 h and 13.2 h. Linear dose-responses were observed and secoisolariciresinol bioavailability correlated (r(2) = 0.835) with cumulative lignan excretion. There were no significant differences in the pharmacokinetics of extracts differing in purity, and steady-state serum lignan concentrations were obtained after one-week of daily dosing. In conclusion, this study defines the pharmacokinetics of secoisolariciresinol-diglycoside and shows it is first hydrolyzed and then metabolized in a time-dependent sequence to secoisolariciresinol, enterodiol and ultimately enterolactone, and these metabolites are efficiently absorbed.


Concluding Commentary: A Call for evidence in CPD and Lifelong Learning.
This article was migrated. The article was marked as recommended. The AMEE CPD Committee was invited to oversee the launch of the first themed edition of MedEdPublish on Continuing Professional Development (CPD) for 2019's first quarter and sent a call for papers on evidence-based discussion on CPD and lifelong learning. The main aim was to highlight research and work supporting healthcare professions continuing education and professional development. A collection of seventeen manuscripts of various types such as "New Education Method and Tools", "Research Article", "Case Study", "Practical Tips or Guidelines", "Report of Meeting or Workshop" and "Commentary" were published. The articles portray fundamental good CPD practices encompassing the array of professional competencies needed to provide high quality healthcare. The manuscripts cover various CPD subthemes among which, mentorship and feedback, interactive learning, learning communities and applied technology, interprofessional education, evaluation and assessment, research in CPD, CPD frameworks, patient safety and quality improvement. They also embrace various perspectives and cultural diversity with the deemed adjustments to the regional healthcare teams' needs. The role and responsibilities of CPD educators are emboldened. This edition was a platform to welcome and discuss CPD under various perspectives among the global CPD community.


The atrial natriuretic factor.
In less than three years since the rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats was reported the factor responsible for the diuretic, natriuretic, and vasodilating activity of the atrial homogenates was isolated, its chemical structure elucidated, and its total synthesis achieved. Also the cDNA and the gene encoding for the atrial natriuretic factor in mice, rats, and man have been cloned and the chromosomal site identified. The major effects of this hormone are vasodilatation, prevention and inhibition of the contraction induced by noradrenaline and angiotensin II, diuresis, and natriuresis associated in most instances with a pronounced increase in glomerular filtration rate and filtration fraction, inhibition of aldosterone secretion, and considerable stimulation of particulate guanylate cyclase activity. High density specific binding sites have been demonstrated in the zona glomerulosa of the adrenal cortex, in the renal glomeruli, and in the collecting ducts, and in the brain areas involved in the regulation of blood pressure and of sodium and water (AV3V region, subfornical organ, nucleus tractus solitarius, area postrema).


Neural and behavioral associations of manipulated determination facial expressions.
Past research associated relative left frontal cortical activity with positive affect and approach motivation, or the urge to move toward a stimulus. Less work has examined relative left frontal activity and positive emotions ranging from low to high approach motivation, to test whether positive affects that differ in approach motivational intensity influence relative left frontal cortical activity. Participants in the present experiment adopted determination (high approach positive), satisfaction (low approach positive), or neutral facial expressions while electroencephalographic (EEG) activity was recorded. Next, participants completed a task measuring motivational persistence behavior and then they completed self-report emotion questionnaires. Determination compared to satisfaction and neutral facial expressions caused greater relative left frontal activity relative to baseline EEG recordings. Facial expressions did not directly influence task persistence. However, relative left frontal activity correlated positively with persistence on insolvable tasks in the determination condition. These results extend embodiment theories and motivational interpretations of relative left frontal activity.


Meiotic DSB patterning: A multifaceted process.
Meiosis is a specialized two-step cell division responsible for genome haploidization and the generation of genetic diversity during gametogenesis. An integral and distinctive feature of the meiotic program is the evolutionarily conserved initiation of homologous recombination (HR) by the developmentally programmed induction of DNA double-strand breaks (DSBs). The inherently dangerous but essential act of DSB formation is subject to multiple forms of stringent and self-corrective regulation that collectively ensure fruitful and appropriate levels of genetic exchange without risk to cellular survival. Within this article we focus upon an emerging element of this control--spatial regulation--detailing recent advances made in understanding how DSBs are evenly distributed across the genome, and present a unified view of the underlying patterning mechanisms employed.


Ultrasensitive and ultrawide range detection of a cardiac biomarker on a surface plasmon resonance platform.
One of the main challenges in the development of new analytical platforms for ultrasensitive bioaffinity detection is jointly achieving a wide dynamic range in target analyte concentration, especially for approaches that rely on multistep processes as a part of the signal amplification mechanism. In this paper, a new surface-based sandwich assay is introduced for the direct detection of B-type natriuretic peptide (BNP), an important biomarker for cardiac failure, at concentrations ranging from 1 aM to 500 nM. This was achieved using nanoparticle-enhanced surface plasmon resonance (SPR) where a DNA aptamer is immobilized on a chemically modified gold surface in conjunction with the specific adsorption of antiBNP coated gold nanocubes in the presence of the biomarker target. A concentration detection range greater than eleven orders of magnitude was achieved through dynamic control of only the secondary nanoparticle probe concentration. Furthermore, detection at low attomolar concentrations was also achieved in undiluted human serum.


[Modern endoscopy in inflammatory bowel disease].
Endoscopic examinations play a very important role in the diagnosis, progress assessment, and therapy of inflammatory bowel diseases (IBD). This includes not only esophagogastroduodenoscopy, sigmoidoscopy, and ileo-colonoscopy, but also assessment of the small intestine. The work-up of the small intestine is primarily carried out using non-invasive techniques (intestinal ultrasound, magnetic resonance enterography (MRE)). However, if the diagnosis remains unclear, a histological proof is necessary or an endoscopic intervention is required, capsule endoscopy and balloon-assisted enteroscopy are used. Furthermore, endoscopic ultrasound is available to assess perianal fistulizing Crohn's disease, and ERCP (endoscopic retrograde cholangiopancreatography) is used in certain patients with IBD-associated primary sclerosing cholangitis (PSC). Given the high resolution of modern endoscopes and the availability of chromoendoscopy, dysplastic lesions are detected earlier and can often be resected endoscopically. In addition, short strictures/stenoses can be treated using balloon dilatations.


Single-Operator Wire-Guided Cannulation Technique for Endoscopic Retrograde Cholangiopancreatography.
BACKGROUND The aim of this prospective study was to evaluate the clinical application value of single-operator cannulation technology (SOCT) for endoscopic retrograde cholangiopancreatography (ERCP). MATERIAL AND METHODS Sixty-nine patients prepared for ERCP were prospectively recruited from February 2014 to January 2017 in the 4th People's Hospital of Jinan. The included 69 patients were randomly divided into an experiment group (n=36) and a control group (n=33). Patients in the experiment group underwent SOCT procedure of ERCP and patients in the control group received the regular procedure of ERCP. The cannulation time, number of cannulations, number of attempts at cannulation, and ERCP procedure-relevant complications were recorded and compared between the 2 groups. RESULTS All of the included 69 patients successfully finished the ERCP procedure, with no peri-operative deaths. The median duration of cannulation for the experiment group was 7.4 (2.3~35.1) min and 7.1 (2.9~26.1) min for the control group, with no significant difference (p>0.05). The distribution of different cannulation periods and cannulation attempts were not significantly different between the 2 groups (p>0.05). The major complications relevant ERCP procedure were pancreatitis and infection. The incidence rate of pancreatitis and infection were 2.8% and 2.8% in the experiment group and 3.0% and 0.0% in control group, and the difference between groups was not significant (p>0.05). CONCLUSIONS Compared with regular ERCP, SOCT achieved the same effects without the help of an experienced assistant, which could make the procedure useful in primary hospitals.


Ultrasound-guided hydrostatic reduction of ileo-colic intussusception in childhood: first-line management for both primary and recurrent cases.
To evaluate the results of ultrasonography-guided hydrostatic reduction in primary and recurrent ileo-colic intussusception in children. The children (<18 years of age) who were managed for ileo-colic intussusception between January 2015 and December 2018 were evaluated retrospectively. Age, gender, presenting complaints, length of the intussuscepted segment, presence of lead point, treatment modalities, recurrence rates and duration of recurrence were evaluated. 108 patients with ileo-colic intussusception were enrolled in the study; 59 were male and 49 were female with a mean age of 2.04 ± 1.71 years. Two patients underwent immediate surgery without any attempt of hydrostatic reduction. Nineteen patients (18%) were managed by conservative measures initially. Seventeen (89.5%) of them have recovered with expectant management and two patients required hydrostatic enema reduction during follow-up. In total, 89 patients underwent hydrostatic reduction; 48 were male and 41were female with a mean age of 1.9 ± 1.65 years. Twelve patients (13.5%) received surgery after failed hydrostatic reduction. In the patients with successful hydrostatic reduction, one more episode of intussusception is seen in 10 patients (13%) and 2 additional episodes in 2 (2.6%). Seven patients with relapse were male and 5 were female with a mean age of 1.16 ± 1.64 years. The median duration of the first relapse episode was 67.5 days (range 18-110 days). The ultrasound-guided hydrostatic reduction was also successful in patients with recurrence. Ultrasound-guided hydrostatic reduction is a non-invasive treatment of ileo-colic intussusception with high success rates in childhood. It can be performed safely in both initial and relapse episodes of intussusception.


Partial credit model and pivot anchoring.
This article contains information on the Rasch measurement partial credit model: what it is, how it differs from other Rasch models, when to use it, and how to use it. The calibration of instruments with increasingly complex items is described, starting with dichotomous items and moving on to polychotomous items using a single rating scale, and mixed polychotomous items using multiple rating scales, and instruments in which each item has its own rating scale. It also introduces a procedure for aligning rating scale categories to be used when more than one rating scale is used in a single instrument. Pivot anchoring is defined and an illustration of its use with the mental health scale of the SF-36 that contains positive and negative worded items is provided. It finally describes the effect of pivot anchoring on step calibrations, the item hierarchy, and person measures.


Differentiating between autism spectrum disorders and other developmental disabilities in children who failed a screening instrument for ASD.
This study compared behavioral presentation of toddlers with autistic spectrum disorders (ASD) and toddlers with global developmental delay (DD) or developmental language disorder (DLD) who display some characteristics of ASD using the diagnostic algorithm items from the Autism Diagnostic Observation Schedule, Generic (ADOS), the Childhood Autism Rating Scale (CARS), and Modified Checklist for Autism in Toddlers (M-CHAT). To date, 195 children have failed the M-CHAT and have been diagnosed with ASD, DD or DLD. Children with ASD had prominent and consistent impairments in socialization skills, especially joint attention skills and were more impaired in some aspects of communication, play, and sensory processing. Children with ASD and children with DD/DLD shared common features, but certain behavioral markers differentiated the two groups.


Bone disease in hypoparathyroidism.
Hypoparathyroidism is a rare disorder that may be acquired or inherited. Postsurgical hypoparathyroidism is responsible for the majority of acquired hypoparathyroidism. Bone disease occurs in hypoparathyroidism due to markedly reduced bone remodeling due to the absence or low levels of parathyroid hormone. Chronically reduced bone turnover in patients with hypoparathyroidism typically leads to higher bone mass than in age- and sex-matched controls. Whether this increased bone density reduces fracture risk is less certain, because while increased bone mineralization may be associated with increased brittleness of bone, this does not appear to be the case in hypoparathyroidism. Treatment of hypoparathyroidism with recombinant parathyroid hormone may reduce bone mineral density but simultaneously strengthen the mechanical properties of bone.


Using brain-based cognitive measures to support clinical decisions in ADHD.
Measures of cognition support diagnostic and treatment decisions in attention deficit hyperactivity disorder. We used an integrative neuroscience framework to assess cognition and associated brain-function correlates in large attention deficit hyperactivity disorder and healthy groups. Matched groups of 175 attention deficit hyperactivity disorder children/adolescents and 175 healthy control subjects were assessed clinically, with the touch screen-based cognitive assessment battery "IntegNeuro" (Brain Resource Ltd., Sydney, Australia) and the "LabNeuro" (Brain Resource Ltd., Sydney, Australia) platform for psychophysiologic recordings of brain function and body arousal. IntegNeuro continuous performance task measures of sustained attention classified 68% of attention deficit hyperactivity disorder patients with 76% specificity, consistent with previous reports. Our additional cognitive measures of impulsivity, intrusive errors, inhibition, and response variability improved sensitivity to 88%, and specificity to 91%. Positive predictive power was 96%, and negative predictive power, 88%. These metrics were stable across attention deficit hyperactivity disorder subtypes and age. Consistent with their brain-based validity, cognitive measures were correlated with corresponding brain-function and body-arousal measures. We propose a combination of candidate cognitive "markers" that define a signature for attention deficit hyperactivity disorder: "sustained attention," "impulsivity," "inhibition," "intrusions," and "response variability." These markers offer a frame of reference to support diagnostic and treatment decisions, and an objective benchmark for monitoring outcomes of interventions.


First in the Nation: One Unit's Journey to Achieving Fragility Fracture Certification.
Osteoporosis is related to more than 2 million fractures and $19 billion in healthcare costs each year (). A fragility fracture (FF) is a low-energy fracture of the distal radius, proximal humerus, ankle, or proximal femur (hip) from minimal trauma such as a fall from a standing height. In addition to cost, FFs often result in the loss of independence and productivity (). In 2015, our orthopaedic unit received the first certification ever awarded for FFs. Fragility fracture certification is a new certification demonstrating that a healthcare facility complies with national patient care standards and uses evidence-based practice guidelines to deliver quality outcomes. Orthopaedic nurses have a critical role in optimizing future bone health and fracture prevention. Our story describes the process and challenges faced becoming the first organization in the nation to be successfully surveyed for The Joint Commission's Fragility Fracture Certification.


Multicanonical sampling of rare events in random matrices.
A method based on multicanonical Monte Carlo is applied to the calculation of large deviations in the largest eigenvalue of random matrices. The method is successfully tested with the Gaussian orthogonal ensemble, sparse random matrices, and matrices whose components are subject to uniform density. Specifically, the probability that all eigenvalues of a matrix are negative is estimated in these cases down to the values of ∼10(-200), a region where simple random sampling is ineffective. The method can be applied to any ensemble of matrices and used for sampling rare events characterized by any statistics.


Drug interactions among commonly used medications. Chart simplifies data from critical literature review.
To simplify risk assessment, we have developed a way to present critically appraised drug interaction information through a chart. Fifty drugs most frequently prescribed by Canadian family physicians and 16 drugs and substances that frequently interact with these drugs were the basis for a literature review. Drug interaction textbooks and MEDLINE (from 1966 to 1994) were searched for documented interactions. Reports of additive effects and animal or in vitro studies were excluded. All reports of interactions were evaluated for clinical effect, clinical significance, and quality of evidence. Of the 464 drug-drug or drug-substance pairs evaluated, 387 (83.4%) demonstrated an interaction, 59 (12.7%) documented no effect, and 18 (3.9%) pairs had conflicting evidence. Five percent of interactions were of major clinical significance; only 1.3% were of major clinical significance and supported by good-quality evidence. By using symbols, colours, and legends in a "grid-map" format, a large amount of drug interaction information was reduced to a single-page chart suitable for a desk reference or wall mounting. Our chart organizes a large amount of drug interaction information in a format that allows for rapid appreciation of outcome, clinical significance, and quality of evidence.


Impact of patient age on family cancer history.
Younger individuals with relatives diagnosed with cancer are at greater risk for developing certain cancer when compared with older individuals with affected relatives. The purpose of this study was to calculate the age-specific proportion of individuals reporting positive family histories for colon, breast, and prostate cancer. Family cancer history information was reviewed on 32,374 adults interviewed for the 2000 National Health Interview Survey. Family histories were categorized as high risk, with a relative diagnosed before 50 years of age or with multiple affected relatives, or moderate risk, with a single relative diagnosed at age 50 years or older. For individuals with a family history of colorectal cancer, the odds of having a high-risk pedigree decreased by 1% (95% confidence interval 0%-2%) for every year of age increase. For women reporting a family breast cancer history, the odds of reporting a pedigree with high-risk features decreased by 3% (95% confidence interval 2%-4%) for each year of age increase. Age was not associated with reporting a high-risk pedigree for prostate cancer. For colorectal and breast cancers, younger individuals reporting a family history of these cancers were more likely to report a pedigree with high-risk features than older individuals.


Assessment of psychopathy among justice-involved adult males with low versus average intelligence: Differential links to violent offending.
Psychopathic personality is a multidimensional construct (De Brito et al., 2021) and the dimensions have differential associations with general and violent offending. Impairment in cognitive functioning, particularly intelligence (IQ), is another construct linked to both general and violent offending. However, the evidence is mixed on whether the combination of elevated psychopathy and low IQ increases the risk for violent offending (Hampton et al., 2014; Heilbrun, 1982; Walsh et al., 2004). Also, before this interaction can be firmly established, assessment of whether psychopathic traits are equivalent among individuals with different levels of IQ, especially those in the justice system, is needed. Using multiple-group confirmatory factor analysis (MG-CFA), this study of justice-involved adult males tested whether Psychopathy Checklist-Revised (PCL-R; Hare, 2003) item parameters were invariant among those with low (< 85) versus average IQ (≥ 85). In addition, moderated nonlinear factor analysis was conducted using continuous IQ scores to test for its effect on a range of model parameters. Both approaches provided evidence of measurement invariance. Adding criminal offenses to the MG-CFA revealed differential associations of the psychopathy dimensions with violent offending. Finally, analysis of variance results suggested an interaction between psychopathy status and IQ level-that is, those meeting diagnostic criterion for psychopathy with low IQ had the highest number of violent offenses. This study provides evidence of measurement invariance for the PCL-R among justice-involved persons with varying levels IQ and helps to extend research on the dynamic associations between psychopathy, IQ, and violent behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Nucleolar organizer region banding in crossbred and non-descript pigs of India.
The objective of this experiment was to study the nucleolar organizer region (NOR)-banding pattern in Large White Yorkshire (LWY) crossbred and non-descript pigs and finding differences in the number of NORs between animals and between genetic groups. The experiment was carried out on 15 females, and 15 males of LWY crossbred and non-descript pigs to study NOR-banding pattern by employing ammoniacal silver staining technique. A total of 63 and 65 number of good metaphases were prepared in LWY crossbred, and non-descript pigs and a total of 168 and 143 number of NORs were detected on the 8th and 10th chromosomes in both genetic groups, respectively. The mean number of NORs per metaphase was 2.67 and 2.20 in LWY crossbred and non-descript pigs, respectively. LWY crossbred pig had high mean number of silver-stained NORs (Ag-NORs) per metaphase compared to non-descript pig. In general, it was observed that the highest frequency of metaphases (%) examined had two number of NORs, while the lowest frequency (%) had four number of NORs. The number of NORs observed per metaphase on secondary constrictions of the 8th and 10th chromosome pair in both genetic groups ranged from 2 to 4. The Chi-square test of significance revealed that the observed frequencies do not differ significantly from the expected frequencies. The results confirmed differences across breeds in occurrence and number of NORs on chromosomes in pigs. The mean numbers of NORs present per metaphase vary between the animals indicating the existence of polymorphism for the number of NORs. A higher number of Ag-NORs were observed on chromosome pair 10 in both the genetic groups. It was concluded that NORs were more morphologically distinct and greater on chromosome pair 10 than on pair 8, which suggests a dominant role of chromosome 10 in the global production of ribosomal RNA.


Radiosensitization of Primary Human Glioblastoma Stem-like Cells with Low-Dose AKT Inhibition.
Glioblastoma (GBM) is the most frequent and lethal brain cancer. The lack of early detection methods, the presence of rapidly growing tumor cells, and the high levels of recurrence due to chemo- and radioresistance make this cancer an extremely difficult disease to treat. Emerging studies have focused on inhibiting AKT activation; here, we demonstrate that in primary GBM tumor samples, full-dose inhibition of AKT activity leads to differential responses among samples in the context of cell death and self-renewal, reinforcing the notion that GBM is a heterogeneous disease. In contrast, low-dose AKT inhibition when combined with fractionation of radiation doses leads to a significant apoptosis-mediated cell death of primary patient-derived GBM cells. Therefore, low-dose-targeted therapies might be better for radiosensitization of primary GBM cells and further allow for reducing the clinical toxicities often associated with targeting the AKT/PI3K/mTOR pathway. This work emphasizes the discrepancies between cell lines and primary tumors in drug testing, and indicates that there are salient differences between patients, highlighting the need for personalized medicine in treating high-grade glioma.


Garlic oil suppressed the hematological disorders induced by chemotherapy and radiotherapy in tumor-bearing mice.
Although the anticancer effects of garlic and its products have been demonstrated by a variety of studies; however, few studies were conducted to investigate the effects of garlic on the adverse effects of chemo/radiotherapy. In order to clarify the above question and make a more comprehensive understanding of the anticancer effects of garlic, tumor xenograft mice model was established by subcutaneous injection of H22 tumor cells, and was used for the investigation of effects of garlic oil (GO) on the chemo/radiotherapy. In the chemotherapy test, tumor-bearing mice were treated with cyclophosphamide (CTX) or CTX plus GO (25 or 50 mg/kg bw) for 14 d, while the mice received a single 5 Gy total body radiation or radiation plus GO (25 or 50 mg/kg bw) in radiotherapy test. The results showed that GO did not increase the tumor inhibitory rate of CTX/radiation, which indicated that GO could not enhance the chemo/radiosensitivity of cancer cells. However, the decrease of the peripheral total white blood cells (WBCs) count induced by CTX/radiation was significantly suppressed by GO cotreatment. Furthermore, GO cotreatment significantly inhibited the decrease of the DNA contents and the micronuclei ratio of the bone marrow. Lastly, the reduction of the endogenous spleen colonies induced by CTX/radiation was significantly suppressed by GO cotreatment. These findings support the idea that GO consumption may benefit for the cancer patients receiving chemotherapy or radiotherapy.


Short review: Geographical distribution of equine-associated pVAPA plasmids in Rhodococcus equi in the world.
Virulent Rhodococcus equi strains expressing virulence-associated 15-17 kDa protein (VapA) and having a large virulence plasmid (pVAPA) of 85-90 kb containing vapA gene are pathogenic for horses. In the last two decades, following pVAPA, two host-associated virulence plasmid types of R. equi have been discovered: a circular plasmid, pVAPB, associated with porcine isolates in 1995, and a recently detected linear plasmid, pVAPN, related to bovine and caprine isolates. Molecular epidemiological studies of R. equi infection in foals on horse-breeding farms in Japan and many countries around the world have been conducted in the last three decades, and the epidemiological studies using restriction enzyme digestion patterns of plasmid DNAs from virulent isolates have shown 14 distinct pVAPA subtypes and their geographical preference. This short review summarizes previous reports regarding equine-associated pVAPA subtypes in the world and discusses their geographic distribution from the standpoint of horse movements.


Thromboxane agonism and antagonism in a mouse sudden death model.
The effects of the stable thromboxane agonist, U46619, and sodium arachidonate were tested by i.v. injection into male and female mice. U46619 produced dose-dependent mortality in both sexes equally, in contrast to the gender-differentiated effects of arachidonic acid. The thromboxane receptor antagonist, SQ 26,536, protected in a dose-dependent manner against both arachidonate and U46619. The thromboxane antagonist was more effective against arachidonate toxicity in male than in female mice, but was equiactive against U46619 in both sexes. Neither the thromboxane synthetase inhibitor, OKY-1581, nor the cyclooxygenase inhibitor, indomethacin, protected against U46619-induced sudden death. However, cortisone acetate increased survival of mice challenged with U46619. The results support the hypothesis that thromboxane A2 mediates arachidonate-induced sudden death. The effects of arachidonate can be mimicked by the thromboxane agonist and are attenuated by the thromboxane antagonist. The gender difference in arachidonate toxicity is apparently not due to differences in sensitivity to thromboxane A2, as the thromboxane agonist was equally toxic in males and females. The greater protective effect of the thromboxane antagonist against arachidonate toxicity in males suggests that thromboxane A2 is a more important mediator of arachidonate-induced sudden death in males compared to female mice.


Investigating KYNA production and kynurenergic manipulation on acute mouse brain slice preparations.
Manipulation of kynurenic acid (KYNA) level through kynurenine aminotransferase-2 (KAT-2) inhibition with the aim of therapy in neuro-psychiatric diseses has been the subject of extensive recent research. Although mouse models are of particular importance, neither the basic mechanism of KYNA production and release nor the relevance of KAT-2 in the mouse brain has yet been clarified. Using acute mouse brain slice preparations, we investigated the basal and L-kynurenine (L-KYN) induced KYNA production and distribution between the extracellular and intracellular compartments. Furthermore, we evaluated the effect of specific KAT-2 inhibition with the irreversible inhibitor PF-04859989. To ascertain that the observed KYNA release is not a simple consequence of general cell degradation, we examined the structural and functional integrity of the brain tissue with biochemical, histological and electrophysiological tools. We did not find relevant change in the viability of the brain tissue after several hours incubation time. HPLC measurements proved that mouse brain slices intensively produce and liberate KYNA to the extracellular compartment, while only a small proportion retained in the tissue both in the basal and L-KYN supplemented state. Finally, specific KAT-2 inhibition significantly reduced the extracellular KYNA content. Taken together, these results provide important data about KYNA production and release, and in vitro evidence for the first time of the function of KAT-2 in the adult mouse brain. Our study extends investigations of KAT-2 manipulation to mice in a bid to fully understand the function; the final, future aim is to assign therapeutical kynurenergic manipulation strategies to humans.


Fludrocortisone therapy for persistent hyperkalaemia.
Type 4 renal tubular acidosis causes hyperkalaemia, for which diabetes and medications commonly used in this patient group are aetiological factors. Here we describe the novel use of fludrocortisone in this difficult condition. A 55-year-old woman with complex co-morbidities, including Type 2 diabetes (HbA1c 37 mmol/mol 5.5%), was admitted with renal failure. Bloods on admission: eGFR 25 ml/min, creatinine 184 ?mol/L, urea 35.9 mmol/L, sodium 128 mmol/L, potassium 5.6 mmol/L, bicarbonate 15 mmol/L, and albumin 30 g/L. Her admission was prolonged, complicated by hospital-acquired sepsis (lower respiratory tract, urinary tract, and infected leg ulcers), poor venous access and severe depression. She had recurrent hyperkalaemia and deteriorating renal function, from presumed Type 4 renal tubular acidosis and excessive fluid losses from leg ulcers. Her renal function recurrently deteriorated, despite conventional treatment methods. After 69 days, she was commenced on fludrocortisone 50 mcg/day. Her renal function and serum potassium stabilized and she was discharged with potassium 4.3 mmol/L, eGFR 42 ml/min, and bicarbonate 23 mmol/L. She has remained stable on this treatment, without requiring further hospital admission for over 6 months, with eGFR 40 ml/min, and potassium 5.5 mmol/L, and albumin 26 g/L. This woman was presumed to have Type 4 renal tubular acidosis and recurrent hyperkalaemia due to renal insufficiency, in the context of underlying diabetes and chronic kidney disease, which was poorly responsive to conventional management. There is limited evidence for using fludrocortisone in this setting. Our case suggests that fludrocortisone might offer a novel therapeutic strategy when conventional management is not working.


Trichoderma viride cellulase induces resistance to the antibiotic pore-forming peptide alamethicin associated with changes in the plasma membrane lipid composition of tobacco BY-2 cells.
Alamethicin is a membrane-active peptide isolated from the beneficial root-colonising fungus Trichoderma viride. This peptide can insert into membranes to form voltage-dependent pores. We have previously shown that alamethicin efficiently permeabilises the plasma membrane, mitochondria and plastids of cultured plant cells. In the present investigation, tobacco cells (Nicotiana tabacum L. cv Bright Yellow-2) were pre-treated with elicitors of defence responses to study whether this would affect permeabilisation. Oxygen consumption experiments showed that added cellulase, already upon a limited cell wall digestion, induced a cellular resistance to alamethicin permeabilisation. This effect could not be elicited by xylanase or bacterial elicitors such as flg22 or elf18. The induction of alamethicin resistance was independent of novel protein synthesis. Also, the permeabilisation was unaffected by the membrane-depolarising agent FCCP. As judged by lipid analyses, isolated plasma membranes from cellulase-pretreated tobacco cells contained less negatively charged phospholipids (PS and PI), yet higher ratios of membrane lipid fatty acid to sterol and to protein, as compared to control membranes. We suggest that altered membrane lipid composition as induced by cellulase activity may render the cells resistant to alamethicin. This induced resistance could reflect a natural process where the plant cells alter their sensitivity to membrane pore-forming agents secreted by Trichoderma spp. to attack other microorganisms, and thus adding to the beneficial effect that Trichoderma has for plant root growth. Furthermore, our data extends previous reports on artificial membranes on the importance of lipid packing and charge for alamethicin permeabilisation to in vivo conditions.


Paraganglioma mimicking a pancreatic neoplasm.
Paragangliomas are rare tumours of neural crest origin. Extra-adrenal pancreatic paragangliomas are exceptionally rare. A 66-year-old man with abdominal pain was noted to have a complex pancreatic head and uncinate process mass on imaging. He underwent complete resection by pancreaticoduodenectomy with final pathology confirming a 6 cm paraganglioma without evidence of metastases. On histology the tumour was arising from the retroperitoneum and abutting the pancreas. The patient was disease free at 14-month follow-up. Pancreatic paragangliomas represent in many cases the retroperitoneal extension of a paraganglioma into the pancreas rather than a true pancreatic neoplasm. Although generally benign, the risk of malignant transformation justifies aggressive management.


Rapid Assembly of Tetrasubstituted Furans via Pummerer-Type Rearrangement.
Despite the many methods available for the synthesis of furans, few methods remain that allow for the custom-made assembly of fully substituted furans. Here we report a powerful protocol to rapidly construct tetrasubstituted, orthogonally functionalized furans under mild reaction conditions. The developed method involves the regioselective ring-opening of readily available 2,5-dihydrothiophenes followed by an oxidative cyclization to provide the heterocycle. The selective oxidation at sulfur is promoted by N-chlorosuccinimide as an inexpensive reagent and proceeds at ambient temperature in high yield within 30 min. The obtained furans serve as exceptionally versatile intermediates and were shown to participate in a series of valuable postmodifications. The fate of the initial sulfonium intermediate was investigated by mechanistic experiments, and computational studies revealed the existence of an unprecedented Pummerer-type rearrangement. The potential for organic synthesis is highlighted by the total synthesis of bisabolene sesquiterpenoids (pleurotins A, B, and D).


Radon (222Rn) in ground water of fractured rocks: a diffusion/ion exchange model.
Ground waters from fractured igneous and high-grade sialic metamorphic rocks frequently have elevated activity of dissolved radon (222Rn). A chemically based model is proposed whereby radium (226Ra) from the decay of uranium (238U) diffuses through the primary porosity of the rock to the water-transmitting fracture where it is sorbed on weathering products. Sorption of 226Ra on the fracture surface maintains an activity gradient in the rock matrix, ensuring a continuous supply of 226Ra to fracture surfaces. As a result of the relatively long half-life of 226Ra (1601 years), significant activity can accumulate on fracture surfaces. The proximity of this sorbed 226Ra to the active ground water flow system allows its decay progeny 222Rn to enter directly into the water. Laboratory analyses of primary porosity and diffusion coefficients of the rock matrix, radon emanation, and ion exchange at fracture surfaces are consistent with the requirements of a diffusion/ion-exchange model. A dipole-brine injection/withdrawal experiment conducted between bedrock boreholes in the high-grade metamorphic and granite rocks at the Hubbard Brook Experimental Forest, Grafton County, New Hampshire, United States (42 degrees 56'N, 71 degrees 43'W) shows a large activity of 226Ra exchanged from fracture surfaces by a magnesium brine. The 226Ra activity removed by the exchange process is 34 times greater than that of 238U activity. These observations are consistent with the diffusion/ion-exchange model. Elutriate isotopic ratios of 223Ra/226Ra and 238U/226Ra are also consistent with the proposed chemically based diffusion/ion-exchange model.


Digitization and validation of the open bite checklist manifesto: a step toward artificial intelligence.
To introduce and validate newly designed computer software to aid in the diagnosis of anterior open bite (AOB). The software was constructed based on the algorithm of a standardized open bite checklist, which considered skeletal, dental, and soft tissue components, as well as smile characteristics. Feeding the software with this input yielded a digital form output (DFO) in the guise of a diagnostic report characterizing the AOB phenotype, contributing components, severity, associated problems, and functional factors. For validation, DFO was compared to a conventional form output (CFO), created in a standardized manner according to expert opinions. Agreement between the DFO and CFO in terms of AOB phenotype was the primary outcome, while the secondary outcome was the number of missing diagnostic components in either method. Percentage of agreement between CFO and DFO was 82.2%, with a kappa coefficient of 0.78, which is considered a good level of agreement. There was a statistically significant relationship between the number of missing diagnostic components in CFO and level of disagreement, which rendered the DFO more reliable. Newly constructed software represents an efficient and valid diagnostic tool for AOB and its contributing components. There was good agreement between CFO and DFO, with the latter being more comprehensive and reliable. The algorithm built in the software can be used as the basis for a future artificial intelligence model to aid in the diagnosis of AOB.


Complications in the 90-day postoperative period following kidney transplant and the relationship of the Charlson Comorbidity Index.
Renal transplant experiences widespread success, but little is published regarding the postoperative complications. The Charlson Comorbidity Index (CCI) is a system of mortality risk assessment. Our purpose is to assess the 90-day postoperative complications after renal transplantation. The secondary objective is to clarify whether CCI predicts complications. We hypothesized increased CCI corresponds to worse complication on the Clavien scale. This is a retrospective analysis of renal recipients at our institution (2011-2013) who were ≥18 years old and received complete follow up. CCI, age, gender, body mass index (BMI), and graft type were extracted from the electronic medical records. Complications were scored using the Clavien scale. Descriptive statistics and logistic regression were used to analyze 198 patients. The mean age was 53 (standard deviation [SD] 14), mean BMI 27.4 (SD 14), median CCI 1. Grade 2 or higher (significant) complications occurred in 60% of patients and Grade 3b or higher (severe) in 15% of patients in the 90-day postoperative period. Sixty-eight different complications were identified, the most common being blood transfusion (19%). Logistic regression suggests a predictive value of CCI (odds ratio [OR] 1.70; 95% confidence interval [CI] 1.3-2.3) for severe complications, with diabetes mellitus and peripheral vascular disease conferring increased risk. Renal transplant carries significant risk. This data can be used to improve patient counselling on the likely postoperative course. Study limitations include the retrospective design, predisposing to potential bias in data capture.


History of Sexual Assault as a Predictor of Response to a Self-Guided Online Program for Sexual Desire and Arousal Difficulties in Women.
Sexual Interest/Arousal Disorder (distressing, long-lasting impairments in sexual desire and/or arousal) is common in women, but few have access to efficacious psychotherapies, including cognitive-behavioral therapy (CBT) and mindfulness-based therapy (MBT). eSense, an online program meant to maximize treatment access, has been shown to be a feasible, satisfactory, and potentially efficacious intervention. However, subpopulations such as sexual assault survivors may find the program less usable or efficacious. The current study compared women with and without a history of sexual assault (SA) regarding their ability to use and benefit from eSense. Forty-four women (22 with a history of SA; M age = 34.20 years) used eSense (CBT or MBT) and completed validated self-report scales of sexual function, sexual distress, treatment satisfaction, and homework compliance. A history of SA did not predict differences in attrition or changes in clinical outcomes. Exploratory analyses suggested that women with a history of SA reported slightly higher difficulty completing homework assignments, but also slightly higher treatment satisfaction. These preliminary results suggest that eSense may be usable and helpful for women with a history of SA. We discuss ways to maximize the acceptability and efficacy of online programs for women with a history of SA.


Relationship Between Maximal Left Ventricular Wall Thickness and Sudden Cardiac Death in Childhood Onset Hypertrophic Cardiomyopathy.
Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort. The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids). MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk. In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.


Modeling rarefied gas-solid surface interactions for Couette flow with different wall temperatures using an unsupervised machine learning technique.
In rarefied gas flows, discontinuity phenomena such as velocity slip and temperature jump commonly appear in the gas layer adjacent to a solid boundary. Due to the physical complexity of the interactions at the gas-solid interface, particularly in the case of systems with local nonequilibrium state, boundary models with limited number of parameters cannot completely describe the reflection of gas molecules at the boundary. In this work, the Gaussian mixture (GM) model, which is an unsupervised machine learning technique, is employed to construct a statistical gas-solid surface scattering model based on the collisional data obtained from molecular dynamics (MD) simulations. The GM model is applied to study Couette flow for different inert gases (Ar and He) confined between two parallel infinite gold walls at different temperatures. A direct comparison between the results obtained from the GM model and the Cercignani-Lampis-Lord (CLL) scattering kernel against the MD collisional data in terms of the distribution of the predicted postcollisional velocities, and accommodation coefficients has shown that the results from the GM model are an excellent match with the MD results outperforming the CLL scattering kernel. As an example, for He gas, while the predicted energy accommodation coefficient by the CLL model is more than two times higher than the MD predictions, the value computed by the GM model is in excellent agreement with the MD results. This superior performance of the GM model confirms its high potential to derive a generalized boundary condition in systems encountered with highly nonequilibrium and complex gas flow conditions.


Kidney Organoids as Disease Models: Strengths, Weaknesses and Perspectives.
Chronic kidney disease is a major global health problem, as it affects 10% of the global population and kills millions of patients every year. It is therefore of the utmost importance to develop models that can help us to understand the pathogenesis of CKD and improve our therapeutic strategies. The discovery of human induced pluripotent stem cells (hiPSCs) and, more recently, the development of methods for the generation of 3D organoids, have opened the way for modeling human kidney development and disease in vitro, and testing new drugs directly on human tissue. In this review we will discuss the most recent advances in the field of kidney organoids for modeling disease, as well as the prospective applications of these models for drug screening. We will also emphasize the impact of CRISPR/cas9 genome engineering on the field, point out the current limitations of the existing organoid technologies, and discuss a set of technical developments that may help to overcome limitations and facilitate the incorporation of these exciting tools into basic biomedical research.


A retrospective study of the changing trends of antimicrobial resistance of Klebsiella pneumoniae isolated from urine samples over last 3 years (2012-2014).
In our country, the problem of antibiotic resistance is compounding because of overuse and misuse of antibiotics. There is no systematic national surveillance of antibiotic resistance and insufficient data are available to quantify the problem. To study the changing pattern of antimicrobial resistance of Klebsiella pneumoniae isolates from patients of urinary tract infections over last 3 years. A retrospective, record-based study carried out based on the records culture sensitivity reports of indoor patients, during past 3 years (2012-2014). The type of organisms most common in urine sample was noted, and the drugs still effective for the particular organism were noted. Klebsiella was the second most frequent isolate throughout the 3 years (14%) of the total isolates). Analysis of the results year wise indicated that the lowest percentage of resistance was manifested against imipenem between 11.94% (2012) and 13.75% (2014). Over the successive years, resistance to ceftriaxone tends to increase from 74.95 % (2012) to 81% (2014). Klebsiella showed very high resistance 90.78% (2012) and 95.63% (2012) to co-trimoxazole and tetracycline, respectively with increasing trend to absolute resistance to both groups over the 3 years period. On an average over the 3 years Klebsiella showed a high amount of resistances to fluoroquinolones (72.71%) and aminoglycosides (76.22%). While multi-drug resistant Klebsiella range between 65% (2012) and 67% (2014). The antimicrobial resistance patterns are constantly evolving and vary from region to region it has become a necessity to do constant antimicrobial sensitivity surveillance. This will help clinicians to provide safe and effective empirical therapies.


Molecular profiling for acromegaly treatment: a validation study.
Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.


Nox1 upregulates the function of vascular T-type calcium channels following chronic nitric oxide deficit.
Cardiovascular disease is characterised by reduced nitric oxide bioavailability resulting from oxidative stress. Our previous studies have shown that nitric oxide deficit per se increases the contribution of T-type calcium channels to vascular tone through increased superoxide from NADPH oxidase (Nox). The aim of the present study was therefore to identify the Nox isoform responsible for modulating T-type channel function, as T-type channels are implicated in several pathophysiological conditions involving oxidative stress. We evaluated T-channel function in skeletal muscle arterioles in vivo, using a novel T-channel blocker, TTA-A2 (3 μmol/L), which demonstrated no cross reactivity with L-type channels. Wild-type and Nox2 knockout (Nox2ko) mice were treated with the nitric oxide synthase inhibitor L-NAME (40 mg/kg/day) for 2 weeks. L-NAME treatment significantly increased systolic blood pressure and the contribution of T-type calcium channels to arteriolar tone in wild-type mice, and this was not prevented by Nox2 deletion. In Nox2ko mice, pharmacological inhibition of Nox1 (10 μmol/L ML171), Nox4 (10 μmol/L VAS2870) and Nox4-derived hydrogen peroxide (500 U/mL catalase) significantly reduced the effect of chronic nitric oxide inhibition on T-type channel function. In contrast, in wild-type mice, ML171 and VAS2870, but not catalase, reduced the contribution of T-type channels to vascular tone, suggesting a role for Nox1 and non-selective actions of VAS2870. We conclude that Nox1, but not Nox2 or Nox4, is responsible for the upregulation of T-type calcium channels elicited by chronic nitric oxide deficit. These data point to an important role for this isoform in increasing T-type channel function during oxidative stress.


Comparative Evaluation of the Treatment of COVID-19 with Multicriteria Decision-Making Techniques.
The outbreak of coronavirus disease 2019 (COVID-19) was first reported in December 2019. Until now, many drugs and methods have been used in the treatment of the disease. However, no effective treatment option has been found and only case-based successes have been achieved so far. This study aims to evaluate COVID-19 treatment options using multicriteria decision-making (MCDM) techniques. In this study, we evaluated the available COVID-19 treatment options by MCDM techniques, namely, fuzzy PROMETHEE and VIKOR. These techniques are based on the evaluation and comparison of complex and multiple criteria to evaluate the most appropriate alternative. We evaluated current treatment options including favipiravir (FPV), lopinavir/ritonavir, hydroxychloroquine, interleukin-1 blocker, intravenous immunoglobulin (IVIG), and plasma exchange. The criteria used for the analysis include side effects, method of administration of the drug, cost, turnover of plasma, level of fever, age, pregnancy, and kidney function. The results showed that plasma exchange was the most preferred alternative, followed by FPV and IVIG, while hydroxychloroquine was the least favorable one. New alternatives could be considered once they are available, and weights could be assigned based on the opinions of the decision-makers (physicians/clinicians). The treatment methods that we evaluated with MCDM methods will be beneficial for both healthcare users and to rapidly end the global pandemic. The proposed method is applicable for analyzing the alternatives to the selection problem with quantitative and qualitative data. In addition, it allows the decision-maker to define the problem simply under uncertainty. Fuzzy PROMETHEE and VIKOR techniques are applied in aiding decision-makers in choosing the right treatment technique for the management of COVID-19.


Thermally induced interfacial stresses in a thin film on an infinite substrate.
The thermally induced stresses in a thin film deposited on an infinite substrate is approximated by means of the theory of elasticity and strain energy minimization. The results are applied to the growth of a thick layer of zinc selenide onto a film of polycrystalline diamond. The conclusion is that the thermally induced stresses alone will be much higher than normally encountered in coating work.


BAK1 gene variation and abdominal aortic aneurysms.
We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene (BAK1) that codes for an apoptotic-promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism (SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in "minority" forms within specific nondiseased tissues and be selected for, when intra- and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny.


Laryngeal dystonia causing inspiratory stridor in children with cerebral palsy.
OBJECTIVE To present three cases of inspiratory stridor caused by laryngeal dystonia (LD) in children with cerebral palsy (CP), one of whom is being treated by periodic botulinum toxin type A (BTX) injection into a vocalis muscle, thereby avoiding tracheostomy. STUDY DESIGN Case series. RESULTS AND CONCLUSIONS Laryngeal dystonia was diagnosed in three children with CP who presented with inspiratory stridor associated with generalized dystonia, all of whom were thought previously to have had laryngomalacia. The inspiratory stridor was severe enough in one patient that a tracheostomy was planned. In common with the movement disorder of generalized dystonia, the inspiratory stridor caused by LD was present in our patients when they were awake, worse when they were excited or agitated, diminished when they were awake and calm, and absent when they were asleep. Although there is overlap between the symptoms of LD and laryngomalacia (and other structural causes of upper airway obstruction) in children with CP, structural causes result in inspiratory stridor that is often persistent when patients are awake and relaxed or when they are asleep. Fiberoptic laryngoscopy in an awake patient with LD reveals vocal cord adduction in inspiration causing inspiratory stridor in association with generalized dystonia. Baclofen and gabapentin used together relieved the inspiratory stridor and improved the generalized dystonia of two patients, confirming the clinical diagnosis of LD, but for the last 2 years the third patient (the one with the most severe inspiratory stridor) also has required a periodic BTX injection into a vocalis muscle (the major vocal cord adductor) to relieve her inspiratory stridor, alternating the side of injection. Her mother considers this is a small price to pay to avoid tracheostomy. This is the first report of LD causing inspiratory stridor in patients with CP and the first reported use of BTX injection into a vocalis muscle for relief of inspiratory stridor due to LD in a child.


The relationship between the T-helper cell and the T-cell involved in the delayed hypersensitivity.
The common cell type involved in the humoral and cellular responses is the T-cell. Functionally the T-cell, active in the humoral response, is known as Thelper (Th), the T-cell active in the cellular response as Tcellular (Tc). The present experiments are used to study the relationship between Tc and Th. IP immunization, with suboptimal doses of antigen, did not result in antibody formation but induced both a DH (equals Tc) and a Th population. Th and Tc activity changed in a similar way with increasing doses of antigen. Spleen cells taken from mice, which were immunized under conditions which only invoke cellular activity, were able to function even in small numbers as Th in transfer experiments. Educated thymus cells and cells obtained from cortisone or CY treated donor mice had an increased Th and Tc activity when transferred into irradiated recipients. Education in the presence of a high antigen dose reduced both activities below control levels. Cross reactivity between HRBC and SRBC in the hormoral response is known to be at the Th level. It was demonstrated that this cross reactivity also exists at the Tc level. Induction of DH with one antigen acted as pre-immunization, for the humoral response, on the cross reactive antigen too. These results suggest a correlation between the T-cells involved in DH and the Th for antibody formation.


Histopathologic study of eyes after iodine I 125 episcleral plaque irradiation for uveal melanoma.
To describe the histopathologic findings attributable to irradiation in eyes with uveal malignant melanoma treated with iodine I 125 brachytherapy and to compare these findings with those reviewed in a previous study that compared histopathologic findings in eyes enucleated after proton beam teletherapy with those seen in eyes in a nonirradiated control group. The slides from 22 eyes with uveal melanoma that had undergone enucleation after the administration of 125I brachytherapy were studied. The histopathologic features of the tumor and the retina were graded. Results were compared with findings from a previously reported group of 47 proton beam-treated eyes and its control group. Patient age, time between irradiation and enucleation, and ciliary body involvement were similar for the 125I brachytherapy-treated group and the proton beam-treated group and its control group. This allows comparison of the histopathologic findings. Comparing the 125I brachytherapy- and proton beam-treated groups, most histopathologic features were similar with nominally statistically significant differences only for cell type, number of mitotic figures, and fibrous metaplasia of the retinal pigment epithelium adjacent to the tumor. Irradiation of uveal melanoma induces changes in the tumor and in the surrounding retina. Brachytherapy and charged particle therapy are the 2 principal methods of irradiation. This study demonstrates that similar changes are produced by 125I plaque irradiation and proton beam irradiation.


Postconditioning leads to an increase in protein S-nitrosylation.
Previous studies have shown a role for nitric oxide and S-nitrosylation (SNO) in postconditioning (PostC), but specific SNO proteins and sites have not been identified in the myocardium after PostC. In this study, we examined SNO signaling in PostC using a Langendorff-perfused mouse heart model. After 20 min of equilibrium perfusion and 25 min of global ischemia, PostC was applied at the beginning of reperfusion with six cycles of 10 s of reperfusion and 10 s of ischemia. The total period of reperfusion was 90 min. Compared with the ischemia-reperfusion (I/R) control, PostC significantly reduced postischemic contractile dysfunction and infarct size. PostC-induced protection was blocked by treatment with N(G)-nitro-l-arginine methyl ester (l-NAME) (10 μmol/l; a constitutive NO synthase inhibitor), but not by either ODQ (10 μmol/l, a highly selective soluble guanylyl cyclase inhibitor) or KT5823 (1 μmol/l, a specific protein kinase G inhibitor). Two biotin switch based methods, two dimensional CyDye-maleimide difference gel electrophoresis (2D CyDye-maleimide DIGE) and SNO-resin-assisted capture (SNO-RAC), were utilized to identify SNO-modified proteins and sites. Using 2D CyDye-maleimide DIGE analysis, PostC was found to cause a 25% or greater increase in SNO of a number of proteins, which was blocked by treatment with l-NAME in parallel with the loss of protection. Using SNO-RAC, we identified 77 unique proteins with SNO sites after PostC. These results suggest that NO-mediated SNO signaling is involved in PostC-induced cardioprotection and these data provide the first set of candidate SNO proteins in PostC hearts.


The EUROpean and Chinese cardiac and renal Remote Ischemic Preconditioning Study (EURO-CRIPS): study design and methods.
Contrast-induced nephropathy (CIN) and periprocedural myocardial infarction (PMI) represent frequent complications of percutaneous coronary intervention (PCI) and negatively impact subsequent length of hospitalization, costs of adjunctive diagnostic-therapeutic measures and mid-term cardiovascular events. The aim of the EURO-CRIPS trial is to test whether remote ischemic preconditioning (RIPC) may reduce the incidence of these complications and improve mid-term outcome. This will be a double-blind, randomized, placebo-controlled multicentre study. Patients will be allocated 1 : 1 to RIPC or standard therapy if they were younger than 85 years old, with a renal clearance in the interval 30-60 ml/min/1.73 m and candidate to PCI for all clinical indications except for primary PCI in ST segment elevation myocardial infarction (STEMI), unstable haemodynamic presentations or ongoing severe arrhythmias. Incidence of CIN will be the primary end point and the amount of periprocedural cardiac enzyme leakage will be the secondary end point. In addition, we will evaluate whether the preconditioned patients will have a reduction of MACCE at 6 months (major adverse cardiac and cerebrovascular event). The EURO-CRIPS Study will be the first large-scale, multicentre clinical trial to test the role of RIPC in current clinical practice. The results of this randomized trial will provide important insights to optimize management strategy of patients undergoing PCI and to improve their outcome.


[Body, aesthetic surgery and public health: a case study].
The body, in the occidental culture, was for many centuries rejected, feared and devaluated; today, differently, it is super valued and became a precious good, for this reason it is well-taken care of and shaped, due to successes and virtues of the individual contemporary being attributed to it. In the search for an ideal body, many people look for aesthetic surgeries as solution for their problems and improvement of their self-esteem. This article aims to understand the relation of the aesthetic surgery with the Public Health and the promotion of health. We carried out a qualitative study, using the case study method, with the objective of understanding the underlying beliefs, attitudes, perceptions and cultural processes to the narratives of the college's students submitted to aesthetic surgery and of the plastic surgeons. The results demonstrate that the body must be understood as something more complex than the physical and visible body, because many of those who look for aesthetic surgery continue unsatisfied, seeing that their dissatisfactions attributed to their body are also a matter of them being attributed to their soul. We conclude that aesthetic beauty is becoming a medical subject and that aesthetic surgery is a question of public health, as the results depend on the motivations and expectations of who searches for this procedure.


A smart phone/tablet based mobile health care system for developing countries.
Increasing cost of health care in developing countries is placing heavy financial burden on its populations. With the advent of mobile and tablet technologies however, it is possible to reduce this burden to some extent through tele-healthcare. In this paper, authors describe their effort to design portable diagnostic devices that can communicate to smart phones and tablets there by making tele-healthcare possible. A possible architecture of their model is presented and components thereof discussed.


Translation and Validation of the Clinician Administered PTSD Scale (CAPS-CA-5) for Portuguese Children and Adolescents.
The aim of this study was to translate and validate into European Portuguese the CAPS-CA-5 (Clinician Administered PTSD Scale for Children and Adolescents), a semi-structured scale for the diagnosis of post-traumatic stress disorder in children and adolescents, according to the DSM-5 criteria. This study was developed in three stages. In the first stage, the translation and back-translation of CAPS-CA-5 into European Portuguese was carried out. In the second stage, the version obtained in the previous step was subjected to a pre-test. In the third stage, the final version of CAPS-CA-5, the KIDCOPE questionnaires and the Depression, Anxiety and Stress Scale-Children were applied to 101 children who had experienced at least one potentially traumatic event. The children included in this study were between seven and 18 years old and had a follow-up period in a Child Psychiatry or Pediatrics Clinic in one of the three hospitals involved in this project of at least one month. Regarding the confirmatory factor analysis, our results show that the CAPS-CA-5 is a suitable psychometric instrument to assess the diagnosis and symptoms severity of post-traumatic stress disorder according to DSM-5. Convergent validity was comparable to its original version. Although there were negative relationships with almost all of its clusters, these were not statistically significant when applied with the positive coping strategies of the KIDCOPE. The European Portuguese version of the CAPS-CA-5 showed a good internal consistency (Cronbach's α for the total scale was 0.89). The European Portuguese version of CAPS-CA-5 has similar psychometric properties to its original version.


Cyanamide-induced liver cell injury. Experimental study in the rat.
Hepatocyte inclusion bodies similar to those described in alcoholics treated with cyanamide were reproduced in the rat. The characteristic inclusions were developed in animals receiving 8 or 16 mg/kg of body weight, whether they were prepared previously with ethanol intake or not. Inclusion bodies consist of round, well-demarcated cytoplasmic areas, which contain a large amount of glycogen disposed in beta-granules, lipid droplets, and secondary lysosomes. They appear at the 13th week of cyanamide treatment onward. Initially, hepatocytes bearing inclusion bodies are located predominantly at the periportal areas, but the lesion later progresses toward the center of the lobule. Prior to the inclusion body development, cyanamide induces another morphologic change in liver cells, consisting of cytoplasmic homogeneous areas, made up of glycogen disposed in alpha-granules and smooth endoplasmic reticulum tubules. This change is described for the first time in relation to this drug.


Nanocrystal superlattices as phonon-engineered solids and acoustic metamaterials.
Phonon engineering of solids enables the creation of materials with tailored heat-transfer properties, controlled elastic and acoustic vibration propagation, and custom phonon-electron and phonon-photon interactions. These can be leveraged for energy transport, harvesting, or isolation applications and in the creation of novel phonon-based devices, including photoacoustic systems and phonon-communication networks. Here we introduce nanocrystal superlattices as a platform for phonon engineering. Using a combination of inelastic neutron scattering and modeling, we characterize superlattice-phonons in assemblies of colloidal nanocrystals and demonstrate that they can be systematically engineered by tailoring the constituent nanocrystals, their surfaces, and the topology of superlattice. This highlights that phonon engineering can be effectively carried out within nanocrystal-based devices to enhance functionality, and that solution processed nanocrystal assemblies hold promise not only as engineered electronic and optical materials, but also as functional metamaterials with phonon energy and length scales that are unreachable by traditional architectures.


The effect of hard tissue defects on the clinical outcome of endodontic microsurgery: a systematic review and meta-analysis.
The purpose of this systematic review was to appraise the existing literature on the effect of hard tissue defects on the clinical outcome of endodontic microsurgery (EMS). MEDLINE (PubMed), Embase, Web of Science, Cochrane Library and grey literature were searched from January 2000 to May 2023. Study selection and data extraction were performed in duplicate. Eligible studies were critically appraised for the risk of bias using the Cochrane Risk of bias tool. The quality of evidence was assessed using GRADE. Review Manager (RevMan Computer program Version 5.4, The Cochrane Collaboration, 2020) was utilized and the Mantel Haenszel fixed or random effects model was applied, depending on the heterogeneity of the studies. Meta-analysis was performed to estimate the Risk ratio (RR) and 95% Confidence Interval (CIs) to correlate the effects of these factors on treatment outcomes. Nineteen studies were included. The EMS overall pooled success rate was 84.5%. Five characteristics of hard tissue were identified. The size of the lesion (Small ≤ 5 mm: 78.4% vs. Large > 5 mm: 63.3%, RR = 1.12, 95% CI 1.00-1.26, P ≤ .05), significantly affected the outcomes of EMS. Endodontic lesions exhibited slightly better outcomes than endodontic-periodontal lesions (81.4% vs. 68.2%, RR = 1.14 95% CI 0.98-1.33, P > .05). Cases with the height of the buccal bone > 3 mm also exhibited slightly better outcomes (91.5% vs. 71.4%, RR = 1.20, 95% CI 0.88-1.62, P > .05). Additionally, through and through lesions exhibited better outcomes when grafting was completed during the EMS procedure both in 2D (RR = 1.12 95% CI 0.97-1.29, P > .05) and 3D evaluation ((RR = 1.28 95% CI 0.69-2.37 P > .05). The overall quality of evidence was graded as low to high. With a low to high quality of evidence, the size of the lesion is a key prognostic variable that significantly affects the outcome of EMS, as lesions ≤ 5 mm exhibit better outcomes as compared to larger lesions. The presence of hard tissue defects can affect the outcome of endodontic microsurgery (EMS). The presented data can aid the clinicians' decision-making process by examining certain pre-operative prognostic variables, when considering EMS as a treatment option. Clinical cases with more favorable hard tissue characteristics lead to a better prognosis in EMS.


QSAR Studies on andrographolide derivatives as α-glucosidase inhibitors.
Andrographolide derivatives were shown to inhibit alpha-glucosidase. To investigate the relationship between activities and structures of andrographolide derivatives, a training set was chosen from 25 andrographolide derivatives by the principal component analysis (PCA) method, and a quantitative structure-activity relationship (QSAR) was established by 2D and 3D QSAR methods. The cross-validation r(2) (0.731) and standard error (0.225) illustrated that the 2D-QSAR model was able to identify the important molecular fragments and the cross-validation r(2) (0.794) and standard error (0.127) demonstrated that the 3D-QSAR model was capable of exploring the spatial distribution of important fragments. The obtained results suggested that proposed combination of 2D and 3D QSAR models could be useful in predicting the alpha-glucosidase inhibiting activity of andrographolide derivatives.


Postural sway and rhythmic electroencephalography analysis of cortical activation during eight balance training tasks.
The purpose of this study was to investigate the changes in the Power Spectrum Density (PSD) of the electroencephalography (EEG) in common sensorimotor balance training tasks of varying difficulty. Sensorimotor balance exercises including alteration of vision, base of support or surface compliance are used to improve postural control. These exercises are presumed to induce supraspinal adaptation, however, there were no studies that investigated the power changes of the cortical activity in these static balance tasks. Our objective was to provide evidence in the cortical involvement with the static balance tasks frequently used in sensorimotor training. Postural sway and EEG changes of alpha, beta and sigma wave bands were measured in seventeen participants during eight balance tasks of varying difficulty with eyes open and closed, feet in tandem or apart and on foam or a firm surface. The power of beta and sigma bands increased significantly at the parietal and central area of the brain in tasks with eyes open together with one sensory factor (base of support or surface compliance) or two sensory factors (base of support and surface compliance) altered, and in task with three sensory factors (vision, base of support and surface compliance) altered from the control task. This study demonstrated the cortical involvement in the sensorimotor balance tasks, suggesting that these exercises may induce cortical adaptation for postural control. The results support subcortical control with increased task difficulty and the increase in cortical processing when task became extremely challenging.


Interpreting translation-invariant wavelet shrinkage as a new image smoothing scale space.
Coifman and Donoho (1995) suggested translation-invariant wavelet shrinkage as a way to remove noise from images. Basically, their technique applies wavelet shrinkage to a two-dimensional (2-D) version of the semi-discrete wavelet representation of Mallat and Zhong (1992), Coifman and Donoho also showed how the method could be implemented in O(Nlog N) operations, where there are N pixels. In this paper, we provide a mathematical framework for iterated translation-invariant wavelet shrinkage, and show, using a theorem of Kato and Masuda (1978), that with orthogonal wavelets it is equivalent to gradient descent in L (2)(I) along the semi-norm for the Besov space B(1) (1)(L(1)(I)), which, in turn, can be interpreted as a new nonlinear wavelet-based image smoothing scale space. Unlike many other scale spaces, the characterization is not in terms of a nonlinear partial differential equation.


Role of γ-glutamyl transferase levels in prediction of high cardiovascular risk among patients with non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) is an important cause of elevated liver functions. There is evidence showing an association between NAFLD and subclinical atherosclerosis independent of traditional risk factors. We undertook this retrospective study to determine the association of Framingham cardiovascular risk scoring system with liver function tests and inflammatory markers and to find the role of liver function tests in determination of CVD risk among non-obese and non-diabetic subjects with non-alcoholic fatty liver disease. A total of 2058 patients were included in the study. Framingham cardiovascular risk scoring was done of all patients according to the age, gender, systolic blood pressure, serum total cholesterol and HDL cholesterol levels, smoking and antihypertensive medication history. Liver function test, lipid profile, insulin, uric acid, ferritin levels, etc. were determined. According to the ultrasonography findings, patients were grouped as without any fatty infiltration of the liver (control group) (n=982), mild (n= 473), moderate (n=363) and severe fatty liver disease (n= 240) groups. In severe fatty liver disease group, the mean Framingham cardiovascular risk score was significantly higher than that of other groups. t0 here was a positive correlation between GGT, uric acid and ferritin levels with Framingham cardiovascular score. In multivariate analysis, high GGT levels were positively associated with high-risk disease presence (OR: 3.02, 95% CI: 2.62-3.42) compared to low GGT levels independent of the age and sex. Cardiovascular disease risk increases with the presence and stage of fatty liver disease. Our findings showed a positive correlation between elevated GGT levels and Framingham cardiovascular risk scoring system among non-diabetic, non-obese adults which could be important in clinical practice. Though in normal limits, elevated GGT levels among patients with fatty liver disease should be regarded as a sign of increased cardiovascular disease risk. Larger studies are warranted to elucidate the role of GGT in prediction of cardiovascular risk.


Validation of accuracy of liver model with temperature-dependent thermal conductivity by comparing the simulation and in vitro RF ablation experiment.
Radiofrequency (RF) ablation is increasingly used to treat cancer because it is minimally invasive. However, it is difficult for operators to control precisely the formation of coagulation zones because of the inadequacies of imaging modalities. To overcome this limitation, we previously proposed a model-based robotic ablation system that can create the required size and shape of coagulation zone based on the dimensions of the tumor. At the heart of such a robotic system is a precise temperature distribution simulator for RF ablation. In this article, we evaluated the simulation accuracy of two numerical simulation liver models, one using a constant thermal conductivity value and the other using temperature-dependent thermal conductivity values, compared with temperatures obtained using in vitro experiments. The liver model that reflected the temperature dependence of thermal conductivity did not result in a large increase of simulation accuracy compared with the temperature-independent model in the temperature range achieved during clinical RF ablation.


Keratan sulfate: structure, biosynthesis, and function.
The last 5 years have seen a marked increase in research on keratan sulfate (KS) and a concomitant increase in our understanding of the range of molecules that carry this adaptable polysaccharide. More than 15 KS-linked proteins have been identified and many of the genes encoding these have been cloned. KS-containing molecules have been identified in numerous epithelial and neural tissues in which KS expression responds to embryonic development, physiological variations, and to wound healing. A corneal cell culture system has been developed in which long-term KS biosynthesis is maintained. Progress has been made toward identification of the glycosyl- and sulfotransferases responsible for KS biosynthesis. A mouse knockout of a corneal KS-proteoglycan has provided the first experimental support for the role of KS in corneal transparency. Evidence has also been presented supporting functional roles of KS in cellular recognition of protein ligands, axonal guidance, cell motility, and in embryo implantation. These findings have served to expand the concept of what keratan sulfate is and the potential roles it may play in the cellular biology of diverse tissues.


Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT).
Although knowledge of human renal cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and their role in xenobiotic and endobiotic metabolism is limited compared with hepatic drug and chemical metabolism, accumulating evidence indicates that human kidney has significant metabolic capacity. Of the drug metabolizing P450s in families 1 to 3, there is definitive evidence for only CYP 2B6 and 3A5 expression in human kidney. CYP 1A1, 1A2, 1B1, 2A6, 2C19, 2D6 and 2E1 are not expressed in human kidney, while data for CYP 2C8, 2C9 and 3A4 expression are equivocal. It is further known that several P450 enzymes involved in the metabolism of arachidonic acid and eicosanoids are expressed in human kidney, CYP 4A11, 4F2, 4F8, 4F11 and 4F12. With the current limited evidence of drug substrates for human renal P450s drug-endobiotic interactions arising from inhibition of renal P450s, particularly effects on arachidonic acid metabolism, appear unlikely. With respect to the UGTs, 1A5, 1A6, 1A7, 1A9, 2B4, 2B7 and 2B17 are expressed in human kidney, whereas UGT 1A1, 1A3, 1A4, 1A8, 1A10, 2B10, 2B11 and 2B15 are not. The most abundantly expressed renal UGTs are 1A9 and 2B7, which play a significant role in the glucuronidation of drugs, arachidonic acid, prostaglandins, leukotrienes and P450 derived arachidonic acid metabolites. Modulation by drug substrates (e.g. NSAIDs) of the intrarenal activity of UGT1A9 and UGT2B7 has the potential to perturb the metabolism of renal mediators including aldosterone, prostaglandins and 20-hydroxyeicosatetraenoic acid, thus disrupting renal homeostasis.


Common genes and recurrent causative variants in 957 Asian patients with pediatric epilepsy.
We aimed to identify common genes and recurrent causative variants in a large group of Asian patients with different epilepsy syndromes and subgroups. Patients with unexplained pediatric onset epilepsy were identified from the in-house Severance Neurodevelopmental Disorders and Epilepsy Database. All patients underwent either exome sequencing or multigene panels from January 2017 to December 2019 at Severance Children's Hospital in Korea. Clinical data were extracted from the medical records. Of the 957 patients studied, 947 (99.0%) were Korean and 570 were male (59.6%). The median age at testing was 4.91 years (interquartile range, 1.53-9.39). The overall diagnostic yield was 32.4% (310/957). Clinical exome sequencing yielded a diagnostic rate of 36.9% (134/363), while the epilepsy panel yielded a diagnostic rate of 29.9% (170/569). Diagnostic yield differed across epilepsy syndromes. It was high in Dravet syndrome (87.2%, 41/47) and early infantile developmental epileptic encephalopathy (60.7%, 17/28), but low in West syndrome (21.8%, 34/156) and myoclonic-atonic epilepsy (4.8%, 1/21). The most frequently implicated genes were SCN1A (n = 49), STXBP1 (n = 15), SCN2A (n = 14), KCNQ2 (n = 13), CDKL5 (n = 11), CHD2 (n = 9), SLC2A1 (n = 9), PCDH19 (n = 8), MECP2 (n = 6), SCN8A (n = 6), and PRRT2 (n = 5). The recurrent genetic abnormalities included 15q11.2 deletion/duplication (n = 9), Xq28 duplication (n = 5), PRRT2 deletion (n = 4), MECP2 duplication (n = 3), SCN1A, c.2556+3A>T (n = 3), and 2q24.3 deletion (n = 3). Here, we present the results of a large-scale study conducted in East Asia, where we identified several common genes and recurrent variants that varied depending on specific epilepsy syndromes. The overall genetic landscape of the Asian population aligns with findings from other populations of varying ethnicities.


Modelling Tools to Characterize Acetaminophen Pharmacokinetics in the Pregnant Population.
This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of distribution (3.5-60.7%) and an increase in the clearance (36.8-84.4%) of acetaminophen in pregnant women compared to non-pregnant women. Only two studies using population PK modelling as a technique were available in the literature. The largest difference in acetaminophen clearance (203%) was observed in women at delivery compared to non-pregnant women. One study using the PBPK technique was found in the literature. This study focused on the formation of metabolites, and the toxic metabolite N-acetyl-p-benzoquinone imine was the highest in the first trimester, followed by the second and third trimester, compared with non-pregnant women. In conclusion, this review gave an overview on acetaminophen PK changes in pregnancy. Also, knowledge gaps, such as fetal and placenta PK parameters, have been identified, which should be explored further before dosing adjustments can be suggested on an evidence-based basis.