Neutrophil Degranulation of Azurophil and Specific Granules.
Neutrophils play a pivotal role in innate immunity and in the inflammatory reactions. Upon activation, neutrophils release several toxic molecules directed against microbial pathogens into the phagosome. These molecules include reactive oxygen species (ROS), myeloperoxidase, glucosidases, proteases, and antibacterial peptides. In resting cells these proteins and the enzyme responsible for ROS production (NOX2) are stored inside or at the membranes of different granules called azurophil or primary, specific or secondary, gelatinase or tertiary, and the secretory vesicles. Each granule has a specific density, content, and markers. Myeloperoxidase (MPO) is the azurophil granule marker, and the neutrophil-gelatinase-associated lipocalin (NGAL) is the specific granule marker. After cell activation by different stimuli, granule contents are released into the phagosome or in the extracellular space through a process called degranulation. Also during this process, membrane granules fuse with the phagosome and plasma membrane allowing expression of new markers at the cell surface. The degranulation can be assessed by measuring either the release of different proteins by neutrophils or the expression of granule markers at the plasma membrane. In this chapter, we describe the techniques used to measure degranulation of azurophil and specific neutrophil granules using different approaches such as measurement of MPO enzymatic activity and detection of MPO and NGAL proteins by SDS-PAGE and Western blot.


Socioeconomic Status and Longitudinal Lung Function of Healthy Mexican Children.
Our aim was to estimate the longitudinal effect of Socioeconomic status (SES) on lung function growth of Mexican children and adolescents. A cohort of Mexican children in third grade of primary school was followed with spirometry twice a year for 6 years through secondary school. Multilevel mixed-effects lineal models were fitted for the spirometric variables of 2,641 respiratory-healthy Mexican children. Monthly family income (in 2002 U.S. dollars [USD]) and parents' years completed at school were used as proxies of SES. Individuals with higher SES tended to have greater height for age, and smaller sitting height/standing height and crude lung function. For each 1-year increase of parents' schooling, Forced expiratory volume in 1 sec (FEV1) and Forced vital capacity (FVC) increased 8.5 (0.4%) and 10.6 mL (0.4%), respectively (p <0.05) when models were adjusted for gender. Impact of education on lung function was reduced drastically or abolished on adjusting by anthropometric variables and ozone. Higher parental schooling and higher monthly family income were associated with higher lung function in healthy Mexican children, with the majority of the effect likely due to the increase in height-for-age.


Twice-daily Thoracic Radiotherapy for Limited-stage Small-cell Lung Cancer Does Not Increase the Incidence of Acute Severe Esophagitis.
Acute esophagitis is common after thoracic radiation therapy (TRT) given with chemotherapy for limited-stage small-cell lung cancer (LS SCLC). Although twice-daily TRT to 45 Gy in 30 fractions is considered standard, some clinicians are reluctant to use this schedule because of its perceived impracticality and risk of severe esophagitis. We reviewed a single-institution experience with severe (grade ≥ 3) esophagitis after TRT with chemotherapy for LS SCLC. A total of 504 patients were identified as having received TRT (≥45 Gy) with platinum-containing chemotherapy for LS SCLC at MD Anderson Cancer Center in 1987 through 2012. Patients with complete or good partial response were offered prophylactic cranial irradiation. Esophagitis was scored retrospectively with the Common Terminology Criteria for Adverse Events, V3.0. Clinical variables were analyzed for possible association with acute grade ≥ 3 esophagitis. At a median follow-up time of 23.9 months (range, 1.2-240.8 months), 103 (20%) patients had experienced grade ≥ 3 esophagitis. In univariate analysis, TRT dose ≥ 60 Gy was the only factor associated with severe esophagitis (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.02-3.30; P = .043); use of twice-daily TRT was not (OR, 0.96; 95% CI, 0.61-1.52; P = .867). The significance of TRT to ≥ 60 Gy was maintained in multivariate Cox regression analysis adjusted for tumor size (OR, 1.91; 95% CI, 1.05-3.46; P = .034). TRT to ≥ 60 Gy predicted acute severe esophagitis, but twice-daily fractionation did not. Standard-dose 45-Gy twice-daily TRT should not be avoided for fear of severe esophagitis.


Immunomodulation of tissue-engineered transplants: in vivo bone generation from methylprednisolone-stimulated chondrocytes.
Subcutaneously implanted, in vitro engineered tissue is generally affected by the immune system of the host even in autogenous transplantation. The aim of this study was to investigate immunomodulation of subcutaneously implanted tissue-engineered cartilage transplants by intramuscular methylprednisolone application. Transplants consisted of auricular rabbit chondrocytes, polylactide-polyglycolide co-polymer fleeces and species-specific fibrin or agarose. The transplants were subcutaneously implanted in the ridge. Thereafter, animals were separated into two groups, one with and one without methylprednisolone treatment. The specimens were histologically investigated after 6 and 12 weeks. Fleece fiber degradation was complete after 12 weeks, and all transplants showed areas of calcification. The corticosteroid-treated group presented pronounced trabecular bone generation without fibrous tissue infiltration. The untreated group showed sporadic islets of calcification without coherent bone formation, and adjacent fibrous tissue had infiltrated the transplants. Native controls and corticoid-treated transplants did not exhibit bone generation or signs of fibrous tissue infiltration. This study found that immunomodulation by intramuscular methylprednisolone application protects tissue-engineered autogenous chondrocyte transplants from fibrous tissue infiltration and induces trabecular bone formation.


Factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion.
Human antibody-secreting cells (ASC) in peripheral blood are found after vaccination or infection but rapidly apoptose unless they migrate to the bone marrow (BM). Yet, elements of the BM microenvironment required to sustain long-lived plasma cells (LLPC) remain elusive. Here, we identify BM factors that maintain human ASC > 50 days in vitro. The critical components of the cell-free in vitro BM mimic consist of products from primary BM mesenchymal stromal cells (MSC), a proliferation-inducing ligand (APRIL), and hypoxic conditions. Comparative analysis of protein-protein interactions between BM-MSC proteomics with differential RNA transcriptomics of blood ASC and BM LLPC identify two major survival factors, fibronectin and YWHAZ. The MSC secretome proteins and hypoxic conditions play a role in LLPC survival utilizing mechanisms that downregulate mTORC1 signaling and upregulate hypoxia signatures. In summary, we identify elements of the BM survival niche critical for maturation of blood ASC to BM LLPC.


Correction to: Rapid reconstitution packages (RRPs) for stable storage and delivery of glucagon.
Following are updated Figs. 1, 3, 5, and 7. The original article has also been updated: Fig. 1 a RRP. b RRP dimensions. c RRP inside of syringe. Fig. 3 RRP activation and fluid flow.


Treatment of neurogenic bowel dysfunction using transanal irrigation: a multicenter Italian study.
Thirty-six patients with unsatisfactory treatment of neurogenic bowel dysfunctions (NBD) were enrolled from Spinal Units and Rehabilitation Centers in Italy. Treatment was for 3 weeks using a newly developed integrated system with an enema continence catheter for transanal irrigation (Peristeen, Coloplast A/S Kokkedal Denmark). To evaluate the effects of Peristeen Anal Irrigation on NBD and patient quality of life (QoL). Italy. Lesion level, ambulatory status and hand functionality were determined in all patients. NBD symptoms and QoL were evaluated before and after treatment, using a specific questionnaire. Statistical analysis was performed using McNemar Test and Sign Test. Thirty-six patients were enrolled, and 32 patients completed the study. At the end of the treatment, 28.6% of patients reduced or eliminated their use of pharmaceuticals. Twenty-four patients became less dependent on their caregiver. There was a significant increase in patients' opinion of their intestinal functionality (P=0.001), QoL score (P=0.001) and their answers regarding their degree of satisfaction (P=0.001). A successful outcome was recorded for 68% of patients with fecal incontinence, and for 63% of patients with constipation. Peristeen Anal Irrigation is a simple therapeutic method for managing NBD and improving QoL. It should be considered as the treatment of choice for NBD, playing a role in the neurogenic bowel analogous to that of intermittent clean catheterization in bladder treatment.


Vaccines and use of immunosuppressive and immunomodulatory therapy in a pediatric dermatology clinic-A single institution experience.
Vaccine type and timing are critical issues to prevent unintended infections in those on immunosuppressive therapies. We retrospectively chart reviewed patients at Children's Wisconsin Pediatric Dermatology Clinic on immunosuppressives and immunomodulators between 11/1/2012 and 6/1/2020 and found that approximately 76% of patient encounters do not have documented vaccine counseling in the medical chart before initiation of immunosuppressives and immunomodulators. As age increased, vaccine counseling was less likely to be documented (odds ratio: 0.89; 95% confidence interval: 0.84-0.95, p = .001). In addition, 13 patient encounters (4%) were not up to date with live vaccines before immunosuppressive or immunomodulating therapy. There is an opportunity to improve clinical processes to ensure documentation of vaccination status and vaccine counseling before starting immunosuppressive and immunomodulator medications in a pediatric dermatology clinic.


Modulation of eosinophil generation and migration by Mangifera indica L. extract (Vimang).
The effects of Vimang, an aqueous extract of the stem bark of Mangifera indica L. (Anacardiaceae), on cell migration in an experimental model of asthma was investigated. In vivo treatment of Toxocara canis-infected BALB/c mice for 18 days with 50 mg/kg Vimang reduced eosinophil migration into the bronchoalveolar space and peritoneal cavity. Also, eosinophil generation in bone marrow and blood eosinophilia were inhibited in infected mice treated with Vimang. This reduction was associated with inhibition of IL-5 production in serum and eotaxin in lung homogenates. In all these cases the effects of Vimang were more selective than those observed with dexamethasone. Moreover, Vimang treatment is not toxic for the animals, as demonstrated by the normal body weight increase during infection. These data confirm the potent anti-inflammatory effect of Vimang and support its potential use as an alternative therapeutic drug to the treatment of eosinophilic disorders including those caused by nematodes and allergic diseases.


Risk factors for morbidity in 1- to 9-day-old dairy calves following caustic paste disbudding.
Calfhood morbidity is an important issue on commercial dairy operations, with substantial production and welfare impacts. The objective of this observational study was to evaluate potential risk factors for morbidity, including disbudding, disbudding pain control, serum total protein (STP) concentrations, and haptoglobin concentrations in young dairy calves. A total of 140 heifer calves from a commercial dairy farm in southwestern Ontario, Canada, were enrolled at 1 to 9 d of age and followed for 1 wk. Calves were scored at enrollment for several health parameters using a scale from 0 to 3, with 0 representing normal and 3 representing severely abnormal. Calves were only included if they were considered healthy enough to participate using cut points of <3 for rectal temperature and fecal score; ≤2 for nasal discharge, ocular discharge, and cough score; and 1 for ear position, navel score, and joint score. To ensure that only calves that were considered healthy on the baseline day were included, 17 calves were excluded from analysis, resulting in a total of 123 calves. These calves were a part of a disbudding trial, with 100 disbudded using a commercial caustic paste and 23 sham disbudded with a placebo paste. The disbudding paste (commercial or sham) was applied to calves on enrollment day (baseline) with health scoring at baseline and 3 and 7 d later. The following health outcomes were analyzed: diarrhea (a fecal consistency score of ≥2), respiratory disease (a total respiratory score of ≥5), and general sickness [suffering from either diarrhea, respiratory disease, or a navel or joint infection (joint or navel score of ≥2)]. The following variables were assessed for association with the outcomes: STP, inadequate transfer of passive immunity (<5.2 g/dL STP), pain control treatment for disbudding (lidocaine nerve block alone, meloxicam alone, lidocaine nerve block and meloxicam, no pain control, sham), disbudding (disbudded or sham), and haptoglobin concentrations (taken on the baseline day, +3 d and +7 d). We did not detect any relationship between the development of a health outcome of interest (diarrhea, respiratory, or sick) and disbudding or pain control on any of the days following disbudding. However, for every 1 g/dL increase in STP concentration, calves had 0.24 and 0.33 times the odds of suffering from diarrhea or any sickness event, respectively, 3 d after disbudding. At 3 d after disbudding, for every 0.1 mg/mL increase in haptoglobin concentration on that day, calves had 1.34 and 1.20 times the odds of having diarrhea or a general sickness, respectively. These findings suggest that disbudding itself or the pain control method does not appear to influence health after the procedure when healthy calves are disbudded. Calves developing an illness 3 d after disbudding were more likely to have had lower STP concentrations and increased haptoglobin concentrations.


Mycotoxigenic infestation in samples of cereal straw from Bihar, India.
A survey of different types of cereal straw samples viz. paddy, maize and wheat, from Bihar State, India, was conducted in order to examine the mould flora and mycotoxin contamination. Out of 170 samples examined for mould flora,Aspergillus flavus group of fungi had highest level of incidence followed byA niger. Isolates ofA flavus, A ochraceus, Fusarium verticillioides andPenicillium citrinum were screened for their mycotoxins producing abilities. Out of 75, 63 and 68 isolates ofA flavus group obtained from stored straw of paddy, maize and wheat samples, respectively, 27 (36%), 14 (22%) and 24 (35%) were found to be toxigenic which produced different combinations of aflatoxins in different concentrations. The percentage toxigenicity was comparatively lower in the isolates of other mycotoxigenic fungi from all types of samples. Out of 222 samples of straw analysed for natural occurrence of different mycotoxins, besides the aflatoxins present, zearalenone, ochratoxin A and citrinin were also recorded alone or as co-contaminants. A conducive climate together with the socioeconomic conditions of this region are important determinants for the high incidence of mycotoxins in cereal straw samples.


Variables affecting the propensity to buy branded beef among groups of Australian beef buyers.
Australian beef consumers have different preferences given their characteristics and the effect on expected quality of cues related to health, production process and eating experience. Beef brands using Meat Standards Australia (MSA) grades can help to signal quality and reduce consumers' uncertainty when shopping. The objective of this study is to identify the characteristics of beef buyers and their perceptions about product attributes that affect the propensity to buy branded beef. Binary logistic models were applied identifying differences between all respondents and the potential target market, including buyers in medium to high income segments, and between buyers in the target market who would buy branded beef for taste and health reasons. Variables increasing the propensity to buy branded beef include previous experience, appreciation for branded cuts and concern about quality more than size. Finally, variations in preferences for marbling and cut were found between buyers who would buy branded beef for taste and health reasons.


Use of physiological information and process optimisation enhances production of extracellular nuclease by a marine strain of Bacillus licheniformis.
The extracellular nuclease, NucB, from Bacillus licheniformis, can digest extracellular DNA in biofilms, causing biofilm dispersal, and may therefore be used commercially to remove biofilms. However, producing quantities of this secreted peptide is difficult and our aim was therefore to improve its laboratory scale production. This study builds on our understanding of B. licheniformis physiology to enhance NucB production. The addition of manganese, which triggers sporulation and enhances NucB expression, lead to a 5-fold increase in NucB production. Optimisation via Placket-Burman design of experiments identified 3 significant medium components and a subsequent Central Composite Design, to determine the optimum levels of these components, resulted in a 10-fold increase to 471U/ml. The optimal phosphate concentration was less than 0.3mM as this is known to inhibit nuclease production. The use of physiologically relevant information combined with optimisation represents a promising approach to increased enzyme production, which may also be widely applicable.


Human sperm endothelial nitric oxide synthase expression: correlation with sperm motility.
To characterize the pattern of endothelial nitric oxide synthase (eNOS) expression on human spermatozoa and to determine whether sperm eNOS expression correlates with sperm function. Prospective, observational study. University infertility clinic. Twelve nonazoospermic infertile men. Semen samples (n=12) obtained from nonazoospermic infertile men were fractionated on discontinuous Percoll gradients. Endothelial nitric oxide synthase staining on spermatozoa was correlated with sperm motility in Percoll gradient-fractionated spermatozoa. Endothelial nitric oxide synthase protein was detected with the use of a previously characterized monoclonal antibody. Control slides were incubated with preabsorbed antibody or mouse immunoglobulin G. Localization of eNOS on human spermatozoa and correlation between the pattern of sperm eNOS expression and sperm motility. Morphologically normal spermatozoa exhibited postacrosomal and equatorial eNOS immunostaining. However, abnormally shaped spermatozoa often exhibited aberrant staining (in the midpiece and/or head region). A significant negative correlation was observed between the percentage of sperm with aberrant eNOS immunostaining and the percentage of motile sperm (r=-.46). The specific localization of eNOS to human spermatozoa suggests that nitric oxide may be involved in normal sperm physiology. However, aberrant patterns of sperm eNOS expression are associated with decreased sperm motility, possibly through the generation of excessive cytotoxic oxidants.


Standard setting for outpatient gynaecology procedures: a multidisciplinary framework for implementation.
This chapter describes the changing cultural background of health care from which any service is delivered. In particular, the authors hope to outline cultural, educational, technical and environmental changes that have been used as opportunities to develop a quality-assessed outpatient hysteroscopic service. Examined within the chapter will be the roles and limitations of evaluation and audit, research and the multidisciplinary team. The importance of process, relationships and collaborative working within organizations will be explored, and outpatient hysteroscopy will be used as a working example of how these inform a model of practice development.


Predicting personal exposure of pregnant women to traffic-related air pollutants.
As epidemiological studies report associations between ambient air pollution and adverse birth outcomes, it is important to understand determinants of exposures among pregnant women. We measured (48-h, personal exposure) and modeled (using outdoor ambient monitors and a traffic-based land-use regression model) NO, NO(2), fine particle mass and absorbance in 62 non-smoking pregnant women in Vancouver, Canada on 1-3 occasions during pregnancy (total N=127). We developed predictive models for personal measurements using modeled ambient concentrations and individual determinants of exposure. Geometric mean exposures of personal samples were relatively low (GM (GSD) NO=37 ppb (2.0); NO(2)=17 ppb (1.6); 'soot', as filter absorbance=0.8 10(-5) m(-1) (1.5); PM(2.2)=10 microg m(-3) (1.6)). Having a gas stove (vs. electric stove) in the home was associated with exposure increases of 89% (NO), 44% (NO(2)), 20% (absorbance) and 35% (fine PM). Interpolated concentrations from outdoor fixed-site monitors were associated with all personal exposures except NO(2). Land-use regression model estimates of outdoor air pollution were associated with personal NO and NO(2) only. The effects of outdoor air pollution on personal samples were consistent, with and without adjustment for other individual determinants (e.g. gas stove). These findings improve our understanding of sources of exposure to air pollutants among pregnant women and support the use of outdoor concentration estimates as proxies for exposure in epidemiologic studies.


On the sufficiency conditions for the stability of bone remodeling equilibrium.
In this technical note a sufficiency condition is established for the stability of a strain-energy-based bone remodeling theory in the special case of a beam loaded by an axial force and a bending moment. In a previous report the same condition was shown to be a necessary condition for stability in the same situation. The remodeling scheme is one characterized by a remodeling stimulus equal to the strain energy density divided by the bulk or apparent density raised to an exponent m as well an elastic modulus proportional to bulk or apparent density raised to an exponent n. In order for a remodeling scheme to be stable for an elastic beam loaded by an axial force and a bending moment, it is established that the condition that m must be greater than n is not only necessary, but also sufficient.


Comparing the efficiency of eight-session versus four-session memory intervention for older adults.
Evidence that reduced treatment achieves similar outcomes is beneficial because shorter interventions may be more cost-effective and more acceptable to participants. We examined the effects of shortening a memory intervention for elders from eight sessions to four sessions. Shortening the intervention had little impact on either self-reported or performance measures of memory and daily living activities. Small to moderate effects were associated with positive changes in both groups. When examining cost-effectiveness, an eight-session intervention produced slightly greater gains in memory performance, but at a higher cost. Future studies should systematically vary key intervention components in more diverse samples.


Characterization of an extensive rainbow trout miRNA transcriptome by next generation sequencing.
MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression in a wide variety of physiological processes. They can control both temporal and spatial gene expression and are believed to regulate 30 to 70% of the genes. Data are however limited for fish species, with only 9 out of the 30,000 fish species present in miRBase. The aim of the current study was to discover and characterize rainbow trout (Oncorhynchus mykiss) miRNAs in a large number of tissues using next-generation sequencing in order to provide an extensive repertoire of rainbow trout miRNAs. A total of 38 different samples corresponding to 16 different tissues or organs were individually sequenced and analyzed independently in order to identify a large number of miRNAs with high confidence. This led to the identification of 2946 miRNA loci in the rainbow trout genome, including 445 already known miRNAs. Differential expression analysis was performed in order to identify miRNAs exhibiting specific or preferential expression among the 16 analyzed tissues. In most cases, miRNAs exhibit a specific pattern of expression in only a few tissues. The expression data from sRNA sequencing were confirmed by RT-qPCR. In addition, novel miRNAs are described in rainbow trout that had not been previously reported in other species. This study represents the first characterization of rainbow trout miRNA transcriptome from a wide variety of tissue and sets an extensive repertoire of rainbow trout miRNAs. It provides a starting point for future studies aimed at understanding the roles of miRNAs in major physiological process such as growth, reproduction or adaptation to stress. These rainbow trout miRNAs repertoire provide a novel resource to advance genomic research in salmonid species.


Immunohistochemical demonstration of the intracellular localization of pituitary adenylate cyclase activating polypeptide-like immunoreactivity in the rat testis using the stamp preparation.
Radioimmunoassay has revealed an abundance of PACAP in the rat testis. In the present study, a novel stamp preparation together with light microscopic immunohistochemistry were used to investigate in detail the intracellular localization of PACAP-like immunoreactivity (PACAP-LI) in rat germ cells. Samples were obtained by pressing the freshly cut surfaces of the testes against glass slides. PACAP-LI was clearly identified in developing acrosomes using five antisera which recognize PACAP 38, or both PACAP 27 and PACAP 38. Immunoreactivity with the antisera specific to PACAP38 was strictly localized in the developing acrosomes of the spermatids but vanished in the mature spermatids. Using an antiserum which detects PACAP 27 specifically, little staining was observed. Based on the specificities of antisera used, it was suggested that the PACAP-LI in the acrosomes represents mainly PACAP 38-LI. In addition, the present results supported the usefulness of the stamp preparation for immunohistochemical study of testicular tissues.


Systematic review of pregnancy and renal outcomes for women with chronic kidney disease receiving assisted reproductive therapy.
As awareness around infertility is increasing among patients with chronic kidney disease (CKD), ever more of them are seeking Assisted Reproductive Technology (ART). Our aim was to perform a systematic review to describe obstetric and renal outcomes in women with CKD following ART. The following databases were searched from 1946 to May 2021: (1) Cochrane Central Register of Controlled Trials (CENTRAL), (2) Cumulative Index to Nursing and Allied Health Literature (CINAHL), (3) Embase and (4) MEDLINE. The database search identified 3520 records, of which 32 publications were suitable. A total of 84 fertility treatment cycles were analysed in 68 women. Median age at time of pregnancy was 32.5 years (IQR 30.0, 33.9 years). There were 60 clinical pregnancies resulting in 70 live births (including 16 multifetal births). Four women developed ovarian hyperstimulation syndrome which were associated with acute kidney injury. Hypertensive disorders complicated 26 pregnancies (38.3%), 24 (35.3%) pregnancies were preterm delivery, and low birth weight was present in 42.6% of pregnancies. Rates of live birth and miscarriage were similar for women with CKD requiring ART or having natural conception. However, more women with ART developed pre-eclampsia (p < 0.05) and had multifetal deliveries (p < 0.001), furthermore the babies were lower gestational ages (p < 0.001) and had lower birth weights (p < 0.001). This systematic review represents the most comprehensive assessment of fertility outcomes in patients with CKD following ART. However, the high reported live birth rate is likely related to reporting bias. Patient selection remains crucial in order to maximise patient safety, screen for adverse events and optimise fertility outcomes.


The role of microRNAs and other endogenous small RNAs in plant stress responses.
Crop yields are significantly reduced by biotic and abiotic stresses throughout the world. To reduce the damage caused by stress factors, plants have evolved sophisticated adaptive responses involving reprogramming gene expression at the transcriptional, post-transcriptional and post-translational levels. A better understanding of such processes will lead to new strategies to improve plant stress tolerance. Recently discovered endogenous small RNAs (microRNAs and small-interfering RNAs) have emerged as important players in plant stress responses. The observation that some of the small RNAs are up- or down-regulated in response to stress implies that these small RNAs have a role in stress tolerance. Stress-induced small RNAs might down-regulate their target genes, which may encode negative regulators of stress responses. Conversely, small RNAs down-regulated in response to stress cause the accumulation of their target mRNAs, which may contribute positively to the adaptation to stress. Here, we review the current status of small RNAs involved in biotic and abiotic stress regulatory networks.


Where we stand, where we are moving: Surveying computational techniques for identifying miRNA genes and uncovering their regulatory role.
Traditional biology was forced to restate some of its principles when the microRNA (miRNA) genes and their regulatory role were firstly discovered. Typically, miRNAs are small non-coding RNA molecules which have the ability to bind to the 3'untraslated region (UTR) of their mRNA target genes for cleavage or translational repression. Existing experimental techniques for their identification and the prediction of the target genes share some important limitations such as low coverage, time consuming experiments and high cost reagents. Hence, many computational methods have been proposed for these tasks to overcome these limitations. Recently, many researchers emphasized on the development of computational approaches to predict the participation of miRNA genes in regulatory networks and to analyze their transcription mechanisms. All these approaches have certain advantages and disadvantages which are going to be described in the present survey. Our work is differentiated from existing review papers by updating the methodologies list and emphasizing on the computational issues that arise from the miRNA data analysis. Furthermore, in the present survey, the various miRNA data analysis steps are treated as an integrated procedure whose aims and scope is to uncover the regulatory role and mechanisms of the miRNA genes. This integrated view of the miRNA data analysis steps may be extremely useful for all researchers even if they work on just a single step.


FLIP and the death effector domain family.
Death effector domains (DEDs) are protein interaction modules found in a number of proteins known to regulate apoptosis from death receptors. The core DED family members that orchestrate programmed cell death from death receptors include the adaptor protein FADD, the initiator caspases procaspases-8 and -10 and the regulatory protein c-FLIP. Through homotypic DED interactions, these proteins assemble into the death-inducing signaling complex (DISC) to regulate initiator caspase activation and launch the apoptotic proteolytic cascade. A considerable body of evidence, however, is revealing that the same core group of DED-containing proteins also paradoxically promotes survival and proliferation in lymphocytes and possibly other cell types. This review delves into recent findings regarding these two opposing functional aspects of the core DED proteins. We discuss the current effort expanding our structural and biochemical view of how DED proteins assemble into the DISC to fully activate initiator caspases and execute cell death, and finally we examine details linking the same proteins to proliferation and describe how this outcome might be achieved through restricted activation of initiator caspases.


Efficacy of quantitative hepatobiliary scintigraphy and fatty-meal sonography for evaluating patients with suspected partial common duct obstruction.
In this study we evaluated by blinded design the diagnostic efficacy of two noninvasive techniques, quantitative hepatobiliary scintigraphy (QHS) and fatty-meal sonography (FMS), for evaluating patients with suspected partial common duct obstruction. Quantitative hepatobiliary scintigraphy was performed on 56 cholecystectomized individuals (22 asymptomatic controls, 28 patients with suspected partial common duct obstruction, and 6 nonjaundiced cirrhotics) and FMS was done in 51 cases. For QHS, time-activity curves were generated for regions of interest over the liver, hepatic hilum, and common duct. For FMS, we measured common duct diameter before and 45 min after a fatty meal (Lipomul, 1.5 ml/kg). Each of the 28 patients with suspected partial common duct obstruction and 6 cirrhotic patients underwent endoscopic retrograde cholangiography, often accompanied by sphincter of Oddi manometry. Findings from these examinations were taken as the gold standard to determine the presence or absence of conditions that could account for intermittent symptomatic partial common duct obstruction. The most sensitive indicators for a positive test were a 45-min isotope clearance of less than 63% for QHS and a common duct increase of greater than or equal to 2 mm after the fatty meal for FMS. Of 28 patients with suspected partial common duct obstruction, 15 were judged to be true-positive and 13 true-negative. The 6 cirrhotic patients were without common duct obstruction. The study findings showed that each test had a 67% sensitivity that improved to 80% when the findings from both test results were combined. The specificity of QHS was 85% and that of FMS was 100%. All 6 cirrhotic patients had negative findings on FMS and 4 were false-positive on QHS. The true-positives included 8 patients with a small common duct stone and 6 with obstructive sphincter of Oddi dysfunction (4 stenosis, 2 dyskinesia). We conclude that noninvasive QHS and FMS afford good sensitivity and specificity for evaluating cholecystectomized patients with suspected partial common duct obstruction.


Inspiratory inhibition of pulmonary rapidly adapting receptor relay neurons in the rat.
Second-order relay neurons (referred to as rapidly adapting pulmonary stretch receptors (RARs)-cells) activated by vagal afferents originating from RARs were identified electrophysiologically in Nembutal-anesthetized, paralyzed and artificially ventilated rats. Their location in the commissural subnucleus of the nucleus tractus solitarii (NTS) and firing properties in response to lung inflations and deflations were studied in detail for the first time in the rat. Importantly, in all the RAR-cells examined, their firing was suppressed to various extent during a period from inspiration to early expiration. This means that the information from the RARs to the central nervous system is gated by the central respiratory system at the level of RAR-cells in the NTS.


MDM2 analysis in the management of benign lipomas versus atypical lipomatous tumors/well-differentiated liposarcomas: A useful prognostication tool?
Well-differentiated liposarcomas (WDLS) are low-grade lipomatous tumors with low malignant potential. Previous review identified controversy on whether upfront wide resection is necessary when they occur on the trunk or the extremities. MDM2 amplification is a genetic mutation typically present in WDLS and absent in benign lipomas (BL). We aimed to study the influence of MDM2 status on the management/recurrences of lipomatous tumors in the trunk or the extremities. All patients with lipomatous tumors with MDM2 testing in the Province of Alberta between 2015 and 2020 were identified from the Cancer Cytogenetics Laboratory dataset. High grade sarcomas, retroperitoneal, head/neck, or groin tumors were excluded. Primary outcome measures including MDM2 status, surgical margin, local recurrence, reoperation rate, dedifferentiation, and metastasis were abstracted from chart review. Descriptive statistics were used to analyse treatment patterns and recurrence rates according to MDM2 status. Total of 764 charts were retrieved, and 282 were included for analysis. 33 showed MDM2 amplification (11.7%), and 2 of them had local recurrence (6.1%). Two patients with recurrent tumors underwent limb-salvaging reoperation (6.1%), but no dedifferentiation or metastasis was seen. Findings in this study confirmed the benign behaviour of truncal/extremities lipomas with no MDM2 amplification. Given we found a 6.1% recurrence rate in MDM2 amplified tumors, a prolong follow up of this subset of patients is warranted. Overall, regardless of the MDM2 status, we believe an initial marginal excision is a reasonable surgical approach as recurrences are rare, and they can be managed with re-excision when they occur.


Screening, prophylaxis and counselling before the start of biological therapies: A practical approach focused on IBD patients.
The standard of care in the management of immune-mediated inflammatory conditions relies on immunomodulators, glucocorticoids, and biologicals (including anti-tumour necrosis factor -α and other monoclonal antibodies). These agents have an overall favourable benefit/risk ratio; however, they modulate the immune response as part of their mechanisms of action, and therefore they may increase the risk of developing infections, particularly in older patients or in patients with concomitant corticosteroids. Some of these infections may be preventable by immunization, chemoprophylaxis or counselling. screening for and monitoring infections throughout these therapies is so mandatory to ensure patients' safety. Still, standardized guidelines focused on these procedures have yet to be established. This review aims to fill such a gap. The authors searched for articles published in English from 2009 until 2017 using PUBMED, with the terms "immunomodulators", "biological drugs", "anti-TNF α", "inflammatory bowel diseases", "immunomediated inflammatory diseases", "risk of infection", "infection prevention", "screening", "immunization", "tuberculosis", "latent tuberculosis", "listeriosis", "endemic mycosis", "Pneumocystis jiroveci pneumonia", "granulomatous infection", "varicella", "herpes virus", "hepatitis B", "hepatitis A", "hepatitis C" and identified the journal articles. Based on the literature and in their own experience the authors established recommendations and a practical guide for infections' screening, monitoring and prevention before and during immunomodulatory and biological therapies.


Mitochondrial health, NLRP3 inflammasome activation, and white matter integrity in adolescent mood disorders: A pilot study.
Adolescence is a particularly important period for brain development and is also when mood disorders typically emerge. Several psychiatric illnesses exhibit mitochondrial dysfunction, elevated inflammation, and impaired white matter integrity. This study explored the intersection of mitochondrial health, NLRP3 inflammasome activation, and white matter integrity in a small cohort of 29 adolescent patients with mood disorders (bipolar disorder (BD): n = 11, major depressive disorder (MDD): n = 19) and 19 healthy controls. In this sample, adolescents with mood disorders showed lower fractional anisotropy of the ventral cingulum bundle than healthy controls. Across all adolescents, we demonstrated a significant relationship between mitochondrial electron transport chain gene expression, and NLRP3 inflammasome gene expression and activation. Furthermore, circulating cell free mitochondrial DNA was associated with lower white matter integrity in the anterior thalamic radiation. Exploratory subgroup analyses revealed that adolescents with bipolar disorder exhibited lower levels of mitochondrial gene expression and volume, along with increased sensitivity to NLRP3 inflammasome activation compared to adolescents with unipolar depression. Overall, our results reveal relationships between peripherally-measured endpoints of mitochondrial health and NLRP3 inflammasome activation, and centrally measured endpoints of white matter integrity in adolescents. Together with subtle patterns of aberrant neural and biological structure and function in association with mood disorder diagnoses, these results may shed light on the pathophysiology of disease in this early phase of illness.


A matter of time: Circadian clocks in osteoarthritis and the potential of chronotherapy.
Osteoarthritis (OA) is a common and debilitating joint disease which develops and progresses with age. Despite extensive research into the disease, potent disease-modifying drugs remain elusive. Changes to the character and function of chondrocytes of the articular cartilage underly the pathogenesis of OA. A recently emerging facet of chondrocyte biology that has been implicated in OA pathogenesis is the role of circadian rhythms, and the cellular clock which governs rhythmic gene transcription. Here, we review the role of the chondrocyte's cellular clock in governing normal homeostasis, and explore the wide range of consequences that contribute to OA development when the clock is dysregulated by aging and other factors. Finally, we explore how harnessing this understanding of clock mechanics in aging and OA can be translated into novel treatment strategies, or 'chronotherapies', for patients.


Retracted: Machine Learning and Image Processing Enabled Evolutionary Framework for Brain MRI Analysis for Alzheimer's Disease Detection.
[This retracts the article DOI: 10.1155/2022/5261942.].


Human OCTN2 (SLC22A5) is down-regulated in virus- and nonvirus-mediated cancer.
The expression of carnitine plasma membrane transporter OCTN2 was evaluated in virus and nonvirus-mediated cancer. Both OCTN2 mRNA and protein levels were reduced in keratinocytes retrotransduced with HPV16 E6 and E7 compared with the control. The OCTN2 expression was reduced also in keratinocytes retrotransduced with the sole HPV16 E6. A similar down-regulation of OCTN2 mRNA level was observed in a naturally HPV16-infected cancer cell line, CaSki, harbouring several copies of HPV16 whole genome. The mechanism of down-regulation is not related to p53 transcriptional activity because in SAOS (p53-null) cell line, the restoration of p53 expression did not rescue OCTN2 expression. The treatment of keratinocytes retrotransduced with HPV16 E6 and E7 with 5-aza-cytidine rescued the OCTN2 expression, indicating that the mechanism of down-regulation is linked to DNA methylation. Low levels of mRNA expression of OCTN2 were found also in several nonvirus-related epithelial cancer cell lines. The treatment of those cell lines with 5-aza-cytidine again rescued the expression of OCTN2 as well. These data demonstrate for the first time that the OCTN2 transporter is generally down-regulated in virus and nonvirus-mediated epithelial cancers, probably via methylation of its promoter region.


HD-tDCS in refractory lateral frontal lobe epilepsy patients.
To evaluate the anticonvulsant effect of the novel high definition transcranial direct current stimulation (HD-tDCS) method on patients with refractory lateral frontal lobe epilepsy. The effects of HD-tDCS on working memory were also examined. 10 adult patients with intractable lateral frontal lobe epilepsy were studied. A central cathode electrode was placed on the epileptogenic zone according to LTM, and 20-min sessions of 2mA HD-tDCS were applied for 10 consecutive days. The primary endpoint was to make changes in the epileptiform discharges (EDs) during a 1-h EEG. Moreover, the seizure frequency based on seizure diary and neuropsychiatric parameters was evaluated. All patients tolerated HD-tDCS stimulation course without any adverse reaction. The frequency of EDs increased immediately and one month after the stimulation course by an average of 6.4% and 1.2%, respectively. However, these changes in the EDs frequency were not statistically significant (p-value >0.05). The mean seizure frequency changes showed decrement by an average of 17.9% immediately, and increment by an average of 38.1% one month after the HD-tDCS. These changes were not significant statistically (p-value >0.05). One patient experienced exacerbation of seizures during the stimulations hence dropped out of the study. Attention and working memory improved significantly immediately and one month after the HD-tDCS in all patients. Changes of EDs and mean seizure frequency caused by HD-tDCS were not statistically significant for the whole group; however, this method could improve the patients' working memory scores.


Evolutionary relationships and implications for the regulation of phospholipase A2 from snake venom to human secreted forms.
The amino acid sequences of 40 secreted phospholipase A2's (PLA2) were aligned and a phylogenetic tree derived that has three main branches corresponding to elapid (group I), viperid (group II), and insect venom types of PLA2. The human pancreatic and recently determined nonpancreatic sequences in the comparison align with the elapid and viperid categories, respectively, indicating that at least two PLA2 genes existed in the vertebrate line before the divergence of reptiles and mammals about 200-300 million years ago. This allows resolution for the first time of major genetic events in the evolution of current PLA2's and the relationship of human PLA2's to those of snake venom, many of which are potent toxins. Implications for possible mechanisms of regulation of mammalian intra- and extracellular PLA2's are discussed, as well as issues relating to the search for the controlling enzymes in arachidonic acid release, prostaglandin generation, and signal transduction.


Interaction of alpha-lactalbumin with phospholipid vesicles as studied by photoactivated hydrophobic labeling.
The alpha-lactalbumin segment which penetrates into phosphatidylserine/phosphatidylethanolamine vesicle bilayer under acidic condition was photoactively labeled with 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine [( 125I]TID) which had been partitioned into the hydrophobic interior of the bilayer. The hydrophobically labeled amino acid residues were identified by trypsin digestion of the alpha-lactalbumin/vesicle complex, extraction and Edman degradation of the membrane embedded fragment. The results are consistent with a notion that the segment exists in the membrane as an alpha-helix and that only one surface of this alpha-helix is exposed to the hydrophobic interior of the bilayer. Possible models are: (a) a loop of tightly held alpha-helix penetrating deep into the bilayer and (b) the helix being located on the interface between bilayer and the aqueous solution. The time-dependent [125I]TID labeling process revealed that the middle part of this segment goes into the bilayer first and is then followed by both ends. The penetration rate is comparable to that of the fusion of the lipid vesicles of the same composition by alpha-lactalbumin at the same pH, which further supports that the penetration is the cause of fusion.


Lipoprotein(a) as a correlate of stroke and transient ischemic attack prevalence in a biracial cohort: the ARIC Study. Atherosclerosis Risk in Communities.
Although both mean lipoprotein(a) [Lp(a)] concentration and national stroke prevalence estimates are consistently higher in American blacks than in whites, no information exists on the relationship of Lp(a) and stroke prevalence in African-Americans. Associations of Lp(a) with stroke or transient ischemic attack (TIA) are addressed in this report for 15,160 participants--4160 blacks and 11,000 whites--in the Atherosclerosis Risk in Communities (ARIC) Study. Lp(a) was measured in ARIC as its total protein component by double-antibody enzyme-linked immunosorbent assay (ELISA) for apo(a) detection. Self-reported stroke/TIA history was assessed as part of a standardized questionnaire, and resulted in age-adjusted stroke/TIA prevalences of 3.0% in blacks (n = 120) and 2.0% in whites (n = 222). Overall, mean Lp(a) protein levels were markedly higher for blacks than for whites (160.5 versus 81.6 micrograms/mL, respectively), and were statistically significantly higher among individuals reporting stroke/TIA history for both races (191.3 versus 159.6 micrograms/mL in blacks; 100.6 versus 81.2 micrograms/mL in whites). Multivariable logistic regression analysis for the association of Lp(a) protein with stroke/TIA status yielded a prevalence odds ratio (OR) (95% confidence intervals) of 1.17 (1.05, 1.30) overall (based on one standard deviation difference, 108.2 micrograms/mL, in Lp[a] protein). Race-specific ORs, after adjustment for the same covariates, were equivalent for blacks [OR = 1.17 (0.99, 1.39)] and whites [OR = 1.19 (1.04, 1.36)]. These data suggest that Lp(a) is an independent risk factor for stroke/TIA in both blacks and whites, and that the relative risk of stroke/TIA associated with Lp(a) protein does not vary by race.(ABSTRACT TRUNCATED AT 250 WORDS)


[Possibility of the development of decompression sickness during testing of G suits].
This paper presents the results of 1179 altitude chamber tests of special suits performed by 193 subjects. The probability of altitude decompression disease observed during 29 experiments (2.5%) in 26 test subjects (13.4%) is calculated. The safety of decompression tables is evaluated as applied to the pressure 14-43 kPa after oxygen breathing for 0.25-2 hrs at sea level or for 1-6 hrs at 40 kPa.


A new enzyme-linked immunosorbent assay recognizing both rat and human activated coagulation Factor XII (FXIIa).
We describe the first sandwich enzyme-linked immunosorbent assay (ELISA) capable of recognizing both rat and human activated coagulation Factor XII (FXIIa). Increased plasma concentrations of FXIIa have been associated with adverse outcomes in several cardiovascular disease states. In humans, the FXIIa antigen in plasma is quantified by a direct sandwich ELISA employing an antibody (mAb 2/215) raised against its β-fragment (β-FXIIa), but this assay is unable to detect rat β-FXIIa antigen. Thus, experimental models are at present limited in their capacity to reveal mechanisms by which FXIIa might contribute to cardiovascular pathology. Consistent with overlap between human and rat FXIIa protein epitope sequences, Western blot analysis and ELISA demonstrate that another previously developed antibody against human FXIIa (mAb 201/9) detects β-FXIIa in both human and rat plasma, with no evidence for cross-reactivity with the FXII zymogen or FXIIa complexed with its endogenous inhibitor. The mAb 201/9 based ELISA identified similar elevations in FXIIa in plasma from rats and humans with chronic renal failure. The capacity of this ELISA to identify rat plasma FXIIa has potential application to a wide range of experimental models of human cardiovascular disease.


Separation of dolichol monophosphate mannose and dolichol monophosphate glucose by thin-layer chromatography.
Dolichol monophosphate mannose and dolichol monophosphate glucose from mammalian or mold cells were separated by thin-layer chromatography. This separation was not due to a difference in the size of the lipid moieties. It was found that the lipid moieties of dolichol monophosphate mannose and dolichol monophosphate glucose are the same size when synthesized by the same cell. The thin-layer chromatographic separation appeared to be due, therefore, to the saccharide part of the molecules.


Smoking and the female professions: pre-occupational influences on the behaviour of recruits to nursing and teaching.
A questionnaire and interview study of female recruits to nursing and teaching showed that occupational differences in the prevalence of smoking are already established at entry to training. The social characteristics of the smokers in the sample corresponded to those of women smokers generally. Differences in education and social origin contributed to occupational variations in behaviour. The influence of sibling behaviour and parental opinion operated differently within the two occupational groups. The psychological attributes of individuals attracted to a particular profession may also contribute to occupational patterns, specifically risk-taking and a concern for personal freedom.


A model-based detector of vertex waves and K complexes in sleep electroencephalogram.
A model of sleep phasic events such as vertex waves, K complexes, delta waves and sleep spindles is proposed. It consists of feedback loops that are driven by white noise (simulating tonic delta and sigma activity) and by isolated random impulses, simulating vertex waves or K complexes, depending on the background tonic activity. A model-based method for the detection of sleep phasic events was implemented in a personal computer. Its performance was investigated using simulated and real whole-night EEG signals. The method was able to detect K complexes and vertex waves in a reliable way in spite of their variable shapes and in the presence of a variety of background activities. The detector appears to have superior performance to those so far reported in the literature. The performance of the detector was also compared to that of an electroencephalographer using normal sleep EEG records of 8 h duration from 6 subjects. The performance was satisfactory both in terms of accuracy and reliability. The problem of detecting K complexes in stages 3 and 4 of sleep is discussed.


Isotopic water dilution technique in body fluid measurement in some domestic animal species.
Dilution procedures using tritiated water and Evans blue dye (T 1824) were applied to estimate total body water and plasma volume in small ruminants, pigs and cockerels during the two different seasons in Zimbabwe. The amounts of total body water (TBW) obtained were between 60% to 85% of the body weight in sheep and goats, 40% to 60% in pigs and 63% to 75% in cockerels. TBW values were significantly higher (P < 0.05) in the small ruminants than in pigs and observed age differences were significant (P < 0.05) in the small ruminants. There were significant (P < 0.05) seasonal differences in the total body water mean values but nonsignificant (P > 0.05) differences in the plasma volume mean values for the domestic species investigated.


Schwann cell caveolin-1 expression increases during myelination and decreases after axotomy.
The caveolins are a family of related proteins that form the structural framework of caveolae. They have been implicated in the regulation of signal transduction, cell cycle control, and cellular transport processes, particularly cholesterol trafficking. Caveolin-1 is expressed by a variety of cell types, including Schwann cells, although its expression is greatest in differentiated cell types, such as endothelial cells and adipocytes. In the present work, we characterize caveolin-1 expression both during rat sciatic nerve development and after axotomy. Schwann cells express little caveolin-1 on postnatal days 1 and 6. By P30, myelinating Schwann cells express caveolin-1, which is localized in the outer/abaxonal myelin membranes as well as intracellularly. After axotomy, Schwann cell caveolin-1 expression in the distal nerve stump decreases as Schwann cells revert to a premyelinating (p75-positive) phenotype; residual caveolin-1 within the nerve largely localizes to myelin debris and infiltrating macrophages. We speculate that caveolin-1 plays a role in the biology of myelinating Schwann cells.


Theoretical Estimation of Important Ferroelectricity-Related Parameters for Molecular Design of Host-Guest Compounds, Substituted Anilinium Tetrafluoroborate 18-Crown-6.
Through rational chemical modification, a series of host-guest complexes, substituted anilinium tetrafluoroborate 18-crown-6, are constructed to achieve excellent ferroelectricity in terms of large spontaneous polarization, high phase transition temperature, and small coercive field. In order to evaluate our new design, computational methods are developed to estimate the ferroelectricity-related parameters, namely, spontaneous polarization, phase transition temperature, and coercive field, in sufficient consideration of structural and symmetrical characteristics of this series of host-guest complexes at the molecular level. In each host-guest crystal, the substituted anilinium acts as a rotator anchoring in the cavity of a stator, 18-crown-6, with three N-H···O hydrogen bonds. This rotator does the pendulum motion of the phenyl ring with its substituent to switch ferroelectric-paraelectric phase transition. High-accuracy quantum chemistry calculations are carried out to obtain complete energy and polarization information along this pendulum-motion-related reaction coordinate. Then the Landau-Devonshire phase transition theory and the Boltzmann statistics are employed to create a bridge between the above ferroelectric molecular behavior and the crystalline macroscopic properties and estimate the phase transition temperatures of these studied host-guest complexes. By virtue of applying an external electric field in our quantum chemistry calculations, the relative magnitude of the coercive field is approximately measured to exhibit the electric-field-responsive behavior of these host-guest self-assemblies. Finally, two candidates, namely, (4-CN-Ani+)(18-crown-6)BF4- and (4-CHO-Ani+)(18-crown-6)BF4-, are designed by us with large excellent ferroelectricity compared to the model system (4-MeO-Ani+)(18-crown-6)BF4-. They would wait for the future experimental confirmation. Our molecular design of these ammonium-crown ether-based host-guest compounds would provide insights into the structure-property relationship of these rotator-stator-type ferroelectrics to help both theoretical and experimental specialists design or/and synthesize new targeted compounds. Our developed computational methods to estimate ferroelectricity-related parameters would also supply ideas for computational scientists to produce new similar methods for some ferroelectrics with specific phase-transition-related molecular dynamics.


Hyperdense internal carotid artery sign: a CT sign of acute ischemia.
The hyperdense middle cerebral artery sign (HMCAS) is a well-established marker of early ischemia on noncontrast computed tomography of the brain (NCCT). Recently the MCA dot sign has been described and proposed to indicate thrombosis of the M2 or M3 middle cerebral artery branches. The purpose of this study was to define the hyperdense ICA sign (HICAS) and determine its prevalence, diagnostic and prognostic value, and its reliability as a marker for ischemia. Noncontrast computed tomography scans of 71 patients with acute ischemic stroke were analyzed for the presence of a HICAS, HMCAS, or MCA dot sign. For the validation of HICA and HMCA signs on NCCT, 32 of 71 patients who underwent gold standard CT angiography (CTA) before thrombolytic therapy were included in the analysis. The presence of a HICAS was correlated with initial neurological severity and the short and long-term outcomes. A HICAS was found in 24% of patients on NCCT. In patients with a HICAS, mean age was 63+/-17.4 and mean time from symptom onset to CT was 103 minutes. Interobserver agreement was excellent for the HICAS. The HICAS has high specificity (100%) and positive predictive value (100%) in predicting the presence of distal internal carotid artery thrombus on CTA. Patients with a HICAS had a more severe initial neurological deficit and worse prognosis than patients without a HICAS. The HICAS is a reliable and a highly specific marker of thromboembolic occlusion of the distal ICA and is associated with severe initial neurological deficit and worse outcome despite thrombolytic therapy.


A method for determining the position of the abutment screw of any cement-retained implant-supported prosthesis.
Removing cement-retained implant-supported prostheses may be challenging for clinicians. A method combining a cone beam computed tomography (CBCT) and a digital scan with a virtual surgical planning software program is described to identify the perforation site of a cement-retained implant-supported prosthesis to locate the abutment screw.


A Case of Titanium Pseudotumor and Systemic Toxicity After Total Hip Arthroplasty Polyethylene Failure.
We describe the case of a 57-year-old female who underwent bilateral ceramic-on-polyethylene total hip arthroplasties performed in 2015. She presented to us in 2018 with headaches, fatigue, and right hip pain 5 months after an atraumatic right polyethylene liner failure for which she did not seek treatment. She was found to have imaging consistent with an adverse local tissue reaction and massive pseudotumor formation. During revision surgery, fracture of the acetabular liner was noted, with ceramic head wear through the titanium cup. In the months after her debridement and prosthesis revision, the patient continued to complain of systemic symptoms including weakness, fatigue, headaches, and vision problems. Serum titanium levels were found to be 100 times higher than normal. This case serves as a rarely reported example of titanium toxicity and titanium pseudotumor formation in the setting of polyethylene failure.


The potential role of human endogenous retrovirus K10 in the pathogenesis of rheumatoid arthritis: a preliminary study.
To examine whether human endogenous retrovirus K10 is associated with autoimmune rheumatic disease. A novel multiplex reverse transcription polymerase chain reaction (RT-PCR) system was developed to investigate HERV-K10 mRNA expression in patients with rheumatoid arthritis. 40 patients with rheumatoid arthritis, 17 with osteoarthritis, and 27 healthy individuals were recruited and total RNA was extracted from peripheral blood mononuclear cells (PBMCs) and analysed using multiplex RT-PCR for the level of HERV-K10 gag mRNA expression. Southern blot and DNA sequencing confirmed the authenticity of the PCR products. Using the histidyl tRNA synthetase (HtRNAS) gene as a housekeeping gene in the optimised multiplex RT-PCR, a significantly higher level of HERV-K10 gag mRNA expression was found in rheumatoid arthritis than in osteoarthritis (p = 0.01) or in the healthy controls (p = 0.02). There is enhanced mRNA expression of the HERV-K10 gag region in rheumatoid arthritis compared with osteoarthritis or healthy controls. This could contribute to the pathogenesis of rheumatoid arthritis.


Sterilization of gentamicin containing collagen/PLGA microparticle composites.
In order to achieve implants which provide sustained release of gentamicin, microparticles based on a 50/50 Resomer 503/Resomer 502H blend were combined with collagen in order to achieve their fixation and to utilize the favorable effect of collagen on wound healing. Ethylene oxide treatment as well as beta- and gamma-irradiation were tested for sterilization of the collagen/PLGA-microparticle composite. All methods resulted in a decrease of molecular weight and glass transition temperature of polymer raw material and microparticles. In addition, ethylene oxide treatment yielded aggregation of microparticles leading to a substantial increase in the initially liberated gentamicin dose. Furthermore, chemical changes of gentamicin after ethylene oxide sterilization could be identified using NMR spectroscopy. Despite a decrease in the molecular weight and glass transition temperature after irradiation, neither morphological changes of the composites nor changes regarding the gentamicin release profile from beta- and gamma-sterilized material were observed. Free radicals, which could only be detected in gentamicin drug substance and at marginal level in gentamicin-loaded MPs, disappeared within 4 weeks. Additional microbiological testing verified the microbiological activity of gentamicin liberated from beta-sterilized composites. Storage of beta-sterilized composite at 4 degrees C/35% r.h. for 3 months did not influence morphology, molecular weight, glass transition temperature, and release profiles of microparticles and composites. However, at 25 degrees C/60% r.h. and 40 degrees C/75% r.h. a marked decrease in molecular weight and glass transition temperature resulted. This effect was due to a higher humidity, water uptake into polymers, and subsequent hydrolysis of polymers and microparticles, which was more pronounced for RG 502H because of its hydrophilicity. Upon storage at 25 degrees C/60% r.h. and 40 degrees C/75% r.h. particles collapsed resulting in an increased gentamicin liberation. Thus, all sterilization techniques have their pros and cons, but based on drug release profile and chemical changes of gentamicin irradiation treatment appears to be more suitable for collagen/gentamicin-loaded PLGA microparticle composites.


Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations.
Congenital disorder of glycosylation Ia (CDG-Ia) is a metabolic disease with a broad spectrum of clinical signs, including recently described mild phenotypes. Our aim was to describe the clinical presentation and follow-up of eight CDG-Ia patients highlighting atypical features and aspects of evolution of the disease. CDG diagnosis was confirmed by enzymatic analysis of phosphomannomutase (PMM2) and molecular studies of the PMM2 gene. Four neonates presented with cerebral haemorrhage (1), failure to thrive (2) and non-immune hydrops (1) and a fatal course to death (2); pathological examination of the brain in one case revealed olivopontocerebellar atrophy of prenatal origin. During infancy failure to thrive, coagulopathy and hepatopathy were the most significant causes of morbidity, but these disappeared after the first years of life in most patients. Three patients are currently in their 20s; they present mental retardation and severe motor impairment but no acute decompensations were noticed after the first decade of life. They do not present spinal or thoracic deformities otherwise observed in patients from northern countries. A 10-year-old patient who manifested gastrointestinal dysfunction in early childhood showed normal neurodevelopment. Mutation analysis of the PMM2 gene showed great variability, with all patients being compound heterozygous for two different mutations. Long-term evolution in our patients indicates that CDG-Ia is a stable systemic and neurological condition after the first decade of life. The diverse phenotypes and atypical manifestations in our series may be due to their genetic heterogeneity.


An improved screening method for microorganisms able to convert crude glycerol to 1,3-propanediol and to tolerate high product concentrations.
A new screening method was developed and established to find high-performance bacteria for the conversion of crude glycerol to 1,3-propanediol. Three soil samples from palm oil-rich habitats were investigated using crude glycerol of a German biodiesel plant. Nine promising 1,3-propanediol producers could be found. Because of a special pH buffer system, a fast evaluation on microscale and high 1,3-propanediol concentrations up to 40 g L⁻¹ could be achieved. Three strains demonstrated very high product tolerance and were identified as Clostridium butyricum. Two strains, AKR91b and AKR102a, grew and produced 1,3-propanediol in the presence of 60 g L⁻¹ initial 1,3-propanediol, the strain AKR92a even in the presence of 77 g L⁻¹ 1,3-propanediol. The strains AKR91b and AKR102a tolerated up to 150 g L⁻¹ crude glycerol and produced 80% of the 1,3-propanediol attained from pure glycerol of the same concentration. Further criteria for the choice of a production strain were the pathogenicity (risk class), ability to grow on low-cost media, e.g., with less yeast extract, and robustness, e.g., process stability after several bioconversions. Overall, the strain C. butyricum AKR102a was chosen for further process optimization and scale-up due to its high productivity and high final concentration in a pH-regulated bioreactor.


Thrombin increases cardiomyocyte acute cell death after ischemia and reperfusion.
Thrombin exerts multiple actions on cardiomyocytes leading to increased intracellular Na+ and Ca2+ concentrations, and to activation of a Ca2+-independent PLA2, and has been proposed to favor the genesis of arrhythmias and ischemic injury in acute coronary syndromes. However, the influence of thrombin on cardiomyocyte cell death during ischemia-reperfusion has not been studied. A beneficial influence of low thrombin concentrations has been described in other cell types. HL-1 cardiomyocytes were subjected to simulated ischemia (SI) and reperfusion (SR) and cell death was assessed by means of LDH release to the incubation media. Thrombin dose-dependently increased cell death in normoxic cells, in cells subjected to SI, and in cells subjected to SR (by 20+/-8%, 95+/-32% and 35+/-9%, respectively, at 100 U/ml). The effects of thrombin were associated to increased cytosolic Ca2+ overload, mimicked by 100 microM PAR-1 agonist peptide SFLLRNPNDKYEPF, and reversed by the direct thrombin inhibitor lepirudin (IC50=1.3+/-0.2 microg/ml). The presence of thrombin during simulated ischemia-reperfusion increases cardiomyocyte cell death by a mechanism that involves activation of PAR-1 receptors and can be prevented by the direct thrombin inhibitor lepirudin.


Management of the immature apex tooth: an online study guide.
The Editorial Board of the Journal of Endodontics has developed a literature-based study guide of topical areas related to endodontics. This study guide is intended to give the reader a focused review of the essential endodontic literature and does not cite all possible articles related to each topic. Although citing all articles would be comprehensive, it would defeat the idea of a study guide. This section will cover apexogenesis, revascularization/regeneration, apexification, and artificial apical barriers.


Chromosome 5 allelic losses are early events in tumours of the papilla of Vater and occur at sites similar to those of gastric cancer.
During our studies of DNA fingerprinting of tumours of the pancreas and papilla (ampulla) of Vater, using arbitrarily primed polymerase chain reaction (AP-PCR), we noticed two bands showing a decreased intensity in six of ten ampullary tumours with respect to matched normal tissues. Those bands were both assigned to chromosome 5. Such a finding was somewhat in contrast with the reportedly low frequency of APC gene mutations in ampullary cancers, located at chromosome 5q21, and suggested that loci different from that of APC might be the target of chromosome 5 allelic losses (LOH) in these tumours. Therefore, we analysed chromosome 5 LOH in a panel of 27 ampullary tumours, including eight adenomas, four early- and 15 advanced-stage cancers, using 16 PCR-amplified CA microsatellite polymorphic markers spanning the entire chromosome. Nineteen cases (70%) showed LOH, and the interstitial deletions found in these tumours described two smallest common deleted regions, in which putative suppressor genes might reside. They were at 5q13.3-q14 and at 5q23-q31 respectively, which correspond to those found in gastric tumours. In addition, the presence of 5q LOH in six of eight adenomas and in three of four early-stage cancers suggests that such phenomena occur at early stages of neoplastic progression of the ampullary epithelium.


Diagnosis of late infantile neuronal "ceroid-lipofuscinosis" from histochemical and ultrastructural changes in dental pulp.
Sections of dental pulp were removed from a tooth of a boy 3 years 10 months of age with myoclonic seizures. When stained with hematoxylin and eosin, these sections showed eosinophilic inclusions. Ultrastructurally, these inclusions were large cytosomes filled with whorls of electron-opaque substance. The opaque material consisted of bilaminate strands, approximately 15 nm in diameter, arranged in a curvilinear pattern compatible with that seen in the late infantile form of "ceroid-lipofuscinosis." Most histochemical staining reactions were compatible with ceroid or lipofuscin, with the exception of the diamine silver reaction. Late infantile ceroid-lipofuscinosis represents another disease in which asymptomatic accumulation of storage material occurs in the dental pulp.


Middle Eastern mothers in Sweden, their experiences of the maternal health service and their partner's involvement.
Traditional patterns relating to how to handle pregnancy and birth are often challenged due to migration. The purpose of this study was to describe Middle Eastern mothers' experiences of the maternal health care services in Sweden and the involvement of their male partner. Thirteen immigrant mothers from the Middle East who had used the maternal health services in Sweden were interviewed using focus group discussions and individual interviews. These were taped, transcribed and analysed according to Content analysis. The four main categories that developed were:* Access to the professional midwife* Useful counselling* Stable motherhood in transition* Being a family living in a different culture According to the respondents in this study, understanding the woman's native language or her culture was not vital to develop a good relationship with the midwife. Instead the immigrant woman developed trust in the midwife based on the knowledge and the empathy the midwife imparted.Increasing the amount of first trimester antenatal visits could avoid spontaneous visits to the emergency clinic. There was a greater need for involvement and support by the father during the perinatal period, such as caring for older children and carrying out household chores since the mothers' earlier female network was often lost. There is a need to involve immigrant parents in the available parental education in order to prepare them for parenthood in their new country as well as to explore their altered family situation. Collecting immigrant women and their partner's, experiences of maternal health care services offers a possibility to improve the existing care, both in content, access and availability where the timing of visits and content require further evaluation.


Synthesis of a new class of camptothecin derivatives, the long-chain fatty acid esters of 10-hydroxycamptothecin, as a potent prodrug candidate, and their in vitro metabolic conversion by carboxylesterases.
Five (20S)-10-hydroxycamptothecin derivatives carrying the long-chain fatty acid esters were prepared for the development of a new class of prodrug-type agents. In vitro experiments using three kinds of purified carboxylesterase isozymes from the liver microsomes of rat, pig, and human demonstrated that these derivatives were efficiently metabolized by enzymes compared with CPT-11.


Maternal and fetal concentrations of morphine after epidural administration during labor.
In this study of 20 healthy women in labor we attempted to determine the efficacy of epidural morphine as an obstetric analgesic. Four patients experienced some relief of pain while 16 patients reported no effect on pain. One newborn infant demonstrated possible morphine-induced respiratory depression. It was concluded that morphine is ineffective as an obstetric analgesic.


Therapeutic strategies to halt renal fibrosis.
Angiotensin II blockade has become a standard anti-fibrotic therapy in renal diseases because it slows progression to end-stage renal disease. However, current data support the notion that angiotensin II blockade alone cannot stop progressive fibrotic disease. Of an increasing number of therapies showing efficacy in animal studies, antibodies to transforming growth factor beta are the most thoroughly studied and are likely to be effective in human clinical trials. However, hints exist in the literature suggesting that no single agent will effectively halt renal fibrosis and that combinations of agents will be required.


Multicentre double-blind comparison of sustained action formulations of tiaprofenic acid and indomethacin in osteoarthritis.
In a randomised double-blind, multicentre, crossover study, the short term efficacy and tolerance of a sustained action preparation of tiaprofenic acid 600 mg once daily was compared with sustained release indomethacin 75 mg once daily in 98 patients with osteoarthritis. After a minimum washout period of 3 days, patients were randomly allocated to receive each treatment in turn for a period of 4 weeks. There were no significant differences between the 2 treatments in the clinical assessments of pain level, duration of morning stiffness, articular index and functional impairment performed at the end of each treatment period. High pain levels on movement were reduced by both treatments, and reduction was also seen in night pain, where initial levels were lower. There was no significant difference between the number of patients who reported side effects on the 2 treatments. 37 patients (39%) reported 49 side effects while taking sustained release tiaprofenic acid, and 35 patients (37%) reported 53 side effects while taking sustained release indomethacin. Daily diary cards showed that both treatments provided improvements in duration of morning stiffness and in pain relief. Thus sustained action tiaprofenic acid and sustained release indomethacin were shown to be equally well tolerated and efficacious.


Initial Contraceptive Choices of Women Enrolled in a Cluster-Randomized Trial in Southwest Trifinio, Guatemala.
The aim of this analysis is to present initial contraceptive choices of women offered postpartum contraception in rural Guatemala. We trained community nurses participating in the delivery of a home-based antepartum and postpartum care program in rural Guatemala in contraceptive implant placement and had them offer condoms, pills, an injection, or an implant at women's home-based 40-day postpartum visit in intervention clusters of a non-blinded, cluster-randomized trial. Women who had already started postpartum contraception or were over the age of 35 were excluded from participation. The primary outcome of the trial was contraceptive use at 3 months postpartum, so this initial analysis describes immediate preferences in the population. Of 208 women enrolled in the study, 108 were in intervention clusters and 100 lived in control clusters. In the intervention group, 32 women declined contraception, 36 women received the injectable, 30 women had an implant placed, 5 women started pills, 2 women chose condoms, and data on 3 women were missing. In the control clusters, 43 women were planning on the injectable, 11 planned on the implant, 10 did not want to start a method, 5 planned on sterilization, 2 aimed for natural family planning, 2 wanted a copper IUD, 1 woman wanted condoms, 18 did not know, and data on 8 women were missing. The contraceptive implant, which was not previously available in this community, had high uptake at 27.8% in the intervention group. Clinicaltrials.gov, NCT04005391; Retrospectively Registered 7/2/2019, https://clinicaltrials.gov/ct2/show/NCT04005391 Protocol: https://doi.org/10.1186/s13063-019-3735-3.


Theoretical study of the product specificity in the hydroxylation of camphor, norcamphor, 5,5-difluorocamphor, and pericyclocamphanone by cytochrome P-450cam.
The hydroxylations of d-camphor, norcamphor, pericyclocamphanone, and 5,5-difluorocamphor by cytochrome P-450cam have been examined using theoretical methods to identify and characterize properties which determine product specificity. Experimental results indicate that each molecule is hydroxylated with quite different regio-specificity when metabolized by P-450cam. This result is surprising in view of their overall structural similiarity. Herein we report the results of calculations on d-camphor and three of its analogues which suggest that all of these molecules should, when metabolized by P-450cam, form hydroxylation products and predict the product distribution for each. Our conclusions are based on two fundamental criteria which are consistent with a generally accepted radical mechanism in determining product specificity in these molecules: 1) relative heats of formation of the radicals formed by abstracting a hydrogen, and 2) orientation of the substrate molecule with respect to the putative active oxygen species bound to iron. Our results explain the experimental observations for camphor and 5,5-difluorocamphor but disagree with original published results for norcamphor and pericyclocamphanone. In light of our results, new experiments have been performed for norcamphor and the original data reexamined for pericyclocamphanone. Our predictions have recently been experimentally confirmed for norcamphor, and unpublished data (Dr. S. Sligar) suggest that the same is true for pericyclocamphanone.


Evaluation of trabecular bone and mandibular cortical thickness in adults with different vertical facial types.
This study investigated differences in trabecular structure and mandibular cortical thickness in adults related to vertical facial type (VFT), sex, and their interactions. Lateral cephalometric radiographs (LCRs) and panoramic radiographs (PRs) of 256 patients were reviewed. The VFT classification into low-angle, normal, and high-angle groups was determined using angular and linear measurements on LCRs. Fractal dimension (FD) values and mandibular radiomorphometric indices (RMIs) were calculated on PRs. Two-way analysis of variance revealed significant differences in FD overall among VFT groups in all sites (P < .001), with pairwise comparisons indicating the greatest values in the high-angle group in the condyle (P < .05) but in the low-angle group elsewhere (P < .001). RMIs were significantly different overall regarding VFT only in the posterior mandible (P = .004), with pairwise comparisons revealing low-angle and normal group values greater than high-angle group values (P < .05). Patient sex and the interaction of facial type and sex had no significant effect on any bone measurements. VFT had significant effects on trabecular structure at all measured sites, but cortical thickness was affected only in 1 location.


Tcrb-V3+ T-cell deletion and a mouse mammary tumor provirus, Mtv-27.
Genes encoding superantigens which delete Tcrb-V3+ T cells co-segregate with mouse mammary tumor proviruses (Mtv), Mtv-1, Mtv-3, Mtv-6, Mtv-13, and Mtv-44. We have examined percentages of Tcrb-V3+ T cells and Mtv integrations in [(B10 x NZB)F1 x B10.BR] mice, and show that Mtv-27 as well as Mtv-3 from NZB mice co-segregate with genes encoding deletion ligands for Tcrb-V3+ T cells without recombination.


Molecular imprint of enzyme active site by camel nanobodies: rapid and efficient approach to produce abzymes with alliinase activity.
Screening of inhibitory Ab1 antibodies is a critical step for producing catalytic antibodies in the anti-idiotypic approach. However, the incompatible surface of the active site of the enzyme and the antigen-binding site of heterotetrameric conventional antibodies become the limiting step. Because camelid-derived nanobodies possess the potential to preferentially bind to the active site of enzymes due to their small size and long CDR3, we have developed a novel approach to produce antibodies with alliinase activities by exploiting the molecular mimicry of camel nanobodies. By screening the camelid-derived variable region of the heavy chain cDNA phage display library with alliinase, we obtained an inhibitory nanobody VHHA4 that recognizes the active site. Further screening with VHHA4 from the same variable domain of the heavy chain of a heavy-chain antibody library led to a higher incidence of anti-idiotypic Ab2 abzymes with alliinase activities. One of the abzymes, VHHC10, showed the highest activity that can be inhibited by Ab1 VHHA4 and alliinase competitive inhibitor penicillamine and significantly suppressed the B16 tumor cell growth in the presence of alliin in vitro. The results highlight the feasibility of producing abzymes via anti-idiotypic nanobody approach.


Temporal Trends for Diabetes Management and Glycemic Control Between 2010 and 2019 in Korean Children and Adolescents with Type 1 Diabetes.
Purpose: There is increasing use of modern devices in the management of patients with type 1 diabetes (T1D). We investigated temporal trends for diabetes management and outcomes in Korean pediatric T1D patients over 10 years. Methods: We retrospectively collected the data from 752 participants (boys: 311, 41.4%) diagnosed with T1D and aged ≤18 years, with ≥1 year of follow-up between 2010 and 2019 in any of the seven study hospitals in Korea. Results: Over the 10-year study period, use of continuous glucose monitoring (CGM) increased from 1.4% to 39.3%. From 2010 to 2019, there was an increased use of multiple daily insulin injections (MDI; 63.9%-77.0%, respectively) and continuous subcutaneous insulin infusion (CSII; 2.1%-14.0%, respectively), but decreased use of conventional insulin therapy (CIT, 33.9%-9.0%, respectively). Mean glycated hemoglobin (HbA1c) decreased from 8.56% to 8.01% (P < 0.001) and was lower in younger patients, boys, and CGM users (P < 0.001). MDI and CSII users had lower mean HbA1c levels than CIT users (P = 0.003). Regarding the acute complications of T1D, CGM use was associated with lower incidences of diabetic ketoacidosis (P = 0.015); CSII users were likely to experience less severe hypoglycemia (P = 0.008). Conclusions: The use of CSII and CGM increased ∼7- and 30-fold, respectively, over the 10-year study period. The glycemic control of pediatric T1D patients in Korea improved from 2010 to 2019, probably because of increased use of T1D technologies.


The surfactant system of the lung in the Mexican axolotl Ambystoma mexicanum.
The broncho-alveolar space of axolotl contains numerous osmiophilic structures, which have been classified morphologically into 3 types of inclusions. Type I inclusions exhibited lattices of square to rectangular grid patterns with membranous elements 6 nm thick. This lattice was crossed by a 2 nm dense line. Type II inclusions were composed of 7 nm dark lines and 15.5 nm light lines in an alternating repeating pattern. Furthermore, the light lines showed an intrapenoid line of 2 nm. Type III inclusions consisted of concentric whorls of lamellae similar in form to spider webs. Only type III inclusions were identified in grand alveolar cells.


Carbo-loading in Coccidioides spp.: A quantitative analysis of CAZyme abundance and resulting glycan populations.
Coccidioides spp. are important pneumonia-causing pathogens of the American southwest, but little is known about their glycobiology and how their glycosylations differ from other pneumonia-causing fungi. There is mounting preliminary evidence to suggest genus or even species-specific glycosylations in the fungal kingdom due to the presence of unique carbohydrate-active enzymes (CAZymes) in fungal genomes (Deshpande et al. 2008, Glycobiology, 18(8), 626-637; Karkowska-Kuleta and Kozik 2015, Acta Biochim Pol., 62(3), 339-351). If Coccidioides spp.-specific glycans can be identified, it may be possible to exploit these differences to develop more specific diagnostic approaches and more effective therapeutics. Herein, we i) mined Coccidioides spp. and other pathogenic fungal genomes to identify CAZymes specific for Coccidioides spp., ii) proteomically determined the Coccidioides spp. "CAZome" produced in vivo and in vitro, and iii) utilized glycomics to differentiate Coccidioides genus-specific N-glycans from other pathogenic fungi. As far as we are aware, this is the first proteomic and glycomic comparison of the N-glycomes and CAZomes of different fungal genera during infection in human hosts.


Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity.
Interleukin-18 (IL-18) is a pleiotropic cytokine that enhances Th1 or Th2 immune response. We show a novel mechanism of gastric cancer cells that allows their immune escape utilizing IL-18. All 4 gastric cancer cell lines, but not colon lines, constitutively expressed IL-18 receptors and IL-18 dose-dependently enhanced their in vitro proliferation accompanied by nuclear factor kappaB activation. When IL-18-pretreated gastric cancer cells were cultured with cytokine-activated peripheral blood killer lymphocytes, the antitumor machineries, perforin or interferon-gamma production of killer lymphocytes decreased, resulting in a decreased susceptibility of cancer cells to killer lymphocytes. Furthermore, gastric cancer cells cultured with IL-18 showed an increased expression of a granzyme B inhibitor, protease inhibitor 9. IL-18 injections into severe combined immuno-deficient mice intraperitoneally inoculated with gastric cancer cells consistently decreased the mouse survival time. Our results indicate that gastric cancers exploit IL-18 to grow/invade and evade immunosurveillance in the hosts.


A Case of Neonatal Severe Hyperparathyroidism: Challenges in Management.
Neonatal severe hyperparathyroidism is a rare disorder arising from inherited defects in the calcium sensing receptor (CaSR) that presents early in life with severe hypercalcemia, failure to thrive, and developmental retardation. The authors describe an infant with neonatal severe hyperparathyroidism due to homozygous CaSR gene mutation presenting with recurrent episodes of severe hypercalcemia, growth retardation, and developmental delay. Medical management served as an effective bridge therapy to surgery. Total parathyroidectomy with right hemithyroidectomy was performed at 7 mo of age and resulted in successful cure and normalization of growth and developmental milestones. Timely medical and surgical management can help prevent mortality and morbidity in the form of neurodevelopmental sequelae. Life-long monitoring and treatment is mandatory for the resultant hypoparathyroidism.


Quantitative in vivo measurement of thyroidal iodine content by static x-ray fluorescent technique: some preliminary clinical observations.
A static x-ray fluorescent technique utilizing an 241Am source of low activity and a wide view diverging collimator which allows in vivo determination of the concentration and total content of iodine in the thyroid is described. Determinations of normal thyroidal iodine concentration and total iodine content were as follows: 0.40 mg/g and 10.6 mg for 16 men, and 0.67 mg/g and 17.6 mg for 14 women. This fluorescent system has been applied to 70 patients to date. Thyroidal iodine concentrations in patients with Graves' disease were approximately equal to those in healthy suspects, and little change was observed among the concentrations in patients before, during, or after treatment. In most of the patients with chronic or subacute thyroiditis, concentrations levels were lower.


Bringing personal perspective elicitation to the heart of shared decision-making: A scoping review.
Proponents of shared decision-making (SDM) advocate the elicitation of the patient's perspective. This scoping review explores if, and to what extent, the personal perspectives of patients are elicited during a clinical encounter, as part of a SDM process. We define personal perspective elicitation (PPE) as: the disclosure (either elicited by the clinician or spontaneously expressed by the patient) of information related to the patient's personal preferences, values and/or context. A search was conducted in five literature databases from inception dates up to July 2020, to identify empirical studies about SDM (with/without SDM instrument). The search identified 4562 abstracts; 263 articles were read in full text, resulting in 99 included studies. Studies reported low levels of PPE. Integration of personal perspectives into the conversation or a future care plan was largely absent. The majority of the discussed content related to physical health, while social and psychological topics were mostly unaddressed. PPE occurs on a very low level in efforts to achieve SDM according to evaluation studies. PPE is advocated but rarely achieved in SDM evaluation studies. Causes should be identified, followed by designing interventions to improve this aspect of SDM.


Effect of quadriceps training at different levels of blood flow restriction on quadriceps strength and thickness in the mid-term postoperative period after anterior cruciate ligament reconstruction: a randomized controlled external pilot study.
More than 2 million anterior cruciate ligament (ACL) injuries occur worldwide each year. Most surgeons suggest that athletes and active persons with significant knee functional demands, including cutting motions, require and should be offered ligament reconstruction surgery. Despite concentrated rehabilitation efforts, deficits in quadriceps size and strength can persist for years after surgery. Blood flow restriction (BFR) training can help overcome disuse muscular atrophy in the mid-term postoperative period after anterior cruciate ligament reconstruction (ACLR) surgery. The purpose of this study was to evaluate the effects of quadriceps training with different levels of blood flow restriction on quadriceps strength and thickness of participants after ACLR. In this study, 30 post-ACL reconstruction participants were randomly divided into three groups (control, 40% Arterial Occlusion Pressure [AOP] and 80% AOP groups). All patients were subjected to different levels of BFR, combined with conventional quadriceps rehabilitation, for 8 weeks. Assessments included scaled maximal isokinetic knee extension strength at 60°/s and 180°/s, the sum of the thickness of the affected femoris rectus and vastus intermedius, Y-balance test performance, and International Knee Documentation Committee questionnaire responses before and after the intervention. In total, 23 participants completed the entire study. The 80% AOP compression group showed an increase in quadriceps femoris muscle strength and muscle thickness (p < 0.01). As compared with the control group, outcome indicators in the 40% AOP and 80% AOP group were improved (p < 0.05). After 8 weeks of experimental BFR intervention, the results were better for the 80% AOP compression group than for the 40% AOP compression group in quadriceps peak torque to body weight at 60°/s and 180°/s angular velocity, as well as the sum of the thickness of the rectus femoris and vastus intermedius. The combination of BFR and low-intensity quadriceps femoris training can effectively improve the muscle strength and thickness of knee extensors in participants with ACLR and help reduce the difference between the healthy and surgical sides of the knee joint while improving knee-joint function. Choosing quadriceps training with 80% AOP compression intensity could provide the most benefits. Meanwhile, BFR can accelerate the rehabilitation process of patients and allow early entry into the next rehabilitation cycle. Trial registration Chinese Clinical Trial Registry, registration number ChiCTR2100050011, date of registration: 15/08/2021.


Incorporation of dielectric constituents to construct ternary heterojunction structures for high-efficiency electromagnetic response.
To satisfy the diverse requirements of low reflection and high absorption of microwave attenuation, the construction of multiple heterojunction structure is imperative. On the one hand, the impedance mismatching could be ameliorated via the addition of new component; on the other hand, the multiple interface polarizations derived from the architecture of heterojunction make for the dissipation of microwave. In this work, the ternary TiO2/RGO/Fe2O3 composites exhibit tremendous superiority compared with single TiO2 or RGO no matter the absorption coefficient or effective bandwidth. The maximum absorption value of the TiO2/RGO/Fe2O3 composites is -44.05dB at 14.48GHz with a low thickness of 2.0mm. In addition, the effective bandwidth (RL<-10dB) reaches 5.6GHz from 11.96 to 17.56GHz. The superior electromagnetic wave absorbing performance of the TiO2/RGO/Fe2O3 composites derived from the appropriate impedance matching as well as the multiple polarization effect. The results adequately demonstrate the accessibility of the prepared TiO2/RGO/Fe2O3 composites as a preeminent absorber.


How effective is periarticular multimodal drug injection in open elbow arthrolysis? A prospective double-blind randomized controlled trial.
Evidence on the efficacy and safety of periarticular multimodal drug injection (PMDI) in open elbow arthrolysis (OEA) is limited. This study aimed to investigate differences in postoperative pain, blood loss, and range of motion (ROM) between PMDI vs. no injection among patients undergoing OEA, and the presence of PMDI-related complications. This prospective, double-blind randomized controlled trial included 59 patients who underwent OEA. Patients randomly received PMDI (ropivacaine, epinephrine, ketoprofen) before wound closure or no injection. The primary outcomes were elbow pain over the first postoperative week at rest and during motion, measured using the visual analog scale (VAS). VAS scores were compared to attain the 20-mm threshold values for a minimum clinically important difference. Parecoxib consumption on OEA night and postoperative days (PODs) 1-3 and total consumption during the first postoperative week were recorded. Blood loss was recorded every 24 hours until POD 3. ROM during rehabilitation was measured daily from day 1 to day 7 after surgery, as well as at 3-month follow-up. Medication-related side effects were recorded prospectively. The mean VAS score showed clinically important differences between PMDI and control groups at rest on OEA night (mean difference [MD], 25 mm; P < .001) and first 3 PODs with motion (POD 1: MD, 28 mm, P < .001; POD 2: MD, 21 mm, P < .001; POD 3: MD, 21 mm, P < .001) but not in other postoperative assessments. Parecoxib consumption was lower in the PMDI group on OEA night and PODs 1-3. Total parecoxib consumption during the first postoperative week was lower in the PMDI group vs. the control group (MD, 148 mg; P < .001). Blood drainage was less in the PMDI group vs. the control group on POD 1 (MD, 38 mL; P = .016) but not on POD 2 (P = .950), POD 3 (P = .259), or total (P = .184). The PMDI group exhibited significantly better ROM during the first 4 PODs than the control group, whereas there was no difference at 3-month follow-up. No medication-related side effects were noted in the PMDI group. PMDI effectively relieves pain and reduces analgesic consumption for OEA patients, without an apparent increase in risks.