Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression.
Hedgehog (Hh) signaling is required for osteoblast differentiation from mesenchymal progenitors during endochondral bone formation. However, the role of Hh signaling in differentiated osteoblasts during adult bone homeostasis remains to be elucidated. We found that in the postnatal bone, Hh signaling activity was progressively reduced as osteoblasts mature. Upregulating Hh signaling selectively in mature osteoblasts led to increased bone formation and excessive bone resorption. As a consequence, these mutant mice showed severe osteopenia. Conversely, inhibition of Hh signaling in mature osteoblasts resulted in increased bone mass and protection from bone loss in older mice. Cellular and molecular studies showed that Hh signaling indirectly induced osteoclast differentiation by upregulating osteoblast expression of PTHrP, which promoted RANKL expression via PKA and its target transcription factor CREB. Our results demonstrate that Hh signaling in mature osteoblasts regulates both bone formation and resorption and that inhibition of Hh signaling reduces bone loss in aged mice.


Cerebral sparganosis masquerading brain neoplasm: A rare incidental case.
Sparganosis is a parasitic infection caused by plerocercoid larvae of the genera Spirometra. Cerebral sparganosis is one of its most serious complications wherein clinical and imaging findings may pose diagnostic challenge. Here we present a case of cerebral sparganosis which mimicked as brain tumour on clinicoradiological examination. The case is reported in view of its rarity in India and the need for awareness of the entity.


Glycoconjugates as noninvasive probes of intrahepatic metabolism: I. Kinetics of label incorporation with evidence of a common precursor UDP-glucose pool for secreted glycoconjugates.
Conditions are described under which hepatic metabolism of administered labeled sugars can be monitored in the intact rat by measuring output of label from the liver in two secreted glycoconjugates derived from intracellular UDP-glucose, namely glucuronic acid linked to an administered drug (acetaminophen), and galactose secreted in glycoproteins. Rats with indwelling intrajugular catheters were given constant infusions of acetaminophen at nontoxic doses, and acetaminophen-glucuronide was isolated from rat urine by HPLC. When an unprimed continuous infusion of [U-14C]glucose or [1-3H]galactose is begun during acetaminophen infusion, labeling of urinary acetaminophen-glucuronide attains a plateau with an apparent half-life of 2.1 h from labeled glucose as the 14C-donor, and 1.2 h from labeled galactose. The times required to attain steady-state are attributable either to formation or to hepatic secretion of the glucuronyl conjugate rather than to mixing in extracellular pools or to delays in renal excretion since the half-time of urinary excretion of intravenously injected acetaminophen-glucuronide is only 21 minutes. Consequently, the excreted glucuronide provides noninvasive evidence of the recent specific activity in the precursor pool of hepatic UDP-glucose feeding glucuronic acid. The second glycoconjugate used for comparison was galactose, isolated from the acute-phase plasma protein alpha 1-acid glycoprotein. This represents hepatic UDP-galactose labeling. Comparison of the labeling patterns of secreted galactose and glucuronic acid demonstrates that they are derived from the same intracellular pool of UDP-glucose. This is in contrast to the patterns of labeling of hepatic glycogen from (1-3H) and [U-14C]glucose which have been shown to diverge from those of secreted glucuronic acid.


Skin Sodium and Hypertension: a Paradigm Shift?
Dietary sodium is an important trigger for hypertension and humans show a heterogeneous blood pressure response to salt intake. The precise mechanisms for this have not been fully explained although renal sodium handling has traditionally been considered to play a central role. Animal studies have shown that dietary salt loading results in non-osmotic sodium accumulation via glycosaminoglycans and lymphangiogenesis in skin mediated by vascular endothelial growth factor-C, both processes attenuating the rise in BP. Studies in humans have shown that skin could be a buffer for sodium and that skin sodium could be a marker of hypertension and salt sensitivity. Skin sodium storage could represent an additional system influencing the response to salt load and blood pressure in humans.


Calcium plus vitamin D supplementation during pregnancy reduces postpartum fat mass in adolescents: A randomized trial.
Pregnancy during adolescence may increase the risk of overweight/obesity. There is evidence that increasing calcium intake, alone or vitamin D-combined, may favor loss of weight and/or fat mass. We hypothesized that calcium supplementation during pregnancy reduces excessive fat accumulation during postpartum period. We aimed to investigate the effect of calcium plus vitamin D supplementation during pregnancy on body composition measurements throughout 1 year postpartum in Brazilian adolescents with habitually low calcium intake (~600 mg/day). Adolescents (14-19 years) were randomly assigned to receive a daily supplement (600 mg of calcium plus 200 UI of cholecalciferol, n = 30) or a placebo (n = 26) from 26 weeks of gestation until parturition. Body composition was determined at 5, 20, and 56 weeks postpartum by dual-energy x-ray absorptiometry. The effects of intervention group, time point, as well as their interaction were assessed using repeated measures mixed-effects models. In the adjusted analysis, those supplemented showed lower total body mass [mean difference = -3.32 kg; confidence interval (CI) 95% -6.12 to -0.52 kg], trunk (-1.25 kg; CI 95% -2.34 to -0.15 kg), android (-0.29 kg; CI 95% -0.53 to -0.04 kg) and subcutaneous (-0.23 kg; CI 95% -0.43 to -0.03 kg) fat masses. In the supplemented group, BMI and postpartum weight retention significantly decreased from 5 to 20 weeks (-0.90 kg/m2 and -1.76 kg, respectively; p < .05). At 56 weeks, BMI was still lower (-1.22 kg/m2 ; p < .05) than 5 weeks. Our findings suggest that increasing calcium intake through supplementation in combination with vitamin D contributes to a more pronounced reduction in total body mass overtime, mostly as a consequence of fat mass reductions in central body regions. This trial was registered at clinicaltrials.gov as NCT01732328.


Prognosis after surgical excision of canine melanomas.
One hundred and thirty-four dogs from which melanomas had been excised were studied until death or for at least 2 years after surgery. Seven of 49 (14%) intraoral and lip tumours and 52 of 85 (61%) skin tumours were histologically benign; in spite of this, three of seven (43%) "benign" oral and four of 52 (8%) "benign" skin lesions led to the eventual death of the host. Thirty eight of 42 (90%) dogs with a histologically malignant melanoma of the lip or oral cavity died because of the tumour but only 15 of 33 (45%) with malignant skin melanomas died. Six of 59 (10%) dogs with a tumour of mitotic index 2 or less died from the tumour 2 years after surgery compared to 19 of 26 (73%) dogs having a tumour with a mitotic index of 3 or more.


Testicular descent, cryptorchidism and inguinal hernia: the Melbourne perspective.
Cryptorchidism is the commonest congenital genitourinary anomaly in males and results when the testis does not descend into its normal intrascrotal position during development. In full-term infants, the incidence is approximately 3% at birth. Cryptorchidism results in several abnormalities, including attenuated spermatogenesis, infertility and a greater risk of malignancy. The normal mechanism of testicular descent appears to be multi-staged, with various anatomical factors and hormonal influences, but the exact process is still unclear. In this article we review the current theories of normal testicular descent, with a focus on the hormones and anatomical factors, and current treatments for undescended testis.


Selective involvement of caspase-3 in ceramide induced apoptosis in AK-5 tumor cells.
Ceramide, a product of sphingomyelin metabolism, is a novel lipid second messenger that mediates diverse cellular functions. The present study demonstrates the activation of caspase-3/CPP-32beta, during apoptosis induced by cell permeable exogenous ceramides, in AK-5 tumor, a spontaneously regressing rat histiocytoma. The apoptotic events were suppressed by the caspase-3 specific tetrapeptide inhibitor DEVD-CHO but not by the caspase-1 inhibitor YVAD-CMK. In cells overexpressing Bcl-2, a significant decrease in cell death was observed after exogenous addition of ceramides. Furthermore the processing of caspase-3 to its active form upon apoptotic stimulus, and the subsequent cleavage of the substrate PARP, suggested a central role for caspase-3 in the ceramide mediated apoptosis in AK-5 tumor cells.


Assessing regional left ventricular thickening dysfunction and dyssynchrony via personalized modeling and 3D wall thickness measurements for acute myocardial infarction.
Existing clinical diagnostic and assessment methods could be improved to facilitate early detection and treatment of cardiac dysfunction associated with acute myocardial infarction (AMI) to reduce morbidity and mortality. To develop 3D personalized left ventricular (LV) models and thickening assessment framework for assessing regional wall thickening dysfunction and dyssynchrony in AMI patients. Retrospective study, diagnostic accuracy. Forty-four subjects consisting of 15 healthy subjects and 29 AMI patients. 1.5T/steady-state free precession cine MRI scans; LGE MRI scans. Quantitative thickening measurements across all cardiac phases were correlated and validated against clinical evaluation of infarct transmurality by an experienced cardiac radiologist based on the American Heart Association (AHA) 17-segment model. Nonparametric 2-k related sample-based Kruskal-Wallis test; Mann-Whitney U-test; Pearson's correlation coefficient. Healthy LV wall segments undergo significant wall thickening (P < 0.05) during ejection and have on average a thicker wall (8.73 ± 1.01 mm) compared with infarcted wall segments (2.86 ± 1.11 mm). Myocardium with thick infarct (ie, >50% transmurality) underwent remarkable wall thinning during contraction (thickening index [TI] = 1.46 ± 0.26 mm) as opposed to healthy myocardium (TI = 4.01 ± 1.04 mm). For AMI patients, LV that showed signs of thinning were found to be associated with a significantly higher percentage of dyssynchrony as compared with healthy subjects (dyssynchrony index [DI] = 15.0 ± 5.0% vs. 7.5 ± 2.0%, P < 0.01). Also, a strong correlation was found between our TI and left ventricular ejection fraction (LVEF) (r = 0.892, P < 0.01), and moderate correlation between DI and LVEF (r = 0.494, P < 0.01). The extracted regional wall thickening and DIs are shown to be strongly correlated with infarct severity, therefore suggestive of possible practical clinical utility. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1006-1019.


Effect of echinomycin on DNA methylation.
Although echinomycin is reported to intercalate and to bind to DNA at CG dinucleotides, the effects of the drug on DNA methylation in vitro and in vivo are much less apparent than are the effects on DNA synthesis and cell growth.


Initial ovarian sensitivity index predicts embryo quality and pregnancy potential in the first days of controlled ovarian stimulation.
To determine if a modified ovarian sensitivity index (MOSI), based on initial follicular measurements and the initial follicle-stimulating hormone (FSH) dose, can predict the production of high-quality embryos for successful implantation during in vitro fertilization (IVF). This study consisted of two phases: 1) a retrospective study and 2) a prospective observational study. For the first phase, 363 patients charts were reviewed, of which 283 had embryos transferred. All women underwent a standardized antagonist-based IVF protocol. At the first follow-up (Day 3/4), the number and size of the follicles were determined. MOSI was calculated as ln (number follicles (≥6 mm) × 1000 / FSH initial dose). Afterward, the number and quality of the ova, embryo development, and the number and quality of the blastocysts were determined. Embryo implantation was confirmed by β-hCG. For the second phase, 337 IVF cycles were followed to determine MOSI's accuracy. MOSI could predict the production of ≥4 high-quality embryos by Day 2 (AUC = 0.69, 95%CI:0.63-0.75), ≥2 blastocysts (AUC = 0.74, 95%CI:0.68-0.79), and ≥ 35% rate of blastocyst formation (AUC = 0.65, 95%CI:0.58-0.72). Using linear regression, MOSI was highly associated with the number of ova captured (β = 5.15), MII oocytes (β = 4.31), embryos produced (β = 2.90), high-quality embryos (β = 0.98), and the blastocyst formation rate (β = 0.06, p < 0.01). Using logistic regression, MOSI was highly associated with achieving ≥4 high-quality embryos (odds ratio = 2.80, 95%CI:1.90-4.13), ≥2 blastocysts (odds ratio = 3.40, 95%CI:2.33-4.95), and ≥ 35% blastocysts formation rate (odds ratio = 1.96, 95%CI:1.31-2.92). This effect was independent of age, BMI, and antral follicle count. For implantation, MOSI was significantly associated with successful implantation (odds ratio = 1.79, 95%CI:1.25-2.57). For the prospective study, MOSI was highly accurate at predicting ≥6 high-quality embryos on Day 2 (accuracy = 68.5%), ≥6 blastocysts (accuracy = 68.0%), and a blastocyst formation rate of ≥35% (accuracy = 61.4%). MOSI was highly correlated with key IVF parameters that are associated with achieved pregnancy. Using this index with antagonist cycles, clinicians may opt to stop an IVF cycle, under the assumption that the cycle will fail to produce good blastocysts, preventing wasting the patient's resources and time.


Long-term course of brain-derived neurotrophic factor serum levels in a patient treated with deep brain stimulation of the lateral habenula.
According to the neurotrophin hypothesis, a brain-derived neurotrophic factor (BDNF) decrease has been postulated as a pivotal pathomechanism in affective disorder, and the treatment-associated increase in peripheral BDNF has been linked to therapeutic efficacy of antidepressant drugs and electroconvulsive therapy. However, in deep brain stimulation (DBS), a still experimental antidepressant treatment approach, this issue has not yet been investigated. We examine the long-term course of serum BDNF levels in a 64-year-old woman who is being treated with DBS of the lateral habenula for severe major depressive disorder. Our main findings are a significant increase in BDNF serum levels following DBS of the lateral habenula and an inverse U-shaped correlation of depression scores and BDNF levels. The data indicate that DBS, like other effective antidepressant treatments, may contribute to an increase in peripheral BDNF levels, which are thought to reflect central nervous DBS-induced neuroplastic changes. Moreover, our observations underscore the complex nature of disease-associated BDNF alterations. Their identification as either state or trait marker remains controversial and requires larger-scale longitudinal studies.


Morphological and molecular identification of lymnaeid snail and trematodes cercariae in different water bodies in Perak, Malaysia.
Lymnaeid snails play a crucial role in the transmission of trematode cercariae as an intermediate host that can infect humans, ruminants like buffalo, and other animals, resulting in serious economic losses. The purpose of the study was to identify the morphological and molecular characteristics of snails and cercariae collected from water bodies near buffalo farms that were integrated with palm oil in Perak, Malaysia. The presence or absence of snails in 35 water bodies was examined via cross-sectional study. From three marsh wetlands, 836 lymnaeid snails were gathered in total. Each snail's shell was morphologically identified to determine its family and species. The cercarial stage inside each snail's body was observed using the crushing method and trematode cercariae types were determined. In addition, the target gene Cytochrome c oxidase subunit 1 (Cox1) and the ribosomal internal transcribed spacer 2 (ITS2) region were used to identify the snail species and cercarial types according to the species level. The findings indicated that the collected snails belong to the family lymnaeidae and Radix rubiginosa species. In snails, the cercarial emergence infection rate was 8.7%. Echinostome, xiphidiocercariae, gymnocephalous, brevifurcate-apharyngeate distome cercariae (BADC), and longifurcate-pharyngeal monostome cercariae (LPMC) are the five morphological cercarial types that were observed. The cercariae were identified using morphological and molecular techniques, and they are members of the four families which are Echinostomatidae, Plagiorchiidae, Fasciolidae, and Schistosomatidae. Interestingly, this is the first study on R. rubiginosa and several trematode cercariae in Perak water bodies near buffalo farms that are integrated with palm oil. In conclusion, our research shown that a variety of parasitic trematodes in Perak use R. rubiginosa as an intermediate host.


Mechanical stimulation in the engineering of heart muscle.
Recreating the beating heart in the laboratory continues to be a formidable bioengineering challenge. The fundamental feature of the heart is its pumping action, requiring considerable mechanical forces to compress a blood filled chamber with a defined in- and outlet. Ventricular output crucially depends on venous loading of the ventricles (preload) and on the force generated by the preloaded ventricles to overcome arterial blood pressure (afterload). The rate of contraction is controlled by the spontaneously active sinus node and transmission of its electrical impulses into the ventricles. The underlying principles for these physiological processes are described by the Frank-Starling mechanism and Bowditch phenomenon. It is essential to consider these principles in the design and evaluation of tissue engineered myocardium. This review focuses on current strategies to evoke mechanical loading in hydrogel-based heart muscle engineering.


[Contributions of cortisol suppression tests to understanding of psychiatric disorders: a narrative review of literature].
Activity of the hypothalamic-pituitary-adrenal axis had been studied for the past half century, when some researchers noted that some patients with Cushing's syndrome and severe mood disorders had high baseline cortisol levels, which resulted in an inhibited response in the 1mg dexamethasone suppression test. Altered dexamethasone suppression test results were subsequently found in many psychiatric diseases, including anorexia nervosa, obsessive-compulsive disorder, degenerative dementia, bipolar disorders, and schizophrenia. The relationship between high baseline cortisol levels and stress has also been studied. Some researches on the genesis of borderline personality disorder focused on traumatic childhood backgrounds. Other investigations aimed at elucidating the relationship between traumatic backgrounds and some psychiatric disorders noted that patients with post-traumatic stress disorder and borderline personality disorder showed an enhanced cortisol suppression with low cortisol doses (0.5 mg). Recent studies showed that use of an ultra-low dose of cortisol during the dexamethasone suppression test may be helpful for detecting disorders with hyperactivity of the hypothalamic-pituitary-adrenal axis. Recent advances in neuroimaging support the existence of hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with borderline personality disorder, relating a decreased pituitary gland volume to major traumatic backgrounds and suicidal attempts. The purpose of this paper is to make a narrative review of research using dexamethasone suppression test in psychiatric disorders, in order to ascertain its value as a supplemental diagnostic test or as a prognostic marker.


Translation and linguistic validation of the Persian version of the International consultation on Incontinence Questionnaire Vaginal Symptoms.
There is no validated measurement tool to assess vaginal symptoms (VS), sexual matter (SS), and quality of life (QOL) among Persian-speaking women. This study aimed at translating and assessing the validity and reliability of the Persian version of the International Consultation on Incontinence Questionnaire for Vaginal Symptoms (PICIQ-VS). In this cross-sectional study, after obtaining permission from the International Consultation on Incontinence Questionnaire (ICIQ) Advisory Board, the English version of ICIQ-VS was translated into Persian per a standard translate and back translate process, and the validity and reliability were studied. Two hundred women with and without pelvic organ prolapse were asked to complete the PICIQ-VS (mean age: 52.1, range: 22-84 years). A panel of 10 experts evaluated the content and face validity of the questionnaire. Cronbach's alpha examined the internal consistency reliability of the measure. To evaluate the test-retest reliability, we redistributed the questionnaire among 30 patients 2 weeks after their initial visit using intra-class correlation coefficient (ICC). Content and face validity of the questionnaire was confirmed after some light modification (content validity ratio ranged from 0.69 to 1.00, and content validity index ranged from 0.79 to 1.00). PICIQ-VS showed an acceptable internal consistency and stability reliability (VS: α = 0.64, ICC = 0.84; SM: α = 0.69, ICC = 0.88; and total scale: α = 0.72, ICC = 0.91, respectively). Significant differences were observed between the asymptomatic and symptomatic groups for VS and the total score (P < 0.05). In the light of the results, interestingly, PICIQ-VS could be utilized as a valid and reliable tool to assess the VS among Persian-speaking women, both in research and clinical practice.


Tunable particle/cell separation across aqueous two-phase system interface by electric pulse in microfluidics.
Separations of particles and cells are indispensable in many microfluidic systems and have numerous applications in chemistry and biomedicine. The interface of aqueous two-phase system (ATPS) can act as a liquid filter. Under electric field stimuli, the selective transfer of targets across the liquid-liquid interface are expected for particles and cells separation. The separations of particles and cells based on ATPS electrophoresis in a microfluidic chip were investigated. A systematical study of the mechanism of ATPS electrophoresis was performed first by employing polystyrene (PS) particles. Subsequently, the separations of particles and microalgae cells were demonstrated. The electrophoretic transfer of particles across the interface of ATPS is determined by multi-parameters, including the strength of electric pulse, particle size, zeta potential, and hydrophobicity of the particle. The continuous separations of particles/cells can be achieved through the controllable transfer of target particles/cells across the interface under electric pulses in a microfluidic chip. By simply turning the magnitude of the applied electric pulse, the technique is suitable for different purposes, for example, the separations of particles and cells, purification of cells, and viability identification of cells. This tunable separation approach opens opportunities in multidimensional particle and cell sorting for the fields of seed selection of microorganisms, environmental assessment, and biomedical research.


Long-term Intensive Soccer Training Induced Dynamic Reconfiguration of Brain Network.
Long-term motor skill learning has been shown to impact the functional plasticity of the brain. Athletes, as a unique population, exhibit remarkable adaptive changes in the static properties of their brain networks. However, studying the differences between expert and novice athletes using a dynamic brain network framework can provide a fresh perspective on how motor skill learning affects the functional organization of the brain. In this study, we investigated the dynamic properties of brain networks in expert and novice soccer players at the whole-brain, network, and region-based levels. Our findings revealed that expert soccer players displayed reduced integration and increased segregation at the whole-brain level. As for network level, experts exhibited increased segregation and reduced flexibility in the visual network, enhanced integration between the visual and ventral attention networks, and decreased integration in the subcortical-sensorimotor and subcortical-cerebellar networks. Additionally, specific brain regions within the visual network exhibited greater recruitment in expert soccer players compared to novices at the nodal level. Furthermore, classification analyses demonstrated the critical role played by the visual network in the classification process. In conclusion, our study provides new insights into the dynamic properties of brain networks in expert and novice soccer players, and suggests that reduced integration and increased segregation in the visual network may be neuroimaging marker that distinguish expert soccer players from novices. Our findings may have implications for the training and development of athletes and advance our understanding of how motor skill learning affects brain functional organization.


Reconstruction of the maxilla with bone grafts supported by the buccal fat pad.
In the usual reconstruction of maxillary contour, the grafts are usually exposed to the antral or nasal cavities. This leads to postponed remodelling and a higher rate of resorption and sequestration. To avoid exposure of the grafts, the buccal fat pad is rotated into the maxillary sinus and lined to the bone grafts. The vascularized buccal fat pad not only contributes to a better integration of the bone grafts but also enables the restoration of normal physiologic function of the maxillary sinus.


Local GHR roles in regulation of mitochondrial function through mitochondrial biogenesis during myoblast differentiation.
Myoblast differentiation requires metabolic reprogramming driven by increased mitochondrial biogenesis and oxidative phosphorylation. The canonical GH-GHR-IGFs axis in liver exhibits a great complexity in response to somatic growth. However, the underlying mechanism of whether local GHR acts as a control valve to regulate mitochondrial function through mitochondrial biogenesis during myoblast differentiation remains unknown. We manipulated the GHR expression in chicken primary myoblast to investigate its roles in mitochondrial biogenesis and function during myoblast differentiation. We reported that GHR is induced during myoblast differentiation. Local GHR promoted mitochondrial biogenesis during myoblast differentiation, as determined by the fluorescence intensity of Mito-Tracker Green staining and MitoTimer reporter system, the expression of mitochondrial biogenesis markers (PGC1α, NRF1, TFAM) and mtDNA encoded gene (ND1, CYTB, COX1, ATP6), as well as mtDNA content. Consistently, local GHR enhanced mitochondrial function during myoblast differentiation, as determined by the oxygen consumption rate, mitochondrial membrane potential, ATP level and ROS production. We next revealed that the regulation of mitochondrial biogenesis and function by GHR depends on IGF1. In terms of the underlying mechanism, we demonstrated that IGF1 regulates mitochondrial biogenesis via PI3K/AKT/CREB pathway. Additionally, GHR knockdown repressed myoblast differentiation. In conclusion, our data corroborate that local GHR acts as a control valve to enhance mitochondrial function by promoting mitochondrial biogenesis via IGF1-PI3K/AKT/CREB pathway during myoblast differentiation. Video Abstract.


The antigen-specific response to Toxoplasma gondii profilin, a TLR11/12 ligand, depends on its intrinsic adjuvant properties.
Agonists that activate Toll-like receptors (TLR) are potential vaccine adjuvants. In particular, Toxoplasma gondii profilin (TgPRF) is recognized by TLR11/12 to generate an inflammatory response. Unlike most TLR ligands, TgPRF is also a protein and can therefore simultaneously induce innate and adaptive immune responses. We found that variations in the conformation of TgPRF can affect its ability to induce a TLR11/12-dependent inflammatory response. The secreted recombinant T. gondii (S2-profilin), produced by Schneider 2 cells, has lost its ability to generate an IL-12 response. Reduction of the intramolecular disulfide bonds in S2-profilin rescued the TLR11/12-dependent IL-12 response. Immunization of mice with reduced S2-profilin induced strong cellular and humoral responses compared to mice immunized with unreduced S2-profilin. A mixed Th1/Th2 response was induced with both S2-profilins. However, a more polarized Th1-type response, which was consistent with the IgG2a-polarized humoral response, was observed with reduced S2-profilin. In conclusion, the intrinsic adjuvant properties of TgPRF had significant consequences on the immune response against TgPRF.


Overlap of direct and indirect alloreactive T-cell repertoires when MHC polymorphism is limited to the peptide binding groove.
The immune response to allogeneic-MHC molecules can be divided into two pathways based on the nature of the antigen. In the direct pathway, T cells respond to intact allogeneic MHC molecules, while in the indirect pathway T cells respond to allo MHC-derived peptides presented by self-MHC. The T-cell repertoire used in the direct and indirect alloresponse have not been compared in the same alloantigen system. Here, HLA-DR transgenic mice are used to compare the repertoires of T cells that respond to the same alloantigen through either the direct or the indirect pathway. Separate direct and indirect DR1 anti-DR4 T-cell lines were generated and the T cell repertoire was analyzed by molecular methods. The same six Vbeta families were involved in both direct and indirect cultures indicating a complete overlap in the Vbeta gene usage. A partial overlap at the clonotype level was observed as two identical clonotypic TCRs were observed in both direct and indirect cultures. Interestingly, the T cells observed in both cultures were public as the same TCRs were identified in cultures developed from independent mice. These results raise the prospect that immune suppression of selected T cells during allo-transplantation can simultaneously modulate direct and indirect alloreactivities.


Chiral structures of electric polarization vectors quantified by X-ray resonant scattering.
Resonant elastic X-ray scattering (REXS) offers a unique tool to investigate solid-state systems providing spatial knowledge from diffraction combined with electronic information through the enhanced absorption process, allowing the probing of magnetic, charge, spin, and orbital degrees of spatial order together with electronic structure. A new promising application of REXS is to elucidate the chiral structure of electrical polarization emergent in a ferroelectric oxide superlattice in which the polarization vectors in the REXS amplitude are implicitly described through an anisotropic tensor corresponding to the quadrupole moment. Here, we present a detailed theoretical framework and analysis to quantitatively analyze the experimental results of Ti L-edge REXS of a polar vortex array formed in a PbTiO3/SrTiO3 superlattice. Based on this theoretical framework, REXS for polar chiral structures can become a useful tool similar to x-ray resonant magnetic scattering (XRMS), enabling a comprehensive study of both electric and magnetic REXS on the chiral structures.


Application of the Rasch model in measuring personality disorders.
To describe item and person parameters obtained with the Rasch model, one of the item response theory models, in the assessment of personality disorders based on Millon's theory. A total of 350 people participated in the study. Age ranged from 18 to 67 years (mean ± standard deviation = 27.02±10.13), and 71.7% of the participants (n = 251) were female. Of the 350 individuals, 21.1% (n = 74) answered affirmatively about being under psychiatric treatment and taking psychiatric medications. The Personality Disorders Dimensional Inventory (PDDI), an instrument designed to assess personality disorders according to Millon's theory, was applied to all participants. Data were analyzed using the Rasch model. Overall, analysis with the Rasch model revealed that the PDDI has adequate psychometric properties for the assessment of personality disorders. Among the contributions of item response theory models for clinical instruments, the Rasch person-item map deserves to be highlighted as a successful attempt to improve the understanding of clinical scores obtained in response to particular test items.


Chronic relapsing experimental autoimmune encephalomyelitis. treatment with combinations of myelin components promotes clinical and structural recovery.
Preliminary results are presented on the treatment of Strain 13 guinea pigs with chronic relapsing experimental autoimmune (allergic) encephalomyelitis (EAE) induced by a single sensitisation with whole spinal cord. Animals were treated at different stages of the disease with injection containing either myelin basic protein (MBP) alone in incomplete Freund's adjuvant (IFA), or MBP in combination with a lipid hapten of myelin, galactocerebroside (GC) in IFA. The rationale for this treatment stemmed from previous work which suggested that MBP was responsible for T cell sensitisation in EAE and that GC was important in producing demyelinating antibodies and that both myelin components were needed in the induction of disease. Although treatment with MBP alone caused some initial stabilisation of the disease process, subsequent relapses occurred in all animals. However, in animals given MBP and GC together, either early or late in the course of the disease, marked clinical improvement has been noted with little or no development of relapses over an observation period of more than one year post-treatment. In addition, evidence of extensive remyelination and oligodendroglial proliferation in CNS lesions has been found in MBP-GC-treated animals suggesting that this therapy might be beneficial for CNS repair and relevant to multiple sclerosis.


Determination and characterization of arginine-vasopressin in extracted and unextracted urine and its urinary excretion in normal children and adolescents.
Arginine-vasopressin (AVP) was measured by radioimmunoassay in extracted and unextracted urine using two different antisera. The specificity of the assay was confirmed by high-performance liquid chromatography. By the use of a high specific antiserum, AVP can reliably be measured in unextracted urine. Measurements with a less specific antiserum revealed higher concentrations, probably due to nonspecific binding. The extraction of AVP by the use of octadecasilyl-silica columns is unable to separate the intact hormone from substances interfering with the assay. The urinary AVP excretion in 34 normal children and adolescents ranged between 3.5 and 120 ng/m2/24 h with a mean of 39.1 +/- 29.9 ng/m2/24 h.


Fluid within preexisting pulmonary air-spaces: a potential pitfall in the CT differentiation of pleural from parenchymal disease.
There have been many reports of the ability of CT to distinguish between parenchymal and pleural disease. The purpose of this report is to describe the appearance of seven cases of intraparenchymal fluid-filled air-spaces (bullae or lung cysts) in which the CT findings may resemble those of pleural disease and, thus, cast doubt on the specificity of the established criteria.


Body mass index trumps age in decision for endometrial biopsy: cohort study of symptomatic premenopausal women.
Clinical guidelines recommend that women with abnormal uterine bleeding with risk factors have an endometrial biopsy to exclude hyperplasia or cancer. Given the majority of endometrial cancer occurs in postmenopausal women, it has not been widely recognized that obesity is a significant risk factor for endometrial hyperplasia and cancer in young, symptomatic, premenopausal women. We sought to evaluate the effect of body mass index on risk of endometrial hyperplasia or cancer in premenopausal women with abnormal uterine bleeding. This was a retrospective cohort study in a single large urban secondary women's health service. Participants were 916 premenopausal women referred for abnormal uterine bleeding of any cause and had an endometrial biopsy from 2008 through 2014. The primary outcome was complex endometrial hyperplasia (with or without atypia) or endometrial cancer. Almost 5% of participants had complex endometrial hyperplasia or cancer. After adjusting for clinical and demographic factors, women with a measured body mass index ≥30 kg/m2 were 4 times more likely to develop complex hyperplasia or cancer (95% confidence interval, 1.36-11.74). Other risk factors were nulliparity (adjusted odds ratio, 3.08; 95% confidence interval, 1.43-6.64) and anemia (adjusted odds ratio, 2.23; 95% confidence interval, 1.14-4.35). Age, diabetes, and menstrual history were not significant. Obesity is an important risk factor for complex endometrial hyperplasia or cancer in premenopausal women with abnormal uterine bleeding who had an endometrial biopsy in a secondary gynecology service. As over half of women with the outcome in this study were age <45 years, deciding to biopsy primarily based on age, as currently recommended in national guidelines, potentially misses many cases or delays diagnosis. Body mass index should be the first stratification in the decision to perform endometrial biopsy and/or to refer secondary gynecology services.


Soft Dynamics simulation. 1. Normal approach of two deformable particles in a viscous fluid and optimal-approach strategy.
Discrete simulation methods are efficient tools to investigate the behaviors of complex fluids such as dry granular materials or dilute suspensions of hard particles. By contrast, materials made of soft and/or concentrated units (emulsions, foams, vesicles, dense suspensions) can exhibit both significant elastic particle deflections (Hertz-like response) and strong viscous forces (squeezed liquid). We point out that the gap between two particles is then not determined solely by the positions of their centers, but rather exhibits its own dynamics. We provide the first ingredients of a new discrete numerical method, named Soft Dynamics, to simulate the combined dynamics of particles and contacts. As an illustration, we present the results for the approach of two particles. We recover the scaling behaviors expected in three limits: the Stokes limit for very large gaps, the Poiseuille-lubricated limit for small gaps and even smaller surface deflections, and the Hertz limit for significant surface deflections. We find that for each gap value, an optimal force achieves the fastest approach velocity. The principle of larger-scale simulations with this new method is provided. They will consitute a promising tool for investigating the collective behaviors of many complex materials.


Whole transcriptome sequencing identifies key circRNAs, lncRNAs, and miRNAs regulating neurogenesis in developing mouse retina.
The molecular complexity of neural retina development remains poorly studied. Knowledge of retinal neurogenesis regulation sheds light on retinal degeneration therapy exploration. Therefore, we integrated the time-series circRNA, lncRNA, miRNA, and mRNA expression profiles of the developing retina through whole-transcriptome sequencing. The key functional ncRNAs and the ceRNA network regulating retinal neurogenesis were identified. Transcriptomic analysis identified circRNA as the most variable ncRNA subtype. We screened a series of neurogenesis-related circRNAs, lncRNAs, and miRNAs using different strategies based on their diversified molecular functions. The expression of circCDYL, circATXN1, circDYM, circPRGRIP, lncRNA Meg3, and lncRNA Vax2os was validated by quantitative real-time PCR. These circRNAs and lncRNAs participate in neurotransmitter transport and multicellular organism growth through the intricate circRNA/lncRNA-miRNA-mRNA network. Whole-transcriptome sequencing and bioinformatics analysis systematically screened key ncRNAs in retinal neurogenesis. The validated ncRNAs and their circRNA/lncRNA-miRNA-mRNA network involve neurotransmitter transport and multicellular organism growth during retinal development.


Relationship between light absorption properties of black carbon and aerosol origin at a background coastal site.
As a potent climate forcer, black carbon (BC) optical properties can have significant impacts on the regional meteorology and climate. To unveil the seasonal differences of BC and its contribution by various emission sources, a one-year continuous monitoring of atmospheric aerosols was conducted at a background coastal site in Eastern China. By comparing the seasonal and diurnal patterns between BC and elemental carbon, we observed that BC were evidently aged with varying extents among all four seasons. The light absorption enhancement of BC (Eabs) was calculated as 1.89 ± 0.46, 2.40 ± 0.69, 1.91 ± 0.60, and 1.34 ± 0.28, from spring to winter, respectively, indicating that BC was more aged in summer. Contrary to the negligible impact of pollution levels on Eabs, the patterns of air masses arriving to the sampling site had a significant impact on the seasonal optical characteristics of BC. Sea breezes evidently exhibited higher Eabs than land-sourced breezes, and BC was more aged and light-absorbing with an increased contribution of marine airflows. By applying a receptor model, we resolved six emission sources as ship emission, traffic emission, secondary pollution, coal combustion, sea salt, and mineral dust. The mass absorption efficiency of BC for each source was estimated, showing the highest from the ship emission sector. This explained the highest Eabs observed in summer and sea breezes. Our study highlights that curbing emission from shipping activities is beneficial for reducing the warming effect of BC in coastal areas, particularly in the context of future rapid development of international shipping.


Clinical effects and adequacy of a new all-in-one dextrose-electrolyte-trace element preparation in patients on prolonged TPN.
We have devised a new all-in-one dextrose/electrolyste/trace element mixture (Polyfusor DY) and tested its efficacy in clinical practice. Polyfusor DY was designed to be combined with an amino-acid preparation and to be infused with lipid in a standard total parenteral nutrition (TPN) regimen. This standard regimen was formulated to provide minimum nitrogen, energy, fluid, electrolyte, vitamin and trace element requirements for the stable patient. The adequacy of currently recommended levels of provision of trace elements was tested in patients receiving long periods of intravenous nutrition. Eleven consecutive patients were fed from 13 to 280 days using TPN prescriptions based on this standard regimen. Two patients died but the nutritional state of the remainder improved. Serum concentrations of zinc, copper, chromium and manganese remained largely within or above the reference ranges, however the selenium content of Polyfusor DY (500 nmol/l) was marginally inadequate to maintain normal biochemistry. Pharmacy compounding time for the standard TPN regimen based on Polyfusor DY was 10.6 +/- 0.19 min (mean +/- SEM) compared with 22.5 +/- 0.30 min for non-standard TPN regimens prescribed independently by other clinicians (P < 0.001). A standard TPN regimen based on Polyfusor DY was clinically effective, in particular giving generally adequate trace element provision with a reduction in pharmacy time and costs.


Hospitals to docs and moms: don't rush the baby.
Hospitals are working to reduce early elective deliveries and cut the chance for harm to infants and mothers. Convincing physicians and women can be difficult; some hospitals have gone so far as to implement "hard stops.


Induced Second Trimester Abortion and Associated Factors at Debre Markos Referral Hospital: Cross-Sectional Study.
Although most induced abortions in Ethiopia are performed in the first trimester, many women will still require second trimester abortions. While access to abortion in Ethiopia is limited, few data are being available concerning the demand for and associated outcomes of second trimester abortions. This knowledge is important for planning the health service response to abortion. The main objective of this study was to determine the proportion and associated factors of second trimester abortion among women presenting for abortion care services at Debre Markos Referral Hospital, Debre Markos, Northwest Ethiopia. An institution-based cross-sectional study was conducted at Debre Markos Referral Hospital on a sample of 262 calculated using the single population proportion formula. Women who sought abortion services were interviewed consecutively from 12 February 2017 to 14 March 2017. Data were collected in a face-to-face exit interview and document review and analyzed using SPSS version 24.0 software. Bivariate and multivariable analyses were undertaken to identify factors. Of the women who presented for abortion care services in Debre Markos Referral Hospital, 73 (29.6%) had induced second trimester abortion. Unmarried women (adjusted odds ratio = 4.93, 95% confidence interval = 1.41-17.16) and women employed at private business (adjusted odds ratio = 6.17, 95% confidence interval = 1.16-32.76) were associated with induced second trimester abortion. This study revealed that almost one-third of women who presented for abortion care services at Debre Markos Referral Hospital had induced second trimester abortions. Raising awareness of the health consequence of second trimester abortion at community levels and counseling to avoid further occurrences are helpful to minimize the problem. Furthermore, early management of induced second trimester abortion is very crucial to prevent further complications.


Comparative proteomic profiling in Chinese shrimp Fenneropenaeus chinensis under low pH stress.
Lower pH gives rise to a harmful stress to crustacean. Here, we analyzed the proteomic response of Fenneropenaeus chinensis from control pH (pH value 8.2) and low pH (pH value 6.5) - treated groups by employing absolute quantitation-based quantitative proteomic (iTRAQ) analysis. Among the identified proteins, a total of 76 proteins differed in their abundance levels, including 45 upregulated and 31 downregulated proteins. The up-regulation of proteins like citrate synthase, cytochrome c oxidase, V-type proton ATPase, glyceraldehyde-3-phosphate dehydrogenase and fructose 1,6-bisphosphate-aldolase as well as the enrichment of the DEPs in multiple metabolic processes and pathways illustrated that increased energy and substrates metabolism was essential for F. chinensis to counteract low pH stress. Ion transporting related proteins, such as Na+/K+/2Cl- cotransporter and calmodulin, participated in the homeostatic maintenance of pH in F. chinensis. There were significant downregulation expressions of lectin, lipopolysaccharide- and beta-1,3-glucan binding protein, chitinase, cathepsin L and beta-glucuronidase, which indicating the immune dysfunction of F. chinensis when exposure to low pH condition. These findings can extend our understanding on the defensive mechanisms of the low pH stress and accelerate the breeding process of low pH tolerance in F. chinensis.


Infectious encephalitis: Management without etiological diagnosis 48hours after onset.
The etiological diagnosis of infectious encephalitis is often not established 48hours after onset. We aimed to review existing literature data before providing management guidelines. We performed a literature search on PubMed using filters such as "since 01/01/2000", "human", "adults", "English or French", and "clinical trial/review/guidelines". We also used the Mesh search terms "encephalitis/therapy" and "encephalitis/diagnosis". With Mesh search terms "encephalitis/therapy" and "encephalitis/diagnosis", we retrieved 223 and 258 articles, respectively. With search terms "encephalitis and corticosteroid", we identified 38 articles, and with "encephalitis and doxycycline" without the above-mentioned filters we identified 85 articles. A total of 210 articles were included in the analysis. Etiological investigations must focus on recent travels, animal exposures, age, immunodeficiency, neurological damage characteristics, and potential extra-neurological signs. The interest of a diagnosis of encephalitis for which there is no specific treatment is also to discontinue any empirical treatments initially prescribed. Physicians must consider and search for autoimmune encephalitis.


Metabolism of phosphatidylinositol in plasma membranes and synaptosomes of rat cerebral cortex: a comparison between endogenous vs exogenous substrate pools.
The metabolism of phosphatidylinositols (PI) labeled with [14C]arachidonic acid within plasma membranes or synaptosomes was compared to the metabolism of PI prelabeled with [14C]arachidonic acid and added exogenously to the same membranes. Incubation of membranes containing the endogenously-labeled PI pool in the presence of Ca2+ resulted in the release of labeled arachidonic acid, as well as a small amount of labeled diacylglycerol. Labeled arachidonic acid was effectively reutilized and returned to the membrane phospholipids in the presence of adenosine triphosphate (ATP), CoA, and lysoPI. Although Ca2+ promoted the release of labeled diacylglycerol from prelabeled plasma membranes, this amount was only 17% of the maximal release, i.e., release in the presence of deoxycholate and Ca2+. This latter condition is known to fully activate the PI-phospholipase C, and incubation of prelabeled plasma membranes resulted in a six-fold increase in labeled diacylglycerols. On the other hand, when exogenously labeled PI were incubated with plasma membranes in the presence of Ca2+, the labeled diacylglycerols released were 59% of that compared to the fully activated condition. The phospholipase C action was calcium-dependent, regardless of whether exogenous or endogenous substrates were used in the incubation. In contrast to plasma membranes, intact synaptosomes had limited ability to metabolize exogenous PI even in the presence of Ca2+, although the activity of phospholipase C was similar to that in the plasma membranes when assayed in the presence of deoxycholate and Ca2+. These results suggest that discrete pools of PI are present in plasma membranes, and that the pool associated with the acyltransferase is apparently not readily accessible to hydrolysis by phospholipase C.


Psychosocial outcomes for adults with spina bifida: a scoping review protocol.
The objective of this scoping review is to explore the evidence on psychosocial needs and related outcomes for adults with spina bifida. Individuals with spinal bifida have complex service needs that can lead to the emergence of secondary conditions and health complications, which can result in serious, life-threatening illnesses. While much is known about the biological impact of spina bifida, there is a dearth of information regarding its psychological and social impact. This scoping review will include adults (18 years and over) with the following diagnoses: spina bifida, neural tube defects, tethered cord, myelodysplasia/myelodysplasias, diastematomyelia/diastematomyelias, meningomyelocele, terminal myelocystocele, fatty thickened filum, split cord malformation, or lipomyelomeningocele. The literature reviewed will explore the range and trend of topics reported from the time data on adults with spinal bifida were first published published to the most current time frame. This review will report on the psychosocial needs identified for adults with spinal bifida, such as access to community-based services and support needed to function independently. There will be no limits to the geographical location or setting (e.g. health care or community-based). The following databases will be accessed for this review: Ovid MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science, PsycINFO, and ERIC, with no date restrictions. Gray literature searches will be included. Potentially relevant studies will be assessed independently by two reviewers for inclusion and conflicts discussed with a third reviewer. The review narrative will be accompanied by findings presented in tabular format.


Mutational analysis of an actin-binding site of cofilin and characterization of chimeric proteins between cofilin and destrin.
Cofilin and destrin are two related low molecular weight mammalian actin-binding proteins. Cofilin is an F-actin side-binding and pH-dependent actin-depolymerizing protein, and destrin is a pH-independent actin-depolymerizing protein. We have introduced a few point mutations within an actin-binding sequence of cofilin. Biochemical analyses of these mutant proteins have clearly shown that Lys112 and Lys114 of cofilin are crucially but differently involved in its interaction with actin and phosphatidylinositol 4,5-bisphosphate. This is the first example among actin-binding proteins whose point mutations inactivate their interaction with actin in vitro. We have also made and characterized a series of chimeric proteins between cofilin and destrin to identify the regions responsible for the pH dependence and the F-actin side binding activity of cofilin. Our results suggest that a central region consisting of 42 amino acid residues and a carboxyl-terminal quarter of cofilin are both involved in regulation of the pH-dependent actin depolymerizing activity and the activity to bind along F-actin.


Hypertension and insulin resistance are not directly related in obese dogs.
In dogs fed a high-fat diet, we determined whether there was a direct relation between obesity-induced insulin resistance and obesity-induced hypertension. Thirty-six adult mongrel dogs were chronically instrumented and assigned to receive either a high-fat diet alone (n=7) or a high-fat diet combined with a low-sodium diet plus furosemide (n=6), prazosin plus atenolol (n=7), clonidine (n=10), or aspirin (n=6). Blood pressure, heart rate, and body weight were measured daily. Insulin resistance was assessed with a single-dose euglycemic hyperinsulinemic clamp (2 mU x kg(-1) x min(-1)) before and after 1, 3, and 6 weeks of the high-fat diet. The low-salt diet plus furosemide, prazosin plus atenolol, and clonidine treatments prevented the hypertension associated with feeding the dogs a high-fat diet. Only clonidine treatment totally prevented the development of insulin resistance, and high-dose aspirin, known to prevent insulin resistance by inhibition of the activity of IkappaB kinase-beta, decreased the degree of insulin resistance by almost 70%. However, aspirin had no effect on the development of hypertension. We conclude that obesity-induced hypertension and obesity-induced insulin resistance are not directly related. In addition, there is a suggestion that insulin resistance in this experimental model is mediated through the central and or peripheral alpha2-adrenoceptors, whereas hypertension is mediated through the alpha1- and or beta-adrenoceptors.


Clinical efficacy of blastocyst culture supernatant transfer in hormone replacement freeze-thaw embryo transfer cycles: A prospective double-blind randomized controlled study.
To investigate the clinical efficacy of blastocyst culture supernatant transfer in hormone replacement freeze-thaw embryo transfer (FET) cycles. The present study was a prospective double-blind randomized controlled study. Patients who met the inclusion criteria for the first hormone replacement freeze-thaw single blastocyst transfer proposed from September 2017 to December 2020 were randomly grouped at the endometrial transformation day of the secretory phase (P + 0). Patients in Group A (the experimental group) received the blastocyst culture supernatant at P + 2 and a single blastocyst at P + 5. Patients in Group B (the control group) received the embryo culture at P + 2 and a single blastocyst at P + 5. The clinical outcomes were compared between the two groups. A total of 288 cycles were included in the present study, with 144 cycles in each group. The clinical pregnancy rate and live birth rate were higher in group A than in group B (54.9% vs 45.8%, and 50% vs 39.6%, respectively), and the differences were more pronounced in patients with the age of ≥35 years (51.7% vs 37.5%, and 44.8% vs 32.1%, respectively), but the differences were not statistically significant. Blastocyst culture supernatant transfer in hormone replacement FET cycles could improve the pregnancy outcomes.


The inverse relationship between species diversity and body mass: do primates play by the "rules"?
Evolutionary biologists have long commented on a seemingly universal "rule" of nature-that in large taxonomic assemblages from groups as diverse as bacteria, plants, insects, marine invertebrates, fish, reptiles, amphibians, birds, and mammals, there exists a frequency distribution of body sizes among species that is highly skewed to the right (positive skewness). This distribution reflects the strong inverse, or negative, relationship often noted between mean body size of taxa and the number of species they contain--i.e., the observation that small body size is often associated with high species diversity (speciosity). This is sometimes "explained" by recourse to the idea that smaller-bodied taxa are able to subdivide their environments more finely than larger-bodied taxa. With but few exceptions, the applicability of this "rule" to the Order Primates has not been studied in any detail. In this study I address the following questions of (paleo)anthropological interest: (1) How speciose is the Order Primates? (2) Does this biological "rule" characterize the Order Primates (at any taxonomic level) in any meaningful way? (3) Does the association between speciosity and body mass within the Order Primates provide any useful models for interpreting and/or predicting speciosity in the fossil primate record? Using phylogenetically independent contrasts methods, I conclude that the answers to those three questions are: (1) not very; (2) no; and (3) not particularly (with the possible exception of larger-bodied taxa).


Cross sectional study to estimate the morbidity pattern in ascetics visited to a largest religious gathering in west central part of India.
Ascetics are otherworldly creatures that have thought of being ethereal. To be spiritual one has to be physically fit because a healthy body has an intimate connection with spiritual health. Cross sectional survey was accomplished in a festive gathering to estimate morbidity pattern among ascetics in central India. The sample size was 960. 352 participants (36.6%) were either overweight or obese, 284 participants (29.6%) had hypertension, 236 (24.6%) were diagnosed with cataract and 194 (20.2%) had anemia, Diabetes was found in 58 participants (6%) and 28 (2.9%) had fever. Obesity (and overweight) and hypertension were the top two morbidities came across during study. Morbidities were found to be more associated with socio-demographical factors than spirituality.


[Self-damaging mechanisms. Motivation of drug- and luxury-abuse, drug consumption, tendency for suicide].
Abuse of legal and illegal drugs, alcohol and cigarettes, and suicide tend to be studied separately from each other, and different organizations concern themselves with their respective treatments. A study of self-damaging behavior patterns conducted at the University of Zurich has shown that one and the same motivational structure is expressed through these different manifestations: Processes of self-devaluation explain a large part of those behaviors that reduce the chances of survival. Since inhibition of self-actualization can be explained by social structures, it follows that preventive medicine has to open a social political dimension. The conference on which this article is based presents numerous unpublished data on alcoholism, cigarette consumption, abuse of legal and illegal drugs, and suicide fantasy. The Zurich project is expected to be terminated in 1977.


Free CPD during pre-congress day at virtual congress.
As part of the International Webinar Vet Virtual Congress, BVA members can benefit from free CPD through BVA's pre-congress day. Zoe Davies, BVA's marketing manager, explains.


Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results.
Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03). To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS). Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial. Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade. Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy. Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib. ClinicalTrials.gov NCT00375674.


Increase of a group of PTC(+) transcripts by curcumin through inhibition of the NMD pathway.
Nonsense-mediated mRNA decay (NMD), an mRNA surveillance mechanism, eliminates premature termination codon-containing (PTC⁺) transcripts. For instance, it maintains the homeostasis of splicing factors and degrades aberrant transcripts of human genetic disease genes. Here we examine the inhibitory effect on the NMD pathway and consequent increase of PTC+ transcripts by the dietary compound curcumin. We have found that several PTC⁺ transcripts including that of serine/arginine-rich splicing factor 1 (SRSF1) were specifically increased in cells by curcumin. We also observed a similar curcumin effect on the PTC⁺ mutant transcript from a Tay-Sachs-causing HEXA allele or from a beta-globin reporter gene. The curcumin effect was accompanied by significantly reduced expression of the NMD factors UPF1, 2, 3A and 3B. Consistently, in chromatin immunoprecipitation assays, curcumin specifically reduced the occupancy of acetyl-histone H3 and RNA polymerase II at the promoter region (-376 to -247nt) of human UPF1, in a time- and dosage-dependent way. Importantly, knocking down UPF1 abolished or substantially reduced the difference of PTC(+) transcript levels between control and curcumin-treated cells. The disrupted curcumin effect was efficiently rescued by expression of exogenous Myc-UPF1 in the knockdown cells. Together, our data demonstrate that a group of PTC⁺ transcripts are stabilized by a dietary compound curcumin through the inhibition of UPF factor expression and the NMD pathway.


Intraoperative echotomographic diagnosis in abdominal and neurosurgery.
In many clinics, intraoperative sonography is used as a routine method in general surgery as well as in neurosurgery. The availability of sterilizable applicators in diverse shapes and sizes enables the optimal approach to the site to be examined. In processes involving the liver, the pancreas, the kidneys, or the brain, ultrasonic examination, together with an exact topographic localization, proved to be helpful in determining the dimensions of an altered structure. In patients with colorectal carcinoma, the discovery of metastases that had not been previously detected by percutaneous sonography proves the necessity of regular intraoperative ultrasonic examination to augment staging accuracy in tumor surgery.


Halothane attenuates calcium sensitization in airway smooth muscle by inhibiting G-proteins.
Halothane directly relaxes airway smooth muscle partly by decreasing the Ca2+ sensitivity. In smooth muscle, receptor stimulation is thought to increase Ca2+ sensitivity via a cascade of heterotrimeric and small monomeric guanine nucleotide-binding proteins (G-proteins). Whether this model is applicable in the airway and where halothane acts in this pathway were investigated. A beta-escin-permeabilized canine tracheal smooth muscle preparation was used. Exoenzyme C3 of Clostridium botulinum, which inactivates Rho monomeric G-proteins, was used to evaluate the involvement of this protein in the Ca2+ sensitization pathway. The effects of halothane on different stimulants acting at different levels of signal transduction were compared: acetylcholine on the muscarinic receptor, aluminum fluoride (AIF4-) on heterotrimeric G-proteins, and guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) on all G-proteins. Exoenzyme C3 equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization, suggesting that these pathways are both mediated by Rho. Halothane applied before stimulation equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization. However, when added after Ca2+ sensitization was established, the effect of halothane was greater during Ca2+ sensitization induced by acetylcholine compared with AIF4-, which, along with the previous result, suggests that halothane may interfere with dissociation of heterotrimeric G-proteins. Halothane applied during GTPgammaS-induced Ca2+ sensitization had no significant effect on force, suggesting that halothane has no effect downstream from monomeric G-proteins. Halothane inhibits increases in Ca2+ sensitivity of canine tracheal smooth muscle primarily by interfering with the activation of heterotrimeric G-proteins, probably by inhibiting their dissociation.


Evolutionary conflict over the control of offspring sex ratio.
There are many theories which predict how animals should control the sex ratio of their offspring. In diploids, however, such control is rarely seen. Two explanations have been suggested for this. One is that parents are simply unable to control the sex ratio of their offspring. The other is that sperm actively oppose such control. This paper examines the possibilities and consequences of parent-gamete conflict over the sex ratio. Such conflict may occur between any of the parties concerned--sperm, ova, fathers, mothers, offspring. It is concluded that gametes are indeed almost always opposed to any parental manipulation of the sex ratio. However, it is probable that the rarity of adaptive parental control of progeny sex ratio in diploids is because parents are physiologically incapable of altering the sex ratio.


Pharmacological and metabolic interactions between ethanol and methyl n-butyl ketone, methyl isobutyl ketone, methyl ethyl ketone, or acetone in mice.
Methyl n-butyl ketone (MnBK), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and acetone are widely used industrial solvents to which certain groups of workers are exposed. Pharmacological and metabolic interactions between these solvents and ethanol were explored in male CD-1 mice. The effects of these solvents on the duration of ethanol-induced loss of righting reflex and on ethanol elimination in mice were studied. The solvents were dissolved in corn oil and injected intraperitoneally 30 min before ethanol 4 g/kg ip. The four solvents prolonged significantly the duration of ethanol-induced loss of righting reflex when given in the following doses (mmol/kg): MnBK, 3.75 and 5; MIBK, 5; MEK, 5 and 10, acetone, 20 and 40. This prolongation was dose related and increased as the dose of the solvent was increased. The concentrations of ethanol in blood or brain on return of the righting reflex were similar in solvent-treated and control animals, with the exception of the group of mice treated with 40 mmol/kg acetone in which the ethanol concentrations were significantly lower than in control animals. The mean elimination rate of ethanol was markedly reduced in mice treated with MnBK 5 mmol/kg, MEK 15 mmol/kg, and acetone 40 mmol/kg. All four solvents reduced the activity of mouse liver alcohol dehydrogenase in vitro. It is concluded that enhancement of the ethanol-induced loss of righting reflex by these solvents in mice is well correlated to reduced elimination rate of ethanol.


Factors Attracting or Deterring Female Medical Students in Asia From Pursuing a Surgical Career, and the Impact of Surgical Clerkship, Mentorship, and Role Models: A Multicultural Asian Perspective From a National Prospective Cohort Study.
Female surgeons are highly underrepresented in Asian countries, where prescriptive gender norms are widespread and more deeply embedded in societies. A nationwide structured questionnaire was completed by 1741 Singaporean third- and fifth-year medical students after the completion of an 8-week general surgery rotation, during 2015-2017. Results were analyzed using mixed-effects hierarchical models which took into account clustering of survey responses under the teaching hospitals which students were posted to and medical students' year of study. Female medical students had a poorer perception of general surgery than male students (3.22 ± 0.91 versus 3.41 ± 0.89; P < 0.0001) before the clerkship. However, the clerkship improved female students' opinion to a greater extent than male students (+0.84 ± 1.06 versus +0.59 ± 1.03; P < 0.0001), resulting in female and male students having comparable attitudes toward surgery after the clerkship (4.06 ± 0.79 versus 4.00 ± 0.87; P = 0.2435). A total of 40.4% of female students responded that they were inspired to pursue a surgical career after the clerkship, and we identified 13 pedagogical traits of faculty and resident mentors which were associated with female students' career aspirations. Female students were more likely to consider intellectual challenges arising from cases (ratio: 1.045 [95% confidence interval 1.004-1.088, P = 0.0292]) and the presence of role models (ratio: 1.068 [95% confidence interval: 1.020-1.118, P = 0.0048]) as "pull" factors compared with their male contemporaries, but were deterred from a surgical career to a greater extent by eight "push" factors. A surgical clerkship itself could be regarded as an effective intervention for improving female medical students' enthusiasm for surgery, which may help to address the "pipeline problem" of few female students applying for surgical training after medical school. A greater emphasis on "pull factors" and pedagogical qualities of mentors could be used to improve the clerkship experience, to attract more female students to surgery.


Right Ventricular Dysfunction During Endurance Exercise as Determined by Pressure-Volume Analysis.
A 37-year-old athlete completed invasive endurance (90 km) bicycle exercise testing for right ventricular pressure-volume analysis. Increased right ventricular afterload caused declines in ventricular-arterial coupling and cardiac output, causing increased arteriovenous oxygen difference to maintain oxygen uptake. These findings demonstrate effects of changes in right ventricular performance on exercise capacity. (Level of Difficulty: Intermediate.).


Repair failure increases the risk of developing secondary glenohumeral osteoarthritis: A long-term follow-up after open repair of large subscapularis tendon tears.
The subscapularis musculotendinous unit provides a stabilizing effect on the glenohumeral joint and thus, enables normal active range of motion. As pathologies of the subscapularis tendon (SSC) are diagnosed with increased regularity, treatment strategies and their long-term consequences are of relevant interest. Therefore, the primary objective of this retrospective case series was to evaluate clinical and radiological long-term results after open repair of large SSC tears. Repair failure negatively influences clinical outcomes and the progression of secondary glenohumeral osteoarthritis (OA). Between 1998 and 2007, 24 patients with traumatic large (Lafosse III and IV) SSC tears were treated with an open transosseous repair technique. Of those, 20 patients (83%) with a mean age of 55±8 years (range, from 31 to 68 years) at the time of surgery were subjected to a long-term follow-up after a mean of 14±3 years (range, from 10 to 18 years). The Subjective Shoulder Value (SSV), the Constant Score (CS), the University of California at Los Angeles (UCLA) Shoulder Score, and the American Society for Shoulder and Elbow Surgeons (ASES) Score were obtained. Magnetic resonance imaging (MRI) was performed to evaluate tendon integrity. The progression of secondary glenohumeral OA from pre- to postoperative was analyzed using the collective instability arthropathy (CIA) score. One patient (5%) had to undergo revision surgery due to a symptomatic re-tear of the SSC tendon. Besides that, the mean SSV of the affected shoulder was 83%±12, the CS 78±10, the UCLA 32±2, and the ASES 89±14 points, respectively. MRI revealed a re-tear of the SSC tendon in 4 patients (29%). On the affected shoulder, glenohumeral OA progressed significantly from pre- (CIA, 0.3±0.5) to postoperative (CIA, 1.7±0.9; p=0.003) and was significantly associated with repair failure (p=0.040). Open repair of large SSC tears yielded good clinical long-term results. Nevertheless, repair failure was common and, in the further course, negatively affected clinical outcomes and the progression of secondary glenohumeral OA. IV; retrospective case series.


Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study.
Older age is associated with poorer outcomes to COVID-19 infection. The Norwegian Institute of Public Health established a longitudinal cohort of adults aged 65-80 years to study the effects of the COVID-19 pandemic. Here we describe the characteristics of the cohort in general, and specifically the immune responses at baseline and after primary and booster vaccination in a subset of longitudinal blood samples, and the epidemiological factors affecting these responses. 4551 participants were recruited, with humoral (n=299) and cellular (n=90) responses measured before vaccination and after two and three vaccine doses. Information on general health, infections, and vaccinations were obtained from questionnaires and national health registries. Half of the participants had a chronic condition. 849 (18·7%) of 4551 were prefrail and 184 (4%) of 4551 were frail. 483 (10·6%) of 4551 had general activity limitations (scored with the Global Activity Limitation Index). After dose two, 295 (98·7%) of 299 participants were seropositive for anti-receptor binding domain IgG, and 210 (100%) of 210 participants after dose three. Spike-specific CD4 and CD8 T cell responses showed high heterogeneity after vaccination and responded to the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529 or BA.1) variants of concern. Cellular responses to seasonal coronaviruses increased after SARS-CoV-2 vaccination. Heterologous prime boosting with mRNA vaccines was associated with the highest antibody (p=0·019) and CD4 T cell responses (p=0·003), and hypertension with lower antibody levels after three doses (p=0·04). Most older adults, including those with comorbidities, generated good serological and cellular responses after two vaccine doses. Responses further improved after three doses, particularly after heterologous boosting. Vaccination also generated cross-reactive T cells against variants of concern and seasonal coronaviruses. Frailty was not associated with impaired immune responses, but hypertension might indicate reduced responsiveness to vaccines even after three doses. Individual differences identified through longitudinal sampling enables better prediction of the variability of vaccine responses, which can help guide future policy on the need for subsequent doses and their timing. Norwegian Institute of Public Health, Norwegian Ministry of Health, Research Council of Norway, and Coalition for Epidemic Preparedness Innovations.


[Closure of the central artery of the retina in progressive scleroderma (author's transl)].
In the present paper a case of generalized scleroderma with concomitant central arterial occlusion is reported. To our knowledge this coincidence of generalized scleroderma and central arterial occlusion has not been described so far. As fibrinoid necrosis and proliferative changes of the choroidal vessels occur with generalized scleroderma the possibility is discussed that the central arterial occlusion may be an effect of the scleroderma.


Endovenous laser treatment to promote venous occlusion.
Current treatment methods of superficial venous insufficiency (SVI) can be painful or result in incomplete occlusion. The objective of this study was to evaluate a technique for laser endovenous ablation with a newly developed diffuser fiber. Six lateral saphenous veins in three goats were used. A specifically designed diffuser laser fiber tip was employed in all trials to deliver a wavelength of 1,064 nm. Each segment was treated with a different energy fluence by changing the power setting of the laser or the withdrawal rate of the fiber. Energy fluence was calculated by dividing the Joules employed for each segment over the internal surface area of the vessel. Segments were evaluated with ultrasound and histologically. Seventy-five percent of the segments were occluded when an energy fluence of greater than 85 J/cm2 was employed. No perforations were observed, but perivascular changes were more common at higher energy fluence. Endovenous laser occlusion of veins with minimal perivascular effects can be achieved with laser wavelengths of 1,064 nm if an energy fluence of 84.9-224 J/cm2 is employed and circumferential effect is achieved.


Abnormal response of osteoblasts from Hyp mice to 1,25-dihydroxyvitamin D3.
To further explore the hypothesis of an osteoblast inappropriate response to 1,25-(OH)2D3 in hypophosphatemic vitamin D-resistant rickets (HYP), osteoblasts were isolated from Hyp mice, the animal model for human HYP, and their response to a physiologic dose of 1,25-(OH)2D3 (10(-10) M) was investigated with respect to alkaline phosphatase (ALP) activity and cell proliferation, and compared to that of normal osteoblasts. Cells in secondary culture were incubated for 72 h while in log phase, with or without 1,25-(OH)2D3, at various medium phosphate (P) concentrations ranging from 0.5 to 4.5 mM. Stimulation of ALP activity and inhibition of cell proliferation was induced by 10(-10)M 1,25-(OH)2D3 in normal cells exposed to medium P concentration corresponding to serum levels observed in normal mice (2.1-2.7 mM P). By contrast, Hyp cells failed to respond to 1,25-(OH)2D3 in that range of P concentrations. Stimulation of ALP activity and inhibition of proliferation of mutant cells were evident at higher medium P concentrations (over 3 mM). 1,25-(OH)2D3 at the supraphysiologic level of 10(-9)M had no consistent effect on ALP activity in normal and Hyp mouse osteoblasts, but inhibited cell proliferation in cultures of both genotypes at all P concentrations tested. These results indicate that extracellular P modulates the action of 1,25-(OH)2D3 on osteoblasts, and that this modulation was altered in osteoblasts from Hyp mice. The failure of Hyp cells to respond to a physiologic dose of 1,25-(OH)2D3 upon normal P concentration may reflect the abnormal response of bone to 1,25-(OH)2D3 observed in Hyp mice and HYP patients.


Epidemiology, risk factors, and applicability of CDC definitions for healthcare-associated bloodstream infections at a level IV neonatal ICU.
We studied the epidemiology of primary bloodstream infections (BSIs), secondary BSIs, and central line-associated BSIs (CLABSIs) and applicability of CDC definitions for primary sources of infection causing secondary BSIs in patients in the neonatal ICU. We classified healthcare-associated BSIs (HABSIs) as primary BSIs, secondary BSIs, and CLABSIs using CDC surveillance definitions and determined their overall incidence and incidence among different gestational age strata. We assessed the applicability of CDC definitions for infection sources causing secondary BSIs. From 2010 to 2019, 141 (32.7%), 202 (46.9%), and 88 (20.4%) HABSIs were classified as primary BSIs, secondary BSIs, and CLABSIs, respectively; all declined during the study period (all p < 0.001). Gestational age <28 weeks was associated with increased incidence of all HABSI types. CDC criteria for site-specific primary sources were met in 137/202 (68%) secondary BSIs. Primary and secondary BSIs were more common than CLABSIs and should be prioritized for prevention.


Fractionation of sheep cheese whey by a scalable method to sequentially isolate bioactive proteins.
This study reports a procedure for the simultaneous purification of glyco(caseino)macropeptide, immunoglobulin, lactoperoxidase, lactoferrin, α-lactalbumin and β-lactoglobulin from sheep cheese sweet whey, an under-utilized by-product of cheese manufacture generated by an emerging sheep dairy industry in New Zealand. These proteins have recognized value in the nutrition, biomedical and health-promoting supplements industries. A sequential fractionation procedure using economical anion and cation exchange chromatography on HiTrap resins was evaluated. The whey protein fractionation is performed under mild conditions, requires only the adjustment of pH between ion exchange chromatography steps, does not require buffer exchange and uses minimal amounts of chemicals. The purity of the whey protein fractions generated were analyzed by reversed phase-high performance liquid chromatography and the identity of the proteins was confirmed by mass spectrometry. This scalable procedure demonstrates that several proteins of recognized value can be fractionated in reasonable yield and purity from sheep cheese whey in one streamlined process.


Drop-out during a randomized trial with adolescents with intellectual disability was associated with participant burden, while drop-out at study exit was associated with carer and household characteristics.
People with intellectual disability are difficult to retain in longitudinal studies. Research on determinants of study retention for individual-carer dyads, and their reasons for drop-out, are limited. To investigate characteristics associated with drop-out, and to investigate whether characteristics varied by stage of drop-out. Data are from an Australian randomized trial with adolescents with intellectual disability living in the community. Characteristics of both the adolescent and their nominated carer were collected at baseline. Carers were sent an exit questionnaire approximately two years after enrolment. Baseline information was available for 566 adolescents: 72(13.0%) withdrew during the study, and 96(17.3%) didn't return exit questionnaires. Characteristics associated with drop-out during the study were being in the intervention group, the carer being younger, and the carer not being one of the adolescent's parents. Characteristics associated with withdrawal at exit were carer having lower education and carer having lower socioeconomic status. No adolescent characteristic was associated with drop-out. Characteristics of drop-outs weren't related to the adolescent and differed according to timing. Drop-out during the study was associated with study burden, whereas characteristics of drop-outs at exit interview were associated with lower social position.


[Clinical application of ROM in psychosis].
The use of 'routine outcome monitoring' (ROM) in mental health care has increased widely during the past decade. However, little is known about the use of ROM outcome in daily clinical practice. We investigated to what extent ROM results were reflected in psychotic patients' treatment plans. Cross-sectional study. The ROM-Phamous, a ROM-protocol for patients with psychotic disorders in which data is collected on the basis of interviews, questionnaires and physical examination was implemented in the northern Netherlands. A random sample of 100 patients was extracted from the 2010 ROM database (n = 1040), from which we determined the prevalence of a number of problem areas. We then investigated whether these problems were reflected in patients' treatment plans. The sample consisted of 63 men and 37 women, with a mean age of 44 years and a mean duration of illness of 18 years. The prevalence of symptoms and psychosocial problems was 13-37%; the prevalence of cardiovascular risk factors was 11-86%. The majority of problems identified with ROM were not reflected in patients' treatment plans; the opposite also occurred: psychosocial problems, in particular, mentioned in the treatment plans were not always identified with ROM. ROM and treatment should ideally be integrated in mental-health services, but currently appear to be separate processes. If improvement of integration of ROM and clinical practice succeeds it could lead to improvement of care for psychiatric patients. Further investigation is warranted. Conflict of interest and financial support: ICMJE forms provided by the authors are available online along with the full text of this article.


The size of the population of weakly coupled chlorophyll pigments involved in thylakoid photoinhibition determined by steady-state fluorescence spectroscopy.
On the basis of experiments with singlet quenchers and in agreement with previous data, it is suggested that a population of energetically weakly coupled chlorophylls may play a central role in photoinhibition in vivo and in vitro. In the present study, we have used steady state fluorescence techniques to gain direct evidence for these uncoupled chlorophylls. Due to the presence of their emission maxima, near 650 nm and more prominently in the 670--675 nm interval both chlorophylls b and a seem to be involved. A straightforward mathematical model is developed to describe the data which allows us to conclude that the uncoupled/weakly coupled population size is in the range of 1--3 molecules per photosystem.


Effects of intravitreal injection of fluorosilicone oil after vitrectomy in the rabbit eye.
Because fluorosilicone oil is heavier than silicone oil, it may be superior in the therapy of proliferative vitreoretinopathy. To evaluate the ocular toxicity of fluorosilicone oil we performed pars plana lentectomy and vitrectomy on 14 rabbit eyes and injected approximately 1.5 mL of the oil (viscosity 10,000 centistoke) into the vitreous chamber of 10. No clinical or histologic evidence of toxic ocular effects was noted up to 2 months after the procedure.


Innovative workflow for the identification of cathepsin K cleavage sites in type I collagen.
Since the late 1990s, cathepsin K cleavage sites in type I collagen have been extensively studied due to its ability to release bone resorption biomarkers such as CTX and NTX. However, gel-based methods and N-sequencing used in these studies lack sensitivity, especially for small to medium peptides. In this work, we propose a degradomics mass spectrometry-based workflow that combines protein digestion, Nano-LC-UDMSE, and several software tools to identify cathepsin K cleavage sites. This workflow not only identified previously known cleavage sites, but also discovered new ones. Multiple cleavage hotspots were found and described in type I α1 and type I α2 collagen, many of which coincided with pyridinoline crosslinks, known to stabilize the triple helix. Our results allowed us to establish a chronology of digestion and conclude that cathepsin K preferentially cleaves the extremities of type I collagen before the helical part. We also found that cathepsin K preferentially cleaves amino acid residues with long and hydrophobic lateral chains at the beginning of digestion, whereas no preferred amino acid residues were identified later in the digestion. In conclusion, our workflow successfully identified new cleavage sites and can be easily applied to other proteins or proteases.


Five new cycloartane triterpenoids from Beesia calthifolia.
Phytochemical study on rhizomes of Beesia calthifolia resulted in the isolation of five new (1-5) and three known (6-8) cycloartane triterpenoids possessing a hemiketal or ketal group at C-24 from the EtOAc fraction of 95% ethanol extract. Their structures were determined by spectroscopic and chemical methods, especially HRMS and 2D NMR techniques. Compounds 3 and 4 showed potential hepatoprotective activities against D-galactosamine induced human hepatic L02 cell damage.


Foot-and-mouth disease virus: a first inter-laboratory comparison trial to evaluate virus isolation and RT-PCR detection methods.
Five European reference laboratories participated in an exercise to evaluate the sensitivity and specificity of their routinely employed RT-PCR tests and cell cultures for the detection and isolation of foot-and-mouth disease (FMD) virus. Five identical sets of 20 coded samples were prepared from 10 vesicular epithelia, which were derived from submissions from suspect cases of FMD or swine vesicular disease (SVD). Sixteen samples were derived from six FMD virus positive epithelia representing four different serotypes (two each of types O and A and one each of types Asia 1 and SAT 2), two from samples which had been found to be negative by antigen ELISA and virus isolation (VI) in cell culture and two from SVD virus positive epithelia. Some of the FMD virus positive samples were prepared from 10-fold serial dilutions of three of the initial suspensions. Each laboratory tested the samples by one or more of its available RT-PCR procedures and inoculated cell cultures that it routinely uses for FMD diagnosis in attempts to isolate virus, the specificity of which was confirmed by antigen ELISA. The best of the RT-PCR assays used in each laboratory gave comparable results while the sensitivity of cell cultures was variable from high in one laboratory, moderate in two and low in two others. This prototype panel of samples would appear suitable for external quality assurance of these tests but would benefit from the inclusion of more negative samples and an extension in the serial dilution range of one or more of the FMD positive sample titration series.


Open-field behavior in mice: generality of results from a diallel analysis of replicate selected lines.
Data from a diallel cross of six lines composing a replicated selection study for open-field behavior in mice are reanalyzed to investigate the generality of the findings. The results support the hypothesis that only additive variation would be found for open-field behavior if additional selection lines were derived from the same foundation population.


Prolonged fasting hypoglycemia due to insulin antibodies in patient with non-insulin-dependent diabetes mellitus: effect of insulin withdrawal on insulin-antibody-binding kinetics.
Fasting hypoglycemia, which persisted for 3 days after insulin treatment was stopped, occurred in a patient with non-insulin-dependent diabetes mellitus who had inappropriate plasma free-insulin levels (18-25 microU/ml) and extremely high antibody-bound insulin (greater than 20,000 microU/ml) but normal counter-regulatory hormone secretion and plasma C-peptide levels. The amount of antibody-bound insulin decreased in a biphasic pattern over 13 mo of observation with an initial half-life of 35 days and a more gradual decrease with a half-life of 160 days. The number of high-affinity antibody binding sites was virtually identical to the amount of antibody-bound insulin in the patient's plasma. We conclude that the patient's fasting hyperinsulinemia and hypoglycemia were due to release of antibody-bound insulin.


Anopheles metabolic proteins in malaria transmission, prevention and control: a review.
The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an effective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identification of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmission exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specificity can yield insecticides with no significant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will significantly help to curb malaria transmission.


Mobile genetic elements profiling, gene flow, and antimicrobial susceptibility profiles, among Pseudomonas aeruginosa isolates, isolated from Al Muthanna hospitals' wound and burn units in Iraq.
The prevalence assessment of integrons among multidrug-resistant strains of Pseudomonas aeruginosa receives much-needed attention from this study, as we achieved our desired objective by conducting a thorough analysis on one hundred swabs obtained from burn and clinical cases at the hospitals present in Al Muthanna governorate during November of the year 2021 through to March of the year 2022. By implementing various methodologies encompassing the scrutiny of growth traits and cellular composition as well as executing biochemical assays, a total of 55 isolates were determined to exhibit the existence of P. aeruginosa. When cultured in Hifluoro agar media, Pseudomonas aeruginosa produced diverse hues; particularly noticeable was its blue-green colour. It was discovered through investigation that there were no intI2 and inti3 genes present in those isolated. Findings from this research disclosed that about one-fifth, or precisely twelve out of fifty-five P. aeruginosa strains screened, had an actively expressed Integrase I gene. The association between elevated rates of resistance to multiple antimicrobial agents and the existence of integrons is worth mentioning. Furthermore, the assemblage of isolates that were efficacious in the presence of integrons demonstrated an augmented resistance towards several frequently employed antibiotics like rifampicin and ceftazidime. In conclusion, it can be stated with confidence that a considerable occurrence of integrons can be observed in Pseudomonas aeruginosa strains that display resistance to numerous pharmaceutical agents. Additionally, the discovery of the intI1 gene in a considerable proportion of isolates underscores the effectiveness of integrons in conferring resistance to a variety of antimicrobial agents. These revelations supplement our insight into antibiotic-resistant mechanisms while also underscoring the necessity for viable strategies aimed at halting and preventing bacterial drug resistance.


Dysregulation of heart and brain specific micro-RNA in sudden infant death syndrome.
Channelopathic heart arrhythmias and dysfunctional autonomic regulation of respiration and arousal based on defects in the brainstem are assumed to be involved in the pathogenesis of SIDS. There is evidence that, apart from mutational alterations in associated genes, disruption of physiological processes and deficient responses to external stressors may be influenced by the dysregulation of organ specific micro-RNA expression. It is unknown, however, whether these small, non-coding regulatory RNA molecules are involved in any SIDS pathomechanism. In a case-control study of two series of fresh-frozen heart tissue (n=14) and formalin fixed, paraffin embedded brainstem tissue (n=11) from SIDS and respective control cases, differential expression of heart and brain specific miR-1/miR-133 and miR-124a/let-7b, respectively, was determined using quantitative PCR analysis. Our results show a significant upregulation of heart specific miR-1 and brainspecific let-7b in SIDS compared to control cases. This pilot study is first to analyze differential miRNA expression in SIDS. Our findings suggest that organ specific miRNA dysregulation may be associated with SIDS pathogenesis and establishes the feasibility of miRNA analysis in different kinds of preserved and archived SIDS tissues.