Implementation and clinical benefit of DPYD genotyping in a Danish cancer population.
In 2020, the European Medicines Agency recommended testing patients for dihydropyrimidine dehydrogenase (DPD) deficiency before systemic treatment with fluoropyrimidines (FP). DPD activity testing identifies patients at elevated risk of severe FP-related toxicity (FP-TOX). The two most used methods for DPD testing are DPYD genotyping and DPD phenotyping (plasma uracil concentration). The primary objective of this study was to compare the overall frequency of overall grade ≥3 FP-TOX before and after the implementation of DPYD genotyping. Two hundred thirty Danish, primarily gastrointestinal cancer patients, were DPYD-genotyped before their first dose of FP, and blood was sampled for post hoc assessment of P-uracil. The initial dose was reduced for variant carriers. Grade ≥3 FP-TOX was registered after the first three treatment cycles of FP. The frequency of toxicity was compared to a historical cohort of 492 patients with post hoc determined DPYD genotype from a biobank. The frequency of overall grade ≥3 FP-TOX was 27% in the DPYD genotype-guided group compared to 24% in the historical cohort. In DPYD variant carriers, DPYD genotyping reduced the frequency of FP-related hospitalization from 19% to 0%. In the control group, 4.8% of DPYD variant carriers died due to FP-TOX compared to 0% in the group receiving DPYD genotype-guided dosing of FP. In the intervention group, wild-type patients with uracil ≥16 ng/ml had a higher frequency of FP-TOX than wild-type patients with uracil <16 ng/ml (55% versus 28%). We found no population-level benefit of DPYD genotyping when comparing the risk of grade ≥3 FP-TOX before and after clinical implementation. We observed no deaths or FP-related hospitalizations in patients whose FP treatment was guided by a variant DPYD genotype. The use of DPD phenotyping may add valuable information in DPYD wild-type patients.


Group II mGluR-induced long term depression in the dentate gyrus in vivo is NMDA receptor-independent and does not require protein synthesis.
Long term depression (LTD) can be induced by low frequency stimulation (LFS) as well as by agonist activation of neurotransmitter receptors. Group II metabotropic glutamate receptors (mGluRs) play an essential role in the regulation of electrically-induced LTD in the hippocampus in vivo: LTD is inhibited by antagonists, and enhanced by agonists of group II mGluRs. Here we investigated induction of LTD by activation of group II mGluRs as well as the cellular mechanisms which might mediate group II mGluR-induced LTD. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Drug application was made through a cannula implanted into the ipsilateral cerebral ventricle. LTD could be induced by agonist activation of either group II mGluRs, or the group II mGluR subtype, mGluR3. Both, group II mGluR-induced LTD and mGluR3-induced LTD were not abolished by mRNA/protein synthesis inhibition. Furthermore, mGluR3-induced LTD was not inhibited by NMDA receptor antagonists or altered by L-type voltage-gated calcium channel blockers. Our data suggest that sole activation of group II mGluRs can mediate LTD in vivo. Intriguingly, this form of LTD is not dependent on protein synthesis or activation of NMDA receptors.


Assessing risk across the spectrum of patients with the metabolic syndrome.
The metabolic syndrome represents a constellation of interrelated risk factors that identify individuals at increased risk for the development of type 2 diabetes mellitus and cardiovascular events. Currently, the major cardiovascular risk factors and validated risk-assessment tools do not adequately account for the increased cardiovascular risk that accompanies the metabolic syndrome. In prospective population studies, cardiovascular risk assessment in individuals with the metabolic syndrome is improved by measures of low-density lipoprotein (LDL) particle number, C-reactive protein, and plasminogen activator inhibitor-1 levels. Although adiponectin and soluble tumor necrosis factor receptor-2 may be more integrally involved in insulin resistance, the studies with these biomarkers are less extensive. Risk assessment models for patients with the metabolic syndrome should consider inclusion of LDL particle number, inflammatory markers, and levels of plasminogen activator inhibitor-1.


The role and function of HDL in patients with diabetes mellitus and the related cardiovascular risk.
Diabetes mellitus (DM) is a major public health problem which prevalence is constantly raising, particularly in low- and middle-income countries. Both diabetes mellitus types (DMT1 and DMT2) are associated with high risk of developing chronic complications, such as retinopathy, nephropathy, neuropathy, endothelial dysfunction, and atherosclerosis. This is a review of available articles concerning HDL subfractions profile in diabetes mellitus and the related cardiovascular risk. In this review, HDL dysfunction in diabetes, the impact of HDL alterations on the risk diabetes development as well as the association between disturbed HDL particle in DM and cardiovascular risk is discussed. Changes in the amount of circulation lipids, including triglycerides and LDL cholesterol as well as the HDL are frequent also in the course of DMT1 and DMT2. In normal state HDL exerts various antiatherogenic properties, including reverse cholesterol transport, antioxidative and anti-inflammatory capacities. However, it has been suggested that in pathological state HDL becomes "dysfunctional" which means that relative composition of lipids and proteins in HDL, as well as enzymatic activities associated to HDL, such as paraoxonase 1 (PON1) and lipoprotein-associated phospholipase 11 (Lp-PLA2) are altered. HDL properties are compromised in patients with diabetes mellitus (DM), due to oxidative modification and glycation of the HDL protein as well as the transformation of the HDL proteome into a proinflammatory protein. Numerous studies confirm that the ability of HDL to suppress inflammatory signals is significantly reduced in this group of patients. However, the exact underlying mechanisms remains to be unravelled in vivo. The understanding of pathological mechanisms underlying HDL dysfunction may enable the development of therapies targeted at specific subpopulations and focusing at the diminishing of cardiovascular risk.


Excessive thyrotropin concentrations in the circulation of the spontaneously hypertensive rat.
Thyroid funct-on in SHR was compared to that of inbred normotensive Wistar rats from Kyoto, and random bred Wistar rats from the United States. A marked increase in circulating thyrotropin concentration was found in SHR compared to controls. Serum thyroxine and T3 concentrations relative to controls, however, were variable and the concentrations in male and female SHR relative to Kyoto controls did not correspond with each other. No ready explanation for the circulating excess of thyrotropin, with mimimal increase in T4 and T3 concentrations, is available.


The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy.
A new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft models. Our results showed that Caba-780 was efficiently absorbed by DU145 and PC-3 cells and that the cytotoxicity of Caba-780 was significantly stronger than that of IR-780 and cabazitaxel. In addition, Caba-780 inhibited the migration and invasion of DU145 and PC-3 cells and promoted apoptosis by prolonging the G2 phase of the cell cycle. Further analysis indicated that Caba-780 could be used to effectively image tumor xenografts. At the same time, this drug inhibited the growth of tumors in vivo. Therefore, the new synthetic drug Caba-780 has potential applications in the diagnosis and treatment of CRPC.


Choroidal Neovascularization and Macular Hemorrhage: Real-World Experience During the New York City COVID-19 Lockdown.
This work reviews ocular, systemic, and demographic factors contributing to presentation of choroidal neovascular membrane (CNVM)-associated macular hemorrhage after the New York City coronavirus disease 2019 (COVID-19) lockdown. A retrospective, consecutive case series was conducted of all established patients presenting with macular hemorrhage between March 22, 2020, and August 10, 2020. Fourteen patients (mean age 82.2 years) were evaluated. Ten patients had active CNVMs, 1 had an inactive lesion that was last injected 2 years prior, and 3 had new conversions from nonexudative age-related macular degeneration. In the actively treated CNVM group there was a delay in expected follow-up from 50.4 days to 125 days. Eight patients with previously active CNVM (73%) had a history of prior macular hemorrhage. Eight patients (57%) were on some form of antiplatelet or anticoagulation therapy. Twelve patients (86%) had COVID-19-specific risk factors besides age, and all but 1 patient (93%) delayed care without discussion with a physician. Ten patients (71%) had more than 1 week of symptoms prior to presentation. Twelve patients (86%) had signs of CNVM on prior optical coherence tomography. Adequate documentation of potential risks for hemorrhage (particularly prior hemorrhage or presence of subclinical type 1 CNVM), as well as COVID-19-specific risk factors, would aid triage of clinic appointments in future lockdowns. High-risk patients would likely benefit from direct physician communication discussing their individual risk profiles to alleviate anxiety over clinic visits and communicate their risk of severe vision loss.


DNA-dependent protein kinase.
DNA-dependent protein kinase (DNA-PK) is a nuclear protein serine/threonine kinase that is activated by DNA double strand breaks (DSBs). It is a component of the DNA DSB repair apparatus, and cells deficient in DNA-PK are hypersensitive to ionising radiation and radio-mimetic drugs. In addition, DNA-PK is required to generate the antigen binding sites of T-cell receptor and immunoglobulin molecules, and the phenotype of the severe combined immunodeficient (scid) mouse is due to a DNA-PK deficiency. Recent data suggest that DNA-PK may also have roles in controlling transcription, apoptosis, and the length of telomeric chromosomal ends. Finally, DNA-PK is related to other proteins involved in DNA damage detection, including the protein defective in the human neurodegenerative and cancer predisposition syndrome ataxia-telangiectasia. Studies on DNA-PK should provide a better understanding of degenerative disease and cancer, and may lead to improved therapies for these conditions.


Updates in primary neuroendocrine breast carcinoma - A case report and review of literature.
We present here a case of a 35-year-old woman diagnosed with primary neuroendocrine carcinoma of the breast (NECB) - small cell type. We discuss the importance of histological and molecular criteria for primary neuroendocrine mammary neoplasm, established by the World Health Organization in 2003 and 2012. We present information about differential diagnosis, prognostic factors, surgical treatment, adjuvant treatment, and novel therapies for primary NECB. Although this disease is not so uncommon but it is highly underreported and with consistent diagnostic criteria, surgeons should be able to keep this entity as differential diagnosis to enable them a timely treatment.


Lattice distortion induced internal electric field in TiO2 photoelectrode for efficient charge separation and transfer.
Providing sufficient driving force for charge separation and transfer (CST) is a critical issue in photoelectrochemical (PEC) energy conversion. Normally, the driving force is derived mainly from band bending at the photoelectrode/electrolyte interface but negligible in the bulk. To boost the bulky driving force, we report a rational strategy to create effective electric field via controllable lattice distortion in the bulk of a semiconductor film. This concept is verified by the lithiation of a classic TiO2 (Li-TiO2) photoelectrode, which leads to significant distortion of the TiO6 unit cells in the bulk with well-aligned dipole moment. A remarkable internal built-in electric field of ~2.1 × 102 V m-1 throughout the Li-TiO2 film is created to provide strong driving force for bulky CST. The photoelectrode demonstrates an over 750% improvement of photocurrent density and 100 mV negative shift of onset potential upon the lithiation compared to that of pristine TiO2 film.


How do the blind 'see'? The role of spontaneous brain activity in self-generated perception.
Spontaneous activity of the human brain has been well documented, but little is known about the functional role of this ubiquitous neural phenomenon. It has previously been hypothesized that spontaneous brain activity underlies unprompted (internally generated) behaviour. We tested whether spontaneous brain activity might underlie internally-generated vision by studying the cortical visual system of five blind/visually-impaired individuals who experience vivid visual hallucinations (Charles Bonnet syndrome). Neural populations in the visual system of these individuals are deprived of external input, which may lead to their hyper-sensitization to spontaneous activity fluctuations. To test whether these spontaneous fluctuations can subserve visual hallucinations, the functional MRI brain activity of participants with Charles Bonnet syndrome obtained while they reported their hallucinations (spontaneous internally-generated vision) was compared to the: (i) brain activity evoked by veridical vision (externally-triggered vision) in sighted controls who were presented with a visual simulation of the hallucinatory streams; and (ii) brain activity of non-hallucinating blind controls during visual imagery (cued internally-generated vision). All conditions showed activity spanning large portions of the visual system. However, only the hallucination condition in the Charles Bonnet syndrome participants demonstrated unique temporal dynamics, characterized by a slow build-up of neural activity prior to the reported onset of hallucinations. This build-up was most pronounced in early visual cortex and then decayed along the visual hierarchy. These results suggest that, in the absence of external visual input, a build-up of spontaneous fluctuations in early visual cortex may activate the visual hierarchy, thereby triggering the experience of vision.


New cationic spiropyrans with photoswitchable NIR fluorescence.
Visible-light-mediated photochromic compounds with NIR absorption and fluorescence are of great interest for use in different biomedical applications. In this work, new representatives of spiropyrans with conjugated cationic 3H-indolium substituents in different positions of 2H-chromene moiety were synthesized. The electron-donating methoxy groups were introduced in the uncharged indoline and charged indolium cycles to form the effective conjugation chain between the hetarene moiety and the cationic fragment for reaching NIR absorption and fluorescence. The molecular structure and the effects of cationic fragment position on the mutual stability of the spirocyclic and merocyanine forms of compounds were carefully studied in the solutions and solid state by NMR, IR, HRMS, single-crystal XRD, and quantum chemical calculations. It was found that the obtained spiropyrans demonstrate positive or negative photochromism depending on the cationic fragment's position. One of spiropyrans has shown bidirectional photochromic properties induced exclusively by visible light of different wavelengths in both directions. The photoinduced merocyanine forms of compounds possessed far-red shifted absorption maxima and NIR fluorescence, which makes them prospective fluorescent probes for bioimaging.


RNA-seq reveals plant virus composition and diversity in alfalfa, thrips, and aphids in Beijing, China.
Viruses are widespread in alfalfa (Medicago sativa L.), representing a key limitation to the production of this important forage plant. Understanding the diversity of plant viruses in alfalfa and their potential vectors will play an important role in management to minimize the emergence, transmission, and impact of viruses. Next-generation sequencing (NGS) targeting the transcriptome was applied to monitor the virus communities in alfalfa and its two main pests, thrips (Odontothrips loti Haliday and Frankliniella intonsa Trybom) and aphids (Acyrthosiphon pisum Mordvilko and Therioaphis trifolii Monell). A comparison of transcriptome datasets with reference databases revealed the presence of eight candidate viruses. Five out of the eight viruses, alfalfa mosaic virus (AMV), Medicago sativa alphapartitivirus 1 (MsAPV1), Medicago sativa deltapartitivirus 1 (MsDPV1), Medicago sativa amalgavirus 1 (MsAV1), and bean yellow mosaic virus (BYMV), were confirmed by RT-PCR. We identified and determined the presence of four RNA viruses from alfalfa samples, two viruses (AMV and MsAPV1) from thrips samples, and one virus (BYMV) from T. trifolii. All sequences isolated from the insect samples were more than 95% identical to the sequences from the alfalfa samples or to sequences from the National Center for Biotechnology Information (NCBI) reference database. The RNA-seq results of this study suggest that AMV and MsAPV1 are the predominant RNA plant viruses infecting alfalfa and that they are carried by the major pests. This lays the foundation for future research on the vectors and transmission of these viruses. In addition, the sequence data have enabled the assembly of the first complete genome sequence of MsDPV1 from alfalfa.


Advanced endoscopy for the management of inflammatory digestive diseases: Review of the Japan Gastroenterological Endoscopy Society core session.
A series of workshops entitled "Advanced endoscopy in the management of inflammatory digestive disease" was held at the 97th to 100th biannual meeting of the Japan Gastroenterological Endoscopy Society. During these core sessions, research findings concerning various endoscopic practices in the field of inflammatory bowel disease (IBD) were presented, and meaningful discussions were shared on the evolving role and future challenges of endoscopy in IBD. This article reviews these core sessions and discusses current topics on the role of endoscopy, focusing on the diagnosis, disease monitoring, mucosal healing assessments, cancer surveillance, and therapeutic interventions in IBD.


Staged bilateral stereotactic pallidothalamotomy for life-threatening dystonia in a child with Hallervorden-Spatz disease.
Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive motor dysfunction and dementia. Dystonia is the most prominent and disabling symptom, responding only to a modest extent to pharmacological therapy. At the moment, only a few cases have been reported to improve dystonia and even fewer to resolve status dystonicus for a longer period in children. The authors present the case of a 10-year-old boy who had progressive generalized dystonia, resulting in spontaneous femur fracture and life-threatening swallowing and respiratory disability. As a rescue solution, staged bilateral pallidothalamotomy was performed. Postoperatively, Burke-Fahn-Marsden Dystonia Rating Scale and Dystonia Disability Rating Scale improved (from 116 and 30 points to 41 and 18 points, respectively) and painful dystonia was resolved, which was still continuous 4 years later (47 and 20 points). Stereotactic staged bilateral pallidothalamotomy should be considered as a potential treatment in the management of life-threatening generalized dystonia related to HSD.


Molecular properties and a nonidentical trimeric structure of purine nucleoside phosphorylase from chicken liver.
Some molecular properties of crystalline purine nucleoside phosphorylase (purine nucleoside: orthophosphate ribosyltransferase, EC 220.127.116.11) from chicken liver were investigated and discussed. The molecular weight of the native enzyme was determined to be 89 000 by gel filtration and sedimentation coefficient, and 90 000 by sedimentation equilibrium, respectively. The enzyme was assumed to be a trimer consisting of one large subunit and two identical small subunits. The molecular weights of two different sized subunits were determined to be 32 000 and 28 000 by sodium dodecyl sulfate gel electrophoresis, and 30 000 and 27 000 by 6 M guanidine hydrochloride gel filtration. The amino acid composition was determined and the partial specific volume was estimated to be 0.735 ml/g.


Agonistic interactions with asymmetric body size in two adult-age groups of the annual killifish Millerichthys robustus (Miller & Hubbs, 1974).
In this study, the author evaluated two adult age groups of the Mexican rivulus Millerichthys robustus with body size asymmetries to determine the strategies used by an annual killifish during agonistic interactions of different ontogenetic stages. To achieve this goal, the author first characterized the ethogram of agonistic interactions of M. robustus composed of seven behavioural units in males and five behavioural units in females. The author then analysed agonistic interaction strategies used by males and females with body size asymmetries in two groups of different adult ages that represent different ontogenetic stages: (a) just after sexual maturity was reached, at 5 weeks of age, and (b) near natural death, at 24 weeks of age. The agonistic behaviour patterns of M. robustus were compatible with the logic of mutual assessment. Large males had an advantage during their interactions in both age groups, winning all of the encounters. Nonetheless, there was more aggression in 5-week-old fish encounters. In addition, small 24-week-old fish were more aggressive than small 5-week-old fish. These changing strategies may be because of the cost-benefits required during a fight at each ontogenetic stage. In the female encounters, size did not predict winners, as both small and large fish won a similar number of encounters, and some contests remained unresolved regardless of age group. There was a tendency for small females of any age to risk more than males in fights to maintain reproductive fitness.


Increasing trend of bilateral neck exploration in primary hyperparathyroidism.
Bilateral neck exploration was the standard operation for primary hyperparathyroidism. With improvements in preoperative localization and use of intraoperative PTH (ioPTH) monitoring, minimally invasive unilateral neck exploration has been widely adopted. This study evaluates the trend in parathyroidectomies for primary hyperparathyroidism. Parathyroidectomy for sporadic primary hyperparathyroidism was analyzed from 2010 to 2017. Exclusion criteria included previous neck surgery and concomitant procedures. The operations were classified as unilateral exploration (UE), UE converted to bilateral exploration (BE), or BE. Variables included preoperative and intraoperative factors. Outcomes included persistence, recurrence, permanent hypocalcemia and recurrent laryngeal nerve (RLN) injury. Four hundred thirty-one patients were reviewed. Since 2010, the rate of BE has increased from 30% to 50%. Disease duration, presence of bone disease, negative localization, baseline ioPTH <100, and ≥2 abnormal glands have increased. Mean operative time has not changed over time. Two percent of patients had persistent disease, <1% had recurrent disease, and 2% have had reoperation. Nine percent had temporary hypoparathyroidism, and 15 patients had temporary RLN injury. This study shows an increasing trend in BE for primary hyperparathyroidism. This increase was associated with lower baseline intraoperative parathyroid hormone (ioPTH) levels and smaller gland size. The operative approach for parathyroidectomy should be individualized and surgeons should not hesitate to perform BE when needed.


The cytokine network in women with an asymptomatic short cervix and the risk of preterm delivery.
To characterize the amniotic fluid (AF) inflammatory-related protein (IRP) network in patients with a sonographic short cervix (SCx) and to determine its relation to early preterm delivery (ePTD). A retrospective cohort study included women with a SCx (≤25 mm; n=223) who had amniocentesis and were classified according to gestational age (GA) at diagnosis and delivery (ePTD <32 weeks of gestation). (i) In women with a SCx ≤ 22 1/7 weeks, the concentration of most IRPs increased as the cervix shortened; those with ePTD had a higher rate of increase in MIP-1α, MCP-1, and IL-6 concentrations than those delivering later; and (ii) the concentration of most IRPs and the correlation between several IRP pairs were higher in the ePTD group than for those delivering later. Women with a SCx at 16-22 1/7 weeks have a unique AF cytokine network that correlates with cervical length at diagnosis and GA at delivery. This network may aid in predicting ePTD.


A mild phenotype of LGI4-Related arthrogryposis multiplex congenita with intrafamilial variability.
Arthrogryposis multiplex congenita (AMC) is a heterogeneous group of congenital disorders characterized by multiple joint contractures. We report a family with two children affected with AMC. First child had a severe AMC phenotype and died in infancy. Second child, currently 4-years-old, was ascertained at the age of 30 months with mild AMC phenotype with cognitive and speech delay. On whole exome sequencing, a novel biallelic sequence variant in initiation codon of LGI4 (leucine-rich glioma-inactivated 4) gene was identified in her. Real-Time PCR revealed 50% reduction in mRNA transcript levels in subject as compared to control which explains the milder phenotype. Till date, only four families with nine affected individuals with LGI4-related AMC have been reported. Except for one child surviving up to 6 years, all others were either terminated after prenatal diagnosis or succumbed in neonatal period. This study adds to mutation spectrum of LGI4 and reports the second case of mild AMC with extended phenotype. We review the existing phenotypic and genotypic information for the individuals with this condition and highlight the intrafamilial and interfamilial variability in these individuals.


Hepatic oleate regulates one-carbon metabolism during high carbohydrate feeding.
Obesity is a major risk factor for type 2 diabetes, coronary heart disease, and strok. These diseases are associated with profound alterations in gene expression in metabolic tissues. Epigenetic-mediated regulation of gene expression is one mechanism through which environmental factors, such as diet, modify gene expression and disease predisposition. However, epigenetic control of gene expression in obesity and insulin resistance is not fully characterized. We discovered that liver-specific stearoyl-CoA desaturase-1 (Scd1) knockout mice (LKO) fed a high-carbohydrate low-fat diet exhibit dramatic changes in hepatic gene expression and metabolites of the folate cycle and one-carbon metabolism respectively for the synthesis of S-adenosylmethionine (SAM). LKO mice show an increased ratio of S-adenosylmethionine to S-adenosylhomocysteine, a marker for increased cellular methylation capacity. Furthermore, expression of DNA and histone methyltransferase genes is up-regulated while the mRNA and protein levels of the non-DNA methyltransferases including phosphatidylethanolamine methyltransferase (PEMT), Betaine homocysteine methyltransferase (Bhmt), and the SAM-utilizing enzymes such as glycine-N-methyltransferase (Gnmt) and guanidinoacetate methyltransferase (Gamt) are generally down-regulated. Feeding LKO mice a high carbohydrate diet supplemented with triolein, but not tristearin, and increased endogenous hepatic synthesis of oleate but not palmitoleate in Scd1 global knockout mice normalized one carbon gene expression and metabolite levels. Additionally, changes in one carbon gene expression are independent of the PGC-1α-mediated ER stress response previously reported in the LKO mice. Together, these results highlight the important role of oleate in maintaining one-carbon cycle homeostasis and point to observed changes in one-carbon metabolism as a novel mediator of the Scd1 deficiency-induced liver phenotype.


STAT2 hypomorphic mutant mice display impaired dendritic cell development and antiviral response.
Interferons (IFNs) are key regulators for both innate and adaptive immune responses. By screening ENU-mutagenized mice, we identified a pedigree- P117 which displayed impaired response to type I, but not type II, IFNs. Through inheritance test, genetic mapping and sequencing, we found a T to A point mutation in the 5' splice site of STAT2 intron 4-5, leading to cryptic splicing and frame shifting. As a result, the expression of STAT2 protein was greatly diminished in the mutant mice. Nonetheless, a trace amount of functional STAT2 protein was still detectable and was capable of inducing, though to a lesser extent, IFNalpha-downstream gene expressions, suggesting that P117 is a STAT2 hypomorphic mutant. The restoration of mouse or human STAT2 gene in P117 MEFs rescued the response to IFNalpha, suggesting that the mutation in STAT2 is most likely the cause of the phenotypes seen in the pedigree. Development of different subsets of lymphocytes appeared to be normal in the mutant mice except that the percentage and basal expression of CD86 in splenic pDC and cDC were reduced. In addition, in vitro Flt3L-dependent DC development and TLR ligand-mediated DC differentiation were also defective in mutant cells. These results suggest that STAT2 positively regulates DC development and differentiation. Interestingly, a severe impairment of antiviral state and increased susceptibility to EMCV infection were observed in the mutant MEFs and mice, respectively, suggesting that the remaining STAT2 is not sufficient to confer antiviral response. In sum, the new allele of STAT2 mutant reported here reveals a role of STAT2 for DC development and a threshold requirement for full functions of type I IFNs.


Photocatalytic reactions of phenanthrene at TiO2/water interfaces.
The photocatalytic oxidation of phenanthrene was investigated in aqueous TiO2 suspensions under UV light irradiation. Chemical oxygen demand (COD) measurements, UV-Vis spectrophotometer, IR spectrometer and gas chromatography-mass spectrometry (GC-MS) analytical techniques were used to monitor the reaction process. Some factors affecting the photodegradation rate were studied and some aromatic intermediates were detected during the reaction process. Fast and complete mineralization of phenanthrene was achieved in this reaction system.


Folinic acid modulation of fluorouracil: tissue kinetics of bolus administration.
Thymidylate synthase (TS) is the enzyme target of 5-fluorouracil (FUra) that recent laboratory and clinical studies with folinic acid (calcium leucovorin) suggest may mediate important antitumor cytotoxicity. Measurement in carcinoma tissue of parameters related to TS inhibition by 5-fluorodeoxyuridylate (FdUMP), by analogy to hormone receptor analysis, should be useful to determine which patients should receive fluoropyrimidine drug therapy and to evaluate folinic acid requirements. Folinic acid is metabolized to 5,10-methylenetetrahydropteroylglutamine (CH2FH4), which must be present in large excess to effect desired levels of maximal inhibition of TS, by promoting formation and stabilization of TS-FdUMP-CH2FH4 ternary complexes. In patients with metastatic disease, serial biopsies of tumor and normal tissues for studies of pharmacodynamic responses to test-dose FUra or folinic acid are shown to be easily added to routine intraoperative management. A suitable methodologic approach is described and examples given of assays of free TS, FdUMP, dUMP, and CH2FH4 levels after FUra or folinic acid, that may be useful in future studies aimed at improving the cost-effectiveness of FUra-folinic acid combinations.


Diagnostic accuracy of modified Hadlock formula for fetal macrosomia in women with gestational diabetes and pregnancy weight gain above recommended.
Women with gestational diabetes (GDM) and weight gain during pregnancy above recommended more often give birth to macrosomic children. The goal of this study was to evaluate the diagnostic accuracy of the modified formula for ultrasound assessment of fetal weight created in a pilot study using a similar specimen in comparison to the Hadlock-2 formula. This is a prospective, cohort, applicative, observational, quantitative, and analytical study, which included 213 pregnant women with a singleton pregnancy, GDM, and pregnancy weight gain above recommended. Participants were consecutively followed in the time period between July 1st, 2016, and August 31st, 2020. Ultrasound estimations were made within three days before the delivery. Fetal weights estimated using both formulas were compared to the newborns' weights. A total of 133 fetal weight estimations were made. In comparison to the newborns' weight modified formula had significantly smaller deviation in weight estimation compared to the Hadlock-2 formula, higher frequency of deviation within 5% of newborns weights (78.2% [95% CI=0.74-0.83] vs. 60.2%), smaller frequency of deviations from 5 to 10% (19.5 vs. 33.8%) and above 10%, which was even more significant among macrosomic children. There were 36/50 (72%) correctly diagnosed cases of macrosomia by modified and 33/50 (66%) by Hadlock-2 formula. Area under the curve (AUC) for the modified formula was 0.854 (95% CI=0.776-0.932), and for the Hadlock-2 formula 0.824 (95% CI=0.740-0.908). The positive predictive value of the modified formula was 81.81%, the negative 97.91%. In cases of greater fetal weights, the modified formula showed greater precision.


Assessment of the effectiveness of a combination product of spinosad and milbemycin oxime on the prophylaxis of canine heartworm infection.
Three separate randomized, blinded, vehicle-controlled studies were conducted to determine the effectiveness of a single treatment and consecutive monthly treatments of a combination flavored tablet product containing spinosad and milbemycin oxime (MBO) in the prevention of the establishment of heartworm infections in dogs challenged with recent field isolates of the heartworm (HW), Dirofilaria immitis. For each study, dogs were allocated randomly based on pre-treatment body weights to treated or control groups of 10 animals each. Dogs were infected once with infective HW larvae, on Day-30, using either a Michigan isolate or a Georgia (MP3) isolate of D. immitis. Treatments of beef-flavored chewable tablets were administered in two studies one time either on Day 0 or Day 15, and in one study twice (Days 0 and 30, or Days 15 and 45) or 3 times (Days 0, 30 and 60). For the combination product groups, dosages were in the range of 30-45 mg/kg (13.6-20.5mg/lb) for spinosad and 0.5-0.75 mg/kg (0.2-0.34 mg/lb) for MBO. Necropsies for heartworm counts were completed following euthanasia on Day 120 or Day 123. A single treatment with the combination product of spinosad and MBO 30 or 45 days post-inoculation with infective HW larvae was completely effective (100%) in preventing establishment of the Michigan D. immitis isolate, but efficacy against the Georgia MP3 isolate was incomplete, with geometric mean reductions in HW counts relative to vehicle treated controls of 99% reduction of the 30 day infection and a 98.9% reduction of the 45 day old infection. Against this same MP3 isolate, 3 consecutive monthly treatments provided complete prevention (100%) against establishment of D. immitis infections. The combination product of spinosad and MBO provides effective control of canine heartworms. A single treatment at 30 days post infection showed high but incomplete effectiveness against a heartworm isolate that had been shown to be partially refractory to treatment with marketed monthly heartworm preventives. Three consecutive monthly treatments provided complete control, providing support to the recommendation that heartworm prophylaxis should be maintained year round for optimal effectiveness.


Injuries and illnesses related to dinghy-sailing on hydrofoiling boats.
Hydrofoil technology has changed sailing, significantly increasing its speed and resulting in spectacularity and mass media interest. Although high speed can expose participants to a risk of high-energy trauma, there are no scientific studies related to trauma in dinghies that exploit this technology. Therefore, this study aims primarily to measure the injury rate, and identify the kind and anatomical distribution of most common injuries and secondarily identify the traumatic dynamics most often involved and the main risk factors. This descriptive epidemiology study examined data relative to injuries and illnesses suffered by 77 sailors (91% males) from 13 nationalities during three international, gathered through a specifically designed questionnaire. The prevalence of illnesses and overuse injuries during the regatta week were 6.5% and 18.2%, respectively, while the incidence of acute injuries was 16/1000 sailor-hours. Upper limbs, lower limbs and lumbar spine were involved in 34.6%, 26.9% and 15.4% of cases of musculoskeletal injuries, respectively. None of the acute injuries reached the maximal score of severity, while the higher score value was 63/100. Most of the reported illnesses (80%; n = 4) were upper respiratory tract infections with a prevalence in the week of the regatta of 5.2% and an incidence of 0.51/1000 sailor-hours. Environmental factors played a role in 77% of the incidents resulting in acute injuries. This study provides valuable information for regatta organizers, boat builders, athletes, coaches, and doctors. In addition, it fosters the importance of ergonomics of boats, adequate clothing and specific physical training for injuries and illnesses prevention.


Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases.
Although lipid lowering drugs are effective in preventing morbidity and mortality from cardiovascular events, the extent of their adverse effects is not clear. This study explored the association between prescription of lipid lowering drugs and the risk of peripheral neuropathy. A population based case-control study was carried out by linkage of several automated databases. Resident population of a northern Italian Province aged 40 years or more. Cases were patients discharged for peripheral neuropathy in 1998-1999. For each case up to 20 controls were randomly selected among those eligible. Altogether 2040 case patients and 36 041 controls were included in the study. Exposure ascertainment: Prescription drug database was used to assess exposure to lipid lowering drugs at any time in the one year period preceding the index date. Conditional logistic regression model for matched data was used to estimate the risk of peripheral neuropathy associated with exposure to statins, fibrates, and other lipid lowering drugs. Weak but significant effects of lipid lowering drugs as a whole (matched odds ratio: 1.27; 95% confidence intervals: 1.05 to 1.55), statins (1.19; 1.00 to 1.40), and fibrates (1.49; 1.03 to 2.17) were observed. Significant linear trends towards increased risk at increased exposure to both statins and fibrates were observed. The use of both statins and fibrates was associated with the risk of peripheral neuropathy. The primary purpose of this exploratory study is signal generation. This requires further investigations to evaluate the causal role of lipid lowering drugs on the onset of peripheral neuropathy.


Stability of plasma and erythrocyte fatty acid composition during cold storage.
The purpose of the present experiment was to determine if the fatty acid composition of plasma and erythrocyte lipids remains stable when stored at -80 degrees C. This was accomplished by repeating the fatty acid analysis of plasma and erythrocyte samples that had been analysed originally as part of two separate experiments. The original plasma and erythrocyte fatty acid analysis was completed on average within 9 and 18 months, respectively, of collecting the blood samples; the repeat analysis was done on average 2.5 and 2 years, respectively, after the initial work. All samples were stored at -80 degrees C. Identical procedures for gas-liquid chromatographic analysis of fatty acids were used for the original and repeat analysis. Plasma triglyceride and erythrocyte phosphatidylcholine fatty acids were measured. The fatty acid compositions of plasma triglyceride and erythrocyte phosphatidylcholine were virtually unchanged between the original and repeat analysis. In combination with the results of other studies that have found fatty acids to be stable for 1 year at -60 degrees C, the present results demonstrate that the fatty acid composition of plasma and erythrocyte lipids is stable for nearly 4 years when stored at -80 degrees C.


Artificial bioinorganic clusters of dinuclear 3d-transition metal ions coordinated by an inorganic coordination ligand.
A new biologically relevant cubane-type artificial inorganic ligand was developed to support 3d-transition metal ions of Mn(II), Co(II), Ni(II), Zn(II), Fe(III), and also In(III). All of the reactions produce dinuclear cationic clusters of [({Co(tacn)}2HMo3O13∙H2O){M(H2O)2}]2n+ (M = Mn2+ (4Mn), Co2+ (4Co), Ni2+ (4Ni), Zn2+ (4Zn), n = 2; M = Fe3+ (5), In3+ (6), n = 4), where tacn is the abbreviation of 1,4,7-triazacyclononane ligand. Clusters 4 do not dissolve in any solvents at all to prevent the recrystallization or the further characterization whereas the high solubility of clusters 5 and 6 allowed us to characterize the solution state properties. The dinuclear cores are separated at a fixed-distance in the range of 5.66-5.77 Å for M(II) complexes and 5.45-5.65 Å for M(III) complexes. Each 3d-transition metal ion is supported by two pairs of cis-oxido groups from a cubane unit formed by CoMo3O3(OH) group, and remaining two sites on the 3d-transition metal centers are occupied by two water molecules. The hydroxido group on the cubane unit provides an interaction route through bifurcated hydrogen bondings between dinuclear centers. Three consecutive stepwise reduction waves were observed at -0.73, -0.91, and -1.16 mV vs Fc+/Fc for 5 in cyclic voltammetry and the comparison with the redox inactive In3+ complex revealed that two iron centers are interacted each other through the inorganic ligand which gave a reduction wave observed at -0.91 mv vs Fc+/Fc.


Continuous-Flow Synthesis of Δ9-Tetrahydrocannabinol and Δ8-Tetrahydrocannabinol from Cannabidiol.
A challenging step in the preparation of tetrahydrocannabinol analogs is an acid-catalyzed intramolecular cyclization of the cannabidiol precursor. This step typically affords a mixture of products, which requires extensive purification to obtain any pure products. We report the development of two continuous-flow protocols for the preparation of (-)-trans-Δ9-tetrahydrocannabinol and (-)-trans-Δ8-tetrahydrocannabinol.


Network Approaches for Dissecting the Immune System.
The immune system is a complex biological network composed of hierarchically organized genes, proteins, and cellular components that combat external pathogens and monitor the onset of internal disease. To meet and ultimately defeat these challenges, the immune system orchestrates an exquisitely complex interplay of numerous cells, often with highly specialized functions, in a tissue-specific manner. One of the major methodologies of systems immunology is to measure quantitatively the components and interaction levels in the immunologic networks to construct a computational network and predict the response of the components to perturbations. The recent advances in high-throughput sequencing techniques have provided us with a powerful approach to dissecting the complexity of the immune system. Here we summarize the latest progress in integrating omics data and network approaches to construct networks and to infer the underlying signaling and transcriptional landscape, as well as cell-cell communication, in the immune system, with a focus on hematopoiesis, adaptive immunity, and tumor immunology. Understanding the network regulation of immune cells has provided new insights into immune homeostasis and disease, with important therapeutic implications for inflammation, cancer, and other immune-mediated disorders.


Smooth muscle Rac1 contributes to pulmonary hypertension.
Pulmonary hypertension (PH) is a multifactorial chronic disease characterized by an increase in pulmonary artery (PA) resistance leading to right ventricle (RV) failure. Endothelial dysfunction and alteration of NO/cGMP signalling in PA plays a major role in PH. We recently described the involvement of the Rho protein Rac1 in the control of systemic blood pressure through its involvement in NO-mediated relaxation of arterial smooth muscle cell (SMC). The aim of this study was to analyse the role of SMC Rac1 in PH. PH is induced by exposure of control and SMC Rac1-deficient (SM-Rac1-KO) mice to chronic hypoxia (10% O2 , 4 weeks). PH is assessed by the measurement of RV systolic pressure and hypertrophy. PA reactivity is analysed by isometric tension measurements. PA remodelling is quantified by immunofluorescence in lung sections and ROS are detected using the dihydroethidium probe and electronic paramagnetic resonance analysis. Rac1 activity is determined by immunofluorescence. Rac1 activation in PA of hypoxic mice and patients with idiopathic PH. Hypoxia-induced rise in RV systolic pressure, RV hypertrophy and loss of endothelium-dependent relaxation were significantly decreased in SM-Rac1-KO mice compared to control mice. SMC Rac1 deletion also limited hypoxia-induced PA remodelling and ROS production in pulmonary artery smooth muscle cells (PASMCs). Our results provide evidence for a protective effect of SM Rac1 deletion against hypoxic PH. Rac1 activity in PASMCs plays a causal role in PH by favouring ROS-dependent PA remodelling and endothelial dysfunction induced by chronic hypoxia.


Increase in C-Reactive Protein Predicts Increase in Rate of Bone Mineral Density Loss: The Study of Women's Health Across the Nation.
This longitudinal cohort study's aim was to detect whether larger increases in C-reactive protein (CRP) predict greater amounts of subsequent bone loss in women transitioning from premenopause to postmenopause. Participants were initially 42 to 52 years of age and premenopausal or early perimenopausal. The sample included 1431 women who were not using hormone therapy and whose CRP values were not consistent with acute inflammation. Individual fixed effects (IFE) models estimated the association of log2 CRP with subsequent bone mineral density (BMD) decline rate, adjusted for menopause transition (MT) stage (1: premenopausal or early perimenopausal; 2: late perimenopausal or early postmenopausal; or 3: late postmenopausal), body mass index, diabetes, smoking, alcohol, bone active medications, and anti-inflammatory medications. BMD decline at both the lumbar spine (LS) and femoral neck (FN) was faster for observations made in MT stage 2 than that during other stages (all p < .001). In adjusted IFE models, MT stage modified the relation between increase in CRP and BMD decline rate (interaction p values <.05). Each within-woman doubling of CRP was associated with a 0.09% faster yearly decline in FN BMD in MT stages 1 (p = .006) and 3 (p = .03), and 0.10% faster decline in LS BMD in MT stage 3 only (p = .007). Within-woman increases in CRP in premenopause and early perimenopause and in late postmenopause predict faster BMD decline in the next ~2 years, but the magnitude of CRP's effect is small. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.


Association of arsenic-induced cardiovascular disease susceptibility with genetic polymorphisms.
Inorganic arsenic (iAs) exposure has been reported to have an impact on cardiovascular diseases (CVD). However, there is not much known about the cardiac tissue injury of CVD patients in relation to iAs exposure and potential role of single nucleotide polymorphisms (SNPs) of genes related to iAs metabolism, oxidative stress, endothelial dysfunction and inflammation which may play important roles in such CVD cases. In this dual center cross-sectional study, based on the exclusion and inclusion criteria, we have recruited 50 patients out of 270, who came from known arsenic-affected and- unaffected areas of mainly Chittagong, Dhaka and Rajshahi divisions of Bangladesh and underwent open-heart surgery at the selected centers during July 2017 to June 2018. We found that the patients from arsenic affected areas contained significantly higher average iAs concentrations in their urine (6.72 ± 0.54 ppb, P = 0.028), nail (529.29 ± 38.76 ppb, P < 0.05) and cardiac tissue (4.83 ± 0.50 ppb, P < 0.05) samples. Patients' age, sex, BMI, hypertension and diabetes status adjusted analysis showed that patients from arsenic-affected areas had significantly higher iAs concentration in cardiac tissue (2.854, 95%CI 1.017-8.012, P = 0.046) reflecting higher cardiac tissue injury among them (1.831, 95%CI 1.032-3.249, P = 0.039), which in turn allowed the analysis to assume that the iAs exposure have played a vital role in patients' disease condition. Adjusted analysis showed significant association between urinary iAs concentration with AA (P = 0.012) and AG (P = 0.034) genotypes and cardiac iAs concentration with AA (P = 0.017) genotype of AS3MT rs10748835. The AG genotype of AS3MT rs10748835 (13.333 95%CI 1.280-138.845, P = 0.013), AA genotype of NOS3 rs3918181 (25.333 95%CI 2.065-310.757, P = 0.002), GG genotype of ICAM1 rs281432 (12.000 95%CI 1.325-108.674, P = 0.010) and AA genotype of SOD2 rs2758331 (13.333 95%CI 1.280-138.845, P = 0.013) were found significantly associated with CVD patients from arsenic-affected areas. Again, adjusted analysis showed significant association of AA genotype of AS3MT rs10748835 with CVD patients from arsenic affected areas. In comparison to the reference genotypes of the selected SNPs, AA of AS3MT 10748835, AG of NOS3 rs3918181 and AC of rs3918188, GG of ICAM1 rs281432, TT of VCAM1 rs3176867, AA of SOD2 rs2758331 and GT of APOE rs405509 significantly increased odds of cardiac tissue injury of CVD patients from arsenic affected areas. The results showed that the selected SNPs played a susceptibility role towards cardiac tissue iAs concentration and injury among CVD patients from iAs affected areas.


Identification and Characterization of a Novel Thermophilic, Organic Solvent Stable Lipase of Bacillus from a Hot Spring.
A novel lipase gene lip256 was cloned and identified from the genomic library of hot spring strain Bacillus sp. HT19. The deduced amino acid sequence of lip256 has less than 32% identity to a predicted esterase (Cog1752) from Photobacterium leiognathi lrivu.4.1 and contains a novel motif (GTSAG) that differs from other clusters in the lipase superfamily. Following purification, a single band was obtained with a molecular mass of 33 kDa by SDS-PAGE, and the optimal temperature and pH for lipolytic activity of Lip25 were 70 °C and 9.0, respectively. Lip256 exhibited high activity at high temperatures, with 40% maximum activity at 80 °C and good stability at temperatures ranges between 50 and 80 °C. Additionally, the enzyme was highly stable in the presence of butyl-alcohol, glycerol, acetonitrile, pyridine, and urea. However, the presence of acetone, methanol, trichloromethane, petroleum ether, hexane, tert-butanol, isopropanol, dithiothreitol, ethylenediaminetetraacetic acid, polyhexamethylene biguanide, dimethyl sulfoxide, benzene, Triton X-100, Tween-20, Tween-80, and sodium dodecyl sulfate suppressed or absolutely inhibited enzyme activity. Furthermore, Ca2+, Mg2+, and Cu2+ suppressed enzyme activity, whereas Na+, Fe3+, K+, Fe2+, and Sr2+ enhanced enzyme activity. The unique characteristics of novel lipase Lip256, including its thermo-alkaliphilic performance, high tolerance toward metal ions, inhibitors, and detergents, and high stability in organic solvents, implied that this enzyme might be an interesting candidate for industrial processes.


Value for money - recasting the problem in terms of dynamic access prioritisation.
To develop an approach for achieving value for money in rehabilitation based on dynamic prioritisation of access to services according to individual capacity to benefit. A critical review of economic evaluation and adaptation of a prioritisation method used in determining access to elective surgical services in New Zealand to a rehabilitation context. The cost-effectiveness frontier is not straight but curved, suggesting that some people benefit more from a given intervention than others. An approach that identifies those most likely to benefit from inpatient rehabilitation following stroke (as an example) and enables access in order of capacity to benefit is presented in the context of a quality improvement programme. The approach is operationalised as a prioritisation tool that is dynamic in the sense that is can be reapplied subject to changes in the patient's clinical status. The steps proposed to develop such a tool include qualitative research with expert clinicians, pair-wise comparison of alternative scenarios (1000Minds survey), construction of an economic model of the tool's operation and an observational cohort study to help populate the model and calibrate the tool. A dynamic prioritisation approach to guide access to scarce health-care resources (such as inpatient rehabilitation following stroke) offers a transparent and equitable way of achieving value for money in the delivery of rehabilitation services.


Impact of early life development on later onset chronic kidney disease and hypertension and the role of evolutionary trade-offs.
What is the topic of this review? In this report, we summarize the latest clinical evidence linking developmental programming in the kidney to later life blood pressure and kidney disease. What advances does it highlight? Population-level studies now show convincingly that low birth weight, fetal growth restriction and preterm birth are associated with and have a synergistic impact on the risk of kidney disease in later life. A new approach also considers how evolutionary selection pressure might fail to select for long-term robustness of kidney function. The global burden of kidney disease is high and rising. The risk of kidney disease among individuals is highly variable, in part related to genetic and environmental factors, but also likely to be modulated by developmental programming of the number of nephrons and kidney function in fetal life. The number of nephrons varies widely across the population and is lower among those who were born small or preterm. Population registry evidence clearly shows an association between these birth circumstances and later-life risk of hypertension and kidney disease, not only for chronic kidney disease but also for acquired kidney disease, demonstrating an inherent susceptibility to kidney disease in these individuals. Gestational stressors impact kidney development, a process that is likely to be layered upon the evolutionary history of the kidney and how the organ has developed in response to selection pressure to support reproductive capacity in early adulthood, but not to withstand multiple stresses later in life. Reducing the global burden of kidney disease in future generations will require both individual- and population/environment-level risks to be addressed.


Using Facebook to increase coverage of HPV vaccination among Danish girls: An assessment of a Danish social media campaign.
In this study we assess how different Facebook (FB) posts resonate with parents hesitant about HPV vaccination and how to engage parents in positive dialogues on FB. Vaccination against human papillomavirus (HPV) was successfully introduced in the Danish childhood vaccination program in 2009 for 12 year-old girls, with coverage reaching approximately 90%. However, negative public debate questioning the safety of the vaccine coincided with a rapid decline in vaccination coverage from 2015. In May 2017, we launched the national campaign Stop HPV - stop cervical cancer with the aim to rebuild trust in the HPV vaccine and increase vaccination coverage. We used a FB page and a social media strategy to engage the campaign's primary target group: mothers hesitant about HPV vaccination of their daughters. We analyzed a variety of posts on the FB page Stop HPV - stop cervical cancer posted from May 2017 to December 2017. We performed analysis documenting post reach, engagement in the posts and sentiment (positive, neutral or negative) of the comments. Focus groups were recruited to provide data about attitudes to the posts and the responses from the FB management team. 84 unique posts were published on the FB page from May 2017 to December 2017 reaching 3,476,023 individual FB profiles. In focus groups, parents requested more in-depth information. However, analyses of FB posts and sentiment of comments showed that personal stories generated higher engagement rates and more positive dialogues compared to factual posts. The FB page Stop HPV - stop cervical cancer has successfully reached and engaged FB users in dialogue about HPV vaccination. Personal stories are effective in creating positive dialogues on FB. However, it remains important to provide factual information to parents to enable informed decision making about HPV vaccination.


[Purification and biological activities analysis of streptococcus suis Serotype 2 suilysin].
To explore the purification methods of wild-type and recombinant suilysin and to evaluate their biological activities. Wild-type suilysin was purified by ammonium sulfate precipitation, anion-exchange chromatography and hydrophobic chromatography in turn, while recombinant suilysin was first refolded and purified by immobilized metal ion affinity chromatography, and further purified by Thiopropyl Sepharose 6B. The biological activities were evaluated by hemolysis test, cytotoxicity assay. Both prepared wild-type and recombinant suilysin, with purify over 90%, have hemolysis activity and could injure target cells at high concentration while cholesterol could completely inhibit their activities. Recombinant suilysin has similar biological activities with wild-type suilysin, and this work contributed to further study the functions of suilysin on pathogenesis of steptococcus suis.


The effect of fluoxetine on bone regeneration in rat calvarial bone defects.
Fluoxetine is one of the most common medications used for the treatment of depression. Recent studies have demonstrated the possible effect of this drug on bone. The purpose of this study was to evaluate the effect of flouxetine on bone in Sprague-Dawley rats randomly divided into 3 groups (n = 7). Two calvarial defects, 5 mm diameter, were prepared in parietal bone. The left defects were filled with natural bovine bone mineral (NBBM) and the right defects were left untreated. The first group did not receive fluoxetine. The second group and the third group received 7.5 mg and 15 mg flouxetine, respectively, daily by gastric gavage. The animals were killed 8 weeks after surgery, and the amount of bone regeneration was evaluated using histometric analysis. The defects showed dose-dependent increase in bone formation. The bone fill length had statistical significant differences between NBBM/flouxetine (15 mg) group and other groups (P < .05). The presence of the NBBM had positive effect on the bone formation in all groups in so far as the maximum amount of the increasing effect was seen in those rats filled with NBBM that received 15 mg flouxetine (P < .05). The minimum bone length in fluoxetine-treated defects was seen in 7.5 mg defects (0.36 mm) Fluoxetine may improve the amount of bone regeneration in the rat calvarial defects.


Farm exposures, parental occupation, and risk of Ewing's sarcoma in Australia: a national case-control study.
It has been suggested that parental occupation, particularly farming, increased the risk of Ewing's sarcoma in the offspring. In a national case-control study we examined the relationship between farm and other parental occupational exposures and the risk of cancer in the offspring. Cases were 106 persons with confirmed Ewing's sarcoma or peripheral primitive neuroectodermal tumor. Population-based controls (344) were selected randomly via telephone. Information was collected by interview (84% face-to-face). We found an excess of case mothers who worked on farms at conception and/or pregnancy (odds ratio (OR)=2.3. 95% confidence interval (CI) 0.5-12.0) and a slightly smaller excess of farming fathers, more case mothers usually worked as laborers, machine operators, or drivers (OR = 1.8, 95% CI 0.9-3.9). Risk doubled for those whose mothers handled pesticides and insecticides, or fathers who handled solvents and glues, and oils and greases. Further, more cases lived on farms (OR= 1.6, 95% CI 0.9-2.8). In the 0-20 years group, the risk doubled for those who ever lived on a farm (OR = 2.0, 95% CI 1.0-3.9), and more than tripled for those with farming fathers at conception and/or pregnancy (OR = 3.5, 95% CI 1.0-1 1.9). Our data support the general hypothesis of an association of Ewing's sarcoma family of tumors with farming, particularly at younger ages. who represent the bulk of cases, and are more likely to share etiologic factors.


Retinoic acid, immunity, and inflammation.
Vitamin A (also called retinol), absorbed in the intestine and stored mainly in the liver and fat, is normally maintained at significant concentrations in the human blood plasma. Vitamin A is constitutively metabolized at high levels in certain tissues such as the small intestine and eyes. Retinoic acid (RA) produced at high levels in the intestine plays important roles in mucosal immunity and immune tolerance. RA at basal levels is required for immune cell survival and activation. During immune responses, enzymes metabolizing vitamin A are induced in certain types of immune cells such as dendritic cells (DCs) and tissue cells for induced production of RA. As a result, induced gradients of RA are formed during immune responses in the body. RA regulates gene expression, differentiation, and function of diverse immune cells. The cells under the influence of RA in terms of differentiation include myeloid cells such as neutrophils, macrophages, and DCs. Also included are lymphoid cells such as effector T cells, regulatory T cells, and B cells. Our current understanding of the function of RA in regulation of these immune cells is reviewed in this chapter.


Genome-wide association study and its applications in the non-model crop Sesamum indicum.
Sesame is a rare example of non-model and minor crop for which numerous genetic loci and candidate genes underlying features of interest have been disclosed at relatively high resolution. These progresses have been achieved thanks to the applications of the genome-wide association study (GWAS) approach. GWAS has benefited from the availability of high-quality genomes, re-sequencing data from thousands of genotypes, extensive transcriptome sequencing, development of haplotype map and web-based functional databases in sesame. In this paper, we reviewed the GWAS methods, the underlying statistical models and the applications for genetic discovery of important traits in sesame. A novel online database SiGeDiD ( http://sigedid.ucad.sn/ ) has been developed to provide access to all genetic and genomic discoveries through GWAS in sesame. We also tested for the first time, applications of various new GWAS multi-locus models in sesame. Collectively, this work portrays steps and provides guidelines for efficient GWAS implementation in sesame, a non-model crop.


An improved synthesis of (+/-)-N'-nitrosonornicotine 5'-acetate.
A concise and efficient route to (+/-)-N'-nitrosonornicotine 5'-acetate (NNN-5'-OAc), a stable precursor of the active metabolite 5'-hydroxy(+/-)-N'-nitrosonornicotine NNN-5'-OH is reported. The synthesis utilizes sulfinimine chemistry to give (+/-)-NNN-5'-OAc in 26% yield over 4 steps.


The association between antibody responses and prolonged viable SARS-CoV-2 shedding in immunocompromised patients: a prospective cohort study.
Immunocompromised COVID-19 patients were prospectively enrolled from March to November 2022 to understand the association between antibody responses and SARS-CoV-2 shedding. A total of 62 patients were analyzed and the results indicated a faster decline in genomic and subgenomic viral RNA in patients with higher neutralizing and S1-specific IgG antibodies (both P < 0.001). Notably, high neutralizing antibody levels were associated with a significantly faster decrease in viable virus cultures (P = 0.04). Our observations suggest the role of neutralizing antibodies in prolonged virus shedding in immunocompromised patients, highlighting the potential benefits of enhancing their humoral immune response through vaccination or monoclonal antibody treatments.


High Virus Removal by Self-Organized Nanostructured 2D Liquid-Crystalline Smectic Membranes for Water Treatment.
To obtain high quality of drinking water free from biocontaminants is especially important issue. A new strategy employing smectic liquid-crystalline ionic membranes exhibiting 2D structures of layered nanochannels for water treatment is proposed for efficient virus removal and sufficient water flux. The smectic A (SmA) liquid-crystalline membranes obtained by in situ polymerization of an ionic mesogenic monomer are examined for removal of three distinct viruses with small size: Qβ bacteriophage, MS2 bacteriophage, and Aichi virus. The semi-bilayer structure of the SmA significantly obstructs the virus penetration with an average log reduction value of 7.3 log10 or the equivalent of reducing 18 million viruses down to 1. Furthermore, the layered nanochannels of the SmA liquid crystal allow efficient water permeation compared to other types of liquid-crystalline membrane consisting of nanopores.


Selenium independent glutathione peroxidase activity associated with cationic forms of glutathione transferase in human heart.
Glutathione peroxidase activity with both hydrogen peroxide and cumene hydroperoxide was measured in the cytosolic fractions prepared from five human hearts obtained from post-mortem victims. In all the samples the activity with cumene hydroperoxide was higher than that obtained with hydrogen peroxide, suggesting that the selenium-independent glutathione peroxidase could also be present in this tissue. To determine its presence in heart tissue we fractionated the cardiac cytosol fraction on a column of Sephadex G-100 and measured glutathione peroxidase activity with both the substrates. Glutathione transferase activity was measured with 1-chloro-2,4-dinitrobenzene in the fractionated cytosol. The results indicated that a selenium-independent glutathione peroxidase activity was present (about 30% of total activity). Fractionation of the cytosol by gel filtration showed that peroxidase activity co-eluted with glutathione transferase activity. Subsequently the fractions containing glutathione transferase and selenium-independent glutathione peroxidase activity obtained from gel filtration experiments were passed through an affinity column and analyzed by isoelectric focusing. It was found that the selenium-independent glutathione peroxidase copurified with three isoenzymes of glutathione transferase which had a pI of 9.2, 8.9 and 8.6 respectively. In contrast the acidic isoenzymes of glutathione transferase lacked peroxidase activity. It is suggested that the selenium-independent glutathione peroxidase may play an important role in neutralizing oxygen toxicity in heart when the selenium-dependent glutathione peroxidase activity is impaired.


Use of biocompatible redox-active polymers based on carbon nanotubes and modified organic matrices for development of a highly sensitive BOD biosensor.
This work investigated the use of redox-active polymers based on bovine serum albumin and chitosan, covalently bound to mediators neutral red and ferrocene and containing carbon nanotubes, for immobilization of Paracoccus yeei VKM B-3302 bacteria. The structures of produced polymers were studied by IR spectroscopy and scanning electron microscopy. Cyclic voltammetry and impedance spectroscopy found the electrochemical characteristics of the investigated systems: the heterogeneous electron transfer rate constant, the constant of the rate of interaction with P. yeei bacteria and the impedance. The systems containing carbon nanotubes and ferrocene-based redox-active polymer proved to be the most promising. Biosensors formed using the hybrid polymers had a high sensitivity with the lower boundary of 0.1 mg/dm3 of the detected BOD5 concentrations and a high correlation (R = 0.9916) with the standard BOD assay of surface water samples.


Age-related changes in corticospinal excitability and intracortical inhibition after upper extremity motor learning: a systematic review and meta-analysis.
It is unclear how old age affects the neuronal mechanisms of motor learning. We reviewed the neuronal mechanisms of how healthy old and young adults acquire motor skills as assessed with transcranial magnetic stimulation. Quantitative meta-analyses of 11 studies, involving ballistic and visuomotor tasks performed by upper extremity muscles in 132 healthy old and 128 young adults, revealed that the motor practice-induced increase in corticospinal excitability (CSE) is task-dependent but not age-dependent, with an increase in CSE in both age groups after visuomotor but not ballistic training. In addition, short-interval intracortical inhibition (SICI) is reduced in old but not young adults, but only after visuomotor practice. In addition, correlation analyses in 123 old and 128 young adults showed that the magnitude of motor skill acquisition did not correlate with increases in CSE or decreases in SICI in either age group. Thus, there are subtle age-related differences in use-dependent plasticity but increases in CSE or decreases in SICI are not related to motor skill acquisition in healthy young or old adults.


White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study.
Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n = 23), weight-recovered women with a past diagnosis of AN (recAN: n = 23), and age-matched healthy control women (HC: n = 24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxelwise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold-free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Clusterwise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for clusterwise AD and RD. Trait-based increases in diffusivity, changes in which have been associated with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.


Oxidative stress modulates nucleobase transport in microvascular endothelial cells.
Purine nucleosides and nucleobases play key roles in the physiological response to vascular ischemia/reperfusion events. The intra- and extracellular concentrations of these compounds are controlled, in part, by equilibrative nucleoside transporter subtype 1 (ENT1; SLC29A1) and by equilibrative nucleobase transporter subtype 1 (ENBT1). These transporters are expressed at the membranes of numerous cell types including microvascular endothelial cells. We studied the impact of reactive oxygen species on the function of ENT1 and ENBT1 in primary (CMVEC) and immortalized (HMEC-1) human microvascular endothelial cells. Both cell types displayed similar transporter expression profiles, with the majority (>90%) of 2-chloro[(3)H]adenosine (nucleoside) uptake mediated by ENT1 and [(3)H]hypoxanthine (nucleobase) uptake mediated by ENBT1. An in vitro mineral oil-overlay model of ischemia/reperfusion had no effect on ENT1 function, but significantly reduced ENBT1 Vmax in both cell types. This decrease in transport function was mimicked by the intracellular superoxide generator menadione and could be reversed by the superoxide dismutase mimetic MnTMPyP. In contrast, neither the extracellular peroxide donor TBHP nor the extracellular peroxynitrite donor 3-morpholinosydnonimine (SIN-1) affected ENBT1-mediated [(3)H]hypoxanthine uptake. SIN-1 did, however, enhance ENT1-mediated 2-chloro[(3)H]adenosine uptake. Our data establish HMEC-1 as an appropriate model for study of purine transport in CMVEC. Additionally, these data suggest that the generation of intracellular superoxide in ischemia/reperfusion leads to the down-regulation of ENBT1 function. Modification of purine transport by oxidant stress may contribute to ischemia/reperfusion induced vascular damage and should be considered in the development of therapeutic strategies.


Performance and quality attributes of okra (Abelmoschus esculentus (L.) Moench) fruits grown under soil applied Zn-fertilizer, green biomass and poultry manure.
Field experiments were carried out in 2018 and 2019 cropping seasons at Landmark University Teaching and Research farm, Omu-Aran Kwara state, Nigeria, to determine the effect of soil applied Zn-fertilizer, Tithonia diversifolia (Ti), Chromolaena odorata (Ch) and poultry manure (PM) on the performance, yield, minerals and vitamins composition of okra fruits. Treatments were combined and tested as follows:-Control (T1), Control + 10 kg ha-1 Zn (T2), 5 t ha-1 Ti + 5 t ha-1 PM (T3), 5 t ha-1 Ch + 5 t ha-1 PM (T4), 5 t ha-1 Ch + 5 t ha-1 Ti (T5), 10 t ha-1 Ti + 0 kg ha-1 Zn (T6), 10 t ha-1 Ti + 10 kg ha-1 Zn (T7), 10 t ha-1 Ch + 0 kg ha-1 Zn (T8), 10 t ha-1 Ch + 10 kg ha-1 Zn (T9), 10 t ha-1 PM + 0 kg ha-1 Zn (T10), and 10 t ha-1 PM + 10 kg ha-1 Zn (T11). The experiment was laid out in a randomized complete block design with four repetitions. Vegetative, yield and quality parameters of okra were taken. Data were subjected to analysis of variance and means were compared using Duncan Multiple Range Test (DMRT) at p ≤ 0.05. Variations were observed on the vegetative parameters, yield, minerals and vitamin composition of okra among the applied amendments. The combined application of green biomass, poultry manure, and Zn-fertilizer improved all the variables tested as compared to when they were applied singly. Application of Zn-fertilizer to some selected plots significantly increased yield, Zn, Mg and vitamins concentration of okra. Application of 5 t ha-1 Ti + 5 t ha-1 PM + 10 kg ha-1 Zn (T3) and 5 t ha-1 Ch + 5 t ha-1 PM + 10 kg ha-1 Zn (T4) significantly improved all the parameters tested but the use of 5 t ha-1 Ti + 5 t ha-1 PM + 10 kg ha-1 Zn (T3) resulted in optimum yield and at the same time increase minerals and vitamin concentration of okra. The results of this study therefore showed that Tithonia diversifolia (Ti) as green biomass contained and released more and quality nutrients than Chromolaena odorata (Ch) when combined with equal rate of Zn fertilizer and poultry manure.


Comparative analysis of various prognostic nodal factors, adjuvant chemotherapy and survival among stage III colon cancer patients over 65 years: an analysis using surveillance, epidemiology and end results (SEER)-Medicare data.
The prognostic effects of chemotherapy and various lymph node measures [positive nodes, total node count and the positive lymph node ratio (PLNR)] have been established. It is unknown whether the cancer-specific survival benefit of chemotherapy differs across these nodal prognostic categories. This retrospective analysis of linked Surveillance, Epidemiology and End Results (SEER) data and Medicare data (SEER-Medicare)included patients ≥ 65 years of age with a diagnosis of stage III colon cancer between 1997 and 2002. We grouped patients according to the number of positive nodes (N1 and N2), total node count (≥ 12 and < 12 total nodes) and PLNR (below the 75th percentile and at least at the 75th percentile of the PLNR). The end point was colon cancer-specific mortality. Fifty-one per cent (3701) of the 7263 patients received adjuvant therapy during the time period 1997-2002. The mean (standard deviation) number of total nodes examined was 13 (9) and the number of positive nodes identified was 3 (3). Patients with N2 disease, < 12 total nodes examined and a high PLNR had a worse survival at 2, 3 and 5 years following colectomy. Utilization of chemotherapy demonstrated a colon cancer-specific survival benefit (hazard ratio at median follow up = 0.7; P < 0.001) that was consistent and statistically significant across the three nodal prognostic categories examined. The benefit of chemotherapy did not vary based on N stage, total node count or PLNR. The results favour a broad-based approach towards increasing the chemotherapy treatment rates in stage III patients of ≥ 65 years of age, rather than an approach that targets clinical subgroups.


Effect of distraction on simulated anterior segment surgical performance.
To determine the effect of distraction on anterior segment surgical performance using a virtual reality simulator in expert and novice surgeons. Horizon Suite Simulation Centre, South Devon Foundation NHS Trust, Devon, England. Cohort study. Expert and novice ophthalmic surgeons completed a standardized and validated surgical task 10 times on a virtual reality simulator (EyeSi). They then completed a cognitive task (arithmetic questions), after which they completed 10 attempts on the simulator module while also completing the cognitive task. For experts (n = 7), the distracting cognitive task had no statistically significant effect on operating scores. The rate of correctly answered questions decreased from 12.3 per minute ± 2.1 (SD) while single tasking to 8.6 ± 3.1 per minute while dual tasking (P=.018). For novices (n = 14), the distracting cognitive task had no effect on any operating score except a small reduction in the penalty odometer score. The rate of correctly answered questions decreased from 11.5 ± 4.1 per minute while single tasking to 7.0 ± 3.2 per minute while dual tasking (P=.001). A distractive cognitive task reduced the ability of novice surgeons and expert surgeons to deal with that cognitive task, although their simulated surgical performance was not overtly compromised. No author has a financial or proprietary interest in any material or method mentioned.


Contribution of retinal versus extraretinal signals towards visual localization in goal-directed movements.
In human subjects, we investigated the accuracy of goal-directed arm movements performed without sight of the arm; errors of target localization and of motor control thus remained uncorrected by visual feedback, and became manifest as pointing errors. Target position was provided either as retinal eccentricity or as eye position. By comparing the results to those obtained previously with combined retinal plus extraretinal position cues, the relative contribution of the two signals towards visual localization could be studied. When target position was provided by retinal signals, pointing responses revealed an over-estimation of retinal eccentricity which was of similar size for all eccentricities tested, and was independent of gaze direction. These findings were interpreted as a magnification effect of perifoveal retinal areas. When target position was provided as eye position, pointing was characterized by a substantial inter-, and intra-subject variability, suggesting that the accuracy of localization by extraretinal signals is rather limited. In light of these two qualitatively different deficits, possible mechanisms are discussed how the two signals may interact towards a more veridical visual localization.


Candida albicans infection and intestinal immunity.
Fungal infections cause high rates of morbidity and mortality in intensive care and immunocompromised patients, and can represent a life-threatening disease. As a microorganism commonly found in the intestine, Candida albicans (C. albicans) can invade the gut epithelium barrier via microfold cells and enter the bloodstream. The defensive potential of the intestinal barrier against invasive C. albicans is dependent on innate and adaptive immune responses which enable the host to eliminate pathogenic fungi. The lamina propria layer of the intestine contains numerous immune cells capable of inducing an innate cellular immune response against invasive fungi. This review focuses on the immune response triggered by a C. albicans infection in the intestine.


A bioinformatic study of IGFBPs in glioma regarding their diagnostic, prognostic, and therapeutic prediction value.
It is essential to develop better biomarkers for diagnosis, prediction, and treating glioma patients to ensure successful clinical outcomes. The clinical application of Insulin-Like Growth Factor Binding Proteins (IGFBPs) for glioma is yet to be investigated. Cohorts were obtained from TCGA, GTEx, CGGA, HPA, Oncomine, CancerSEA, TISCH, etc. The expressions, methylation, and survival association of IGFBPs were analyzed. The Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to construct a prognostic model. The correlation of IGFBPs and immune cells or immune molecules was analyzed. The effect of IGFBPs on immune therapy and chemotherapy was analyzed. The top 500 correlated genes of IGFBPs were enriched in GO terms. Correlations between IGFBPs and functional states in glioma single-cells and correlations between IGFBPs and chemokines in samples were analyzed. IGFBPs were overexpressed in glioma. Malignant cells were the major cell types that expressed IGFBPs. Higher-grade glioma had a higher expression of IGFBPs, which were associated with worse survival. A survival model of IGFBPs for glioma patients was trained and validated. A nomogram was generated. Generally, IGFBPs mRNA expression was negatively correlated with B cells and T cells. IGFBPs were associated with multiple immune molecules and drug sensitivity. IGFBPs were powerful diagnostic, prognostic, and therapeutic prediction biomarkers for glioma.


Cytoplasmic tethering of a RING protein RBCK1 by its splice variant lacking the RING domain.
RBCC protein interacting with PKC 1 (RBCK1) is a transcription factor belonging to the RING-IBR protein family and has been shown to shuttle between the nucleus and cytoplasm, possessing both the nuclear export and localization signals within its amino acid sequence. RBCK2, lacking the C-terminal half of RBCK1 including the RING-IBR domain, has also been identified as an alternative splice variant of RBCK1. RBCK2 shows no transcriptional activity and instead it represses the transcriptional activity of RBCK1. Here, we show that RBCK2 is present usually in the cytoplasm containing two Leu-rich regions that presumably serve as a nuclear export signal (NES). Moreover, an NES-disrupted RBCK1 that is mostly localized within the nucleus is translocated to the cytoplasm when coexpressed with RBCK2, suggesting that RBCK2 serves as a cytoplasmic tethering protein for RBCK1. We propose a novel and general function of RING-lacking splice variants of RING proteins to control the intracellular localization and functions of the parental RING proteins by forming a hetero-oligomeric complex.


The critical role of the nucleolus in cell differentiation and stem cell development - the concept as it applies to erythropoiesis.
There is evidence to suggest that nucleated red blood cells (normoblasts) are derived from a fixed reticulum cell lining that marrow sinusoids. The reticulum cell is transformed into a nucleolated stem cell which gives rise to a cluster of normoblasts by a special process of clonal division. The problem, which is paramount to myeloid development, is what happens to the large numbers of nuclei which are extruded from the normoblasts during the freeing of the haemoglobinised plastid. They seem to disappear without a trace, and in order to explain this phenomenon the hypothesis is made that the extruded nuclei are transformed into cells of the neutrophil series, and evidence is presented to support this viewpoint.


Histopathological features of fibrous cephalic plaques in tuberous sclerosis complex.
Fibrous cephalic plaques (FCPs) in individuals with tuberous sclerosis complex (TSC) may be excised for cosmetic reasons or biopsied to confirm lesion identification and TSC diagnosis. The aim of this study was to determine the range of histopathological features of FCPs. A retrospective analysis was conducted on 119 adults with TSC. Twenty-one lesions from 16 individuals were evaluated by a dermatopathologist. Additionally, we assessed whether lesion colour or histology varied by anatomical location. Seventy-six lesions were observed in 36 of 119 individuals. Erythematous lesions were more commonly found on the forehead, face or neck than on the scalp (odds ratio = 12.6, P = 0.0001). Thickened and disorganised collagen fibre bundles were present in 95% (20/21) of lesions. Perifollicular fibrosis was observed in 95% (20/21) of lesions, enhanced vascularity was observed in 52% (11/21) of lesions, and features of fibrofolliculoma were observed in 43% (9/21) of lesions. Other abnormalities included features similar to trichofolliculoma, follicular-derived, infundibular-type cysts, and abnormally arranged primitive hair follicles. FCPs in TSC show thickened bundles of collagen, and hamartomatous changes involving hair follicles. Recognition of these histopathological features may raise the possibility of unsuspected TSC or confirm FCP identification.


Associations between executive functions and mental health outcomes for adults with autism spectrum disorder.
Associations between executive functions (EF) and mental-health in adults with autism spectrum disorder (ASD) were examined. Forty-two adults with ASD completed measures of EF, mood and self-concept. Better concept formation and social inference skills were significantly associated with fewer anxiety symptoms. Conversely, participants with better non-verbal reasoning, cognitive flexibility and social cognition reported more negative self-concept and lower self-esteem. Overall, individuals with impaired EF are more prone to anxiety, whereas those with stronger EF are more likely to experience negative self-concept. Screening for and monitoring mental-health concerns in people with ASD regardless of their level of EF is recommended.


Special stains in Mohs surgery.
The excellent cure rates associated with Mohs micrographic surgery depend on accurate interpretation of complete and high-quality microscopic frozen sections. Reliable interpretation of microscopic slides is only possible if the surgeon can distinguish tumor cells from surrounding normal tissue. By highlighting tumor cells with a chromogen that is visible on light microscopy, immunostaining allows the Mohs surgeon to distinguish tumor from normal cells in these challenging scenarios. This article focuses on practical aspects involving the most commonly used immunostains in dermatologic surgery, including MART-1 for melanocytic neoplasms, cytokeratin stains for keratinocytic neoplasms, and CD34 stains for dermatofibrosarcoma protuberans.


Oxaliplatin long-circulating liposomes improved therapeutic index of colorectal carcinoma.
Cytotoxic drugs are non-selective between normal and pathological tissue, and this poses a challenge regarding the strategy for treatment of tumors. To achieve sufficient antitumor activity for colorectal carcinoma, optimization of the therapeutic regimen is of great importance. We investigated the ability of oxaliplatin long-circulating liposomes (PEG-liposomal L-oHP) to provide an improved therapeutic index of colorectal carcinoma. We determined that PEG- liposomes conjugated with cells at 2 h, with a mean fluorescence intensity that was enhanced upon extended induction time. The PEG-liposomal L-oHP induced a significant apoptotic response as compared with free L-oHP, 23.21% ± 3.38% vs. 16.85% ± 0.98%, respectively. Fluorescence imaging with In-Vivo Imaging demonstrated that PEG- liposomes specifically targeted tumour tissue. After intravenous injections of PEG-liposomal L-oHP or free L-oHP, the tumour volume suppression ratio was 26.08% ± 12.43% and 18.19% ± 7.09%, respectively, the percentage increased life span (ILS%) was 45.36% and 76.19%, respectively, and Bcl-2, Bax mRNA and protein expression in tumour tissue was 0.27-fold vs. 0.88-fold and 1.32-fold vs. 1.61-fold compared with free L-oHP, respectively. The PEG-liposomal L-oHP exhibited a tendency to target tumour tissue and demonstrated a significantly greater impact on apoptosis compared to free oxaliplatin.


Primo vascular system as a new morphofunctional integrated system.
The purpose of this review is to describe the methodology, instruments, and subject animals used until now for studies of the meridian (Kyungrak) system and the primo vascular system (PVS). The PVS is observed as an anatomical system distributed in cavities, organs, and tissues throughout the body. We analyzed the most important points of the PVS based on the results obtained until the present. Our main effort has been directed to describing the main thesis relating to the morphological structures and their topography, the functional mechanisms of the PVS, and possible roles of the PVS in pathological processes. The substance of the PVS in all its aspects is as a system covering the whole body and regulating and coordinating the biological processes that are the basis for life. In conclusion, we suggest that the finding of the PVS represents the discovery of a new integrated morphological-functional system.


[EEG diagnosticsof non-convulsive status epilepticus in critically ill patients].
Critically ill patients are at high risk of non-convulsive status epilepticus (NCSE). As clinical signs of NCSE are subtle and unspecific, EEG is necessary to make the diagnosis. This is a review of the terminology for EEG reporting and the criteria for NCSE in critically ill patients. We discuss the newly proposed ictal-interictal continuum, and how caution is needed when assessing EEG criteria in order to avoid both over- and undertreatment. Finally, we discuss how specific EEG findings, in combination with clinical information, can help infer treatment decision and need for continuous EEG monitoring.


Illicit opioid use following changes in opioids prescribed for chronic non-cancer pain.
After decades of increased opioid pain reliever prescribing, providers are rapidly reducing prescribing. We hypothesized that reduced access to prescribed opioid pain relievers among patients previously reliant upon opioid pain relievers would result in increased illicit opioid use. We conducted a retrospective cohort study among 602 publicly insured primary care patients who had been prescribed opioids for chronic non-cancer pain for at least three consecutive months in San Francisco, recruited through convenience sampling. We conducted a historical reconstruction interview and medical chart abstraction focused on illicit substance use and opioid pain reliever prescriptions, respectively, from 2012 through the interview date in 2017-2018. We used a nested-cohort design, in which patients were classified, based on opioid pain reliever dose change, into a series of nested cohorts starting with each follow-up quarter. Using continuation-ratio models, we estimated associations between opioid prescription discontinuation or 30% increase or decrease in dose, relative to no change, and subsequent frequency of heroin and non-prescribed opioid pain reliever use, separately. Models controlled for demographics, clinical and behavioral characteristics, and past use of heroin or non-prescribed opioid pain relievers. A total of 56,372 and 56,484 participant-quarter observations were included from the 597 and 598 participants available for analyses of heroin and non-prescribed opioid pain reliever outcomes, respectively. Participants discontinued from prescribed opioids were more likely to use heroin (Adjusted Odds Ratio (AOR) = 1.57, 95% CI: 1.25-1.97) and non-prescribed opioid pain relievers (AOR = 1.75, 1.45-2.11) more frequently in subsequent quarters compared to participants with unchanged opioid prescriptions. Participants whose opioid pain reliever dose increased were more likely to use heroin more frequently (AOR = 1.67, 1.32-2.12). Results held throughout sensitivity analyses. The main limitations were the observational nature of results and limited generalizability beyond safety-net settings. Discontinuation of prescribed opioid pain relievers was associated with more frequent non-prescribed opioid pain reliever and heroin use; increased dose was also associated with more frequent heroin use. Clinicians should be aware of these risks in determining pain management approaches.


Crystal structure of (E)-1-([1,1'-biphen-yl]-4-yl)-3-(3-nitro-phen-yl)prop-2-en-1-one.
In the title compound, C21H15NO3, the mol-ecule has an E conformation about the C=C bond, and the C-C=C-C torsion angle is -178.24 (18)°. In the mol-ecule, the planes of the terminal rings are twisted by an angle of 42.19 (10)°, while the biphenyl part is not planar, with a dihedral angle between the rings of 39.2 (1)°. The dihedral angle between the nitro-phenyl ring and the inner benzene ring is 5.56 (9)°. The 3-nitro group is approximately coplanar with the benzene ring to which it is attached [O-N-C-C = 0.1 (3)°]. In the crystal, mol-ecules are linked via C-H⋯π inter-actions, involving the terminal benzene rings, forming corrugated layers parallel to (100).


Advances in novel devices for the treatment of heart failure.
Heart failure (HF) is one of the leading causes of global health impairment. Current drugs are still limited in their effectiveness in the treatment and reversal of HF: for example, drugs for acute HF (AHF) help to reduce congestion and relieve symptoms, but they do little to improve survival; most conventional drugs for HF with preserved ejection fraction (HFpEF) do not improve the prognosis; and drugs have extremely limited effects on advanced HF. In recent years, progress in device therapies has bridged this gap to a certain extent. For example, the availability of the left ventricular assist device has brought new options to numerous advanced HF patients. In addition to this recognizable device, a range of promising novel devices with preclinical or clinical trial results are emerging that seek to treat or reverse HF by providing circulatory support, repairing structural abnormalities in the heart, or providing electrical stimulation. These devices may be useful for the treatment of HF. In this review, we summarized recent advances in novel devices for AHF, HFpEF, and HF with reduced ejection fraction (HFrEF) with the aim of providing a reference for clinical treatment and inspiration for novel device development.


A meta-analysis of randomized controlled trials of fixation versus nonfixation of mesh in laparoscopic total extraperitoneal inguinal hernia repair.
Mesh fixation during laparoscopic total extraperitoneal (TEP) inguinal hernia repair is still controversial. Although many surgeons considered it necessary to fix the mesh, some published studies supported elimination of mesh fixation. Therefore, a meta-analysis based on randomized controlled trials (RCTs) was conducted to compare the effectiveness and safety of fixation versus nonfixation of mesh in TEP. RCTs were identified from PubMed, Embase, the Cochrane Library, SCI, and the Chinese Biomedical Literature Database (CBM). Two reviewers assessed the quality of the studies and extracted data independently. The methodological quality was evaluated according to the Cochrane Handbook 5.0.2. Statistical analysis was conducted using the Cochrane software RevMan 5.0.21. Six RCTs involving 772 patients were included. The nonfixation group had advantages in length of hospital stay [MD =-0.37, 95% CI (-0.57, -0.17), p = 0.0003], operative time [MD = -4.19, 95% CI (-7.77, -0.61), p = 0.02], and costs. However, there was no statistically significant difference in hernia recurrence [OR = 2.01, 95% CI (0.37, 11.03), p = 0.42], time to return to normal activities [MD = -0.13, 95% CI (-0.45, 0.19), p = 0.43], seroma [OR = 1.25, 95% CI (0.30, 5.18), p = 0.75], and postoperative pain on postoperative day 1 [MD = -0.21, 95% CI (-0.52, 0.10), p = 0.18] and day 7 [MD = -0.11, 95% CI (-0.42, 0.20), p = 0.47]. Without increasing the risk of early hernia recurrence, the nonfixation of mesh in TEP appears to be a safe alternative that is associated with less costs, shorter operative time, and hospital stay for the selected patients. Further adequately powered RCTs are required to clarify whether mesh fixation is necessary for the patients with different types of hernias and larger hernia defects.