Small heat-shock proteins function in the insoluble protein complex.
Small heat-shock proteins (sHSPs) represent an abundant and ubiquitous family of molecular chaperones. The current model proposes that sHSPs function to prevent irreversible aggregation of non-native proteins by forming soluble complex. The chaperone activity of sHSPs is usually determined by the capacity to suppress thermally or chemically induced protein aggregation. However, sHSPs were frequently found in the insoluble complex particularly in vivo. In this report, it is clearly revealed that the insoluble sHSP/substrate complex is formed when sHSP is overloaded with non-native substrates, which is the very case under in vivo conditions. The proposal that sHSPs function to prevent the protein aggregation seems misleading. sHSPs appear to promote the elimination of protein aggregates by incorporating into the insoluble protein complex.


The Problems Experienced by Parents Providing Postoperative Home Care Following Their Child's Surgery for Developmental Dysplasia of the Hip.
Families, especially mothers, experience problems providing home care after their child's surgery for developmental dysplasia of the hip (DDH). To assess the problems experienced by parents providing postoperative home care to their child after DDH surgery. This was a descriptive cross-sectional study. The sample consisted of 33 parents. Data were collected through a survey conducted at the hospital following the child's surgery and by telephone 4-6 weeks after surgery. Frequencies, means, percentages, and chi-square tests were used to analyze the data. The parents (93.9% women) provided postoperative care for approximately 3 months. Nearly all of the parents (97%) had physical (96.9%), psychological (65.6%), and social (75.0%) problems in addition to child care problems. We recommend preparing a comprehensive discharge-training package for parents after their child's DDH surgery, supplementing home care instructions with visual training materials, and providing telephone counseling to parents after discharge.


[Study of the relationships between the "locomotor regions" of the subthalamus and midbrain in rats].
Responses of single neurons in the midbrain tegmentum to stimuli applied to the subthalamic "locomotor region" were recorded extracellularly. In various units the latencies of responses were from 1 to 13 ms. Thresholds of the unit responses usually were not higher than the thresholds for eliciting locomotion. Obtained data evidence for a direct and oligosynaptic connections between subthalamic and midbrain "locomotor region".


Risk factors for tuberculin skin test conversion among HIV-infected patients in New York City.
We assessed the incidence of and risk factors for tuberculin skin test (TST) conversion among HIV-infected adults at a New York City clinic. All adult HIV-infected patients were eligible for inclusion if they had a negative baseline TST result and at least one subsequent documented TST test result. A total of 414 HIV-infected patients had a negative baseline TST result; 288 (69.6%) were male. Among 348 patients who had a place of birth documented, 50% were born outside of mainland USA. Twenty-two (5.3%) of 414 patients had documented TST conversions, giving a crude incidence rate of 1.77 per 100 person-years. Being a foreign-born Asian individual (p=0.02), having lived in a shelter (p=0.004), and having an increase in CD4 cell count (p=0.02) while under care were independent risk factors for TST conversion. We found a high TST conversion rate among HIV-infected patients attending an urban clinic. Annual TST testing is particularly important for patients who are foreign-born from high-endemic countries, those with a history of homelessness, and those with an increase in CD4 cell count since the baseline negative TST test.


Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis.
β-Thalassaemia results from defects in β-globin chain production, leading to ineffective erythropoiesis and subsequently to severe anaemia and other complications. Apoptosis and autophagy are the main pathways that regulate the balance between cell survival and cell death in response to diverse cellular stresses. Herein, the death of erythroid lineage cells in the bone marrow from both βIVS2-654-thalassaemic mice and β-thalassaemia/HbE patients was investigated. Phosphatidylserine (PS)-bearing basophilic erythroblasts and polychromatophilic erythroblasts were significantly increased in β-thalassaemia as compared to controls. However, the activation of caspase 8, caspase 9 and caspase 3 was minimal and not different from control in both murine and human thalassaemic erythroblasts. Interestingly, bone marrow erythroblasts from both β-thalassaemic mice and β-thalassaemia/HbE patients had significantly increased autophagy as shown by increased autophagosomes and increased co-localization between LC3 and LAMP-1. Inhibition of autophagy by chloroquine caused significantly increased erythroblast apoptosis. We have demonstrated increased autophagy which led to minimal apoptosis in β-thalassaemic erythroblasts. However, increased PS exposure occurring through other mechanisms in thalassaemic erythroblasts might cause rapid phagocytic removal by macrophages and consequently ineffective erythropoiesis in β-thalassaemia.


A review of ethylphenidate in deaths in east and west Scotland.
Ethylphenidate is a psychostimulant and analogue of methylphenidate. Interestingly it is also produced as a metabolite from the co-ingestion of methylphenidate and alcohol (ethanol). In the UK, between April and June 2015, ethylphenidate and 6 other methylphenidate based novel psychoactive substances (NPS) were subjected to a temporary class drug order under the Misuse of Drugs Act 1971. Ethylphenidate is being abused by both novel and habitual drug users, more prominently in the East of Scotland. What is unknown in the literature is the contribution of ethylphenidate in deaths. A search was conducted for an 18 month period (July 2013 to December 2014) to identify cases where ethylphenidate was detected during post-mortem toxicological analysis. Nineteen cases were identified and these cases were examined with regards to case circumstances, pathology findings, toxicology results and adverse effects. The individuals ranged in age from 20 to 54 (median 37) and the majority were male (n=14) and from the East of Scotland (n=16), more specifically Edinburgh and surrounding area. Current or previous heroin abuse was a common theme in these cases (n=16) and injection was a common route of administration of "legal highs" or "burst". The concentration of ethylphenidate in the cases ranged from 0.008 mg/L to over 2 mg/L in post-mortem femoral blood (median 0.25 mg/L, average 0.39 mg/L). Other drugs commonly detected were benzodiazepines (n=15), followed by opiates (n=11, 4 of which were positive for 6-monoacetylmorphine) and then methadone (n=8). All 19 cases received a full post-mortem examination and there were 10 cases where drug toxicity was the sole or potentially contributory factor to the cause of death. Ethylphenidate was specifically mentioned in the cause of death for 5 cases, chronic intravenous (IV) drug use was named as part of the cause of death for 2 cases and in 6 cases there was evidence of complications and infections through IV drug use. As far as it is known to the authors, this is the first review of post-mortem cases involving the use of ethylphenidate in East and West Scotland. This study can be used as a guide for toxicologists and pathologists when interpreting cases which are positive for ethylphenidate.


Abnormal uterine artery remodelling in the stroke prone spontaneously hypertensive rat.
The stroke prone spontaneously hypertensive rat (SHRSP) is an established model of human cardiovascular risk. We sought to characterise the uteroplacental vascular response to pregnancy in this model and determine whether this is affected by the pre-existing maternal hypertension. Doppler ultrasound and myography were utilised to assess uterine artery functional and structural changes pre-pregnancy and at gestational day 18 in SHRSP (untreated and nifedipine treated) and in the normotensive Wistar-Kyoto (WKY) rat. Maternal adaptations to pregnancy were also assessed along with histology and expression of genes involved in oxidative stress in the placenta. SHRSP uterine arteries had a pulsatile blood flow and were significantly smaller (70906 ± 3903 μm(2) vs. 95656 ± 8524 μm(2) cross-sectional area; p < 0.01), had a significant increase in contractile response (57.3 ± 10.5 kPa vs 27.7 ± 1.9 kPa; p < 0.01) and exhibited impaired endothelium-dependent vasorelaxation (58.0 ± 5.9% vs 13.9 ± 4.6%; p < 0.01) compared to WKY. Despite significant blood pressure lowering, nifedipine did not improve uterine artery remodelling, function or blood flow in SHRSP. Maternal plasma sFLT-1/PlGF ratio (5.3 ± 0.3 vs 4.6 ± 0.1; p < 0.01) and the urinary albumin/creatinine ratio (1.9 ± 0.2 vs 0.6 ± 0.1; p < 0.01) was increased in SHRSP vs WKY. The SHRSP placenta had a significant reduction in glycogen cell content and an increase in Hif1α, Sod1 and Vegf. We conclude that the SHRSP exhibits a number of promising characteristics as a model of spontaneous deficient uteroplacental remodelling that adversely affect pregnancy outcome, independent of pre-existing hypertension.


NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells.
Nucleophosmin (NPM), a multifunctional nucleolar phosphoprotein is dysregulated in human malignancies leading to anti-apoptosis and inhibition of differentiation. We evaluated the precise three-dimensional structure of NPM based on the highly conserved structure of Xenopus NO38 and its requirement to form dimers and pentamers via its N-terminal domain (residues, 1-107). We hypothesized that a small molecular inhibitor (SMI) that could disrupt the formation of dimers would inhibit aberrant NPM function(s) in cancer cells. Molecular modeling, pharmacophore design, in silico screening and interactive docking identified NSC348884 as a putative NPM SMI that disrupts a defined hydrophobic pocket required for oligomerization. NSC348884 inhibited cell proliferation at an IC(50) of 1.7-4.0 muM in distinct cancer cell lines and disrupted NPM oligomer formation by native polyacrylamide gel electrophoresis assay. Treatment of several different cancer cell types with NSC348884 upregulated p53 (increased Ser15 phosphorylation) and induced apoptosis in a dose-dependent manner that correlated with apoptotic markers: H2AX phosphorylation, poly(ADP-ribose) polymerase cleavage and Annexin V labeling. Further, NSC348884 synergized doxorubicin cytotoxicity on cancer cell viability. The data together show that NSC348884 is an SMI of NPM oligomer formation, upregulates p53, induces apoptosis and synergizes with chemotherapy. Hence, an SMI to NPM may be a useful approach to anticancer therapy.


Two distinct amplification events of the c-myc locus in a colorectal tumour.
Southern hybridisation of genomic DNA extracted from a human primary colorectal carcinoma revealed amplification of a fragment containing the wild-type c-myc locus. Two additional rearranged DNA fragments, lying upstream of c-myc, fused to distant non-contiguous sequences from the same chromosome, with an opposite configuration (head to head vs. head to tail), were also found to be amplified. Sequences analysis suggested that these rearrangements resulted from illegitimate recombination at two distinct points within the DNA sequence just upstream of the c-myc ORF and further that these events triggered two different amplification mechanisms, only one of which, involving a strand invasion event following DNA double strand breaks, increased the copy number of the c-myc ORF.


Deep learning in cancer pathology: a new generation of clinical biomarkers.
Clinical workflows in oncology rely on predictive and prognostic molecular biomarkers. However, the growing number of these complex biomarkers tends to increase the cost and time for decision-making in routine daily oncology practice; furthermore, biomarkers often require tumour tissue on top of routine diagnostic material. Nevertheless, routinely available tumour tissue contains an abundance of clinically relevant information that is currently not fully exploited. Advances in deep learning (DL), an artificial intelligence (AI) technology, have enabled the extraction of previously hidden information directly from routine histology images of cancer, providing potentially clinically useful information. Here, we outline emerging concepts of how DL can extract biomarkers directly from histology images and summarise studies of basic and advanced image analysis for cancer histology. Basic image analysis tasks include detection, grading and subtyping of tumour tissue in histology images; they are aimed at automating pathology workflows and consequently do not immediately translate into clinical decisions. Exceeding such basic approaches, DL has also been used for advanced image analysis tasks, which have the potential of directly affecting clinical decision-making processes. These advanced approaches include inference of molecular features, prediction of survival and end-to-end prediction of therapy response. Predictions made by such DL systems could simplify and enrich clinical decision-making, but require rigorous external validation in clinical settings.


[Postoperative nausea and vomiting (PONV). Clinical significance, basic principles, prevention and therapy].
The incidence of postoperative nausea and vomiting (PONV) of in- and outpatient surgical patients is about 30% (range 2-45%). Based on etiology, anatomy and physiology, this review article provides a critical evaluation of the present PONV literature with the aim of outlining current prophylaxis and treatment strategies. PONV is often associated with postoperative pain and its treatment. Patients are often more compromised by PONV than by postoperative pain. Surveys demonstrate that 78% of the surgeons consider PONV to be a relevant problem in clinical practice; 82% argue for better management of PONV. However, only 28% of the general surgical patients with PONV received sufficient antiemetic therapy. Studies demonstrate that the prophylactic use of antiemetics in patients at risk can lead to complete symptom control in 85% of the cases. Combination therapy of different antiemetic strategies can further increase the rate up to 96%. There is a need for surgeons to pay more attention to patient-related symptoms.


[Systemic lupus erythematosus in the elderly].
Late-onset systemic lupus erythematosus (SLE) usually appears in patients older than 65 years and has clinical features different from the classical form observed in younger patients. In the elderly, SLE represents 10-20% of all SLE cases, shows a different and less aggressive clinical evolution and the first manifestations are non-specific. A significantly higher incidence of late-onset SLE in males, and the fact that postmenopausal women have a more benign disease, suggests that the estrogenic status may influence the activity of the disease. Owing to the insidious onset and the non-specific clinical manifestations on presentation, there is commonly a delayed diagnosis of late-onset SLE. Furthermore, the presence of comorbidities and concomitant therapies in elderly patients may limit the therapeutic options for SLE. The treatment of choice of joint symptoms and serositis includes non-steroidal anti-inflammatory drugs and low-dose steroids for short periods. In addition to the need for adopting a multidisciplinary approach, it is fundamental to obtain information about the functional, cognitive and social status of these patients in order to make appropriate healthcare decisions.


Histologic distinction between malignant mesothelioma, benign pleural lesion and carcinoma metastasis. Evaluation of the application of morphometry combined with histochemistry and immunostaining.
Thirty men and 7 women with malignant mesothelioma seen at the Free University Hospital from 1st January 1960 until 1st July 1981 were reviewed. The histological, histochemical and morphometrical findings are reported. These findings are compared with 25 cases of pleural metastatic carcinoma and 25 cases of reactive pleural lesions. Fourty-nine percent of malignant mesotheliomas produced hyaluronic acid, however all cases of pleural metastatic carcinomas failed to produce this substance. All cases of malignant mesothelioma were D-PAS negative while 15 cases of pleural metastatic carcinoma showed reactivity to D-PAS. All cases of malignant mesothelioma and 9 cases of metastases were CEA negative. To distinguish malignant mesothelioma from metastases it is advisable to perform the D-PAS staining first. If it is negative mesothelioma can be confirmed by showing hyaluronic acid activity. A positive CEA staining rules out mesothelioma. In our study it was shown that with these methods 18 of 37 mesotheliomas could be identified with certainty, and 22 of the 25 carcinoma metastases. Morphometrically the malignant mesotheliomas could not be distinguished from the metastases, however the reactive pleural lesions had smaller nuclei than the malignant cells with mean values below 30 mu2. In the malignant cases these values had a range from 36 to 101 mu2. In distinguishing between reactive pleural lesions and malignant mesothelioma the production of hyaluronic acid points to the malignant character of the lesion. Thus histochemistry and immunostaining are important in the distinction of malignant mesothelioma from metastases, while the value of morphometry lies mainly in the seperation of reactive lesions from malignant mesothelioma.


Chronic invasive monitoring for identifying seizure foci in children.
In both children and adults, it has been well established that the precise localization of a seizure focus allows for the best possible resection and outcome. Long-term invasive monitoring with DE has been the most widely used modality to evaluate patients with intractable seizures of temporal lobe origin. The study of epilepsy in children, however, requires assessment of the cause of the seizures with a resultant decision regarding the optimal modality of study for the particular problem. Complex partial seizures of medial temporal lobe origin without clear concordance or lateralizing information are best studied using DE. With MR imaging anatomic localization, stereotactic insertion of DE can be performed accurately and relatively safely. The information obtained permits lateralization and focus localization if the lesion is within the medial structures. The ability of DE to study epilepsy outside of the medial temporal lobe, however, is suboptimal. Many centers have used surface electrodes to map temporal lobe foci successfully. SE and SGE have not been widely used in children. Subdural electrode arrays, however, are superior to DE in extratemporal epilepsy because the cortical surface contacts provide the best recordings of epileptiform activity from a wide range of extratemporal regions. The limitations of intraoperative ECoG in the awake child are well understood. It is rare that a child can undergo surgery under local anesthesia and cooperate to the extent necessary for definitive mapping of the seizure focus and eloquent areas. Thus, invasive long-term monitoring would seem ideal in the epileptic pediatric patient because it allows for a more relaxed pace in which to record events, and because of the indwelling nature of these electrodes, it is possible for the investigator to map eloquent areas of the brain before resection. This type of evaluation completely and accurately maps interictal and ictal activity, and through cortical stimulation or mapping of somatosensory areas by evoked potentials, eloquent areas of the brain, such as motor and speech regions, can be identified. This method is limited to older children because the young child often has inadequate cortical development to localize these areas definitively. One should note that in young children (under the age of 4 years), the absence of a response to standard cortical stimulation does not indicate nonfunctional cortex. Long-term intractable seizures and significant antiepileptic drug requirements may contribute to developmental and psychosocial deficiencies in the epileptic patient.(ABSTRACT TRUNCATED AT 400 WORDS)


Optimisation of acid fast smears for the direct detection of mycobacteria in clinical samples.
Despite its long history, the acid fast smear remains unstandardised. Technical variations in both the preparation of clinical material and subsequent staining mean that smear sensitivity relative to culture may vary from 50% to over 80%. This study assessed the sensitivity of acid fast microscopy at each of five stages of sample preparation and by both commonly used staining methods. Sputum samples thought for varying reasons to be highly likely to be culture positive were used to prepare a series of smears in which the effects of digestion (liquefaction), concentration (centrifugation), and decontamination (sodium hydroxide) could be assessed, together with a comparison of staining by the auramine/phenol and Ziehl-Neelsen techniques. The most effective method for the demonstration of acid fast organisms in sputum was found to be an auramine phenol stain applied to a liquefied, concentrated sample and examined before the decontamination process. The auramine phenol stain applied to a liquefied, concentrated sample and examined before the decontamination process is the most effective method for the demonstration of acid fast organisms in sputum.


Solar ultraviolet radiation cataract.
Despite being a treatable disease, cataract is still the leading cause for blindness in the world. Solar ultraviolet radiation is epidemiologically linked to cataract development, while animal and in vitro studies prove a causal relationship. However, the pathogenetic pathways for the disease are not fully understood and there is still no perfect model for human age related cataract. This non-comprehensive overview focus on recent developments regarding effects of solar UV radiation wavebands on the lens. A smaller number of fundamental papers are also included to provide a backdrop for the overview. Future studies are expected to further clarify the cellular and subcellular mechanisms for UV radiation-induced cataract and especially the isolated or combined temporal and spatial effects of UVA and UVB in the pathogenesis of human cataract. Regardless of the cause for cataract, there is a need for advances in pharmaceutical or other treatment modalities that do not require surgical replacement of the lens.


Comparative proteomics dataset of skimmed milk samples from Holstein and Jersey dairy cattle.
Milk samples were collected from Holstein and Jersey breeds of dairy cattle maintained under the same management practices and environmental conditions over a seven-day period. Milk samples were collected twice daily from six cows of each breed as previously described (Tacoma et al., 2016) [1]. Samples were composited within individual cow over the experimental period and skimmed to remove the fat layer. Skimmed milk samples were fractionated using CaCl2 precipitation, ultracentrifugation and ProteoMiner treatment to remove the high abundance milk proteins. Separation of the low abundance proteins was achieved using SDS-PAGE. Differential protein abundances were analyzed by mass spectrometry-based proteomic approaches followed by statistical analyses of the peptide count data. The complete list of low-abundance proteins identified in both breeds is provided in the dataset as well as the total number of distinct sequenced peptides and gene ontology functions for each protein. The relative abundance of a select few proteins is depicted using the SIEVE software.


Clinical features of spinal muscular atrophy (SMA) type 3 (Kugelberg-Welander disease).
Spinal muscular atrophy type 3 (SMA3), also called Kugelberg-Welander SMA, typically presents with muscle fatigue, slowly progressive weakness and atrophy of lower limbs once they have already acquired independent ambulation. Visceral involvement frequent in type 1 and 2 subtypes is rare in SMA3. Hypotonia, hyperlaxity and absent osteo-tendinous reflexes are typical features. By definition, standing or walking without support is achieved but the vast majority of SMA3 patients lose ambulation with time. Lifespan is normal. In some classifications, an additional subtype is included in the mild end of the spectrum, namely spinal muscular atrophy type 4 (SMA4). In this rare subtype, symptoms begin in adulthood; patients remain ambulatory at least until the fifth decade and have a normal respiratory function. Molecular genetic testing is the gold standard tool for diagnosis of SMA. However, diagnosis in a child affected with SMA3 is often challenging because clinical presentation mimics a muscular dystrophy. Electrodiagnostic studies and muscle biopsy are useful tools for demonstrating the presence of denervation but sometimes may not show meaningful differences to help distinguish between SMA and myopathy. Recent specific therapies show promising results before severe neuronal degeneration and motor dysfunction is installed. Therefore, high suspicion should be maintained and genetic analysis performed early in the diagnostic process when facing patients with symmetric and prominent proximal weakness, especially if they present progressive motor impairment. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.


Factorial kriging and stepwise regression approach to identify environmental factors influencing spatial multi-scale variability of heavy metals in soils.
The knowledge about spatial variations of heavy metals in soils and their relationships with environmental factors is important for human impact assessment and soil management. Surface soils from Rizhao city, Eastern China with rapid urbanization and industrialization were analyzed for six key heavy metals and characterized by parent material and land use using GIS-based data. Factorial kriging analysis and stepwise multiple regression were applied to examine the scale-dependent relationships among heavy metals and to identify environmental factors affecting spatial variability at each spatial scale. Linear model of coregionalization fitting showed that spatial multi-scale variation of heavy metals in soils consisted of nugget effect, an exponential structure with the range of 12 km (short-range scale), as well as a spherical structure with the range of 36 km (long-range scale). The short-range variation of Cd, Pb and Zn were controlled by land use, with higher values in urban areas as well as cultivated land in mountain area, and were related to human influence; while parent material dominated the long structure variations of these elements. Spatial variations of Cr and Ni were associated with natural geochemical sources at short- and long-range scales. At both two scales, Hg dominated by land use, corresponded well to spatial distributions of urban areas, and was attributed to anthropic emissions and atmosphere deposition.


Grooming Behavior as a Mechanism of Insect Disease Defense.
Grooming is a well-recognized, multipurpose, behavior in arthropods and vertebrates. In this paper, we review the literature to highlight the physical function, neurophysiological mechanisms, and role that grooming plays in insect defense against pathogenic infection. The intricate relationships between the physical, neurological and immunological mechanisms of grooming are discussed to illustrate the importance of this behavior when examining the ecology of insect-pathogen interactions.


Using FACS to trace the neural specializations underlying the recognition of facial expressions: A commentary on Waller et al. (2020).
In the recent review by Waller et al. (2020) the authors discuss how the Facial Action Coding System (FACS) can be used to study the evolution of facial behaviors. This is a timely and thought-provoking review which highlights the numerous ways in which FACS could be used to compare the mechanisms responsible for the production of facial behaviors across species. We propose that FACS could also be used to study the recognition of facial behaviors in nonhuman subjects where one of the key challenges is finding suitable stimuli that convey different emotions. By using FACS-rated images in awake neuroimaging experiments, researchers could accurately identify the brain mechanisms responsible for recognizing expressions across mammalian species. This approach would reveal neural homologs and deepen our understanding of how nonverbal social communication has evolved.


Highly efficient enzymatic preparation of c-di-AMP using the diadenylate cyclase DisA from Bacillus thuringiensis.
Cyclic 3',5'-diadenosine monophosphate (c-di-AMP) is a newly recognized bacterial nucleotide second messenger molecule. In addition, it has been shown to be a potential vaccine adjuvant. Although multiple methods are available for c-di-AMP synthesis, the yields are low and the purification procedures are laborious. Here, we report an enzymatic method for more efficient and economical c-di-AMP synthesis using a diadenylate cyclase DisA from Bacillus thuringiensis BMB 171 (btDisA). After overexpression and purification of btDisA, the enzyme-catalyzed reaction conditions were further investigated. Under the optimum conditions, in which 100mM CHES (pH 9.5) containing 2μM btDisA, 10mM ATP, and 10mM MgCl2 was incubated at 50°C for 4h, a high conversion rate of c-di-AMP was obtained. Coupling this process with HPLC purification and lyophilization yielded 100mg of highly pure c-di-AMP that was harvested in white powder form from a 50mL enzyme-catalyzed reaction system. The protocol is not only directly applicable for preparing abundant amounts of c-di-AMP for extensive biochemical and immunological use, but can also be scaled up to meet the requirements for medical applications.


High Performance Polarization-Resolved Photodetectors Based on Intrinsically Stretchable Organic Semiconductors.
Polarization-sensitive photodetectors based on anisotropic semiconductors sense both the intensity and polarization state information without extra optical components. Here, a self-powered organic photodetector (OPD) composed of intrinsically stretchable polymer donor PNTB6-Cl and non-fullerene acceptor Y6 is reported. The PNTB6-Cl:Y6 photoactive film accommodates a remarkable 100% strain without fracture, exhibiting a high optical anisotropy of 1.8 after strain alignment. The resulting OPD not only shows an impressive faint-light detection capability (high spectral responsivity of 0.45 A W-1 and high specific detectivity of 1012 Jones), but also has a high anisotropic responsivity ratio of 1.42 under the illumination of parallel and traversed polarized light. To the best of the authors' knowledge, both the detector performance and polarization features are among the best-performing OPDs and polarization-sensitive photodetectors. As a proof-of-concept, polarization-sensitive OPDs are also utilized to set up a polarimetric imaging system and full-Stokes polarimeter. This work explores the potential of highly stretchable organic semiconductors for state-of-art polarization imaging and spectroscopy applications.


Stress Ulcer Prophylaxis in Hospitalized Patients, Subsequent Use in Primary Care, and Physicians' Opinions About Acid-Suppressive Therapy.
Stress ulcer prophylaxis (SUP) is not indicated in most hospitalized patients. This study determined the prevalence of the use of proton pump inhibitors (PPI) and histamine receptor 2 blockers (H2B) in hospitalized patients, continued PPI/H2B use after discharge, and physicians' opinions about SUP. A retrospective electronic chart review, as well as a national survey of residents and faculty in primary care residency programs to determine the appropriateness of SUP. Of 753 charts reviewed, 332 hospitalized patients with outpatient follow-up were included; 303 of them had either PPI or H2B ordered during hospitalization, but only 120 patients had an indication for SUP. Stepwise logistic regression results showed patients with a history of PPI/H2B use were 16.6 times more likely to receive SUP (odds ratio 16.6; 95% confidence interval 2.2-124.7). In addition, a PPI/H2B indication also significantly predicted SUP use (odds ratio 5.1; 95% confidence interval 1.2-22.2). A total of 171 completed surveys were received: 73% residents and 27% faculty. Only 24% reported being aware of SUP guidelines; 17% reported using electronic health record order set suggestions for SUP. More than 90% of hospitalized patients received SUP; less than half of them had an indication for needing SUP. A large number of patients discharged on PPI/H2B continued to receive it in the outpatient setting at 6 months follow-up. Only 24% of physicians reported using SUP based on guidelines. Physician education and evidence-based validation of electronic health record order sets are potential areas for improvement.


Relationship of noradrenergic locus coeruleus neurones to vestibulospinal reflexes.
The electrical activity of presumably noradrenergic locus coeruleus (LC) neurones was recorded in decerebrate cats during roll tilt of the animal at 0.15 Hz, +/- 10 degrees, leading to sinusoidal labyrinth stimulation. Among the tested units, some of which projected to the lumbosacral spinal cord, 56.7% responded to animal tilt. Most of these neurones were activated during side-up and depressed during side-down tilt of the animal, while a smaller proportion of units showed the opposite response pattern. This predominant response pattern of LC neurones and coeruleospinal (CS) neurones to animal tilt was opposite in activation polarity to that of vestibulospinal (VS) neurones projecting to the same segments of the spinal cord. Both the VS and the CS neurones exert a direct excitatory influence on ipsilateral limb extensor motoneurones. However, VS neurones excite corresponding Renshaw (R) cells, though due to activation of limb extensor motoneurones and their recurrent collaterals, the CS neurones may inhibit them. It appears, therefore, that during side-down animal tilt, the motoneurones innervating the ipsilateral limb extensors are excited by the increased discharge of VS neurones, while the corresponding R-cells are disinhibited due to the reduced discharge of CS neurones. The functional coupling between ipsilateral limb extensor motoneurones and the corresponding R-cells would then increase, just at the time in which these motoneurones are driven by the excitatory VS volleys, thus limiting the response gain of limb extensors to labyrinth stimulation. This hypothesis is supported by two facts: (1) R-cells linked with limb extensor motoneurones discharge during side-down tilt, thus firing in phase with the excitatory VS volleys, and (2) functional inactivation of the noradrenergic LC neurones increases the gain of the vestibulospinal reflexes acting on limb extensors.


Asymptomatic hyperuricemia: is it time to intervene?
Whether to treat hyperuricemia uncomplicated by articular gout, urolithiasis, or uric acid nephropathy is an exercise in clinical judgment and universal agreement is lacking. Patients with coronary artery disease, chronic kidney disease, and early onset hypertension with persistent hyperuricemia are likely to be benefited with urate-lowering therapy. The paradigm of the causative association of hyperuricemia with cardiovascular and chronic kidney diseases seems to have progressed from skepticism to increasing evidence of a true relationship. Although such evidences are mounting, they are not enough to support pharmacotherapy for all patients with asymptomatic hyperuricemia. Further studies are needed to determine which patients are likely to get beneficial effects from pharmacotherapy and the minimum threshold of uric acid level required to experience clinical benefits.


Getting Access to Low-Complexity Domain Modifications.
Low-complexity (LC) domains regulate the aggregation and phase transition of proteins in a modification-dependent manner. The study of LC domain modifications has now become feasible, as shown by genetic variants of the carboxy-terminal domain (CTD) of RNA Polymerase II (Pol II) that provide access to the type and position of modifications of a LC domain by mass spectrometry (MS).


Influence of family history and smoking habits on the incidence of self-reported physician's diagnosis of COPD.
The incidence of chronic obstructive pulmonary disease (COPD) is little investigated. This study assessed the incidence of a self-reported physician's diagnosis of chronic bronchitis and/or emphysema (CBE) and/or COPD (CBE/COPD), and investigated the effects of a family history of CBE in 1992 and change in smoking habits (assessed in 1992 and 2000) on this incidence. A follow-up study in 2000 of 4933 subjects who responded to a respiratory questionnaire study in 1992 was performed. Response rate was 86.8%. Odds ratios (ORs) for incident cases of CBE/COPD were calculated by multiple Logistic regression. The cumulative incidence of a physician's diagnosis of CBE/COPD was 2.9%. A family history of CBE predicted incident cases of CBE/COPD, OR 2.7 (95% CI 1.5-5.1). Also continuous smoking, relapse into smoking, or having stopped smoking between 1992 and 2000 had elevated ORs for incident cases of CBE/COPD, 2.6 (1.4-4.7), 7.2 (2.7-18.7), and 2.6 (1.3-5.3), while the OR for ex-smoking in 1992 as well as 2000 was 0.9 (0.4-1.8). A family history of CBE increases the risk for development of CBE/COPD. Sustained smoking cessation over many years may be required to significantly reduce the risk of developing CBE/COPD.


Notch3 signaling initiates choroid plexus tumor formation.
Notch3 has been studied in the context of brain development, but whether it plays a role in the formation of brain tumors is unclear. We demonstrate that the introduction of constitutively active Notch3 into periventricular cells of embryonic day 9.5 mice causes the formation of choroid plexus tumors (CPTs). Tumors arose in the fourth ventricles in 83% of animals and were associated with hydrocephalus. They were microscopically highly similar to choroid plexus papillomas in humans, with an ongoing proliferation rate of 4-6%. Signs of Notch pathway activity were also present in human choroid plexus lesions, and receptor mRNA levels in papillomas were elevated over those in non-neoplastic choroid plexus. Notch2 was overexpressed approximately 500-fold in one case, suggesting that the role of this pathway in CPTs may not be specific to Notch3. Our findings indicate that activated Notch3 can function as an oncogene in the developing brain, and link the Notch pathway to human CPT pathogenesis.


Overexpression of lncRNA Gm43050 alleviates apoptosis and inflammation response induced by sevoflurane treatment by regulating miR-640/ZFP91.
The present study investigated the function and mechanism of lncRNA Gm43050 in sevoflurane-induced abnormal cognition. Primary hippocampal neurons were used to establish the model of abnormal cognitive disorder. Overexpression and knockdown experiments were performed to analyze cell death rates, proliferation, apoptosis and the inflammatory response. The dual-luciferase reporter assay was used to analyze the potential binding targets of lncRNA Gm43050. Rescue experiments were used to assess the downstream targets of Gm43050. We found that lncRNA Gm43050 was in the cytoplasm. Overexpression of lncRNA Gm43050 had no impact on proliferation but significantly reduced the cell death rates and apoptosis. The inflammation markers IL-6, IL-1β, IL-8 and TNF-α were manifestly downregulated in the overexpression group. Opposite effects were detected in the lncRNA Gm43050 knockdown group. Bioinformatics analysis showed that miR-640 may be the potential target of Gm43050. Additionally, we found that ZFP91 was the downstream target of miR-640. We provided comprehensive data of the function and mechanism of lncRNA Gm43050 in abnormal cognition. Our study showed that lncRNA Gm43050 exerted its important role via the regulation of miR-640 and ZFP91.


Gastrointestinal hormone receptors in primary human colorectal carcinomas.
In this study, the prevalence and identity of the cells expressing functional receptors for the gastrointestinal (GI) peptide hormones: gastrin, bombesin, and neurotensin in dissociated cells from 20 freshly resected human primary colorectal carcinomas were determined. GI peptide hormone-induced increases in the concentration of free intracellular Ca(2+) ([Ca(2+)](i)) were used as an assay for the detection of functional receptors. Reverse-transcription polymerase chain reaction (RT-PCR) was performed in a subset of tumor samples. Agonist-responsive cells were identified as either of epithelial or stromal origin by immunocytochemistry with cytokeratin and vimentin antibodies, respectively. Overall, expression of GI peptide hormone receptors was more frequent in stromal cells when compared to epithelial cells. Of the three receptors, expression of bombesin receptor (95%) was most prevalent in vimentin-positive (stromal) cells; whereas, gastrin receptor expression by cytokeratin-positive (epithelial) cells was more common (39%). A single gastrin receptor splice variant differentially regulates [Ca(2+)](i) in a cell-type specific manner. The gastrin receptor-expression profile in the 11 colon cancer-derived cell lines did not reflect the prevalence of expression in primary human cancers. The Ca(2+) assay is a sensitive method for detecting functional GI peptide hormone receptor expression by colon cancer cells. Because this approach utilizes living cells, it is amenable to further functional analyses of signal transduction mechanisms at the single cell level. Importantly, our data provide a rationale for examining of the role of these GI peptide hormones and their cognate receptors in mesenchymal cell biology.


Interaction of tetrahydropapaveroline with inhibition of dopa-decarboxylase by Ro 4-4602 in brain: effects on alcohol drinking in the rat.
The effects of the 1-aromatic amino acid decarboxylase inhibitor, Ro 4-4602 (benserazide), was determined on alcohol drinking induced in the rat by tetrahydropapaveroline (THP) injected by the intracerebroventricular (ICV) route. After ICV guide cannulae were implanted stereotaxically in 19 Sprague-Dawley rats, an artificial CSF solution containing 5.0 ng/micrograms THP was infused twice daily for 3 days in a volume of 5.0 microliters. Following a standard self-selection procedure, concentrations of alcohol which ranged from 3-30% were presented to the rats. A single maximally preferred solution, which in these rats ranged from 9-12% alcohol, was then offered in the presence of water. After a 4-day pretest in which alcohol intakes had stabilized, either 50 or 100 micrograms Ro 4-4602 plus THP were infused ICV to the animal during a 3-day period. Both doses of Ro 4-4602 significantly antagonized the g amount and proportional intakes of alcohol, but the higher dose was nearly twice as potent as the lower. During the 4-day postdrug test period, alcohol drinking continued to be suppressed. When THP was infused ICV over a 3-day period following the injections of Ro 4-4602, the predrug alcohol intake was partially reinstated, suggesting that this TIQ, when delivered directly into the brain, partly reversed the potent central action of Ro 4-4602. These results show that interference with the functional activity of central catecholamine pathways in the rat, by means of the inhibition of dopamine synthesis, serves to modify markedly the mechanisms underlying alcohol drinking in this species.(ABSTRACT TRUNCATED AT 250 WORDS)


Intracavernous methoxamine in the treatment of priapism.
Methoxamine is an alpha-adrenergic drug, its unique pharmacokinetics and mechanism of action on alpha-1 receptors lead to consider it, similarly to phenylephrine, as a first-choice drug for treating drug-induced or veno-occlusive priapism. The experience obtained with its use in the management of three cases of priapism lasting over 7 h and one case of sustained rigid erection caused during anesthetic induction are reported.


There is high incidence of skin cells in the first and third drops of cerebrospinal fluid in spinal anesthesia.
Skin fragments during lumbar punctures may develop intraspinal epidermoid tumors. The aim of this study was to determine the incidence of epithelial cells that reflow along with the first and third drops of CSF of patients undergoing spinal anesthesia. Samples of the first and third drops of cerebrospinal fluid were collected from 39 adult patients undergoing spinal anesthesia with a 25G Quincke needle. Four microscope slides were prepared: one for the first drop, one for third drop, one for the needle, and one with a drop of saline for control. A pathologist examined the slides randomly. Squamous epithelial cells were identified in 35 (89.7%) samples from the first drop, 34 (87.2%) from the third drop, and 24 (61.5%) from spinal needle. The third drop showed a mean number of cells larger than the first drop (p=0.046). Nucleated epithelial cells were found in a sample of the first drop (2.56%), in four samples of third drop (10.25%), and in one spinal needle (2.56%). Third drop showed a mean number of nucleated cells higher than first drop with no statistical difference (p=0.257). High percentage of epithelial cells was found in the first (89.7%) and third (87.2%) drops of CSF reflow and in used needles (61.5%). Skin cells were found even using small gauge disposable needles with well-adapted mandrel.


Secretory expression of β-mannanase in Saccharomyces cerevisiae and its high efficiency for hydrolysis of mannans to mannooligosaccharides.
Degradation of mannans is a key process in the production of foods and prebiotics. β-Mannanase is the key enzyme that hydrolyzes 1,4-β-D-mannosidic linkages in mannans. Heterogeneous expression of β-mannanase in Pichia pastoris systems is widely used; however, Saccharomyces cerevisiae expression systems are more reliable and safer. We optimized β-mannanase gene from Aspergillus sulphureus and expressed it in five S. cerevisiae strains. Haploid and diploid strains, and strains with constitutive promoter TEF1 or inducible promoter GAL1, were tested for enzyme expression in synthetic auxotrophic or complex medium. Highest efficiency expression was observed for haploid strain BY4741 integrated with β-mannanase gene under constitutive promoter TEF1, cultured in complex medium. In fed-batch culture in a fermentor, enzyme activity reached ~ 24 U/mL after 36 h, and production efficiency reached 16 U/mL/day. Optimal enzyme pH was 2.0-7.0, and optimal temperature was 60 °C. In studies of β-mannanase kinetic parameters for two substrates, locust bean gum galactomannan (LBG) gave Km = 24.13 mg/mL and Vmax = 715 U/mg, while konjac glucomannan (KGM) gave Km = 33 mg/mL and Vmax = 625 U/mg. One-hour hydrolysis efficiency values were 57% for 1% LBG, 74% for 1% KGM, 39% for 10% LBG, and 53% for 10% KGM. HPLC analysis revealed that the major hydrolysis products were the oligosaccharides mannose, mannobiose, mannotriose, mannotetraose, mannopentaose, and mannohexaose. Our findings show that this β-mannanase has high efficiency for hydrolysis of mannans to mannooligosaccharides, a type of prebiotic, suggesting strong potential application in food industries.


Geographical and temporal origins of Neocaridina species (Decapoda: Caridea: Atyidae) in Taiwan.
The freshwater species on Taiwan Island have been documented to have originated from mainland China and the Japanese islands from multiple events and by multiple colonization routes. Moreover, the sequences from the mitochondrial DNA cytochrome c oxidase subunit I (COI) have been used for DNA barcoding to identify the species. This study used the COI sequences to identify Neocaridina species in Taiwan and to examine their geographical and temporal origins. In total, 479 specimens were collected from 35 localities, which covered almost all rivers in Taiwan. In addition, some sequences were downloaded from GenBank. The maximum likelihood (ML) tree displayed that all sequences were sorted into 13 taxa (clades), and all sequences in Taiwan were sorted into four clades. The Bayesian skyline plots revealed that these four Neocaridina species have declined recently in Taiwan. All results support that (1) there are four Neocaridina species in Taiwan, which are N. davidi, N. saccam, N. ketagalan and an undescribed Neocaridina species (N. sp.); (2) these four species colonized Taiwan Island in four colonization events; (3) N. sp. colonized Taiwan first; (4) after the island reached its shape, N. ketagalan and N. saccam colonized Taiwan from the Japanese islands and mainland China, respectively; (5) N. davidi colonized northern Taiwan last; and (6) the cyclic glacial and landform changes in East Asia shaped the colonization events and population structures of the Neocaridina species.


Selective inhibition of STAT3 phosphorylation by sodium salicylate in cardiac fibroblasts.
The effects of salicylate on the phosphorylation and nuclear translocation of signal transducers and activators of transcription (STATs) induced by interferon-gamma (IFN-gamma) were studied in rat cardiac fibroblasts as a possible model for the anti-inflammatory effects of salicylate on this signaling pathway. Salicylate inhibited the tyrosine phosphorylation of both STAT1 and STAT3, but had a more pronounced effect on STAT3 activation. Salicylate pretreatment prevented both the nuclear translocation and the DNA-binding activity of STAT1 and STAT3, assessed by immunoblotting and gel shift assays, respectively. In addition to causing phosphorylation at tyrosine residues, IFN-gamma also phosphorylated STAT3 and STAT1 at serine 727. Salicylate attenuated both tyrosine and serine phosphorylations of STAT3, and also suppressed extracellular signal-regulated kinase (ERK) activation, implicating the effect of salicylate on ERK as a possible mechanism for attenuating STAT3 activation. The possibility that salicylate might affect signaling cascades by altering the redox state of the cells was examined, and its effects differed from those of other reducing agents. Salicylate did attenuate the effects of hydrogen peroxide on STAT phosphorylation, consistent with a mechanism involving an interaction between salicylate and reactive oxygen species within the cell.


A novel immunoglobulin G monolayer silver bio-nanocomposite.
Nanoparticles have a large number of surface atoms, which translates into a significant increase in the surface energy. Once introduced in a biological environment they tend to interact with proteins and form a protein corona shell. The aim of this study was to develop a novel, silver based, bio-nanocomposite for biological applications. Immunoglobulin G (IgG) molecule was chosen for the passivation of the silver nanoparticles (AgNPs) in order to avoid macrophage recognition of the synthesized structures. Monodisperse IgG-folinate functionalized silver nanoparticles were obtained, with sizes around 39 nm. UV-Vis and UATR-FT-IR spectroscopies were employed to confirm the successful functionalization of the silver nanoparticles. Atomic force microscopy and dynamic light scattering measurements gave information about the size and shape of the nanoparticles prior and after the passivation with IgG. Immunoglobulin G formed a monolayer around the nanoparticles with the binding site seemingly in the Fc domain, leaving the two Fab regions available for antigen binding. To our knowledge, this is the first report of an IgG-folinate functionalized AgNP bionanostructure developed for biological applications. Graphical abstract:Graphical illustration for IgG-folinate silver nanoparticles functionalization steps.


The paradox of paclitaxel neurotoxicity: Mechanisms and unanswered questions.
Paclitaxel is a microtubule-binding compound that is widely used as a chemotherapeutic in the treatment of common cancers, including breast and ovarian cancer. Paclitaxel binding along the length of microtubules stabilizes them and suppresses their dynamics, leading to mitotic arrest and apoptosis in dividing cells. Though they are not dividing cells, neurons are also susceptible to paclitaxel, and paclitaxel exposure results in axonal degeneration. Thus a frequent side effect of paclitaxel treatment in patients is peripheral neuropathy, which can necessitate dose reductions and have lasting symptoms. An understanding of the mechanisms underlying paclitaxel's neurotoxicity is important for development of therapeutics to prevent and alleviate the neuropathy. Here we will review approaches taken to investigate mechanisms of paclitaxel-induced neuropathy and evidence for potential mechanisms of the axonal degeneration downstream of or distinct from microtubule stabilization by paclitaxel. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.


New approaches for the evaluation of pulmonary toxicity: bronchoalveolar lavage fluid analysis.
Analysis of bronchoalveolar lavage fluid (BAL) is an effective method of detecting an inflammatory response in the lungs of animals in toxicological studies. Alterations in BAL that are the most sensitive indications of an inflammatory response are an increased content of serum proteins and an influx of neutrophils (PMNs). Elevation of the cytoplasmic enzyme lactate dehydrogenase (LDH) is a useful indicator of cytotoxicity. The pulmonary inflammatory response to particles (either mineral dusts or soot) in the lung includes greatly increased activities of such lysosomal enzymes as beta-glucuronidase and beta-N-acetylglucosaminidase in BAL. Examination of alterations in BAL in rats and mice during chronic exposure to high levels of diluted diesel exhaust revealed that steadily increasing levels of LDH, beta-glucuronidase, and hydroxyproline in BAL correlated better with the development of pulmonary fibrosis than did measures of an inflammatory response (protein, PMNs). Analysis of BAL has proven useful, both for detection of lung injury in toxicological screening tests and for determination of the mechanisms of developing chronic lung disease. Future work shows promise of developing assays for BAL analysis to identify the specific site or type of pulmonary injury present.


Impact of oral preoperative and perioperative immunonutrition on postoperative infection and mortality in patients undergoing cancer surgery: systematic review and meta-analysis with trial sequential analysis.
Infectious complications occur in 4-22 per cent of patients undergoing surgical resection of malignant solid tumours. Improving the patient's immune system in relation to oncological surgery with immunonutrition may play an important role in reducing postoperative infections. A meta-analysis was undertaken to evaluate the potential clinical benefits of immunonutrition on postoperative infections and 30-day mortality in patients undergoing oncological surgery. PubMed, Embase and Cochrane Library databases were searched to identify eligible studies. Eligible studies had to include patients undergoing elective curative surgery for a solid malignant tumour and receiving immunonutrition orally before surgery, including patients who continued immunonutrition into the postoperative period. The main outcome was overall infectious complications; secondary outcomes were surgical-site infection (SSI) and 30-day mortality, described by relative risk (RR) with trial sequential analysis (TSA). Risk of bias was assessed according to Cochrane methodology. Some 22 RCTs with 2159 participants were eligible for meta-analysis. Compared with the control group, immunonutrition reduced overall infectious complications (RR 0·58, 95 per cent c.i. 0·48 to 0·70; I2 = 7 per cent; TSA-adjusted 95 per cent c.i. 0·28 to 1·21) and SSI (RR 0·65, 95 per cent c.i. 0·50 to 0·85; I2 = 0 per cent; TSA-adjusted 95 per cent c.i. 0·21 to 2·04). Thirty-day mortality was not altered by immunonutrition (RR 0·69, 0·33 to 1·40; I2 = 0 per cent). Immunonutrition reduced overall infectious complications, even after controlling for random error, and also reduced SSI. The quality of evidence was moderate, and mortality was not affected by immunonutrition (low quality). Oral immunonutrition merits consideration as a means of reducing overall infectious complications after cancer surgery.


PREVALENCE OF FALLS AND ASSOCIATED RISK FACTORS AMONG AGED POPULATION: COMMUNITY BASED CROSS-SECTIONAL STUDY FROM TURKEY.
The aim of the study was to examine the prevalence and risk factors of falls among persons aged 65 years and older in Qanakkale, Turkey. A community based cross-sectional study was conducted between May-September 2013. A total of 1,001 elderly living in Çanakkale city centre were included into our study. The research was carried out with face-to-face interviews and survey forms. The survey form consists of seven sections: demographic characteristics, significance of ageing, daily activities, quality of life and social network in old age, use of health services and health problems, bad habits, and the European Health Impact Scale. Data analysis was performed using the SPSS software version 19.0. For data investigation the chi-square and logistic regression analyses were used. The prevalence of falls at home or outside was 32.1% among elderly in the last six months period. The prevalence of falling for women at home as well as outside was statistically significantly higher than for men (p < 0.05). According to multivariate analysis results the risk of falling at home or outside was increased by 2.7 times in women (95% CI: 1.90-3.75), by. 2.1 times in those who cannot take care of themselves (95% Cl: 1.33-3.29), and by 1.7 times in those who have low quality of life (95% Cl: 1.24-2.43). This community based cross-sectional study showed that prevalence of falling was high in aged persons living in centre of Çanakkale located in the western part of Turkey. Moreover, the risk was increased in women, those who cannot take care for themselves, and those with low standard of living.


Interactions of some modified mono- and bis-beta-cyclodextrins with bovine serum albumin.
Two mono-substituted beta-cyclodextrins and two bridged bis-beta-cyclodextrins, that is, mono(6-(2-aminoethylamino)-6-deoxy)-beta-cyclodextrin (1), mono(6-(2-(2-aminoethylamino)ethylamino)-6-deoxy)-beta-cyclodextrin (2), ethylene-1,2-diamino bis-6-(6-deoxy-beta-cyclodextrin) (3), and iminodiethylene-2,2'-diamino bis-6-(6-deoxy-beta-cyclodextrin) (4), were prepared from beta-cyclodextrin. Their binding ability with bovine serum albumin as a model protein was investigated through proton magnetic resonance (1H NMR), ultraviolet visible spectroscopy (UV-vis), circular dichroism (CD), and fluorescence spectroscopy. In the 1H NMR spectra of the modified cyclodextrins, the resolution of proton signals decreases after the addition of BSA. From the UV and CD spectra, it is found that both the UV absorption and the alpha-helix content of BSA increase with the concentration of the modified cyclodextrins. The protein-ligand interactions cause a fluorescence quenching. The quenching constants are determined using the Stern-Volmer equation to provide an observation of the binding affinity between modified cyclodextrins and BSA. All these results indicate that the modified cyclodextrins can interact with BSA and the bridged bis(beta-cyclodextrin)s (3 and 4) have much stronger interactions than the mono-substituted beta-cyclodextrins (1 and 2). The strong binding stability of bis-cyclodextrins should be attributed to the cooperative effect of two adjacent cyclodextrin moieties. Job's plot shows that the complex stoichiometries of BSA to the modified cyclodextrins were 1:4 for 1 and 2, as well as 1:3 for 3 and 4, respectively.


Phase instability induced by polar nanoregions in a relaxor ferroelectric system.
Relaxor ferroelectrics are a special class of material that exhibit an enormous electromechanical response and are easily polarized with an external field. These properties make them attractive for applications as sensors and actuators. Local clusters of randomly oriented polarization, known as polar nanoregions (PNRs), are specific to relaxor ferroelectrics and play a key role in governing their dielectric properties. Here, we show through neutron inelastic scattering experiments that the PNRs can also significantly affect the structural properties of the relaxor ferroelectric Pb(Zn(1/3)Nb(2/3))O(3)-4.5%PbTiO(3) (PZN-4.5%PT). A strong interaction is found between the PNRs and the propagation of acoustic phonons. A comparison between acoustic phonons propagating along different directions reveals a large asymmetry in the lattice dynamics that is induced by the PNRs. We suggest that a phase instability induced by this PNR-phonon interaction may contribute to the ultrahigh piezoelectric response of this and related relaxor ferroelectric materials. Our results naturally explain the emergence of the various observed monoclinic phases in these systems.


Actions of insulin and hydrocortisone on macromolecular synthesis in primary epithelial cell cultures from mouse mammary glands.
Monolayer cultures of mammary gland epithelial cells were prepared from the abdominal glands of midpregnancy mice. After collagenase digestion of mammary tissue and separation by differential centrifugation, the isolated epithelial cells were cultured in Eagle's Minimal Essential Medium supplemented with 10% fetal bovine serum and insulin (6 micrograms/ml). Six days later, when the cultures were in log growth and nearly confluent, the effects of insulin and/or hydrocortisone on the rates of RNA, DNA, and protein synthesis were determined in a serum-free medium. At physiological concentrations, insulin enhanced the rates of uptake and incorporation of [3H]uridine into RNA, of [3H]thymidine into DNA, and of [3H]leucine into protein. Hydrocortisone was shown to be biphasic with regard to concentration in attenuating or augmenting insulin's effects on macromolecular synthesis.


Are micromegakaryocytes specific for refractory cytopenia of childhood (RCC)? A study of 38 pediatric patients with thrombocytopenia unrelated to RCC.
Micromegakaryocytes (microMKs) are considered the most reliable dysplastic feature for myelodysplastic syndrome (MDS), particularly refractory cytopenia of childhood (RCC); there is no minimal threshold for the diagnosis of RCC. Since most RCC patients present with thrombocytopenia, the presence of microMKs should raise concern for MDS/RCC. This study attempted to investigate the prevalence of microMKs and associated marrow fibrosis in patients with thrombocytopenia unrelated to MDS/RCC and the need for establishing a threshold for microMKs for the diagnosis of MDS/RCC. Bone marrow biopsies of pediatric patients with thrombocytopenia unrelated to RCC were examined for microMKs and fibrosis by CD61 immunohistochemical and reticulin stains respectively. Thirty eight patients (1-18 years old) were included: 33 immune thrombocytopenia (ITP), 3 chronic thrombocytopenia, and 2 inherited macrothrombocytopenia. Fourteen cases (37%) had microMKs; four cases showed increased marrow fibrosis associated with microMKs (two had ITP and two had macrothrombocytopenia). All patients are alive and none developed MDS (follow up: 3months to 4 years). MicroMKs can be seen in pediatric patients with thrombocytopenia unrelated to RCC. Hence the mere presence of microMKs is insufficient for the diagnosis of RCC in the pediatric population, and a quantitative threshold needs to be established.


Colorblind Algorithms: Racism in the Era of COVID-19.
This commentary offers a critique of the recent policy document issued by White et al. (2020) to guide critical care resource (e.g. ventilators) allocation during public health emergencies such as COVID-19. We argue that, if disseminated widely, this criteria would result in a racially inequitable resource distribution in the current COVID-19 crisis. We link the White et al. (2020) resource distribution protocol to other "colorblind" healthcare algorithms that have relied on seemingly objective but fundamentally biased data, thereby reinforcing and exacerbating pre-existing racial health disparities. We suggest a health equity framework to ensure unbiased distribution of critical care resources during COVID-19 and in general practice.


Ovarian endometrioma increases the embryo aneuploid rate: an analysis of 7092 biopsied blastocysts from fertile monogenetic disease carriers.
Endometriosis affects many reproductive aged patients with fertility decline and poor outcomes of assisted reproductive treatments, mainly by decreased ovarian reserve and lower fertilization and implantation rates. In recent decade, altered oocyte microenvironments and abnormal spindle organization have been reported to be critical to oocyte chromosomal segregation, organization and aneuploid formation. However, clinical evidences are still limited on whether endometriosis influences oocyte and embryo development. We aimed to figure out the impact of endometrioma on embryo aneuploid formation. This retrospective cohort study included 1,021 patients (7,092 biopsied embryos) from January 2012 to December 2020. Fertile patients without a history of miscarriage who underwent PGT-M treatment with aneuploid screening were included. Patients with ovarian endometrioma were defined as the study group, while patients without endometriosis were defined as the control group. All demographic, controlled ovarian stimulation treatment and aneuploid screening data were recorded and compared. The incidence of endometrioma in our study population was 6.5%. There were 7,092 embryos biopsied in total, with 308 embryos in the study group and 6,784 embryos in the control groups. The demographic characteristics were comparable between the two groups except the basal FSH level (6.02 IU/L vs. 5.52 IU/L, p = 0.012). The euploid rate of the study group was significantly lower than that of the control group (52.6% vs. 61.8%, p = 0.012), while the oocyte maturation, fertilization, usable embryo and blastocyst formation rates were comparable. Adjusted for basal FSH level, starting stimulating gonadotropin dosage, total gonadotropin dosage and FSH level on hCG day, euploid rate was still negatively related to endometrioma status. Endometrioma status disturbs oocyte and embryo development. For infertile patients with endometrioma who require assisted reproductive treatment, pre-treatment is necessary to improve treatment outcomes. Not applicable.


KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway.
Tumor metastasis is the main cause of death in advanced colorectal cancer. Our previous research showed that upregulation of KIAA1199 predicted poorer outcomes, and promoted cell motility and tumor metastasis in colorectal cancer, with the mechanisms not being fully elucidated. Here, we demonstrate that silencing of KIAA1199 results in reduced tumor metastasis in the orthotopic transplantation tumor model of colorectal cancer. Importantly, we find that KIAA1199 interacts with protein phosphatase 2A (PP2A) through the C-terminal domain and increases phosphatase activity of PP2A, which is essential for KIAA1199-mediated cell motility. Moreover, we identify stathmin, a microtubule-destabilizing protein, as a downstream of KIAA1199-PP2A complex. KIAA1199-induced dephosphorylation of stathmin results in microtubule destabilization and leads to enhanced cell motility. Furthermore, a microtubule-stabilizing drug paclitaxel could prevent KIAA1199-induced microtubule destabilization, and inhibit cell migration and invasion in vitro and tumor metastasis in vivo in colorectal cancer. Collectively, our study reveals that KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway, and suggests that KIAA1199 may be a promising target for preventing metastasis in colorectal cancer.


Extent of EEG monitoring for detecting epileptic spasms.
Epileptic spasms (ES) are the ictal manifestation of West syndrome. Due to poor interrater reliability in diagnosing hypsarrhythmia, identification of ES - ideally on video EEG monitoring - is important to start proper treatment. We retrospectively analyzed inpatient video EEG recordings of 42 patients with new onset ES and calculated the time needed to capture the first ES, along with time to first sleep epoch, among other data. The average time to capture ES was 188.36 min with a 95 percent confidence interval from 116.95 to 259.76 min. The average onset of sleep occurred at 30.8 min with 95% Confidence interval between 19.9 and 41.9 min. There was no significant correlation between duration of symptoms and etiology and the time needed to detect first spasm on EEG. Routine or short duration EEGs are not sufficient to capture ES in most patients. 4-5-hour VEEG monitoring duration should be considered to capture ictal data in patients suspected of having ES.


Deubiquitinase OTUD5 as a Novel Protector against 4-HNE-Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury.
Despite the development of advanced technologies for interventional coronary reperfusion after myocardial infarction, a substantial number of patients experience high mortality due to myocardial ischemia-reperfusion (MI/R) injury. An in-depth understanding of the mechanisms underlying MI/R injury can provide crucial strategies for mitigating myocardial damage and improving patient survival. Here, it is discovered that the 4-hydroxy-2-nonenal (4-HNE) accumulates during MI/R, accompanied by high rates of myocardial ferroptosis. The loss-of-function of aldehyde dehydrogenase 2 (ALDH2), which dissipates 4-HNE, aggravates myocardial ferroptosis, whereas the activation of ALDH2 mitigates ferroptosis. Mechanistically, 4-HNE targets glutathione peroxidase 4 (GPX4) for K48-linked polyubiquitin-related degradation, which 4-HNE-GPX4 axis commits to myocyte ferroptosis and forms a positive feedback circuit. 4-HNE blocks the interaction between GPX4 and ovarian tumor (OTU) deubiquitinase 5 (OTUD5) by directly carbonylating their cysteine residues at C93 of GPX4 and C247 of OTUD5, identifying OTUD5 as the novel deubiquitinase for GPX4. Consequently, the elevation of OTUD5 deubiquitinates and stabilizes GPX4 to reverse 4-HNE-induced ferroptosis and alleviate MI/R injury. The data unravel the mechanism of 4-HNE in GPX4-dependent ferroptosis and identify OTUD5 as a novel therapeutic target for the treatment of MI/R injury.


Acute Hospital Outcomes for Renal Transplantation in Patients With Moderate or Severe Congenital Heart Disease.
Children and adults with congenital heart disease (CHD) are increasingly recognized to be at risk for acute and chronic renal injury. Some of these may progress to the need for renal transplantation. We hypothesized that patients with underlying moderate or severe CHD who undergo renal transplantation will have worse acute hospital outcomes. Using a national administrative database, we queried for admissions aged 0 to 50 years with moderate or severe CHD and renal transplantation and compared these to admissions without CHD. There were 56 admissions for renal transplantation in the CHD group (0.04%) and 26,285 admissions in the group without CHD (0.21%, p<0.001). The CHD group were younger, had a higher proportion of Whites, longer length of stay, higher complication rates, higher in-hospital mortality, and higher costs. In conclusion, although renal transplantation is still relatively uncommon in the CHD population, there is an increasing recognition of severe chronic renal disease in the setting of CHD, making it important to understand the potential implications of these findings.


Vagotomy and antrectomy impairs canine fat absorption from solid but not liquid dietary sources.
Mild steatorrhea is common after all ulcer operations except parietal cell vagotomy. As these operations impair the grinding and sieving of solid food, we sought to determine the effect of vagotomy and antrectomy on fat absorption from solid (e.g., liver) as compared with liquid (e.g., margarine) dietary sources in the proximal small intestine. Midgut fistulas were placed in 13 dogs; 7 were controls and 6 underwent concurrent vagotomy and antrectomy. To label solid fat, the livers of live chickens were labeled with intravenous [14C]triolein and [3H]glycerol triether, an absorbable and nonabsorbable fat label, respectively. For the liquid fat label, these markers were mixed with margarine. A standard meal of steak, liver, bread, margarine, and water, with either the liver or margarine fat labeled, was fed and the midgut effluent was sieved and centrifuged to obtain four phases: large particles (greater than 0.5 mm), small particles (less than 0.5 mm), aqueous, and oil, which were extracted and counted for 14C and 3H. The ratio of 14C to 3H in each fraction was used to determine how much fat was absorbed from each phase of chyme. With liver fat labeled, 48.3% +/- 8.1% of the [3H]glycerol triether remained in large particles after vagotomy and antrectomy compared with 3.1% +/- 1.0% in controls at midintestine (p less than 0.001). After vagotomy and antrectomy, more than half of the liver fat (solid fat) was malabsorbed (57.1% +/- 6.5% vs. 23.1% +/- 6.6% malabsorbed, p less than 0.01, vagotomy and antrectomy vs. controls), whereas fat absorption from margarine (liquid fat) was not reduced compared with controls (8.8% +/- 2.5% vs. 13.6% +/- 5.5% malabsorbed, p greater than 0.05, vagotomy and antrectomy vs. controls). These observations indicate that by reducing gastric trituration and releasing large particles of poorly digested food into the intestine, vagotomy and antrectomy impairs the absorption of fat selectively from solid, but not from liquid, dietary sources.


[Elimination of quinones from aqueous environments by phenols and the effect of their mixtures on the luminescence of Beneckea harveyi bacteria].
In the mixture of hydroquinone with other phenols the content of quinones has been measured by potentiometrical and polarographical methods. The decrease of quinone content in the mixture in comparison with the pure solution has been noted. The toxicity of solution estimated according to extinction of luminescence of bacteria at adding other phenols decreases.


Short communication: distal adrenergic innervation remains normal after perivascular sympathectomy.
Perivascular sympathectomy, which has been used for vasospastic disorders of the hands, was examined in experimental models. Perivascular sympathectomy was performed on the central ear vessels and forepaw metacarpal vessels of the rabbit and on the common digital vessels in the monkey. The effects on adrenergic nerves were studied using a glyoxylic acid-induced fluorescence method. Adrenergic nerves were removed only at the site of the perivascular sympathectomy and the distal adrenergic innervation appeared normal. Because the distal sympathetic nerves appeared normal after the operation, it should rather be called adventitectomy and we feel its clinical effects should be reevaluated.


Acute heart failure as manifestation of metastatic uterine leiomyosarcoma to the heart and lung.
Uterine leiomyosarcoma is an uncommon malignant neoplasm that frequently metastasizes through the bloodstream to distant organs such as the lung, bone, and brain. We report on and discuss a patient who had sudden onset of acute heart failure with pulmonary edema and bilateral pleural effusions, resulting from a high-grade uterine leiomyosarcoma metastatic to the left atrium. Surgical removal of the tumor terminated the acute heart failure and pulmonary edema. Other unusual features of this case include the metastatic leiomyosarcoma to the left atrium with expression of acute heart failure and the pulmonary tumor lesion obscured by the shadows of pleural effusion, pulmonary edema, and the breast.


[Quinine-induced renal bilateral cortical necrosis].
Acute bilateral renal cortical necrosis is a rare cause of renal failure frequently induced by disseminated intravascular coagulation (Dic) following obstetrical complications, sepsis and drugs. We describe a case of Dic with bilateral cortical necrosis after ingestion of only one tablet of quinine. A 41-year-old woman was admitted for severe abdominal pain, melaena, fever and anuria two hours after quinine tablet intake for nocturnal leg cramps. Her medical history included angioneurotic edema caused by chloroquine for malaria prevention. Physical examination was normal. Laboratory data showed acute renal failure, hemolytic anemia without schistocytes and Dic. Platelet antibodies were negative. Ultrasonographic examination showed a complete defect of renal perfusion with permeable renal arteries. Results of abdominal CT scan and MAG3 scintigraphy led to the diagnosis of bilateral renal cortical necrosis. The patient underwent plasma exchanges with fresh frozen plasma which induced rapid resolution of Dic. She remained dependent on chronic hemodialysis. Quinine-induced microangiopathic hemolytic anemia and Dic is a rare described entity. These complications occur typically in quinine-sensitized subjects. The presence of acute renal failure is generally associated with poor prognosis in case of bilateral renal cortical necrosis. Caution is required for the prescription of quinine derivates, which should be avoided in patients experienced on adverse reaction to the drug.


Examination of skin lesions for cancer: which clinical decision aids and tools are available in general practice?
While skin cancer incidence is rising throughout Europe, general practitioners (GP) feel unsure about their ability to diagnose skin malignancies. Objectives To evaluate whether the GP has sufficient validated clinical decision aids and tools for the examination of potentially malignant skin lesions. We conducted a review searching Medline and the Cochrane Library. In addition, reference lists and personal archives were examined. Outcome measures were sensitivity and specificity but also the advantages and disadvantages of different clinical decision aids and tools. No clinical decision aids or tools for the examination of non-pigmented lesions are available. Clinical decision aids and tools for the examination of pigmented lesions have mostly been studied in secondary care and, in primary care, randomised clinical trials comparing the additional value of a clinical decision aid or tools to care are scarce. Sufficiently validated clinical decision aids and tools for the examination of potentially malignant skin lesions are lacking in general practice. The clinical decision aids and tools available in primary care need to be studied.


Macrophage activity in rabies virus infection of genetically selected high and low antibody responder lines of mice.
After infection with the Pasteur strain of fixed rabies virus, the onset of disease, mortality, interferon (IFN) synthesis and interaction of the virus with macrophages were investigated in high (HI) and low (LI) antibody responder lines of mice. The HI mice were shown to be more resistant than the LI mice, and resistance was age-dependent, since mice from both mouse lines were fully susceptible up to 2 weeks of age. IFN synthesis studies of the serum indicated that, after rabies infection, HI mice produced a slightly higher amount of IFN, which was determined to be predominantly IFN-gamma. In the brains of LI mice, only IFN-alpha/beta was found, in contrast to the mixture of IFN-alpha/beta and IFN-gamma observed in the brains of HI mice. Although macrophages from the two mouse lines expressed the same degree of extrinsic activity, their intrinsic activities were quite different; the LI mice showed a greater ability to uptake and process the virus or ingest C3 (IgM) sheep red blood cells. The present findings attribute the higher antibody response and IFN-gamma synthesis observed in HI mice during rabies infection to slower processing of the rabies antigen in their macrophages, thus conferring upon them a greater ability to present it to the immune system, leading to a higher degree of resistance to rabies infection.


Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity.
α-Synuclein (α-syn) is a presynaptic protein present at most nerve terminals, but its function remains largely unknown. The familial forms of Parkinson's disease associated with multiplications of the α-syn gene locus indicate that overabundance of this protein might have a detrimental effect on dopaminergic transmission. To investigate this hypothesis, we use adeno-associated viral (AAV) vectors to overexpress human α-syn in the rat substantia nigra. Moderate overexpression of either wild-type (WT) or A30P α-syn differs in the motor phenotypes induced, with only the WT form generating hemiparkinsonian impairments. Wild-type α-syn causes a reduction of dopamine release in the striatum that exceeds the loss of dopaminergic neurons, axonal fibers, and the reduction in total dopamine. At the ultrastructural level, the reduced dopamine release corresponds to a decreased density of dopaminergic vesicles and synaptic contacts in striatal terminals. Interestingly, the membrane-binding-deficient A30P mutant does neither notably reduce dopamine release nor it cause ultrastructural changes in dopaminergic axons, showing that α-syn's membrane-binding properties are critically involved in the presynaptic defects. To further determine if the affinity of the protein for membranes determines the extent of motor defects, we compare three forms of α-syn in conditions leading to pronounced degeneration. While membrane-binding α-syns (wild-type and A53T) induce severe motor impairments, an N-terminal deleted form with attenuated affinity for membranes is inefficient in inducing motor defects. Overall, these results demonstrate that α-syn overabundance is detrimental to dopamine neurotransmission at early stages of the degeneration of nigrostriatal dopaminergic axons.


Maternal depressive symptoms following autism spectrum diagnosis.
The current study examined depressive symptoms, concerning the week following autism spectrum diagnosis and an average of 1.4 years later, in mothers (n = 75) of young children diagnosed with an autism spectrum disorder (ASD). Over three-quarters of mothers (78.7%) provided retrospective reports of clinically significant depressive symptoms regarding the week following their child's ASD diagnosis, with some 37.3% continuing to report clinically significant levels of depressive symptoms at follow-up. Depressive symptoms immediately following diagnosis were not related to initial global characteristics of child functioning, but were related to reported child problem behaviors and financial barriers at follow-up. Results of this study underscore the importance of attention to caregiver distress and depression within models of autism detection and intervention.


Navigating care in rural areas: Strategies employed by older adults with continuing care needs and their impact on social exclusion.
The literature recognizes the great diversity of care arrangements among rural-dwelling older people. However, little is known about the complex relationships between spatial, social and infrastructural characteristics of place and the strategies that older people develop to navigate care. Even less is known about how navigating care impacts social exclusion from the perspective of older adults themselves. To fill this gap, in this secondary analysis we draw on data from twenty-one in-depth interviews from two studies conducted in rural environments in Germany and Poland. We identify three main strategies of navigating care in the rural environment: adaptation to circumstances, making use of the environment, and shaping circumstances. We present details from four cases that exemplify how strategies are interconnected with characteristics of place. The relationships between place and navigating care in rural environments is discussed with reference to the overall level of social exclusion experienced by rural-dwelling older adults with continuing care needs.


New insights on amygdala: Basomedial amygdala regulates the physiological response to social novelty.
The amygdala has been associated with a variety of functions linked to physiological, behavioral and endocrine responses during emotional situations. This brain region is comprised of multiple sub-nuclei. These sub-nuclei belong to the same structure, but may be involved in different functions, thereby making the study of each sub-nuclei important. Yet, the involvement of the basomedial amygdala (BMA) in the regulation of emotional states has yet to be defined. Therefore, the aim of our study was to investigate the regulatory role of the BMA on the responses evoked during a social novelty model and whether the regulatory role depended on an interaction with the dorsomedial hypothalamus (DMH). Our results showed that the chemical inhibition of the BMA by the microinjection of muscimol (γ-aminobutyric acid (GABAA) agonist) promoted increases in mean arterial pressure (MAP) and heart rate (HR), whereas the chemical inhibition of regions near the BMA did not induce such cardiovascular changes. In contrast, the BMA chemical activation by the bilateral microinjection of bicuculline methiodide (BMI; GABAA antagonist), blocked the increases in MAP and HR observed when an intruder rat was suddenly introduced into the cage of a resident rat, and confined to the small cage for 15min. Additionally, the increase in HR and MAP induced by BMA inhibition were eliminated by DMH chemical inhibition. Thus, our data reveal that the BMA is under continuous GABAergic influence, and that its hyperactivation can reduce the physiological response induced by a social novelty condition, possibly by inhibiting DMH neurons.


Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation.
Obesity is a major risk factor for cardiovascular disease, stroke, and type 2 diabetes (T2D). Excessive accumulation of fat in the abdomen further increases T2D risk. Abdominal obesity is measured by calculating the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI), a trait with a significant genetic inheritance. Genetic loci associated with WHRadjBMI identified in genome-wide association studies are predicted to act through adipose tissues, but many of the exact molecular mechanisms underlying fat distribution and its consequences for T2D risk are poorly understood. Further, mechanisms that uncouple the genetic inheritance of abdominal obesity from T2D risk have not yet been described. Here we utilize multi-omic data to predict mechanisms of action at loci associated with discordant effects on abdominal obesity and T2D risk. We find six genetic signals in five loci associated with protection from T2D but also with increased abdominal obesity. We predict the tissues of action at these discordant loci and the likely effector Genes (eGenes) at three discordant loci, from which we predict significant involvement of adipose biology. We then evaluate the relationship between adipose gene expression of eGenes with adipogenesis, obesity, and diabetic physiological phenotypes. By integrating these analyses with prior literature, we propose models that resolve the discordant associations at two of the five loci. While experimental validation is required to validate predictions, these hypotheses provide potential mechanisms underlying T2D risk stratification within abdominal obesity.


Characterizing the Inflammatory Microenvironment in K14-HPV16 Transgenic Mice: Mast Cell Infiltration and MicroRNA Expression.
High-risk human papillomavirus (HPV) is the etiologic agent of several types of cancer. Mast cells' role as either a driving or opposing force for cancer progression remains controversial. MicroRNAs are dysregulated in several HPV-induced cancers, and can influence mast cell biology. The aim of this study was to evaluate mast cell infiltration and to identify microRNAs potentially regulating this process. Transgenic male mice (K14-HPV16; HPV+) and matched wild-type mice (HPV−) received 7,12-Dimethylbenz[a]anthracene (DMBA) (or vehicle) over 17 weeks. Following euthanasia, chest skin and ear tissue samples were collected. Mast cell infiltration was evaluated by immunohistochemistry. MicroRNAs associated with mast cell infiltration were identified using bioinformatic tools. MicroRNA and mRNA relative expression was evaluated by RT-qPCR. Immunohistochemistry showed increased mast cell infiltration in HPV+ mice (p < 0.001). DMBA did not have any statistically significant influence on this distribution. Ear tissue of HPV+ mice showed increased mast cell infiltration (p < 0.01) when compared with chest skin samples. Additionally, reduced relative expression of miR-125b-5p (p = 0.008, 2−ΔΔCt = 2.09) and miR-223-3p (p = 0.013, 2−ΔΔCt = 4.42) seems to be associated with mast cell infiltration and increased expression of target gene Cxcl10. These results indicate that HPV16 may increase mast cell infiltration by down-regulating miR-223-3p and miR-125b-5p.


The long-term impact of elevated C-reactive protein levels during pregnancy on brain morphology in late childhood.
Animal studies show that Maternal Immune Activation (MIA) may have detrimental effects on fetal brain development. Clinical studies provide evidence for structural brain abnormalities in human neonates following MIA, but no study has investigated the long-term effects of MIA (as measured with biomarkers) on human brain morphology ten years after the exposure. Our aim was to evaluate the long-term impact of MIA on brain morphology in 10-year-old children, including the possible mediating role of gestational age at birth. We leveraged data from Generation R, a large-scale prospective pregnancy cohort study. Pregnant women were included between 2002 and 2006, and their children were invited to participate in the MRI study between 2013 and 2015. To be included, mother-child dyads had to have data on maternal C-reactive protein levels during gestation and a good quality MRI-scan of the child's brain at age 10 years. Of the 3,992 children scanned, a total of 2,053 10-year-old children were included in this study. Maternal C-reactive protein was measured in the first 18 weeks of gestation. For the analyses we used both a continuous approach as well as a categorical approach based on clinical cut-offs to determine if there was a dose-response relationship. High-resolution MRI brain morphology measures were used as the primary outcome. Gestational age at birth, established using ultrasound, was included as a mediator using a causal mediation analysis. Corrections were made for relevant confounders and multiple comparisons. Biological sex was investigated as moderator. We found a direct association between continuous MIA and lower cerebellar volume. In girls, we demonstrated a negative indirect association between continuous MIA and total brain volume, through the mediator gestational age at birth. We observed no associations with categorical MIA after multiple testing correction. Our results suggest sex-specific long-term effects in brain morphology after MIA. Categorical analyses suggest that this association might be driven by acute infections or other sources of severe inflammation, which is of clinical relevance given that the COVID-19 pandemic is currently affecting millions of pregnant women worldwide.


Laparoscopic radical prostatectomy.
Prostate cancer is the second leading cause of cancer deaths among men, after lung cancer. Traditionally, the traumatic open radical prostatectomy procedure was the only treatment option available. Although nerve-sparing techniques have evolved, the development of laparoscopic radical prostatectomy (LRP) has been one of the most significant changes in surgical treatment of the disease. Like many minimally invasive abdominal procedures, LRP reduces trauma, resulting in less postoperative pain, reduced length of hospital stay, and more rapid return to normal activity when compared to open radical prostatectomy. This article describes the preoperative, intraoperative, and postoperative care of a patient undergoing LRP. It is anticipated that LRP will be the future standard for treatment of prostate cancer that requires radical surgery.


[Palmar scaphoid dislocation associated with dorsal perilunate dislocation. A case report and review of the literature].
Most carpal dislocations occur in the lunate bone or around it (perilunate). An isolated dislocation of the carpal scaphoid is a rare injury. We report a case of a palmar scaphoid dislocation combined with a dorsal perilunate dislocation, which was treated with open reduction, fixed with two Kirschner wires and ligament repair, with a good result.


Intracardiac echogenic focus and fetal outcome.
To study the outcome of the fetuses with intracardiac echogenic focus (ICEF). All patients who were found to have one or more ICEF on sonographic (US) examination at our center from January 2007 through January 2009 were included in this retrospective study. ICEF was defined as a discrete area of echogenicity noted in the left or right ventricle, which was as bright as bone. Patients were followed up to know pregnancy outcome. Of 762 fetuses evaluated by US, 48 (6.3%) were found to have an ICEF. Thirty-one of these 48 fetuses had an isolated ICEF; 11 had associated major malformations, and the remaining 6 had no major US abnormalities but were found to have other soft markers. Invasive prenatal testing was done in 21 cases for risk factors other than ICEF and was found to be abnormal in two cases. Seven pregnancies were terminated due to associated major malformations. The prevalence of ICEF was 6.3%. Of 31 fetuses with an isolated ICEF, outcomes of 28 fetuses are known and all neonates were reported to be normal at birth. Thus we infer that the presence of an isolated ICEF has no adverse effect on outcome of the neonate.


Tn-polyagglutinability of red blood cells and acquired A-like specificity.
A woman whose red blood cells are polyagglutinable due to Tn-activation is reported. The true blood group of the patient is B but her cells have an acquired A-like specificity. The importance of the lectins, especially of Salvia sclarae extract, for the identification of Tn-polyagglutinability is demonstrated. The possibilities of A-like specificity of Tn-activated group B red blood cells is discussed.


Modified LC3 Dot Quantification Method.
Since the discovery of autophagy genes and proteins in the early1990s, numerous previously unknown physiological and pathological functions have been discovered for autophagy. At the same time, precise monitoring of autophagy has become important, and western blotting and fluorescence microscopy of the marker protein LC3 is widely used for this purpose. Here, we describe a modification of the widely used method, number of LC3 dots per cell. This protocol provides the proportion of vesicular LC3 staining over the total LC3 staining in the same cell. The approach is well suitable for quantification of endogenous LC3.


Identification of flowering-related genes between early flowering trifoliate orange mutant and wild-type trifoliate orange (Poncirus trifoliata L. Raf.) by suppression subtraction hybridization (SSH) and macroarray.
To gain a better understanding of gene expression in early flowering trifoliate orange mutant (precocious trifoliate orange, Poncirus trifoliata L. Raf.), we performed suppression subtractive hybridization, which allowed identification of flowering-related genes in the mutant and the wild type in the juvenile phase. Using macroarray analysis, we identified 125 and 149 non-redundant expressed sequence tags (ESTs) in the forward-subtracted and the reverse-subtracted library. These cDNAs covered a broad repertoire of flowering development related genes, provided helpful information for understanding genetic mechanism underlying the signaling and regulation in transition from the vegetative to reproductive phase. We have investigated the temporal and spatial expression pattern of some SSH-enriched flowering-related genes in the mutant and the wild type. Of these genes, three genes (BARELY ANY MERITED, FLOWERING LOCUS T and TERMINAL FLOWER1) encoding proteins previously reported to be associated with, or involved in, developmental processes in other species were identified and further investigated by in situ hybridization. Specific spatial and/or temporal patterns were detected, and differences were observed between the mutant and the wild type during flower development. Meanwhile, the temporal expression of these genes was further examined by real-time PCR, the results showed that FT and BAM transcripts accumulated to higher levels and TFL1 transcripts accumulated to lower levels in mutant juvenile tissues relative to wild-type juvenile tissues. In the adult stage, FT, BAM and TFL1 expression patterns were closely correlated with flowering development, suggesting that these three genes may play a critical role in the early flowering process of precocious trifoliate orange.