Quantitative imaging of tongue kinematics during infant feeding and adult swallowing reveals highly conserved patterns.
Tongue motility is an essential physiological component of human feeding from infancy through adulthood. At present, it is a challenge to distinguish among the many pathologies of swallowing due to the absence of quantitative tools. We objectively quantified tongue kinematics from ultrasound imaging during infant and adult feeding. The functional advantage of this method is presented in several subjects with swallowing difficulties. We demonstrated for the first time the differences in tongue kinematics during breast- and bottle-feeding, showing the arrhythmic sucking pattern during bottle-feeding as compared with breastfeeding in the same infant with torticollis. The method clearly displayed the improvement of tongue motility after frenotomy in infants with either tongue-tie or restrictive labial frenulum. The analysis also revealed the absence of posterior tongue peristalsis required for safe swallowing in an infant with dysphagia. We also analyzed for the first time the tongue kinematics in an adult during water bolus swallowing demonstrating tongue peristaltic-like movements in both anterior and posterior segments. First, the anterior segment undulates to close off the oral cavity and the posterior segment held the bolus, and then, the posterior tongue propelled the bolus to the pharynx. The present methodology of quantitative imaging revealed highly conserved patterns of tongue kinematics that can differentiate between swallowing pathologies and evaluate treatment interventions. The method is novel and objective and has the potential to advance knowledge about the normal swallowing and management of feeding disorders.


Understanding olfactory and behavioural responses to dietary cues in age-1 lake sturgeon Acipenser fulvescens.
Detection of environmental cues is essential for all vertebrates and is typically established by the olfactory epithelium and olfactory sensory neurons (OSNs). In fishes, microvillous and ciliated OSNs are the principal types, typically detecting amino acids and bile salts, respectively. Activation of OSN receptors by specific ligands initiate downstream signal processing often leading to behavioural responses. In this study we used electrophysiological and behavioural techniques to evaluate olfactory detection and behaviour in juvenile lake sturgeon Acipenser fulvescens in response to hatchery- and natural dietary cues. We hypothesized that electro-olfactogram (EOG) and behavioural responses would be dependent on diet type. We predicted that inhibition of the phospholipase C/inositol 1,4,5-triphosphate (PLC/IP3) secondary transduction pathway would reduce EOG responses to dietary cues and, inhibition of the adenylyl cyclase/adenosine 3,5-cyclic monophosphate (cAMP) pathway, would have no effect. Furthermore, we predicted a strong EOG response would be manifested in a change in behaviour. We observed that both the PLC/IP3 and cAMP pathways were significantly involved in the detection of dietary cues. However, EOG responses did not manifest to behavioural responses, although the foraging activity to the hatchery cue was significantly greater compared to the control. Our results support the notion that lake sturgeon raised in a hatchery and fed a commercial pelleted diet may become accustomed to it prior to release into the wild. Further, this study suggests that, in conservation aquaculture settings, lake sturgeon should be exposed to natural dietary cues prior to release as one strategy to promote food recognition.


Effects of ingestion of bicarbonate, citrate, lactate, and chloride on sprint running.
Ingestion of sodium bicarbonate is known to enhance sprint performance, probably via increased buffering of intracellular acidity. The goal was to compare the effect of ingestion of sodium bicarbonate with that of other potential buffering agents (sodium citrate and sodium lactate) and of a placebo (sodium chloride) on sprinting. In a double-blind randomized crossover trial, 15 competitive male endurance runners performed a run to exhaustion 90 min after ingestion of each of the agents in the same osmolar dose relative to body mass (3.6 mosmol x kg) on separate days. The agents were packed in gelatin capsules and ingested with 750 mL of water over 90 min. During each treatment we assayed serial finger-prick blood samples for lactate and bicarbonate. A familiarization trial was used to set a treadmill speed for each runner's set of runs. We converted changes in run time between treatments into changes in a time trial of similar duration using the critical-power model, and we estimated likelihood of practical benefit using 0.5% as the smallest worthwhile change in time-trial performance. The mean run times to exhaustion for each treatment were: bicarbonate 82.3 s, lactate 80.2 s, citrate 78.2 s, and chloride 77.4 s. Relative to bicarbonate, the effects on equivalent time-trial time were lactate 1.0%, citrate 2.2%, and chloride 2.7% (90% likely limits +/- 2.1%). Ingested lactate and citrate both appeared to be converted to bicarbonate before the run. There were no substantial differences in gut discomfort between the buffer treatments. Bicarbonate is possibly more beneficial to sprint performance than lactate and probably more beneficial than citrate or chloride. We recommend ingestion of sodium bicarbonate to enhance sprint performance.


Malakoplakia of the tongue--a case report.
Malakoplakia of the tongue occurring in a nine year old Caucasian boy is reported. This rare chronic inflammatory disease usually occurs in the urinary tract, especially the bladder, and is uncommon in children. Presenting symptoms included a tongue mass mimicking tumor and dysphagia. Treatment consisted of biopsy and subsequent antibiotics toward suspected gram-negative organisms. The patient recovered uneventfully and has remained well.


Pulmonary cellular dysfunction in endotoxin shock: metabolic and transport derangements.
Lung cell metabolic and ion transport alterations in endotoxin shock have been studied to elucidate mechanisms of endotoxin-induced pulmonary dysfunction. Glucose oxidation to lactate as well as to CO2 is significantly increased with a decrease in the lung ATP contents. Active Na+ transport is impaired, indicating an increase in lung intracellular fluid. The altered glucose metabolism and active ion transport could potentially contribute to lung edemagenesis in endotoxicosis.


Six-day amoxicillin vs. ten-day penicillin V therapy for group A streptococcal tonsillopharyngitis.
To compare the efficacy and safety of amoxicillin (50 mg/kg/day divided twice daily) for 6 days and penicillin V (45 mg/kg/day divided into three doses/day) for 10 days in children with group A streptococcal (GAS) tonsillopharyngitis. In a prospective, comparative, open, randomized, multicenter trial, children were scheduled to return for visits 4 days (main end point) and 1 month after the completion of treatment for clinical and bacteriologic assessment. Total DNA restriction fragment length polymorphism was used to compare pre- and posttreatment GAS isolates. Between September, 1993, and February, 1995, 321 children (161 amoxicillin, 160 penicillin V) were enrolled, among whom 318 (160 amoxicillin, 158 penicillin V) were evaluable for safety, and 277 were evaluable for efficacy. Four days after the completion of treatment, pretreatment GAS were eradicated from 118 of the 141 children receiving amoxicillin (83.7%) and 116 of the 136 (85.3%) taking penicillin. One month after the outset of treatment, bacteriologic relapses were observed in 9.9% (n = 11) of the children receiving amoxicillin and 5.7% (n = 6) of those treated with penicillin V, bacteriologic recurrences in 5 and 3 patients, respectively. Adverse events related to the study medications were reported in 4 patients in the amoxicillin group and 8 in the penicillin V group. Drug-related adverse events leading to treatment discontinuation occurred in 3 patients, all in the penicillin V group. Compliance, based on diary cards and the weight of study drugs returned, was significantly better in the amoxicillin group. CONCLUSIONS. The efficacy and safety of amoxicillin (50 mg/kg/day twice daily) for 6 days were not statistically different from those of penicillin (45 mg/kg/d three times a day) for 10 days in the treatment of GAS tonsillopharyngitis.


Expression of metallothionein II in intestinal metaplasia, dysplasia, and gastric cancer.
Differential display is a valuable tool for the identification of differentially expressed genes in human carcinogenesis and development. The search for differentially expressed genes in gastric cancer and its premalignant lesions may help to define molecular alterations in the gastric mucosa that may precede the development of gastric cancer. Using the differential display technique, we identified a cDNA fragment, encoding metallothionein (MT) IIa mRNA. We performed immunohistochemical analysis using a monoclonal antibody directed against human MT and tissues obtained from 34 patients with gastric cancer and 20 healthy individuals to determine the expression and localization of MT in gastric cancer and its associated premalignant lesions and to correlate our findings with histomorphological features and Helicobacter pylori status. In addition, MT expression was assessed in gastric tissues obtained from patients with gastric cancer and first-degree relatives of patients with gastric cancers and healthy individuals using reverse transcription-PCR analysis. Northern blot analysis confirmed the overexpression of MT IIa in gastric cancer. In the normal gastric tissues, no MT immunoreactivity was observed at the superficial gastric epithelium toward the top of gastric glands. However, MT immunoreactivity was detected at the foveolar neck of the gastric glands. Immunohistochemical analysis revealed an intense MT immunoreactivity in gastric cancer cells, independent of tumor stage, grade of differentiation, or tumor type. Furthermore, areas of dysplasia and intestinal metaplasia also exhibited intense MT immunoreactivity. Reverse transcription-PCR analysis of gastric biopsies obtained from first-degree relatives of patients with gastric cancer revealed the frequent expression of MT Ia in this high-risk group as compared with healthy subjects (P < 0.01). The overexpression of MT in gastric cancer and the expression of MT in intestinal metaplasia and dysplasia, as well as the expression of MT in the gastric mucosa of first-degree relatives of patients with gastric cancer, point to a role for MT in the early process of malignant transformation of the gastric mucosa.


Concerning the deactivation of cobalt(III)-based porphyrin and salen catalysts in epoxide/CO2 copolymerization.
Functioning as active catalysts for propylene oxide (PO) and carbon dioxide copolymerization, cobalt(III)-based salen and porphyrin complexes have drawn great attention owing to their readily modifiable nature and promising catalytic behavior, such as high selectivity for the copolymer formation and good regioselectivity with respect to the polymer microstructure. Both cobalt(III)-salen and porphyrin catalysts have been found to undergo reduction reactions to their corresponding catalytically inactive cobalt(II) species in the presence of propylene oxide, as evidenced by UV/Vis and NMR spectroscopies and X-ray crystallography (for cobalt(II)-salen). Further investigations on a TPPCoCl (TPP = tetraphenylporphyrin) and NaOMe system reveal that such a catalyst reduction is attributed to the presence of alkoxide anions. Kinetic studies of the redox reaction of TPPCoCl with NaOMe suggests a pseudo-first order in cobalt(III)-porphyrin. The addition of a co-catalyst, namely bis(triphenylphosphine)iminium chloride (PPNCl), into the reaction system of cobalt(III)-salen/porphyrin and PO shows no direct stabilizing effect. However, the results of PO/CO2 copolymerization by cobalt(III)-salen/porphyrin with PPNCl suggest a suppressed catalyst reduction. This phenomenon is explained by a rapid transformation of the alkoxide into the carbonate chain end in the course of the polymer formation, greatly shortening the lifetime of the autoreducible PO-ring-opening intermediates, cobalt(III)-salen/porphyrin alkoxides.


Transcranial direct current stimulation modulates brain functional connectivity in autism.
Autism spectrum disorder (ASD) is characterized by deficits in social interactions, impairments in language and communication, and highly restricted behavioral interests. Transcranial direct current stimulation (tDCS) is a widely used form of noninvasive stimulation and may have therapeutic potential for ASD. So far, despite the widespread use of this technique in the neuroscience field, its effects on network-level neural activity and the underlying mechanisms of any effects are still unclear. In the present study, we used electroencephalography (EEG) to investigate tDCS induced brain network changes in children with ASD before and after active and sham stimulation. We recorded 5 min of resting state EEG before and after a single session of tDCS (of approximately 20 min) over dorsolateral prefrontal cortex (DLPFC). Two network-based methods were applied to investigate tDCS modulation on brain networks: 1) temporal network dynamics were analyzed by comparing "flexibility" changes before vs after stimulation, and 2) frequency specific network changes were identified using non-negative matrix factorization (NMF). We found 1) an increase in network flexibility following tDCS (rapid network configuration of dynamic network communities), 2) specific increase in interhemispheric connectivity within the alpha frequency band following tDCS. Together, these results demonstrate that tDCS could help modify both local and global brain network dynamics, and highlight stimulation-induced differences in the manifestation of network reconfiguration. Meanwhile, frequency-specific subnetworks, as a way to index local and global information processing, highlight the core modulatory effects of tDCS on the modular architecture of the functional connectivity patterns within higher frequency bands.


Relationship of glioblastoma multiforme to the lateral ventricles predicts survival following tumor resection.
There has been an increased focus on the region adjacent to the lateral ventricles (LV) as a potential source of malignant tumors and/or more aggressive disease. We set out to determine if glioblastoma multiforme (GBM) bordering the LV was associated with decreased survival as compared to non-LV GBM. We reviewed the clinical records of 69 consecutive patients undergoing craniotomy for GBM at a single academic institution. Twenty-six patients were identified with contrast-enhancing lesions (CEL) bordering the LV (LV CEL). These 26 patients were matched with 26 patients with CEL not bordering the LV (non-LV CEL). These cohorts were matched for factors consistently shown to be associated with survival, which were age, tumor size, Karnofsky performance score, extent of resection, Gliadel implantation, and Temodar chemotherapy. Overall survival was compared between the cohorts via Log-rank analysis. Despite similarities in pre-operative clinical status, tumor size, peri-operative outcome, and treatment regimens, the median survival for patients with LV CEL was significantly decreased as compared to patients with non-LV CEL (8 months vs. 11 months), P = 0.02. Additionally, survival analysis in patients stratified by primary and secondary resection also demonstrated a strong trend towards decreased survival after resection of LV CEL. After primary and secondary resection, patients with LV CEL versus non-LV CEL had a median survival of 11 months vs. 14 months (P = 0.10) and 7 months vs. 10 months (P = 0.11), respectively. While the causal factors underlying this observation are not provided with this observational study, GBM bordering the LV may carry a prognostic significance.


Cardiopulmonary resuscitation with vasopressin in a dog.
That endogenous vasopressin levels in successfully resuscitated human patients were significantly higher than in patients who died pointed to the possible benefit of administering vasopressin during cardiopulmonary resuscitation (CPR). Several CPR studies in pigs showed that vasopressin improved blood flow to vital organs, cerebral oxygen delivery, resuscitability and neurological outcome when compared with epinephrine. In a small clinical study, vasopressin significantly improved short-term survival when compared with epinephrine indicating its potential as an alternative pressor to epinephrine during CPR in human beings. As there was little clinical data available at that time, its recommended use was limited to adult human beings with shock-refractory ventricular fibrillation. In this report, we present the case of a dog in which the successful management of intraoperative asystolic cardiac arrest involved vasopressin. Unexpected cardiac arrest occurred during anaesthesia for the surgical removal of multiple mammary adenocarcinomata in a 11-year-old Yorkshire terrier. Despite an ASA physical status assignation of III, the dog was successfully resuscitated with external chest compressions, intermittent positive pressure ventilation and vasopressin (2 doses of 0.8 IU kg(-1)) and was discharged 3 days later without signs of neurological injury. We believe vasopressin contributed to restoring spontaneous circulation. It may prove increasingly useful in perioperative resuscitation in dogs.


Expression of complement proteins C2 and factor B in transfected L cells.
Factor B and C2 are structurally and functionally similar complement proteins encoded by genes that are closely linked within the class III region of the major histocompatibility complex (MHC). In this study, restriction endonuclease digestion of cosmid DNAs isolated from an H-2d murine genomic library indicated that the chromosomal organization of these two genes was similar in mouse to that in man. To further characterize their expression, cosmid DNAs encoding human and murine factor B and C2 were introduced into mouse L cells by DNA-mediated gene transfer. Factor B expression was demonstrated in cells transfected with either the human or the murine gene, but not in cells transfected with a control plasmid. Synthesis and secretion of factor B by L cells transfected with the human and murine cosmids was similar to that of human and murine cells in primary culture. An interspecies variation between human and murine factor B was identified and reproduced with extraordinary fidelity by the mouse fibroblast. In contrast, C2 RNA and protein were expressed by L cells alone and by L cells transfected with a control plasmid, as well as by L cells transfected with cosmids encoding human and murine complement genes. Expression of the transferred human C2 gene was demonstrated by the presence of a new distinct C2 RNA transcript and secretion of biologically active human C2. These results demonstrate the similarity of organization of the murine and human class III MHC regions. Expression of the two closely linked gene products, C2 and factor B, after DNA-mediated gene transfer provides a system for further analysis of regulation in both normal and deficient states.


miRNA-based therapies for the irritable bowel syndrome.
The irritable bowel syndrome (IBS) is a common disorder of unknown etiology. Recently, a group of dysregulated microRNAs (miRNAs) in blood microvesicles and in colon tissue have been identified in IBS patients. miRNAs have been shown to modulate specific biological processes such as differentiation, proliferation, apoptosis and metabolism. The ideal strategy would be to use specific miRNAs as both diagnostic and therapeutic tools to recover intestinal function and treat intractable gastrointestinal symptoms. In conclusion, further study of the functional role of miRNAs will lead to a better understanding of the dysregulation of intestinal pathways in IBS patients. The results may lead to preventive and/or therapeutic strategies that use small molecules (such as mimics or inhibitors of specific miRNAs) to affect genetic and epigenetic control. Future clinical trials may use microvesicle-associated miRNA-based therapies by using specific inhibitors/mimics of miRNA to target gene expression and treat IBS.


Expression of estrogen receptor coactivators in the rat uterus.
Nuclear receptor coactivators associate in a ligand-dependent manner with estrogen receptors (ER) and other nuclear receptors, and they enhance ligand-dependent transcriptional activation. This study examined basal coactivator expression in rat uterus to investigate if expression of these genes is regulated by estradiol-17 beta or tamoxifen. Ovariectomized mature and immature rats were injected with estradiol-17 beta, tamoxifen, or vehicle (i.e., sesame oil) alone. Uteri were collected and analyzed for changes in coactivator mRNA expression using Northern blot and in situ hybridization analyses. Constitutive uterine mRNA expression of switch protein for antagonist (SPA), SRC-1, GRIP1, RAC3, RIP140, and p300 mRNAs was observed in control uteri, and treatment with ER ligands did not alter coactivator mRNA levels. The data suggest that expression of these coactivator genes is not sensitive to estradiol or tamoxifen in the rat uterus. No cell type-specific pattern of expression was apparent in uterine sections from mature and immature rats; however, silver grains were more abundant in luminal and glandular epithelial cells compared with the stroma and myometrium, indicating that coactivator mRNA levels vary among the uterine compartments. Thus, to our knowledge, we show for the first time that there is constitutive expression of several uterine nuclear receptor coactivators in a physiological setting that remains insensitive to estrogenic regulation. Furthermore, we speculate that higher constitutive levels of coactivator expression in glandular and luminal epithelial cells may be associated with increased hormonal responsiveness by these uterine compartments.


Volumetric display system based on three-dimensional scanning of inclined optical image.
A volumetric display system based on three-dimensional (3D) scanning of an inclined image is reported. An optical image of a two-dimensional (2D) display, which is a vector-scan display monitor placed obliquely in an optical imaging system, is moved laterally by a galvanometric mirror scanner. Inclined cross-sectional images of a 3D object are displayed on the 2D display in accordance with the position of the image plane to form a 3D image. Three-dimensional images formed by this display system satisfy all the criteria for stereoscopic vision because they are real images formed in a 3D space. Experimental results of volumetric imaging from computed-tomography images and 3D animated images are presented.


Neighborhood conditions, diabetes, and risk of lower-body functional limitations among middle-aged African Americans: a cohort study.
The relationship between presence of diabetes and adverse neighborhood and housing conditions and their effect on functional decline is unclear. We examined the association of adverse neighborhood (block face) and housing conditions with incidence of lower-body functional limitations among persons with and those without diabetes using a prospective population-based cohort study of 563 African Americans 49-65 years of age at their 2000-2001 baseline interviews. Participants were randomly sampled African Americans living in the St. Louis area (response rate: 76%). Physician-diagnosed diabetes was self reported at baseline interview. Lower-body functional limitations were self reported based on the Nagi physical performance scale at baseline and the three-year follow-up interviews. The external appearance of the block the respondent lived on and five housing conditions were rated by study interviewers. All analyses were done using propensity score methods to control for confounders. 109 (19.4%) of subjects experienced incident lower-body functional limitations at three-year follow-up. In adjusted analysis, persons with diabetes who lived on block faces rated as fair-poor on each of the five conditions had higher odds (7.79 [95% confidence interval: 1.36-37.55] to 144.6 [95% confidence interval: 4.45-775.53]) of developing lower-body functional limitations than the referent group of persons without diabetes who lived on block faces rated as good-excellent. At least 80 percent of incident lower-body functional limitations was attributable to the interaction between block face conditions and diabetes status. Adverse neighborhood conditions appear to exacerbate the detrimental effects on lower-body functioning associated with diabetes.


[Enzymatic examination of citrate-isocitrate accumulation in yeasts].
The activities of the enzymes citrate synthase, aconitate hydratase, isocitrate dehydrogenase and isocitrate lyase in cell homogenates of n-paraffin grown citrate plus isocitrate accumulating yeasts (C. lipolytica high rate accumulating strain and C. guilliermondii low rate accumulating strain) were determined. It is shown that the activities of the enzymes decline after transition from tropho- to idiophase and remain constant with exception of isocitrate lyase which diminishes slowly. The decline in activity of the isocitrate lyase was greatest in the cells of C. guilliermondii. It is discussed that the differences of the enzymatic activities in the tropho- and idiophase, resp. may be artefacts due to changes in the structure of cellular envelope, but that the decline of lyase activity in the idiophase could be one factor determining the rate of citric- and isocitric acid overproduction. The diminishing of isocitrate lyase in the course of idiophase is interpreted as example of a disappearing enzyme no further needed for normal function of the cells.


The interaction of beta-arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits.
Beta-arrestins are cytosolic proteins that regulate the signaling and the internalization of G protein-coupled receptors (GPCRs). Although termination of receptor coupling requires beta-arrestin binding to agonist-activated receptors, GPCR endocytosis involves the coordinate interactions between receptor-beta-arrestin complexes and other endocytic proteins such as adaptor protein 2 (AP-2) and clathrin. Clathrin interacts with a conserved motif in the beta-arrestin C-terminal tail; however, the specific molecular determinants in beta-arrestin that bind AP-2 have not been identified. Moreover, the respective contributions of the interactions of beta-arrestin with AP-2 and clathrin toward the targeting of GPCRs to clathrin-coated vesicles have not been established. Here, we identify specific arginine residues (Arg(394) and Arg(396)) in the beta-arrestin 2 C terminus that mediate beta-arrestin binding to AP-2 and show, in vitro, that these domains in beta-arrestin 1 and 2 interact equally well with AP-2 independently of clathrin binding. We demonstrate in HEK 293 cells by fluorescence microscopy that beta(2)-adrenergic receptor-beta-arrestin complexes lacking the beta-arrestin-clathrin binding motif are still targeted to clathrin-coated pits. In marked contrast, receptor-beta-arrestin complexes lacking the beta-arrestin/AP-2 interactions are not effectively compartmentalized in punctated areas of the plasma membrane. These results reveal that the binding of a receptor-beta-arrestin complex to AP-2, not to clathrin, is necessary for the initial targeting of beta(2)-adrenergic receptor to clathrin-coated pits.


Small vessel occlusion in acute acalculous cholecystitis.
Ischemia is one mechanism implicated in the pathogenesis of acute acalculous cholecystitis. Gallbladder specimen arteriography was performed to define the comparative status of cystic artery runoff in the macroscopically normal gallbladder (n = 10), in acute gallstone-associated cholecystitis (n = 10), and in acute acalculous cholecystitis (n = 7). Standardized film exposure and quantity of contrast medium administered permitted objective intergroup comparison. Compared to the macroscopically normal gallbladder, specimens of acute gallstone-associated cholecystitis exhibited arterial dilatation and extensive venous filling. In contrast, multiple arterial occlusions, with absent or minimal venous filling, were consistent features of acute acalculous cholecystitis; the degree of arteriographic abnormality for acute acalculous cholecystitis corresponded to the severity of gallbladder pathologic findings. Small vessel occlusion, on the basis of low splanchnic flow or intravascular coagulation, may be a fundamental element in the pathogenesis of acute acalculous cholecystitis.


The impact of acute kidney injury on mortality and clinical outcomes in patients with alcoholic cirrhosis in the USA.
Acute kidney injury (AKI) is associated with increased morbidity and mortality in patients with chronic liver disease. Although the impact of AKI on patients with liver disease has been established, its impact on alcoholic cirrhosis has not been studied. Our study utilized data from the National Inpatient Sample for the year 2016 for all patients with a diagnosis of alcoholic cirrhosis and AKI. Primary outcomes were mortality, length of stay (LOS) and hospitalization cost were compared. Secondary outcomes were complications of cirrhosis and its impact on mortality. Multivariate logistic regression analysis and propensity-score matching were used to compare the two groups. A total of 29 906 patients were included and 6733 (22.5%) had AKI. Propensity-matched multivariate analysis demonstrates that AKI was associated with a significant increase risk of mortality [odds ratio (OR): 8.09; 95% confidence interval (CI), 6.68-9.79; P < 0.0001]. AKI prolonged the hospital stay by 3.68 days (95% CI, 3.42-3.93; P < 0.0001) and increased total hospital charges by $50 284 (95% CI, 45 829-54 739; P < 0.0001). AKI increased the risk of complications of cirrhosis, including hepatorenal syndrome (OR: 19.15; 95% CI, 16.1-22.76), ascites (OR: 2.27; 95% CI, 2.11-2.44), hepatic encephalopathy (OR: 2.54; 95% CI, 1.87-3.47) and portal hypertension (OR: 1.08; 95% CI, 1.01-1.16). AKI in alcoholic cirrhosis significantly increases the risk of mortality, hospitalizations costs and LOS. Further studies are needed on addressing renal failure and treatment options for patients with alcoholic cirrhosis.


Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants.
The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed. Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.


Intravitreal methotrexate infusion for prophylaxis of proliferative vitreoretinopathy after pars plana vitrectomy for rhegmatogenous retinal detachment.
Proliferative vitreoretinopathy (PVR) is the leading cause of recurrent retinal detachment after surgical repair of rhegmatogenous retinal detachment (RRD). Our study aimed to assess the efficacy and safety of intravitreal methotrexate infusion (IMI) for the prevention of PVR after pars plana vitrectomy (PPV) in eyes with RRD. This prospective comparative interventional study was conducted from September 2020 to November 2021 at Ain Shams University Hospitals, Egypt. We recruited a consecutive, non-randomized sample of 47 eyes of 47 patients with RRD undergoing PPV. Participants were allocated to a control group or an intervention group that received IMI during surgery. Each group was subdivided into subgroups of eyes at high-risk of developing PVR and eyes with established preoperative PVR grade C. Outcome measures at the 3-month postoperative follow-up were the rate of retinal attachment, incidence of PVR, reoperation rate to flatten the retina, and changes in the retina and/or optic nerve function as assessed by full-field electroretinogram and flash visual evoked potential. Data from 47 eyes (23 and 24 eyes in the intervention and control groups, respectively) were evaluated. Subgroups IA, IB, and IIB each included 12 eyes, subgroup IIA included 11 eyes, and all subgroups had comparable sex ratios and age distributions. Postoperative PVR at 1 month and between 1 and 3 months was present in 13% and 4% of eyes in the intervention group, respectively. Reoperation to flatten the retina was required in 2 (9%) eyes in the intervention group, while 22 eyes (96%) had complete flattening of the retina at 3 months. No significant differences were found between the study groups and the corresponding subgroups regarding the outcome measures (all P > 0.05). No adverse events attributable to IMI were detected up to 3 months postoperatively. Although IMI was safe for intraocular use in eyes with RRD and PVR grade C or a high risk of developing PVR, it did not affect the anatomical success rate or development of PVR up to 3 months after PPV. Further multicenter randomized clinical trials with longer follow-up periods and larger sample sizes are needed to verify these preliminary outcomes.


Identification of a lysosomal protein causing lipid transfer, using a fluorescence assay designed to monitor membrane fusion between rat liver endosomes and lysosomes.
In the present and previous studies [Mullock, Perez, Kuwana, Gray and Luzio (1994) J. Cell Biol. 126, 1173-1182], we have attempted to investigate endosome-lysosome fusion using an assay based on the dilution of the self-quenching fluorescent lipid probe octadecylrhodamine. Although some characteristics of fluorescence dequenching were consistent with those observed in other cell-free assays, we have now demonstrated that increased fluorescence was due to leakage of an intralysosomal lipid-transfer protein. This protein was purified and found to be a 22 kDa molecule with sequence, immunological and functional characteristics strongly suggesting that it is the rat homologue of human GM2-activator protein. Both the 22 kDa protein and recombinant human GM2-activator protein caused fluorescence dequenching either when mixed with octadecylrhodamine-loaded endosomes and lysosomal membranes or in a liposome system. The data were consistent with GM2-activator protein acting as an octadecylrhodamine-transfer protein. Antibodies to the 22 kDa protein added to cell-free endosome-lysosome content-mixing assays had no effect, although they could inhibit fluorescence dequenching caused by the protein. Thus this protein is not required in any fusion event involved in delivery of ligands from endosomes to lysosomes. The existence within an intracellular organelle of a protein capable of acting as an octadecylrhodamine-transfer protein suggests the need for caution in the interpretation of fluorescence-dequenching assays using mammalian subcellular fractions.


[Changes in pulmonary ventilation after shafts in acid-base equilibrium in the skeletal muscles of the cat].
In anesthetized cats, perfusion of the m. gastrocnemius with solutions simulating metabolic acidosis produces a reflex enhancement of breathing proportional to the acidosis degree. Perfusion with solutions having pH 7.0, 6.8 and 6.3 induced 4.6 +/- 1.0, 6.3 +/- 0.5 and 10.3 +/- 1.2% increases of the minute volume of ventilation, resp. These increases were mainly due to increases of the tidal volume rather than of respiratory rate. An increase of the mean blood pressure also occurred whereas heart rate did not change significantly. Hindlimb perfusion experiments revealed that reflex changes of the blood pressure and breathing depended on the muscle mass perfused. Possible participation of the muscle receptors sensitive to changes of metabolism in exercise hyperpnea, is discussed.


Establishment of a 3D Co-culture With MDA-MB-231 Breast Cancer Cell Line and Patient-Derived Immune Cells for Application in the Development of Immunotherapies.
3D cell culture including different cell types, such as immune cells, is a representative platform that mimics the tumor microenvironment. Here we disclose an easy-to-handle 3D co-culture protocol using a scaffold-free technique with the breast cancer cell line MDA-MB-231 and breast cancer patient-derived immune cells from peripheral blood. The method presented is simple, less time-consuming and less expensive when compared to other 3D techniques. Additionally, this is an optimized protocol for the establishment of a 3D system for this cell line, which is normally seen as challenging to spontaneously form spheroids. The addition of patient-derived immune cells to the cancer cells' spheroid allows the study of the crosstalk between both cell types, as well as the assessment of individual therapeutic approaches to intensify the antitumor immune response. In fact, with this model, we observed that patients' immune cells exhibit a wide range of antitumor responses and we further demonstrated that it is possible to manipulate the less effective ones with a canonical stimulus, as a proof-of-concept, in order to improve their ability to lower the viability of tumor cells. Therefore, this platform could be applied for a personalized immune-based drug screening, with results after a maximum of 10 days of culture, in order to develop more tailored breast cancer treatments and ameliorate patients' survival rate.


Isolation of modulators of the liver-specific organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae).
Organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are liver-specific transporters that mediate the uptake of a broad range of drugs into hepatocytes, including statins, antibiotics, and many anticancer drugs. Compounds that alter transport by one or both of these OATPs could potentially be used to target drugs to hepatocytes or improve the bioavailability of drugs that are cleared by the liver. In this study, we applied a bioassay-guided isolation approach to identify such compounds from the organic extract of Rollinia emarginata Schlecht (Annonaceae). Fractions of the plant extract were screened for effects on OATP1B1- and OATP1B3-mediated transport of the model substrates estradiol-17β-glucuronide and estrone-3-sulfate. We isolated three compounds, ursolic acid, oleanolic acid, and 8-trans-p-coumaroyloxy-α-terpineol, which inhibited estradiol-17β-glucuronide uptake by OATP1B1 but not OATP1B3. In addition, a rare compound, quercetin 3-O-α-l-arabinopyranosyl(1→2) α-L-rhamnopyranoside, was identified that had distinct effects on each OATP. OATP1B1 was strongly inhibited, as was OATP1B3-mediated transport of estradiol-17β-glucuronide. However, OATP1B3-mediated uptake of estrone-3-sulfate was stimulated 4- to 5-fold. Kinetic analysis of this stimulation revealed that the apparent affinity for estrone-3-sulfate was increased (decreased K(m)), whereas the maximal rate of transport (V(max)) was significantly reduced. These results demonstrate a mechanism through which the hepatic uptake of drug OATP substrates could be stimulated.


Evaluating the role of inbreeding depression in heterozygosity-fitness correlations: how useful are tests for identity disequilibrium?
Heterozygosity-fitness correlations (HFCs) have been observed for several decades, but their causes are often elusive. Tests for identity disequilibrium (ID, correlated heterozygosity between loci) are commonly used to determine if inbreeding depression is a possible cause of HFCs. We used computer simulations to determine how often ID is detected when HFCs are caused by inbreeding depression. We also used ID in conjunction with HFCs to estimate the proportion of variation (r(2)) in fitness explained by the individual inbreeding coefficient (F). ID was not detected in a large proportion of populations with statistically significant HFCs (sample size = 120 individuals) unless the variance of F was high (σ(2)(F) ≥ 0.005) or many loci were used (100 microsatellites or 1000 SNPs). For example, with 25 microsatellites, ID was not detected in 49% of populations when HFCs were caused by six lethal equivalents and σ(2)(F) was typical of vertebrate populations (σ(2)(F) ≈ 0.002). Estimates of r(2) between survival and F based on ID and HFCs were imprecise unless ID was strong and highly statistically significant (P ≈ 0.01). These results suggest that failing to detect ID in HFC studies should not be taken as evidence that inbreeding depression is absent. The number of markers necessary to simultaneously detect HFC and ID depends strongly on σ(2)(F). Thus the mating system and demography of populations, which influence σ(2) (F), should be considered when designing HFC studies. ID should be used in conjunction with HFCs to estimate the correlation between fitness and F, because HFCs alone reveal little about the strength of inbreeding depression.


MiR-422a acts as a tumor suppressor in glioblastoma by targeting PIK3CA.
Although surgical treatment, chemotherapy, and radiotherapy have improved the overall survival rate in glioblastoma multiforme (GBM), further intensive research of GBM's molecular mechanism is still needed. In this study, we observed that miR-422a was downregulated in GBM tissues and cell lines by quantitative real-time polymerase chain reaction (PCR) and primer extension assay. Overexpression of miR-422a significantly reduced the cell proliferation, migration, and invasion of GBM cells. Functional study indicated that miR-422a inhibited cell proliferation, invasion, and migration by targeting PIK3CA, an important member of PI3K/Akt signal pathway. These results demonstrate that the miR-422a/PIK3CA axis may constitute a potential target for GBM therapy.


[Pancreatic pseudocysts (ultrasonic location data and their morphology at different periods of occurrence)].
The work makes parallels between findings of ultrasonic location and the morphology of pancreatic pseudocysts in different periods of their existence. According to results of a histological investigation the pseudocysts can be divided into those being formed (less than 3 months of their existence), formed (more than 3 months of their existence) and isolated ones (after 1-1.5 years). Each period has its peculiar picture of the ultrasonic investigation. The wall of the forming pseudocysts is not dense enough for performing the internal drainage, external drainage having the worst immediate and long-term results. So, the pseudocysts must be operated upon during the 13th-16th weeks of their existence. The isolated pseudocysts are removable, but waiting for this period is not possible because of the probability of extremely dangerous complications.


Intracranial pressure changes during bilateral radical neck dissections.
The management of the contralateral neck in patients with head and neck cancer who have undergone a radical neck dissection (RND) is controversial. A number of these patients will require a second RND. Sacrifice of both internal jugular veins (IJV) has been felt to lead to increased intracranial pressure (ICP) with subsequent neurologic sequelae. From 1987 to 1991 four patients had staged bilateral RNDs at the West Virginia University. In these patients a subarachnoid bolt was placed to directly monitor ICP. Jugular bulb, mean arterial, pulmonary artery, and central venous pressures were monitored. Electroencephalographic (EEG) monitoring was also performed. All patients demonstrated elevations in ICP immediately on head rotation. Further marked elevations were noted immediately after IJV ligation with a maximum peak at 30 minutes. Pressure levels of greater than 40 mm Hg were observed in three of four patients. Systemic hypertension was observed in response to elevated ICP (Cushing's reflex). All patients studied recovered from surgery without significant sequelae. Within 24 hours the ICP had returned to normal in all patients. Three patients required intraoperative intervention to lower their ICP. We demonstrate that even in a staged second RND there are significant rises in ICP. These are to a level that suggests emergency medical intervention is required. We feel that when the second IJV is sacrificed an increase in ICP should be anticipated, monitored, and treated accordingly.


Psychometric characteristics of a self-report questionnaire (HPIQ) focusing on health promotion interventions in mental health services.
The aim of this study was to develop and investigate psychometric properties of the Health Promotion Intervention Questionnaire, a newly developed instrument intended to measure patients' subjective experiences of health promotion interventions in the mental health services. Health promotion practice has often been contested; therefore, it is important to produce convincing evidence that health promotion initiated by the health-care services actually works. A cross-sectional study was performed in order to investigate health promotion interventions among mental health service outpatients. A sample of 135 patients was used to test the psychometric properties of a new questionnaire designed to measure subjective experiences of health promotion interventions carried out by the mental health services. The factor structure of the questionnaire was tested by means of principal component factor analysis with varimax rotation. Reliability was measured in terms of internal consistency of the factors and test-retest reliability in a subsample of patients. The final scale contained 19 items derived from four factors: alliance, empowerment, educational support, and practical support. In terms of internal consistency, reliability was found to be good, both for the overall scale and the subscales. Test-retest reliability was moderate or higher in 13 out of 19 items and poor in only one item. This questionnaire, developed to evaluate patients' experiences of health promotion interventions in mental health services, may be used as an alternative in further empirical studies. With additional testing, the questionnaire could facilitate the work of defining and evaluating health promotion interventions conducted by the mental health services.


High serum adiponectin levels predict incident falls among middle-aged and older adults: a prospective cohort study.
adiponectin is an adipocyte-derived hormone with anti-obesity and anti-diabetic properties. However, higher circulating adiponectin levels are related to poor muscle function and physical disability, which suggests a potential link between adiponectin and risk of falls. Nevertheless, no direct association between circulating adiponectin levels and incident fall risk has been reported. Therefore, this study aimed to investigate the relationship between serum adiponectin levels and incident falls in a population of middle-aged and older adults. a prospective cohort study. Oroshisho Center in Sendai City, Japan. Japanese adults who were ≥45 years old (n = 430). serum adiponectin levels were measured at baseline, and the subjects were divided into sex-specific tertiles. Data regarding a history of falls were collected via participant recall using a self-reported questionnaire. Incident falls were defined as falls that were experienced by people without a history of falls at baseline. during the 2-year follow-up, 15.6% (67/430) of the subjects experienced an incident fall. In the univariate logistic regression analysis, incident falls were significantly more frequent across the increasing sex-specific serum adiponectin tertiles (P for trend = 0.008). Adjusted odds ratios (95% confidence interval) for incident falls were 2.31 (1.07-4.98) in the middle tertile and 3.61 (1.63-7.99) in the highest tertile; this risk was significantly higher than that for the lowest adiponectin tertile (P for trend = 0.002). the findings of this prospective cohort study indicate that higher serum adiponectin levels may be a predictor of incident falls.


Assessing Surface Coverage of Aminophenyl Bonding Sites on Diazotised Glassy Carbon Electrodes for Optimised Electrochemical Biosensor Performance.
Electrochemical biosensors using carbon-based electrodes are being widely developed for the detection of a range of different diseases. Since their sensitivity depends on the surface coverage of bioreceptor moieties, it necessarily depends on the surface coverage of amine precursors. Electrochemical techniques, using ferrocene carboxylic acid as a rapid and cheap assay, were used to assess the surface coverage of amino-phenyl groups attached to the carbon electrode. While the number of electrons transferred in the first step of diazotisation indicated a surface coverage of 8.02 ± 0.2 × l0-10 (mol/cm2), and those transferred in the second step, a reduction of nitrophenyl to amino-phenyl, indicated an amine surface coverage of 4-5 × l0-10 (mol/cm2), the number of electrons transferred during attachment of the amine coupling assay compound, ferrocene carboxylic acid, indicated a much lower available amine coverage of only 2.2 × l0-11 (mol/cm2). Furthermore, the available amine coverage was critically dependent upon the number of cyclic voltammetry cycles used in the reduction, and thus the procedures used in this step influenced the sensitivity of any subsequent sensor. Amine coupling of a carboxyl terminated anti-beta amyloid antibody specific to Aβ(1-42) peptide, a potential marker for Alzheimer's disease, followed the same pattern of coverage as that observed with ferrocene carboxylic acid, and at optimum amine coverage, the sensitivity of the differential pulse voltammetry sensor was in the range 0-200 ng/mL with the slope of 5.07 µA/ng.mL-1 and R2 = 0.98.


[Effectiveness of the new aminoglycoside sisomicin in surgery].
Antimicrobial activity of sisomicin against causative agents of wound infections was studied. It was shown that by its antimicrobial activity and the rate of bactericidal effect attainment sisomicin is superior to other aminoglycosides, such as gentamicin and tobramycin. Individual variability of the pharmacokinetics of sisomicin on its intravenous and intramuscular injection to patients with wound infections was observed. For prediction of the treatment efficacy it is suggested that the drug be used under the control of its blood levels in comparison to the MTC for the isolated causative agent.


Compliance of Specific Provisions of Tobacco Control Law around Educational Institutions in Delhi, India.
Tobacco use is leading preventable cause of premature deaths. Sales of tobacco products within 100 yards of educational institutions (EIs) in India are restricted under Section 6 of Cigarettes and Other Tobacco Products Act (COTPA), 2003. This study accessed compliance of Section 6 of COTPA around EIs in Delhi. A cross-sectional study was conducted in randomly selected 100 EIs from 6600 schools/colleges in Delhi. Activities related to Section 6 of COTPA around EIs, such as the sale of tobacco products within a radius of 100 yards, sale of tobacco products to and by minors, and existence of display boards prohibiting sale of tobacco products were observed using Global Positioning System (GPS)-enabled tablet computers preloaded with maps and Open Data Kit software. Data analysis was done using Epi Info version 7. Among the 100 EIs surveyed (53 government, 47 private), tobacco products were sold at 43 outlets within a radius of 100 yards of 27 EIs. No outlet had a display board prohibiting sale of tobacco products to minors. One outlet sold tobacco products to minors during the period of observation, but sale of tobacco products by minors was not observed. Only 38% of EIs displayed board prohibiting tobacco sales; private EIs were significantly less likely to display signs prohibiting tobacco sales than government EIs (45% vs. 81%; P < 0.001). Sale of tobacco products is common around EIs in Delhi. The use of simple technology provided quick results to policy-makers. Similar periodic surveys should help regulatory agencies to strictly enforce provisions of COTPA.


Disparities in Snacking Trends in US Adults over a 35 Year Period from 1977 to 2012.
Previous studies have indicated that snacking is contributing to increased calories in the American diet, and that the contribution of snacks to energy intake has increased in recent decades. The objective was to examine trends in the energy intake deriving from snacks and food sources of snacks for US adults over 35 years from 1977 to 2012, and whether these trends differ across sociodemographic groups. Participants included 74,291 US adults aged ≥19 years who participated in the 1977-1978 Nationwide Food Consumption Survey (NFCS); the 1989-1991 Continuing Survey of Food Intake by Individuals (CSFII), the 1994-1996 CSFII, the 1997-1998 CSFII, National Health and Nutrition Examination Survey (NHANES) 2003-2004, NHANES 2005-2006, NHANES 2009-2010 and NHANES 2011-2012; all surveys are a stratified random sample of the total civilian, non-institutionalized US population. Overall patterns of snacking, trends in energy intake from snacking, trends in snacking food and beverage sources and energy intake from snacks across racial/ethnic, age, education and income groups were examined. For all US adults there was a significant increase in per capita energy intake from snacks from 1977 to 2012 (p < 0.01). Non-Hispanic blacks had the highest snacking energy intake from sugar-sweetened beverages (SSBs) in each year (p < 0.01 for all), with a peak intake in 2003-2006 of 76 kcal per capita per day. Intake of salty snacks increased in all groups between 1977 and 2012, with non-Hispanic blacks having the highest intake in 2009-2012 (p < 0.01). No significant differences were found between income or education groups. Results show that snacking remains a significant component of the US diet and the foods consumed at these snacks (SSBs, desserts and sweets and salty snacks) are not the types of foods recommended by the US dietary guidelines. Our finding that non-Hispanic blacks are consuming a higher proportion of SSBs and salty snacks than other groups, and showing the largest increase in energy intake deriving from snacks overall over the past 35 years, is indeed concerning.


Psychotropic prescribing patterns among adolescents in Northern Ireland presenting with psychotic symptoms during a 5-year period.
To report new prescriptions of psychotropic medications among adolescents presenting with new onset psychotic symptoms during a 5-year period. The Northern Ireland Early Onset Psychosis Study is a naturalistic longitudinal observational study of patients with an early onset first psychotic episode. All patients aged <18 years presenting to specialist mental health services across Northern Ireland with new onset psychotic symptoms between 2001 and 2006 were recruited (n=113). Clinical case notes were analysed retrospectively for details of subsequent treatment with psychotropic medications. A total of 100 patients (88.5%) were prescribed some form of psychotropic medication. Over three-quarters of patients received an antipsychotic as their first medication. Risperidone (45.8%), olanzapine (24.0%) and chlorpromazine (12.5%) were the most commonly prescribed first-line antipsychotic medications. Of a total of 160 antipsychotic prescriptions, 81 (50.6%) were off-label. Prescriptions were most likely to have been deemed off-label owing to medications not being licensed in under-18s (71.6% of off-label prescriptions) but other reasons were medications being used outside licensed age ranges (23.5%) and outside licensed indications (4.9%). This is the first study examining psychotropic prescribing patterns in a complete sample of all children and adolescents presenting with early onset psychotic episodes in a single geographical area. The observation of risperidone as the most commonly prescribed antipsychotic was in keeping with previous studies in child and adolescent populations. Rates of off-label prescribing were lower than previously observed although our study was the first to investigate off-label prescribing solely in children and adolescents presenting with psychotic symptoms.


The small heat shock protein 20 RSI2 interacts with and is required for stability and function of tomato resistance protein I-2.
Race-specific disease resistance in plants depends on the presence of resistance (R) genes. Most R genes encode NB-ARC-LRR proteins that carry a C-terminal leucine-rich repeat (LRR). Of the few proteins found to interact with the LRR domain, most have proposed (co)chaperone activity. Here, we report the identification of RSI2 (Required for Stability of I-2) as a protein that interacts with the LRR domain of the tomato R protein I-2. RSI2 belongs to the family of small heat shock proteins (sHSPs or HSP20s). HSP20s are ATP-independent chaperones that form oligomeric complexes with client proteins to prevent unfolding and subsequent aggregation. Silencing of RSI2-related HSP20s in Nicotiana benthamiana compromised the hypersensitive response that is normally induced by auto-active variants of I-2 and Mi-1, a second tomato R protein. As many HSP20s have chaperone properties, the involvement of RSI2 and other R protein (co)chaperones in I-2 and Mi-1 protein stability was examined. RSI2 silencing compromised the accumulation of full-length I-2 in planta, but did not affect Mi-1 levels. Silencing of heat shock protein 90 (HSP90) and SGT1 led to an almost complete loss of full-length I-2 accumulation and a reduction in Mi-1 protein levels. In contrast to SGT1 and HSP90, RSI2 silencing led to accumulation of I-2 breakdown products. This difference suggests that RSI2 and HSP90/SGT1 chaperone the I-2 protein using different molecular mechanisms. We conclude that I-2 protein function requires RSI2, either through direct interaction with, and stabilization of I-2 protein or by affecting signalling components involved in initiation of the hypersensitive response.


Drosophila as a model for assessing nanopesticide toxicity.
One of the fastest-moving fields in today's world of applied science, nanotechnology allows the control and design of matter on an extremely small scale, so it has now become an integral part of various industries and scientific areas, such as agriculture, food sector, healthcare and engineering. Understanding the interactions between nanopesticides and edible plants, as well as non-target animals, is crucial in assessing the potential impact of nanotechnology products on the environment, agriculture and human health. The dramatic increase in efforts to use nanopesticides renders the risk assessment of their toxicity and genotoxicity highly crucial due to the potential adverse impact of this relatively uncharted territory. Such widespread use naturally increases our exposure to nanopesticides, raising concerns over their possible adverse effects on humans and non-target organisms, which might include severe impairment of both male and female reproductive capacity. We therefore need better insight into such effects to derive conclusive evidence on the safety or toxicity/genotoxicity of nanopesticides, and Drosophila melanogaster (fruit fly) can prove an ideal model organism for the risk assessment and toxicological classification of nanopesticides, as it bears striking similarities to various systems in human body. This editorial review attempts to summarize our current knowledge derived from previous in vivo studies to examine the impact of several nanomaterials on various species of mammals and non-target model organisms at the genetic, cellular, and molecular levels, attracting attention to the possible mechanisms and potential toxic/genotoxic effects of nanopesticides widely used in agriculture on D. melanogaster as a non-target organism.


Deaf-mutia. Responses to alienation by the deaf in the mid-nineteenth century.
The development of the deaf community in the mid-nineteenth century was intimately linked to schooling. Although a matrix of variables contributed, a major factor underlying the community's enduring strength was the alienation suffered by deaf persons in society. To counter this alienation, proposals emerged throughout the nineteenth century for the formation of a separate deaf state. The most significant of these was the plan of Flournoy in the late 1850s.


Animal evolution. Cope's rule in the evolution of marine animals.
Cope's rule proposes that animal lineages evolve toward larger body size over time. To test this hypothesis across all marine animals, we compiled a data set of body sizes for 17,208 genera of marine animals spanning the past 542 million years. Mean biovolume across genera has increased by a factor of 150 since the Cambrian, whereas minimum biovolume has decreased by less than a factor of 10, and maximum biovolume has increased by more than a factor of 100,000. Neutral drift from a small initial value cannot explain this pattern. Instead, most of the size increase reflects differential diversification across classes, indicating that the pattern does not reflect a simple scaling-up of widespread and persistent selection for larger size within populations.


Evidence that cytochrome b559 is involved in superoxide production in photosystem II: effect of synthetic short-chain plastoquinones in a cytochrome b559 tobacco mutant.
Light-induced production of superoxide (O2*-) in spinach PSII (photosystem II) membrane particles was studied using EPR spin-trapping spectroscopy. The presence of exogenous PQs (plastoquinones) with a different side-chain length (PQ-n, n isoprenoid units in the side-chain) enhanced O2*- production in the following order: PQ-1>PQ-2>>PQ-9. In PSII membrane particles isolated from the tobacco cyt (cytochrome) b559 mutant which carries a single-point mutation in the beta-subunit and also has a decreased amount of the alpha-subunit, the effect of PQ-1 was less than in the wild-type. The increase in LP (low-potential) cyt b559 content, induced by the incubation of spinach PSII membrane particles at low pH, resulted in a significant increase in O2*- formation in the presence of PQ-1, whereas it had little effect on O2*- production in the absence of PQ-1. The enhancement of O2*- formation induced by PQ-1 was not abolished by DCMU [3-(3,4-dichlorophenyl)-1,1-dimethylurea]. Under anaerobic conditions, dark oxidation of LP cyt b559 increased, as pH was decreased. The presence of molecular oxygen significantly enhanced dark oxidation of LP cyt b559. Based on these findings it is suggested that short-chain PQs stimulate O2*- production via a mechanism that involves electron transfer from Pheo- (pheophytin) to LP cyt b559 and subsequent auto-oxidation of LP cyt b559.


Extended, relaxed, and condensed conformations of hyaluronan observed by atomic force microscopy.
The conformation of the polysaccharide hyaluronan (HA) has been investigated by tapping mode atomic force microscopy in air. HA deposited on a prehydrated mica surface favored an extended conformation, attributed to molecular combing and inhibition of subsequent chain recoil by adhesion to the structured water layer covering the surface. HA deposited on freshly cleaved mica served as a defect in a partially structured water layer, and favored relaxed, weakly helical, coiled conformations. Intramolecularly condensed forms of HA were also observed, ranging from pearl necklace forms to thick rods. The condensation is attributed to weak adhesion to the mica surface, counterion-mediated attractive electrostatic interactions between polyelectrolytes, and hydration effects. Intermolecular association of both extended and condensed forms of HA was observed to result in the formation of networks and twisted fibers, in which the chain direction is not necessarily parallel to the fiber direction. Whereas the relaxed coil and partially condensed conformations of HA are relevant to the native structure of liquid connective tissues, fully condensed rods may be more relevant for HA tethered to a cell surface or intracellular HA, and fibrous forms may be relevant for HA subjected to shear flow in tight intercellular spaces or in protein-HA complexes.


Snowblading injuries in Eastern Canada.
To evaluate injury patterns of snowbladers and compare them with those of skiers and snowboarders. To determine possible effects of helmet use in these sports on injury to the head and neck. This prospective case series observational study was conducted by collecting the injury reports from the ski patrol during the 1999-2000 season at Mont Tremblant ski resort, Quebec. All participants in downhill winter sports who presented themselves to the ski patrol with traumatic injury related to their sport were included. A concussion was defined as any loss of consciousness, amnesia, confusion, disorientation, vertigo, or headache that resulted from injury. The ski patroller reported helmet use on the accident report at the time of injury. Snowbladers present with a unique pattern of injury compared with skiers and snowboarders. The incidence of leg, knee, and ankle/foot injuries were 20.5%, 25.6%, and 10.3% respectively. Concussions represented 11% of all injuries. There was no increase in other injury, including neck injury, related to helmet use. Unique injury patterns in snowbladers warrant reconsideration of equipment design. Concussion is a common injury on the ski slope. Although the effects of helmet use on concussion rate are inconclusive based on this study, helmet use did not increase the rate of neck injury, even when adjusted for age.


Draft genome sequence of a highly proteolytic Staphylococcus aureus USA300 isolate from human urine.
The secreted proteases of Staphylococcus aureus have been shown to be critical during infection. Here, we present the draft genome sequence of S. aureus TGH337, a hyper-proteolytic USA300 strain isolated from human urine.


Analysis of large structural changes of the factor VIII gene, involving intron 1 and 22, in severe hemophilia A.
Hemophilia A (HA), the deficiency of coagulation factor VIII (FVIII), is the most common, sex-linked inherited bleeding disorder. The disease is caused by FVIII gene intron 22 inversion in approximately 50% of the patients, and by intron 1 inversion in 5% of the patients with severe HA. Both inversions occur as a result of intrachromosomal recombination between homologous regions, in intron 1 or 22, and their extragenic copy located telomeric to the FVIII gene. The goal of the present study was to analyze the presence of large structural changes in the FVIII gene in patients with severe hemophilia A. We studied 104 unrelated, severe HA-patients or obligate carriers for the presence of intron 22 and intron 1 inversions by Southern blotting, long-distance polymerase chain reaction (PCR), and simple PCR. We found altered intron 22 restriction profiles by Southern analyses in 58 cases: 43 type 1, 11 type 2 inversions and 4 unusual patterns. Upon further examination of the last 4 cases, large deletions involving intron 22 were demonstrated in two cases. In the remaining two patients extra homologous regions were detected by Southern analysis, and long-distance PCR showed the presence of unaltered intra- and extragenic copies together with one inversion-affected copy, suggesting that an additional intronic fragment participated in the inversion process and was inserted in the genome. During screening for intron 1 inversion among 43 patients, who were intron 22 inversion negative, we identified only wild type individuals. The relatively large proportion of unusual patterns further supports the observation that the structure of FVIII intron 22 represents a hot spot for large gene rearrangements with various mechanisms, while intron 1 inversion seems to be not common in Hungary.


Dietary supplementation of vitamin D prevents the development of western diet-induced metabolic, hepatic and cardiovascular abnormalities in rats.
The western diet high in fat and fructose may cause metabolic disorders and cardiovascular diseases. To evaluate whether long-term daily vitamin D3 supplementation prevents hepatic steatosis and cardiovascular abnormalities and restores insulin sensitivity caused by fat diet in rats without vitamin D deficiency. Three groups of rats were fed for 6 months with standard diet (SD), western diet (WD) or WD containing 23 IU/day/rat vitamin D3, respectively. Tail-cuff systolic blood pressure (SBP)measurements in conscious rats and transthoracic echocardiography were performed in basal condition, and after 3 and 6 months of diet. Hepatic steatosis and myocardial fibrosis were assessed in liver and cardiac tissues using standard methods. Serum insulin and 25(OH)D3 concentrations were determined using rat-specific ELISA kits. Insulin resistance was determined according to the homeostasis model assessment of insulin resistance (HOMA-IR) method. Sixty-one per cent of hepatocytes in WD rats had steatotic vacuoles compared with just 27% in rats on a WD plus vitamin D3 (p < 0.05).HOMA-IR was reduced in rats with vitamin D supplementation compared with WD alone (19.4 ± 5.2 vs 41.9 ± 8.9, p < 0.05). Rat blood pressure and left ventricular mass were both reduced by vitamin D3 supplementation. In animal models of liver and cardiovascular metabolic damage, the supplementation of vitamin D3 shows liver and cardio-protective effects.


Consumer experiences in a consumer-driven health plan.
To assess the experience of enrollees in a consumer-driven health plan (CDHP). Survey of University of Minnesota employees regarding their 2002 health benefits. Comparison of regression-adjusted mean values for CDHP and other plan enrollees: customer service, plan paperwork, overall satisfaction, and plan switching. For CDHP enrollees only, use of plan features, willingness to recommend the plan to others, and reports of particularly negative or positive experiences. There were significant differences in experiences of CDHP enrollees versus enrollees in other plans with customer service and paperwork, but similar levels of satisfaction (on a 10-point scale) with health plans. Eight percent of CDHP enrollees left their plan after one year, compared to 5 percent of enrollees leaving other plans. A minority of CDHP enrollees used online plan features, but enrollees generally were satisfied with the amount and quality of the information provided by the CDHP. Almost half reported a particularly positive experience, compared to a quarter reporting a particularly negative experience. Thirty percent said they would recommend the plan to others, while an additional 57 percent said they would recommend it depending on the situation. Much more work is needed to determine how consumer experience varies with the number and type of plan options available, the design of the CDHP, and the length of time in the CDHP. Research also is needed on the factors that affect consumer decisions to leave CDHPs.


Screening of novel chemical compounds as possible inhibitors of carbonic anhydrase and photosynthetic activity of photosystem II.
Thirty novel chemical compounds were designed and synthesized expecting that they would be possible inhibitors. From this number eleven were organic bases, twenty-four were their organic derivatives and fourteen were metal complexes. Screening of these chemicals by their action on photosynthetic electron transfer (PET) and carbonic anhydrase (CA) activity (CAA) of photosystem II (PSII), α-CA, as well as β-CA was done. Several groups were revealed among them. Some of them are capable to suppress either one, two, three, or even all of the measured activities. As example, one of the Cu(II)-phenyl sulfonylhydrazone complexes (compound 25) suppresses CAA of α-CA by 88%, CAA of β-CA by 100% inhibition; CAA of PSII by 100% and the PSII photosynthetic activity by 66.2%. The Schiff base compounds (12, 15) and Cu(II)-phenyl sulfonylhydrazone complexes (25, 26) inhibited the CAA and PET of PSII significantly. The obtained data indicate that the PSII donor side is a target of the inhibitory action of these agents. Some physico- or electrochemical properties such as diffusion coefficient, number of transferred electrons, peak potential and heterogeneous standard rate constants of the compounds were determined in nonaqueous media. pKa values were also determined in nonaqueous and aqueous media. Availability in the studied group of novel chemical agents possessing different inhibitory activity allow in future to isolate the "active part" in the structure of the inhibitors responsible for different inhibitory mechanisms, as well as to determine the influence of side substituters on its inhibitory efficiency.


Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: ionic diversity in smooth muscle cells.
Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O2-sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E(M)), thereby activating Ca2+ influx via voltage-gated Ca2+ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O2-sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kv-inhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K+ current (I(K)) and a more hyperpolarized E(M) and were uniquely O2- and correolide-sensitive. The O2-sensitive current (active at -65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited I(K) 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide's effects. The hypoxia-sensitive, correolide-insensitive I(K) (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5>Kv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O2- and correolide-sensitive I(K) like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O2-sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O2-sensitive Kv-channels.


Germacrone protects renal tubular cells against ferroptotic death and ROS release by re-activating mitophagy in diabetic nephropathy.
Mitophagy is a critical intracellular event during the progression of diabetic nephropathy (DN). Our previous study demonstrated that germacrone has anti-ferroptotic properties and is a potential therapeutic agent for DN. However, the relationship among germacrone, mitophagy, and ferroptosis in DN remains unclear. In this study, the data confirmed that germacrone ameliorates high glucose (HG)-induced ferroptosis through limiting Fe (2+) content and lipid reactive oxygen species (ROS) accumulation in human kidney 2 (HK-2) cells. Germacrone reversed HG-mediated inhibition of mitophagy. Mitophagy inhibition and anabatic mitochondrial ROS abrogate germacrone-mediated protective effects against ferroptotic death, resulting in the subsequent activation of mitochondrial DNA (mtDNA) cytosolic leakage-induced stimulator of interferon response CGAMP interactor 1 (STING) signaling. The combination of a mitochondrial ROS antagonist and germacrone acts synergistically to alleviate the ferroptotic death of tubular cells and DN symptoms. In summary, germacrone ameliorated ferroptotic death in tubular cells by reactivating mitophagy and inhibiting mtDNA-STING signaling in DN. This study provides a novel insight into germacrone-mediated protection against DN progression and further confirms that antioxidant pharmacological strategies facilitate the treatment of DN.


Early mechanical complications of a multidirectional mobile-bearing total knee replacement.
Between April 2004 and July 2007, we performed 241 primary total knee replacements in 204 patients using the e.motion posterior cruciate-retaining, multidirectional mobile-bearing prosthesis. Of these, 100 were carried out using an image-free navigation system, and the remaining 141 with the conventional technique. We conducted a retrospective study from the prospectively collected data of these patients to assess the early results of this new mobile-bearing design. At a mean follow-up of 49 months (32 to 71), 18 knees (7.5%) had mechanical complications of which 13 required revision. Three of these had a peri-prosthetic fracture, and were removed from the study. The indication for revision in the remaining ten was loosening of the femoral component in two, tibiofemoral dislocation in three, disassociation of the polyethylene liner in four, and a broken polyethyene liner in one. There were eight further mechanically unstable knees which presented with recurrent disassociation of the polyethylene liner. There was no significant difference in the incidence of mechanical instability between the navigation-assisted procedures (8 of 99, 8.1%) and the conventionally implanted knees (10 of 139, 7.2%). In our view, the relatively high rate of mechanical complications and revision within 30 months precludes the further use of new design of knee replacement.


The natural progression of synovial fluid white blood-cell counts and the percentage of polymorphonuclear cells after primary total knee arthroplasty: a multicenter study.
Assessments of the synovial fluid white blood-cell (WBC) count and percentage of polymorphonuclear cells (PMNs) have been reported to be useful in the diagnosis of periprosthetic joint infection. The purpose of this multicenter retrospective study was to evaluate the natural progression of the synovial fluid WBC count, PMN percentage, and total neutrophil count in patients who underwent knee aspiration during the first two years after primary total knee arthroplasty and had no evidence of periprosthetic joint infection. From April 1999 to March 2012, 571 patients who presented within the first two years after primary total knee arthroplasty underwent knee aspiration as part of an evaluation for periprosthetic joint infection. Patients were categorized into four groups on the basis of the number of days between surgery and arthrocentesis. The synovial fluid WBC count, PMN percentage, and total neutrophil count were compared among the four time periods with use of separate one-way analyses of variance and Tamhane post-hoc analyses. Four hundred and fifty-two samples not associated with a periprosthetic joint infection were adequate for analysis. The synovial fluid WBC count, PMN percentage, and total neutrophil count all decreased after the first ninety postoperative days. The synovial fluid WBC count showed an earlier return to a level similar to the two-year time point than the PMN percentage did. The mean total neutrophil count decreased from 2533.2 cells/μL during the first forty-five days to 649.0 cells/μL from forty-six to ninety days, 269.5 cells/μL from three months to one year, and 240.8 cells/μL from one to two years. The synovial fluid WBC count and PMN percentage changed at different rates over the first two years after total knee arthroplasty, with the WBC count exhibiting an initially more rapid decrease and the PMN percentage demonstrating a more linear decrease. Hence, the total neutrophil count, which combines these two parameters, may provide a better method to identify patients with a periprosthetic joint infection. Values for the synovial fluid WBC count, PMN percentage, and total neutrophil count were all significantly elevated in the early postoperative period, and the use of standard cutoff values for the diagnosis of periprosthetic joint infection can lead to false-positive results.


Methane aqueous fluids in montmorillonite clay interlayer under near-surface geological conditions: a grand canonical Monte Carlo and molecular dynamics simulation study.
The grand-canonical Monte Carlo (GCMC) and molecular dynamics (MD) simulations are performed to investigate the methane aqueous fluids in Na-montmorillonite clay interlayer under near-surface geological temperature and pressure conditions (T = 300 K and P = 20-50 bar). The chemical potentials of water and methane under these T/P conditions are calculated using the Widom's insertion method. These chemical potentials are used in the GCMC simulations to determine the contents of different species in the clay interlayer, especially in those that correspond to the equilibrium stable spacing distances. Simulation results show that initial clay swelling is dominated by water adsorption into the clay interlayer, followed by the intercalation of methane as the basal spacing increases. However, it is found that this methane intercalation process is strongly influenced by the relative humidity and the total gas pressure of the system. High relative humidity may facilitate water molecules entering the clay interlayer region and inhibit the intercalation of methane molecules. MD simulations show that sodium ions are fully hydrated by water molecules and clay surface oxygen atoms, while methane molecules are not fully coordinated. This situation is attributed to the less water content in clay interlayer and the subsequent formation of methane dimer or trimer clusters due to the hydrophobic nature of small hydrocarbon molecules.


[Medico-social legislation of Ukraine: organizational-legal aspects of management in the sphere of community health care (current state, problems and perspectives)].
The authors analyzed organizational-legal aspects of management in the sphere of community health care. The foundation of medical-legal base of public health is substantiated in the article. It enables to form new mechanisms aimed at improvement of medical care, creation of data-analytical system, unification of health care and diagnostics standards.


In vivo imaging of mesenchymal-epithelial transition factor (c-Met) expression using an optical imaging system.
Mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase that has been shown to be overexpressed and mutated in a variety of malignancies, such as glioma. We have recently found that an (125)I-radiolabeled Gly-Gly-Gly (GGG)- or 8-aminooctanoic acid (AOC)-containing c-Met binding peptide (cMBP) specifically targets c-Met receptor in vivo and in vitro. In this report, cyanine dye 5.5 (Cy5.5)-conjugated GGG- or AOC-containing cMBPs were evaluated in human cancer cell xenografts in order to investigate the possibility of c-Met receptor targeting using an optical imaging system. The receptor binding affinity of Cy5.5-conjugated peptides was tested in 96-well plates coated with a c-Met/Fc chimeric protein. Optical imaging studies were performed in U87MG and Ramos bearing athymic mice. The binding affinities of Cy5.5-conjugated GGG- or AOC-containing cMBPs were determined to be 0.318 and 0.342 microM, respectively. Confocal images show that Cy5.5-conjugated peptides bound mainly to the cell surface and that peptide binding was clearly inhibited by free cMBP. Subcutaneous U87MG tumors were clearly visualized with each of the two fluorescent probes. Of the two, cMBP-AOC-Cy5.5 displayed higher tumor uptake and tumor-to-normal tissue ratios at 10 min to 24 h postinjection in the U87MG tumor model. For the in vivo blocking study, cMBP-AOC-Cy5.5 (4 nmol) was co-injected with cold cMBP (0.13 micromol) into the U87MG xenograft mice. Image-based tumoral uptake decreased up to approximately 35%. These results suggest that Cy5.5-conjugated cMBP could potentially be used to detect c-Met-positive cancers in vivo. However, additional modifications to this optical imaging agent are needed to further improve its efficacy.


Practical approaches to supporting young women with intellectual disabilities and high support needs with their menstruation.
Menstrual myths may influence decisions about menstrual and fertility management for women with intellectual disabilities and high support needs. We identify six myths (related to menstruation, menstrual management, communication, sexual feelings, menstrual difficulties, and surgical elimination) and the evidence that dispels these myths. We provide reflexive questions for practitioners to help them critically reflect on their own approaches to menstrual management. We encourage those supporting women with disabilities to consider the reflective questions we have provided and to strive to support informed decision-making about menstruation and the related areas of fertility and sexual feelings.


Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat.
Laboratory rats were given unlimited access to intravenous cocaine hydrochloride or heroin hydrochloride. Animals self-administering cocaine quickly developed a pattern of episodic drug intake, with periods of excessive cocaine self-administration alternating with brief periods of abstinence. Subjects allowed continuous access to intravenous heroin showed stable drug self-administration, with a gradual increase in daily heroin intake over the first two weeks of testing. The general health of the animals became markedly different: those self-administering heroin maintained grooming behavior, pretesting body weight, and a good state of general health; rats self-administering cocaine tended to cease grooming behavior, to lose up to 47% of their pretesting body weight, and to show a pronounced deterioration in general health. The mortality rate for 30 days of continuous testing was 36% for animals self-administering heroin and 90% for those self-administering cocaine. These results suggest that cocaine is a much more toxic compound than heroin when animals are given unlimited access to intravenous drug.


Effects of [15N]leucine infused at low rates on leucine metabolism in humans.
The present studies were carried out to determine whether infusions of [15N]leucine at low rates affect estimates of leucine oxidation and of proteolysis and protein synthesis in humans. Three groups of normal subjects were infused for 3 h with either [15N]leucine at a rate of 0.16 or 0.26 mumol X kg-1 X min-1 or saline using [2H3]leucine and alpha-[14C]ketoisocaproate as isotopic tracers of leucine metabolism. Data were analyzed at steady state using both single- and dual-isotope models. Preliminary studies were carried out to characterize the dual-isotope model in humans using infusions of [3H]leucine and alpha-[14C]ketoisocaproate. In the postabsorptive state estimates of leucine appearance, disappearance, and oxidation derived from the two isotope models were in good agreement. Infusion of stable isotope up to approximately 10% of the leucine carbon flux do not have a significant effect on leucine metabolism, but the data derived from such studies must be properly controlled and interpreted with care because these tracers are not massless.


Concentrating membrane proteins using asymmetric traps and AC electric fields.
Membrane proteins are key components of the plasma membrane and are responsible for control of chemical ionic gradients, metabolite and nutrient transfer, and signal transduction between the interior of cells and the external environment. Of the genes in the human genome, 30% code for membrane proteins (Krogh et al. J. Mol. Biol.2001, 305, 567). Furthermore, many FDA-approved drugs target such proteins (Overington et al. Nat. Rev. Drug Discovery 2006, 5, 993). However, the structure-function relationships of these are notably sparse because of difficulties in their purification and handling outside of their membranous environment. Methods that permit the manipulation of membrane components while they are still in the membrane would find widespread application in separation, purification, and eventual structure-function determination of these species (Poo et al. Nature 1977, 265, 602). Here we show that asymmetrically patterned supported lipid bilayers in combination with AC electric fields can lead to efficient manipulation of charged components. We demonstrate the concentration and trapping of such components through the use of a "nested trap" and show that this method is capable of yielding an approximately 30-fold increase in the average protein concentration. Upon removal of the field, the material remains trapped for several hours as a result of topographically restricted diffusion. Our results indicate that this method can be used for concentrating and trapping charged membrane components while they are still within their membranous environment. We anticipate that our approach could find widespread application in the manipulation and study of membrane proteins.


Determining level of postural control in young adults using force-sensing resistors.
A force-sensing platform (FSP), sensitive to changes of the postural control system was designed. The platform measured effects of postural perturbations in static and dynamic conditions. This paper describes the implementation of an FSP using force-sensing resistors as sensing elements. Real-time qualitative assessment utilized a rainbow color scale to identify areas with high force concentration. Postprocessing of the logged data provided end-users with quantitative measures of postural control. The objective of this research was to establish the feasibility of using an FSP to test and gauge human postural control. Tests were conducted in eye open and eye close states. Readings obtained were tested for repeatability using a one-way analysis of variance test. The platform gauged postural sway by measuring the area of distribution for the weighted center of applied pressure at the foot. A fuzzy clustering algorithm was applied to identify regions of the foot with repetitive pressure concentration. Potential application of the platform in a clinical setting includes monitoring rehabilitation progress of stability dysfunction. The platform functions as a qualitative tool for initial, on-the-spot assessment, and quantitative measure for postacquisition assessment on balance abilities.


Increased chemotaxis of leukocytes from mice bearing tumors.
Increased chemotaxis toward activated serum was demonstrated by leukocytes from bone marrow, spleen, and peripheral blood of tumor-bearing mice as compared with those of normal mice. Increased chemotaxis was correlated with duration of tumor growth, which, in turn, was correlated with size of tumor. Upon surgical tumor removal, chemotaxis fell to normal levels unless metastasis had occurred, in which case, the extent of chemotaxis was correlated with the volume of the metastasis. Increased chemotaxis was seen in relation to the growth of a mammary adenocarcinoma as well as that of a chemically induced fibrosarcoma. The major chemotactant in serum was shown to be complement derived, and sera from tumor-bearing and normal animals were equally effective. The presence of a tumor resulted in an increase in the percentage of polymorphonuclear cells in the bone marrow. The numbers of cells which migrated were independent of the cellular composition of the bone marrow in normal mice. In contrast, a negative correlation was found between the percentage of lymphocytes present and the number of bone marrow cells which migrated toward activated serum when the cells originated in a tumor-bearing mouse. The data suggested the increased chemotaxis was a property of the cells rather than the soluble substances in the serum.


[Postactivation changes in the ultrastructure of motor neurons].
The prolonged high-frequency synaptic activation of the frog spinal motoneurons suppressing their firing, leads to an increase in the size of synapses and to a considerable shift in their ultrastructure. Restoration of the functional and morphological alterations in the cells after cessation of their rhythmical activation proceeds with different speed: the restoration of neurons' ability to generate synaptic and spike potentials in response to testing stimulation of afferents occurs much earlier than the restoration of the cells' ultrastructure and size. Neurons with obviously changed ultrastructure of soma and synaptic apparatus are capable of generating synaptic and spike potentials in response to stimulation. At the same time, the size of the neurons returns to normal either than the normalizing of cell ultrastructures whose speed of restoration varies as well.


LncRNA DCST1-AS1 Was Upregulated in Endometrial Carcinoma and May Sponge miR-92a-3p to Upregulate Notch1.
The functions of DCST1-AS1 have been investigated in liver cancer, while its role in endometrial carcinoma (EC) remains hardly known. This study aimed to analyze the role of DCST1-AS1 in EC. Paired EC and non-tumor tissue samples were obtained from 62 EC patients. These patients were followed up for 5 years since their admission to record their survival conditions. HEC-1 cells were transfected with DCST1-AS1, Notch1 vectors, miRNA negative control or miR-92a-3p mimic. Luciferase activity was measured. QPCR and Western blot were applied to determine the RNA level and protein expression, respectively. The invasion and migration of HEC-1 cells were analyzed by Transwell assay. We in this study found that DCST1-AS1 was upregulated in EC. Survival analysis revealed that high levels of DCST1-AS1 expression predicted poor survival of EC patients. Bioinformatics analysis revealed that miR-92a-3p may bind DCST1-AS1 and the interaction between them was further confirmed by dual-luciferase activity assay. However, overexpression of miR-92a-3p and DCST1-AS1 failed to affect the expression of each other. Moreover, DCST1-AS1 overexpression led to upregulated Notch1 and increased cancer cell invasion and migration rates. Overexpression of miR-92a-3p played an opposite role and attenuated the effects of DCST1-AS1 overexpression. DCST1-AS1 is downregulated in EC and may sponge miR-92a-3p, thereby promoting cancer cell invasion and migration.


Clinical trials with new radiation modalities.
I would suggest that the investigation of a new clinical modality involves a major commitment by the whole clinical group of the department involved and not just by the people chosen to be the primary investigators. As a base for comparison, it requires a detailed knowledge of the results and sites of failures and complications of the therapy used by that department. To make adequate relative biologic effect studies for the new modality, suitable comparative, quantitative tissue and tumor assays have to be done with photons and these could be done and established before the new modality came on line. For the Phase III trial, which is usually considered a randomized comparative trial, it can be argued (and a method is proposed) for the use of a non-randomized study to make the maximum use of patients coming to the centre.


Cost-effectiveness of intensive atorvastatin therapy in secondary cardiovascular prevention in the United Kingdom, Spain, and Germany, based on the Treating to New Targets study.
The Treating to New Targets (TNT) clinical trial found that intensive 80 mg atorvastatin (A80) treatment reduced cardiovascular events by 22% when compared to 10 mg atorvastatin (A10) treatment. We evaluated the cost-effectiveness of intensive A80 vs A10 treatment in the United Kingdom (UK), Spain, and Germany. A lifetime Markov model was developed to predict cardiovascular disease-related events, costs, survival, and quality-adjusted life-years (QALYs). Treatment-specific event probabilities were estimated from the TNT clinical trial. Post-event survival, health-related quality of life, and country-specific medical-care costs were estimated using published sources. Intensive treatment with A80 increased both the per-patient QALYs and corresponding costs of care, when compared to the A10 treatment, in all three countries. The incremental cost per QALY gained was <euro> 9,500, <euro> 21,000, and <euro> 15,000 in the UK, Spain, and Germany, respectively. Intensive A80 treatment is estimated to be cost-effective when compared to A10 treatment in secondary cardiovascular prevention.


An adaptive fuzzy controller based on sliding mode for robot manipulators.
This paper considers adaptive fuzzy control of robotic manipulators based on sliding mode. It is first shown that an adaptive fuzzy system with the system representative point (RP, or as is often termed, a switching function in variable structure control (VSC) theory) and its derivative as inputs, can approximate the robot nonlinear dynamics in the neighborhood of the switching hyperplane. Then a new method for designing an adaptive fuzzy control system based on sliding mode is proposed for the trajectory tracking control of a robot with unknown nonlinear dynamics. The system stability and tracking error convergence are also proved by Lyapunov techniques.