Herpes Zoster reactivation in patients with chronic hepatitis C under treatment with directly acting antiviral agents: A case series.
We report a series of cutaneous Herpes Zoster (HZ) reactivation cases in patients with hepatitis C virus (HCV) infection treated with directly acting antiviral (DAA) agents. Five cases were detected among 2133 treated patients with DAAs at one of the specialized viral hepatitis treatment centers in Egypt. A control group including 2300 age and sex matched HCV patients who were previously treated with pegylated interferon and ribavirin did not show any HZ reactivation reports while on treatment. None of cases had an evidence of immunosuppression or a risk factor for HZ reactivation. The DAAs used regimens were sofosbuvir/daclatasvir in 4 cases and sofosbuvir/simeprevir in one case. HCV clearance with antiviral therapy may bring immune changes causing reactivation of other latent viral infections like HZ. A high index of clinical suspicion may be needed to guarantee early and prompt management of such cases.


Motor primitives of pointing movements in a three-dimensional workspace.
A central question of motor control is how the motor system deals with redundant degrees of freedom. Redundancy can be reduced by coupling multiple degrees of freedom into a single motor primitive. Previous studies measuring motor primitives in aimed limb movements were restricted to two-dimensional target planes. We asked whether a limited number of motor primitives would also be sufficient to capture the posture variance of aimed limb movements in a three-dimensional target volume. To this end, participants had to point towards virtual targets uniformly spaced in a three-dimensional workspace. Results showed that three motor primitives captured 89.7 ± 2.8 % of the data variance of unrestrained pointing movements. Each motor primitive corresponded to a valid movement of the arm. The findings imply that complex postures in a three-dimensional target volume can be reduced to three motor primitives. The reduction results in a unique mapping of target position and posture and, thus, solves the redundancy problem. The reduction further indicates that, in a pointing task, the motor system does not control hand rotation independent of hand translation.


Ocular manifestations of renal ciliopathies.
Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina ( https://www.proteinatlas.org/humanproteome/tissue ) and for an ocular phenotype in mouse models ( http://www.informatics.jax.org/ ). Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. Diseases associated with pathogenic variants in ANK6, MAPKBP1, NEK8, and TCTN1 have no reported ocular manifestations, as well as low retinal expression and no ocular features in mouse models. Ocular abnormalities are not associated with the most common adult-onset "cystic" kidney diseases, namely, autosomal dominant (AD) polycystic kidney disease and the AD tubulointerstitial kidney diseases (ADTKD). However, other kidney syndromes with cysts have ocular features including papillorenal syndrome (optic disc dysplasia), Hereditary Angiopathy Nephropathy, Aneurysms and muscle Cramps (HANAC) (tortuous retinal vessels), tuberous sclerosis (retinal hamartomas), von Hippel-Lindau syndrome (retinal hemangiomas), and Alport syndrome (lenticonus, fleck retinopathy). Ocular abnormalities are associated with many pediatric-onset renal ciliopathies but are uncommon in adult-onset cystic kidney disease. However the demonstration of ocular manifestations may be helpful diagnostically and the features may require monitoring or treatment.


A stepwise retro-imino-ene as a key step in the mechanism of allene formation via the Crabbé acetylene homologation.
The mechanism of the acetylene homologation procedure accidentally discovered and further developed by Crabbé and coworkers is unknown. Kinetic isotope effect (KIE) experiments, however, suggest that an intramolecular hydrogen shift is the key step of the transformation. In this work, we present a computational study of this mechanism. We found that the reaction proceeds via an unexpected stepwise retro-imino-ene rearrangement. This mechanism justifies the role of Cu(I) as a reaction catalyst and is also compatible with the KIE experiments reported.


Simultaneous correction of Ca deficiency and acidosis in fasting obese patients as a prevention of bone demineralisation.
Short-term starvation in the obese induces metabolic acidosis and increased calciuria resulting in severe negative Ca balance. Oral administration of 5 g Ca-lactate daily is capable of correcting acidosis, reducing calciuria and providing the body with 650 mg Ca daily, thereby maintaining a positive Ca balance throughout the period of starvation. We therefore propose administering this amount of the preparation to obese individuals during starvation as a simple and cheap preventive measure against bone demineralisation.


CT image evaluation of one-screw fixation in the Latarjet procedure.
In the Latarjet procedure, two screws are used for secure fixation. However, when the graft is small, two-screw fixation is technically difficult. The purpose of this study was to evaluate the bone union of one-screw fixation on CT images. Ten shoulders with anterior recurrent dislocation underwent the open Latarjet procedure using one-screw fixation combined with arthroscopic Bankart repair. The bone union and the graft position were evaluated on CT images at 3, 6, and 12 months after the operation. Seven of 10 shoulders showed bone union at 3 months after the operation. In two shoulders, the removal of cortex was insufficient, and bone union was observed at 6 months. In one shoulder, the distal part of the graft was not in contact with the glenoid, and bone union was observed at 12 months. In one shoulder, the graft was healed in a 70-degree-rotated position. The average thickness of the graft was 7.2 ± 1.0 mm. One-screw fixation in the Latarjet procedure did not show non-union. Sufficient removal of the graft cortex and good contact were needed for early union.


Genomic characterization of Citrobacter freundii strains coproducing OXA-48 and VIM-1 carbapenemase enzymes isolated in leukemic patient in Spain.
The emergence of carbapenemase-producing (CP) Citrobacter freundii poses a significant threat to public health, especially in high-risk populations. In this study, whole genome sequencing was used to characterize the carbapenem resistance mechanism of three C. freundii clinical isolates recovered from fecal samples of patients with acute leukemia (AL) from Spain. Twelve fecal samples, collected between 2013 and 2015 from 9 patients with AL, were screened for the presence of CP strains by selecting them on MacConkey agar supplemented with ertapenem (0.5 mg/L). Bacteria were identified by MALDI-TOF mass spectrometry and were phenotypically characterized. Whole genome sequencing of C. freundii isolates was performed using the MinION and MiSeq Illumina sequencers. Bioinformatic analysis was performed in order to identify the molecular support of carbapenem resistance and to study the genetic environment of carbapenem resistance encoding genes. Three carbapenem-resistant C. freundii strains (imipenem MIC≥32 mg/L) corresponding to three different AL patients were isolated. Positive modified Carba NP test results suggested carbapenemase production. The genomes of each C. freundii tested were assembled into a single chromosomal contig and plasmids contig. In all the strains, the carbapenem resistance was due to the coproduction of OXA-48 and VIM-1 enzymes encoded by genes located on chromosome and on an IncHI2 plasmid, respectively. According to the MLST and the SNPs analysis, all strains belonged to the same clone ST169. We report in our study, the intestinal carrying of C. freundii clone ST169 coproducing OXA-48 and VIM-1 identified in leukemic patients.


Base-excision repair of oxidative DNA damage by DNA glycosylases.
Oxidative damage to DNA caused by free radicals and other oxidants generate base and sugar damage, strand breaks, clustered sites, tandem lesions and DNA-protein cross-links. Oxidative DNA damage is mainly repaired by base-excision repair in living cells with the involvement of DNA glycosylases in the first step and other enzymes in subsequent steps. DNA glycosylases remove modified bases from DNA, generating an apurinic/apyrimidinic (AP) site. Some of these enzymes that remove oxidatively modified DNA bases also possess AP-lyase activity to cleave DNA at AP sites. DNA glycosylases possess varying substrate specificities, and some of them exhibit cross-activity for removal of both pyrimidine- and purine-derived lesions. Most studies on substrate specificities and excision kinetics of DNA glycosylases were performed using oligonucleotides with a single modified base incorporated at a specific position. Other studies used high-molecular weight DNA containing multiple pyrimidine- and purine-derived lesions. In this case, substrate specificities and excision kinetics were found to be different from those observed with oligonucleotides. This paper reviews substrate specificities and excision kinetics of DNA glycosylases for removal of pyrimidine- and purine-derived lesions in high-molecular weight DNA.


Cervical cancer screening and vaccination: knowledge, awareness, and attitude of female staff in a Nigerian University.
Poor knowledge and awareness of cervical cancer screening and vaccination are significant barriers to effective cervical cancer prevention in developing countries. Knowledge of cervical cancer and vaccination against cervical cancer remains low in Nigeria. The purpose of this study was to assess the knowledge, awareness, and attitude of female staff of Afe Babalola University towards cervical cancer screening and vaccinations. This study was a cross-sectional study conducted using a semi-structured questionnaire among female staff of Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria. The workers' knowledge and awareness were assessed using yes and no questions while the attitude was assessed using Likert scale questions. The workers' knowledge was ranked as good (≥ 50%) and poor (< 50%) while attitude was ranked as positive (≥ 50%) and negative (< 50%). The relationship between demographics, attitude and knowledge of cervical cancer screening and vaccination was carried out using the Chi-square test. Analyses were conducted using SPSS software version 20. A total of 200 staff consented to participate in the study out of which 64% were married with mean age 32.81 ± 8.164 years. Majority (60.5%) of the participants knew the causes of cervical cancer while 7.5% strongly agreed that they do not see the need for cervical screening. Majority (63.5%) of the participants showed good knowledge while 46% had a positive attitude towards cervical cancer screening and vaccination. The study participants showed good knowledge and awareness but poor attitude towards cervical cancer screening and vaccinations. Interventions and continuous education are needed to improve the population's attitude and eliminate misconceptions.


Targeting EphA2 in cancer.
Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success. The present review briefly describes the contribution of EphA2-ephrin A1 signaling axis to carcinogenesis. In addition, the roles of EphA2 in resistance to molecular-targeted agents were examined. In particular, we focused on EphA2's potential as a target for cancer treatment to provide insights into the application of EphA2 targeting in anticancer strategies. Overall, EphA2 represents a potential target for treating malignant tumors.


Abnormal phosphorylation of Tie2/Akt/eNOS signaling pathway and decreased number or function of circulating endothelial progenitor cells in prehypertensive premenopausal women with diabetes mellitus.
The number and activity of circulating endothelial progenitor cells (EPCs) in prehypertension is preserved in premenopausal women. However, whether this favorable effect still exists in prehypertensive premenopausal women with diabetes is not clear. This study compared the number and functional activity of circulating EPCs in normotensive or prehypertensive premenopausal women without diabetes mellitus and normotensive or prehypertensive premenopausal women with diabetes mellitus, evaluated the vascular endothelial function in each groups, and investigated the possible underlying mechanism. We found that compared with normotensive premenopausal women, the number and function of circulating EPCs, as well as endothelial function evaluated by flow-mediated dilatation (FMD) in prehypertensive premenopausal women were preserved. In parallel, the Tie2/Akt/eNOS signaling pathway and the plasma NO level or NO secretion of circulating EPCs in prehypertensive premenopausal women was also retained. However, in presence of normotension or prehypertension with diabetes mellitus, the number or function of circulating EPCs and FMD in premenopausal women decreased. Similarly, the phosphorylation of Tie2/Akt/eNOS signaling pathway and the plasma NO level or NO secretion of circulating EPCs was reduced in prehypertension premenopausal with diabetes mellitus. The present findings firstly demonstrate that the unfavorable effects of diabetes mellitus on number and activity of circulating EPCs in prehypertension premenopausal women, which is at least partially related to the abnormal phosphorylation of Tie2/Akt/eNOS signaling pathway and subsequently reduced nitric oxide bioavailability. The Tie2/Akt/eNOS signaling pathway may be a potential target of vascular protection in prehypertensive premenopausal women with diabetes mellitus.


Differential effects of cartilage-derived growth factor stimulation of collagen secretion by bovine aortic and microvascular endothelial cells.
Cartilage-derived growth factor (CDGF), a protein closely related to basic fibroblast growth factor, is known to have both mitogenic and chemokinetic properties in microvascular endothelial cells (MVEC). Because of the angiogenic properties of CDGF and its rate in accelerating wound repair, the capacity of this factor to stimulate both proliferation and matrix synthesis was compared in distinct populations of vascular endothelial cells: MVEC from bovine adrenal cortex and macrovascular endothelial cells from the bovine aorta (BAEC). No significant differences in the responses to mitogenic stimulation using CDGF (5-100 units/ml) were observed using MVEC and BAEC. Only rapidly dividing MVEC, however, showed significant increases in collagen secretion in the presence of CDGF. The differential responsiveness of these two cell populations to a defined growth factor underscores the phenotypic diversity of endothelium.


Percutaneous penetration in the hairless dog, weanling pig and grafted athymic nude mouse: evaluation of models for predicting skin penetration in man.
The human skin grafted congenitally athymic (nude) mouse, pig skin grafted nude mouse, hairless dog, and weanling Yorkshire pig were evaluated as models for predicting skin penetration in man. Nine radiolabelled compounds previously tested on man were applied topically (4 micrograms/cm2) to each model. These compounds included caffeine, benzoic acid, N, N-diethyl-m-toluamide, three steroids, and three insecticides. To correct for incomplete excretion of the label following topical absorption, per cent penetration was calculated by dividing the per cent of the topically applied radioactive dose recovered in the excreta by the corresponding percentage after parenteral administration and multiplication by 100. Calculated values of per cent penetration were confirmed in the case of the grafted nude mouse because significant correlations (r = 0.78 for human skin grafted athymic nude mouse and r = 0.97 for pig skin grafted athymic nude mouse) were found between the calculated values and the actual values obtained by summing the radioactivity recovered in the urine, faeces, tissues, and carcass. The results also revealed a significant correlation between human skin grafted athymic nude mouse values and human values (r = 0.74, P = 0.05) and between weanling Yorkshire pig values and human values (r = 0.83, P = 0.05). In contrast, no significant correlation existed between human values and those of the hairless dog and the pig skin grafted athymic nude mouse.


An intensive care unit outbreak with multi-drug-resistant Pseudomonas aeruginosa - spotlight on sinks.
Pseudomonas aeruginosa and other Gram-negative bacteria have the ability to persist in moist environments in healthcare settings, but their spread from these areas can result in outbreaks of healthcare-associated infections. This study reports the investigation and containment of a multi-drug-resistant P. aeruginosa outbreak in three intensive care units of a Swiss university hospital. In total, 255 patients and 276 environmental samples were screened for the multi-drug-resistant P. aeruginosa outbreak strain. The environmental sampling and molecular characterization of patient and environmental strains, and control strategies implemented, including waterless patient care, are described. Between March and November 2019, the outbreak affected 29 patients. Environmental sampling detected the outbreak strain in nine samples of sink siphons of three different intensive care units with a common water sewage system, and on one gastroscope. Three weeks after replacement of the sink siphons, the outbreak strain re-grew in siphon-derived samples and newly affected patients were identified. The outbreak ceased after removal of all sinks in the proximity of patients and in medication preparation areas, and minimization of tap water use. Multi-locus sequence typing indicated clonality (sequence type 316) in 28/29 patient isolates and all 10 environmental samples. Sink removal combined with the introduction of waterless patient care terminated the multi-drug-resistant P. aeruginosa outbreak. Sinks in intensive care units may pose a risk for point source outbreaks with P. aeruginosa and other bacteria persisting in moist environments.


Conservative management of placenta praevia with a high risk of placenta accreta.
This case demonstrates that placenta praevia with a risk of placenta accreta can be managed conservatively with removal of the placenta once the serum beta human chorionic gonadotrophin level (beta HCG) is negative and there is absence of sonographically evident vascularity within the placenta.


Erectile and urinary function in men with rectal cancer treated by neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy alone: a randomized trial report.
The aim was to evaluate erectile and urinary function of male patients with rectal cancer treated by neoadjuvant (NA) chemoradiotherapy (CRT) or NA chemotherapy only. In this prospective randomized trial (ClinicalTrials.gov NCT01211210; "FOWARC"), we included 102 men who received NA therapy for stage II-III rectal cancer between January 2011 and June 2013. Before surgery, patients received either NA mFOLFOX6 chemotherapy with radiation (RCS group, n = 54) or NA mFOLFOX6 chemotherapy alone (CS group, n = 48). Erectile and urinary dysfunctions were assessed with the five-item International Index of Erectile Function (IIEF-5) scale and the International Prostatic Symptom Score (IPSS), respectively. Questionnaires were completed at baseline and at 3, 6, and 12 months (t0-t3, respectively) after surgery. At t3, mean IIEF-5 score was significant higher in the CS group (15.3 ± 5.5) than in the RCS group (12.6 ± 5.7; P < 0.05). And score difference was statistically higher in RCS group compared with CS group at t2 and t3, especially t3 (9.3 ± 5.5 vs. 6.1 ± 5.1, P < 0.01). Univariate analysis of the RCS group's IIEF-5 scores associated age, stoma, location, and tumor size to erectile dysfunction. However, mean IPSS scores did not differ between the two groups at any point. Compared with the CS group, erectile and urinary functions were significantly affected by NA CRT. Age, stoma, tumor location, and tumor size were also correlated with erectile dysfunction in the RCS group.


Voltage- and calcium-dependent inactivation in high voltage-gated Ca(2+) channels.
Calcium influx into cardiac myocytes via voltage-gated Ca channels is a key step in initiating the contractile response. During prolonged depolarizations, toxic Ca(2+) overload is prevented by channel inactivation occurring through two different processes identified by their primary trigger: voltage or intracellular Ca(2+). In physiological situations, cardiac L-type (Ca(V)1.2) Ca(2+) channels inactivate primarily via Ca(2+)-dependent inactivation (CDI), while neuronal P/Q (Ca(V)2.1) Ca(2+) channels use preferentially voltage-dependent inactivation (VDI). In certain situations however, these two types of channels have been shown to be able to inactivate by both processes. From a structural view point, the rearrangement occurring during CDI and VDI is not precisely known, but functional studies have underlined the role played by at least 2 channel sequences: a C-terminal binding site for the Ca(2+) sensor calmodulin, essential for CDI, and the loop connecting domains I and II, essential for VDI. The conserved regulation of VDI and CDI by the auxiliary channel beta subunit strongly suggests that these two mechanisms may use a set of common protein-protein interactions that are influenced by the auxiliary subunit. We will review our current knowledge of these interactions. New data are presented on L-P/Q (Ca(V)1.2/Ca(V)2.1) channel chimera that confirm the role of the I-II loop in VDI and CDI, and reveal some of the essential steps in Ca(2+) channel inactivation.


Membrane interiorization by phagocytosing macrophages--an ultrastructural morphometric approach.
Stereological methods have been used to quantify selected membrane compartments of normal and activated rat peritoneal macrophages, before and after phagocytosis of latex beads. Despite being rounder, activated cells are more efficient phagocytes: 30 min after latex challenge they suffer a greater nett depletion of plasma membrane and sequester more and larger phagocytic vacuoles. However, phagocytosis of latex is not the major route of membrane interiorization.


Medical and surgical characteristics of fusobacterium necrophorum mastoiditis in children.
To evaluate and compare characteristics of Fusobacterium necrophorum mastoiditis (FnM) to characteristics of acute mastoiditis (AM) caused by other bacteria in tertiary children hospital Methods : Children with FnM (N=43) and non FnM (N=88). Assess medical, microbiologic and imaging characteristics, surgical findings and postoperative recovery. Children with FnM had a positive history of otitis media, ear discharge and sub-periosteal abscess (p=0.0004, 0.09, 0.0003, respectively) at presentation. Their temperature, WBC and CRP were significantly higher (39.8 vs. 37.9, 19.4K vs. 16.1K, 21 vs. 8.7, p=0.0001). Positive culture was found in 46% of patients; 64% were diagnosed by PCR. CT scan was indicated in 95% and surgical intervention in 93% of children with FnM, compared to 15% and 9.7% of children in the non-FnM group (p=0.0001). Complex post-operative course was frequent for the FnM group: 88% of children had persistent fever, 46% had additional imaging and 14% additional surgical intervention. Children with FnM were treated with IV antibiotics for an average of 22 compared to seven days for non-FnM children (p=0.0001). Fusobacterium should be suspect in a child presenting with AM, a septic appearance, high fever and increased inflammation markers. A regimen of two antibiotics should be empirically started, then proceed to imaging and early surgical intervention. A relatively slow post-operative recovery process should be expected; however, prognosis is good.


Ag/Ag2SO3 plasmonic catalysts with high activity and stability for CO2 reduction with water vapor under visible light.
The conversion of CO2 into useful raw materials for fuels and chemicals by solar energy is described using a plasmonic photocatalyst comprised of Ag supported on Ag2SO3 (Ag/Ag2SO3) fabricated by a facile solid-state ion-exchange method and subsequent reduction with hydrazine hydrate. The optimum molar ratio of Ag(0)/Ag(+) was 5 %. Visible light irradiation (>400 nm) of the Ag/Ag2SO3 powder in the presence of CO2 and water vapor led to the formation of CH4 and CO with a quantum yield of 0.126 %, and an energy returned on energy invested of 0.156 %. The Ag/Ag2SO3 retained high catalytic activity after ten successive experimental cycles. The catalysts were characterized using X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy with energy-dispersive X-ray analysis, UV/Vis absorption spectroscopy, and Brunauer-Emmett-Teller analyses, as well as photocurrent action spectroscopy. It is proposed that the photocatalytic activity of the catalysts is initiated by energy conversion from incident photons to localized surface plasmon resonance oscillations of silver nanoparticles. This plasmonic energy is transferred to the Ag2SO3 by direct electron transfer and/or resonant energy transfer, causing the separation of photogenerated electron/hole pairs.


An oxidatively releasable caging group that senses lipid peroxidation.
A new radical-sensitive caging technique releases a caged molecule under lipid peroxidation conditions. In a competitive oxidation study with a model lipid, methyl linoleate, the oxidatively releasable xanthenyl caging groups is found to be 1.93+/-0.55 times more reactive than the lipid model compound.


Various factors contribute to graft extrusion in lateral meniscus allograft transplantation.
Lateral meniscus allograft transplantation (LMAT) is a feasible surgical option for young meniscus-deficient patients. Although several studies have explored the factors that contribute to graft extrusion, they have not been fully elucidated. The aim of this study was to determine the various factors that contribute to graft extrusion. Patients with knees that had received LMAT using a keyhole technique (n = 87 knees in 82 patients) were reviewed. The median age of these patients was 22 years (range 19-54 years), and the median postprocedural follow-up interval was 5 days (range 1-136 days). Twelve magnetic resonance imaging (MRI) measurement parameters (axial and coronal location of the bone block) that could potentially influence graft extrusion were evaluated, along with absolute graft extrusion and relative percentage of extrusion (RPE). A significant correlation was found between 8 of the 12 MRI measurement parameters and both the absolute extrusion and RPE (r = 0.241-0.438, p < 0.05). The absolute middle distance and depth of the bone block were independent predictors of the absolute extrusion (β = 0.30 and 0.15, respectively; p < 0.05), and the relative middle distance and relative bone-block elevation were found to be predictors of RPE (β = 2.29 and 1.44, respectively; p < 0.05). The rate of graft extrusions after LMAT was high in this study. Both the coronal and axial locations of the bone block were found to influence graft extrusion in LMAT. Therefore, correct positioning of the bone block, including in both the axial and coronal planes, is essential to minimize graft extrusion. Future studies need to investigate the long-term clinical outcome and longevity of extruded menisci after transplantation. Therapeutic case series, Level IV.


The separate and combined effects of alcohol and nicotine on anticipatory anxiety: a multidimensional analysis.
Individuals who smoke cigarettes are significantly more likely to smoke more when they drink alcohol. Indeed, smoking and drinking appear strongly linked, at both between- and within-person levels of analyses. Anecdotal evidence further suggests that alcohol consumption in combination with smoking cigarettes reduces anxiety, yet the mechanisms by which this may occur are not well understood. The current study assessed the separate and combined effects of alcohol and nicotine on self-reported and psychophysiological (startle eyeblink magnitude) indices of anxiety. Results indicated that alcohol provided anxiolytic benefits alone and in combination with nicotine, as evidenced by significant reductions in startle eyeblink magnitude. According to self-reported anxiety, alcohol and nicotine exerted a conjoint effect on diminishing increases in anxiety subsequent to a speech stressor. These data highlight the importance of studying both the separate and combined effects of these two widely used substances, as well as the advantages of employing a multimodal assessment of emotional response.


Role of transnasal flexible laryngo-oesophagoscopy (TNFLO) in investigating patients with globus symptoms.
To explore the rationale for investigating patients presenting with globus symptoms. In this regard, we also assess the efficacy and safety of transnasal flexible laryngo-oesophagoscopy (TNFLO). A prospective study in a head and neck cancer centre of patients with persistent globus symptoms with normal flexible nasoendoscopy/indirect mirror laryngoscopy and failure of first-line medical treatment. The role of TNFLO in investigating these patients was assessed. A total of 218 patients were recruited in this study. Positive findings included upper aerodigestive cancers in two patients, other pathologies included reflux (four patients), cricopharyngeus-related pathologies (19 patients), candida (five patients). There were only five re-referrals of patients who were discharged following normal examination with TNFLO. In nine patients, TNFLO could not be completed and they went on to have other diagnostic procedures CONCLUSION: This article is the largest to date in the UK to assess the role of TNFLO in investigating patients with globus symptoms. TNFLO is equal to rigid endoscopy as a diagnostic tool. However, it is superior in terms of image clarity, ability to record video images and safety.


Distal myopathy with coexisting heterozygous TIA1 and MYH7 Variants.
TIA1 mutations cause Welander distal myopathy. MYH7 mutations result in various clinical phenotypes, including Laing distal myopathy and cardiomyopathy. We describe a family with coexisting TIA1 and MYH7 variants. The proband is a 67-year-old woman with easy tripping since childhood and progressive asymmetric distal limb weakness, but no cardiac involvement. Muscle biopsy showed rare rimmed vacuoles, minicore-like structures and congophilic inclusions. Her 66-year-old sister has a mild distal myopathy, supraventricular tachycardia and hypertrophic cardiomyopathy. Both sisters carry the only known pathogenic TIA1 mutation and a heterozygous MYH7 variant (c.5459G > A; p.Arg1820Gln). Another sibling with isolated distal myopathy carries only the TIA1 mutation. MYH7 p.Arg1820Gln involves a highly conserved residue and is predicted to be deleterious. Furthermore, the proband's childhood-onset distal leg weakness and sister's cardiomyopathy suggest that MYH7 p.Arg1820Gln likely affects function, favoring a digenic etiology of the myopathy.


Lipids and the exocytotic machinery of eukaryotic cells.
The molecular machines that drive protein transport through the secretory pathway function exert their activities on the surfaces of membrane bilayers. It is now clear that the various lipid components of these bilayers play direct and versatile roles in modulating the activity of proteins that either themselves constitute core components of the membrane trafficking machinery, or represent proteins that regulate such core components.


Loureirin B promotes insulin secretion through GLP-1R and AKT/PDX1 pathways.
Loureirin B (LB), a natural product derived from Sanguis draconis, has hypoglycemic effects in diabetic mice. However, there are no studies on how LB lowers blood glucose. In this study, we first treated a diabetic model in mice with LB, and the results showed that LB lowered blood glucose and alleviated islet damage in mice. Next, Ins-1 cells were treated with LB. The results showed that LB could promote cell proliferation and reduce apoptosis of Ins-1 cells. Loureirin B (LB), a natural product derived from Sanguis draconis, has hypoglycemic effects in diabetic mice. However, there are no studies on how LB lowers blood glucose. In this study, we first treated mice with LB in a diabetic model and showed that LB lowered blood glucose and reduced islet damage in mice. Next, Ins-1 cells were treated with LB. The results showed that LB could promote cell proliferation and reduce apoptosis of Ins-1 cells. Further, after inhibiting GLP-1R activity, the results showed that LB promoted insulin secretion, Ins-1 cell proliferation and reduced Ins-1 cell apoptosis with reduced effect, indicating that LB achieved the above effects by activating GLP-1Ra. Meanwhile, cellular cAMP levels increased when GLP-1R was overexpressed, which also demonstrated the interaction between LB and GLP-1R. Subsequently, the effect of LB on cellular potassium channels was examined by membrane clamp, and the results showed that LB increased intracellular Ca2+ concentration and stimulated insulin secretion by activating GLP-1R and thus closing the ATP-sensitive potassium channels. On the other hand, the activation effect of LB on AKT/PDX1 signaling pathway was verified.


Localization of growth hormone-releasing factor-like immunoreactivity in the hypothalamo-hypophysial system of some teleost species.
An antiserum to growth hormone-releasing factor (GRF) 1-44 was applied on brain and pituitary sections of nine teleost species. Immunoreactive (ir) perikarya were demonstrated in parvo- and magnocellular portions of the preoptic nucleus (PON) and occasionally in the nucleus lateralis tuberis. The two tracts originating in the PON ran ventro-laterally toward the optic chiasm and then caudally in the basal hypothalamus. In the pars distalis (PD) of the eel, carp, goldfish and salmonids, GRF-ir fibers did not enter the rostral PD and few fibers passed close to somatotropes. In Myoxocephalus and Mugil, a variable number of ir-fibers passed close to cells of the rostral and proximal PD. In the neurointermediate lobe, GRF-ir fibers were located exclusively in the neural tissue of the eel and trout. In goldfish, carp and Myoxocephalus, GRF-ir fibers entered the intermediate lobe. This antiserum also labeled corticotrops and, to a lesser extent, melanotrops in the pituitary of cyprinids. A variable number of perikarya contained both GRF and vasotocin in the PON of the eel. In all teleost species studied so far, the distribution patterns of GRF are different, and the function of the various adenohypophysial cell types appears to be differently modulated, according to the variable distribution of GRF in the pituitary.


Survey on management strategies of rheumatoid arthritis in Saudi Arabia: a Saudi Society for Rheumatology Initiative.
Currently there are no national recommendation guidelines for the management of rheumatoid arthritis (RA) in Saudi Arabia, which has led to a lack of standard of care. The aim of this study is to explore RA management strategies in practicing rheumatologists in Saudi Arabia. A 38 questions survey was designed using an electronic website. The survey was distributed through the official email of the Saudi Society for Rheumatology. Rheumatologists with at least 1 year of experience were included. Descriptive analysis was used to report demographics and participants' answers. Chi-square and Fischer's exact test were used to evaluate the relation between the characteristics of participants and their answers. Out of 120 registered practicing adult rheumatologists, 54 (45%) completed the survey. The majority were male 31 (57.4%) and Saudis 36 (66.7%). Forty-two participants (77.8%) use clinical outcome measures in daily clinical practice to guide treatment decisions with the majority using the Disease Activity Score of 28 joints (61.1%). Quality of life measures were used by 22 (40.7%) participants with statistically significant male predominance (P = 0.043). Time consumption was the most important cause for not using any outcome measures. Thirteen (24.1%) and 17 (31.5%) participants do not use parenteral methotrexate and leflunomide, respectively, because of unavailability in the hospital formulary. Nine (16.7%) and 38 (70.37%) participants do not see a role for tofacitinib and biosimilars, respectively, in the management of RA. This survey has highlighted many areas of improvement in the practice of rheumatologists in Saudi Arabia and should be the focus of future educational activities.


Persistence or recurrence of non-psychotic comorbid mental disorders associated with 6-year poor functional outcomes in patients at ultra high risk for psychosis.
Patients at ultra-high risk for psychosis (UHR) are a highly heterogeneous group in terms of clinical and functional outcomes. Several non-psychotic mental disorders co-occur together with the UHR state. Little is known about the impact of non-psychotic comorbid mental disorders on clinical and functional outcomes of UHR patients. The sample included 154 UHR help-seeking patients (identified with the CAARMS, comprehensive assessment of the at-risk mental state), evaluated at baseline on the Ham-D, Ham-A (Hamilton depression/anxiety rating scale), and PANSS (positive and negative syndrome scale). 74 patients completed the 6-year follow-up assessment (mean=6.19, SD=1.87). Comorbid disorders at follow-up were assessed with the SCID I and II. Global functioning was rated on the global assessment of functioning (GAF) scale. In the present sample, 6-year risk of psychosis transition was 28.4%. Among non-transitioned UHR patients, 28.3% reported attenuated psychotic symptoms (APS) and 45.3% remained functionally impaired at follow-up (GAF<60). 56.8% patients were affected by at least one comorbid disorder at follow-up. Among UHR patients who presented with some comorbid disorder at baseline, 61.5% had persistent or recurrent course. Incident comorbid disorders emerged in 45.4% of baseline UHR patients. The persistence or recurrence of non-psychotic comorbid mental disorders was associated with poorer global functional outcomes at follow-up. A substantial proportion of the initial sample was not available for follow-up interviews and some groups in the analyses had small sample size. Predictors of longitudinal outcomes were not explored. Among UHR patients, persistence or recurrence of non-psychotic comorbid mental disorders, mostly affective disorders, is associated with 6-year poor functional outcomes.


Higher-order effects, continuous species interactions, and trait evolution shape microbial spatial dynamics.
The assembly and maintenance of microbial diversity in natural communities, despite the abundance of toxin-based antagonistic interactions, presents major challenges for biological understanding. A common framework for investigating such antagonistic interactions involves cyclic dominance games with pairwise interactions. The incorporation of higher-order interactions in such models permits increased levels of microbial diversity, especially in communities in which antibiotic-producing, sensitive, and resistant strains coexist. However, most such models involve a small number of discrete species, assume a notion of pure cyclic dominance, and focus on low mutation rate regimes, none of which well represent the highly interlinked, quickly evolving, and continuous nature of microbial phenotypic space. Here, we present an alternative vision of spatial dynamics for microbial communities based on antagonistic interactions-one in which a large number of species interact in continuous phenotypic space, are capable of rapid mutation, and engage in both direct and higher-order interactions mediated by production of and resistance to antibiotics. Focusing on toxin production, vulnerability, and inhibition among species, we observe highly divergent patterns of diversity and spatial community dynamics. We find that species interaction constraints (rather than mobility) best predict spatiotemporal disturbance regimes, whereas community formation time, mobility, and mutation size best explain patterns of diversity. We also report an intriguing relationship among community formation time, spatial disturbance regimes, and diversity dynamics. This relationship, which suggests that both higher-order interactions and rapid evolution are critical for the origin and maintenance of microbial diversity, has broad-ranging links to the maintenance of diversity in other systems.


Caring for Children in Immigrant Families: Vulnerabilities, Resilience, and Opportunities.
Demographics indicate that pediatricians increasingly care for children in immigrant families in routine practice. Although these children may be at risk for health disparities relating to socioeconomic disadvantage and cultural or linguistic challenges, immigrant families have unique strengths and potential for resilience. Adaptive and acculturation processes concerning health and well-being can be mediated by cultural media. Pediatricians have a professional responsibility to address the medical, mental health, and social needs of immigrant families. Advocacy and research at the practice level and beyond can further explore the unique needs of this population and evidence-based strategies for health promotion.


Dynamic ultrasonography of rotator cuff muscles.
To confirm the neuromuscular integrity of the rotator cuff and to investigate the effect of different contraction patterns on shoulder function, we sonographically analyzed dynamic contraction patterns of this muscle group. Fifty supra- and 50 infraspinatus muscle contraction patterns of patients with different shoulder pathologies examined with a 7.5-MHz transducer were recorded and saved as video files. Both data sets were analyzed by 3 independent observers who then assigned a grade to each contraction pattern: normal, slightly disturbed, severely disturbed, or no contraction. Intra- and inter-observer variations were calculated. In 43 patients with isolated supraspinatus tears, the clinical relation to shoulder function as measured with the Constant score was evaluated. In the 100 cases tested, the intraclass correlations for the 3 observers were 0.82, 0.88, and 0.88. The inter-observer reliability was 0.74. No pair of first and second readings for either the supraspinatus or infraspinatus muscle differed by more than 1 grade. In patients with a supraspinatus tear, the contraction type of the supraspinatus correlated significantly with the Constant score (p=0.02). When dynamic ultrasonography is used to assess the contraction patterns of the supra- and infraspinatus muscles, good intra- and inter-observer reliability is attained. Because a better contraction type correlates significantly with better shoulder function, this new diagnostic criterion may improve decision-making in the treatment of shoulder diseases.


Wagering the future: Cognitive distortions, impulsivity, delay discounting, and time perspective in adolescent gambling.
This study investigated the relationship of cognitive distortions, self-reported impulsivity, delay discounting, and time perspective to gambling severity in Italian adolescents. One thousand and thirty high school students were administered the South Oaks Gambling Screen Revised for Adolescents (SOGS-RA), the Gambling Related Cognitions Scale (GRCS), the Barratt Impulsiveness Scale (BIS-11), the Monetary Choice Questionnaire (MCQ), and the Consideration of Future Consequences Scale (CFC-14). A factor analysis, used to evaluate common factors assessed by the different measures, revealed a three-factor structure of Cognitive distortions, Impulsive present orientation, and Delay discounting. The results of regression analysis using factor scores showed that males scored higher than females on the SOGS-RA and that gambling severity correlated positively with high scores on the three factors. These results indicate that cognitive distortions associated with gambling are a powerful predictor of gambling severity, and that adolescent gamblers are impaired in their abilities to think about the future.


Characteristics of N400 component elicited in patients who have migraine with aura.
This study aimed to examine the N400 effect and event-related potentials (ERPs) elicited from congruent and incongruent stimuli in patients who have migraines with aura (MwA). A total of 33 MwA patients and 20 healthy controls (HCs) were studied. They were balanced in age (35.12 ± 8.94 vs 34.70 ± 9.59 years, p = 0.872) and sex (69.7 vs 75.0% females, p = 0.761). ERPs were measured in response to both stimuli, where pictures were preceded with an object name that either matched or mismatched with the object. Averaged amplitudes, peaks, peak latencies, difference waves and topography were compared between MwA and HCs. MwA patients had significantly lower averaged amplitudes at the Fz and F4 sites during incongruent stimuli, as well as reduced peaks at the C3 and Pz sites. Topography showed a more widespread N400 effect over scalp relative to HCs. The difference ERP waveforms did not differ in the N400 effect between groups, but the P600 effect was significantly stronger in the HCs group relative to the MwA group at the Pz (6.52 ± 2.57 vs. 3.50 ± 3.15, p = 0.001) and P4 (5.86 ± 2.79 vs. 3.95 ± 3.64, p = 0.040) sites. Picture-word matching tasks could serve as a potential new method for the investigation of semantic processing in MwA patients.


CD13/aminopeptidase N is a negative regulator of mast cell activation.
Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high-affinity receptors for IgE (FcεRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcεRI regulation is thus required. We have identified a functional interaction between FcεRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcεRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcεRI-dependent manner. These data are indicative of a functional interaction between FcεRI and CD13 on MCs. To determine the role of this interaction, CD13-deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen-dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 ± 0.6°C) and by CD13 deficiency (-8.8 ± 0.6°C) in contrast to controls (-1.2 ± 1.97°C). Importantly, bestatin does not aggravate anaphylaxis in CD13-deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo-Zotz, J. S., Wölbing, F., Lassnig, C., Kauffmann, M., Schulte, U., Kolb, A., Whitelaw, B., Müller, M., Biedermann, T., Huber, M. CD13/aminopeptidase N is a negative regulator of mast cell activation.


[A new case of the "double hypophysis--multiple congenital developmental defects" complex].
The results from clinical and genetic analysis of a case with "double hypophysis--multiple malformations" complex and data from literature are presented. The complex is supposed to be a consequence of "midline" field disturbance with multifactorial mode of inheritance.


Characterization of polyphosphoinositide-specific phospholipase C in rat parotid gland membranes.
Hydrolysis of exogenously added, [3H]inositol-labeled, phosphatidylinositol 4,5-bisphosphate (PIP2) by rat parotid membranes was increased, dose-dependently, by the muscarinic cholinergic agonist carbamylcholine (carbachol) in the presence of guanosine 5'-O-thiotriphosphate (GTP gamma S). The stimulation was inhibited by atropine and guanosine 5'-O-thiodiphosphate (GDP beta S). GTP gamma S alone stimulated PIP2 hydrolysis, with half-maximal activation at 0.1 microM. This was inhibited by GDP beta S but not by atropine. Agonist stimulation of PIP2 hydrolysis was dependent on the presence of lipids (phosphatidylserine:phosphatidylethanolamine:PIP2 = 1:1:1). When PIP2 was added as micelles with detergent (sodium deoxycholate) only, basal hydrolysis was elevated, thus decreasing the relative stimulation by GTP gamma S and carbachol. The water-soluble hydrolysis products formed under either condition were 1,4,5-inositol trisphosphate, 1,4-inositol bisphosphate, and cyclic inositol trisphosphate. Hydrolysis of exogenous phosphatidylinositol (PI) was also stimulated by carbachol in the presence of GTP gamma S but the extent of PI hydrolysis was 44-fold lower than PIP2 hydrolysis. When [Ca2+] in the medium was increased from 100 nM to 1 microM, basal hydrolysis of both PI and PIP2 increased (9.3- and 19.2-fold, respectively). However, levels of basal and stimulated PIP2 hydrolysis were higher (37.9- and 29.6-fold, respectively) than those of PI hydrolysis. Antibodies (both polyclonal and monoclonal) raised against phospholipase C (PLC beta 1) from bovine brain did not react with any component in either rat parotid membranes or cytosol, although a reactivity was detected in rat brain membranes. A monoclonal antibody against bovine brain PLC gamma 1 detected a approximately 150-kDa protein only in the parotid cytosol, while antisera against bovine brain PLC delta 1 enzyme showed no reactivity with parotid membranes or cytosol. Together, these observations suggest that while there appears to be a protein similar to bovine brain PLC gamma 1 in parotid gland cytosol, the PLC which mediates PIP2 hydrolysis in rat parotid membranes and can be regulated by the muscarinic receptor via a G-protein is distinct from the well-characterized PLC enzymes gamma 1, delta 1, and beta 1.


Visualization of spatiotemporal activation of Notch signaling: live monitoring and significance in neural development.
Notch signaling plays various key roles in cell fate determination during CNS development in a context-dependent fashion. However, its precise physiological role and the localization of its target cells remain unclear. To address this issue, we developed a new reporter system for assessing the RBP-J-mediated activation of Notch signaling target genes in living cells and tissues using a fluorescent protein Venus. Our reporter system revealed that Notch signaling is selectively activated in neurosphere-initiating multipotent neural stem cells in vitro and in radial glia in the embryonic forebrain in vivo. Furthermore, the activation of Notch signaling occurs during gliogenesis and is required in the early stage of astroglial development. Consistent with these findings, the persistent activation of Notch signaling inhibits the differentiation of GFAP-positive astrocytes. Thus, the development of our RBP-J-dependent live reporter system, which is activated upon Notch activation, together with a stage-dependent gain-of-function analysis allowed us to gain further insight into the complexity of Notch signaling in mammalian CNS development.


Pectus excavatum deformities simulating mediastinal masses.
Three patients with various pectus excavatum deformities in whom radiographic findings suggested hilar and mediastinal masses are presented. Computed tomography of the chest yielded valuable diagnostic information and made it possible to exclude the existence of these masses. Compression deformity of the heart and great vessels by the pectus deformity is the most likely explanation for these findings.


[Infection after long lasting procedure in neurosurgery].
A retrospective study was performed to appreciate the frequency of infectious complications following long duration neurosurgical procedure with or without antibiotic prophylaxis. Among the 6,702 surgical procedures studied 87 lasted more than 6 hours. The frequency of wound infections of those 87 patients was 13.8% whereas it was only 1.43% for the whole group. There was no significant statistical difference between patients who were treated with antibiotics and those who were not. The high frequency of infection by Klebsiella (25% of the identified germs) was caused by a contamination of the intensive care unit. Duration of the surgical procedure, synthetic material and repetitive procedures are important points to analyse when comparing the different publications. If any antibiotic prophylaxis is to be used, it must be adapted to the microbial environment of each care unit.


The calcaneo-stop procedure.
Flexible flatfoot is one of the most common deformities. Arthroereisis procedures are designed to correct this deformity. Among them, the calcaneo-stop is a procedure with both biomechanical and proprioceptive properties. It is designed for pediatric treatment. Results similar to endorthesis procedure are reported. Theoretically the procedure can be applied to adults if combined with other procedures to obtain a stable plantigrade foot, but medium-term follow up studies are missing.


Steady state free precession magnetization transfer imaging.
The formerly proposed concept for magnetization transfer imaging (MTI) using balanced steady-state free precession (SSFP) image acquisitions is in this work extended to nonbalanced protocols. This allows SSFP-based MTI of targets with high susceptibility variation (such as the musculoskeletal system), or at ultra-high magnetic fields (where balanced SSFP suffers from considerable off-resonance related image degradations). In the first part, SSFP-based MTI in human brain is analyzed based on magnetization transfer ratio (MTR) histograms. High correlations are observed among all different SSFP MTI protocols and thereby ensure proper conceptual extension to nonbalanced SSFP. The second part demonstrates SSFP-based MTI allowing fast acquisition of high resolution volumetric MTR data from human brain and cartilage at low (1.5T) to ultra-high (7.0T) magnetic fields.


Phase II study of nedaplatin and irinotecan followed by gefitinib for elderly patients with unresectable non-small cell lung cancer.
We conducted a phase II study of combination chemotherapy with nedaplatin (NP) and irinotecan (CPT) followed by gefitinib to determine the effects and toxicities in patients 70 years or older with unresectable non-small cell lung cancer (NSCLC). Eligible patients were entered to receive 3 courses of 50 mg/m(2) NP and 60 mg/m(2) CPT on days 1 and 8 every 4 weeks and sequential gefitinib 250 mg po once a day was followed until tumor progression. Twenty-eight patients received NP and CPT combination chemotherapy. One patient achieved CR, 10 PR, 14 SD and 3 PD, and the response rate was 39.3%. Twenty-one patients received gefitinib 250 mg per day until tumor progression after completion of the NP and CPT chemotherapy. Two patients with SD after NP and CPT chemotherapy achieved PR. For the 3-drug combination, there were 13 responders and the overall response rate was 42.9%. Of the toxicities associated with NP and CPT chemotherapy, grade 4 neutropenia, and grade 3 febrile neutropenia were observed in 24 (33.8%) and 3 (4.2%) courses, respectively. Of the toxicities associated with gefitinib treatment, grade 3 anemia, and SGOT and SGPT elevation were observed in one patient (4.8%) each, respectively. The median survival time was 8.7 months, and the 1- and 2-year survival rates were 42.9 and 32.1%, respectively. NP and CPT followed by gefitinib is feasible for elderly patients with unresectable NSCLC.


Improvement of Definite Diagnosis of Familial Hypercholesterolemia Using an Expanding Genetic Analysis.
The deeper understanding of the complex hereditary basis of familial hypercholesterolemia (FH) has raised the rationale of genetic testing, which has been underutilized in clinical practice. The present study aimed to explore the variant spectrum of FH in an expanding manner and compare its diagnostic performance. A total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable FH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of 9 genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8) including the evaluations of small-scale variants and large-scale copy number variants (CNVs). Among the 169 clinical FH patients included, 98 (58.0%) were men. A total of 85 (68.5%) index cases carried FH-associated variants. The proportion of FH caused by small-scale variants in LDLR, APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were further included. Furthermore, the variants in LDLR, APOB, and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were 8 non-LDLR CNVs detected in the present study. LDLR, APOB, and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic FH, suggesting that an expanding genetic testing may be considered to further explain phenotypic FH.


Delta hepatitis in inapparent carriers of hepatitis B surface antigen. A disease simulating acute hepatitis B progressive to chronicity.
Infection with the hepatitis B surface antigen (HBsAg)-associated delta agent (delta) was determined in a series of Italian patients with a diagnosis of acute hepatitis B (HBsAg-positive) progressive to chronicity. Twenty-two of 27 (81%) and 12 of 18 (67%) patients collected, respectively, in Naples and Cagliari, where delta is highly endemic, developed immunoglobulin M antibody to delta and/or rising titers of immunoglobulin G anti-delta during the initial acute phase of the disease. In each of them, anti-delta increased to a high-titered plateau indicative of chronic delta infection. Delta markers were found in none of the 13 patients collected in Siena, where the prevalence of delta infection is low. The great majority of the patients with anti-delta and a progressive form of HBsAg-positive hepatitis lacked the IgM antibody to hepatitis B core antigen. They were presumably unrecognized carriers of HBsAg who became infected by delta and developed hepatitis induced by this agent. In areas where delta is endemic, it may represent the true cause of seemingly type B hepatitis progressing to chronic HBsAg-positive liver disease.


Same as it ever was: Bird nest (a)symmetry?
A recent publication analyzing data collected by citizen scientists on the rufous hornero (Furnarius rufus) revealed consistent among-individual variation in nest asymmetry (left vs. right entrance). We summarize this result and discuss: (1) nest building as a useful model system to study different questions, and, (2) what the repeatability found in the featured paper could reveal regarding nest-building decisions.


Urinary excretion of 2, 3-dinor-6-keto prostaglandin F1 alpha and platelet thromboxane formation during ethanol withdrawal in alcoholics.
The excretion of 2,3-dinor-6-keto prostaglandin F1 alpha, a major urinary metabolite of prostacyclin, and the formation of thromboxane B2, a stable metabolite of thromboxane A2, by platelets stimulated by adenosine diphosphate, were studied in alcoholics, who had been admitted for detoxification. Once prolonged heavy drinking had stopped, platelet count and thromboxane formation, calculated either per 10(7) platelets or per litre of blood, significantly increased (p less than 0.05), while the skin bleeding time and urinary excretion of the metabolite of prostacyclin decreased (p less than 0.05). The balance between prostacyclin and thromboxane therefore seemed to favour the excretion of prostacyclin while it shifted to favour thromboxane formation about a week later.


A photonic frequency discriminator based on a two wavelength delayed self-heterodyne interferometer for low phase noise tunable micro/mm wave synthesis.
Low phase noise frequency synthesizers are of paramount interest in many areas of micro-mm wave technology, encompassing for example advanced wireless communication, radar, radio-astronomy, and precision instrumentation. Although this broad research field is not bereft of methods for the generation of either low phase noise micro- or mm waves, no universal system applicable to low phase noise generation for micro and mm waves has yet been demonstrated. Here we propose a new photonic frequency discriminator based on a two wavelength delayed self-heterodyne interferometer which is compatible with such an objective. The photonic frequency discriminator can be a reference both for micro and mm waves to lower their phase noise. As a proof-of-concept, we demonstrate a low phase noise tunable OEO (6-18 GHz) and locking of a heterodyne beat between two cw lasers (10-400 GHz) with low relative phase noise. The required components for the photonic frequency discriminator are off-the-shelf and can be readily assembled. We believe this new type of photonic frequency discriminator will enable a new generation of universal precision tunable sources for the X, K, V, W and mm-bands and beyond.


Bonding performance of experimental HEMA-free two-step universal adhesives to low C-factor flat dentin.
Experimental two-step universal adhesives (2-UAs) providing a particle-filled hydrophobic adhesive resin with a significant film thickness to hydrophobically seal the adhesive interface were designed and synthesized. This study aimed to characterize their interfacial interaction with dentin, to determine whether the 2-UA formulations achieve durable bonding to low C-factor flat dentin and to measure their water sorption. Bonding effectiveness of 2-UAs that combine a 10-MDP-based primer with hydrophobic adhesive resins differing only for filler (BZF-21, BZF-29, and BZF-29_hv) were comparatively investigated with the commercial adhesive Clearfil SE Bond 2 (C-SE2, Kuraray Noritake). Adhesive-dentin interfaces were characterized with TEM. Adhesive-resin disks were immersed in distilled water at 37 °C for 1 week, 6 months and 1 year to measure water sorption and solubility. 'Immediate' and 'aged' micro-tensile bond strength (μTBS) of the adhesives applied in etch-and-rinse (E&R) and self-etch (SE) bonding mode to low C-factor flat dentin were measured. Statistical analyses involved linear mixed-effects (LME) modelling and Kruskal-Wallis testing (p < 0.05). TEM revealed that E&R hybrid layers were more sensitive to aging than SE hybrid layers. Lower water sorption was recorded for all UAs compared with C-SE2. The immediate μTBS of BZF-21 and BZF-29 was not significantly different from that of C-SE2. The 1-year aged μTBS of all 2-UAs was significantly lower than that of C-SE2, except for BZF-29 applied in E&R mode. A significant reduction in μTBS upon 1-year aging was recorded for BZF-21 and BZF-29 applied in E&R mode. A significant difference in μTBS between E&R and SE bonding modes was recorded for all adhesives except BZF-21. Experimental 2-UAs with a hydrophobic adhesive-resin design produced± 20-μm thick adhesive-resin layers, absorbed less water and resulted in bonding performance that was more aging-resistant when applied in SE than in E&R bonding mode. The silica-filled BZF-29 2-UA revealed the most comparable bonding performance with C-SE2 in a low C-factor condition (flat dentin).


Cardiac allografts from high-risk donors: excellent clinical results.
Rising waiting list mortality and increasing demand for donor organs have led to extension of traditionally accepted criteria for evaluation of cardiac grafts. From December 1985 to June 1992, 188 cardiac grafts were orthotopically transplanted into 178 recipients. Of these grafts, 38.3% (72/188) were defined as high-risk donors. Risk criteria included prolonged cardiopulmonary resuscitation, age greater than 40 years, high inotrope requirements, undersizing by more than 20% body weight, significant wall motion impairment by echocardiography, elevation of myocardial enzyme levels, and cold ischemia time greater than 4 hours. There were no recipient deaths attributable to primary graft failure in the perioperative period. Operative (30-day), 1-year and 5-year survival was 95.5%, 86.1%, and 77.3%, respectively, in the high-risk group compared with 93.7%, 86.0%, and 67.2%, respectively, in the low-risk donor cohort (p = 0.94). Comparison of duration of postoperative inotrope use, intensive care unit stay, total hospital stay, and in-hospital costs revealed no significant trends favoring either group in postoperative morbidity. Among long-term survivors, development of graft coronary disease was noted in 47.1% (24/51) of the high-risk donor group and only 17.4% (12/69) of the remaining group (p = 0.0005). Left ventricular ejection fractions in the high risk donor group were 0.58 +/- 0.01 at 2 years. Review of this series suggests that selective use of apparently compromised cardiac donors is compatible with excellent cardiac function and survival. Higher incidence of graft vasculopathy may cause significant morbidity during late follow-up.


HIV-1 envelope glycoprotein trimers display open quaternary conformation when bound to the gp41 membrane-proximal external-region-directed broadly neutralizing antibody Z13e1.
We describe cryo-electron microscopic studies of the interaction between the ectodomain of the trimeric HIV-1 envelope glycoprotein (Env) and Z13e1, a broadly neutralizing antibody that targets the membrane-proximal external region (MPER) of the gp41 subunit. We show that Z13e1-bound Env displays an open quaternary conformation similar to the CD4-bound conformation. Our results support the idea that MPER-directed antibodies, such as Z13e1, block viral entry by interacting with Env at a step after CD4 activation.


Effects of montmorillonite on the adsorption of Fe(II) by ferrihydrite and its phase transformation at different pH.
Recently, there has been a clear understanding of the mechanism and influencing factors of ferrihydrite (Fh) phase transformation catalyzed by Fe(II); however, these factors mainly belong to environmental conditions and exogenous substances. And there is a lack of research on the effect of soil composition and structure on the phase transformation of Fh. Therefore, this study investigated the effects of montmorillonite (Mt) on the adsorption of Fe(II) and phase transformation of Fh under near-neutral pH. The initial rates ([Formula: see text]) of Elovich equation demonstrated the addition of Mt inhibited the adsorption of Fh but simultaneously accelerated the initial adsorption, thus increasing the adsorption of the system (e.g., 22.09-25.03 mg/g as increased Mt under pH 6.5) due to its high surface charge density. Increased pH enhances the surface charge density by promoting the deprotonation of the surface group (Fe-OH, Al-OH, and Si-OH) and consequently increases adsorption of Fe(II) (e.g., 17.97-22.09 mg/g as increased pH of pure Fh). Based on the previous method of extracting labile Fe(III), we found that pH promotes the initial formation of labile Fe(III) by increasing electron transfer and promoting recrystallization caused by bridging condensation, via increased -OH. Although Mt inhibits the adsorption of Fh, it promotes the formation of labile Fe(III) by increasing the system adsorption and bond with Fh. The results of the analysis of variance showed both pH and solid ratio influence significantly on the maximum adsorption (p = 6.81 × 10-9 and 2.54 × 10-3) and the conversion ratios of labile Fe(III) (p = 3.43 × 10-24 and 9.16 × 10-43).


Osteosclerotic lesions in sarcoidosis. Report of a case.
In a 36-year-old black American male, sarcoidosis produced multiple osteoblastic lesions instead of the lytic lesion characteristic of the disease.


Metal- and base-free reductive coupling reaction of P(O)-H with aryl/alkyl sulfonyl chlorides: a novel protocol for the construction of P-S-C bonds.
Novel and efficient synthesis of S-aryl/alkyl phosphinothioates from P(O)-H and aryl/alkyl sulfonyl chlorides under metal- and base-free conditions is described. This reaction provides an alternative strategy for the construction of P-S-C bonds in moderate to excellent yields. Moreover, this method can be readily applied to gram-scale preparation.


Esophageal motility disorders (distal esophageal spasm, nutcracker esophagus, and hypertensive lower esophageal sphincter): modern management.
The group of hypercontractile esophageal motility disorders includes distal esophageal spasm (DES), nutcracker esophagus (NE), and hypertensive lower esophageal sphincter (LES). The clinical relevance of these abnormalities identified during esophageal manometry is debated, and their management can be challenging. Hypercontractile esophageal motility abnormalities are defined through specific manometric criteria. Current pathophysiologic concepts for these abnormalities include defects in the nitronergic neural pathways and imbalances between the cholinergic and nitronergic pathway. Proposed treatments for NE, DES, and hypertensive LES include proton-pump inhibitors, nitrates, calcium channel blockers, phosphodiasterase inhibitors, and tricyclic antidepressants or serotonin reuptake inhibitors. Small case series reported benefits after botulinum toxin injections, dilatations, and myotomies. The optional management of esophageal spasm, NE, and hypertensive LES is still debated. Treatment recommendations are based on controlled studies with small numbers of patients or on case series. Medical treatment, including acid suppression, smooth muscle relaxants, and visceral analgesics, should be tried first. In nonresponding patients, botulinum toxin injections or balloon dilatations can be tried. Pneumatic dilatations or myotomies should be regarded as last-option treatments for nonresponding patients.


A new view of water dynamics in immobilized proteins.
The inflection frequency of the deuteron magnetic relaxation dispersion from water in rotationally immobilized protein samples has recently been found to be essentially independent of temperature and protein structure. This remarkable invariance has been interpreted in terms of a universal residence time of 1 microseconds for protein-associated water molecules. We demonstrate here that this interpretation is an artifact of the conventional perturbation theory of spin relaxation, which is not valid for rotationally immobile proteins. Using a newly developed non-perturbative, stochastic theory of spin relaxation, we identify the apparent correlation time of 1 microseconds with the inverse of the nuclear quadrupole frequency, thus explaining its invariance. The observed dispersion profiles are consistent with a broad distribution of residence times, spanning the microseconds range. Furthermore, we argue that the deuteron dispersion is due to buried water molecules rather than to the traditional surface hydration previously invoked, and that the contribution from rapidly exchanging protein hydrogens cannot be neglected. The conclusions of the present work are also relevant to proton relaxation in immobilized protein samples and to magnetic resonance imaging of soft tissue.


Methylprednisolone vs. dexamethasone in the prevention of postoperative nausea and vomiting: a prospective, randomised, double-blind, placebo-controlled trial.
Dexamethasone and methylprednisolone have been proven effective in the prevention of nausea after chemotherapy. Dexamethasone has been proven effective in the prophylaxis of late PONV. Literature about methylprednisolone in PONV prophylaxis is rare. We randomized 118 patients in a double blind way to receive either dexamethasone 8 mg, methylprednisolone 40 mg or placebo as prophylactic agent. Duration of anaesthesia was significantly longer and significantly more sufentanil was used in the methylprednisolone group. Despite these 2 risk factors, methylprednisolone was significantly better than placebo in the prevention of late nausea, retching and PONV. There was a beneficial clinical effect of dexamethasone in this population, although not significant. A possible explanation lies in the fact that monotherapy is mostly insufficient in a population at risk like ours. This study confirms that steroids are mostly effective in the prevention of late PONV, less effective in early PONV.


Efficacy of vonoprazan 10 mg compared with 20 mg for the initial treatment in patients with erosive esophagitis: a randomized pilot study.
The study aimed to investigate the efficacy of vonoprazan 10 mg compared with 20 mg in patients with erosive esophagitis. Seventy-three patients with erosive esophagitis were randomly divided into two groups either vonoprazan 20 mg (n = 37) or 10 mg (n = 36). They were administered each dose for 4 weeks as the initial treatment followed by maintenance treatment with 10 mg for 8 weeks. The primary endpoints were mucosal healing rate and symptom relief at 4 weeks. The secondary endpoint was symptom relief at 12 weeks after the maintenance treatment. Mucosal healing was assessed endoscopically, and symptom relief was assessed using the FSSG score. At 4 weeks, the endoscopic healing rates of the 20 mg and 10 mg groups were 94.6% and 94.4%, respectively. The FSSG scores of the 20 mg and 10 mg groups were significantly decreased in both treatment groups from 13 (4-39) to 4 (0-25) and 14 (4-40) to 3 (0-29), respectively. At 12 weeks, the scores further decreased to 2 (0-13) and 2 (0-26), respectively. The vonoprazan 10 mg group showed a similar therapeutic effect to the 20 mg group in mucosal healing at 4 weeks and in symptom relief throughout the study period. When stratified by esophagitis grading, these findings were still demonstrated in grade A/B patients but not in grade C/D patients. Our findings suggest that initial treatment with vonoprazan 10 mg might be useful especially in patients with mild erosive esophagitis. Large controlled studies are warranted to confirm our investigation.


A highly stretchable, UV resistant and underwater adhesive hydrogel based on xylan derivative for sensing.
Hydrogels with fascinating adhesion have been demonstrated great potential in various applications. However, most hydrogels lose their adhesion in wet or underwater environments due to the influence of interfacial water. Inspired by mussel, an underwater adhesive hydrogel was facilely fabricated by introducing electrostatic interactions, which consisted of poly (acrylic acid) (PAA), quaternized xylan (QAX) and tannic acid (TA). In this hydrogel, -COO- from PAA, -N+(CH3)3 from QAX and catechol group from TA resembled amino acids with negative and positive charges and 3,4-dihydroxyphenylalanine units in mussel, which endowed the hydrogels with great underwater adhesion through multiple interactions. Notably, acrylic acid (AA) played a key role in the dispersion of the system. QAX, a biomass derived from plants with excellent properties, worked with PAA to construct hydrogel networks. The resultant hydrogels exhibited excellent mechanical properties including remarkable stretchability (>4000 %) and compressibility. Moreover, the hydrogels had superior UV-blocking (~99.96 %), and showed good adhesion both in air and underwater. The hydrogels can be exploited as a wearable sensor to monitor human motions and even subtle motions, which have the potential to be explored in human health monitoring.


Exceptional high fatigue strength in Cu-15at.%Al alloy with moderate grain size.
It is commonly proposed that the fatigue strength can be enhanced by increasing the tensile strength, but this conclusion needs to be reconsidered according to our study. Here a recrystallized α-Cu-15at.%Al alloy with moderate grain size of 0.62 μm was fabricated by cold rolling and annealing, and this alloy achieved exceptional high fatigue strength of 280 MPa at 10(7) cycles. This value is much higher than the fatigue strength of 200 MPa for the nano-crystalline counterpart (0.04 μm in grain size) despite its higher tensile strength. The remarkable improvement of fatigue strength should be mainly attributed to the microstructure optimization, which helps achieve the reduction of initial damage and the dispersion of accumulated damage. A new strategy of "damage reduction" was then proposed for fatigue strength improvement, to supplement the former strengthening principle. The methods and strategies summarized in this work offer a general pathway for further improvement of fatigue strength, in order to ensure the long-term safety of structural materials.


LC-ESI-MS/MS on an ion trap for the determination of LSD, iso-LSD, nor-LSD and 2-oxo-3-hydroxy-LSD in blood, urine and vitreous humor.
A method has been developed for the simultaneous determination of lysergic acid diethylamide (LSD), its epimer iso-LSD, and its main metabolites nor-LSD and 2-oxo-3-hydroxy LSD in blood, urine, and, for the first time, vitreous humor samples. The method is based on liquid/liquid extraction and liquid chromatography-multiple mass spectrometry detection in an ion trap mass spectrometer, in positive ion electrospray ionization conditions. Five microliter of sample are injected and analysis time is 12 min. The method is specific, selective and sensitive, and achieves limits of quantification of 20 pg/ml for both LSD and nor-LSD in blood, urine, and vitreous humor. No significant interfering substance or ion suppression was identified for LSD, iso-LSD, and nor-LSD. The interassay reproducibilities for LSD at 20 pg/ml and 2 ng/ml in urine were 8.3 and 5.6%, respectively. Within-run precision using control samples at 20 pg/ml and 2 ng/ml was 6.9 and 3.9%. Mean recoveries of two concentrations spiked into drug free samples were in the range 60-107% in blood, 50-105% in urine, and 65-105% in vitreous humor. The method was successfully applied to the forensic determination of postmortem LSD levels in the biological fluids of a multi drug abuser; for the first time, LSD could be detected in vitreous humor.


Structural biology of NCAM homophilic binding and activation of FGFR.
In this review, we analyse the structural basis of the homophilic interactions of the neural cell adhesion molecule (NCAM) and the NCAM-mediated activation of the fibroblast growth factor receptor (FGFR). Recent structural evidence suggests that NCAM molecules form cis-dimers in the cell membrane through a high affinity interaction. These cis-dimers, in turn, mediate low affinity trans-interactions between cells via formation of either one- or two-dimensional 'zippers'. We provide evidence that FGFR is probably activated by NCAM very differently from the way by which it is activated by FGFs, reflecting the different conditions for NCAM-FGFR and FGF-FGFR interactions. The affinity of FGF for FGFR is approximately 10(6) times higher than that of NCAM for FGFR. Moreover, in the brain NCAM is constantly present on the cell surface in a concentration of about 50 microm, whereas FGFs only appear transiently in the extracellular environment and in concentrations in the nanomolar range. We discuss the structural basis for the regulation of NCAM-FGFR interactions by two molecular 'switches', polysialic acid (PSA) and adenosine triphosphate (ATP), which determine whether NCAM acts as a signalling or an adhesion molecule.


Hypergastrinemia is associated with adenocarcinomas in the gastric corpus and shorter patient survival.
Hypergastrinemia causes carcinoids or carcinomas in the gastric corpus in animal models. Helicobacter pylori (HP) infection in patients causes atrophy, hypergastrinemia and promotes gastric carcinogenesis. Many patients with gastric cancer have hypergastrinemia and it has therefore been hypothesized that hypergastrinemia promotes carcinogenesis. We have examined the associations between serum gastrin, the anatomical localization of gastric cancer, histological classification and patient survival. Patients with non-cardia gastric adenocarcinomas were included prospectively (n = 80). Tumour localization, histological classification according to Laurén and disease stage were recorded. Preoperative fasting serum gastrin was analysed by radioimmunoassay and HP serology by ELISA. Patient survival was determined after a median postoperative follow-up of 16.5 years. Hypergastrinemic patients had carcinomas located in the gastric corpus more often compared to normogastrinemic patients (81.8 vs 36.2%, p = 0.002). Patients with disease stage 2-4 and hypergastrinemia had shorter survival than normogastrinemic patients [5.0 (1.1-8.9) vs 10.0 (6.4-13.6) months (p = 0.04)]. There was no significant difference in serum gastrin or survival between patients with intestinal and diffuse type carcinomas. Hypergastrinemia was associated with adenocarcinomas in the gastric corpus and shorter survival. The findings support the hypothesis that hypergastrinemia promotes carcinogenesis and affects biological behaviour.


Quantification of T(2) relaxation changes in articular cartilage with in situ mechanical loading of the knee.
To devise a method for producing in vivo MRI images of the knee under physiologically significant loading, and to compare and evaluate the changes in cartilage characteristics before and during in situ compression of the knee. A total of 26 asymptomatic subjects were imaged on a 1.5 Tesla Philips Intera scanner using a commercially available knee coil. Routine anatomical images were followed by T(2) map acquisition. These scans were repeated following in situ compression of the knee using a MR compatible loading jig. Following loading to body weight, several regions of femoral cartilage show early alteration of T(2) relaxation time, most significantly in the medial and lateral peripheral zones. There were no significant changes in the tibial cartilage. The results establish the feasibility of measuring changes on MRI with in situ axial loading.


No Weekday Effect in Bariatric Surgery-a Retrospective Cohort Study.
Major abdominal surgery carried out in the later part of the week has been associated with increased complication rates. The aim of this study was to explore whether the weekday of surgery affects the 30-day complication risks after primary Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Prospectively collected data, extracted from the Scandinavian Obesity Surgery Registry (SOReg), of all patients who underwent primary laparoscopic RYGB or SG between 2010 and 2017 were included in this retrospective cohort study. Multivariate logistic regression adjusted for differences in case-mix and operating center by weekday of surgery. In total, 49,349 patients were included in this study. The overall 30-day complication rate was 7.2% (n = 3574), whereof 2.9% (n = 1428) had a severe complication, i.e., requiring intervention in general anesthesia or more. The 30-day mortality rate and readmission rate were 0.02% (n = 12) and 7.6% (n = 3726), respectively. The highest overall complication rate was seen in patients operated on Wednesdays and Thursdays (7.7%), while severe complications were most common on Wednesdays (3.3%). However, a large variation in severe complications was seen between centers, from 0.4 to 8.0%. After adjustment for case-mix and operating center, there was no significant increased risk of overall complications, severe complications, or readmission rates by weekday of surgery, except for a lower readmission rate in patients operated on Tuesdays. The result of the present study supports the notion that bariatric surgery can be performed safely on all weekdays.


Physicochemical properties of recombinant hepatitis B surface antigen expressed in mammalian cell (C127).
The physicochemical properties of recombinant hepatitis B surface antigen (r-HBsAg), which was expressed in C127 mammalian cell were studied. Using roller bottle culture in DMEM supplemented with fetal bovine serum, 10-15 mg/L of r-HBsAg was produced with about 31% of purification yield. The purity of r-HBsAg by HPLC was 99.8% and electron microscopic examination showed homogeneous spherical particle with 22 nm in diameter, a morphological characteristic of HBsAg. The density of r-HBsAg by CsCl density gradient method was 1.19 g/ml and the isoelectric point by Mono P HR 5/20 column was 4.6. The analysis of subunit protein pattern using SDS-PAGE followed by scanning densitometry gave 81.3% of S protein and 18.7% of pre-S protein. Fluorophore-assisted-carbohydrate-electrophoresis analysis showed the relative amount of carbohydrate to protein was 1.7% and its major component was N-acetyl glucosamine, which was about 39% of total carbohydrate. The relative amount of lipid to protein determined by vanillin phosphoric acid method was 32.5% and its major component was phospholipid, which was about 70% of total lipid. The physicochemical properties of C127 mammalian cell-derived r-HBsAg are similar to those of p-HBsAg, suggesting that the r-HBsAg can be used in developing a new preventive vaccine against hepatitis B.


A novel shape representation of the dental arch and its applications in some dentistry problems.
Standardized digital images of maxillary dental casts of 47 subjects were analyzed using MATLAB software whereby the two hamular notches and the incisive papilla defines the Cartesian vertical and horizontal axes, as well as the origin. The angle and length of the midpoints of the anterior teeth, mesiobuccal and distobuccal cusp of the posterior teeth were measured from the origin and denoted as θ(1), …, θ(18) and l(1), …, l(18) respectively. These values were collectively used to represent the shape of each dental cast. Clustering and principal component analyses were employed to find possible groups of dental arches using the above measure of shape. The main result of this study is that the 3 groups of dental arch shape may be represented by the novel feature vector v(k) = (θ(k)(1), l(k)(1), θ(k)(3), l(k)(3), θ(k)(5), l(k)(5), θ(k)(13), l(k)(13)), k = 1, 2, 3. Knowledge of v(k) implies three impression trays should be sufficient in a particular prosthetic dentistry application for Malaysian patients. Further, given that v(k) are accurately measured they may be potential candidates as evidence in specific application of forensic dentistry.


Gold and silver nanoparticles functionalized with 4',7-dihydroxyflavone exhibit activity against Leishmania donovani.
Leishmaniasis is a neglected tropical disease that has been burdening the world for over a century. Though there are drugs to treat leishmaniasis, the repertoire suffers several drawbacks like toxicity and low therapeutic value. Therefore, there is a rising concern to develop new anti-leishmanial strategies. In this study, we report, for the first time, the one-pot synthesis method and functionalization of gold and silver nanoparticles with 4',7-dihydroxyflavone (Au-47DHF and Ag-47DHF)) and their anti-leishmanial activity. Oval and spherical-shaped Au-47DHF nanoparticles were obtained with an average size of 5.8 ± 0.1 nm and while synthesized dodecahedron-shaped Ag-47DHF had an average size of 25.1 ± 1 nm. The zeta potential of Au-47DHF and Ag-47DHF were measured to be stable with values of 40 mV and 60 mV, respectively. The functionalization of nanoparticles with 4',7-dihydroxyflavone was confirmed by FTIR spectra. Both Au-47DHF and Ag-47DHF exhibited promising anti-leishmanial activity against the promastigote forms with IC50 values of 0.1226 ± 0.02 µg/ml and 0.8483 ± 0.14 µg/ml, respectively. The nanoparticles were also capable of anti-intracellular amastigote activity with 0.121 ± 0.36 µg/ml and 0.215 ± 0.85 µg/ml for Au-47DHF and Ag-47DHF, respectively. Interestingly, the treatment with Au-47DHF and Ag-47DHF nanoparticles generated high ROS concentrations in the parasites suggesting a ROS-mediated anti-leishmanial activity of Au-47DHF and Ag-47DHF. Concluding from the results, we present here a novel synthesis method of Au-47DHF and Ag-47DHF nanoparticles that have immense potential to be anti-leishmanial agents.


Virtual volunteers: the importance of restructuring medical volunteering during the COVID-19 pandemic.
Healthcare systems have postponed medical volunteering services in response to the COVID-19 pandemic. However, much of the aid provided by these volunteers is crucial to patient care and hospital functioning in the American healthcare system. The adoption of online video conferencing platforms in healthcare-telehealth-offers a novel solution for volunteering during this pandemic. Virtual volunteering can alleviate pressures on medical workers, enhance patient experiences, reduce the risk of viral infection and provide a sense of normalcy for patients and families. Although further study is required, this should be an avenue considered by health systems.


Malignant vesical tumors following spinal cord injury.
We present 11 male patients with spinal cord injury and neurogenic bladder disease in whom malignant vesical tumors developed. The incidence of these tumors in our spinal cord injury unit was 2.3 per cent. We investigated retrospectively the clinical, endoscopic and radiographic diagnoses, and analyzed the treatment. The most common presenting symptoms were recurrent urinary infections, hematuria and stone disease. Two patients presented with abdominal symptomatology (a large abdominopelvic mass and peritonitis). Endoscopic evaluation was nonspecific in 8 patients (72 per cent). Squamous cell carcinoma was present in 9 patients (81 per cent). One patient had pure transitional cell carcinoma, and 1 had mixed squamous and transitional cell cancer. Cytology was of no value in these patients. The presence of local invasion and bulky disease suggests that ultrasonography or computerized tomography of the abdomen and pelvis should be included during followup. Radical cystoprostatectomy with pelvic lymphadenectomy is the recommended therapy for localized disease. The presence of active or recurrent urethral disease in 55 per cent of the patients indicated that urethrectomy also should be performed.


The role of the calcitonin receptor in protecting against induced hypercalcemia is mediated via its actions in osteoclasts to inhibit bone resorption.
Despite the therapeutic value of calcitonin in treating bone disease, a biological role of endogenous calcitonin is controversial. Having previously demonstrated that the CTR has a biological role in protecting against calcium stress using a global CTRKO mouse model, the purpose of this study was to determine whether the protection conferred by the CTR during induced hypercalcemia is mediated via CTR expression on osteoclasts. Mice were generated, in which the CTR was deleted specifically within osteoclasts (OCL-CTRKOs) and compared with mice in which the CTR was deleted globally (global CTRKOs). Significantly, peak serum calcium levels following induced hypercalcemia were >18% higher in global-CTRKOs and OCL-CTRKOs than controls (P<0.01) due to increased bone resorption (P<0.05). Peak serum calcium levels relative to controls were greater in global-CTRKO males than OCL-CTRKO males (P<0.001), which may, at least in part, be due to increased reabsorption of calcium in the kidney (P<0.01). Controls for all analyses were sex-matched littermates with normal CTR expression. In conclusion, the CTR protects against hypercalcemia predominantly via its inhibitory action on osteoclasts.


Responsive Fluorescent PNA Analogue as a Tool for Detecting G-quadruplex Motifs of Oncogenes and Activity of Toxic Ribosome-Inactivating Proteins.
Fluorescent oligomers that are resistant to enzymatic degradation and report their binding to target oligonucleotides (ONs) by changes in fluorescence properties are highly useful in developing nucleic-acid-based diagnostic tools and therapeutic strategies. Here, we describe the synthesis and photophysical characterization of fluorescent peptide nucleic acid (PNA) building blocks made of microenvironment-sensitive 5-(benzofuran-2-yl)- and 5-(benzothiophen-2-yl)-uracil cores. The emissive monomers, when incorporated into PNA oligomers and hybridized to complementary ONs, are minimally perturbing and are highly sensitive to their neighboring base environment. In particular, benzothiophene-modified PNA reports the hybridization process with significant enhancement in fluorescence intensity, even when placed in the vicinity of guanine residues, which often quench fluorescence. This feature was used in the turn-on detection of G-quadruplex-forming promoter DNA sequences of human proto-oncogenes (c-myc and c-kit). Furthermore, the ability of benzothiophene-modified PNA oligomer to report the presence of an abasic site in RNA enabled us to develop a simple fluorescence hybridization assay to detect and estimate the depurination activity of ribosome-inactivating protein toxins. Our results demonstrate that this approach with responsive PNA probes will provide new opportunities to develop robust tools to study nucleic acids.


Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides.
Preclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches. dKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8 - 11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals. Nucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy. Our results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype. This work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


[Study on human leukocyte antigen G1 reducing xeno-cell-rejection by transfecting porcine endothelial cells].
To study whether the porcine endothelial cells (PECs) lines transfected by HLA-G1 can alter the lysis mediated by human peripheral blood mononuclear cell (PBMC) and natural killer cell 92 (NK-92). By use of liposomes pack, the pcDNA3. 0 eukaryotic expression vector carrying HLA-G1 was transfected into PECs. Using indirect immunofluorescence and RT-PCR assays, the HLA-G1 expression in PECs was detected. The alteration of the lysis mediated by PBMC and NK-92 was detected by 51Cr-release assays. HLA-G1 expression could be detected in PECs after transfection of HLA-G1 at the levels of protein and RNA. It also could be found that the survival rate of transfected PECs was much higher than that of non-transfected PECs, when both of them faced the lysis mediated by human PBMC and NK-92. After transfecting the expression of HLA-G1 could be found in the transfected PECs and the lysis mediated by PBMC and NK-92 to PECs decreased obviously (P<0.05). The PECs transfected by HLA-G1 can decrease the NK lysis, so that it may provide us a new thought to inhibit the xeno-cell-rejection.


Factors of quality of care and their association with smartphone based PHR adoption in South Korean hospitals.
Healthcare organizations have begun to adopt personal health records (PHR) systems to engage patients, but little is known about factors associated with the adoption of PHR systems at an organizational level. The objective of this study is to investigate factors associated with healthcare organizations' adoption of PHR systems in South Korea. The units of analysis were hospitals with more than 100 beds. Study data of 313 hospitals were collected from May 1 to June 30, 2020. The PHR adoption status for each hospital was collected from PHR vendors and online searches. Adoption was then confirmed by downloading the hospital's PHR app and the PHR app was examined to ascertain its available functions. One major outcome variable was PHR adoption status at hospital level. Data were analysed by logistic regressions using SAS 9.4 version. Out of 313 hospitals, 103 (32.9%) hospitals adopted PHR systems. The nurse-patient ratio was significantly associated with PHR adoption (OR 0.758; 0.624 to 0.920, p = 0.005). The number of health information management staff was associated with PHR adoption (OR 1.622; 1.228 to 2.141, p = 0.001). The number of CTs was positively associated with PHR adoption (OR 5.346; 1.962 to 14.568, p = 0.001). Among the hospital characteristics, the number of beds was significantly related with PHR adoption in the model of standard of nursing care (OR 1.003; 1.001 to 1.005, p < 0.001), HIM staff (OR 1.004; 1.002 to 1.006, p < 0.001), and technological infrastructure (OR 1.050; 1.003 to 1.006, p < 0.001). One-third of study hospitals had adopted PHR systems. Standard of nursing care as well as information technology infrastructure in terms of human resources for health information management and advanced technologies were significantly associated with adoption of PHR systems. A favourable environment for adopting new technologies in general may be associated with the adoption and use of PHR systems.