Proctoclysis for rehydration in children - A scoping review and a pilot survey among medical doctors.
Although proctoclysis (enema) is a historically proven, safe and cost-effective rehydration method that needs little training for users and can effectively replace intravenous hydration in different care settings, it is an uncommon choice for hydration in children with fever and is often missing in official guidelines. To evaluate the usefulness of proctoclysis, this study provides a scoping review of the existing literature. The matched literature was labelled in 5 categories, identifying 6 indication fields that are emphasized in the literature on rectal rehydration. The analysis showed that proctoclysis is mostly used in the context of diagnostic procedures, constipation or in the treatment of a gastrointestinal disease. It is also described as a quick, safe and cost-effective intervention for fluid replacement in emergency, critical care or resource-scarce settings. There are also socio-cultural variations in its use Additionally, we performed a survey on attitudes and experience of medical doctors towards proctoclysis based on a semi-structured questionnaire. In the survey, we analysed the experience of 35 medical doctors from 8 countries. Although we found a general acceptance of enema as beneficial in both hospitalized patients and in home care, doctors expressed the need for more experience with enema and the need for more education materials in order to effectively perform the procedure. Based on our findings, we suggest that further research is necessary examining the attitude towards proctoclysis among parents, nurses and doctors. Enema can have a considerable clinical advantage during home care for gastroenteritis or other infectious diseases with fever to prevent insufficient oral fluid intake resulting in a negative fluid balance. Risks and safety issues are rare and should be considered. However, due to its low level of social acceptability in order to reduce refusal rate, more education is necessary for both medical providers and parents.


Comparative sequence analysis of the large polymerase protein (L) gene of peste-des-petits ruminants (PPR) vaccine virus of Indian origin.
The complete nucleotide sequence of the large polymerase (L) protein of the peste-des-petits ruminants (PPR) vaccine virus (PPRV Sungri/96) belonging to the Asian lineage was determined. The gene was 6643 nucleotides in length from the gene-start to the gene-end and encoded a polypeptide of 2183 amino acids. The PPRV Sungri/96 has a nucleotide homology of 94.1% for PPRV Nigeria 75/1 to 64.4% for Canine distemper virus. At amino acid level PPRV Sungri/96 has an amino acid identity of 96.2% with PPRV Nigeria 75/1 and 70.4% to 74.8% with other morbilliviruses. All the established domains in L protein characteristic of paramyxoviruses were also found to be present in PPRV Sungri/96. Phylogenetic analysis of different L proteins of morbilliviruses revealed five well-defined clusters as observed previously. The 3' trailer sequence of PPRV Sungri/96 is of 37 nucleotides long which is very similar to that of other morbilliviruses. To the best of our knowledge this is the first report describing the polymerase gene sequence of PPRV Indian isolate.


Angiotensin-(1-7) protects from experimental acute lung injury.
Recently, recombinant angiotensin-converting enzyme 2 was shown to protect mice from acute lung injury, an effect attributed to reduced bioavailability of angiotensin II. Since angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7), we hypothesized that this effect is alternatively mediated by angiotensin-(1-7) and activation of its receptor(s). To test this hypothesis, we investigated the effects of intravenously infused angiotensin-(1-7) in three experimental models of acute lung injury. Animal research laboratory. Male Sprague-Dawley rats, Balb/c mice, and C57Bl6/J mice. Angiotensin-(1-7) was administered with ventilator- or acid aspiration-induced lung injury in mice or 30 minutes after oleic acid infusion in rats. In vitro, the effect of angiotensin-(1-7) on transendothelial electrical resistance of human pulmonary microvascular endothelial cells was analyzed. Infusion of angiotensin-(1-7) starting 30 minutes after oleic acid administration protected rats from acute lung injury as evident by reduced lung edema, myeloperoxidase activity, histological lung injury score, and pulmonary vascular resistance while systemic arterial pressure was stabilized. Such effects were largely reproduced by the nonpeptidic angiotensin-(1-7) analog AVE0991. Infusion of angiotensin-(1-7) was equally protective in murine models of ventilator- or acid aspiration-induced lung injury. In the oleic acid model, the two distinct angiotensin-(1-7) receptor blockers A779 and D-Pro-angiotensin-(1-7) reversed the normalizing effects of angiotensin-(1-7) on systemic and pulmonary hemodynamics, but only D-Pro-angiotensin-(1-7) blocked the protection from lung edema and protein leak, whereas A779 restored the infiltration of neutrophils. Rats were also protected from acute lung injury by the AT1 antagonist irbesartan; however, this effect was again blocked by A779 and D-Pro-angiotensin-(1-7). In vitro, angiotensin-(1-7) protected pulmonary microvascular endothelial cells from thrombin-induced barrier failure, yet D-Pro-angiotensin-(1-7) or NO synthase inhibition blocked this effect. Angiotensin-(1-7) or its analogs attenuate the key features of acute lung injury and may present a promising therapeutic strategy for the treatment of this disease.


Ovulation induction is associated with altered growth but with preservation of normal metabolic function in murine offspring.
To study the effects of ovulation induction on mouse postnatal health, with a focus on growth pattern and glucose tolerance. To study the effect of ovulation induction on DNA methylation, we took advantage of the agouti viable yellow (Avy) mouse. Animal study. University Setting. Agouti viable yellow (Avy) mice on a C57BL/6 background. Avy female mice were either allowed to mate spontaneously (control group, C) or after superovulation with 5 IU of PMSG and hCG (ovulation induction group, OI). Birth parameters and postnatal growth of the offspring were followed up to 29 weeks of age. Body composition analysis was performed by EchoMRI; fasting insulin, intraperitoneal glucose tolerance tests, and glucose-stimulated insulin secretion by beta cells were assessed to study glucose metabolism. Mice born to superovulated dams had lower survival rates, shorter anogenital distances, and shorter crown-rump lengths. Female mice generated by OI weighed less at birth, whereas male mice generated by OI had lower weight gain and had reduced lean mass. Glucose parameters, including islet functions, did not differ between the groups. No difference in agouti coat color was noted between the groups. Ovulation induction resulted in mice having increased morphometric differences at birth and male mice showing reduced weight gain but no difference in glucose tolerance or agouti coat color.


Scanning Laser Ophthalmoscopy Demonstrates Disc and Peripapillary Strain During Horizontal Eye Rotation in Adults.
We used automated image analysis of scanning laser ophthalmoscopy (SLO) to investigate mechanical strains imposed on disc, and retinal and choroidal vessels during horizontal duction in adults. Deep learning analysis of optical images. The peripapillary region was imaged by SLO in central gaze, and 35° abduction and adduction, in younger and older healthy adults. Automated image registration was followed by deep learning-based optical flow analysis to track determine local tissue deformations quantified as horizontal, vertical, and shear strain maps relative to central gaze. Choroidal vessel displacements were observed when fundus pigment was light. Strains in the retina and disc could be quantified in 22 younger (mean ± SEM, 26 ± 5 years) and 19 older (64 ± 10 years) healthy volunteers. Strains were predominantly horizontal and greater for adduction than for abduction. During adduction, maximum horizontal strain was tensile in the nasal hemi-disc, and declined progressively with distance from it. Strain in the temporal hemi-retina during adduction was minimal, except for compressive strain on the disc of older subjects. In abduction, horizontal strains were less and largely confined to the disc, greater in older subjects, and generally tensile. Vertical and shear strains were small. Nasal to the disc, choroidal vessels shifted nasally relative to overlying peripapillary retinal vessels. Strain analysis during horizontal duction suggests that the optic nerve displaces the optic canal, choroid, and peripapillary sclera relative to the overlying disc and retina. This peripapillary shearing of the optic nerve relative to the choroid and sclera may be a driver of disc tilting and peripapillary atrophy.


Autoantibodies to the core proteins of hnRNPs.
A novel autoantibody reacting the the core polypeptides of hnRNP particles has been detected in the serum of a patient with systemic lupus erythematosus (SLE) and Sjögren's syndrome manifestations. Immunoblot analysis, using either rat liver or HeLa nuclear extracts as the antigen source, demonstrated that the autoantibody interacts with a specific subgroup of the core polypeptides of hnRNP particles, namely A2, B1 and B2, but not with A1, C1 and C2.


EFFECT OF PEGAPTANIB AND RANIBIZUMAB ON PLASMA AND VITREOUS HOMOCYSTEINE IN PATIENTS WITH EXUDATIVE AGE-RELATED MACULAR DEGENERATION.
To investigate homocysteine (Hcy) concentration in the blood plasma and the vitreous in patients with exudative age-related macular degeneration receiving intravitreal anti-vascular endothelial growth factor therapy. Plasma Hcy and vitreous Hcy levels were analyzed in 73 exudative age-related macular degeneration patients (50.7% received pegaptanib 0.3 mg and 50.3% received ranibizumab 0.5 mg) and compared with 80 controls and 40 patients with idiopathic epiretinal membranes, respectively. Homocysteine concentration was measured by immunonephelometric particle test, and it was determined before and after antiangiogenic therapy. The mean Hcy concentrations (± SD) of blood plasma and vitreous were 13.0 ± 4.2 μmol/L and 1.00 ± 0.3 μmol/L in patients treated with pegaptanib; in ranibizumab group, they were 12.8 ± 2.5 μmol/L and 1.4 ± 0.6 μmol/L, respectively. The results of plasma and vitreous Hcy indicated statistically significant differences between exudative age-related macular degeneration patients and control groups (P = 0.03 and P = 0.02). After 6 months with both intravitreal therapies, the plasma and vitreous Hcy concentrations did not change significantly (P = 0.1). Pegaptanib and ranibizumab did not increase the plasma or vitreous Hcy concentrations.


Parent's risk preference and childhood vaccination: evidence from Indonesia.
A vaccines advisory group to the World Health Organization (WHO) identified complacency, inconvenience in accessing vaccines, and lack of confidence as key reasons for hesitancy. In childhood vaccination, the decision to take a vaccine relies on parents' decisions. Our study explored the relationship between parents' risk aversion and complete childhood vaccination status to identify whether demand contributes to vaccine hesitancy in Indonesia. We examined risk aversion using data from the fifth-wave Indonesian Family Life Survey (IFLS), focusing on parents with extreme risk aversion or fear of uncertainty. The logistic regression shows a negligible relationship between parents' risk aversion and childhood vaccination; nevertheless, parents who fear uncertainty tend to avoid vaccination. The results of this study encourage public health professionals and policymakers to properly design vaccine campaigns with careful consideration of the risk preference dimension of the targeted beneficiaries.


The Case for Modernizing Biomedical Research in Ireland through the Creation of an Irish 3Rs Centre.
Since its publication, the 3Rs principle has provided a cornerstone for more ethical and humane biomedical and regulatory research. In Europe, the 3Rs principle has been incorporated into the European Directive 63/2010/EU, with the ultimate aim of fully replacing the procedures on live animals for scientific and educational purposes as soon as it is scientifically possible to do so. Thus, a critical shift in the discussion on animal use in biomedical and regulatory research is undergoing in Europe, a discussion where satisfying the "replacement" principle is becoming more and more defined as a scientific rather than ethical need. 3Rs Centres have been established in recent years across Europe. To date, Ireland has no 3Rs Centre, and the uptake of the 3Rs principle, and in particular of the "replacement" aspect, has been slow. In this Commentary, we present the Irish context of the use of animal models in biomedical and regulatory research, and urge for what, in the authors' opinion, are the most critical actions that Ireland must undertake to align its biomedical (basic, applied and translational) research with the European 3Rs strategy.


Relaxing incisions in the correction of penile deformity due to Peyronie's disease.
The use of tunica albuginea relaxing incisions, a common component of several operative techniques for correction of penile deformity due to Peyronie's disease, is reviewed. Of 93 operations performed for penile straightening 24 involved relaxing incisions with penile prosthesis implantation but no grafts and 69 involved autologous free grafts into relaxing incisions without use of an implant. Relaxing incisions were uniformly effective in correcting penile curvature when used in conjunction with a prosthesis. When autologous grafts were used without an implant, more than 80% of the patients with dorsal or ventral bending had a good result, compared to only 17% with lateral bending. Relaxing incisions are an effective technique for changing the shape of the erect penis by altering the configuration of the tunica albuginea at maximal extension.


Role of preexisting inhibitory control deficits vs. drug use history in mediating insensitivity to aversive consequences in a rat model of polysubstance use.
The nature and predictors of insensitivity to aversive consequences of heroin + cocaine polysubstance use are not well characterized. Translational methods incorporating a tightly controlled animal model of drug self-administration and measures of inhibitory control and avoidance behavior might be helpful for clarifying this issue. The key approach for distinguishing potential contributions of pre-existing inhibitory control deficits vs. drug use history in meditating insensitivity to aversive consequences was comparison of two rat strains: Wistar (WIS/Crl), an outbred strain, and the spontaneously hypertensive rat (SHR/NCrl), an inbred strain shown previously to exhibit heightened cocaine and heroin self-administration and poor inhibitory control relative to WIS/Crl. In separate tasks, SHR/NCrl displayed greater impulsive action and compulsive-like behavior than WIS/Crl prior to drug exposure. Under two different schedules of drug delivery, SHR/NCrl self-administered more cocaine than WIS/Crl, but self-administered a similar amount of heroin + cocaine as WIS/Crl. When half the session cycles were punished by random foot shock, SHR/NCrl initially were less sensitive to punishment than WIS/Crl when self-administering cocaine, but were similarly insensitive to punishment when self-administering heroin + cocaine. Based on correlation analyses, only trait impulsivity predicted avoidance capacity in rats self-administering cocaine and receiving yoked-saline. In contrast, only amount of drug use predicted avoidance capacity in rats self-administering heroin + cocaine. Additionally, baseline drug seeking and taking predicted punishment insensitivity in rats self-administering cocaine or heroin + cocaine. Based on the findings revealed in this animal model, human laboratory research concerning the nature and predictors of insensitivity to aversive consequences in heroin and cocaine polysubstance vs. monosubstance users is warranted.


Learner handover: Perspectives and recommendations from the front-line.
Current medical education models increasingly rely on longitudinal assessments to document learner progress over time. This longitudinal focus has re-kindled discussion regarding learner handover-where assessments are shared across supervisors, rotations, and educational phases, to support learner growth and ease transitions. The authors explored the opinions of, experiences with, and recommendations for successful implementation of learner handover among clinical supervisors. Clinical supervisors from five postgraduate medical education programs at one institution completed an online questionnaire exploring their views regarding learner handover, specifically: potential benefits, risks, and suggestions for implementation. Survey items included open-ended and numerical responses. The authors used an inductive content analysis approach to analyze the open-ended questionnaire responses, and descriptive and correlational analyses for numerical data. Seventy-two participants completed the questionnaire. Their perspectives varied widely. Suggested benefits of learner handover included tailored learning, improved assessments, and enhanced patient safety. The main reported risk was the potential for learner handover to bias supervisors' perceptions of learners, thereby affecting the validity of future assessments and influencing the learner's educational opportunities and well-being. Participants' suggestions for implementation focused on who should be involved, when and for whom it should occur, and the content that should be shared. The diverse opinions of, and recommendations for, learner handover highlight the necessity for handover to maximize learning potential while minimizing potential harms. Supervisors' suggestions for handover implementation reveal tensions between assessment-of and for-learning.


[Outpatient prescription of atypical antipsychotics for schizophrenic patients after discharge from hospital treatment].
There are complaints of an undertreatment of schizophrenic patients with atypical antipsychotics in German outpatients. Together with reluctance to start treatment with second generation antipsychotics, change of medication after inpatient treatment is often held responsible for the more frequent use of typical compounds. However, global statistics of prescriptions are difficult to interpret. To get data of the current practice, 132 patients treated with atypical antipsychotics in a university clinic were followed-up one year later. Of the patients that could be reached and still received medication, 82 (94%) were treated with atypical antipsychotics. The results indicate that change to conventional antipsychotics in outpatients does not considerably contribute to the low prescription of atypical antipsychotics.


High-throughput analysis of lipidomic phenotypes of methicillin-resistant Staphylococcus aureus by coupling in situ 96-well cultivation and HILIC-ion mobility-mass spectrometry.
Antimicrobial resistance is a major threat to human health as resistant pathogens spread globally, and the development of new antimicrobials is slow. Since many antimicrobials function by targeting cell wall and membrane components, high-throughput lipidomics for bacterial phenotyping is of high interest for researchers to unveil lipid-mediated pathways when dealing with a large number of lab-selected or clinical strains. However, current practice for lipidomic analysis requires the cultivation of bacteria on a large scale, which does not replicate the growth conditions for high-throughput bioassays that are normally carried out in 96-well plates, such as susceptibility tests, growth curve measurements, and biofilm quantitation. Analysis of bacteria grown under the same condition as other bioassays would better inform the differences in susceptibility and other biological metrics. In this work, a high-throughput method for cultivation and lipidomic analysis of antimicrobial-resistant bacteria was developed for standard 96-well plates exemplified by methicillin-resistant Staphylococcus aureus (MRSA). By combining a 30-mm liquid chromatography (LC) column with ion mobility (IM) separation, elution time could be dramatically shortened to 3.6 min for a single LC run without losing major lipid features. Peak capacity was largely rescued by the addition of the IM dimension. Through multi-linear calibration, the deviation of retention time can be limited to within 5%, making database-based automatic lipid identification feasible. This high-throughput method was further validated by characterizing the lipidomic phenotypes of antimicrobial-resistant mutants derived from the MRSA strain, W308, grown in a 96-well plate.


[Problems of vascular injuries at a large industrial-accident hospital (19 year experiences at the industrial-accident hospital Vienna XII)].
This report covers 213 vessel injuries out of 840 000 injuries through accident. Even considering that these are mostly cases of polytrauma, the results could be improved significantly. This however, only under the condition that all traumatologists and surgeons active in traumatology receive practical training in vessel surgery.


Caenorhabditis elegans transfers across a gap under an electric field as dispersal behavior.
Interactions between different animal species are a critical determinant of each species' evolution and range expansion. Chemical, visual, and mechanical interactions have been abundantly reported, but the importance of electric interactions is not well understood. Here, we report the discovery that the nematode Caenorhabditis elegans transfers across electric fields to achieve phoretic attachment to insects. First, we found that dauer larvae of C. elegans nictating on a substrate in a Petri dish moved directly to the lid through the air due to the electrostatic force from the lid. To more systematically investigate the transfer behavior, we constructed an assay system with well-controlled electric fields: the worms flew up regardless of whether a positive or negative electric field was applied, suggesting that an induced charge within the worm is related to this transfer. The mean take-off speed is 0.86 m/s, and the worm flies up under an electric field exceeding 200 kV/m. This worm transfer occurs even when the worms form a nictation column composed of up to 100 worms; we term this behavior "multiworm transfer." These observations led us to conclude that C. elegans can transfer and attach to the bumblebee Bombus terrestris, which was charged by rubbing with flower pollen in the lab. The charge on the bumblebee was measured with a coulomb-meter to be 806 pC, which was within the range of bumblebee charges and of the same order of flying insect charges observed in nature, suggesting that electrical interactions occur among different species.


Effect of local anesthetics on intraocular penetration of subconjunctival antibiotics.
The combination of the subconjunctival injection of lidocaine HCl or procaine HCl with the subconjunctival injection of penicillin G, methicillin, cephaloridine, or gentamicin did not influence their intraocular penetration or subsequent antibiotic activity in aqueous humor of experimental animals.


Possible Role of Trichophytin Antigen in Inducing Impaired Immunological Clearance of Fungus in Onychomycosis.
The immunology of onychomycosis is poorly understood. Th1 and Th17 are the principal effector cells responsible for protective immunity against fungi, while it is assumed that Th2 responses are associated with deleterious effects. The study was conducted to appraise the role of interleukin-6 (IL-6), transforming growth factor β (TGF-β) and immunoglobulin E (IgE) in onychomycosis patients and to study skin reactivity to trichophytin antigen in them. Serum samples of 60 cases of chronic onychomycosis and 30 healthy controls were assayed for serum IgE, IL-6 and TGF-β levels using specific immunoassay kits; 0.01 ml of trichophytin antigen, Candida antigen and phosphate-buffered saline using separate syringes were injected intradermal at three independent sites of the forearm in cases and controls. Serum IL-6 levels were significantly lower in cases as compared to controls, while serum TGF-β levels in both cases and controls were comparable. Serum IgE levels in cases were significantly higher when compared with controls. Thirty-eight patients showed immediate hypersensitivity response to trichophytin antigen, while none showed delayed hypersensitivity reaction to trichophytin antigen. Constant fungal antigenic stimuli induce a state of anergy as indicated by low serum IL-6 levels and the absence of delayed hypersensitivity reaction to trichophytin antigen in cases, leading to chronicity of infection. High total IgE may indicate a high probability of prior fungal sensitization.


Changes in bone matrix mineralization after growth hormone treatment in children and adolescents with chronic kidney failure treated by dialysis: a paired biopsy study.
Patients with chronic kidney disease (CKD) develop renal osteodystrophy with alterations in bone turnover, mineralization, and volume (TMV). A specific skeletal complication in children is growth impairment, which currently is treated by recombinant human growth hormone (rhGH). The effects on bone material properties are poorly understood. This study assesses the effects of rhGH treatment on bone matrix mineralization. Observational study. 18 short children and adolescents (aged 3.6-16 years) with CKD on dialysis therapy. rhGH treatment for 1 year. Tetracycline-labeled bone biopsy classified according to the TMV system. Bone mineralization density distribution (BMDD) was evaluated by quantitative backscattered electron imaging in trabecular and cortical compartments. Additional data for patients' height and biochemical bone serum parameters were obtained. Prior to rhGH treatment, our cohort showed low bone turnover and high mineralization densities versus reference data: Ca(mean) (weighted mean calcium content) in cancellous bone, +3.3% (P = 0.04); Ca(mean) in cortical bone, +6.7% (P < 0.001); Ca(peak) (mode of the BMDD) in cancellous bone, +5.0% (P < 0.001); Ca(peak) in cortical bone, +8.2% (P < 0.001); Ca(width) (heterogeneity in mineralization), no significant difference for cancellous (P = 0.2) and cortical (P = 0.1) bone; Ca(high) (portion of fully mineralized bone) in cancellous bone, 5-fold greater (P < 0.001); Ca(high) in cortical bone, 14-fold greater (P < 0.001); Ca(low) (portion of low mineralized bone) in cancellous bone, +23.9% (P = 0.02); Ca(low) in cortical bone, -22.2% (P = 0.05). After rhGH treatment, height increased by 9.1 cm (P < 0.001) and bone turnover indices to normal values or beyond. Matrix mineralization was lesser and more heterogeneous compared to baseline: Ca(width) for cancellous bone, +15.3% (P < 0.001); Ca(width) for cortical bone, +34.1% (P < 0.001). Ca(mean), Ca(peak), and Ca(high) for cancellous bone and Ca(mean) and Ca(peak) for cortical bone were no longer significantly different from reference data. Ca(high) for cortical bone dramatically decreased after treatment but was still substantially greater than reference data. Low case number per TMV subgroup, no measurements of fibroblast growth factor 23. Children and adolescents with CKD and growth deficiency are at risk of having low bone turnover. rhGH treatment improves height and concomitantly bone modeling/remodeling, which appears beneficial for bone matrix mineralization.


[Graded volume loading in the diagnosis of early heart failure among myocardial infarct patients].
The method of graded physical exercise with the plotting of the functional curves and calculating of the functional coefficient (FC) was used in the study. No relationship was detected between the initial level of the cardiac output and the direction of the functional curve. A negative FC was more frequently recorded in patients with Q-index 25.


Adrenalectomy increases phosphoinositide hydrolysis induced by norepinephrine or excitatory amino acids in rat hippocampal slices.
Phosphoinositide hydrolysis induced by norepinephrine, quisqualate, or trans-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD), but not by carbachol, was approximately 50% greater in hippocampal slices from adrenalectomized (14 days) rats compared with controls. These changes appeared to be selective for the hippocampus because no effects of adrenalectomy on phosphoinositide hydrolysis were detected in cortical or striatal slices. The enhanced response to norepinephrine in hippocampal slices after adrenalectomy was observed throughout the effective concentration range of norepinephrine, was not influenced by in vitro addition of corticosterone, was not mimicked or altered by incubation with dibutyryl cyclic adenosine 3',5'-monophosphate (AMP), and did not appear to be due to impaired inhibition of the response to norepinephrine which was elicited by activation of protein kinase C or by inclusion of an inhibitory concentration of quisqualate. These findings indicate that adrenalectomy either removes an inhibitory influence of glucocorticoids on the phosphoinositide system in the hippocampus or that the neurodegeneration of granule cells in the dentate gyrus following adrenalectomy is associated with neurotransmitter-selective increases in phosphoinositide hydrolysis. These data provide further evidence that glucocorticoids modify signal transduction in the brain and extends their known influence to the phosphoinositide second messenger system.


Management of Pediatric Obstructive Sleep Apnea After Failed Tonsillectomy and Adenoidectomy.
Pediatric obstructive sleep apnea (OSA) represents a different entity from its adult counterpart and therefore requires a different therapeutic approach. Adenotonsillectomy (AT) is the primary treatment of pediatric OSA, and evidence shows it is very effective. However, there is a growing understanding that residual OSA is common, and next steps for patients who fail primary AT are less certain. This article reviews current methods of evaluating and treating these complex patients.


One-dose and multiple-dose kinetics of minocycline in patients with renal disease.
Kinetic analysis of minocycline concentrations in plasma and urine resulted in the following findings: In normal subjects the biological half-life is about 17 hours after the first dose and 21 hours after repeated administration. The renal drug clearance is only about 8% of the overall plasma clearance which is independent of renal function with a mean value of 47 ml/min. The fraction of the absorbed dose eliminated unchanged in the urine is only 9--19%. As a consequence the elimination rate of the drug is practically independent of renal function and decreases only 9--19% in anuric patients. The renal drug clearance depends linearly on renal function. The gastro-intestinal bio-availability of minocycline from the coated tablet preparation is incomplete. The cumulative behaviour of the drug corresponds to the kinetic parameters determined after repeated administration. It is suggested that the usual dosage regimen should be used in patients with renal disease.


Oxidation of chlorfenvinphos in ultrapure and natural waters by ozonation and photochemical processes.
The chemical oxidation of the organophosphorus insecticide chlorfenvinphos, a priority pollutant in aquatic environments, has been conducted in ultrapure water, by means of single degradation agents (ozone and UV radiation), and by the Advanced Oxidation Processes constituted by combinations of these oxidants (O(3)/H(2)O(2) and UV/H(2)O(2)). The influence of the operating variables was discussed, and the degradation rates were evaluated by determining the rate constants for the reactions with ozone (k(O)(3)=3.7+/-0.2 L mol(-1)s(-1)) and OH radicals (k(OH)=(3.2+/-0.2)x10(9) L mol(-1)s(-1)), as well as the quantum yield for the photodegradation (around 0.1 mol E(-1), depending on the pH). Additionally, the ozonation of chlorfenvinphos in a natural water system (a surface water from a reservoir) was studied. The influence of the operating conditions on the insecticide removal efficiency was established, and the R(ct) parameter was evaluated. A kinetic model was proposed for the prediction of the elimination rate of chlorfenvinphos in the ozonation process and the results obtained reveal a good agreement between experimental results and predicted values.


Axillary reverse mapping in patients undergoing axillary dissection -a short review of the literature.
Axillary lymph node dissection (ALND) can be avoided not only in patients with negative sentinel lymph nodes (SLNs) but also in those with one or two positive SLNs receiving breast or axillary radiation. However, ALND has remained the standard treatment for patients with clinically positive nodes (cN+). Although axillary reverse mapping (ARM) was developed to map and preserve arm lymphatic drainage during ALND, it could not be indicated for cN + patients because metastatic rate of ARM nodes is high. However, a new type of conservative ALND with ARM attempts to preserve ARM lymphatics and nodes except SLNs and other suspicious palpable nodes, including suspicious ARM nodes. This procedure allowed reduction of the rate of arm lymphedema without increasing axillary recurrence, although patients received postoperative chemotherapy and high-risk patients underwent axillary radiation. Thus, a traditional full ALND may not be necessary for cN + patients in the era of effective multimodality therapy.


Magmatic tempo of Earth's youngest exposed plutons as revealed by detrital zircon U-Pb geochronology.
Plutons are formed by protracted crystallization of magma bodies several kilometers deep within the crust. The temporal frequency (i.e. episodicity or 'tempo') of pluton formation is often poorly constrained as timescales of pluton formation are largely variable and may be difficult to resolve by traditional dating methods. The Hida Mountain Range of central Japan hosts the youngest exposed plutons on Earth and provides a unique opportunity to assess the temporal and spatial characteristics of pluton emplacement at high temporal resolution. Here we apply U-Pb geochronology to zircon from the Quaternary Kurobegawa Granite and Takidani Granodiorite in the Hida Mountain Range, and from modern river sediments whose fluvial catchments include these plutons in order to reconstruct their formation. The U-Pb data demonstrate that the Kurobegawa pluton experienced two magmatic pulses at ~2.3 Ma and ~0.9 Ma; whereas, to the south, the Takidani pluton experienced only one magmatic pulse at ~1.6 Ma. These data imply that each of these magmatic systems were both spatially and temporally distinct. The apparent ~0.7 Myr age gap between each of the three magmatic pulses potentially constrains the recharge duration of a single pluton within a larger arc plutonic complex.


Rumination network dysfunction in major depression: A brain connectome study.
Rumination is a central feature of major depressive disorder (MDD). Knowledge of the neural structures that underpin rumination offers significant insight into depressive pathophysiology and may help to develop potential intervention strategies for MDD, a mental illness that has become the leading cause of disability worldwide. Using resting-state fMRI and graph theory, this study adopted a connectome approach to examine the functional topological organization of the neural network associated with rumination in MDD. Data from 96 participants were analyzed, including 51 patients with MDD and 45 healthy controls. We found altered functional integration and segregation of neural networks associated with depressive rumination as indicated by reduced global and local efficiency in MDD patients compared with controls. Interestingly, these metrics correlated positively with depression severity, as measured by the Hamilton Depression Rating Scale. Moreover, mediation analysis indicated that the association between network metrics and depression severity was mediated by the ruminative tendency of patients. Disrupted nodal centralities were located in regions associated with emotional processing, visual mental imagery, and attentional control. Our results highlight rumination as a two-edged sword that reflects a disease-specific neuropathology but also points to a functionality of depressive symptoms with evolutionary meaning.


Diffusion tractography predicts propagated high-frequency activity during epileptic spasms.
To determine the structural networks that constrain propagation of ictal oscillations during epileptic spasm events, and compare the observed propagation patterns across patients with successful or unsuccessful surgical outcomes. Subdural electrode recordings of 18 young patients (age 1-11 years) were analyzed during epileptic spasm events to determine ictal networks and quantify the amplitude and onset time of ictal oscillations across the cortical surface. Corresponding structural networks were generated with diffusion magnetic resonance imaging (MRI) tractography by seeding the cortical region associated with the earliest average oscillation onset time, and white matter pathways connecting active electrode regions within the ictal network were isolated. Properties of this structural network were used to predict oscillation onset times and amplitudes, and this relationship was compared across patients who did and did not achieve seizure freedom following resective surgery. Onset propagation patterns were relatively consistent across each patient's spasm events. An electrode's average ictal oscillation onset latency was most significantly associated with the length of direct corticocortical tracts connecting to the area with the earliest average oscillation onset (p < .001, model R2 = .54). Moreover, patients demonstrating a faster propagation of ictal oscillation signals within the corticocortical network were more likely to have seizure recurrence following resective surgery (p = .039). In addition, ictal oscillation amplitude was associated with connecting tractography length and weighted fractional anisotropy (FA) measures along these pathways (p = .002/.030, model R2 = .31/.25). Characteristics of analogous corticothalamic pathways did not show significant associations with ictal oscillation onset latency or amplitude. Spatiotemporal propagation patterns of high-frequency activity in epileptic spasms align with length and FA measures from onset-originating corticocortical pathways. Considering the data in this individualized framework may help inform surgical decision-making and expectations of surgical outcomes.


Neural activity-dependent regulation of gene expression in developing and mature neurons.
Neurons can change their gene expression patterns according to the inputs they have received. This activity-dependent gene regulation mechanism plays an important role in the formation of neural circuits during development. Further, by regulating the synaptic plasticity, this mechanism may function as an essential one for each organism to adapt flexibly to its environment. This review summarizes our current knowledge about the activity-dependent gene regulation mechanism in neurons, focusing on the transcription factors and signaling pathways involved in this mechanism.


Verteporfin without light stimulation inhibits YAP activation in trabecular meshwork cells: Implications for glaucoma treatment.
Verteporfin, a photosensitizer, is used in photodynamic therapy to treat age-related macular degeneration. In a glaucoma mouse model, Verteporfin without light stimulation has been shown to reduce intraocular pressure (IOP) but the mechanism is unknown. Recent studies have shown that Verteporfin inhibits YAP without light stimulation in cancer cells. Additionally, YAP has emerged as an important molecule in the pathogenesis of glaucoma. We hypothesize that YAP inactivation by Verteporfin in trabecular meshwork (TM) may be related to the reduced IOP observed in vivo. As contractility of TM tissues is associated with IOP, collagen gel contraction assay was used to assess the effect of Verteporfin on contractility of TM cells. Human TM cells were embedded in collagen gel and treated with Verteporfin for 48 h. Areas of collagen gel sizes were quantified by ImageJ. To assess the effect of Verteporfin on the expression of YAP, human TM cells were treated with Verteporfin for 24 h and the expression of YAP was determined by Western blotting. To determine the cytotoxic effect of Verteporfin, human TM cells were treated with Verteporfin for 24 h, and then the cell viability was assessed by WST-1. We demonstrated here that Verteporfin (i) abolishes TM cell-mediated collagen gel contraction in a dose-dependent manner, (ii) attenuates expression of YAP and CTGF (connective tissue growth factor, a direct YAP target gene) in a dose-dependent manner, and (iii) has no significant cytotoxicity below 2 μM. Taken together, Verteporfin may facilitate aqueous humor outflow through the conventional outflow system and reduce IOP by inactivating YAP.


Proteasome inhibitors for cancer therapy.
Proteasome, a large multicatalytic proteinase complex that plays an important role in processing of proteins, has been shown to possess multiple catalytic activities. Among its various activities, the 'chymotrypsin-like' activity of proteasome has emerged as the focus of drug discovery efforts in cancer therapy. Herein we report chiral boronate derived novel, potent, selective and cell-permeable peptidomimetic inhibitors 6 and 7 that displayed activity against various rodent and human tumor cell lines (in vitro).


Lower 1,5-anhydroglucitol is associated with adverse clinical events after percutaneous coronary intervention.
Diabetes mellitus and impaired glucose tolerance are well-known risk factors for coronary artery disease (CAD) and adverse clinical events after percutaneous coronary intervention (PCI). Postprandial hyperglycemia is an important risk factor for CAD and serum 1,5-anhydroglucitol (1,5-AG) reflects postprandial hyperglycemia more robustly than hemoglobin (Hb)A1c. We aimed to clarify the relationship between serum 1,5-AG level and adverse clinical events after PCI. We enrolled 141 patients after PCI with follow-up coronary angiography. We evaluated associations between glycemic biomarkers including HbA1c and 1,5-AG and cardiovascular events during follow-up. Median serum 1,5-AG level was significantly lower in patients with any coronary revascularization and target lesion revascularization (TLR) [13.4 µg/ml (first quartile, third quartile 9.80, 18.3) vs. 18.7 (12.8, 24.2), p = 0.005; 13.4 µg/ml (10.2, 16.4) vs. 18.7 (12.9, 24.2), p = 0.001, respectively]. Multivariate logistic analysis showed lower 1,5-AG was independently associated with any coronary revascularization and TLR (odds ratio 0.93, 95 % confidence interval 0.86-0.99, p = 0.04; 0.90, 0.81-0.99, p = 0.044, respectively), whereas higher HbA1c was not. Postprandial hyperglycemia and lower 1,5-AG are important risk factors for adverse clinical events after PCI.


Real-time monitoring of intracellular wax ester metabolism.
Wax esters are industrially relevant molecules exploited in several applications of oleochemistry and food industry. At the moment, the production processes mostly rely on chemical synthesis from rather expensive starting materials, and therefore solutions are sought from biotechnology. Bacterial wax esters are attractive alternatives, and especially the wax ester metabolism of Acinetobacter sp. has been extensively studied. However, the lack of suitable tools for rapid and simple monitoring of wax ester metabolism in vivo has partly restricted the screening and analyses of potential hosts and optimal conditions. Based on sensitive and specific detection of intracellular long-chain aldehydes, specific intermediates of wax ester synthesis, bacterial luciferase (LuxAB) was exploited in studying the wax ester metabolism in Acinetobacter baylyi ADP1. Luminescence was detected in the cultivation of the strain producing wax esters, and the changes in signal levels could be linked to corresponding cell growth and wax ester synthesis phases. The monitoring system showed correlation between wax ester synthesis pattern and luminescent signal. The system shows potential for real-time screening purposes and studies on bacterial wax esters, revealing new aspects to dynamics and role of wax ester metabolism in bacteria.


Long-term outcomes of patients with Streptococcus suis infection in Viet Nam: A case-control study.
Streptococcus suis is a zoonotic cause of severe meningitis and sepsis in humans. We aimed to assess the long-term outcomes in patients who survived S. suis infection, in particular the progress and impact of vestibulocochlear sequelae. This case-control study evaluated outcomes of S. suis infection at discharge and 3 and 9 months post-discharge for 47 prospectively enrolled cases and at 11-34 months for 31 retrospectively enrolled cases. Outcomes in patients were compared to 270 controls matched for age, sex and residency. The prevalence ratio (PR) of moderate-to-complete hearing loss was 5.0(95%CI 3.6-7.1) in cases at discharge, 3.7(2.5-5.4) at 3 months, 3.2(2.2-4.7) at 9 months, and 3.1(2.1-4.4) in retrospective cases compared to controls. Hearing improvement occurred mostly within the first 3 months with a change in hearing level of 11.1%(95%CI 7.0-15.1%) compared to discharge. The PR of vestibular dysfunction was 2.4(95%CI 1.7-3.3) at discharge, 2.2(1.4-3.1) at 3 months, 1.8(1.1-2.5) at 9 months, and 1.8(1.1-2.6) for retrospective cases compared to controls. Cases also indicated more problems with mobility, self-care and usual activities. Both hearing and vestibular impairment were common and persist in cases. Appropriate patient management strategies are needed to reduce the incidence and impact of these sequelae.


"An integrated clip-shaped costal cartilage carving approach for rhinoplasty".
Nasal tip management is considered to be one of the most complicated and challenging parts of rhinoplasty in East Asian patients. Within current rhinoplasty surgical practice, costal cartilage serves as an ideal source for grafting due to its ability to provide strong support to the nasal tip. From March 2013 to December 2021, integrated clip-shaped costal cartilage grafts were applied to patients with primary (n = 12) or secondary (n = 3) short nose deformities. The costal cartilage was carved into an monobloc clip-shaped cartilage graft and then placed on the nasal septum and fixed with sutures. The nasal length index, projection index, and nasolabial angles were measured preoperatively and postoperatively. Postoperative evaluation at 8 months was performed using a grading scale. A total of 15 patients were included in this study with an average age of 23.7 ± 3.6 years. The mean follow-up period was 14.3 ± 5.3 months and ranged from 8 to 26 months. There were statistically significant differences between the preoperative and postoperative values in nose length index and projection index. Also, the nasolabial angle was significantly reduced. Postoperative evaluation, conducted at a minimum of 8 months following surgery, showed that 86.6% (13/15) of patients felt that their surgical results were good or excellent. No patients rated the results as "poor". The integrated clip-shaped costal cartilage carving approach has been shown to be a practical method of obtaining satisfactory esthetic outcomes in patients with nasal deformities.


Characterization of biological response modifier release by human monocytes cultured in suspension in serum-free medium.
Human monocytes have been shown to be critical immunoregulatory cells for a variety of frequently measured in vitro human immune functions and are secretors of potent biologic response modifiers ( BRMs ). These BRMs , such as interferon (IFN), colony stimulating factor (CSF) and prostaglandin E (PGE), may play important roles in the host immune response to cancer. A new approach for culturing circulating peripheral blood monocytes has been developed to retain the native characteristics of these cells, avoiding possible alteration or activation by adherence. The ability of elutriator-purified human monocytes to secrete IFN and PGE was examined under conditions of suspension culture as well as after adherence, and no difference in secretion of these BRMs was noted. In contrast, Teflon-cultured monocytes demonstrated a significantly enhanced CSF release over culturing in polystyrene plates. A new serum-free medium has also been developed, and monocytes cultured in vitro in this medium showed a 5-fold increase in IFN release, and up to a 72% increase in CSF release when compared to optimal standard culture medium (containing 10% AB serum) and an increased stimulation index for PGE release. By these procedures, hundreds of millions of highly purified human monocytes can be sterilely isolated in suspension and cultured in suspension in serum-free medium with retention of BRM-releasing capabilities. This system should permit more detailed molecular studies of monocytes (in which serum can be an impediment) and may also facilitate clinical therapy studies involving the in vivo transfer of monocytes activated in suspension in vitro.


Biological activities of monoclonal antibodies reactive with antigenic sites mapped on the G1 glycoprotein of La Crosse virus.
Monoclonal antibodies have been prepared which are specific for the G1 glycoprotein of La Crosse virus. By competitive radioimmunoassay, 20 IgG-producing clones were found to map in eight antigenic sites; three distinct and five which showed individual patterns of partial competition indicating they may be in close proximity. Unique in situ trypsin cleavage sites on G1 have helped in orienting these defined epitopes relative to the viral membrane. Antibody molecules belonging to one epitope (H) mapped on the trypsin-resistant part of G1 and had negative or extremely low neutralizing and hemagglutination inhibition activities. Seven epitopes were located on the trypsin-sensitive part of G1, a 25,000-Da region which is probably the amino terminus of the protein. Antibodies binding to six of these seven epitopes (A, B, D, E, F, and G) were positive for neutralization and inhibition of hemagglutination, but exhibited a wide range of activities. Epitopes A, F, and G seem to be in an immunodominant region containing the primary site(s) for attachment to cell receptors. Antibody specific for the remaining epitope (C) was unique in that it bound to a site closely adjacent to neutralizing antibody sites, enhanced antibody binding to epitopes A and G, but lacked the capacity to neutralize viral infectivity or inhibit hemagglutination. Enhancement of antibody binding also occurred between two other closely adjacent sites (B and D) and one other distinct epitope (G). In addition, antibody from an IgM-producing clone competed with antibodies to these same four epitopes (B, C, D, and G), indicating they are in close proximity. These data have been used to construct an antigenic map that may now be used as a working model for the study of virus neutralization.


Sensorimotor developmental delays and lower anxiety in rats prenatally exposed to cadmium.
Pregnant rats were treated with 0.3 or 0.6 mg cadmium (CdCl2) kg(-1) injected subcutaneously on a daily basis from gestational day 7 to day 15 (organogenesis period). One control group was not injected and the other received saline. Offspring were tested for ontogeny of sensorimotor development and at 45 or 90 days of age for anxiety behavior. The study of sensorimotor development showed that gestational exposure to 0.6 mg Cd kg(-1) produced a delay in the development of the righting reflex and of the cliff aversion in the pups. No differences were observed in the development of the negative geotaxis, nor in the ages of eye and ear opening. Anxiety studies using an elevated plus maze showed a lower anxiety in all the offspring prenatally exposed to 0.6 mg Cd kg(-1) as these rats spent more time and entered the open arms more times compared with those of the other groups. The results demonstrate that exposure to low levels of Cd during organogenesis may modify some central nervous system functions.


Sleep duration and body mass index in twins: a gene-environment interaction.
To examine whether sleep duration modifies genetic and environmental influences on body mass index (BMI). Genotype-environment interaction twin study. University of Washington Twin Registry. A population-based sample of US twins (1,088 pairs, 604 monozygotic, 484 dizygotic; 66% female; mean age = 36.6 yr, standard deviation (SD) = 15.9 yr). N/A. Participants self-reported information on height, weight, and sleep. Mean BMI was calculated as 25.3 kg/m² (SD = 5.4) and mean habitual sleep duration was 7.2 hr/night (SD = 1.2). Data were analyzed using biometric genetic interaction models. Overall the heritability of sleep duration was 34%. Longer sleep duration was associated with decreased BMI (P < 0.05). The heritability of BMI when sleep duration was < 7 hr (h² = 70%) was more than twice as large as the heritability of BMI when sleep duration was ≥ 9 hr (h² = 32%); this interaction was significant (P < 0.05). Shorter sleep duration is associated with increased BMI and increased genetic influences on BMI, suggesting that shorter sleep duration increases expression of genetic risks for high body weight. At the same time, longer sleep duration may suppress genetic influences on body weight. Future research aiming to identify specific genotypes for BMI may benefit by considering the moderating role of sleep duration.


Detection of heterozygotes of X-linked ichthyosis by measuring steroid sulphatase activity of lymphocytes. Mode of inheritance in three families.
Steroid sulphatase activity in peripheral blood lymphocytes was assayed in all available members of three families in which cases of X-linked ichthyosis were frequently seen. Lymphocytes from all the patients with this disease lacked steroid sulphatase activity and some female members who were probably heterozygotes, showed significantly lower enzyme activity compared with other healthy family members and normal controls. This suggest that females heterozygous for X-linked ichthyosis in these families could be traced enzymatically. Three childless females in these families were found to be possible heterozygotes in view of their lower enzyme levels. It was found that polyacrylamide gel electrophoretic mobility of serum low-density lipoproteins was increased in X-linked ichthyosis patients but was not changed in the probable heterozygotes. The detection of individuals heterozygous for X-linked ichthyosis, for the purpose of precise genetic counselling, may be possible by measuring steroid sulphatase activity of peripheral blood lymphocytes.


National culture and the demand for physical money during the first year of the COVID-19 pandemic.
There was a significant increase in the demand for physical money during the COVID-19 pandemic. This stood in stark contrast to the decline in demand witnessed during previous pandemics. However, the change was not uniform and varied significantly between countries. By employing the "national culture" framework to identify the drivers of this variation, this study found that uncertainty avoidance, as well as social norms regarding gratification, played a major role. This suggests that some central banks should hold larger cash reserves to mitigate the risk of uncertainty and that the national culture framework may prove useful in researching the international differences in past, present, and future money demand.


Geriatric Medicine Principles in Conservative Kidney Management: Frailty, Functional Assessments, and Selective Deprescribing.
Conservative kidney management is a nondialytic treatment option for advanced chronic kidney disease that involves interventions to delay kidney function loss, medications to treat symptoms, and psychosocial support for patients and their loved ones. Several geriatric medicine principles are applicable to patients who are considering or receiving conservative kidney management, including the integration of physical, psychological, and social factors into medical care and medical decisions; careful review of medication lists with selective deprescribing; and screening for geriatric syndromes such as frailty and functional impairment. In this review, we discuss how functional and frailty assessments as well as selective deprescribing can be useful for patients considering or receiving conservative kidney management.


A three-dimensional microfluidic approach to scaling up microencapsulation of cells.
Current applications of the microencapsulation technique include the use of encapsulated islet cells to treat Type 1 diabetes, and encapsulated hepatocytes for providing temporary but adequate metabolic support to allow spontaneous liver regeneration, or as a bridge to liver transplantation for patients with chronic liver disease. Also, microcapsules can be used for controlled delivery of therapeutic drugs. The two most widely used devices for microencapsulation are the air-syringe pump droplet generator and the electrostatic bead generator, each of which is fitted with a single needle through which droplets of cells suspended in alginate solution are produced and cross-linked into microbeads. A major drawback in the design of these instruments is that they are incapable of producing sufficient numbers of microcapsules in a short-time period to permit mass production of encapsulated and viable cells for transplantation in large animals and humans. We present in this paper a microfluidic approach to scaling up cell and protein encapsulations. The microfluidic chip consists of a 3D air supply and multi-nozzle outlet for microcapsule generation. It has one alginate inlet and one compressed air intlet. The outlet has 8 nozzles, each having 380 micrometers inner diameter, which produce hydrogel microspheres ranging from 500 to 700 μm in diameter. These nozzles are concentrically surrounded by air nozzles with 2 mm inner diameter. There are two tubes connected at the top to allow the air to escape as the alginate solution fills up the chamber. A variable flow pump 115 V is used to pump alginate solution and Tygon® tubing is used to connect in-house air supply to the air channel and peristaltic/syringe pump to the alginate chamber. A pressure regulator is used to control the flow rate of air. We have encapsulated islets and proteins with this high throughput device, which is expected to improve product quality control in microencapsulation of cells, and hence the outcome of their transplantation.


Surface water quality analysis using multivariate statistical techniques: a case study of Fars Province rivers, Iran.
This study aimed to transform the input of a large dataset into the output of interpretable information. Hence, multivariate statistical methods were carried out to analyze physicochemical parameters in 34 rivers during a 17-year period (1997-2014). Cluster analysis divided the study area into spatially different riverine water quality sub-regions described in ascending order of water quality as severely polluted (SP), highly polluted (HP), polluted (P), moderately polluted (MP), lightly polluted (LP), and not polluted (NP). By diagnosing threats and identifying fragile zones, water contamination sources responsible for impaired water quality in the study area recognized as natural pollutants in LP, municipal wastes in P, discharge of industrial effluents in MP, natural geochemical formations in SP and HP, and superficial flows of agricultural lands in SP, HP, and MP. The dominant water type in each zone was classified into Na-Cl, Na-Cl, Na-Mg-Ca-Cl-SO4, Na-Ca-Mg-Cl-SO4, Na-Ca-Cl, and Ca-Mg-HCO3-SO4 groups for SP, HP, P, MP, LP, and NP, respectively. To explore aesthetic aspects of drinking water application, hazard quotient (HQ) was applied for children and adults in terms of ingestion and dermal exposure. Overall health risk assessment revealed the order of impacts of the secondary water quality parameters as Cl- > Na+ > total dissolved solids (TDS) > Ca2+ > SO42- > Mg2+. Furthermore, hazard index (HI) ranged from 0.011 to 31.439 and 0.010 to 30.122 for children and adults, respectively, indicating a potential health risk regarding chloride throughout the whole region excluding NP. To identify significant agents in water quality, principal component analysis extracted 3 varifactors (VFs), with the eigenvalues of 4.74, 1.19, and 0.85, respectively, explained about 83% of the variance. The most important parameters in the first factor were TDS, electrical conductivity, SAR, TH, Na+, Cl-, and SO42- accounting for 58% of the total variance. The most influenced parameters in the second and third factors were pH and HCO3-, respectively, with variance coverage of 26%. These factors indicated that the hydrochemical characteristics of the water originated by natural interactions (existing salt domes, evaporation, weathering, and soil erosion) and anthropogenic activities (fertilizer-rich flows of agro-fields and domestic/industrial disposals), which must be minimized in rivers to supply the population with hygienic water.


Limitations of Cockcroft-Gault and MDRD formulas in estimating GFR among top-level rugby players.
We measured serum creatinine concentrations in 17 male athletes of the Italian national rugby team. Blood was obtained before the start of training and during the competitive season. Serum creatinine level was measured by Jaffé reaction at 4 time points during the season, with a formal measure of creatinine clearance in midseason. The values of estimated glomerular filtration rate (eGFR) calculated with the Cockcroft-Gault (CG) equation were higher than those calculated with the Modification of Diet in Renal Disease (MDRD) Study formula (p<0.001). This difference was significantly decreased but still present when the MDRD formula was corrected for body surface area (BSA). When compared with measured creatinine clearance (CrCl), the MDRD underestimates the CrCl by 51 ml/min (95% confidence interval [95% CI], 36-67 ml/min, p<0.0001). When corrected for BSA, this difference falls to 27 ml/min (95% CI, 13-44 ml/min, p=0.001). The CG eGFR gave a better estimate of CrCl, differing by 1 ml/min (95% CI, -16 to +17 ml/min, p=NS). The MDRD formula underestimates the CrCl in rugby players, even when corrected for BSA. Conversely, the CG formula more closely approximates the actual CrCl measurement. The equations to estimate GFR should be used with caution in subjects having atypical anthropometric characteristics.


Quantifying transient interactions between amide groups and the guanidinium cation.
We study the interaction of the guanidinium cation, a widely used protein denaturant, with amide groups, the common structural motif of proteins. Our results provide evidence for direct contact between guanidinium and ∼2 amide groups, but the interaction is transient and weaker than for other cations with high charge-density.


Induction of c-fos during myelomonocytic differentiation and macrophage proliferation.
Previous studies have suggested a role for c-fos in cellular differentiation in fetal membranes, haematopoietic cells and teratocarcinoma stem cells. In other cell types, such as fibroblasts, c-fos expression is normally very low, but is rapidly induced by peptide growth factors, implicating c-fos in growth control mechanisms. Here, we show that the TPA (12-O-tetradecanoylphorbol-13-acetate)-induced macrophage-like differentiation of HL60 human promyelocytic precursor cells is accompanied by the induction of both c-fos mRNA and protein within 15 min after treatment, suggesting a functional role for c-fos in this differentiation system. In quiescent terminally differentiated macrophages, expression of c-fos is inducible by the macrophage-specific growth factor colony-stimulating factor-1 (CSF-1). The kinetics of c-fos induction, however, are entirely different from those in growth factor-stimulated fibroblasts, supporting the view that the c-fos gene product may serve different functions in different cell types.


Implementing Programs to Initiate Buprenorphine for Opioid Use Disorder Treatment in High-Need, Low-Resource Emergency Departments: A Nonrandomized Controlled Trial.
We hypothesized that implementation facilitation would enable us to rapidly and effectively implement emergency department (ED)-initiated buprenorphine programs in rural and urban settings with high-need, limited resources and dissimilar staffing structures. This multicenter implementation study employed implementation facilitation using a participatory action research approach to develop, introduce, and refine site-specific clinical protocols for ED-initiated buprenorphine and referral in 3 EDs not previously initiating buprenorphine. We assessed feasibility, acceptability, and effectiveness by triangulating mixed-methods formative evaluation data (focus groups/interviews and pre/post surveys involving staff, patients, and stakeholders), patients' medical records, and 30-day outcomes from a purposive sample of 40 buprenorphine-receiving patient-participants who met research eligibility criteria (English-speaking, medically stable, locator information, nonprisoners). We estimated the primary implementation outcome (proportion receiving ED-initiated buprenorphine among candidates) and the main secondary outcome (30-day treatment engagement) using Bayesian methods. Within 3 months of initiating the implementation facilitation activities, each site implemented buprenorphine programs. During the 6-month programmatic evaluation, there were 134 ED-buprenorphine candidates among 2,522 encounters involving opioid use. A total of 52 (41.6%) practitioners initiated buprenorphine administration to 112 (85.1%; 95% confidence interval [CI] 79.7% to 90.4%) unique patients. Among 40 enrolled patient-participants, 49.0% (35.6% to 62.5%) were engaged in addiction treatment 30 days later (confirmed); 26 (68.4%) reported attending one or more treatment visits; there was a 4-fold decrease in self-reported overdose events (odds ratio [OR] 4.03; 95% CI 1.27 to 12.75). The ED clinician readiness increased by a median of 5.02 (95% CI: 3.56 to 6.47) from 1.92/10 to 6.95/10 (n(pre)=80, n(post)=83). The implementation facilitation enabled us to effectively implement ED-based buprenorphine programs across heterogeneous ED settings rapidly, which was associated with promising implementation and exploratory patient-level outcomes.


The vicious cycle between α-synuclein aggregation and autophagic-lysosomal dysfunction.
The accumulation and misfolding of α-synuclein (α-syn) represent the main pathological hallmark of PD. Overexpression of α-syn and failure of cellular protein degradation systems play a major role in α-syn aggregation. The discovery of PD-associated genes related to the autophagic-lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α-syn accumulates, suggesting that a crosstalk between α-syn aggregation and autophagic-lysosomal impairment may exist. The understanding of autophagic-lysosomal pathway dysfunctions' role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic-lysosomal pathway impairment and misfolded α-syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic-lysosomal pathway restoration as a disease-modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society.


The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models.
Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overcome crizotinib resistance in our resistant cells. Nevertheless, we were able to show that metformin induces a G1-cell cycle arrest and apoptosis alone and in combination with crizotinib. Also, consistent with earlier work, the addition of insulin-like growth factor-1 (IGF-1) to EML4-ALK positive cancer cells reduced cell killing by crizotinib. We therefore hypothesised that the effect of metformin in vivo was not due to direct cytotoxicity on cancer cells, but by modulation of IGF-1 expression. We therefore measured levels of IGF-1 in plasma taken from mice treated with metformin, but found no difference between the drug treatment and control groups. We further hypothesised that the effect of metformin could be due to modulation of thrombospondin 1 (TSP-1), which metformin has been proposed to regulatein vivo, but again we found no difference between the experimental groups. Finally, we investigated the potential for liver and kidney toxicity, as well as CYP3A based interactions, from the combination of metformin with crizotinib.


Adverse Childhood Experiences and Aging-Associated Functional Impairment in a National Sample of Older Community-Dwelling Adults.
Prior research on the health implications of adverse childhood experiences (ACEs) has focused on early or midlife adults, not older adults who bear the greatest burden of health-related functional impairment. To examine associations between ACEs, objectively measured physical mobility and cognitive impairment, and functional disability in older community-dwelling adults. Cross-sectional analysis. Community-dwelling older U.S. adults ages 50 years and older. Participants completed structured questionnaires assessing history of ACEs (childhood experience of violence/abuse, witnessing of violence, financial insecurity, parental separation, or serious illness), underwent standardized physical performance testing (tandem balance, 3-m walk, chair stand test) and cognitive testing (survey adaptation of the Montreal Cognitive Assessment), and reported functional disability (difficulty with activities of daily living). Among the 3387 participants (aged 50 to 97 years; 54% female), 44% reported a history of one or more types of ACEs. Thirty-five percent met criteria for physical mobility impairment, 24% for cognitive impairment, and 24% for functional disability. After adjusting for age, gender, race, and ethnicity, participants reporting any ACE history were more likely to demonstrate physical mobility impairment (OR 1.30, 95% CI 1.11-1.52) and cognitive impairment (OR 1.26, 95% CI 1.03-1.54) and report functional disability (OR 1.69, 95% CI 1.38-2.07), compared to those with no ACE history. Childhood experience of violence was associated with greater physical mobility impairment (OR 1.38, 95% CI 1.11-1.71) and functional disability (OR 1.86, 95% CI 1.49-2.33). Older adults with a history of ACEs are more likely to experience physical and cognitive functional impairment, suggesting that efforts to mitigate ACEs may have implications for aging-associated functional decline. Findings support the need for trauma-informed approaches to geriatric care that consider the potential role of early life traumatic experiences in shaping or complicating late-life functional challenges.


The major-element composition of Mercury's surface from MESSENGER X-ray spectrometry.
X-ray fluorescence spectra obtained by the MESSENGER spacecraft orbiting Mercury indicate that the planet's surface differs in composition from those of other terrestrial planets. Relatively high Mg/Si and low Al/Si and Ca/Si ratios rule out a lunarlike feldspar-rich crust. The sulfur abundance is at least 10 times higher than that of the silicate portion of Earth or the Moon, and this observation, together with a low surface Fe abundance, supports the view that Mercury formed from highly reduced precursor materials, perhaps akin to enstatite chondrite meteorites or anhydrous cometary dust particles. Low Fe and Ti abundances do not support the proposal that opaque oxides of these elements contribute substantially to Mercury's low and variable surface reflectance.


Late closure of the ductus arteriosus using indomethacin in the preterm infant.
Several studies have shown a lack of effect of indomethacin therapy for the closure of a patent ductus arteriosus (PDA) in premature infants over 14 days of postnatal age. In this report we describe two cases in which a hemodynamically significant PDA was closed with indomethacin in preterm infants over 20 days of age. The response to indomethacin may be more related to postconceptual age than to actual postnatal age. We suggest that intravenous indomethacin therapy should be attempted before surgical ligation is performed in those premature infants under 34 weeks postconceptual age who have a hemodynamically significant patent ductus arteriosus.


Topographical relationship between the accessory hepatic duct and the hepatic artery system.
Hepatic biliary injury is one of the most common complications in cholecystectomy and is frequently accompanied by arterial injuries. Because there are several anatomical variations of the hepatic ducts, including the accessory hepatic ducts (AHDs), it is important to consider not only the anatomical position of the hepatic ducts but also those of the AHDs in cholecystectomy. However, the topographical relationships between the AHDs and the hepatic arteries are still poorly understood. In the present study we show that AHDs were observed in 7 out of 59 (11.9%) of the cadavers. There was a single AHD in the 6 out of the 7 cadavers and double AHDs in one. In these cases, the right AHDs emerged from the anterior medial segment of the liver piercing the parenchyma, while the left AHDs emerged directly from the anterior part of the caudate lobe. The right AHDs ran anterior to the right hepatic artery, while the left AHDs ran posterior to the hepatic arteries. The topographical relationship between the AHD and the hepatic artery system was thus reversed in the cases of the right and the left AHDs.


In vitro and in vivo imaging of cell migration: two interdepending methods to unravel metastasis formation.
Metastasis development requires the migratory activity of tumor cells. It is therefore important to understand the molecular mechanisms of this migration in order to prevent metastasis development, which is the pernicious step in most solid tumor diseases. A lot of methods have been invented to investigate tumor cell migration, but not all are equally suited and no method alone is able to deliver a complete picture of tumor cell migration. We herein suggest a combination of three-dimensional in vitro and in vivo methods for the investigation of tumor cell migration and summarize the knowledge, which has been reached so far.


Nitrogen transformations and nitrous oxide flux in a tropical deciduous forest in México.
Emissions of nitrous oxide and soil nitrogen pools and transformations were measured over an annual cycle in two forests and one pasture in tropical deciduous forest near Chamela, México. Nitrous oxide flux was moderately high (0.5-2.5 ng cm-2 h-1) during the wet season and low (<0.3 ng cm-2 h-1) during the dry season. Annual emissions of nitrogen as nitrous oxide were calculated to be 0.5-0.7 kg ha-1 y-1, with no substantial difference between the forests and pasture. Wetting of dry soil caused a large but short-lived pulse of N2O flux that accounted for <2% of annual flux. Variation in soil water through the season was the primary controlling factor for pool sizes of ammonium and nitrate, nitrogen transformations, and N2O flux.


The effects of a sound-field amplification system on managerial time in middle school physical education settings.
The focus of this research effort was to examine the effect of a sound-field amplification system on managerial time in the beginning of class in a physical education setting. A multiple baseline design across participants was used to measure change in the managerial time of 2 middle school female physical education teachers using a portable sound-field amplification system. Managerial time is defined as the cumulative amount of time that students spend on organizational, transitional, and nonsubject matter tasks in a lesson. The findings showed that the amount of managerial time at the beginning of class clearly decreased when the teacher used sound-field amplification feedback to physical education students. Findings indicate an immediate need for administrators to determine the most appropriate, cost-effective procedure to support sound-field amplification systems in existing physical education settings.


On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development.
The drug development process is divided into phases with decisions required on compound selection and promotion to each subsequent development phase. In preclinical drug development the main objective is to bring the compound into human trials and there is an inability of many preclinical information packages to predict clinical responses. Since clinical responses are functions of the dose, the human dose anticipation should be a key deliverable of any preclinical package of drug candidate. The human dose should be anticipated by integration of information from multiple sources, in vitro and in vivo, non-human and human, using a variety of methodologies and approaches. Prediction of human safe and active dose relies on the availability of validated animal models for effect. Although there are many exceptions to the rule, the paper defines a four-step approach for the anticipation of human dose for first-in-man trials: 1, characterization of non-human exposure-response relationships; 2, correction for interspecies differences; 3, diagnosing compound absorption, distribution, metabolism and excretion (ADME) properties and prediction of human pharmacokinetics; and 4, prediction of human dose-responses and dose selection for phase I protocols.


Insufficient Sleep Duration And Its Association With Breakfast Intake, Overweight/Obesity, Socio-Demographics And Selected Lifestyle Behaviors Among Saudi School Children.
Adequate sleep is an important factor for maintaining good health among children. However, there have been few studies reporting on the association of sleep duration with breakfast intake frequency. This study examined the prevalence of nocturnal sleep duration among Saudi children and its association with breakfast intake, screen time, physical activity levels and socio-demographic variables. A multistage stratified cluster random sampling technique was used to select 1051 elementary school children in Riyadh. Weight and height were measured and body mass index was computed. The sleep duration, daily breakfast intake frequency, socio-demographic and lifestyle behaviors were assessed using a specifically designed self-reported questionnaire filled by the children's parents. Over 71% of the Saudi school children did not attain the recommended sufficient sleep duration at night. Results of logistic regression analysis, adjusted for confounders, exhibited significant associations between longer sleep duration and younger age (aOR=1.12, p=0.046), being female (aOR=1.39, p=0.037), higher father educational levels, daily breakfast intake (aOR=1.44, p=0.049) and lower screen time (aOR for >2 hrs/day=0.69, p=0.033). However, no significant (p> 0.05) association was found for mother education, family income, number of family member in the house, overweight/obesity, or physical activity levels. The prevalence of insufficient nocturnal sleep among Saudi children was high. Insufficient sleep was associated with breakfast and several important socio-demographic and lifestyle behaviors. The findings of this study support the development of interventions to prevent insufficient sleep and help Saudi children improve their sleeping habits.


A comparison of AmBisome to amphotericin B for treatment of systemic candidiasis in very low birth weight infants.
Amphotericin B is considered the treatment of choice for systemic candidiasis, but adverse effects may limit its use. An alternative option for the treatment of candidiasis includes lipid preparations of amphotericin B. This study investigated the safety and efficacy of AmBisome, a lipid formulation of amphotericin B containing liposomal structures, for the treatment of systemic candidiasis in very low birth weight infants (VLBWI). Data from 26 VLBWI treated with AmBisome in the study group (AmBisome group) from October 2003 to July 2006 were compared with data from 20 VLBWI treated with amphotericin B as a historical control (Amphotericin group). This study was a prospective, historical control, multi-center trial. Candida spp. was isolated in 73% (19/26) of the cases for the AmBisome group and 90% (18/20) of the cases for the Amphotericin group. The fungal eradication rate and the time to eradication was 84% (16/19) and 9+/-8 days in the AmBisome group, and 89% (16/18) and 10+/-9 days in the Amphotericin group, respectively (p=0.680 vs p=0.712). The major adverse effects were lower in the AmBisome group (renal toxicity, 21% vs 55%, p=0.029; hepatotoxity, 25% vs 65%, p=0.014, AmBisome group vs Amphotericin group, respectively). There was no significant difference in mortality attributed to systemic candidiasis (12% in the AmBisome group, 10% in the Amphotericin group, p=0.868). AmBisome is effective and safe for treating systemic fungal infections in VLBWI.


Comparison of osteogenesis and osseointegration following implant placement with simultaneous maxillary sinus augmentation using particulate and collagenated block types of deproteinized porcine bone mineral: a radiographic and histomorphometric analysis.
This study aimed to compare osseointegration and osteogenesis after single-stage maxillary sinus augmentation with the lateral window using particulate deproteinized porcine bone mineral (PDPBM) and collagenated block deproteinized porcine bone mineral (BDPBM). Bi-maxillary premolars of six beagle dogs were extracted. Eight weeks later, an implant was placed into each augmented sinus with PDPBM or BDPBM according to a split-mouth design. Eight weeks later, all specimens were harvested. Each specimen was separated into the region of interest with the implant (ROI-I) and region of interest with sinus augmented area (ROI-S) 5 mm away from ROI-I. ROI-I and ROI-S were evaluated through micro-computed tomography and histomorphometry. Bone substitute insertion took longer for the PDPBM group than for the BDPBM group (P = 0.002). In ROI-I, three-dimensional bone-to-implant contact (BIC) did not show statistically significant differences between the groups. Two-dimensional BIC also showed comparable values for both groups. In ROI-S, the graft material volume/tissue volume, trabecular bone pattern factor, and structural model index were higher in the BDPBM group than in the PDPBM group (P < 0.05). The proportions of new bone, graft material, and connective tissue were not significantly statistically different between groups. Less new bone was found in the apical area than in the coronal or middle areas in the BCPBM group (P < 0.05). BDPBM may save time in inserting bone substitutes and provide comparable osteogenesis and osseointegration to PDPBM. When performing sinus augmentation, BDPBM might improve operator's convenience with comparable biological results compared to PDPBM.


Nickel carcinogenesis mechanism: cell cycle dysregulation.
Nickel (Ni) is a widely distributed metal in the environment and an important pollutant due to its widespread industrial applications. Ni has various toxicity in humans and experimental animals, including carcinogenicity. However, the carcinogenic effects of Ni remain troublesome. Cell cycle dysregulation may be an important carcinogenic mechanism and is also a potential molecular mechanism for Ni complexes anti-cancerous effects. Therefore, we conducted a literature review to summarize the effects of Ni on cell cycle. Up to now, there were three different reports on Ni-induced cell cycle arrest: (i) Ni can induce cell cycle arrest in G0/G1 phase, phosphorylation and degradation of IkappaB kinase-alpha (IKKα)-dependent cyclin D1 and phosphoinositide-3-kinase (PI3K)/serine-threonine kinase (Akt) pathway-mediated down-regulation of expressions of cyclin-dependent kinases 4 (CDK4) play important role in it; (ii) Ni can induce cell cycle arrest in S phase, but the molecular mechanism is not known; (iii) G2/M phase is the target of Ni toxicity, and Ni compounds cause G2/M cell cycle phase arrest by reducing cyclinB1/Cdc2 interaction through the activation of the ataxia telangiectasia mutated (ATM)-p53-p21 and ATM-checkpoint kinase inhibitor 1 (Chk1)/Chk2-cell division cycle 25 (Cdc25) pathways. Revealing the mechanisms of cell cycle dysregulation associated with Ni exposure may help in the prevention and treatment of Ni-related carcinogenicity and toxicology.


A simple solution to create a custom scalp-sparing helmet to prevent alopecia in patients undergoing total skin electron beam therapy for cutaneous T cell lymphoma.
Total skin electron beam therapy (TSEBT) is effective for patients with refractory or diffuse skin involvement of cutaneous T cell lymphomas (CTCL). A common concern for patients undergoing TSEBT is the development of alopecia. Patients are already burdened with the physical symptoms associated with their disease; therefore, mitigating additional physical side effects of treatment, including cosmetic concerns, is important. As such, the purpose of this study is to evaluate a novel technique to prevent alopecia after TSEBT. Prior scalp sparing techniques have relied largely on materials found in the radiation department (e.g., lead, Superflab bolus), but in this report, we utilized a custom blue wax polyethylene material to create a custom scalp-sparing, dose attenuating, helmet. The priorities that lead to investigating this solution included patient comfort, full scalp protection, and practicality. We wanted to find a light weight, snug fitting, helmet to protect the entire hair line, that could be easily fabricated for any patient. In the end, we found success in our efforts to minimize radiation to the scalp for indistinguishable hair volume changes.


The coupling valve graft: a procedure for double-valve replacement.
Coupling valve grafting, a procedure to enlarge the annulus of the aortic valve and of the mitral valve simultaneously, is described. It consists of extending the J-shaped aortotomy through the middle of the noncoronary cusp into the superior aspect of the left atrium and down the anterior leaflet of the mitral valve. Then the mitral and aortic valves are replaced with a coupling valve graft, a vascular prosthesis attached to two prosthetic valves. This technique seems to be most suitable for patients in whom the valves of both annuli are narrow, as is often seen in aortic and mitral stenosis. Since both valve annuli can be enlarged greatly in this procedure, combinations of prosthetic valve sizes can be freely chosen for the two valves.


A pitfall in two-site sandwich 'one-step' immunoassay with monoclonal antibodies for the determination of human alpha-fetoprotein.
Utilizing monoclonal antibodies directed to 2 distinct antigenic determinants of the human alpha-fetoprotein (AFP), Uotila, Ruoslahti and Engvall developed the 2-site sandwich immunoassay. They found that due to the different specificities of monoclonal antibodies, 2 antigen-antibody reactions, AFP with immobilized antibody and AFP with labeled antibody, could be accomplished in a single step. We have found, however, that above a certain concentration, AFP detectable by their method decreased because the labeled antibody tended to bind with AFP that failed to react with the immobilized antibody. Consequently, 2 different AFP concentrations produced the same result, and an extremely high, still clinically expectable concentration gave a false negative result. Such an inhibition in high AFP concentrations was not observed in the conventional '2-step' immunoassay within the range of concentrations tested (0.1 ng-3 mg/ml). On the basis of these observations, the 2-site '1-step' immunoassay for AFP would have to be applied on multiple dilutions of the serum to avoid an erroneous interpretation of the results.


A multiple-contact EMG recording array for mapping single muscle unit territories.
The glycogen-depletion technique has become a well-established method for determining histologically the cross-sectional distribution of a single muscle unit. A major drawback of this method is its low yield of one depleted unit per experiment. Furthermore, this technique is particularly unsuited for determining the longitudinal distribution of single muscle units in long, broad muscles because of the formidable serial sectioning job that would be required. Our alternative, electrophysiological method utilizes a multiple-contact, two-dimensional EMG recording array to map efficiently the cross-sectional and longitudinal distributions of numerous single muscle units in anatomically diverse muscles. Additionally, architectural information on muscle fiber lengths, end-plate locations, motor subunit (MSU) arrangements and muscle conduction velocities can be determined.


Sensitivity evaluation of 2019 novel coronavirus (SARS-CoV-2) RT-PCR detection kits and strategy to reduce false negative.
The early detection and differential diagnosis of respiratory infections increase the chances for successful control of COVID-19 disease. The nucleic acid RT-PCR test is regarded as the current standard for molecular diagnosis. However, the maximal specificity confirmation target ORF1ab gene is considered to be less sensitive than other targets in clinical application. In addition, recent evidence indicated that the initial missed diagnosis of asymptomatic patients with SARS-CoV-2 and discharged patients with "re-examination positive" might be due to low viral load, and the ability of rapid mutation of SARS-CoV-2 also increases the rate of false-negative results. Moreover, the mixed sample nucleic acid detection is helpful in seeking out the early community transmission of SARS-CoV-2 rapidly, but the detection kit needs ultra-high detection sensitivity. Herein, the lowest detection concentration of different nucleic acid detection kits was evaluated and compared to provide direct evidence for the selection of kits for mixed sample detection or make recommendations for the selection of validation kit, which is of great significance for the prevention and control of the current epidemic and the discharge criteria of low viral load patients.


[A woman with a remarkable prolapse].
A 59-year-old woman (para 3) felt something protruding from the vagina after a violent cough, followed by an extreme abdominal pain. A spontaneous small bowel evisceration through a vaginal herniation was diagnosed.


Paget's disease of bone: evidence for complex pathogenetic interactions.
Paget's disease of bone (PDB), with a prevalence of 2 to 5% in Caucasians >55 years, is the second most frequent metabolic bone disease, after osteoporosis. PDB characteristics are bone lesions with an imbalanced bone remodeling, resulting in disorganized and nonfully fledged new bone. PDB etiology is not completely understood. In this review, current views on the etiology, clinical aspects, and PDB treatment are summarized and discussed. The PubMed database was searched using the keywords PDB, sequestosome1 (SQSTM1), valosin-containing protein (VCP), receptor activator of nuclear factor-κB (RANK), osteoprotegerin (OPG), RANK ligand (RANKL), mutation, genetic variants, virus, osteosarcoma, bisphosphonates, and denosumab. Environmental evidence (e.g. viruses) and also genetic risk factors have been found for PDB. Until now, SQSTM1 was the only PDB-causing gene identified. However, PDB patients without SQSTM1 mutations seem to have susceptibility genetic polymorphisms in regions containing the CaSR, ESR1, TNFRSF11B (OPG), TNFRSF11A (RANK), CSF1 (M-CSF), OPTN, TM7SF4 (DC-STAMP), VCP, NUP205, RIN3, PML, and GOLGA6A genes, resulting in an increased risk of developing PDB. The nature of these genes indicates that the regulation of osteoclastogenesis is a key process in PDB pathogenesis. Furthermore, with the involvement of SQSTM1 and VCP in autophagy and in forming protein aggregates, this might also indicate that a disturbance of these processes might be a risk factor. Unraveling the PDB genetic background is instrumental to understanding the PDB pathogenesis and the role of slow viruses. Furthermore, it might make early detection and subsequently treatment of risk individuals possible.


Structure and protein design of a human platelet function inhibitor.
Hematophagous arthropods secrete a salivary apyrase that inhibits platelet activation by catabolizing ADP released from damaged tissues and blood cells. We report the X-ray crystal structures of a human enzyme of the soluble apyrase family in its apo state and bound to a substrate analog. The structures reveal a nucleotide binding domain comprising a five-blade beta propeller, binding determinants of the substrate and the active site, and an unusual calcium binding site with a potential regulatory function. Using a comparative structural biology approach, we were able to redesign the human apyrase so as to enhance its ADPase activity by more than 100-fold. The engineered enzyme is a potent inhibitor of platelet aggregation and may serve as the basis for the development of a new class of antithrombotic agents.


Integrated MEG/fMRI model validated using real auditory data.
The main objective of this paper is to present methods and results for the estimation of parameters of our proposed integrated magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) model. We use real auditory MEG and fMRI datasets from 7 normal subjects to estimate the parameters of the model. The MEG and fMRI data were acquired at different times, but the stimulus profile was the same for both techniques. We use independent component analysis (ICA) to extract activation-related signal from the MEG data. The stimulus-correlated ICA component is used to estimate MEG parameters of the model. The temporal and spatial information of the fMRI datasets are used to estimate fMRI parameters of the model. The estimated parameters have reasonable means and standard deviations for all subjects. Goodness of fit of the real data to our model shows the possibility of using the proposed model to simulate realistic datasets for evaluation of integrated MEG/fMRI analysis methods.


Carbon tetrachloride-induced nephrotoxicity and protective effect of betaine in Sprague-Dawley rats.
To observe the changes in the antioxidative defense enzymes and to detect the alterations of renal microscopy after carbon tetrachloride (CCl4) administration in rats and to investigate the possible protective effects of betaine against CCl4-induced renal damage. Thirty-two adult Sprague-Dawley rats were divided into four groups as follows: control group, betaine group, CCl4 group, and CCl4 + betaine group. CCl4 was given subcutaneously at 1 mL/kg. In the CCl4 + betaine group, rats were pretreated with betaine, then exposed to CCl4 at the same dose. Betaine group rats received concentrated betaine solution. The rats were killed and the kidneys taken for enzyme analyses and histologic examination. Glutathione peroxidase, superoxide dismutase, and catalase activities were measured in right kidney homogenates. Left kidneys were processed for light microscopic evaluation. In the CCl4-treated group, significant increases in kidney superoxide dismutase and catalase activities and significant decrease in glutathione peroxidase activity were observed (P <0.01). These changes were found to be normalized in the CCl4 + betaine group. Betaine did not change the enzyme activities. Exposure to CCl4 resulted in glomerular and tubular alterations in the renal cortex. These alterations were found to be prevented by betaine pretreatment. These results indicate that exposure to CCl4 leads to renal damage in rats and betaine exerts an improvement on nephrotoxic effects of CCl4.


Vaginal progesterone for the prevention of recurrent spontaneous preterm birth.
After the United States Food and Drug Administration pulled 17-alpha hydroxyprogesterone caproate from the market for its use in prevention of recurrent spontaneous preterm birth, national societies have had mixed recommendations regarding the management of patients with a singleton pregnancy and previous spontaneous preterm birth. Herein we highlight the randomized trial data and translational evidence supporting the use of vaginal progesterone for prevention of recurrent spontaneous preterm birth in singleton pregnancies. Prophylactic vaginal progesterone starting at 16 weeks and 0 days every night should be offered to patients with singletons and previous singleton spontaneous preterm birth regardless of cervical length, and continued along with placement of cerclage if a transvaginal ultrasound cervical length ≤25 mm is detected at <24 weeks.