Decreased expression of the m6A RNA methyltransferase METTL3 is associated with residual ridge resorption.
N6-methyladenosine (m6A) methylation and its regulators play crucial roles in the progression of osteoporosis (OP) by regulating the expression of osteoporosis-related genes. In this study, we have analyzed the expression of methyltransferase-like 3 (METTL3) and its target gene Runt-related transcription factor 2 (RUNX2) in patients with residual ridge resorption (RRR). A total 50 number of participants were included in this comparative study (RRR - n25 and healthy control - n25). Total RNA was extracted from peripheral blood and converted into cDNA. METTL3 and RUNX2 expression levels were quantified using RT-qPCR with GAPDH as the reference gene. Bioinformatics tools were used to identify gene functions and pathways. Real-time polymerase chain reaction (qPCR) revealed that METTL3 and RUNX2 expression was downregulated in the RRR group compared to that in healthy controls (P < 0.05). In silico functional analysis provided information regarding the role of METTL3 in various biological processes. Our findings suggest that METTL3 dysregulation contributes to RRR pathogenesis. Further large-scale samples and functional studies are required to identify their therapeutic potential.


Polymorphic CAG repeat length in the androgen receptor gene and association with neurodegeneration in a heterozygous female carrier of Kennedy's disease.
Kennedy's disease (spinobulbar muscular atrophy) is an X-linked form of motor neuron disease affecting adult males carrying a CAG trinucleotide repeat expansion within the androgen receptor gene. While expression of Kennedy's disease is thought to be confined to males carrying the causative mutation, subclinical manifestations have been reported in a few female carriers of the disease. The reasons that females are protected from the disease are not clear, especially given that all other diseases caused by CAG expansions display dominant expression. In the current study, we report the identification of a heterozygote female carrying the Kennedy's disease mutation who was clinically diagnosed with motor neuron disease. We describe analysis of CAG repeat number in this individual as well as 33 relatives within the pedigree, including two male carriers of the Kennedy's mutation. The female heterozygote carried one expanded allele of the androgen receptor gene with CAG repeats numbering in the Kennedy's disease range (44 CAGs),with the normal allele numbering in the uppernormal range (28 CAGs). The subject has two sons, one of whom carries the mutant allele of the gene and has been clinically diagnosed with Kennedy's disease, whilst the other son carries the second allele of the gene with CAGs numbering in the upper normal range and displays a normal phenotype. This coexistence of motor neuron disease and the presence of one expanded allele and one allele at the upper limit of the normal range may be a coincidence. However, we hypothesize that the expression of the Kennedy's disease mutation combined with a second allele with a large but normal CAG repeat sequence may have contributed to the motor neuron degeneration displayed in the heterozygote female and discuss the possible reasons for phenotypic expression in particular individuals.


Effect of omeprazole treatment on feed intake and blood gastrin and pepsinogen levels in the calf.
Previous work has shown blood gastrin levels to be elevated and appetite depressed in ostertagia-infected calves. A possible relationship between raised blood gastrin values and feed intake was investigated in worm-free animals using the human gastric acid secretion inhibitor, omeprazole. An initial dose-titration experiment established that administration of the drug by intravenous injection at 1.95 mg kg-1 (four times the recommended human dose rate) resulted in a marked (5.2-fold) increase in blood gastrin levels in the calf. Daily administration of omeprazole by intravenous injection at 2 mg kg-1 for four days in a subsequent experiment resulted in a significant depression in feed intake (up to 40.4 per cent) which was accompanied by a significant rise in blood gastrin levels (peak 940 pg ml-1; 6.5-fold increase over control values). It is suggested that such a rise in hormone levels would reduce reticuloruminal and abomasal motility, slow down the passage of ingesta and, in turn, lead to a reduction in appetite.


The Reemergence of Measles.
Measles, or rubeola, is a highly infectious, acute viral illness of childhood that is considered eliminated in the USA but has reemerged in the past few years. Globally, an estimated 20 million cases of measles continue to occur, and it remains a leading cause of death among young children. It is rare in the USA and other first world countries, but numerous outbreaks have occurred in the USA recently, due to a combination of factors including poor vaccine coverage and importation of cases among travelers returning from endemic areas. The diagnosis of measles is usually made clinically, when an individual presents with a constellation of symptoms including cough, coryza, conjunctivitis, high fever, and an erythematous maculopapular rash in a cephalocaudal distribution. Complications are common and include otitis media, pneumonia, encephalitis, and rarely death. A measles vaccine is available in two doses and provides excellent protection against the disease. Despite this, vaccination coverage, especially among young adults, remains poor. Given its resurgence in the USA and other countries, interventions are urgently needed to address low vaccination rates and vaccine hesitancy. Measles awareness should also be a priority among young clinicians, who may have never seen a case or are not familiar with the disease.


The hypothalamic-pituitary-adrenal axis in infantile malnutrition.
We studied the circadian rhythm and the response of the hypothalamic-pituitary-adrenal (HPA) axis to ovine corticotrophin releasing hormone (oCRH) stimulation and dexamethasone suppression in 32 children with grade II-III marasmus. Children were studied prior to and after nutritional rehabilitation. Mean baseline plasma cortisol concentrations were elevated at admission and decreased significantly after nutritional rehabilitation. Mean +/- SEM plasma cortisol response to oCRH increased from a basal of 480 +/- 41 to a peak of 582 +/- 58 nmol/l at the time of admission, and from a basal of 234 +/- 27 to a peak of 532 +/- 41 nmol/l after caloric rehabilitation. Dexamethasone suppression in the malnourished group was associated with a decrease in the mean +/- SEM basal plasma cortisol concentration from 397 +/- 44 to 171 +/- 44 nmol/l. After caloric rehabilitation, basal cortisol levels decreased from 259 +/- 27 to 22 +/- 5 nmol/l following dexamethasone. Our results support the concept that malnutrition is associated with decreased responsiveness to oCRH and incomplete dexamethasone suppression, and that these abnormalities are restored after nutritional rehabilitation.


Effects of conditioning voices as reinforcers for listener responses on rate of learning, awareness, and preferences for listening to stories in preschoolers with autism.
We used a delayed non-concurrent pre- and post-intervention probe design to test the effects of a voice conditioning protocol (VCP) with 3 preschoolers with autism on (a) rate of acquisition of listener curricular objectives, (b) observing voices and the presence of adults across 3 settings, (c) selecting to listen to adults tell stories in free play setting, and (d) the occurrence of stereotypy in the story setting. The VCP conditioned voices as reinforcers for listening to recordings of voices via stimulus-stimulus pairing, which resulted in the children listening to audio recordings of voices in 90% of intervals in 5-min concurrent-operant preference tests. After voices became conditioned reinforcers, all 3 children's learning accelerated; 2 children's observing responses increased in the 3 settings; and 2 children selected to listen to stories and also showed decreased stereotypy in the story setting. The data suggest that conditioned reinforcement for observing responses may be a verbal behavior developmental cusp that acts to accelerate learning that involves listening, and that the cusp may be induced using the VCP.


Intermittent coronary sinus occlusion in dogs: reduction of infarct size 10 days after reperfusion.
Intermittent balloon occlusion of the coronary sinus was applied to 11 open chest dogs subjected to 3 hours of ligation of the left anterior descending coronary artery followed by 8 to 12 days of reperfusion. Anticoagulants were not given during the reperfusion period. Risk region was assessed by planimetry of autoradiographs made from ventricular slices. Infarct size was equivalent when assessed by planimetry of ventricular slices before and after staining with triphenyltetrazolium chloride. In the seven survivors, 30 +/- 8% of the risk region was infarcted. Seven of 11 control dogs survived (p = NS); 75 +/- 4% of the risk region was infarcted in the control animals (p less than 0.01 versus treated survivors). Light microscopic inspection of specimens stained with hematoxylin-eosin confirmed the border between necrotic and preserved myocardium. Thrombus was observed in the coronary sinus in all survivors in the treatment group. These findings confirm earlier short-term studies that demonstrated a potent anti-ischemic effect of intermittent coronary sinus occlusion. At the same time, coronary sinus thrombosis warrants caution in the application of this technique to myocardial ischemia in humans.


CD34+ fibrocytes in tubular carcinomas and radial scars of the breast.
The present study was undertaken to analyze whether and to what extent CD34+ fibrocytes and alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts occur in the stroma of radial scars and tubular carcinoma of the breast. We investigated a total of 24 radial scars obtained from 23 females and a total of 43 tubular carcinomas. All tubular carcinomas showed a virtually complete loss of CD34+ fibrocytes paralleled by a gain of alpha-SMA-positive myofibroblasts. The peripheral parts of radial scars harbored CD34+ fibrocytes comparable to normal breast tissue. In 23 of 24 radial scars, the central core was characterized by a loss of CD34+ fibrocytes accompanied by the presence of alpha-SMA-positive myofibroblasts in six cases, a pattern that up to now has only been described in malignant breast lesions. This finding underlines the close relationship between tubular carcinomas and radial scars. We conclude CD34- and alpha-SMA immunohistochemistry to be valuable adjunctive tools in distinguishing radial scars from tubular carcinomas. In the present study, the presence of CD34+ fibrocytes excluded malignancy. The absence of CD34+ fibrocytes paralleled by the presence of alpha-SMA myofibroblasts indicated malignancy in most cases, although it has to be carefully considered that in a minority of cases (6 of 24) the central core of radial scars may disclose this stromal composition.


Characterization, chromosomal assignment, and role of LIFR in early embryogenesis and stem cell establishment of rabbits.
Leukemia inhibitory factor (LIF) is a multifunctional cytokine with an important role during early embryonic development, implantation, and as an inhibitor of murine embryonic stem cell differentiation. It exerts its effects by binding to the leukemia inhibitory factor receptor, a heterodimer of two transmembrane proteins, the specific leukemia inhibitory factor receptor subunit, and the common gp130. A partial cDNA clone coding for the membrane-bound form of the specific rabbit leukemia inhibitory factor receptor was isolated from the genital ridge of 13.5 days postcoitum fetus. Fluorescent in situ hybridization analysis revealed that the rabbit leukemia inhibitory factor receptor gene is located on chromosome OCU11p11.1. It has been shown that the membrane-bound rabbit leukemia inhibitory factor receptor mRNA is expressed during embryo implantation but not at earlier developmental stages. Rabbit embryonic stem cell-like line establishment is improved in the presence of LIF, and those cells express both leukemia inhibitory factor and its receptor. The withdrawal of leukemia inhibitory factor results the differentiation of embryonic stem cell-like cells to beating myocardial-like cells. Our findings suggest that the self-renewal mechanism is similar in mouse and rabbit embryonic stem cells, and expands our knowledge on the role of the LIF-LIFR signal pathway in early rabbit embryogenesis and rabbit embryonic stem cell establishment.


Morphometric development of the human fetal cerebellum during the early second trimester.
The protracted nature of development makes the cerebellum vulnerable to a broad spectrum of pathologic conditions, especially during the early fetal period. This study aims to characterize normal cerebellar growth in human fetuses during the early second trimester. We manually segmented the fetal cerebellum using 7.0-T high-resolution MR images obtained in 35 specimens with gestational ages ranging from 15 to 22 weeks. Volume measurements and shape analysis were performed to quantitatively evaluate global and regional cerebellar growth. The absolute volume of the fetal cerebellum showed a quadratic growth with increasing gestational age, while the pattern of relative volume changes revealed that the cerebellum grew at a greater pace than the cerebrum after 17 gestational weeks. Shape analysis was used to examine the distinctive development of subregions of the cerebellum. The extreme lateral portions of both cerebellar hemispheres showed the lowest rate of growth. The anterior lobe grew faster than most of the posterior lobe. These findings expand our understanding of the early growth pattern of the human cerebellum and could be further used to assess the developmental conditions of the fetal brain.


VEGF-PLGA controlled-release microspheres enhanced angiogenesis in encephalomyosynangiosis-based chronic cerebral hypoperfusion.
Treatments enhancing angiogenesis for chronic cerebral hypoperfusion (CCH) are still in the research stage. Although encephalomyosynangiosis (EMS) is a common indirect anastomosis for the treatment of CCH, the effectiveness to promote angiogenesis is not satisfactory. Vascular endothelial growth factors (VEGF) is a cytokine found to specifically act directly on vascular endothelial cells, promote neovascularization, and enhance capillary permeability. However, the short half life and unstable property of VEGF underlies the need to explore available delivery system. In this study, poly (lactide-co-glycolide) (PLGA) was used to prepare VEGF controlled-release microspheres. In vitro and in vivo analysis of release kinetics showed that the microspheres could release VEGF continuously within 30 days. Then, modified chronic cerebral hypoperfusion rat model was established by ligation of bilateral internal carotid artery and one vertebral artery. At 14 days after ischemia, the EMS and the VEGF microspheres injection were performed. At 30 days after the injection, the result of Morris water maze displayed that combinating VEGF microspheres and EMS significantly ameliorated cognitive deficit after ischemia. We observed that combinating VEGF microspheres and EMS could further significantly increase cerebral blood flow. We speculated that this enhancement of cerebral blood flow was attributed to more angiogenesis induced by combination of VEGF microspheres and EMS, which verified by more collateral circulation with cerebral angiography and higher expression of CD31 or α-SMA. Our study demonstrated that combinating VEGF-PLGA controlled-release microspheres could significantly promote angiogenesis in EMS-based CCH rats model, providing new ideas for clinical treatment of CCH.


Orientational anisotropic studies by field rotation technique: near zero-field pulsed EPR experiments of pentacene doped in p-terphenyl.
We report a new technique to map the orientational anisotropy of paramagnetic systems without physically changing the crystal orientations in near zero-field (NZF) pulsed EPR experiments. By implementing three sets of orthogonal coils around the sample, we are ble to create a magnetic vector up to 2 mT in any three-dimensional orientation in space. In NZF region, the hyperfine tensor elements are comparable to the electronic Zeeman interaction energy, thus very rich spectral patterns can be obtained by "dialing" in a magnetic field vector without moving the sample. The technique further allows us to examine the site symmetry of organic crystals and powdered solids doped with chromophores which can be photo-excited to the triplet state by laser light. The technique is exemplified in the study of pentacene in p-terphenyl crystals.


Characteristics of corneal microcysts in Hong Kong children wearing orthokeratology.
To report the characteristics (prevalence, severity, and location) of corneal epithelial microcysts and investigate associated risk factors in children wearing orthokeratology (ortho-k) lenses. Ninety-five myopic children wearing ortho-k lenses (examined by one of three independent investigators from March to September 2020) were included in this retrospective cross-sectional study. Pertinent data at baseline before ortho-k treatment and at the aftercare visits (the first visit when the microcysts were observed for children with microcysts, and the last visit before October 2020 for children without microcysts) were retrieved and analysed. A microcystic response was observed in 52.6% of children wearing ortho-k lenses. Children with high myopia (≥ 5.00 D) had a higher prevalence (100.0%, 23/23) and severity (69.5% (16/23) > grade 2 Efron scale) compared to children with low myopia (≤ 4.00 D) (prevalence of 37.5% (27/72) and 7.0% (5/72) > grade 2, p < 0.001). Microcysts were predominantly (86.0%) observed in the region of the inferior pigmented arc, typically originating in the inferior mid-peripheral cornea, and expanding over time into a semi- or whole annulus. Baseline myopia and topographical change at the treatment zone centre were significantly greater (p < 0.05) in low myopic children with microcysts (univariate analyses). During the COVID-19 pandemic, probably due to lifestyle changes, microcysts were frequently observed in children wearing ortho-k lenses and were associated with higher baseline myopia. Practitioners should examine ortho-k wearers with caution using a slit lamp with high magnification and illumination, especially the mid-peripheral cornea. The use of highly oxygen permeable lenses and frequent aftercare are necessary for ortho-k wearers, especially those with higher myopia.


Bovine bronchial epithelial cells metabolize L-arginine to L-citrulline: possible role of nitric oxide synthase.
The conversion of L-arginine to L-citrulline is catalyzed by nitric oxide synthase (NOS), and results in the release of nitric oxide (NO). We hypothesized that bronchial epithelial cells metabolize L-arginine to L-citrulline. We found that cell lysates obtained from unstimulated, cultured bovine bronchial epithelial cells (BBECs) converted L-[3H]arginine to L-[3H]citrulline. This conversion was attenuated by three competitive NOS inhibitors and modulated by lipopolysaccharide and cigarette smoke extract (p < 0.01, all comparisons). These data demonstrate that BBECs metabolize L-arginine to L-citrulline and implicate a role for the L-arginine:NOS biosynthetic pathway in modulating airway responses.


Effects of growth temperature and winter duration on leaf phenology of Erythronium japonicum, a forest spring geophyte.
The effects of growth temperature and winter duration on the leaf phenology of Erythronium japonicum were examined in two experiments. Bulbs wintered in the field were cultivated at 10 and 20° C and the bulbs were cultivated at 15° C after chilling treatment at 3° C for 60 and 120 days and without chilling in winter. The plants cultivated at 20° C showed significantly earlier leaf emergence, a more rapid rate of leaf extension and shorter leaf longevity than those cultivated at 10° C. The decrease in the leaf longevity at 20° C resulted from the decreases in the durations of all of the developmental, mature, and senescent phases. The bulbs without chilling treatment did not sprout leaves and those with chilling treatment sprouted leaves. The increase in the length of chilling treatment from 60 to 120 days affected leaf phenology in same manner as the increase in the growth temperature from 10 to 20° C.


Assessment of the eye irritation potential of chemicals: A comparison study between two test methods based on human 3D hemi-cornea models.
We have recently developed two hemi-cornea models (Bartok et al., Toxicol in Vitro 29, 72, 2015; Zorn-Kruppa et al. PLoS One 9, e114181, 2014), which allow the correct prediction of eye irritation potential of chemicals according to the United Nations globally harmonized system of classification and labeling of chemicals (UN GHS). Both models comprise a multilayered epithelium and a stroma with embedded keratocytes in a collagenous matrix. These two models were compared, using a set of fourteen test chemicals. Their effects after 10 and 60 minutes (min) exposure were assessed from the quantification of cell viability using the MTT reduction assay. The first approach separately quantifies the damage inflicted to the epithelium and the stroma. The second approach quantifies the depth of injury by recording cell death as a function of depth. The classification obtained by the two models was compared to the Draize rabbit eye test and an ex vivo model using rabbit cornea (Jester et al. Toxicol in Vitro. 24, 597-604, 2010). With a 60 min exposure, both of our models are able to clearly differentiate UN GHS Category 1 and UN GHS Category 2 test chemicals.


'What price do you put on your health?': Medical cannabis, financial toxicity and patient perspectives on medication access in advanced cancer.
Following 2016 legislation permitting limited access to cannabis for research and medicinal purposes, the number of randomized clinical trials (RCTs) investigating the effectiveness of medicinal cannabis (MC) on symptom burden relief in cancer contexts has increased in Australia. This study aimed to understand the perceptions, hopes and concerns of people with advanced cancer regarding the future availability and regulation of MC in Australia. This qualitative study draws on semistructured interviews conducted between February 2019 and October 2020 in Brisbane, Australia, as part of an MC RCT substudy. Interviews were undertaken on 48 patients with advanced cancer in palliative care eligible to participate in an MC trial (n = 26 participated in an RCT; n = 2 participated in a pilot study; n = 20 declined). Interviews included a discussion of patients' decision-making regarding trial participation, concerns about MC and perceptions of future availability, including cost. Transcribed interviews were analysed inductively and abductively, informed by constructivist thematic analysis conventions. Overall, participants supported making MC legally accessible as a prescription-only medication. Fear of financial toxicity, however, compromised this pathway. Steep posttrial costs of accessing MC prompted several people to decline trial participation, and others to predict-if found effective-that many would either access MC through alternative pathways or reduce their prescribed dosage to enable affordable access. These findings suggest that-despite a relatively robust universal healthcare system-Australians are potentially vulnerable to and fearful of financial toxicity. Prevalent in the United States, financial toxicity occurs when disadvantaged cancer patients access necessary but expensive medications with lasting consequences: bankruptcy, ongoing anxiety and cancer worry. Interview transcripts indicate that financial fears-and the systems sustaining them-may pose a threat to RCT completion and to equitable access to legal MC. Such findings support calls for embedding qualitative substudies and community partnerships within RCTs, while also suggesting the importance of subsidisation to overcoming injustices. A patient advisory committee informed RCT design. This qualitative substudy foregrounds patients' decision-making, perceptions and experiences.


[Infected false aneurysm at the level of an aortotomy cicatrix 5 years after mechanical replacement of the aortic valve].
The authors report the case of Streptococcus Bovis Infection of a pseudoaneurysm which developed in the aortotomy suture line five years after aortic valve replacement with a Bjork-Shiley prosthesis. This was an isolated lesion without involvement of the prosthesis or aortic ring and was an operative finding.


The X chromosome deletion in HYP mice extends into the intergenic region but does not include the SAT gene downstream from Phex.
The murine Hyp mutation is a model for X-linked hypophosphatemia (XLH), the most prevalent form of inherited rickets in humans. Although mutations in the murine Phex gene and the human PHEX gene have been identified in both murine and human disorders, the extent of the Hyp deletion on the mouse X chromosome has not been delineated. In the present study we demonstrate that the Hyp deletion starts in the middle of Phex intron 15 and includes approximately 48 kb of the 3' region of the Phex gene and approximately 10 kb of intergenic sequence on the mouse X chromosome. In addition, we show that the Hyp deletion does not involve the downstream spermidine/spermine N1-acetyl transferase (Sat; formerly Ssat) gene and thus is not a contiguous gene deletion syndrome. Our data indicate that the Hyp mouse is a true homolog of XLH in humans and underscore the validity of this murine model in studies of XLH pathophysiology and for testing novel treatment modalities.


Expression of vasopressin in the hypothalamus of active and passive rats with poststress depression.
No interstrain differences were revealed in vasopressin concentration in the hypothalamus of control and treated active and passive rats with poststress depression. Changes in vasopressin immunoreactivity corresponded to variations in corticotropin-releasing hormone concentration observed in this model of depression. These data suggest that vasopressin contributes to the development of this experimental psychopathology.


Disease-specific non-reducing end carbohydrate biomarkers for mucopolysaccharidoses.
A considerable need exists for improved biomarkers for differential diagnosis, prognosis and monitoring of therapeutic interventions for mucopolysaccharidoses (MPS), inherited metabolic disorders that involve lysosomal storage of glycosaminoglycans. Here we report a simple, reliable method based on the detection of abundant nonreducing ends of the glycosaminoglycans that accumulate in cells, blood and urine of individuals with MPS. In this method, glycosaminoglycans are enzymatically depolymerized, releasing unique mono-, di- or trisaccharides from the nonreducing ends of the chains. The composition of the released mono- and oligosaccharides depends on the nature of the lysosomal enzyme deficiency, and therefore they serve as diagnostic biomarkers. Analysis by LC/MS allowed qualitative and quantitative assessment of the biomarkers in biological samples. We provide a simple conceptual scheme for diagnosing MPS in uncharacterized samples and a method to monitor efficacy of enzyme replacement therapy or other forms of treatment.


Computational and In Vitro Experimental Investigations Reveal Anti-Viral Activity of Licorice and Glycyrrhizin against Severe Acute Respiratory Syndrome Coronavirus 2.
Without effective antivirals, the COVID-19 pandemic will likely continue to substantially affect public health. Medicinal plants and phytochemicals are attractive therapeutic options, particularly those targeting viral proteins essential for replication cycle. Herein, a total 179 phytochemicals of licorice (Glycyrrhiza glabra) were screened and scrutinized against the SARS-CoV-2 main protease (Mpro) with considerable binding affinities in the range of -9.831 to -2.710 kcal/mol. The top 10 compounds with the best docking scores, licuraside, glucoliquiritin apioside, 7,3'-Dihydroxy-5'-methoxyisoflavone, licuroside, kanzonol R, neoisoliquiritin, licochalcone-A, formononetin, isomucronulatol, and licoricone, were redocked using AutoDock Vina, yielding -8.7 to -7.3 kcal/mol binding energy against Glycyrrhizin (-8.0 kcal/mol) as a reference ligand. Four compounds, licuraside, glucoliquiritin apioside, 7,3'-Dihydroxy-5'-methoxyisoflavone, and licuroside, with glycyrrhizin (reference ligand) were considered for the 100 ns MD simulation and post-simulation analysis which support the stability of docked bioactive compounds with viral protein. In vitro studies demonstrated robust anti-SARS-CoV-2 activity of licorice and glycyrrhizin under different treatment protocols (simulations treatment with viral infection, post-infection treatment, and pre-treatment), suggesting multiple mechanisms for action. Although both compounds inhibited SARS-CoV-2 replication, the half-maximal inhibitory concentration (IC50) of glycyrrhizin was substantially lower than licorice. This study supports proceeding with in vivo experimentation and clinical trials and highlights licorice and glycyrrhizin as potential therapeutics for COVID-19.


Identifying high-risk population of depression: association between metabolic syndrome and depression using a health checkup and claims database.
Depression and metabolic syndrome (MetS) are correlated, leading to an increased healthcare burden and decreased productivity. We aimed to investigate the association between MetS-related factors and depression using a health checkup and claims database. Individuals aged 18-75 years who underwent health examinations between 2014 and 2019 were enrolled in the study. Among 76,277 participants, "ever" and "incident" antidepressant users exhibited worse metabolic profiles and were more likely to be prescribed hypnotics and anxiolytics than "never" users. In a nested case-control study with a 1:10 ratio of incident users to controls, MetS was associated with incident antidepressant use (odds ratio, 1.53 [95% confidence interval 1.24-1.88]) adjusted for lifestyle information obtained from a self-administered questionnaire, medical history, and medications. Other metabolic traits also showed significant associations: body mass index (1.04 [1.02-1.06]), abdominal circumference per 10 cm (1.17 [1.08-1.27]), high blood pressure (1.17 [1.00-1.37]), glucose intolerance (1.29 [1.05-1.58]), and dyslipidemia (1.27 [1.08-1.51]). A bodyweight increase > 10 kg from age 20 years (1.46 [1.25-1.70]) was also significantly associated with incident antidepressant use. In conclusion, metabolic abnormalities were associated with incident antidepressant use and can be useful in identifying populations at high risk of depression.


Pharmacological activities and pharmacokinetics of liquiritin: A review.
Liquiritin is a flavonoid derived from Radix et Rhizoma Glycyrrhizae, which is a widely used traditional Chinese medicine with the effects of invigorating spleen qi, clearing heat, resolving toxins, and dispelling phlegm to stop coughs. In this review,the pharmacokinetics and pharmacological activities of liquiritin have been summarized. The information on liquiritin up to 2021 was collected from PubMed, Web of Science, Springer Link, and China National Knowledge Infrastructure databases. The key words were "liquiritin", "nerve", "tumor", "cardiac", etc. RESULTS: The absorption mechanism of liquiritin conforms to the passive diffusion and first-order kinetics while with low bioavailability. Liquiritin can penetrate the blood-brain-barrier. Besides, liquiritin displays numerous pharmacological effects including anti-Alzheimer's disease, antidepressant, antitumor, anti-inflammatory, cardiovascular protection, antitussive, hepatoprotection, and skin protective effects. In addition, the novel preparations, new pharmacological effects,and cdusafty of liquiritin are also discussed in this review. This review provides a comprehensive state of knowledge on the pharmacokinetics and pharmacological activities of liquiritin, and makes a forecast for its research directions and applications in clinic.


Modulation of the Ca2+-sensing function of parathyroid cells in vitro and in hyperparathyroidism.
When raising the extracellular Ca2+ concentration stepwise from 0.5 to 3.0 mM, bovine parathyroid cells reacted with initial transient and sustained elevations of the cytoplasmic Ca2+ concentration (Ca2+i), as well as more than 50% inhibition of parathyroid hormone (PTH) release. Human parathyroid adenoma cells and bovine cells cultured for 1 day or exposed to a low concentration of a monoclonal antiparathyroid antibody exhibited right-shifted dependencies of PTH release and Ca2+i on extracellular Ca2+ and reduced Ca2+i transients. The protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA) further right-shifted the dose response relationship for Ca2+ regulated Ca2+i of the adenoma cells, whereas the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) tended to normalize it, without affecting Ca2+i of normal bovine cells. In cells from an oxyphil adenoma and a parathyroid carcinoma as well as in bovine cells cultured 4 days or exposed to a high concentration of the antiparathyroid antibody, there were no Ca2+i transients, very small increases in steady-state Ca2+i and nonsuppressible PTH release. The results suggest that reduced availability of a putative Ca2+-receptor and increased protein kinase C activity may be important factors in the decreased Ca2+ sensitivity of abnormal parathyroid cells.


Study of the relation of clinical and demographic factors with morbidity in a tertiary care teaching hospital in India.
The emergency department of every tertiary care teaching hospital is the backbone of community health care service. This study was undertaken to identify the pattern of emergencies in the hospital, and to identify the risk factors associated with these emergencies. This was a retrospective record analysis of the emergency department from Jan 2010 to Dec 2010. The data were analyzed for various types of medical emergencies presented at the hospital at Guru Gobind Singh Medical College and Hospital, Faridkot. A total of 2310 patients presented in the emergency department of which nearly half were males; a great majority were in the age group of 15-40 years. The diseases related to the cardiovascular system, 367 (15.89%), topped the list of which hypertension was noted in 267 (11.56%) cases. This was followed by morbidities related to the neurological system, diabetes, hepatobiliary, respiratory, renal 168 (7.27%), poisoning, pyrexia of unknown origin, and multi-organ involvement. With regard to the specific diseases, the majority were contributed by coronary artery disease 217 (9.39%), stroke 178 (7.71%), alcoholic liver disease 160 (6.93%), and chronic obstructive lung diseases 90 (3.90%). In our series, we noted that a great majority of cases were in the 41-60 age groups except poisoning (majority less than 40 years). The age groups were significantly related with selected morbidities. There are transparent evidence that we need an organized emergency care system in India as relatively the younger age group (15-40 years) comprised nearly half cases.


Structural biology of the S1P1 receptor.
The sphingosine 1 phosphate receptor family has been studied widely since the initial discovery of its first member, endothelium differentiation gene 1. Since this initial discovery, the family has been renamed and the primary member of the family, the S1P1 receptor, has been targeted for a variety of disease indications and successfully drugged for the treatment of patients with relapsing multiple sclerosis. Recently, the three-dimensional structure of the S1P1 receptor has been determined by X-ray crystallography and the specifics of the sphingosine 1 phosphate ligand binding pocket mapped. Key structural features for the S1P1 receptor will be reviewed and the potential binding modes of additional pharmacologically active agents against the receptor will be analyzed in an effort to better understand the structural basis of important receptor-ligand interactions.


Endodontic management of a maxillary first molar with two palatal roots and a single fused buccal root diagnosed with spiral computed tomography - a case report.
The aim of this case report is to present an endodontically managed maxillary first molar with an unusual morphology of 2 palatal roots and a single fused buccal root. An accurate assessment of this morphology was made with the help of spiral computerized tomography, which revealed that the contralateral tooth also had a similar morphology.


Localizing subprocesses of visual search by correlating local brain activation in fMRI with response time model parameters.
In a complex cognitive task such as overt visual search, several subprocesses interact in quick alternation, such as attentional selections (i.e., spatially constrained modulation of perception) and attentional shifts/eye movements. Since temporal resolution in fMRI is low, it is difficult to assign local brain activations to these subprocesses with traditional analysis. The present paper investigates a new approach: with the response time model STRAVIS [Müller-Plath G, Pollmann S. Determining subprocesses of visual feature search with reaction time models. Psychol Res 2003;67:80-105], a visual search process is decomposed into hypothetical cognitive subprocesses and quantitatively described by individually estimated parameters like the size of the attentional focus or the attentional dwell time. In the fMRI experiment we administered the search task, correlated the estimated model parameter values for dwell time and (reciprocal) focus size to BOLD-responses, and thereby identified putative neural networks that are jointly active in the task but differentially specialized to the subprocesses attentional selection and attentional shift. First, the methodological approach was validated by the results agreeing with the literature for predefined brain areas. Second, our findings might add to the literature by specifying several more brain areas probably belonging to the two networks. Third, compared to a more traditional data analysis (contrasts of mean BOLD responses in the factorial experimental design) the method of individually correlating model parameters to BOLD proved superior provided one accepts the theoretical assumptions underlying each of the approaches. Our results demonstrate the utility of combining mathematical modeling and fMRI to investigate the neural substrates of a complex task such as visual search.


A correlation of responses of the resistance and capacitance vessels of the intestine and kidney to changes of impulse in postganglionic nerves under pressor reflexes.
The responses of resistance vessels of the intestine and kidney were induced by high amplitude impulses (over 15 muV), while those of capacitance vessels in these organs were induced by low amplitude impulses (15 muV and lower) of postganglionic sympathetic fibres.


Summer water relations of the desert phreatophyte Prosopis glandulosa in the Sonoran Desert of southern California.
Prosopis is a genus of phreatophytic trees inhabiting hot deserts and semiarid grasslands of the world. Although desert trees are exposed to unusual environmental temperature and water stress, few investigations have evaluated their water relations. This is particularly true for Prosopis species growing in areas where a large portion of their water use comes from ground water.Water relations components for Prosopis glandulosa were studied at Harper's Well, near the Salton Sea, California during the summer months of 1980. Maximum temperatures (49° C), irradiance (2,000 μE/m2/sec), and vapor pressure deficit (5.3 kPa) were reached in July. During this time Prosopis glandulosa predawn xylem pressure potentials were below-3.0 MPa. Prosopis glandulosa at Harper's Well is able to maintain open stomata during high temperatures, high vapor pressure deficit and at low estimated turgor pressure. Leaf resistance measurements indicate that stomata are open primarily in the morning, but may reopen in the afternoon in trees with greater water resources. Osmotic potentials of juvenile shoots were higher (-1.0 to-2.5 MPa) than mature shoots (-3.5 MPa). Estimated turgor potential remained low (0.1-0.2 MPa) during the morning and early afternoon. Estimated turgor pressure increased from August to September as temperatures and vapor pressure deficit decreased. Leaf conductance was strongly associated with leaf vapor pressure deficit and estimated turgor potential but poorly associated with xylem pressure potential. Prosopis stomata seem to be uncoupled from tissue water potential until-4.8 MPa is reached.


Reactive oxygen species production and antioxidant enzyme activity during epididymal sperm maturation in Corynorhinus mexicanus bats.
Prolonged sperm storage in the epididymis of Corynorhinus mexicanus bats after testicular regression has been associated with epididymal sperm maturation in the caudal region, although the precise factors linked with this phenomenon are unknown. The aim of this work is to determine the role of reactive oxygen species (ROS) and changes in antioxidant enzymatic activity occurring in the spermatozoa and epididymal fluid over time, in sperm maturation and storage in the caput, corpus and cauda of the bat epididymis. Our data showed that an increment in ROS production coincided with an increase in superoxide dismutase (SOD) activity in epididymal fluid and with a decrease in glutathione peroxidase (GPX) activity in the spermatozoa in at different time points and epididymal regions. The increase in ROS production was not associated with oxidative damage measured by lipid peroxidation. The results of the current study suggest the existence of a shift in the redox balance, which might be associated with sperm maturation and storage.


The emetic action of L-dopa and its effect on the swallowing reflex in the cat.
In adults cats anesthetized with urethane it was shown that facilitation of reflexly-induced swallowing by dopaminomimetics is caused by a central action independent of the emetic of such drugs. It is suggested that this modulatory influence is mediated by dopamine receptors associated with the amygdala and ventral basal striatum.


THe "U" technique: a new method for Norplant implants removal.
The standard technique for Norplant implants removal was compared with a new technique called the "U" technique, which employs the use of a modified no-scalpel vas deferens holding forceps to grasp and remove the capsules. Seventy-six women requesting Norplant implants removal were randomly assigned to Group 1 (standard removal technique) or Group 2 ("U" removal technique). Variables measured included: (a) time required for complete removal, (b) number of capsules not broken or damaged during removal, and (c) number of incisions required for removal of all six capsules. In clients with visible or palpable capsules, the standard removal technique required significantly more time to remove all six capsules, on average, than the "U" technique (19 versus 7 minutes, p < 0.001); also more capsules were damaged during removal (5.6 undamaged versus 6.0, p < 0.01). In addition, with the standard technique, five clients required two incisions for removal of all six capsules while none of the clients required more than one incision with the "U" technique. Our conclusion is that the "U" technique is a quicker and easier method of removing Norplant capsules than the standard technique.


Impact of adapting paediatric intensive care units for adult care during the COVID-19 pandemic: a scoping review.
The objectives were to categorise the evidence, map out the existing studies and explore what was known about the organisation of paediatric intensive care units (PICUs) during the first 18 months of the COVID-19 pandemic. Additionally, this review set out to identify any knowledge gaps in the literature and recommend areas for future research. Scoping review. This study used Arksey and O'Malley's six-stage scoping review framework. A comprehensive search was conducted using the following databases, CINAHL Complete; MEDLINE; PsycINFO; PsycARTICLES and EMBASE and grey literature search engines. A search strategy with predefined inclusion criteria was used to uncover relevant research in this area. Screening and data collection were done in duplicate. 47 631 articles were obtained through searching. However, only 25 articles met the inclusion criteria and were included in the analysis. Three dominant themes emerged from the literature: (1) the reorganisation of space for managing increased capacity; (2) increased staffing and support; and (3) the resulting challenges. COVID-19 has strained institutional resources across the globe. To relieve the burden on intensive care units (ICUs), some PICUs adjusted their units to care for critically ill adults, with other PICUs making significant changes, including the redeployment of staff to adult ICUs to provide extra care for adults. Overall, PICUs were collectively well equipped to care for adult patients, with care enhanced by implementing elements of holistic, family-centred PICU practices. The pandemic fostered a collaborative approach among PICU teams and wider hospital communities. However, specific healthcare guidelines had to be created to safely care for adult patients.


Sympathetic nerve disturbance and fine structure of adrenergic nerve terminals in nasal mucosa after experimentally-induced nasal hypersensitivity.
Electron microscopic observations were used to study the relation between the adrenergic nerve terminal and the effector cell in the nasal mucosa of toluene diisocyanate-sensitized and non-sensitized guinea pigs. Adrenergic nerve terminals were abundantly distributed in the adventitia of arterioles, however, no synapse formation was observed in smooth muscle cells of the mesothelium, i.e., effector cells. Adrenergic nerve terminals were observed separated from smooth muscle cells of the mesothelium of the arteriole by distances of 1000 A-3000 A. Neurotransmission by the sympathetic nerve in the nasal mucosa is assumed to be by diffusion of norepinephrine (NE) or by diffusive synaptic conduction. The mechanism of sympathetic hypofunction in the nasal mucosa in nasal hypersensitivity is assumed to be as follows: Released histamine directly stimulates H-1 receptors at the sympathetic nerve terminal, leading to the release of NE. Once released, NE is not readily reabsorbed, and is gradually depleted in the sympathetic nerve terminal, leading to hypofunction of the sympathetic nerve.


An ultra-sensitive SPR immunosensor for quantitative determination of human cartilage oligomeric matrix protein biomarker.
This paper reports the development of a novel surface plasmon resonance (SPR) immunosensor for ultra-sensitive quantitative determination of human articular cartilage oligomeric matrix protein (COMP), a major component of the extracellular matrix and an exploratory biomarker. Capture antibodies against human COMP (anti-COMP16F12) were covalently immobilized on an 11-mercaptoundecanoic acid (11-MUA) self-assembled monolayer (SAM)-coated SPR sensor disk and a dual sandwich-type signal amplification strategy using biotinylated detection antibodies against COMP (anti-COMP17C10-biot) and streptavidin-conjugated quantum dots (SAv‒QDs) were used for the development of an immunosensor. The binding of high-mass SAv‒QDs via biotin-streptavidin interaction to the surface of the immunosensor resulted in a drastic increase in the sensitivity. The developed immunosensor was able to detect concentrations of COMP in a range from 2.80 to 680.54 fM with a limit of detection (LOD) and a limit of quantification (LOQ) of 0.15 and 0.50 fM, respectively. The immunosensor exhibited good repeatability (relative standard deviation (RSD) 8.05%) and reproducibility (RSD 9.88%) as well as excellent operational stability (2.14 % decrease in SPR signal after 13 days). In addition, the analysis of secretomes of human knee articular cartilage explants from patients with osteoarthritis revealed that the immunosensor has good accuracy (analytical error less than 5 %). These results indicate that the immunosensor developed may be suitable for quantitative determination of COMP derived from articular cartilage and other synovial joint tissues in clinical studies.


Slope until reaching the plateau: a new predictor of valve response obtained by lumbar infusion test for idiopathic normal pressure hydrocephalus.
Diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is based on clinical, radiological, and hydrodynamic data of cerebrospinal fluid (CSF) obtained by invasive methods such as lumbar infusion test, which is used to determine the resistance to CSF outflow (Rout). However, Rout has limitations, and its value as predictor of valve response is questioned. Other variables can be obtained by lumbar infusion test, such as the time to reach the plateau (TRP) and the slope until reaching the plateau (SRP). The objectives were to determine if SRP could be a predictor of response to ventriculoperitoneal shunt (VPS) and what variable (Rout versus SRP) would have greater predictive value. Patients with probable iNPH who underwent a lumbar infusion test and were indicated for a VPS were retrospectively studied. Two groups were established, responders and non-responders. Rout, TRP (period between the start of infusion until reaching the plateau measured in seconds) and SRP ((plateau pressure-opening pressure)/TRP) were obtained. For Rout and SRP, the receiver operating curves (ROC) with its areas under the curve (AUC) were calculated. One hundred ten patients were included, being 86 responders (78.20%). Shunt responders had a significantly greater Rout (17.02 (14.45-20.23) versus 13.34 (12.10-16.28) mmHg/ml/min, p = 0.002) and SRP (0.049 (0.043-0.054) versus 0.031 (0.026-0.036) mmHg/sec, p < 0.001) and smaller TRP (641.28 (584.83-697.73) versus 777.65 (654.03-901.27) sec, p = 0.028) than non-responders. The AUC for SRP was greater than the AUC for Rout (0.763 (95 % CI 0.655-0.871, p < 0.001) versus 0.673 (95 % CI 0.595-0.801, p = 0.008), respectively), but the differences were not significant (p = 0.180). SRP could be considered predictor of response to VPS, and its accuracy tends to be better than Rout. So, this variable may be a useful tool to select shunt candidates among patients with probable iNPH.


Comparison of 90-day re-admission rates between open retropubic radical prostatectomy (RRP), laparoscopic RP (LRP) and robot-assisted laparoscopic prostatectomy (RALP).
Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? With the increased use of laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic prostatectomy (RALP), a growing number of publications have sought to compare these more advanced techniques to retropubic RP (RRP). Many studies have found RALP and LRP to be associated with lower blood loss, postoperative pain, and hospital stay when compared with RRP. The present study showed that, after adjusting for potential confounders, patients undergoing RALP had a lower risk of 90-day re-admission than patients undergoing RRP. However, there was no significant difference in the odds of being re-admitted ≤ 90 days after RP between patients undergoing a LRP and RRP. • To examine the risk of 90-day re-admission among patients undergoing retropubic radical prostatectomy (RRP), laparoscopic RP (LRP), and robot-assisted laparoscopic prostatectomy (RALP) in Taiwan. • We identified 2741 hospitalised patients who underwent a RP. Of these 2741 cases, 1773 patients underwent RRP, 694 LRP, and 274 RALP. • We performed a conditional (fixed-effect) logistic regression model to explore the odds of 90-day re-admission from RP among patients undergoing RRP, LRP, and RALP. • In all, 257 of the 2741 (9.4%) sampled subjects were re-admitted ≤ 90 days of the index RP. • Patients undergoing a RALP had a significantly lower incidence rate of 90-day re-admission than patients undergoing a RRP or LRP (3.6% vs 10.7% vs 8.2%, P < 0.001). • Compared with patients undergoing a RRP, the odds ratio (OR) of 90-day re-admission for patients undergoing a RALP was only 0.35 (95% confidence interval [CI] 0.19-0.68) after adjusting for patient age, geographic region, year of surgery, Charlson Co-morbidity Index score, and surgeon age and the number of RP cases/year. • However, there was no significant difference in the odds of being re-admitted ≤ 90 days of RP between patients undergoing a LRP and RRP. • The adjusted odds of 90-day re-admission for patients undergoing a RALP were 0.46 (95% CI 0.23-0.94) those of patients undergoing a LRP. • Our study shows that patients undergoing a RALP had a lower adjusted risk of 90-day re-admission than patients undergoing RRP. However, no significant differences were identified between LRP and RRP.


An investigation of the colorectal cancer experience and receptivity to family-based cancer prevention programs.
Cancer is a shared family experience and may provide a "teachable moment" to motivate at-risk family members to adopt cancer prevention and health promotion behaviors. This study explored how a diagnosis of colorectal cancer (CRC) is experienced by family members and may be used to develop a family-based CRC prevention program. Preferences regarding content, timing, and modes of program delivery were examined. Social cognitive theory provided the conceptual framework for the study. This study employed mixed methodology (semi-structured interviews and self-report questionnaires). Participants included 73 adults (21 patients, 52 family members) from 23 families (two patients were deceased prior to being interviewed). Most patients (n = 14; 67 %) were interviewed 1-5 years post-diagnosis. Individual interviews were audio-recorded, transcribed, and content analyzed. For many, a CRC diagnosis was described as a shared family experience. Family members supported each other's efforts to prevent CRC through screening, exercising, and maintaining a healthy diet. Teachable moments for introducing a family-based program included the time of the patient's initial cancer surgery and post-chemotherapy. Reported willingness to participate in a family-based program was associated with risk perception, self-efficacy, outcome expectancies, and the social/community context in which the program would be embedded. Program preferences included cancer screening, diet/nutrition, weight management, stress reduction, and exercise. Challenges included geographic dispersion, variation in education levels, generational differences, and scheduling. CRC patients and family members are receptive to family-based programs. Feasibility concerns, which may be mitigated but not eliminated with technological advances, must be addressed for successful family-based programs.


Sorption studies of lead (II) onto crosslinked and non crosslinked biopolymeric blends.
The removal of Pb (II) ions from aqueous solution by crosslinked (glutaraldehyde-chitosan/Nylon6/Polyurethane foam) and non crosslinked (chitosan/Nylon6/Polyurethane foam) blends has been investigated. Chitosan solution was blended with Nylon6 and Polyurethane foam in the ratio of 2:1:1 with and without crosslinking agent (glutaraldehyde), in order to obtain sorbents that are insoluble in aqueous acidic and basic solution. Batch adsorption studies were performed as a function of pH, contact time and adsorbent dose. The optimum pH required for maximum adsorption of lead was found to be 5. The equilibrium adsorption data has been tested for the Langmuir, Freundlich and Temkin isotherms. The data were suitable to Freundlich isotherm model for both the blends. The kinetic parameters of the adsorption process were estimated using the pseudo-first and pseudo-second order models. These data indicated that the adsorption process followed the pseudo-first-order kinetics.


Clinical outcomes of the PAUL® glaucoma implant: One-year results.
To report one-year outcomes from a single-centre cohort undergoing PAUL® Glaucoma Implant (PGI) surgery. Retrospective review of patients undergoing PGI surgery at the University Eye Hospital Bonn, Germany, from April 2021 to September 2021. Forty-five eyes of 41 patients were included. Qualified and complete success rates (95% CI) were 95.6% (88.9%-100%) and 73.3% (60%-86.7%) for Criterion A (IOP ≤ 21 mmHg), 84.4% (73.3%-93.3%) and 74.4% (51.1%-80.0%) for Criterion B (IOP ≤ 18 mmHg), 62.2% (48.9%-75.6%) and 46.7% (31.2%-62.2%) for Criterion C (IOP ≤ 15 mmHg) and 26.7% (13.3%-40.0%) and 22.2% (11.1%-33.3%) for Criterion D (IOP ≤ 12 mmHg), respectively. Mean IOP decreased from 26.1 mmHg (7-48 mmHg) to 12.0 mmHg (3-24 mmHg) (reduction of 48.83%) after 12 months with a reduction of IOP-lowering agents from 0.5 (0-3). One eye (2.2%) needed an injection of viscoelastic due to significant hypotony with AC shallowing, and four eyes (8.9%) developed choroidal detachments due to hypotony which resolved without further interventions after 6 weeks. Three patients (6.7%) developed tube exposure which required conjunctival revision with an additional pericardial patch graft. An intraluminal prolene stent was removed in 19 eyes (42.2%) after a mean time period of 8.4 months (2-12 m). Mean IOP before the removal was 21.9 mmHg (12-38 mmHg) and decreased to 11.3 mmHg (6-16 mmHg). PGI surgery is an effective procedure for reducing IOP and pressure-lowering therapy. An intraluminal prolene stent impedes hypotony in the early postoperative phase and enables further IOP lowering without additional interventions during the postoperative course.


Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT): A review of the evidence and expert opinion.
Serogroups A, B, C, W, X, and Y of Neisseria meningitidis are responsible for almost all cases of invasive meningococcal disease. In Italy, vaccination against serogroup B is recommended at 3-13 months, C at 13-15 months, and A, C, Y and W in adolescents (12-18 years). Four quadrivalent meningococcal conjugate vaccines are available. This review describes the available data on a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT; MenQuadfi®; Sanofi). We identified articles on quadrivalent meningococcal conjugate vaccines indexed on PubMed since 2000. Of the 524 studies identified, 10 human studies investigating the immunogenicity and safety of MenACYW-TT in toddlers, children aged 2-9 years, and individuals 10-55 or ≥56 years are described in detail. In Italy, pediatric and public health groups recommend amending the current vaccination schedule to include a booster dose between 6 and 9 years and quadrivalent vaccine in young adults (≥19 years), targeting waning protection after childhood vaccination and the age cohort with the highest carrier prevalence (adolescents and young adults). MenACYW-TT is a suitable meningococcal vaccine for current and pending recommendations based on high seroprotection rates and a low incidence of adverse events in these age groups. Moreover, it does not require reconstitution.


Comparison of severity and prognosis of jaundice due to Rh incompatibility and G6PD deficiency.
Undiagnosed and untreated hyperbilirubinemia in infants may result in Kernicterus Spectrum Disorder and poor prognoses. Rhesus incompatibility and glucose-6-phosphate dehydrogenase (G6PD) deficiency are among the known causes of infantile jaundice. This study was designed to define the severity and prognosis in jaundiced infants with Rh incompatibility or G6PD deficiency. A total of 144 term, 2- 14 days old jaundiced infants (bilirubin > 20 mg/dl) with Rh incompatibility(85 infant) or G6PD deficiency(59 infant) were included in this cohort study with 24-month follow-up through available sampling at Ghaem hospital between 2015 and 2022. Denver II test was used at 6, 12, 18, and 24-month ages after discharge. Infants with Rh incompatibility or G6PD deficiency were assigned into two groups of favorable and poor prognosis. Following that, the bilirubin levels of these infants were compared at the time of admission. The bilirubin level in G6PD deficient infants with poor prognoses (37.96 ± 9.25 mg/dl) and neonates with Rh incompatibility (36.23 ± 5.08 mg/dl) almost was the same (P = 0.232). 40 babies (47%) caused by Rh incompatibility and 33 (56%) babies caused by G6PD deficiency had a poor prognosis (P = 0.465). Average bilirubin in babies with RH incompatibility with favorable prognosis is 21.8 and poor prognosis is 36.2 mg/dl. In infants with G6PD deficiency, it was 24 mg/dl with favorable prognosis and 38 mg/dl with poor prognosis (P < 0.0001). The severity of hyperbilirubinemia had a significant role in the prognosis of infants in both groups (P < 0.0001). The two-year prognoses of hyperbilirubinemia caused by G6PD deficiency are as poor as that of Rh incompatibility. The severity of hyperbilirubinemia had a significant role in the prognosis of infants in both groups.Exchange transfusion in cases with bilirubin < 25 mg/dl can improve the prognosis in both groups, especially in infants with Rh incompatibility.


Hormone-dependent, aggressive angiomyxoma of the vulva.
Aggressive angiomyxoma is a rare neoplasm of undetermined etiology that occurs mainly in the female vulva and perineum. It tends to recur but does not metastasize. This case report describes findings suggestive of the possible hormone dependency of this neoplasm. A 41-year-old gravid woman developed an aggressive angiomyxoma of the left vulva with growth apparently related to the length of the pregnancy. The neoplasm marked strongly for progesterone receptors by immunohistochemical methods but was estrogen-receptor negative. The growth of the neoplasm during pregnancy and the nuclear-positive staining for progesterone receptors suggest a possible hormone (progesterone) dependency for at least some cases of aggressive angiomyxoma.


Investigation of Antibiofilm and Antibacterial Properties of Green Synthesized Silver Nanoparticles from Aqueous Extract of Rumex sp.
The decrease in the effectiveness of conventional drugs as a result of the growth of resistance to antibiotics has increased the need for innovative tools to control the infections. At this point, metallic nanoparticles, in particular silver nanoparticles, have appeared as a promising method. In the current study, the extract of Rumex sp. (Labada, dock) leaves was used as a reducing agent for the formation of silver nanoparticles. Unlike similar studies, in this study the synthesis conditions were optimized by changing the extract ratio and silver nitrate concentration. Morphological investigations of synthesized silver nanoparticles showed that spherical homogeneous particles at size under 100 nm had been produced. SEM/EDS and FTIR analyses showed that plant components are involved in the synthesis of nanoparticles. It was also determined that higher extract ratio reduced nanoparticle size. The antimicrobial effects of the synthesized nanoparticles against Gram-positive and Gram-negative bacteria were tested, and it was determined that all nanoparticles exhibited activity against both groups. Rumex sp. silver nanoparticles (NPs) were revealed to exhibit antibiofilm activity against three different isolates with moderate and strong biofilm-forming ability. The NPs reduced the biofilm-forming capacity of Acinetobacter baumannii and Klebsiella pneumonaie by 2.66-fold and 3.25-fold, whereas they decreased the Escherichia coli biofilm-forming capacity by 1.25-fold. The investigation of microbial biofilm could play an important role in developing new strategies for treatment options. Our results suggest that Rumex sp. silver NPs may have a high potential for use in the treatment of pathogenic strains.


Hydrogenase activity in the dry state: isotope exchange and reversible oxidoreduction of cytochrome c3.
Hydrogenase (hydrogen:ferricytochrome c3 oxidoreductase, EC 188.8.131.52) catalyzes three types of reactions, i.e., (1) conversion between hydrogen modifications, para-H2 and ortho-H2, (2) exchange reaction between hydrogen isotopes, and (3) reversible oxidoreduction of an electron carrier with H2 and protons. We observed that purified desulfovibrio hydrogenase in the dry state could catalyze not only the conversion and exchange reactions (Yagi, T., Tsuda, M., Mori, Y. and Inokuchi, H. (1969) J. Am. Chem. Soc. 91, 2801) but also the reversible oxidoreduction of the electron carrier, cytochrome c3 with H2. The rate of the conversion was in the range from 0.1 to 0.65 mol H2 converted per mol hydrogenase per s, and the ratio of the conversion rate to the exchange rate was near 5. The rate of oxidoreduction of cytochrome c3 in the dry state was 0.015 mol H2 taken up in the forward reaction and 0.003 mol H2 released in the reverse reaction per mol hydrogenase per s. The process of these reactions could be explained by the observations that the hydrogenase molecule in the dry state has protons which are directly exchangeable with H2 during catalytic process. The reversible oxidoreduction of cytochrome c3 is also explained by inter- and intramolecular electron transfer among cytochrome c3 molecules.


Radiation educational program significantly reduces intraoperative fluoroscopy time during locking plate fixation for distal radius fractures.
The use of C-arm fluoroscopy poses a risk of radiation exposure to the surgeons. This study aimed to examine the intraoperative fluoroscopy time of the distal radius plating before and after radiation educational program. A total of 68 cases (48 women and 20 men; average age, 61.8 years) were reviewed between July 2017 and October 2019. All patients were treated with volar locking plate fixation for distal radius fractures. On October 2018, we had a 1-h radiation educational program for orthopedic surgeons. Intraoperative fluoroscopy time was compared between 34 cases in the preintervention group (group A) and 34 cases in the postintervention group (group B). Radiographic correction loss of the fracture was assessed by ulnar variance (UV), radial inclination (RI), and volar tilt (VT) between immediately after surgery and at the time of bone union. A significant difference was found in intraoperative fluoroscopy time between 329 s in group A and 123 s in group B. ΔUV between immediately after surgery and at the time of bone union was 0.6 mm in group A and 0.3 mm in group B; ΔRI was -0.3° in group A, -0.1° in group B, ΔVT is -0.4° in group A, and -0.1° in group B. No significant difference was found among them. After an educational program on radiation exposure, the intraoperative fluoroscopy time was significantly saved in the plating surgery for the distal radius fractures. The shortening of the intraoperative fluoroscopy time did not affect the loss of radiographic correction of the fractures.


[The paralyzed eyelid: an alternative to gold weight, levator palpebrae lengthening].
Patients with complete facial nerve palsy are at risk of severe eye complications due to corneal exposure. The aim of this study was to highlight the effects of using a gold weight in paralyzed eyelid, and to prove the safety of the levator palpebrae lengthening. This retrospective study compared the records of 24 patients who received a gold weight of the upper eyelid between 1976 and 2003 with those of 22 patients who benefit from levator palpebrae lengthening between 1997 and 2005. Two endpoints were seen in postoperative: the occurrence of complications related to lagophthalmia secondary to facial palsy, and the occurrence of complications related to surgical technique. The occurrence of a complication related to the facial palsy is significantly associated with the surgical technique. Patients with gold weight had significantly more complications related to their pathology than others (67% versus 18%, respectively, p=0.001). The occurrence of a surgical complication was significantly associated with the surgical technique. Patients with gold weight have significantly more complications due to surgery than others (83% versus 5%, respectively, p<0.0001). Our clinical study and statistical comparison of the two surgical techniques for paralysed eyelid clearly show that the oldest is unsatisfactory and that it should be abandoned. Levator palpebrae lengthening improves eye symptoms with a very low morbidity.


Surface EMG and fatigue.
This article reviews the use of spectral analysis techniques to study muscle fatigue; considers technical issues and limitations of spectral analysis; and discusses potential applications of spectral analysis methods.


Right siting of complex acute wound management---preliminary study of teleconsultation wound services between acute and primary care in Singapore.
This study aimed to provide preliminary evidence on feasibility of the inaugural use of teleconsultation between acute hospitals and primary care for acute wound management in Singapore. Post-surgical patients with carbuncle wounds, perianal abscess wounds or surgical abdominal dehiscence wounds were recruited from an acute hospital. Instead of receiving their follow up care at the acute care tertiary hospital, patients were given the option to receive their care at primary care facilities instead, supported by teleconsultation wound services provided by wound care nurses from the hospital. The following outcome measures were collected: number of care sessions required (until wound healed), readmissions or referrals back to hospital, cost (patient's and healthcare provider's perspective), patients' and nurses' satisfaction. In total, 18 patients were recruited and completed the study (teleconsult group = 5; tertiary care clinic group = 13). The mean age (SD) of patients were 63.2 (SD 11.5) years old in the teleconsult group and 47.9 years old (SD 11.5) in the tertiary care clinic group. There were 7 female (54%), and 6 male (46%) in the tertiary care clinic group whereas teleconsult group consisted of male only (n = 5). Most had carbuncle wounds (teleconsult group: n = 4; 80%); tertiary care clinic group: (n = 10; 77%). For patients with carbuncle wounds, the average number of care sessions required were 21 and 33 for the tertiary care clinic and teleconsult respectively. None of the patients in the teleconsult group were referred back to the tertiary care hospital. All 16 nurses (n = 6 from acute care hospital, n = 10 from polyclinics) who participated in the feedback survey cited convenience, ease of tracking wound sizes, and closer collaboration between the acute care and primary care nurses as advantages of the service. Wound teleconsultation is feasible and potentially cost savings for patients with acute complex wounds.


N-methyl-d-aspartate Receptor-mediated Preconditioning Mitigates Excitotoxicity in Human Induced Pluripotent Stem Cell-derived Brain Organoids.
Studies in rodent models of acute and chronic neurodegenerative disorders have uncovered that glutamate-induced excitotoxic cell death is mediated primarily by extrasynaptic N-methyl-d-aspartate receptors (NMDARs). Rodent neurons can also build up in an activity-dependent manner a protective shield against excitotoxicity. This form of acquired neuroprotection is induced by preconditioning with low doses of NMDA or by activation of synaptic NMDARs triggered by bursts of action potentials. Whether NMDARs in human neurons have similar dichotomous actions in cell death and survival is unknown. To investigate this, we established an induced pluripotent stem cell (iPSC)-derived forebrain organoid model for excitotoxic cell death and explored conditions of NMDAR activation that promote neuronal survival when applied prior to a toxic insult. We found that glutamate-induced excitotoxicity in human iPSC-derived neurons is mediated by NMDARs. Treatment of organoids with high concentrations of glutamate or NMDA caused the typical excitotoxicity pathology, comprising structural disintegration, neurite blebbing, shut-off of the transcription factor CRE binding protein (CREB), and cell death. In contrast, bath-applied low doses of NMDA elicited synaptic activity, a robust and sustained increase in CREB phosphorylation as well as function, and upregulation of immediate-early genes, including neuroprotective genes. Moreover, we found that conditions of enhanced synaptic activity increased survival of human iPSC-derived neurons if applied as pre-treatment before toxic NMDA application. These results revealed that both toxic and protective actions of NMDARs are preserved in human neurons. The experimental platform described in this study may prove useful for the validation of neuroprotective gene products and drugs in human neurons.


TGF-β1 polymorphism in American tegumentary leishmaniasis in a Southern Brazilian population.
Genetic polymorphisms define the cytokine production leading to susceptibility or resistance to diseases. We studied the cytokine polymorphism in the development of tegumentary leishmaniasis (TL). Genotyping of TNF-α, TGF-β1, IFN-γ, IL-6, and IL-10 were performed by polymerase chain reaction assay. G and C alleles of TGF- β1 (codon 25) were the most common in controls and patients, respectively. G/G was the most frequent genotype in controls, and G/C and C/C in patients. G/G genotype of codon 25 in TGF-β1 appeared to confer resistance, and G/C and C/C genotypes, susceptibility to TL in this population.


Benzenediamine analog FC-99 inhibits TLR2 and TLR4 signaling in peritoneal macrophage in vitro.
Inflammatory bowel disease (IBD) is an inflammatory disorder, characterized by abnormally increased expression of Toll-like receptors TLR2 and TLR4 in the colon and increased pro-inflammatory cytokine production by macrophages. In the present study, we explored the effect of FC-99, a novel benzenediamine analog, on dextran sulfate sodium (DSS)-induced mouse colitis and investigated its potential mechanism. The results revealed that FC-99 improved the colon morphology and the clinical parameters in DSS-induced mouse colitis. FC-99 inhibited the increase of DSS-induced T helper cells (Th) 1 and Th17 and enhanced the number of regulatory T cells (Treg) in mesenteric lymph nodes (MLN), but had no effect on Th2 cells. FC-99 also suppressed the DSS-induced secretion of interleukin (IL)-1β, IL-6, and the tumor necrosis factor (TNF)-α in the colon and hindered the infiltration of macrophages into colon lamina propria. Flow cytometric analysis also confirmed that FC-99 reduced CD11b(+)F4/80(+) colon macrophages, and down-regulated TNF-α level in situ. Moreover, FC-99 inhibited concentration-dependently the expression of TNF-α and IL-6 in vitro from mouse peritoneal macrophages, which were induced by TLR ligands: PamCSK4 and peptidoglycan (PGN, TLR2 ligand) as well as LPS (TLR4 ligand). Of note, FC-99 also suppressed the activation of TLR2 and TLR4 signaling pathways and the downstream nuclear factor-κB (NF-κB) in the DSS-induced mouse colitis. FC-99 improved the condition of DSS-induced mouse colitis by inhibiting the activation of TLR2 and TLR4 signaling pathways in macrophage. These results suggest that FC-99 may be developed as a new therapeutic drug for IBD.


Control of salivary secretions in esophageal atresia with laryngeal cleft using Botulinum toxin Type A.
A baby born with esophageal atresia and a laryngeal cleft is presented. Retained salivary secretions and aspiration were a constant management problem whilst the baby was waiting for delayed primary repair of the atresia. The use of anticholinergic agents resulted in thickening of secretions which were difficult to suction and ultimately led to increasing respiratory compromise. Intraglandular salivary gland injection of Botulinum toxin type A was performed using ultrasound guidance. The mean daily salivary flow output prior to treatment was 59 ml. On glycopyrrolate the mean daily salivary output on glycopyrrolate was 16 ml. After Botulinum injection the mean daily salivary output was 7 ml in the 3 weeks after injection. Over the next 14 weeks this increased to 34 ml. There were no adverse effects or significant thickening of secretions after BTX injection. This is the first reported use of Botulinum toxin injection in the management of salivary aspiration in esophageal atresia with laryngeal cleft.


Thai and American mothers socialize preschoolers' emotional development differently.
Cultures vary in beliefs about appropriate display of emotion. Children rely on adults to help them understand emotional experiences and display emotions in a culturally appropriate manner. The present study compared how emotion display differs between Thai and American mother-child interactions during preschool. Language samples from 21 Thai and 21 American mother-child dyads were elicited using prompted reminiscing, book reading, toy play, and child personal narrative tasks. Results revealed group differences in emotion talk and behavior. American dyads expressed more intense emotions during interactions compared to Thai dyads. American dyads also displayed more emotion behaviors than Thai dyads, whereas Thai dyads used more emotion words compared to American dyads. Additionally, there were gender differences in the expression of emotion, with boy dyads more emotionally intense than girl dyads in both groups. Boys displayed more negative emotion behaviors compared to girls during prompted reminiscing, whereas girls used more negative emotion words than boys during the personal narrative task. These findings demonstrate cultural and gender differences in socialization goals and practices regarding emotion display and underscore the influence of mothers' scaffolding on children's emotional development. This research reveals the variability in beliefs and values that underlie emotional development across sociocultural contexts.


The AIDS and Cancer Specimen Resource (ACSR): HIV malignancy specimens and data available at no cost.
The goal of the AIDS and Cancer Specimen Resource (ACSR) is to play a major role in the advancement of HIV/AIDS cancer-related research/treatment by providing richly annotated biospecimens and data to researchers at no cost. The ACSR acquires, stores, and equitably distributes these samples and associated clinical data to investigators conducting HIV/AIDS-related research, at no costs. Currently, it is the only biorepository of human biospecimens from people with HIV and cancer available to eligible researchers globally who are studying HIV associated malignancies.This review describes the history and organizational structure of the ACSR, its types of specimens in its inventory, and the process of requesting specimens. In addition, the review provides an overview of research that was performed over the last 5 years with its support and gives a summary of important new findings acquired by this research into the development of cancers in people with HIV, including both Aids-related and non-Aids-related malignancies.


Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family.
To describe a large family with autosomal dominant parkinsonism. Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several multigenerational large families known with no identifiable mutation. Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2, SCA3, UCHL1, SNCA, LRRK2, PINK1, PRKN, PGRN, FMR1 premutation, and MAPT. The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for alpha-synuclein. Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.


[Keratodermic genodermatosis with hydrocystomas, miliary cysts, xanthelasmas, nail and dental dystrophies, and basal cell epitheliomas].
Two cases of a condition including palms and soles keratoderma, ectodermal dysplasias and basal cell epitheliomas are reported by the authors, with clinical, genetical and pathological data. The condition is called Keratodermal Genodermatose with hydrocystomas, milium cysts, xanthelasma, dental and nail dysplasias and basal cell epitheliomata (Borda's syndrome).


Inhibition of HIV-1 expression by HIV-2.
HIV-1 and HIV-2 are co-endemic in certain geographic areas. HIV-2 is more weakly pathogenic than HIV-1, and progression to AIDS occurs less frequently and over a longer period of time. Recent epidemiologic studies suggest that individuals infected with HIV-2 have a lower risk of HIV-1 infection. Both immune mechanisms and various modes of viral interference have been proposed to account for these results. Our findings, described in this paper, suggest that HIV-2 inhibits HIV-1 replication. To study the molecular interactions between HIV-1 and HIV-2, proviral clones were transfected alone or in combination into the human T cell line CEM. LTR-CAT indicator constructs were included for the purpose of monitoring viral promoter activity. Viral replication in transfected cells was monitored by p24 antigen capture assay of cell culture supernatants and Western blot analysis of cell extracts. HIV-2 inhibited HIV-1 replication as determined by intracellular and extracellular p24 antigen levels. Similar results were obtained with simultaneous virus infection using HIV-1 and HIV-2, rather than transfections of proviral DNA. Using cotransfection of HIV-1 and HIV-2 LTR indicator gene constructs, the mechanism of inhibition was found to be suppression of the HIV-1 LTR by HIV-2. The inhibitory effect of HIV-2 is not due to Tat-2, but appears to discriminate between the HIV-1 and HIV-2 LTRs based on differences in the Tat activation response element, TAR. These results suggest both a molecular mechanism for HIV-2 interference with HIV-1 replication and a potential molecular approach to therapy.


Osteomas of Temporal Bone: A Retrospective Study.
Osteomas of temporal bone are rare, slow growing benign tumours and they are reported in all parts of temporal bone. This study is a retrospective study of the clinical presentation, management and complications of temporal bone osteoma done from January 1999 through January 2017. The study population is thirteen patients, all who has been radiologically and histopathologically proven to be a case of osteoma. Total number of patients were 13 of which 7 were females and rest 6 were male. Presenting complaints included swelling behind the ear (6 cases), reduced hearing in 4 cases, 2 cases had ear discharge, 3 of them were asymptomatic in whom it was diagnosed accidently. The duration of symptoms ranged from 1 month to 10 years. Of total 13 patients 7 had external auditory canal involvement and 4 cases had mastoid region. Two patients were managed conservatively, one refused surgery and rest ten cases underwent excision. The specimen was sent for histopathological examination and diagnosis of osteoma was confirmed. The decision regarding whether to operate or not depends on each case depending on its size, symptoms and more importantly the complications. Excision of osteoma remains the treatment of choice.


Effect of visceral adipose tissue on the accuracy of preoperative T-staging of gastric cancer.
Due to the anatomical characteristics of the tumor and the specific variables of the patients, the accuracy of preoperative T-staging of gastric cancer needs to be further improved. This study investigated the effect of visceral adipose tissue (VAT) on the accuracy of clinical T-staging of gastric cancer. The clinical data of 455 patients who underwent gastrectomy from January 2013 to December 2018 were analyzed retrospectively. Taking the postoperative pathological results as the reference standard, the patients were divided into accurate staging group and mistaken staging group according to the comparison of clinical T stage (cT) and pathological T stage (pT). The individual characteristics of the two groups were compared, including visceral fat content at L2/L3 level calculated on computed tomography, age, sex, tumor size, tumor location (cardia, stomach body, stomach antrum), and degree of differentiation. Multivariate logistic regression was used to determine the independent factors affecting the accuracy of cT staging. Among the 455 patients, 355 patients (78.0 %) had accurate preoperative cT staging and 100 patients (22.0 %) had inaccurate preoperative cT staging. The average area of VAT in the accurate staging group was (129.8 ± 72.6) cm2 and that in the mistaken staging group was (74.6 ± 61.6) cm2 (P < 0.001). The optimal cut-off value of VAT was 97.8 cm2 calculated according to the Yoden index. Multivariate logistic regression analysis showed that VAT, tumor location and tumor size were independent predictors of cT accuracy. Patients with lower visceral fat content (<97.8 cm2) based on L2/L3 level had a higher risk of false staging in preoperative clinical T staging.


A high-throughput method for fast detecting unfolding of monoclonal antibodies on cation exchange resins.
A fast method for assessing the stability of monoclonal antibodies (mAbs) adsorbed on ion exchange resins has been developed. The method exploited a real time polymerase chain reaction equipment to determine the temperature of protein phase transition, i.e., the so called melting temperature, based on differential scanning fluorimetry. Changes to the melting temperature were screened under various adsorption conditions and correlated with the protein stability upon adsorption. The method was tested for two different mAbs bound to various types of strong cation exchangers at different pH and loading concentrations. The mAbs destabilized upon adsorption due to strong binding, which manifested itself in aggregate formation and recovery reduction. The phenomenon depended on the resin type and binding conditions. However, regardless of the process conditions and resins used, drop in the melting temperatures to a critical value of about 30° could serve as an indicator of destructive changes in the protein structure in the adsorbed phase. The measurements were simultaneously accomplished for a number of samples with very small material consumption. Therefore, the method may be applied for screening resins and operating variables for a given mAb to exclude conditions that induce structure destabilization and aggregation.


Nanoparticle (NP) Loading by Direct Incubation with Extracellular Vesicles-Secretor Cells: NP Encapsulation and Exosome Characterization.
Exosomes are small vesicles released by all types of cells, and they have been postulated as a promising natural way to carry information amongst cells. Exosomes might serve as mediators for intercellular communication through the delivery of their endogenous cargo to neighbor or distant cells. Recently, this ability to transfer their cargo has open a new therapeutic approach and exosomes have been investigated as vectors for the delivery of the loaded cargo, for instance nanoparticles (NPs).Currently, several methods to load exosomes with NPs have been described; however, the maintenance of the membrane integrity on the vesicle has to be taken into consideration, in order to choose one or another methodology. Here we describe the NP encapsulation through the incubation of the cells with the NPs and the subsequential methods to determine their cargo and to discard detrimental alterations on the loaded exosomes.


Effects of halothane and isoflurane on acetylcholine-induced, endothelium-dependent vasodilation in perfused rat mesenteric arterial beds.
The present study was designed to examine the effects of halothane and isoflurane on acetylcholine-induced, endothelium-dependent vasodilation in rat mesenteric arterial beds perfused at a constant flow both in vitro and in situ. In the in-vitro preparation, the mesenteric artery was cannulated and perfused (5 ml x min(-1)). The perfusion pressure was continuously monitored. Under active tone induced by methoxamine, the effects of halothane and isoflurane on the vasodilator response to acetylcholine in either the presence or absence of NG-nitro-L-arginine (L-NA), tetraethylammonium (TEA), or KCl (30 mM)-depolarization were examined. All experiments in these preparations were performed in the presence of indomethacin (10 mM). In the in-situ experimental model, rats were anesthetized with pentobarbital and the lungs were mechanically ventilated via a tracheostomy with a ventilator. The superior mesenteric artery was cannulated and used for the monitoring of the perfusion pressure. Blood shunting with constant flow (2 ml x min(-1)) from the carotid artery to the superior mesenteric artery was introduced with clamping at the immediately distal portion of the mesenteric artery branching. Following 20-min ventilation with halothane or isoflurane at 1 minimum alveolar concentration (MAC) in oxygen, acetylcholine was given from the mesenteric artery, under active tone induced by norepinephrine (100 mg x kg(-1) x hr(-1)). In the in-vitro preparation, the nitric oxide synthase inhibitor, L-NA (100 microM) did not affect vasodilations to acetylcholine (1, 10 nM), while the K+ channel inhibitor TEA (10 mM), as well as KCl (30 mM), significantly reduced these vasodilations. However, only in the presence of L-NA, TEA and KCl completely abolished the vasodilations produced by acetylcholine. The higher concentrations of halothane (2.0%, 3.0%), but neither isoflurane (3.0%) nor the lower concentration of halothane (1.0%), significantly impaired vasodilator responses to acetylcholine in the presence of L-NA, whereas the volatile anesthetics did not affect these vasodilations in the absence of L-NA. Halothane (2.0%) did not alter the vasodilation produced by acetylcholine in the presence of TEA or KCl. In the in-vivo preparation, the vasodilator effects of acetylcholine (1 and 10 nmol) were not affected by the inhalation of halothane (1.0%) or isoflurane (1.3%). These results suggest that, in resistance arteries in conditions of constant flow, halothane and isoflurane do not affect vasodilations in response to an endothelium-dependent agonist. However, in these preparations, once the enzymatic activity of nitric oxide synthase is inhibited, higher concentrations of halothane, but neither isoflurane nor the lower concentration of halothane, appear to impair endothelium-dependent relaxations, probably mediated by TEA-sensitive K+ channels.


Recognizing the Need for Oncology Education in Canadian Baccalaureate Nursing Programs.
There is a critical need for quality oncology education in Canadian baccalaureate nursing programs considering the vast amount of cancer diagnoses and deaths in the Canadian population, as well as the likelihood that all nurses will care for oncology patients in various settings. The incidence and mortality of cancer within the Canadian population impact the need to incorporate an all-inclusive view of cancer care into baccalaureate nursing curriculums and develop nurse leaders in oncology at this level. Currently, Canadian nursing programs are generalist programs and provide little oncology content especially in the clinical setting. It is essential that baccalaureate nursing programs examine strategies to incorporate a comprehensive view of cancer care into programs to ensure that baccalaureate nursing students meet the entry to practice competencies to care for patients across the cancer care trajectory.


Increased average number of medical publications per interviewee from 2009 to 2018: a study of 100 interviewees to an academic gastroenterology fellowship program.
Gastroenterology fellowship candidates may strive to improve their qualifications for this extremely competitive fellowship. To analyze whether extreme competitiveness of gastroenterology fellowship positions has affected fellowship interview selection by statistically analyzing 13 parameters of interviewees to identify statistically significant time changes during last 10 years. Retrospective time-trend-analyses (performed 2018) on thirteen prospectively-obtained-parameters of 47 interviewees (2009-2011) vs. 53 interviewees (2016-2018) for gastroenterology fellowship. William-Beaumont-Hospital, Royal-Oak: academic fully-accredited gastroenterology fellowship, teaching hospital of Oakland-University-William-Beaumont-School-of-Medicine, tertiary-care hospital, GI fellowship since 1973. Statistically significant increases occurred from 2009 to 2011 vs. 2016-2018 in number of publications, including mean number of: abstracts (1.69 ± 0.37 vs. 7.54 ± 1.16, p < 0.0001); peer-reviewed articles (1.48 ± 0.30 vs. 6.13 ± 1.29, p < 0.0001); and total publications (3.17 ± 0.48 vs. 12.76 ± 1.99, p < 0.0001). Increased publications were associated with graduating from foreign medical schools (correlation coefficient = 0.26, p = .03), and were, surprisingly, correlated with lower letters-of-recommendation-scores (Kruskal-Wallis-statistic = 5.82, p = .002). USMLE-Step-1 scores significantly increased from 2009 to 2011 to 2016-2018 (235 ± 14.1 vs. 244.9 ± 13.5, p = 0.001) (previously reported finding). Nine other parameters did not significantly change with time. Current report of >four-fold-increase in publications by gastroenterology fellowship interviewees at one academic-medical-center is novel. Increased focus on scholarship by applicants may be explained by their having only three parameters to improve their credentials during residency: publications, letters-of-recommendation, and honors awarded during residency (other parameters determined before residency and immutable). Current findings may benefit medical residents/medical-residency-program-directors by focusing more on publications for applications. Association between research productivity and medical promotions likely strongly motivates medical research of residents and may motivate academic faculty. Increased exposure to research/publications may improve the clinical acumen of GI fellowship applicants by enhancing their skills in critically reading the medical literature.


Tumoral calcinosis of the gluteal region in a child: case report with overview of different soft-tissue calcifications.
Tumoral calcinosis is a distinct clinical and histologic entity that is characterized by a large deposition of calcium that resembles a neoplasm and is found predominantly in adolescents and young adults in the periarticular tissues of large joints. The authors describe the clinical presentation of a 15-year-old boy admitted at our pediatric day-surgery center for surgical management of tumoral calcinosis of the left gluteal region. Complete surgical excision is the treatment of choice.


Differential screening-selected gene aberrative in neuroblastoma (DAN) is increased in the CSF of patients with MS and may be induced by therapy with interferon-β.
Bone morphogenic proteins (BMPs) signaling blockade induce neurogenesis and oligodendrogenesis. Differential screening-selected gene aberrative in neuroblastoma (DAN) is a glycoprotein that antagonizes BMPs. We found that DAN levels were higher in CSF compared to serum in all participants. CSF-DAN levels were elevated in RR-and progresssive MS patients compared to controls. Moreover, serum-DAN levels were reduced in those patients, but elevated in IFN-β1a treated patients. The main source of DAN is apparently CNS- resident cells. The enhanced levels of CSF-DAN in MS patients suggest a tendency to induce neurogenesis/oligodendrogenesis in the patients CNS. Our results suggest an unreported mode of action of IFN-β1a.


Surgical treatment of primary hyperparathyroidism.
Our reported experience with ninety-seven hypercalcemic patients having resected adenomas with no recurrent hypercalcemia or hypocalcemia had led us to continue a conservative approach. Twelve patients with multiple parathyroid gland involvement proven by biopsy were treated with three and one-half gland resection and autotransplantation.


The effect of adulteration with a bitter tastant, denatonium benzoate, on the reinforcing value of sucrose.
According to the Multiplicative Hyperbolic Model of reinforcer value (MHM), the value of a reinforcer is an increasing hyperbolic function of its size (q). A recent experiment examined the effect of adulterating a sucrose solution with citric acid on the value of a sucrose reinforcer. In contrast to expectations derived from MHM, the effect of citric acid was consistent with the summation of positive (sucrose) and negative (citric acid) values. The present experiment extended these observations to a bitter tastant, denatonium benzoate (DB). Rats were trained under an adjusting-magnitude schedule in which a response on lever B delivered a fixed volume of a sucrose/DB mixture, while a response on lever A delivered a sucrose solution, the volume of which, qA, was adjusted according to the rats' choices. When B was preferred in a given block of trials, qA was increased in the following block; when A was preferred, qA was reduced in the following block. qB was varied across five phases of the experiment and the corresponding indifference magnitudes of A were measured. The results indicated that, as was the case with citric acid, the value of the mixture reflected the summation of positive (sucrose) and negative (DB) values.