Necrotic cell death: From reversible mitochondrial uncoupling to irreversible lysosomal permeabilization.
Dictyostelium atg1- mutant cells provide an experimentally and genetically favorable model to study necrotic cell death (NCD) with no interference from apoptosis or autophagy. In such cells subjected to starvation and cAMP, induction by the differentiation-inducing factor DIF or by classical uncouplers led within minutes to mitochondrial uncoupling, which causally initiated NCD. We now report that (1) in this model, NCD included a mitochondrial-lysosomal cascade of events, (2) mitochondrial uncoupling and therefore initial stages of death showed reversibility for a surprisingly long time, (3) subsequent lysosomal permeabilization could be demonstrated using Lysosensor blue, acridin orange, Texas red-dextran and cathepsin B substrate, (4) this lysosomal permeabilization was irreversible, and (5) the presence of the uncoupler was required to maintain mitochondrial lesions but also to induce lysosomal lesions, suggesting that signaling from mitochondria to lysosomes must be sustained by the continuous presence of the uncoupler. These results further characterized the NCD pathway in this priviledged model, contributed to a definition of NCD at the lysosomal level, and suggested that in mammalian NCD even late reversibility attempts by removal of the inducer may be of therapeutic interest.


The nature and content of rumination for head and neck cancer survivors.
Head and neck cancer (HNC) diagnosis and treatment can be a significant life trauma. Some HNC survivors experience post-traumatic growth (PTG), which has been linked with better health-related quality-of-life. Empirical research on PTG, and theoretical models, point to the importance of being able to purposely make sense of the traumatic experience. Intrusive rumination, by contrast, is linked to poorer outcomes. This study explored HNC survivors' experiences of rumination. Twenty HNC survivors between 9 months and 5 years post-diagnosis were recruited (11 male, 9 female, age range 46-83). They had a range of HNC sub-types and cancer treatments. Participants underwent a semi-structured interview about their cancer diagnosis and treatment. Reflexive thematic analysis identified themes and sub-themes around rumination. Four themes with linked subthemes on the content and process of rumination were identified. Theme 1 was rumination and worry related to diagnosis. Here, survivors discussed how the HNC diagnosis and plans for treatment had dominated their initial thoughts. Theme 2 was processing the trauma of HNC. This theme reflected rumination on the traumatic experience of diagnosis and treatment and how the participant was reacting to it. Theme 3 was considering the impact. This theme encompassed retrospective thinking (e.g., on treatment decisions made) and comparisons between the participant now versus the early days after diagnosis. Theme 4 was continued rumination. This theme included ongoing intrusive and distressing rumination about the trauma and impact of cancer. Those who expressed ongoing rumination revisited fears (e.g., concerns about their future) or returned to negative experiences (e.g., distressing exchanges with healthcare professionals or what they perceived as poor care). This study uniquely describes the nature and content of rumination following HNC. Early intrusive rumination is common and may reflect perceptions of cancer as an existential threat. Over time, rumination can become more reflective and move towards deliberate meaning-making. Some HNC survivors may benefit from interventions to reduce barriers to this transition. The content of distressing and difficult to control rumination (commonly focused on ongoing fears or inability to resolve difficult experiences) helps to identify those who may benefit from more directed psychological support.


Development of a simple multiresidue extraction method for the quantification of a wide polarity range list of pesticides and transformation products in eggs by liquid chromatography and tandem mass spectrometry.
Waterfowl populations have been decreasing in Europe for the last years and pollution appears to be one of the main factors. This study was conducted to develop a single sensitive and robust analytical method for the monitoring of 2 fungicides, 15 herbicides, 3 insecticides and 24 transformation products in wild bird eggs. One of the major challenges addressed was the characterization of chemicals with large logP range (from -1.9 to 4.8). A total of 11 different extraction parameters were tested in triplicate to optimize the extraction protocol, on generic parameters, buffer addition and use of clean-up steps. Quantification was based on matrix-match approach with hen eggs as reference matrix (34 analytes with r²>0.99). Particular attention was payed to matrix effects (-28% on average), quantification limits (0.5 to 25 ng.g-1 dry mass / 0.2 to 7.5 ng.g-1 fresh mass) and extraction yields (46 to 87% with 25 analytes up to 70%) to ensure the relevance of the method and its compatibility with ultra-trace analysis. It led to a simple solid/liquid low temperature partitioning extraction method followed by LC-MS/MS. Analysis of 29 field samples from 3 waterfowl species revealed that eggs were slightly contaminated with pesticides as only one egg presented a contamination (terbutryn, herbicide, 0.7 ng.g-1) and confirmed the relevance of the method.


Chronic developmental exposure to phenytoin has long-term behavioral consequences.
Anti-epileptic compounds have been linked to several developmental disorders. Specifically, fetal exposure to phenytoin is linked to fetal hydantoin syndrome in humans. We have developed a rat model of fetal hydantoin syndrome in an effort to explore the relationship between drug exposure, development, and learning and memory. Previous studies of this animal model have used various embryological periods of exposure; however, the human syndrome is reported in the offspring of mothers that maintain drug regimens throughout gestation and nursing. To that end, the present study investigated associative learning in rats exposed to therapeutic levels of phenytoin throughout prenatal development and the postnatal pre-weaning period. We used an instrumental appetitive-to-aversive transfer paradigm, which has hippocampal-dependent components, and an avoidance-conditioning paradigm to test simple associative learning and higher-order learning and memory. Compared to controls, we report increased rates of acquisition and performance by the phenytoin group in both the appetitive and the avoidance learning paradigm, and a substantial impairment in avoidance learning following the transfer from appetitive to aversive conditioning. The positive deficit observed with simple associative learning and the negative transfer effect associated with higher order learning suggests that chronic exposure to phenytoin throughout gestation disrupts hippocampal development, which subsequently leads to impaired function in adulthood.


Fractionation of carrier ampholytes for isoelectric focusing.
A simple method for fractionating synthetic carrier ampholytes is reported, based on the principle of continuous-flow isoelectric focusing in gel-stabilized layers. An 8% ampholyte solution, encompassing the pH range 3-9.5, is separated into 12 fractions in a chamber filled with Sephadex G-100 by a continuous-flow technique. We are thus able to obtain ampholytes of narrow pH range, encompassing approximately 2 pH units, whose resolving power is comparable with that obtained with commercial Ampholine covering similar pH ranges.


A Standardized Lepidopteran Bioassay to Investigate the Bioactivity of Insecticidal Proteins Produced in Transgenic Crops.
Insecticidal bioassays are the only reliable method to investigate the biological activity of an insecticidal protein and therefore provide an essential toolkit for the characterization and potency determination of these proteins. Here we present a standardized method for a lepidopteran larval bioassay, which is optimized to specifically estimate activity of insecticidal proteins produced in transgenic plants. The treatment can be either applied to the surface of the artificial diet, or blended into the diet.


The carbon tip electrode.
The development of the carbon tip electrode and its low chronic threshold behavior are described. Compared to presently used electrode material, carbon tip electrodes result in lower chronic stimulation thresholds. In a group of 43 patients, chronic pulse generator output has been favorably reduced in association with this type of electrode. Thus the use of activated carbon tip electrodes may result in the routine implantation of low output pacemakers.


Effects of ovarian hormones on levels of luteinizing hormone in plasma and on serotonin concentrations in discrete brain nuclei.
Levels of serotonin were measureed in microdissected, individual brain nuclei in ovariectomized rats after treatment with ovarian hormones. Regions sampled included nuclei in the forebrain, rostral and medial hypothalamus, and midbrain tegmentum. Estradiol benzoate decreased levels of luteinizing hormone in plasma but did not affect serotonin levels in any region. Progesterone alone elevated serotonin content in the nucleus tractus diagonalis and ventral tegmental area. The combined estrogen plus progesterone regime produced a surge in plasma luteinizing hormone and also markedly elevated serotonin in the median eminence. These results may be of significance for ovarian hormonal regulation of gonadotropin secretion and reproductive behavior.


Sensory preferences of supplemented food products among cancer patients: a systematic review.
Oral nutritional supplements and fortified foods, here considered supplemented food products (SFP), are recommended as part of nutrition therapy guidelines to treat malnutrition among cancer patients. However, their successful use is limited by patients' failure to meet recommended intakes. This systematic review aimed to identify sensory preferences for SFP among cancer patients and evaluate the methodologies employed in sensory preference assessment. A systematic search was conducted in several relevant databases yielding 1056 papers of which 19 met the inclusion criteria. Two authors independently selected papers and extracted findings. The included papers were categorized according to the focus of the preference assessment. Studies comparing sensory preferences for SFP of cancer patients with those of a control group suggested that the liking for SFP by cancer patients differs from healthy participants. Patient heterogeneity in site and stage of tumor, variation in study methodologies, and type of treatment complicated a conclusion regarding the effects of cancer treatment and taste changes on taste preferences. However, some general results were observed among the studies, such as the preference for fresh milk-based supplements when compared with other supplement types. This review highlighted the need for consistent reporting and control of variables that influence the sensory characteristics of SFP when sensory preferences are assessed in the clinical setting. Attention to these methodological details will enhance the reliability and accuracy of sensory preference assessment among cancer patients for realistic evaluation of SFP targeted to their nutritional needs.


Tuberous sclerosis: CT findings and differential diagnosis.
The CT findings in a patient with tuberous sclerosis are described with special emphasis upon the differential diagnosis. The presence of multiple bilateral subependymal nodular nonenhancing hyperdense calcified lesions is relatively characteristic of tuberous sclerosis when combined with the appropriate clinical findings. In some cases, cerebral cortical heterotopias are visualized as hypodense nonenhancing subependymal lesions. The finding of a subependymal giant cell astrocytoma is sometimes seen in patients with tuberous sclerosis, and the finding of a subependymal hyperdense enhancing lesion is consistent with this diagnosis.


Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline.
In order to further evaluate the extent to which particular 5-HT receptor subtypes (5-HT1, 5-HT2) might be involved in the behavioral effects of hallucinogenic drugs, rats were trained to discriminate mescaline (10 mg/kg i.p.) from saline and were given substitution (generalization) and combination (antagonism) tests with putatively selective serotonergic and related neuroactive compounds. The mescaline cue generalized to relatively high doses of the 5-HT2 agonists, 2,5-dimethoxy-4-methylamphetamine (DOM), LSD and psilocybin; the extent of generalization to 5-HT1 agonists (8-hydroxy-2-[diethylamino]tetralin (8-OHDPAT), RU-24969 and 8-hydroxy-2-[di-n-propylamino]tetralin (TFMPP] was unclear. Combinations of the training drug and sufficiently high doses of 5-HT2 antagonists (ketanserin, LY-53857, pirenperone) were followed by saline-lever responding; less selective central 5-HT (metergoline), and DA (SCH-23390, haloperidol) antagonists, did not block the mescaline cue. These data suggest that 5-HT2 receptors are involved in the stimulus properties of mescaline.


Deferasirox plus ciprofloxacin combination therapy after rapid diagnosis of Vibrio vulnificus sepsis using real-time polymerase chain reaction.
We report a case of Vibrio vulnificus sepsis developed during deferoxamine therapy for transfusional iron overload due to secondary hemochromatosis of myelodysplastic syndrome. The patient was treated with adjuvant deferasirox in combination with ciprofloxacin, after rapid diagnosis of V. vulnificus sepsis using real-time polymerase chain reaction (PCR). This case suggests that since V. vulnificus DNA can be detected by real-time PCR for several days even after patients receive antibiotics, real-time PCR for V. vulnificus is a very useful test for establishing an early diagnosis, even if a patient has been treated with antibiotics prior to admission.


Brain-derived neurotrophic factor not associated with metabolic syndrome but inversely correlated with vascular cell adhesion molecule-1 in men without diabetes.
Excessive visceral fat with unbalanced adipokines is a critical pathogenic factor of metabolic syndrome (MetS), which is associated with disorders of the central nervous system and cardiovascular disease. Because brain-derived neurotrophic factor (BDNF) plays an important role in neurons, we examined the relationship of BDNF to MetS, adipose tissue and biomarkers in men. Thirty-four non-diabetic men with MetS and another 24 age-matched men without MetS were enrolled. In addition to fasting blood samples, the area of adipose tissue at the waist was assessed by magnetic resonance imaging (MRI). There was no significant difference in serum BDNF concentrations between men with or without MetS (40.9±8.0 vs. 43.2±6.1 ng/ml, P=0.235). However, the serum concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) was higher in the subjects with a lower BDNF level (737±230 vs. 628±115 ng/ml, P=0.025). An inverse correlation between VCAM-1 and BDNF was observed (r=-0.391, P=0.002). After adjusting for visceral adipose tissue, VCAM-1 was found to be independently associated with BDNF [95% confidence interval (-0.025, -0.005), P=0.004]. These data show no difference in serum BDNF levels between the men with MetS and controls. However, serum BDNF was inversely correlated with serum VCAM-1 in men without diabetes.


Validation of biomarkers for neonicotinoid exposure in Folsomia candida under mutual exposure to diethyl maleate.
Neonicotinoid insecticides are harmful to non-target soil invertebrates, which are crucial for sustainable agriculture. Gene expression biomarkers could provide economic and high-throughput metrics of neonicotinoid exposure and toxicity to non-target invertebrates. Thereby, biomarkers can help guide remediation efforts or policy enforcement. Gene expression of Glutathione S-Transferase 3 (GST3) has previously been proposed as a biomarker for the neonicotinoid imidacloprid in the soil ecotoxicological model species Folsomia candida (Collembola). However, it remains unclear how reliably gene expression of neonicotinoid biomarkers, such as GST3, can indicate the exposure to the broader neonicotinoid family under putative GST enzymatic inhibition. In this work, we exposed springtails to two neonicotinoids, thiacloprid and imidacloprid, alongside diethyl maleate (DEM), a known GST metabolic inhibitor that imposes oxidative stress. First, we determined the influence of DEM on neonicotinoid toxicity to springtail fecundity. Second, we surveyed the gene expression of four biomarkers, including GST3, under mutual exposure to neonicotinoids and DEM. We observed no effect of DEM on springtail fecundity. Moreover, the expression of GST3 was only influenced by DEM under mutual exposure with thiacloprid but not with imidacloprid. The results indicate that GST3 is not a robust indicator of neonicotinoid exposure and that probable GST enzymatic inhibition mediates the toxicity of imidacloprid and thiacloprid differentially. Future research should investigate biomarker reliability under shifting metabolic conditions such as provided by DEM exposure.


Aortic origin of right hepatic artery and superior mesenteric origin of splenic artery: two rare variations demonstrated angiographically.
Anatomical variations of the celiac trunk and superior mesenteric artery are not infrequent. Knowledge of the existing aberrations is important in planning and conducting surgical or radiological procedures. A case of right hepatic artery arising independently from the aorta supplying an hepatocellular carcinoma was identified, through which transarterial chemoembolization was successfully performed. A second case is presented with a common splenomesenteric trunk branching into the splenic and superior mesenteric arteries. These two cases represent exceptional arterial variations in the upper abdomen.


Negative associations of ideal family size achievement with hypertension, obesity and maternal age in women with and without polycystic ovary syndrome.
To investigate lifetime reproductive outcomes and the relationship of ideal family size (IFS) achievement with metabolic, psychiatric and reproductive history in women with and without polycystic ovary syndrome (PCOS). Cross-sectional. A total of 9034 women with (n = 778) and without self-reported PCOS (n = 8256) born between 1973 and 1978 in the Australian Longitudinal Study on Women's Health. Self-reported IFS achievement and total number of live births. Women with and without PCOS aspired for similar IFS. Compared with women without PCOS, significantly less women with PCOS achieved their IFS (53.08% vs. 60.47%, p < 0.001). Higher proportion of women with PCOS did not achieve a live birth (37.15% vs. 31.64%, p = 0.002) and their median total number of live births was also lower (1 vs. 2, p < 0.001) than women without PCOS. After controlling for sociodemographic factors, negative associations were observed between IFS achievement and PCOS status, various metabolic, psychiatric and reproductive history. However, only hypertension (adjusted odds ratio [OR]: 0.82, 95% confidence interval [CI]: 0.67-1.00), obesity (adjusted OR: 0.79, 95% CI: 0.69-0.90), history of in vitro fertilisation use (IVF) (adjusted OR: 0.49, 95% CI: 0.38-0.63) and maternal age at first childbirth (adjusted OR: 0.92, 95% CI: 0.91-0.93) remained inversely associated with achievement of IFS in further multivariable regression models. Metabolic conditions and reproductive history of maternal age at first childbirth and history of IVF use, but not psychological conditions, were associated with reduced odds of achieving IFS. Early family planning/initiation and optimisation of metabolic health may help to improve reproductive outcomes.


Implications of dysregulated endogenous cannabinoid family members in the pathophysiology of endometriosis.
To determine the involvement of the endocannabinoid (EC) family member in the pathophysiology of endometriosis (EMS). Mass spectrometry analysis of plasma and tissue samples from patients with EMS, controls, and a mouse model of EMS and messenger RNA and immunohistochemistry analysis of the samples from patients with EMS and controls. Academic teaching hospital and university. Patients with EMS and healthy fertile control subjects. None. Endocannabinoid analysis in patient plasma, EMS lesions, and healthy endometrial samples. Circulating ECs were detected in the plasma samples, whereas no significant changes were observed in patients with EMS compared with healthy fertile controls. However, the palmitoylethanolamide levels were significantly higher in the EMS lesions than in the endometrium from patients with EMS. Similarly, genes involved in the EC signaling pathways were differentially expressed in the EMS lesions. Analysis of cannabinoid 1 and 2 receptors in the EMS lesions revealed a significantly lower cannabinoid 2 receptor expression, whereas no significant changes were observed in cannabinoid 1 receptor expression compared with those in the endometrium from both patients with EMS and healthy fertile controls. The palmitoylethanolamide levels were significantly elevated in plasma from EMS mice compared with that from sham controls and in EMS lesions compared with uterine samples. Together, we provide evidence toward dysregulation of members of the ECs in both patients with EMS and the mouse model of EMS. These findings will advance the knowledge of the role of ECs in EMS and their potential implications as therapeutic targets.


Silencing VP28 gene of white spot syndrome virus of shrimp by bacterially expressed dsRNA.
An in vivo expression system to produce large amounts of virus-derived dsRNAs in bacteria to provide a practical control of white spot syndrome virus (WSSV) in shrimp was developed. The bacterially synthesized dsRNA specific to VP28 gene of WSSV promoted gene-specific interference with the WSSV infection in shrimp. Virus infectivity was significantly reduced in WSSV-challenged shrimp injected with VP28-dsRNA and 100% survival was recorded. The inhibition of the expression of WSSV VP28 gene in experimentally challenged animals by VP28-dsRNA was confirmed by RT-PCR and Western blot analyses. Furthermore, we have demonstrated the efficacy of bacterially expressed VP28-dsRNA to silence VP28 gene expression in SISK cell line transfected with eukaryotic expression vector (pcDNA3.1) inserted with VP28 gene of WSSV. The expression level of VP28 gene in SISK cells was determined by fluorescent microscopy and ELISA. The results showed that the expression was significantly reduced in cells transfected with VP28dsRNA, whereas the cells transected with pcDNA-VP28 alone showed higher expression. The in vivo production of dsRNA using prokaryotic expression system could be an alternative to in vitro method for large-scale production of dsRNA corresponding to VP28 gene of WSSV for practical application to control the WSSV in shrimp farming.


Evidence for endothelial-to-mesenchymal transition in human brain arteriovenous malformations.
Brain arteriovenous malformations (AVMs) are rare, potentially devastating cerebrovascular lesions that can occur in both children and adults. AVMs are largely sporadic and the basic disease biology remains unclear, limiting advances in both detection and treatment. This study aimed to investigate human brain AVMs for endothelial-to-mesenchymal transition (EndMT), a process recently implicated in cerebral cavernous malformations (CCMs). We used 29 paraffin-embedded and 13 fresh/frozen human brain AVM samples to profile expression of panels of EndMT-associated proteins and RNAs. CCMs, a cerebrovascular disease also characterized by abnormal vasculature, were used as a primary comparison, given that EndMT specifically contributes to CCM disease biology. AVM-derived cell lines were isolated from three fresh, surgical AVM samples and characterized by protein expression. We observed high collagen deposition, high PAI-1 expression, and expression of EndMT-associated transcription factors such as KLF4, SNAI1, and SNAI2 and mesenchymal-associated markers such as VIM, ACTA2, and S100A4. SMAD-dependent TGF-β signaling was not strongly activated in AVMs and this pathway may be only partially involved in mediating EndMT. Using serum-free culture conditions, we isolated myofibroblast-like cell populations from AVMs that expressed a unique range of proteins associated with mature cell types and with EndMT. Conditioned medium from these cells led to increased proliferation of HUVECs and SMCs. Collectively, our results suggest a role for EndMT in AVM disease. This may lead to new avenues for disease models to further our understanding of disease mechanisms, and to the development of improved diagnostics and therapeutics.


Effects of dietary terrestrial oils supplemented with L-carnitine on growth, antioxidant capacity, lipid metabolism and inflammation in large yellow croaker (Larimichthys crocea).
The present study was conducted to determine the effects of dietary terrestrial oils (TO) supplemented with L-carnitine on growth performance, biochemical and antioxidant response, lipid metabolism and inflammation in large yellow croaker (Larimichthys crocea). Three iso-nitrogenous and iso-lipidic experimental diets were formulated with FO (fish oil, the control group), 75% TO (75% FO was substituted by the oil mixture with equal amounts of soybean oil, linseed oil and pork lard) and 75% TOC (75% TO supplemented with 800 mg/kg L-carnitine), respectively. Compared to the control group, feed efficiency ratio and specific growth rate were significantly increased in fish fed diets with 75% TO and 75% TOC. Hepatic lipid content, serum triglyceride level, low-density lipoprotein-cholesterol level and the mRNA expression of pro-inflammatory genes (tnfα and ifnγ) were significantly increased in fish fed the diet with 75% TO compared to the control group. However, the supplementation of 800 mg/kg L-carnitine in the 75% TO diet repressed hepatic lipid content, serum low-density lipoprotein-cholesterol level and the mRNA expression of tnfα and ifnγ in fish compared to fish fed the diet with 75% TO. Total antioxidant capacity, the activity of superoxide dismutase, the mRNA expression of cpt-I and the activity of CPT-I were significantly increased in fish fed the diet with 75% TOC compared to 75% TO. In conclusion, these results suggested that the supplementation of 800 mg/kg L-carnitine in the diet with terrestrial oils mixture could increase growth, antioxidant capacity, fatty acid oxidation and decrease the expression of inflammatory genes in large yellow croaker.


Lung SOD3 limits neurovascular reperfusion injury and systemic immune activation following transient global cerebral ischemia.
Studies implicate the lung in moderating systemic immune activation via effects on circulating leukocytes. In this study, we investigated whether targeted expression of the antioxidant extracellular superoxide dismutase (SOD3) within the lung would influence post-ischemic peripheral neutrophil activation and CNS reperfusion injury. Adult, male mice expressing human SOD3 within type II pneumocytes were subjected to 15 min of transient global cerebral ischemia. Three days post-reperfusion, lung and brain tissue was collected and analyzed by immunohistochemistry for inflammation and injury markers. In vitro motility and neurotoxicity assays were conducted to ascertain the direct effects of hSOD3 on PMN activation. Results were compared against C57BL/6 age and sex-matched controls. Relative to wild-type controls, hSOD3 heterozygous mice exhibited a reduction in lung inflammation, blood-brain barrier damage, and post-ischemic neuronal injury within the hippocampus and cortex. PMNs harvested from hSOD3 mice were also resistant to LPS priming, slower-moving, and less toxic to primary neuronal cultures. Constitutive, focal expression of hSOD3 is neuroprotective in a model of global cerebral ischemia-reperfusion injury. The underlying mechanism of SOD3-dependent protection is attributable in part to effects on the activation state and toxic potential of circulating neutrophils. These results implicate lung-brain coupling as a determinant of cerebral ischemia-reperfusion injury and highlight post-stroke lung inflammation as a potential therapeutic target in acute ischemic cerebrovascular injuries.


The influence of different sub-bandage pressure values in the prevention of recurrence of venous ulceration-A ten year follow-up.
The aim of this study was to establish the efficacy of three different strengths of compression systems in the prevention of venous leg ulcer (VLU) recurrences during a 10-year follow up period. An open, prospective, randomized, single-center study included 477 patients (240 men, 237 women; mean age 59 years). Patients were randomized into three groups: Group A) 149 patients (allocated to wear elastic stocking 18-25 mmHg). Group B) 167 patients (wearing compression device exerting 25-35 mmHg), and Group C) 161 patients (treated with multilayer compression system exerting 35-50 mmHg). Overall, 65% (234/360) of patients had recurrent VLU within 10 years. Recurrence occurred in 120 (96%) of 125 in group A, in 89 (66.9%) of 133 patients in group B and in 25 (24.5%) of 102 patients in group C (p < 0.05). Compression systems with the higher compression class provide lower recurrence rate.


Clinical diagnosis of immune inner-ear disease.
The purpose of this study was to develop a high-risk clinical profile of patients with autoimmune (immune-mediated) inner-ear disease. The records of 52 patients diagnosed over the past 5 years were reviewed. Age, sex, bilateral versus unilateral involvement, otologic symptoms, concomitant systemic immune disease, and presenting clinical diagnoses were recorded. The presenting diagnoses were Cogan's syndrome, Meniere's syndrome, Dandy's syndrome without hearing loss, or progressive sensorineural hearing loss without dizziness. Because Cogan's and Dandy's syndromes were relatively uncommon, the typical high-risk clinical profile was a middle-aged patient (often female) with bilateral, asymmetric, progressive sensorineural hearing loss, with or without dizziness, and occasional systemic immune disease such as rheumatoid arthritis. When a more common clinical diagnosis cannot be reached in suspicious patients, immune laboratory tests should be obtained and a trial of immunotherapy offered. Positive test results and beneficial response to therapy support a presumptive diagnosis of immune inner-ear disease.


Nomogram model based on radiomics signatures and age to assist in the diagnosis of knee osteoarthritis.
Knee osteoarthritis (KOA) is a common disease in the elderly. An effective method for accurate diagnosis could affect the management and prognosis of patients. To develop a nomogram model based on X-ray imaging data and age, and to evaluate its effectiveness in the diagnosis of KOA. A total of 4403 knee X-rays from 1174 patients (July 2017 to November 2018) were retrospectively analyzed. Radiomics features were extracted and selected from the X-ray image data to quantify the phenotypic characteristics of the lesion region. Feature selection was performed in three steps to enable the derivation of robust and effective radiomics signatures. Then, logistic regression (LR), support vector machine (SVM) AdaBoost, gradient boosting decision tree (GBDT), and multi-layer perceptron (MLP) was adopted to verify the performance of radiomics signatures. In addition, a nomogram model combining age with radiomics signatures was constructed. At last, receiver operating characteristic (ROC) curve, calibration and decision curves were used to evaluate the discriminative performance. The LR model has the best classification performance among the four radiomics models in testing cohort (LR AUC vs. SVM AUC: 0.843 vs. 0.818, DeLong test P = 0.0024; LR AUC vs. GBDT AUC: 0.843 vs. 0.821, P = 0.0028; LR AUC vs. MLP AUC: 0.843 vs. 0.822, P = 0.0019). The nomogram model achieved better predictive efficacy than the radiomics model in testing cohort compared to radiomics models although the statistical difference was not significant (Nomogram AUC vs. Radiomics AUC: 0.847 vs. 0.843, P = 0.06). The decision curve analysis revealed that the constructed nomogram had clinical usefulness. The nomogram model combining radiomics signatures with age has good performance for the accurate diagnosis of KOA and may help to improve clinical decision-making.


Mechanisms of Epstein-Barr virus nuclear antigen 1 favor Tregs accumulation in nasopharyngeal carcinoma.
Documented reports proved that Epstein-Barr virus (EBV) infection increased infiltration of Tregs in malignancy. However, the mechanism of EBV recruitment Tregs into nasopharyngeal carcinoma (NPC) tissues has not been detailed discussion. Expression of EBV nuclear antigen 1 (EBNA1) and Foxp3 in NPC tissue samples was detected by immunohistochemistry. EBNA1+ NPC cell lines were used to coculture with PBMC, naïve T cells, Tregs, and monocytes. Percent of Treg was detected by flow cytometry. EBNA1 protein was overexpressed in NPC tissues, and was associated with a number of infiltrated Tregs. EBNA1+ NPC cells converted naïve T cells into Tregs by up-regulated TGF-β1. Enhanced CCL20 production in EBNA1-expressed tumor cells increased Tregs migration. Polarized-M2 macrophages by EBNA1 expression cells converted naïve T cells into Tregs. EBNA1 favors accumulation of Tregs in NPC through: (a) upregulated TGF-β1 converted naïve T cell into Treg; (b) upregulated CCL20 increased Treg migration; and (c) polarized-M2 macrophage converted naïve T cell into Treg.


Knockdown of the small conductance Ca(2+) -activated K(+) channels is potently cytotoxic in breast cancer cell lines.
Small conductance calcium-activated potassium (KCa 2.x) channels have a widely accepted canonical function in regulating cellular excitability. In this study, we address a potential non-canonical function of KCa 2.x channels in breast cancer cell survival, using in vitro models. The expression of all KCa 2.x channel isoforms was initially probed using RT-PCR, Western blotting and microarray analysis in five widely studied breast cancer cell lines. In order to assess the effect of pharmacological blockade and siRNA-mediated knockdown of KCa 2.x channels on these cell lines, we utilized MTS proliferation assays and also followed the corresponding expression of apoptotic markers. All of the breast cancer cell lines, regardless of their lineage or endocrine responsiveness, were highly sensitive to KCa 2.x channel blockade. UCL1684 caused cytotoxicity, with LD50 values in the low nanomolar range, in all cell lines. The role of KCa 2.x channels was confirmed using pharmacological inhibition and siRNA-mediated knockdown. This reduced cell viability and also reduced expression of Bcl-2 but increased expression of active caspase-7 and caspase-9. Complementary to these results, a variety of cell lines can be protected from apoptosis induced by staurosporine using the KCa 2.x channel activator CyPPA. In addition to a well-established role for KCa 2.x channels in migration, blockade of these channels was potently cytotoxic in breast cancer cell lines, pointing to modulation of KCa 2.x channels as a potential therapeutic approach to breast cancer.


Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type.
Several lines of evidence support a role for brain-derived neurotrophic factor (BDNF) alterations in the etiology of eating disorders (EDs). BDNF heterozygous knockout mice show alterations in eating behavior, increased body weight and adipocyte hypertrophy. BDNF also regulates the synaptic efficiency through the modulation of key neurotransmitter systems previously known to be involved in ED. These findings, together with the fact that this neurotrophin is expressed in the hypothalamus nuclei associated with weight regulation and feeding control, led us to propose BDNF as a candidate gene for ED. To investigate the possible involvement of this neurotrophin in eating behavior, we screened the BDNF gene in 95 ED patients and identified four sequence variants. Two of them, -374A/T and -256G/A, were found in two patients with anorexia nervosa (AN) and consisted of single-nucleotide mutations within the 5' untranslated region (5'UTR). The other two polymorphisms resulted in a C to T transition located at the 5'UTR of the BDNF gene and an amino-acid substitution within the BDNF precursor protein (Val66Met). We performed a case-control study for these two Single-nucleotide polymorphisms in a sample of 143 ED patients and 112 unrelated controls and found a strong association of restricting AN (ANR) with the Met allele of the Val66Met BDNF polymorphism (2p=0.002). There was also evidence for a significant effect of this sequence variant on the minimum body mass index (MBMI) (2p=0.006). These results suggest that the BDNF Met66 variant may be a susceptibility factor to ED, mainly to ANR and low MBMI.


Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: 2-Year Interim Results from the Phase 3 Rising Up Study.
Upadacitinib, an oral, selective Janus kinase inhibitor, is approved in Japan for the treatment of moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous morphology and intense itch. Rising Up is an ongoing phase 3, randomized, multicenter study evaluating the long-term safety and efficacy of upadacitinib in Japan. Patients with moderate-to-severe AD were randomized 1:1:1 to topical corticosteroids plus upadacitinib 15 mg (UPA15), upadacitinib 30 mg (UPA30), or placebo at baseline; at week 16, placebo patients were rerandomized 1:1 to UPA15 or UPA30 (plus topical corticosteroids per investigator discretion). This 2-year interim analysis evaluated safety and efficacy through 112 weeks (data cutoff date: 11 August 2021). Adverse events (AEs), AEs of special interest (AESIs), and laboratory data were assessed. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), achievement of clear or almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), and ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS). A total of 272 patients were enrolled and 242 were ongoing at data cutoff (UPA15, n = 120; UPA30, n = 122). After 112 weeks of treatment, serious AEs, AEs leading to discontinuation, and most AESIs were generally infrequent, and rates were similar between the two upadacitinib groups. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombosis events were observed. The most common AEs included acne, nasopharyngitis, and herpes zoster. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were maintained through week 112. UPA15 and UPA30 were well tolerated through 112 weeks of treatment with similar safety profiles to short-term studies and demonstrated durable long-term efficacy for the treatment of moderate-to-severe AD in adults and adolescents. ClinicalTrials.gov identifier, NCT03661138.


Genetic findings in miscarriages and their relation to the number of previous miscarriages.
Early pregnancy loss leads to a devastating situation for many couples. Genetic disorders found in the pregnancy tissue are a frequent cause of miscarriages. It is unclear whether maternal age or previous miscarriages are associated with a higher chromosomal anomaly rate. This study aimed to determine the cytogenetical distribution of chromosomal disorders in couples after one or more previous miscarriages as well as the influence of maternal age. 406 fetal tissue samples obtained after spontaneous abortion between 2010 and 2014 were successfully karyotyped. This included 132 couples with at least two losses and 274 couples with sporadic miscarriage. Normal and abnormal karyotype rate was determined for age, parity, gravidity, gestational week and number of previous miscarriages by logistic regression analysis. 145 (35.71%) fetal tissue samples had a normal karyotype, and 261 (64.8%) did not. After adjusting for age, older patients have a statistically significantly higher probability of genetic disorders in the pregnancy tissue (p < 0.001, OR 1.064, 95% CI 1.03-1.11). With each additional year, the probability of finding chromosomal abnormalities in a miscarriage increased by 6.4%. Patients younger than 35 years have a lower probability of having chromosomal disorders in the aborted material after two or more miscarriages than after sporadic miscarriages (50.7 vs. 58.9%) (p = 0.014, OR 0.67, 95% CI 0.48-0.914). Nevertheless, the risk of embryonic chromosomal disorders in patients aged 35 and above increased from 75.5% in sporadic miscarriages to 82.4% after more than one pregnancy losses (p = 0.59, OR 1.14, 95% CI - 0.72 to 1.92). Chromosomal disorders found after one or more previous miscarriages are related to patients' age. Couples suffering two or more miscarriages should be further researched, especially in younger patients.


Determination of cadmium in used engine oil, gasoline and diesel by electrothermal atomic absorption spectrometry using magnetic ionic liquid-based dispersive liquid-liquid microextraction.
In this study, a sensitive and matrix-effect free analytical method for Cd determination in engine oils and fuel samples by dispersive liquid-liquid microextraction with electrothermal atomic absorption spectrometry has been successfully developed. The extractant solvent used for the microextraction procedure was a magnetic ionic liquid (MIL) (i.e., bis(1-ethyl-3-methylimidazolium) tetrathiocyanatocobaltate (II) [Emim]2[Co(SCN)4]), which presents a paramagnetic property, and allows an easy phase separation using a magnet. In order to eliminate the well-known drawbacks of direct introduction of MIL in the graphite furnace, a back-extraction procedure was performed to transfer the analyte into an aqueous phase. The main experimental factors affecting the extraction of Cd (i.e., amount of sample and MIL, extraction and back-extraction time and concentration and amount of nitric acid) were optimized using a multivariate analysis consisting in two steps: a Plackett-Burman design followed by a circumscribed central composite design. Under optimum conditions (i.e., amount of sample: 6.2 g; amount of MIL: 119 mg; extraction time: 1 min; amount of nitric acid: 200 mg; nitric acid concentration: 1 mol L-1 and back-extraction time: 1 min), the proposed analytical method was validated and successfully used to analyze three real-world samples (i.e., used engine oil, gasoline and diesel). The three samples were spiked at two levels (i.e., 10 and 20 μg kg-1 of Cd for used engine oil and 1 and 3 μg kg-1 of Cd for gasoline and diesel). RSD and recovery values were within the range of 6-11% and 95-110%, respectively.


Ground and Excited-Electronic-State Dissociations of Hydrogen-Rich and Hydrogen-Deficient Tyrosine Peptide Cation Radicals.
We report a comprehensive study of collision-induced dissociation (CID) and near-UV photodissociation (UVPD) of a series of tyrosine-containing peptide cation radicals of the hydrogen-rich and hydrogen-deficient types. Stable, long-lived, hydrogen-rich peptide cation radicals, such as [AAAYR + 2H](+●) and several of its sequence and homology variants, were generated by electron transfer dissociation (ETD) of peptide-crown-ether complexes, and their CID-MS(3) dissociations were found to be dramatically different from those upon ETD of the respective peptide dications. All of the hydrogen-rich peptide cation radicals contained major (77%-94%) fractions of species having radical chromophores created by ETD that underwent photodissociation at 355 nm. Analysis of the CID and UVPD spectra pointed to arginine guanidinium radicals as the major components of the hydrogen-rich peptide cation radical population. Hydrogen-deficient peptide cation radicals were generated by intramolecular electron transfer in Cu(II)(2,2':6',2″-terpyridine) complexes and shown to contain chromophores absorbing at 355 nm and undergoing photodissociation. The CID and UVPD spectra showed major differences in fragmentation for [AAAYR](+●) that diminished as the Tyr residue was moved along the peptide chain. UVPD was found to be superior to CID in localizing Cα-radical positions in peptide cation radical intermediates. Graphical Abstract .


Deterioration of building materials in Roman catacombs: the influence of visitors.
In the last decades, damages on building materials and mural paintings were observed in Roman catacombs. The damages were due to extensive formation of biofilms induced by artificial illumination and humidity. Microenvironmental data (temperature, CO(2) concentration, humidity, and atmospheric pressure) clearly showed the negative influence of visitors. Increasing heat, light and water vapour condensation into corridors and cubicles favoured biofilm development. The composition of biofilms was different and depended mainly on distance to illumination sources and humidity, thus denoting the influence of light on the growth of phototrophic microorganisms in the catacombs. In addition, biofilm distribution was governed by the type of material to be colonised. This study shows that countermeasures are needed to prevent deterioration of hypogean environments.


Sex differences in myocardial contractility in the rat.
We examined the intrinsic contractile performance of papillary muscles removed from the left ventricle of male and female Wistar rats. Muscles were studied isometrically and isotonically, stimulated at 0.1 Hz, perfused with Tyrode's solution having an external calcium concentration = 2.4 and maintained at 30 degrees C. In addition, we examined muscle response to changes in external calcium, added norepinephrine or verapamil and alterations in contraction frequency. No significant change in peak isometric development tension was observed between male and female preparations. However, muscles from male rats showed a significantly greater isometric time-to-peak tension and time to 1/2 relaxation with a depression of both the maximum rate of tension rise and maximum rate of tension decay. Isotonically, although peak shortening showed no difference between male and female preparations, the maximum velocities of shortening and relaxation were significantly depressed in muscles from male rats. Muscles from male animals also displayed significant prolongation of the time-to-peak shortening and time-to-peak velocity of shortening. These differences in papillary muscle performance were found over a wide range of muscle lengths, stimulus frequencies and bath concentrations of calcium, norepinephrine and verapamil. Thus differences in the intrinsic contractile performance between papillary muscle from male and female rats have been characterized.


Rat brain regional distribution and spinal cord neuronal pathway of FLFQPQRF-NH2, a mammalian FMRF-NH2-like peptide.
Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (F-8-NH2) is a peptide, originally detected by FMRF-NH2 antisera, and subsequently isolated from bovine brain. Using a specific radioimmunoassay for F-8-F-NH2, we have examined the regional distribution and characteristics of F-8-F-NH2 immunoreactivity (IR) in rat brain, spinal cord and pituitary gland. In CNS, F-8-F-NH2-IR is highly concentrated in the spinal cord, hypothalamus and pons-medulla (368, 202 and 136 fmol per mg protein, respectively); lowest values are in the cortex and hippocampus. A modest rostrocaudal gradient of F-8-F-NH2-IR was observed; levels in the sacral cord are 50% higher than in the cervical cord. Dorsal cord content is 8 times higher than in the ventral cord. Dorsal rhizotomy failed to change F-8-F-NH2-IR in the affected regions of the spinal cord while significantly reducing substance P levels. F-8-F-NH2-IR was significantly decreased caudal to a spinal transection, indicating the presence of a descending pathway within the spinal cord. The highest concentration of F-8-F-NH2-IR (1008 fmol per mg protein) was found in the neurointermediate lobe of the pituitary, while no F-8-F-NH2-IR could be detected in the anterior lobe. Immunohistochemically, F-8-F-NH2-IR was confined to nerve terminal-like structures in the neural lobe. The anterior and intermediate lobes were devoid of immunoreactive structures. HPLC characterization of F-8-F-NH2-IR in the dorsal spinal cord, medulla-pons and pituitary revealed one major immunoreactive peak which is more hydrophobic than bovine F-8-F-NH2. In addition to this material, the hypothalamus was found to contain another, more abundant F-8-F-NH2-immunoreactive peak. Analysis of F-8-F-NH2-IR from posterior pituitary with various antisera having differing affinities for F-8-F-NH2 and gamma 1-MSH indicates that the F-8-F-NH2-IR of rat pituitary is not due to gamma 1-MSH. The high concentration of F-8-F-NH2-like peptide in the dorsal spinal cord supports a role in mediating nociceptive transmission while the localization of F-8-F-NH2-IR in the posterior pituitary suggests an additional autonomic or endocrine function.


Illuminating the functional and structural repertoire of human TBC/RABGAPs.
The Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs) are characterized by the presence of highly conserved TBC domains and act as negative regulators of RABs. The importance of TBC/RABGAPs in the regulation of specific intracellular trafficking routes is now emerging, as is their role in different diseases. Importantly, TBC/RABGAPs act as key regulatory nodes, integrating signalling between RABs and other small GTPases and ensuring the appropriate retrieval, transport and delivery of different intracellular vesicles.


Therapeutic Effect of Multi-Channel Transcranial Direct Current Stimulation (M-tDCS) on Recovery of Cognitive Domains, Motor Functions of Paretic Hand and Gait in Subacute Stroke Survivors-A Randomized Controlled Trial Protocol.
There has been rapid drift of rehabilitation professionals toward the clinical use of technology aided electrical interventions. Brain is a cortical hub of functionally related neural connections. Motor learning entails strong interaction with the cognitive domains. So better outcomes may be expected by optimally targeting functionally correlated areas simultaneously through tDCS. To determine the therapeutic effect of Multi Channel tDCS in combination with Functional electrical stimulation, SaeboFlex and conventional rehabilitation on recovery of Cognitive Domains, Motor Functions of Paretic Hand, and Gait in individuals with subacute Stroke. This is prospective, randomized, double blind controlled clinical trial. Subacute Stroke Survivors with the age Group (40-75 years) will constitute the Population of the study. Participants will be randomly allocated to experimental or control group. Participants of Experimental group will receive Multi channel tDCS, Functional electrical stimulation, Saebo Flex Training and conventional rehabilitation. Participants of the group B will receive FES, training with SaeboFlex, conventional physiotherapy intervention similar to as given to the participants of group A and sham multi channel tDCS. The primary outcome measures of the study will be Fugl Meyer assessment, Electroencephalogram and secondary outcome measures of the study will be Grip strength, Pinch strength, Nine hole peg test( NHPT), Wisconsin gait scale, Montreal cognitive assessment, Electroencephaloraphy to observe the cortical changes and tDCS adverse effect questionnaire and stroke specific quality of Life scale. The primary analysis of the study will be done at the end of 4 weeks. Statistical analysis of data will be done using SPSS Version 22 with the help of a statistician. An insight into the therapeutic interventions augmenting, cognitive and motor domains simultaneously may yield better outcomes in the field of stroke rehabilitation thereby improving quality of life of stroke survivors.


Long-term monitoring of intravital biological processes using fluorescent protein-assisted NIR-II imaging.
High spatial resolution, low background, and deep tissue penetration have made near-infrared II (NIR-II) fluorescence imaging one of the most critical tools for in vivo observation and measurement. However, the relatively short retention time and potential toxicity of synthetic NIR-II fluorophores limit their long-term application. Here, we report the use of infrared fluorescent proteins (iRFPs) as in vitro and in vivo NIR-II probes permitting prolonged continuous imaging (up to 15 months). As a representative example, iRFP713 is knocked into the mouse genome to generate a transgenic model to allow temporal and/or spatial expression control of the probe. To demonstrate its feasibility in a genuine diagnostic context, we adopt two liver regeneration models and successfully track the process for a week. The performance and monitoring efficacy are comparable to those of μCT and superior to those of indocyanine green dye. We are also able to effectively observe the pancreas, despite its deep location, under both physiological and pathological conditions. These results indicate that the iRFP-assisted NIR-II fluorescence system is suitable for monitoring various tissues and in vivo biological processes, providing a powerful noninvasive long-term imaging platform.


Age-related factors in cancers of the breast, ovary, and endometrium.
The most central epidemiological feature of cancers of the breast, ovary and endometrium is the enormous protective effect of menopause. Simple mathematical "models" of the age-incidence of these tumours suggests that their incidence by age 70 would be between 4 and 8-fold increased if women continued to menstruate into old age. Using the notion of "effective cell-cycle time" to explain this phenomenon, different "models" are constructed for each of these three tumour sites and shown to provide an excellent description of most of the known epidemiology of each of the cancers, and to provide a basis for predicting the long-term effects of various factors on the risk of these diseases. In particular, the model suggests that 5 years of combination-type oral contraceptive use will approximately halve the lifelong risk of both ovarian cancer and endometrial cancer.


Tumor necrosis factor-α-mediated downregulation of the cystic fibrosis transmembrane conductance regulator drives pathological sphingosine-1-phosphate signaling in a mouse model of heart failure.
Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzyme sphingosine kinase 1 and its functional antagonist S1P phosphohydrolase-1. The intracellular localization of S1P phosphohydrolase-1 necessitates the import of extracellular S1P into the intracellular compartment before its degradation. The present investigation proposes that the cystic fibrosis transmembrane conductance regulator transports extracellular S1P and hence modulates microvascular S1P signaling in health and disease. In cultured murine vascular smooth muscle cells in vitro and isolated murine mesenteric and posterior cerebral resistance arteries ex vivo, the cystic fibrosis transmembrane conductance regulator (1) is critical for S1P uptake; (2) modulates S1P-dependent responses; and (3) is downregulated in vitro and in vivo by tumor necrosis factor-α, with significant functional consequences for S1P signaling and vascular tone. In heart failure, tumor necrosis factor-α downregulates the cystic fibrosis transmembrane conductance regulator across several organs, including the heart, lung, and brain, suggesting that it is a fundamental mechanism with implications for systemic S1P effects. We identify the cystic fibrosis transmembrane conductance regulator as a critical regulatory site for S1P signaling; its tumor necrosis factor-α-dependent downregulation in heart failure underlies an enhancement in microvascular tone. This molecular mechanism potentially represents a novel and highly strategic therapeutic target for cardiovascular conditions involving inflammation.


Simultaneous analysis of beauvericin and moniliformin in fungal cultures and in cereal grain samples.
Species ofFusarium subglutinans andFusarium proliferation have been found to produce two mycotoxins, beauvericin and moniliformin, under labolatory conditions as well as in infected ears. A method for simultaneous extraction, analysis and quantitation of both metabolites was elaborated. Recoveries were 85-97 % and 78-94 % for the first and the latter mycotoxin, respectively. Detection limit of beauvericin on high- performance thin- layer chromatography plates (Merck 5633) after exposure to iodine vapours was 3 μg/g and by high- performance liquid chromatography method 0.07 μg/g while moniliformin was analyzed at concentration level 1 μg/g by thin- layer chromatography and 0.05 μg/g by high- performance liquid chromatography method.


3-D optimized classification and characterization artificial intelligence paradigm for cardiovascular/stroke risk stratification using carotid ultrasound-based delineated plaque: Atheromatic™ 2.0.
Atherosclerotic plaque tissue rupture is one of the leading causes of strokes. Early carotid plaque monitoring can help reduce cardiovascular morbidity and mortality. Manual ultrasound plaque classification and characterization methods are time-consuming and can be imprecise due to significant variations in tissue characteristics. We report a novel artificial intelligence (AI)-based plaque tissue classification and characterization system. We hypothesize that symptomatic plaque is hypoechoic due to its large lipid core and minimal collagen, as well as its heterogeneous makeup. Meanwhile, asymptomatic plaque is hyperechoic due to its small lipid core, abundant collagen, and the fact that it is often calcified. We designed a computer-aided diagnosis (CADx) system consisting of three kinds of deep learning (DL) classification paradigms: Deep Convolutional Neural Network (DCNN), Visual Geometric Group-16 (VGG16), and transfer learning, (tCNN). DCNN was 3-D optimized by varying the number of CNN layers and data augmentation frameworks. The DL systems were benchmarked against four types of machine learning (ML) classification systems, and the CADx system was characterized using two novel strategies consisting of DL mean feature strength (MFS) and a bispectrum model using higher-order spectra. After balancing symptomatic and asymptomatic plaque classes, a five-fold augmentation process was applied, yielding 1000 carotid scans in each class. Then, using a K10 protocol (trained to test the ratio of 90%-10%), tCNN and DCNN yielded accuracy (area under the curve (AUC)) pairs of 83.33%, 0.833 (p < 0.0001) and 95.66%, 0.956 (p < 0.0001), respectively. DCNN was superior to ML by 7.01%. As part of the characterization process, the MFS of the symptomatic plaque was found to be higher compared to the asymptomatic plaque by 17.5% (p < 0.0001). A similar pattern was seen in the bispectrum, which was higher for symptomatic plaque by 5.4% (p < 0.0001). It took <2 s to perform the online CADx process on a supercomputer. The performance order of the three AI systems was DCNN > tCNN > ML. Bispectrum-based on higher-order spectra proved a powerful paradigm for plaque tissue characterization. Overall, the AI-based systems offer a powerful solution for plaque tissue classification and characterization.


A synchronous presentation of malignant melanoma and dermatofibrosarcoma protuberans in a Nigerian female: A case report.
The simultaneous occurrence of multiple primary malignancies in a patient has been widely reported. Oral mucosal malignant melanoma is a rare lesion of the oral cavity. The occurrence of this lesion with a very rare skin sarcoma at the same time has never to the best of our knowledge been reported previously. A 64 year-old Nigerian woman with a 27-year history of a dark lesion in the right maxillary buccal and palatal mucosa with an anterior abdominal swelling of 24 years which was discovered on systemic examination. Both lesions were later discovered to be malignant melanoma and dermatofibrosarcoma protuberans respectively. She had a right hemimaxillectomy for the maxillary lesion and wide excision of the abdominal wall lesion, followed by six courses of chemotherapy. She has been undergoing regular reviews for the past 5 years and remains free of all malignancy; however, she died shortly after noticing the reappearance of both lesions. While evaluating patients with a tumor, it will be rewarding to rule out other similar swellings in the body. This is important to avoid metastasis or multiple primary malignancies, which can help prolong patient life. The synchronous occurrence of two different neoplastic lesions is rare. Our literature search revealed no previous report of such occurrence of oral malignant melanoma and DFSP at the same time in one patient. The importance of thorough examination of patients cannot be overemphasized as concurrent lesions may be missed.


The significance for chronic rejection of cardiac allograft of regulated upon activation normal T-cell cytokine and its CCR5 receptor.
We sought to characterize the expression of regulated upon activation normal T cell expressed and secreted (RANTES) and its receptor CCR5, which can activate normal T cells during chronic rejection after cardiac allografting. The rat model of cervical cardiac transplantation using a cuff technique was established in Wistar donors and Sprague-Dawley (SD) recipients. Cardiac allograft vasculopathy (CAV), myofibrosis as well as RANTES and CCR5 expressions were analyzed in the allografts. Immunohistochemical staining demonstrated reduced expression of RANTES and CCR5 in allograft muscle and coronary arteries when the recipients were pretreated with donor splenocytes plus cyclophosphamide. CAV and myocardial fibrosis were remarkably reduced and graft survival extended compared with non-pretreated recipients (P < .05). We suggest that the expression of RANTES and CCR5 in cardiac allografts may play important roles in chronic rejection.


Public health interventionists, penny capitalists, or sources of risk?: assessing street syringe sellers in Hartford, Connecticut.
Improved access to sterile syringes decreases risks related to blood-borne transmission of HIV and hepatitis among injection drug users (IDUs). While syringe exchange programs and pharmacy sales of over-the-counter syringes have received considerable attention from researchers and interventionists during the past decade, little is known about informal economy street syringe sellers. In Hartford, CT. as well as other regions throughout the United States a large percentage of IDUs utilize street sellers to facilitate their injection activities. A qualitative and ethnographic study was conducted in Hartford between 1999 and 2001 to help elucidate the public health risks and benefits of street syringe sellers.


Better than the real thing? Success of a virtual platform for an established "Train the Trainer" course.
The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) uses the Laparoscopic colectomy Train the Trainer (Lapco TT) framework for standardization of instructor training for Hands-On surgical skills courses. The curriculum focuses on teaching structure, skills deconstruction, trainer intervention framework, and performance enhancing feedback. A halt in the in-person Lapco TT courses due to the Coronavirus Disease 2019 (COVID-19) pandemic necessitated creation of a virtual alternative. We investigated the effectiveness of this virtual course. Adaptation of the in-person Lapco TT course to the virtual format retained the majority of content as well as the 4:6 instructor-to-participant ratio. The virtual platform and simulators chosen allowed maximal interactivity and ease of use. After participating in the day and one half course, participants completed an 8-item post-course survey using a 5-point Likert scale related to the training experience. In addition, they had the opportunity to provide answers to several open-ended questions regarding the course. For the survey, frequency counts provided an assessment of each item. For the open questions, qualitative analysis included determination of themes for each question. Frequency counts of each theme provided quantitative analysis. Thirty-six total participants completed a Lapco TT virtual course (six sessions of six participants). Of this number, 32 participants completed post-course surveys and questions. All the participants completing the survey would very likely or definitely (Likert scale 4, 5) recommend the course to a colleague and incorporate the teaching in their practice. The majority of participants completing open-ended questions felt the virtual course format was effective; half thought that post-course follow-up would be useful. Technical concerns were an issue using the virtual format. A virtual Lapco TT course is feasible and well received by participants. It presents a potentially more cost effective option to faculty development.


A retained retrobulbar catheter for repetitive injection of anesthetics during ophthalmic surgery.
For extending the period of retrobulbar anesthesia, an Angiocath was retrobulbarly retained for repetitive delivery of local anesthetics. The retrobulbar placement of the cannula made possible easy and safe addition of local anesthetics by any time, amount and frequency.


Accuracy of transcutaneous bilirubin measurement in preterm low-birth-weight neonates.
The objective of this study was to evaluate the correlation and agreement between transcutaneous and serum bilirubin among preterm low-birth-weight neonates. Neonates born at <35 weeks of gestation with birth weight <2,000 g were enrolled prospectively. Transcutaneous bilirubin (TcB) was measured at forehead, sternum, and abdomen at 24 ± 6 and 72 ± 12 h after birth and when icterus involved arms or legs (Kramer zone 4-5). Serum total bilirubin (STB) was measured by microbilimeter (STB-M) at all these time-points and by high-performance liquid chromatography (STB-H) at one randomly chosen time-point. A total of 1,619 observations were made in 256 neonates (median gestation, 34 weeks (IQR, 32-35), birth weight 1,522 ± 288 g). Overall there was excellent correlation and agreement between TcB and STB-M with TcB on forehead being most accurate (r = 0.84, mean difference, 0.3 ± 1.9 mg/dL) followed by TcB on abdomen (r = 0.73, mean difference, 1.5 ± 2.6 mg/dL) and sternum (r = 0.72, mean difference, 1.5 ± 2.6 mg/dL). TcB performed well at all three points of measurement with best correlations being observed at icterus level 4/5. Correlation between TcB and STB-H measured by high-performance liquid chromatography was less strong but significant (r = 0.59 to 0.69 at different time points of measurement). TcB has good correlation and agreement with STB in preterm low-birth-weight neonates born at ≥28 weeks of gestation.


YC-1 alleviates bone loss in ovariectomized rats by inhibiting bone resorption and inducing extrinsic apoptosis in osteoclasts.
Osteoporosis is a major health problem in postmenopausal women and the elderly that leads to fractures associated with substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, and the risk of fragility fractures has not yet been eliminated. There remains an unmet need for a broader range of therapeutics. Previous studies have shown that YC-1 has important regulatory functions in the cardiovascular and nervous systems. Many of the YC-1 effector molecules in platelets, smooth muscle cells and neurons, such as cGMP and μ-calpain, also have important functions in osteoclasts. In this study, we explored the effects of YC-1 on bone remodeling and determined the potential of YC-1 as a treatment for postmenopausal osteoporosis. Micro-computed tomography of lumbar vertebrae showed that YC-1 significantly improved trabecular bone microarchitecture in ovariectomized rats compared with sham-operated rats. YC-1 also significantly reversed the increases in serum bone resorption and formation in these rats, as measured by enzyme immunoassays for serum CTX-1 and P1NP, respectively. Actin ring and pit formation assays and TRAP staining analysis showed that YC-1 inhibited osteoclast activity and survival. YC-1 induced extrinsic apoptosis in osteoclasts by activating caspase-3 and caspase-8. In osteoclasts, YC-1 stimulated μ-calpain activity and inhibited Src activity. Our findings provide proof-of-concept for YC-1 as a novel antiresorptive treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone.


Facial swelling associated with impaction of the deciduous and permanent maxillary fourth premolars in a dog with patent ductus arteriosus.
A three-year-old Labrador retriever was referred for decreased appetite, a painful swelling in the region of the maxillary right fourth premolar, and a heart murmur indicative of patent ductus arteriosus (PDA) diagnosed 1.5-weeks prior to presentation. Oral examination and intraoral dental radiographs showed impaction of the maxillary right fourth premolar surrounded by reactive alveolar bone. Necrotic bone, remnants of the deciduous maxillary right fourth premolar, and the impacted permanent maxillary right fourth premolar were removed following surgical exploration of the area. The PDA was repaired without complication 2-weeks following oral surgery. The extraction site was healing appropriately, and the dog's inappetence and painful facial swelling had resolved.


Conscientiousness as a Predictor of the Gender Gap in Academic Achievement.
In recent decades, female students have been more successful in higher education than their male counterparts in the United States and other industrialized countries. A promising explanation for this gender gap are differences in personality, particularly higher levels of conscientiousness among women. Using Structural Equation Modeling on data from 4719 Dutch university students, this study examined to what extent conscientiousness can account for the gender gap in achievement. We also examined whether the role of conscientiousness in accounting for the gender gap differed for students with a non-dominant ethnic background compared to students with a dominant ethnic background. In line with our expectations, we found that conscientiousness fully mediated the gender gap in achievement, even when controlling for prior achievement in high school. This was the case among both groups of students. These findings provide insight into the mechanisms underlying the gender gap in achievement in postsecondary education settings. The current study suggests that the use of conscientiousness measures in university admission procedures may disadvantage male students. Instead, the use of such measures may be a fruitful way to identify those students who may benefit from interventions to improve their conscientiousness. Future research could examine how conscientiousness can be fostered among students who are low in conscientiousness.


Evaluation of bronchial hyperreactivity with mannitol dry powder challenge test in a paediatric population with intermittent allergic asthma or allergic rhinitis.
We evaluated the bronchial hyperreactivity (BHR) with a new bronchial challenge test, mannitol dry powder, in a paediatric population with intermittent allergic asthma or allergic rhinitis who did not respond to an exercise challenge test. We selected 50 children, aged 9-16 years, with intermittent allergic bronchial asthma (Group 1) or allergic rhinitis without clinical manifestation of asthma for at least 12 months (Group 2). All patients performed the following tests in three different days (≥ 48 hours apart): Day 1: exhaled nitric oxide (FeNO) determination followed by baseline spirometry and reversibility to inhaled beta2-agonists; Day 2: exercise challenge test followed by FeNO determination; Day 3: mannitol challenge test followed by FeNO determination. Forty children completed the study. Eighteen subjects of Group 1 (90 percent) and 5 subjects of Group 2 (25 percent) resulted positive to the mannitol test. Positive mannitol challenge subjects showed no statistically significant differences compared to negative subjects as regard baseline spirometry, reversibility to salbutamol and response to the exercise challenge test, but they had significantly higher FeNO values. In conclusion, the mannitol challenge test can be a diagnostic tool more useful than the exercise challenge test to identify BHR in a paediatric population with intermittent allergic asthma or allergic rhinitis because it is better reproducible, quick and easy to perform and well tolerated.


Calcium influx mediates the chemoattractant-induced translocation of the arrestin-related protein AdcC in Dictyostelium.
Arrestins are key adaptor proteins that control the fate of cell-surface membrane proteins and modulate downstream signaling cascades. The Dictyostelium discoideum genome encodes six arrestin-related proteins, harboring additional modules besides the arrestin domain. Here, we studied AdcB and AdcC, two homologs that contain C2 and SAM domains. We showed that AdcC - in contrast to AdcB - responds to various stimuli (such as the chemoattractants cAMP and folate) known to induce an increase in cytosolic calcium by transiently translocating to the plasma membrane, and that calcium is a direct regulator of AdcC localization. This response requires the calcium-dependent membrane-targeting C2 domain and the double SAM domain involved in AdcC oligomerization, revealing a mode of membrane targeting and regulation unique among members of the arrestin clan. AdcB shares several biochemical properties with AdcC, including in vitro binding to anionic lipids in a calcium-dependent manner and auto-assembly as large homo-oligomers. AdcB can interact with AdcC; however, its intracellular localization is insensitive to calcium. Therefore, despite their high degree of homology and common characteristics, AdcB and AdcC are likely to fulfill distinct functions in amoebae.


Immobilized artificial membrane chromatography: supports composed of membrane lipids.
Cell membranes provide an environment for several types of molecular processes and we are attempting to mimic the cell membranes' environment on a chromatography solid support. Chromatography solid supports utilizing lecithin as the bonded phase were synthesized and the HPLC behavior of hydrophilic peptides evaluated. A diC14 lecithin containing a terminal carboxy group on the C2 fatty acid chain was amidated with the surface amines of Nucleosil-300 (7NH2) silica particles. Based on elemental analysis, lecithin was coupled to Nucleosil-300 (7NH2) at a surface density near that of lecithin found in biological membranes and this novel chromatographic support material is denoted as Nucleosil-lecithin, the prototype immobilized artificial membrane. Infrared difference spectra of Nucleosil-lecithin minus Nucleosil-300 (7NH2) clearly showed amide I (1653.1 cm-1) and amide II (1550.9 cm-1) bands, giving direct spectroscopic evidence for the amide linkage. Spectral deconvolution resolved two peaks for the amide I band, and three peaks for the amide II band. This demonstrates lecithin interchain amide hydrogen bonding and/or hydrogen bonds between the lecithin amide link and unreacted silica surface amines. Nucleosil-lecithin as a solid phase mimics membranes and can be used to study the interactions of biomolecules with membranes. Our primary objective is to develop HPLC methods for studying the interaction between cell membranes and peptide sequences found near the interfaces of cell membranes. A frequency distribution of amino acids bracketing approximately 400 transmembrane peptide sequences showed Cys to be the least frequently occurring amino acid at this putative interfacial membrane region. Hydrophilic peptide analogs bearing Cys were used as model compounds to test Nucleosil-lecithin solid supports. Small peptides, six to eight amino acids in length, containing Cys bind approximately 2X tighter to Nucleosil-lecithin compared to identical peptides without the Cys residue. Thus, Cys at the interface of cells may stabilize protein-lipid interactions.


Immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in a complex environmental mixture from the Love Canal.
The organic phase of the leachate (OPL) from the Love Canal chemical dump site contains more than 100 organic compounds including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The immunotoxic potential of OPL was determined in two mouse strains which differ in their sensitivity to aromatic hydrocarbon (Ah) receptor-mediated toxicity. OPL was administered in corn oil in a single oral gavage to male BALB/cByJ (Ahb/Ahb) mice (0.5, 0.8, or 1.1 g/kg) and DBA/2J (Ahd/Ahd) mice (0.6, 0.9, or 1.3 g/kg). TCDD was similarly administered at 0.25, 1.0, 4.0, or 16.0 micrograms/kg. Two days later all mice were immunized with sheep erythrocytes (SRBC). The antibody response (PFC) and organ weights were evaluated 4 days later. OPL produced thymic atrophy and hepatomegaly in both strains at all dose levels. The PFC/spleen in BALB/cByJ mice was significantly reduced at the three doses to 34, 13, and 15%, respectively, of the control response. Serum anti-SRBC antibody levels and relative spleen weights were also reduced. The only immune effect in the DBA/2J mice was a decrease of the PFC/spleen to 58% of the control at the highest dose. TCDD decreased the relative thymus and spleen weights only in BALB/cByJ mice. However, TCDD produced hepatomegaly, a decrease in serum antibody, and a decrease in PFC/spleen in both BALB/cByJ and DBA/2J mice to 3 and 15%, respectively, at 16 micrograms/kg. Thus, the TCDD dose required to cause a 50% suppression (ED50) of PFC/spleen for the BALB/cByJ and DBA/2J strains was 1.84 and 3.89 micrograms/kg, respectively. The ED50 for OPL was 0.24 g/kg in BALB/cByJ mice. The TCDD concentration in the OPL was estimated to be 7.6 ppm, which agrees closely with the chemical analysis (3 ppm). The results suggest that the immunosuppression caused by OPL in BALB/cByJ mice was primarily due to TCDD, that the non-TCDD components of OPL diminished the TCDD immunotoxicity in the DBA/2J strain, and that the thymic atrophy and hepatomegaly were caused primarily by the non-TCDD components of the OPL.


Development of homospecific activity of GABA-transaminase in the mouse cerebral cortex and cerebellum and in neurons cultured from these brain areas.
The homospecific activity of GABA-transaminase (EC 188.8.131.52; GABA-T) in brain or neurons was determined as a function of development in vivo or in culture by measuring the enzyme activity together with the relative amount of GABA-T apoenzyme by the aid of a monospecific anti-GABA-T antibody. It was observed that both in cerebral cortex and cerebellum in vivo and in neurons cultured from these brain regions the homospecific activity of GABA-T changed during development. By incubation of tissue extracts with similar extracts in which GABA-T activity had been selectively and irreversibly destroyed with gamma-vinyl GABA (Vigabatrin) it was established that this change in homospecific activity was at least partly due to the presence of an endogenous activator of GABA-T. The results point towards a rather complex endogenous regulation of GABA-T during development in vivo and in vitro.


Succinate promotes stem cell migration through the GPR91-dependent regulation of DRP1-mediated mitochondrial fission.
The role of metabolites produced from stem cell metabolism has been emerged as signaling molecules to regulate stem cell behaviors such as migration. The mitochondrial morphology is closely associated with the metabolic balance and stem cell function. However, the physiological role of succinate on human mesenchymal stem cell (hMSC) migration by regulating the mitochondrial morphology remains unclear. Here, we investigate the effect of succinate on hMSC migration via regulation of mitochondrial dynamics and its related signaling pathway. Succinate (50 μM) significantly accelerates hMSC migration. Succinate increases phosphorylation of pan-PKC, especially the atypical PKCζ level which was blocked by the knockdown of Gαq and Gα12. Activated PKCζ subsequently phosphorylates p38 MAPK. Cytosolic DRP1 is phosphorylated by p38 MAPK and results in DRP1 translocation to the mitochondria outer membrane, eventually inducing mitochondrial fragmentation. Mitochondrial fission-induced mitochondrial function elevates mitochondrial ROS (mtROS) levels and activates Rho GTPases, which then induces F-actin formation. Furthermore, in a skin excisional wound model, we found the effects of succinate-pretreated hMSC enhanced wound closure, vascularization and re-epithelialization and confirmed that DRP1 has a vital role in injured tissue regeneration. Overall, succinate promotes DRP1-mediated mitochondrial fission via GPR91, consequently stimulating the hMSC migration through mtROS-induced F-actin formation.


Modeling competitive cytokine adsorption dynamics within hemoadsorption beads used to treat sepsis.
Extracorporeal blood purification is a promising therapeutic modality for sepsis, a potentially fatal, dysfunctional immunologic state caused by infection. Removal of inflammatory mediators such as cytokines from the blood may help attenuate hyper-inflammatory signaling during sepsis and improve patient outcomes. We are developing a hemoadsorption device to remove cytokines from the circulating blood using biocompatible, porous sorbent beads. In this work, we investigated whether competitive adsorption of serum solutes affects cytokine removal dynamics within the hemoadsorption beads. Confocal laser scanning microscopy (CLSM) was used to quantify intraparticle adsorption profiles of fluorescently labeled IL-6 in horse serum, and results were compared to predictions of a two component competitive adsorption model. Supraphysiologic IL-6 concentrations were necessary to obtain adequate CLSM signal, therefore unknown model parameters were fit to CLSM data at high IL-6 concentrations, and the fitted model was used to simulate cytokine adsorption behavior at physiologically relevant levels which were below the microscopy detection threshold. CLSM intraparticle IL-6 adsorption profiles agreed with predictions of the competitive adsorption model, indicating displacement of cytokine by high affinity serum solutes. However, competitive adsorption effects were predicted using the model to be negligible at physiologic cytokine concentrations associated with hemoadsorption therapy.


Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation.
The purpose of this study is to determine the impacts of CYP3A5 polymorphism on tacrolimus concentration and the proportion of patients within a target therapeutic range during the first week after transplantation together with the 3-month acute rejection rate in kidney transplant patients receiving a minimized tacrolimus regimen. A total of 164 patients participated in the study. All received oral tacrolimus twice daily starting on the day of surgery with the target pre-dose (trough) concentration of 4-8 ng/ml for prevention of allograft rejection. Cytochrome P450 (CYP) 3A5 genotypes were determined. The patients were divided into CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (homozygous CYP3A5*3). Whole blood tacrolimus concentrations on days 3 and 7 posttransplantation and the incidence of biopsy-proven acute rejection (BPAR) at 3-month posttransplantation were compared between groups. On day 3, the median (IQR) dose-and-weight-normalized trough concentration in expressers and nonexpressers were 54.61 (31.98, 78.87) and 91.80 (57.60, 130.20) ng/ml per mg/kg/day, respectively (p < 0.001). Although only 47 and 42% of expressers and nonexpressers were within the target range on day 3, approximately 60% of both groups were within the target range on day 7. Proportions of BPAR among expressers and nonexpressers were 6.0 and 7.4 %, respectively (p = 0.723). The median (IQR) times to the first rejection in CYP3A5 expressers and nonexpressers were 32 (12, 68) and 15 (12, 37) days, respectively (p = 0.410). Although CYP3A5 polymorphism significantly influenced the tacrolimus dose required to achieve the target concentration, the impact of CYP3A5 polymorphism on BPAR was not observed in this study.


Susceptibility to auditory closed-loop stimulation of sleep slow oscillations changes with age.
Cortical slow oscillations (SOs) and thalamocortical sleep spindles hallmark slow wave sleep and facilitate memory consolidation, both of which are reduced with age. Experiments utilizing auditory closed-loop stimulation to enhance these oscillations showed great potential in young and older subjects. However, the magnitude of responses has yet to be compared between these age groups. We examined the possibility of enhancing SOs and performance on different memory tasks in a healthy middle-aged population using this stimulation and contrast effects to younger adults. In a within-subject design, 17 subjects (55.7 ± 1.0 years) received auditory stimulation in synchrony with SO up-states, which was compared to a no-stimulation sham condition. Overnight memory consolidation was assessed for declarative word-pairs and procedural finger-tapping skill. Post-sleep encoding capabilities were tested with a picture recognition task. Electrophysiological effects of stimulation were compared to a previous younger cohort (n = 11, 24.2 ± 0.9 years). Overnight retention and post-sleep encoding performance of the older cohort revealed no beneficial effect of stimulation, which contrasts with the enhancing effect the same stimulation protocol had in our younger cohort. Auditory stimulation prolonged endogenous SO trains and induced sleep spindles phase-locked to SO up-states in the older population. However, responses were markedly reduced compared to younger subjects. Additionally, the temporal dynamics of stimulation effects on SOs and spindles differed between age groups. Our findings suggest that the susceptibility to auditory stimulation during sleep drastically changes with age and reveal the difficulties of translating a functional protocol from younger to older populations.


Initial experience with a universal-length copolymer ureteral stent.
A universal-length ureteral stent made of a biocompatible copolymer was designed specifically for easy antegrade internal placement. The double-looped distal end of the stent eliminates the need to measure the distance from the ureteropelvic to ureterovesical junction. If additional length is required, a portion of the distal loop is incorporated into the stent shaft. Interventional radiology practices benefit economically, as the universal-length stent is the only size required for the treatment of most ureteral obstructions.


Longevity of occlusally-stressed restorations in posterior primary teeth.
To compile a survey of the longevity and reasons for failure of stainless steel crowns, amalgam, glass-ionomer, composite and compomer restorations in stress-bearing cavities of primary molars. This work reviewed the dental literature of 1971 up to July 2003 for longitudinal, controlled clinical studies and retrospective cross-sectional studies. Only studies investigating the clinical performance of restorations in primary teeth with an observation period of at least 2 years were included. Annual failure rates of stainless steel crowns, amalgam, glass-ionomer, composite and compomer restorations were determined and failure reasons were discussed. Annual failure rates in stress-bearing cavities of primary molars were determined to be: 0-14% for stainless steel crowns, 0-35.3% for amalgam restorations, 0-25.8% for glass-ionomer restorations, 2-29.1% for atraumatic restorative treatments, 0-15% for composite restorations, and 0-11 for compomer restorations. Main reasons for failure were secondary caries, marginal deficiencies, fracture, and wear.


Clinico-Bacteriological Study of Chronic Otitis Media and its Prevalence in Tertiary Care Hospital.
This Retrospective observational study was done over a period of 5 years, consisting of 2530 patients with chronic otitis media (COM) attended ENT OPD of a tertiary care hospital of Central India.COM commonly occurs in the age group from 11 to 20 years (37.12%). Females are more predominantly effected than males. Mucosal type (76.4%) is more common. Complications were associated with squamous type of COM.Pus culture showed positive growth of Pseudomonas in 33.9% cases. COM is a common public health problem that is often wrongly trivialized by people. Health awareness campaign, improved health education and easy accessibility to health care facilities can reduce the morbidity and mortality of this disease and therefore can reduce the incidence of this disease.


Characterization of binding sites for the angiotensin II antagonist 125I-[Sarc1,Ile8]-angiotensin II on murine neuroblastoma N1E-115 cells.
The murine neuroblastoma N1E-115 cell line contains binding sites for the angiotensin II (Ang II) receptor antagonist 125I-[Sarc1,Ile8]-Ang II (125I-SARILE). Binding of 125I-SARILE to N1E-115 membranes was rapid, reversible, and specific for Ang II-related peptides. The rank order potency of 125I-SARILE binding was the following: [Sarc1]-Ang II = [Sarc1,Ile8]-Ang II greater than Ang II greater than Ang III = [Sarc1,Thr8]-Ang II much greater than Ang I. Scatchard analysis of membranes prepared from confluent monolayers revealed a homogenous population of high affinity (KD = 383 +/- 60 pM) binding sites with a Bmax of 25.4 +/- 1.6 fmol/mg of protein. Moreover, the density, but not the affinity, of the binding sites increased as the cells progressed from logarithmic to stationary growth in culture. Finally, agonist, but not antagonist, binding to N1E-115 cells was regulated by guanine nucleotides. Collectively, these results suggest that the murine neuroblastoma N1E-115 cell line may provide a useful model in which to investigate the signal transduction mechanisms utilized by neuronal Ang II receptors.


[Clinical analysis of diplopia in 68 cases with orbital fractures].
To explore the cause of orbital fracture associated with diplopia by summarizing 68 cases,in order to offer reference for clinical treatment. 68 cases of orbital fracture associated with diplopia were examined by maxillofacial surgeon and oculist,by analyzing the CT and X-ray films of whom to make clear the reasons of diplopia. Of the 68 cases,male was more than female,vertical diplopia was dominant,and generally with the changes of the orbital structure. The main cause of diplopia is for the changes of orbital structures. The doctors must take it seriously and give the patients timely treatment.


Management of adult patients with type 1 diabetes mellitus in Africa: A post-hoc cohort analysis of 12 African countries participating in the International Diabetes Management Practices Study (Wave 7).
There is a paucity of information on real world management of African adult patients with type 1 diabetes mellitus (T1DM). We aimed to describe a cohort of African adults with T1DM.The International Diabetes Management Practices Study is an observational survey conducted from 2005 to 2017. Data were collected in seven individual waves from countries in Asia, Africa, East Europe, and Latin America. Wave 7 was conducted from 2016 to 2017 and the African cohort included 12 countries. Questionnaires were administered to clinicians and patients. Analyses were mainly descriptive. Logistic regressions were performed to identify predictive factors for glycaemic control.A total of 788 patients were enrolled in the study. HbA1c values were available for 712 patients; only 16.6% had HbA1c values <7%. A total of 196 (24.9%) reported being hospitalized in the preceding year, with the most common reasons being diabetic ketoacidosis (58.1%, 93/160) and hypoglycaemia (31.1%; 52/167). Over half of the patients (55.4%) stated that the cost of test strips limited regular glycemic monitoring; a minority of patients (15%, 120/788) received structured diabetes education. Predictors of HbA1c <7% included patients receiving diabetes education (odds ratio [OR] [95% confidence interval, CI] = 2.707 [1.157-6.335] P = .022), following a healthy diet and exercise plan (OR [95% CI] = 2.253 [1.206-4.209], P < .001) and self-managing (monitoring glucose levels and adjusting insulin accordingly) (OR [95% CI] 2.508 [1.500-4.191] P < .001).African adults with T1DM have suboptimal glycemic control with almost one-quarter reporting hospitalization within the preceding year. Most patients felt comfortable with self-adjustment of insulin dose but said that the cost of test strips was the main factor that limited regular monitoring. Reducing direct costs of testing strips and insulin, and improving education will address major challenges within these settings.


Hydroxyurea in the management of sickle cell disease: pharmacogenomics and enzymatic metabolism.
Hydroxyurea (HU) was approved to be used in the treatment of sickle cell disease (SCD) because of its anti-sickling potential. However, there is variability in HU response among SCD patients and this can be due to physiological, socioeconomic, environmental, metabolic and/or genetic factors. The present review focuses on the latter two. Three quantitative trait loci, HBG2, BCL11A and HMIP, have been suggested as important markers for HU response. Other genes (ASS1, KLF10, HAO2, MAP3K5, PDE7B, TOX, NOS1, NOS2A, FLT1, ARG1, ARG2, UGT1A1, OR51B5/6, SIN3A, SALL2, SAR1A, UTB, OCTN1, CYP2C9, AQP9, MPO, CYP2E1, and GSTT1) have also been considered. Studies implicate catalase, urease, horseradish peroxidase and enzymes of CYP450 family in HU metabolism. However, little is known about these enzymes. Therefore, further studies are needed to elucidate the metabolic pathway of HU, which will facilitate pharmacogenomic studies and help in identification of candidate genes for predicting HU response.


Analysis of CNS sympatho-inhibition produced by guanabenz.
The effects of guanabenz on several autonomic systems were observed in vagotomized, anesthetized cats with the aim of determining, in a quantitative sense, the degree to which guanabenz produces a clonidine-like central nervous system action. Guanabenz given as a single dose (50 micrograms/kg i.v.) produced a transient hypertension associated with a more sustained bradycardia and depression of centrally (hypothalamic) evoked electrodermal responses (EDR). Increasing cumulative doses of guanabenz (3-1000 micrograms/kg i.v.) also resulted in a dose-related depression of EDR amplitude, transient hypertension followed by hypotension, sustained bradycardia, and mydriasis. All responses were antagonized by pretreatment with yohimbine (0.5 mg/kg i.v.). The ED50 for depression of the centrally evoked EDR was in the range of 50-100 micrograms/kg i.v. in the non-pretreated preparations. Guanabenz (100 micrograms/kg i.v.) was shown to be devoid of significant ganglionic blocking properties. These experiments suggest that guanabenz acts like clonidine in the CNS and that an alpha 2-adrenergic inhibitory mechanism is involved in its myriad of central autonomic effects.


[Post-operative surveillance and intensive care after orthopedic procedures of the vertebral column (author's transl)].
113 corrective procedures of the vertebral column by ventral and/or dorsal approach have been analysed. The post-operative findings have been reported, including blood-gas analysis, hemoglobin and hematocrit, electrolytes, and fluid balance. A correlative-statistical analysis of the scoliosis group was carried out according to number of involved segments, degree of curvature, age, length of operative time and total blood loss. The post-operative complications were related to preexisting risk factors.


["He does not know it yet"-Triadic communication and its pitfalls exemplified by an oncological ward round consultation].
Medical communication is an effective instrument for the medical practice. Due to the low status that medical communication still has within medicine and medical education, many physicians do not know how to use this instrument professionally. Using medical communication in a way that patients are well informed and involved is a prerequisite for them to make self-determined decisions. In this paper I analyze a consultation in an oncology ward to show the pitfalls of medical communication, especially in triadic communication, based on a case study to work out suggestions for optimization from the transcript. Mistakes in conducting conversations, which can be recognized as such in theory, unfortunately still happen in practice, which is why this case study is intended as an invitation to critically reflect on one's own conduct of conversations. The conclusion contains suggestions for the preparation as well as the conduct of the consultation during medical rounds.