Predicting Social Distancing Intention and Behavior During the COVID-19 Pandemic: An Integrated Social Cognition Model.
Social distancing is a key behavior to minimize COVID-19 infections. Identification of potentially modifiable determinants of social distancing behavior may provide essential evidence to inform social distancing behavioral interventions. The current study applied an integrated social cognition model to identify the determinants of social distancing behavior, and the processes involved, in the context of the COVID-19 pandemic. In a prospective correlational survey study, samples of Australian (N = 365) and U.S. (N = 440) residents completed online self-report measures of social cognition constructs (attitude, subjective norm, moral norm, anticipated regret, and perceived behavioral control [PBC]), intention, action planning, habit, and past behavior with respect to social distancing behavior at an initial occasion. Follow-up measures of habit and social distancing behavior were taken 1 week later. Structural equation models indicated that subjective norm, moral norm, and PBC were consistent predictors of intention in both samples. Intention, action planning, and habit at follow-up were consistent predictors of social distancing behavior in both samples. Action planning did not have consistent effects mediating or moderating the intention-behavior relationship. Inclusion of past behavior in the model attenuated effects among constructs, although the effects of the determinants of intention and behavior remained. Current findings highlight the importance of subjective norm, moral obligation, and PBC as determinants of social distancing intention and intention and habit as behavioral determinants. Future research on long-range predictors of social distancing behavior and reciprocal effects in the integrated model is warranted.


The binding sites of cytochalasin D. I. Evidence that they may be peripheral membrane proteins.
Binding sites for tritiated cytochalasin D (3H-CD) on the isolated plasma membrane from HEp-2 cells were reversibly inactivated, but not dissociated from the membrane, by dialysis in 0.6 M KCl. Activity was restored by subsequent dialysis in 0.06 M KCl. Treatment with 0.2 mM ATP at low ionic strength also inactivated these sites, apparently irreversibly. Extraction of the membrane with 6% Triton X-100 removed 75% of its protein, resulting in a two-fold increase in specific binding activity for 3H-CD. Both high and low affinity binding sites were retained by the detergent-extracted membrane; at least 60% of the high affinity sites were resistant to this treatment. Evidence is presented for the attachment to the HEp-2 plasma membrane of both actin and myosin. The results support the tentative conclusion that plasma membrane binding sites for 3H-CD are peripheral proteins on the cytoplasmic face of the membrane. They are consistent with the hypothesis that myosin may be the location of the high affinity binding site and actomyosin may be the low affinity site. Comparison of these observations with those reported for the congeneric drug, cytochalasin B, suggests that CD binding sites differ from the high affinity site for cytochalasin B.


Induction of lamina propria Th17 cells by intestinal commensal bacteria.
Th17 cells constitute a subset of activated CD4(+) T cells, characterized by their production of interleukin (IL)-17, IL-17F, and IL-22, that play a critical role in host defence against extracellular pathogens. An intriguing feature of these cells is their selective and constitutive presence in the intestinal lamina propria. The development of intestinal Th17 cells is controlled by intestinal commensal bacteria. Recently, segmented filamentous bacterium (SFB) was identified as a specific bacterial taxon that promotes Th17 differentiation in the small intestine of mice. We discuss the recent advances in our understanding of the mechanism of intestinal Th17 synthesis and its potential implications for the treatment of inflammatory bowel diseases.


Endophytic fungal community of Rosa damascena Mill. as a promising source of indigenous biostimulants: Elucidating its spatial distribution, chemical diversity, and ecological functions.
The role of endophytes in maintaining healthy plant ecosystems and holding promise for agriculture and food security is deeply appreciated. In the current study, we determine the community structure, spatial distribution, chemical diversity, and ecological functions of fungal endophytes of Rosa damascena growing in the North-Western Himalayas. Culture-dependent methods revealed that R. damascena supported a rich endophyte diversity comprising 32 genera and 68 OTUs. The diversity was governed by climate, altitude, and tissue type. Species of Aspergillus, Cladosporium, Penicillium, and Diaporthe were the core endophytes of the host plant consisting of 48.8% of the endophytes collectively. The predominant pathogen of the host was Alternaria spp., especially A. alternata. GC-MS analyses affirmed the production of diverse arrays of volatile organic compounds (VOC) by individual endophytes. Among the primary rose oil components, Diaporthe melonis RDE257, and Periconia verrucosa RDE85 produced phenyl ethyl alcohol (PEA) and benzyl alcohol (BA). The endophytes displayed varied levels of plant growth-promoting, colonization, and anti-pathogenic traits. Between the selected endophytes, P. verrucosa and D. melonis significantly potentiated plant growth and the flavonoids and chlorophyll content in the host. The potential of these two endophytes and their metabolites PEA and BA was confirmed on Nicotiana tabacum. The treatments of the metabolites and individual endophytes enhanced the growth parameters in the model plant significantly. The results imply that P. verrucosa and D. melonis are potential plant growth enhancers and their activity may be partially due to the production of PEA and BA. Thus, R. damascena harbors diverse endophytes with potential applications in disease suppression and host growth promotion. Further investigations at the molecular level are warranted to develop green endophytic agents for sustainable cultivation of R. damascena and biocontrol of leaf spot disease.


Cholesterol modulates the physiological response to nanoparticles by changing the composition of protein corona.
Nanoparticles (NPs) in biological fluids form a layer of biomolecules known as the protein corona. The protein corona has been shown to determine the biological identity and in vivo fate of NPs, but whether and how metabolites, especially disease-related small molecules, regulate the protein corona and subsequently impact NP fate in vivo is relatively poorly understood. Here we report on the effects of cholesterol on the generation of protein corona and subsequent effects. We find that high levels of cholesterol, as in hypercholesterolemia, result in a protein corona with enriched apolipoproteins and reduced complement proteins by altering the binding affinity of the proteins to the NPs. The cholesterol-mediated protein corona can induce stronger inflammatory responses to NPs in macrophages and promote the cellular uptake of NPs in hepatocytes by enhancing the recognition of lipoprotein receptors when compared with normal protein corona. The result of in vivo biodistribution assays shows that, compared with healthy mice, NPs in hypercholesterolemic mice were more likely to be delivered to the liver, spleen and brain, and less likely to be delivered to the lungs. Our findings reveal that the metabolome profile is an unexploited factor impacting the target efficacy and safety of nanomedicines, providing a way to develop personalized nanomedicines by harnessing disease-related metabolites.


Inhibition of cardiac Na+ current by primaquine.
The electrophysiological effects of the anti-malarial drug primaquine on cardiac Na(+) channels were examined in isolated rat ventricular muscle and myocytes. In isolated ventricular muscle, primaquine produced a dose-dependent and reversible depression of dV/dt during the upstroke of the action potential. In ventricular myocytes, primaquine blocked I(Na)(+) in a dose-dependent manner, with a K(d) of 8.2 microM. Primaquine (i) increased the time to peak current, (ii) depressed the slow time constant of I(Na)(+) inactivation, and (iii) slowed the fast component for recovery of I(Na)(+) from inactivation. Primaquine had no effect on: (i) the shape of the I - V curve, (ii) the reversal potential for Na(+), (iii) the steady-state inactivation and g(Na)(+) curves, (iv) the fast time constant of inactivation of I(Na)(+), and (v) the slow component of recovery from inactivation. Block of I(Na)(+) by primaquine was use-dependent. Data obtained using a post-rest stimulation protocol suggested that there was no closed channel block of Na(+) channels by primaquine. These results suggest that primaquine blocks cardiac Na(+) channels by binding to open channels and unbinding either when channels move between inactivated states or from an inactivated state to a closed state. Cardiotoxicity observed in patients undergoing malaria therapy with aminoquinolines may therefore be due to block of Na(+) channels, with subsequent disturbances of impulse conductance and contractility.


NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II.
The vasoactive peptide urotensin-II (U-II) has been associated with vascular remodeling in different cardiovascular disorders. Although U-II can induce reactive oxygen species (ROS) by the NADPH oxidase NOX4 and stimulate smooth muscle cell (SMC) proliferation, the precise mechanisms linking U-II to vascular remodeling processes remain unclear. Forkhead Box O (FoxO) transcription factors have been associated with redox signaling and control of proliferation and apoptosis. We thus hypothesized that FoxOs are involved in the SMC response toward U-II and NOX4. We found that U-II and NOX4 stimulated FoxO activity and identified matrix metalloproteinase-2 (MMP2) as target gene of FoxO3a. FoxO3a activation by U-II was preceded by NOX4-dependent phosphorylation of c-Jun NH(2)-terminal kinase and 14-3-3 and decreased interaction of FoxO3a with its inhibitor 14-3-3, allowing MMP2 transcription. Functional studies in FoxO3a-depleted SMCs and in FoxO3a(-/-) mice showed that FoxO3a was important for basal and U-II-stimulated proliferation and vascular outgrowth, whereas treatment with an MMP2 inhibitor blocked these responses. Our study identified U-II and NOX4 as new activators of FoxO3a, and MMP2 as a novel target gene of FoxO3a, and showed that activation of FoxO3a by this pathway promotes vascular growth. FoxO3a may thus contribute to progression of cardiovascular diseases associated with vascular remodeling.


Effects of dividing attention on memory for declarative and procedural aspects of tool use.
Tool-related knowledge and skills are supported by a complex set of memory processes that are not well understood. Some aspects of tools are mediated by either declarative or procedural memory, while other aspects may rely on an interaction of both systems. Although motor skill learning is believed to be primarily supported by procedural memory, there is debate in the current literature regarding the role of declarative memory. Growing evidence suggests that declarative memory may be involved during early stages of motor skill learning, although findings have been mixed. In the current experiment, healthy, younger adults were trained to use a set of novel complex tools and were tested on their memory for various aspects of the tools. Declarative memory encoding was interrupted by dividing attention during training. Findings showed that dividing attention during training was detrimental for subsequent memory for tool attributes as well as accurate demonstration of tool use and tool grasping. However, dividing attention did not interfere with motor skill learning, suggesting that declarative memory is not essential for skill learning associated with tools.


Isothermal DNA amplification combined with lateral flow dipsticks for detection of biothreat agents.
The recently developed methods of nucleic acids isothermal amplification are promising tools for point-of-care diagnostics and in the field detection of pathogenic microorganisms. However, application of these methods outside a laboratory faces some challenges such as the rapid and sensitive detection of amplified products and the absence of cross-reactivity with genetically related microorganisms. In the presented study we compared three methods of isothermal DNA amplification loop-mediated isothermal amplification (LAMP), recombinase polymerase amplification (RPA) and thermophilic helicase-dependent isothermal DNA amplification (tHDA), for detection of highly dangerous pathogens, such as Bacillus anthracis, Francisella tularensis and Yersinia pestis, and combined them with lateral flow dipsticks for the rapid visualization of amplified products. We observed low specificity of the three methods for B. antharcis, medium for Y. pestis and high for F. tularensis detection. Sensitivity and the detection limit were high and comparable for all the methods. We concluded that the lateral flow dipsticks have been a very useful tool for product detection of the isothermal amplification methods and enable reading the results without the use of any equipment. However, our results showed that the use of isothermal amplification methods is strongly related to the risk of false positive results.


Burst discharges of thalamic reticular neurons: an intracellular analysis in anesthetized rats.
In order to analyze the mechanism of burst discharges intracellular recordings were made from 27 somatosensory thalamic reticular (S-TR) neurons in urethane-anesthetized rats. Burst discharges, composed of 2-7 spikes, were always superposed on a slow depolarization (SD) lasting for 40-60 ms, which appeared only when the membrane was hyperpolarized. The number of spikes superposed on an SD varied depending upon the amplitude of the SD. A single shock stimulation of the lemniscus medialis elicited a series of SDs, each without being preceded by a phasic hyperpolarizing potential. The SDs were repeated with spindle rhythms. Evidence has been provided that EPSPs contribute to the mechanism for triggering SDs. In spontaneous rhythmic SDs occurring with the rhythm of EEG spindles, steps representing EPSPs were recordable on the rising phase of each SD. It is suggested that excitatory synaptic inputs to S-TR neurons with the spindle rhythm are responsible for the rhythmic generation of SDs. Ventrobasal relay neurons are presumed as the source of the inputs.


Azathioprine in hidradenitis suppurativa with inflammatory phenotype: a case series of 11 patients.
Hidradenitis suppurativa (HS) is a chronic inflammatory disease that negatively impacts the quality of life of patients. It presents as deep-seated nodules, abscesses, fistulae, sinus tracts, and scars in the axilla, inguinal area, submammary folds, and perianal area. Recently, two phenotypes have been described: a follicular phenotype and an inflammatory phenotype. Numerous medical treatments are available for hidradenitis suppurativa, with particular importance of antitumor necrosis factor antibodies. Due to the association of HS with other conditions with a pro-inflammatory state, particularly Crohn's disease, it has been suggested that azathioprine may have a role in the treatment of HS. To assess the effectiveness of azathioprine monotherapy in patients with moderate-severe HS. We retrospectively studied patients with HS treated with azathioprine in monotherapy. We performed both clinical and ultrasound evaluation at baseline as well as in the follow-up visits. Their baseline score on the iHS4 and DLQI scales and 12-16 weeks after starting the treatment were compared. We also registered the number of patients who achieved HiSCR. Six patients presented significant improvement, reducing their score in iHS4 and DLQI scales and achieving HiSCR. Another patient had clinical improvement, meaning reduction in iHS4 and DLQI, but without achieving HiSCR. Two patients stopped the treatment before week 12 because of adverse events. The remaining two patients presented no improvement. The median (Q3-Q1) baseline iHS4 score was 6 (12-6), and follow-up iHS4 score, 4 (6-2), being these differences statistically significant (P = 0.006). Median (Q3-Q1) baseline DLQI scores and 12-16 weeks after treatment were 17 (23-11) and 14 (18-9) although statistically nonsignificant (P = 0.099). We present a case series of 11 patients treated with azathioprine with good clinical and ultrasonographic response. We suggest that azathioprine may benefit a certain patient profile with the inflammatory phenotype.


Failure of cycloheximide to alter rate of recovery of temperature following acute DFP treatment.
Cycloheximide, 400 microgram intraventricularly 4 h after a 1 mg/kg i.m. injection of the irreversible anticholinesterase DFP, failed to alter the rate of recovery of temperature to normal. Tolerance to the hypothermic effects of DFP developed at the same rate in cycloheximide-treated rats. These findings suggest that neither recovery from the acute effects of DFP nor tolerance to its chronic effects depends on protein synthesis.


Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples.
Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 x 10(-4) for SREBF1 (rs11868035, odd ration (OR)=1.26, 95% confidence interval (CI) (1.09-1.45)) and 4 x 10(-5) for SREBF2 (rs1057217, OR=1.39, 95% CI (1.19-1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.


Cancer chemopreventive effects of constituents of Caesalpinia ferrea and related compounds.
The anti-tumor promoting effects of fruits of Caesalpinia ferrea MART. (Leguminosae) were tested by the in vitro Epstein-Barr virus early antigen (EBV-EA) activation assay, and its active constituents were identified as gallic acid (1) and methyl gallate (2). A total of 49 related compounds of 1 and 2 were analysed for the effects by this assay, and the structure activity relationships have been proposed. Three acetophenone derivatives, 2,6-dihydroxyacetophenone (48), 2,3,4-trihydroxyacetophenone (50) and 2,4,6-trihydroxy- acetophenone (51) were found to show potent inhibitory activity.


JAK1 Takes a FERM Hold of Type II Cytokine Receptors.
Janus kinases (JAKs) initiate the intracellular signaling cascade triggered by exposure of cells to cytokines and interferons. In order to achieve this, JAKs are bound to the intracellular domain of specific cytokine receptors immediately adjacent to the cell membrane. In this issue of Structure, Ferrao et al. (2016) provide structural details of such an interaction and in doing so, identify for the first time the motif used by type II cytokine receptors to recruit JAK1.


Simultaneous extensive extracranial and coronary revascularization. Long-term follow-up up to 13 years.
Simultaneous surgery for extensive extracranial and coronary revascularization was performed in 168 patients (mean age 61 years), from 1974 up to June 1987; 116 patients (69%) were in NYHA class III or IV, 133 (79%) had triple vessel disease and 51 (30%) had left main stem lesions. One or more previous myocardial infarctions were present in 96 patients (57%); normal preoperative left ventricular function was present in only 35%. In 22 cases, additional cardiac procedures were performed. Symptomatic extracranial disease was present in 76 patients (45%), arch vessel surgery was performed in 29 (17%) and bilateral haemodynamically significant carotid disease was present in 58 (35%). Operative mortality (3%) was mainly cardiac and operative morbidity mainly neurological (7%). Actuarial survival at 5 years (75%) and 10 years (57%) was mainly determined by the cardiac survival (87% at 5 years and 70% at 10 years), while neurological follow-up deaths were rare (neurological survival 97% at 5 years and 91% at 10 years). Late morbidity was more cardiac than neurologically determined; actuarial curves showed 72% to be free of all serious events or death at 5 years, and 47% at 10 years.


Pattern, Cause of Childhood Burn injuries and their Management Outcome At Jimma Medical Center, Jimma Zone, Oromia Region, Southwest Ethiopia.
Burn injuries are prevalent worldwide, especially in developing countries; and there are significant pediatric burn injuries in Ethiopia. This study was performed to analyze the pattern, cause, and management outcome of burn injuries in Jimma Medical Center. A hospital‑based retrospective cross‑sectional study was conducted at Jimma university medical center burn unit. Data were collected through chart review of pediatric patients aged 0 to 14 years who were admitted to the burn unit with a burn injury. A total of 92 hospitalized children were studied from Jan 1, 2020 to Dec 31, 2021 GC. Data were analyzed using SPSS version 25. The statistical significance was determined using odds ratio (OR) with a 95% confidence interval (CI) and the corresponding P-value of less than 0.05. The majority of the patients were males (52.2%). Scald burn was the most common cause of burn in 57(62.0%). The TBSA of majority of the patients (52.2%) was found to be between 11% and 20%. After adjusting for possible confounders in the multivariate analysis, preexisting illness and time of presentation to care were found to have a statistically significant association with the outcome of burn at discharge (P= 0.007) (P= 0.021) respectively. The most common cause of burn in our setup was scald burn; upper extremities were also the most affected site. According to our study, the factors associated with the outcome of burn injury were preexisting illness and late presentation to health facilities.


Acid-sensitive ion channel 1a regulates TNF-α expression in LPS-induced acute lung injury via ERS-CHOP-C/EBPα signaling pathway.
Acute lung injury (ALI) is the local inflammatory response of the lungs involved in a variety of inflammatory cells. Macrophages are immune cells and inflammatory cells widely distributed in the body. Acid-sensitive ion channel 1a (ASIC1a) is involved in the occurrence of ALI, but the mechanism is still unclear. Kunming mouse were stimulated by Lipopolysaccharides (LPS) to establish ALI model in vivo, and RAW264.7 cells were stimulated by LPS to establish inflammatory model in vitro. Amiloride was used as a blocker of ASIC1a to treat mice, and dexamethasone was used as a positive drug for ALI. After blockers and RNAi blocked or silenced the expression of ASIC1a, the expressions of ASIC1a, endoplasmic reticulum-related proteins GRP78, CHOP, C/EBPα and TNF-α were detected. The Ca2+ concentration was measured by a laser confocal microscope. The interaction between CHOP and C/EBPα and the effect of C/EBPα on the activity of TNF-α promoter were detected by immunoprecipitation and luciferase reporter. The expressions of ASIC1a and TNF-α were increased significantly in LPS group. After the blocker and RNAi blocked or silenced ASIC1a, the expressions of TNF-α, GRP78, CHOP were reduced, and the intracellular Ca2+ influx was weakened. The results of immunoprecipitation showed that CHOP and C/EBPα interacted in the macrophages. After silencing CHOP, C/EBPα expression was increased, and TNF-α expression was decreased. The results of the luciferase reporter indicated that C/EBPα directly binds to TNF-α. ASIC1a regulates the expression of TNF-α in LPS-induced acute lung injury via ERS-CHOP-C/EBPα signaling pathway.


Distinguishing homogeneous advanced oxidation processes in bulk water from heterogeneous surface reactions in organic oxidation.
Clarifying the reaction pathways at the solid-water interface and in bulk water solution is of great significance for the design of heterogeneous catalysts for selective oxidation of organic pollutants. However, achieving this goal is daunting because of the intricate interfacial reactions at the catalyst surface. Herein, we unravel the origin of the organic oxidation reactions with metal oxide catalysts, revealing that the radical-based advanced oxidation processes (AOPs) prevail in bulk water but not on the solid catalyst surfaces. We show that such differing reaction pathways widely exist in various chemical oxidation (e.g., high-valent Mn3+ and MnOX) and Fenton and Fenton-like catalytic oxidation (e.g., Fe2+ and FeOCl catalyzing H2O2, Co2+ and Co3O4 catalyzing persulfate) systems. Compared with the radical-based degradation and polymerization pathways of one-electron indirect AOP in homogeneous reactions, the heterogeneous catalysts provide unique surface properties to trigger surface-dependent coupling and polymerization pathways of a two-electron direct oxidative transfer process. These findings provide a fundamental understanding of catalytic organic oxidation processes at the solid-water interface, which could guide the design of heterogeneous nanocatalysts.


Nuclear imaging in the genitourinary tract: recent advances and future directions.
For almost three decades, noninvasive radionuclide procedures for the evaluation of renal disease have been important components of nuclear medicine practice. With the introduction of new imaging agents and procedures, these techniques can provide valuable data on perfusion and function of individual kidneys. In general, these procedures are easy to perform and carry a low radiation burden and sedation is not required. Moreover, radionuclide imaging of the genitourinary tract has become an invaluable asset to clinicians in the evaluation of renal parenchyma and urologic abnormalities.


Assessment of symptoms in adult survivors of incest: a factor analytic study of the Responses to Childhood Incest Questionnaire.
Although research has established the long-term damaging effects of incest, these efforts have suffered from the lack of valid, standardized assessment instruments. The present study reports on the construction and factor validation of the Response to Childhood Incest Questionnaire (RCIQ), a self-report instrument that assesses a range of commonly reported symptoms experienced by adult survivors of incest. A clinical population of 104 adult women who had experienced childhood or adolescent incest completed the RCIQ. A factor analysis of the RCIQ items revealed seven factors which corresponded to hypothesized stress response themes experienced by survivors of traumatic events. These factors include vulnerability and isolation, fear and anxiety, anger and betrayal, reaction to the abuser, sadness and loss, and powerlessness. In addition, four factors corresponded to the diagnostic criteria for post-traumatic stress disorder: intrusive thoughts, avoidance and intrusive emotions, detachment, and emotional control and numbness. The usefulness of the RCIQ as a pre- and post-treatment measure and the need for further research is discussed.


HILIC-UPLC-MS for high throughput and isomeric N-glycan separation and characterization in Congenital Disorders Glycosylation and human diseases.
N-glycan analyses may serve uncovering disease-associated biomarkers, as well as for profiling distinctive changes supporting diagnosis of genetic disorders of glycan biosynthesis named congenital disorders of glycosylation (CDG). Strategies based on liquid chromatography (LC) preferentially coupled to electrospray ionization (ESI) - mass spectrometry (MS) have emerged as powerful analytical methods for N-glycan identification and characterization. To enhance detection sensitivity, glycans are commonly labelled with a functional tag prior to LC-MS analysis. Since most derivatization techniques are notoriously time-consuming, some commercial analytical kits have been developed to speed up N-deglycosylation and N-glycan labelling of glycoproteins of pharmaceutical and biological interest such as monoclonal antibodies (mAbs). We exploited the analytical capabilities of RapiFluor-MS (RFMS) to perform, by a slightly modified protocol, a detailed N-glycan characterization of total serum and single serum glycoproteins from specific patients with CDG (MAN1B1-CDG, ALG12-CDG, MOGS-CDG, TMEM199-CDG). This strategy, accomplished by Hydrophilic Interaction Chromatography (HILIC)-UPLC-ESI-MS separation of the RFMS derivatized N-glycans, allowed us to uncover structural details of patients serum released N-glycans, thus extending the current knowledge on glycan profiles in these individual glycosylation diseases. The applied methodology enabled to differentiate in some cases either structural isomers and isomers differing in the linkage type. All the here reported applications demonstrated that RFMS method, coupled to HILIC-UPLC-ESI-MS, represents a sensitive high throughput approach for serum N-glycome analysis and a valuable option for glycan detection and separation particularly for isomeric species.


A rapid and sensitive micro-assay to determine the capacity of quinones to undergo redox cycling.
Using a series of aziridinyl-benzoquinones it is shown that the conversion of oxyhemoglobin to methemoglobin in sheep erythrocytes is correlated with the capacity of each quinone to undergo redox cycling. Based on these findings a semiquantitative assay is developed for the rapid screening of redox cycling quinones.


Evaluation of the effects of deltamethrin on the fetal rat testis.
Pregnant Sprague-Dawley rats were administered deltamethrin, at doses 0.1, 1, 5 or 10 mg kg(-1) day(-1) , or di-n-hexyl phthalate (DnHP) (250 mg kg(-1) day(-1) ), by gavage, from gestational day 13 to 19. Maternal toxicity was observed at 10 mg kg(-1) day(-1) , as evidenced by transient clinical signs of neurotoxicity and reductions in body weight, body weight gain and corrected weight gain. Deltamethrin had no statistically significant effect on the incidence of post-implantation loss, fetal weight or anogenital distance in the male fetuses. Unlike DnHP, deltamethrin induced no changes in the expression of several genes involved in cholesterol transport or in the steroid synthesis pathway in the testes of gestational day 19.5 male fetuses (SRB1, StAR, P450scc, 3βHSD, P450 17 A1, 17βHSD). Fetal testicular levels of P450scc and P450 17 A1 protein were also unaffected by deltamethrin. No statistically significant differences were observed in the ex vivo fetal testicular production of testosterone and androstenedione after deltamethrin exposure, whereas DnHP markedly reduced these parameters. The deltamethrin metabolite, 3-phenoxybenzoic acid, was detected in amniotic fluid. In summary, our results demonstrate that in utero exposure to deltamethrin during the period of sexual differentiation had no significant effect on the testosterone synthesis pathway in the male rat fetus up to a maternal toxic dose. Copyright © 2016 John Wiley & Sons, Ltd.


Sex differences of the influence of T3 on the topical distribution of phosphoenolpyruvate carboxykinase activity in the liver acinus.
Phosphoenolpyruvate carboxykinase (PEPCK) activity was investigated in livers of triiodothyronine (T3) treated male and female rats with special regard to its intraacinar localization. In untreated controls of both, male and female rats, the activity was heterotopically distributed within the acinus with highest values in the periportal zone, and with lowest values in the perivenous zone. This periportal to perivenous activity gradient revealed to be under the influence of T3. Application of T3 resulted in a relative increase of PEPCK activity which was much greater in the livers of females than in males. The extent of T3-induced augmentation of PEPCK activity was dependent on the intraacinar position. In both sexes greatest relative activation was found in the perivenous zone. In female animals, the perivenous activity of T3 treated livers was comparable to that observed in the periportal zone of controls.


Phenanthrenes from Juncus effusus.
A chemical investigation of the EtOAc-soluble fraction from the ethanol extract of the medullae of Juncus effusus led to the isolation of three new 9,10-dihydrophenanthrenes, juncuenins E-G (1-3); two new phenanthrenes, dehydrojuncuenins D-E (4-5); one new feruloylated glycoside (6); and one known 9,10-dihydrophenanthrene (7). The structures of these compounds were determined by analyzing their spectroscopic data. Metabolites 1-4 and 7 were further evaluated for their in vitro cytotoxic activities against seven human cancer lines (A549, MCF-7, BEL-7402, HeLa, COLO205, BGC-823, and SK-OV-3). Among them, compound 1 exhibited weak cytotoxicity against MCF-7 and HeLa cell lines. Compound 7 showed moderate cytotoxicity against MCF-7 and HeLa cell lines, with IC50 values of 9.17 and 19.6 µM, respectively.


Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study.
Chronic fatigue syndrome (CFS) is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue-segmented T(1)-weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging ((1)H MRSI) in 16 subjects with CFS (modified US Centers for Disease Control and Prevention criteria) with those in 14 patients with generalized anxiety disorder (GAD) and in 15 healthy volunteers, matched group-wise for age, sex, body mass index, handedness, and IQ. Mean lateral ventricular lactate concentrations measured by (1)H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate. CFS is associated with significantly raised concentrations of ventricular lactate, potentially consistent with recent evidence of decreased cortical blood flow, secondary mitochondrial dysfunction, and/or oxidative stress abnormalities in the disorder.


Changes in cardiac and vascular haemodynamics as potential mediators of improvements in cardiovascular and kidney outcomes with empagliflozin in type 2 diabetes.
Evaluate changes in haemodynamic markers as mediators of cardiovascular (CV) and kidney benefits with empagliflozin. Post-hoc analysis of EMPA-REG OUTCOME in patients with type 2 diabetes (T2D) and established CV disease receiving empagliflozin (10 and 25 mg) or placebo. Outcomes were CV death, hospitalisation for heart failure [HF], HF death, incident/worsening nephropathy, new onset macroalbuminuria, and the composite of sustained estimated glomerular filtration rate decline ≥40 % from baseline, renal replacement therapy or renal death. To be considered a mediator, changes in variable (pulse pressure, mean arterial pressure and cardiac workload) over time had to be (1) affected by active treatment, (2) associated with the outcome, and (3) adjustment for changes over time must reduce treatment effect versus an unadjusted analysis. Variables were evaluated in Cox regression analyses. Pulse pressure, mean arterial pressure and cardiac workload were significantly reduced by empagliflozin vs placebo. Using change from baseline to Week 12 or sensitivity analyses (time-dependent updated mean and current change from baseline) of these CV parameters, only small impacts on empagliflozin effect on CV and kidney outcomes were shown. Improvements in haemodynamic parameters did not substantially mediate empagliflozin benefits on CV and kidney outcomes in patients with T2DM and established CV disease.


Potential for therapeutic gain similar to pions by daily combinations of neutrons and low-LET radiations.
Biological studies with negative pi mesons (pions) at the Los Alamos Meson Physics Facility (LAMPF) have shown a relatively constant reduction of shoulder of the survival curve for single cell cultures and relatively constant reduction in the no response region for multicellular tumor spheroids (MTS) with little change in sensitivity (or slope), in both single dose and fractionated experiments. In clinical studies, a trend toward therapeutic gain for pions has been demonstrated in patients treated at LAMPF, with marked, rapid turmor regression for relatively mild acute normal tissue injury and no untoward effects observed over 7 to 24 months. Since the pion beams used therapeutically at LAMPF are characterized by a small amount of high-linear-energy-transfer (LET) radiation (in the range 10 to 20%), it is hypothesized that pion radiation as compared to x-rays increased the differential tolerance to sublethal injury in favor of normal tissues, resulting in therapeutic gain. It is further proposed that the near simultaneous application of high-LET radiation (such as neutrons) and low-LET radiation (such as x-rays) might create a bilogical situation similar to that of pion treatment, potentially resulting in therapeutic gain, although without the added benefit of dose localization obtainable with pions.


Comparison of flutamide and Emcyt in hormone-refractory metastatic prostatic cancer.
A prospective randomized trial for metastatic prostatic cancer in 220 patients who were refractory to hormone therapy was conducted by the National Prostatic Cancer Project from 1984 to 1985. As of July, 1986, the evaluation of these patients reflected no difference in response to either estramustine phosphate (Emcyt) or flutamide. Toxicities were minimal, and the observed survival and progression-free survival intervals were noteworthy in view of the overall prospects for such patients. Future studies dealing with specific quality of life issues seem to be indicated by our results.


Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity.
Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somatoautonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by cytotoxic drugs such as cisplatin is associated with an increase in the concentration of 5-hydroxytryptamine (5-HT) in the intestine and the brainstem. It is proposed that cytotoxic drugs evoke 5-HT release from the enterochromaffin (EC) cells in the intestinal mucosa and that the released 5-HT stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells seems to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The release of 5-HT from the EC cells, however, is regulated by polymodal mechanisms on autoreceptors or heteroreceptors. The precise role of 5-HT on the occurrence of vomiting has not been fully elucidated. The present review aims to describe the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagus nerve activity. Various methods for predicting emesis are also evaluated.


"What I was and what I am": A qualitative study of survivors' experience of urological cancer.
Most qualitative studies do not explore experience throughout the urologic cancer survival trajectory. Moreover, the evidence of the experience of cancer survivors that focuses on the contextual aspects of culture is scarce in oncology literature. This study aimed to analyze the survival experience of urological cancer from the perspective of men. This was a narrative research based on the concepts of culture derived from the interpretative medical anthropologic approach. Semi-structured interviews were conducted with 10 male survivors of urological cancer at different survival seasons. Seven participants agreed to a second interview, which resulted in 17 interviews. The data were analyzed using a five-phase thematic analysis approach. The findings are presented as narrative syntheses. The standards for reporting qualitative research (SPQR) was used in this study. Two narrative syntheses were constructed: "The journey of urological cancer: discovering oneself as a survivor" and "What I was and what I am today": the disruption on the body and life. The narrative synthesis shows that survivors undergo transitions of identity from being healthy men to wrecked men. The survivors tried to present themselves as normal men to keep their masculinity intact. However, the experience of survival constituted a process of liminality and biographical disruption. The experience of surviving urological cancer has highlighted the physical, emotional, and social challenges experienced by these male survivors. It is recommended to oncology nurses that nursing care should be planned along survival seasons considering the survivors' individual and subjective experiences.


Slippery surfaces of carnivorous plants: composition of epicuticular wax crystals in Nepenthes alata Blanco pitchers.
Plants in the genus Nepenthes obtain a substantial nutrient supply by trapping insects in highly modified leaves. A broad zone of the inner surface of these pitchers is densely covered with wax crystals on which most insects lose their footing. This slippery wax surface, capturing prey and preventing its escape from the trap, plays a pivotal role in the carnivorous syndrome. To understand the mechanism of slipperiness, the present investigation aimed at an ultrastructural and physico-chemical characterization of the wax crystals in pitchers of N. alata Blanco. Scanning electron microscopy revealed that entire platelets protruded perpendicularly from the surface. Methods were developed that allowed the mechanical removal of wax crystals from the pitcher surface. It could be shown that the sampling was selective for the epicuticular wax, relevant for plant-insect interactions. The crystals consisted of a mixture of aliphatic compounds dominated by very-long-chain aldehydes. Triacontanal, at 43% the most abundant constituent, was largely responsible for crystal formation. Solubility data indicate that the Nepenthes crystals contained polymeric forms of this aldehyde. The resulting mechanical properties of the polymer crystals and the mechanism of slipperiness are discussed.


Use of sophisticated intra-operative monitoring in resuscitation of unexpected cardiovascular collapse during general anaesthesia.
The diagnosis of intraoperative anaphylaxis is important but can be difficult as the symptoms can be varying and dependent on patient factors. We describe an acute, unexpected and life threatening cardiovascular (CV) collapse, presumed to be due to an acute anaphylactic reaction secondary to gelatin administration, following induction of general anaesthesia (GA), in an ASA 3 patient scheduled for axillo-bifemoral bypass. The management of the profound cardiovascular (CV) collapse was greatly assisted by sophisticated haemodynamic, depth of anaesthesia and cerebral oximetry monitoring.(1) As far as we are aware this is the first such case where the full haemodynamic, depth of anaesthesia and cerebral oxygenation changes during CV collapse, presumed due to an acute anaphylactic reaction under GA have been fully documented. The use of advanced monitoring intraoperatively proved extremely useful in guiding the resuscitation of a life threatening allergic reaction under general anaesthesia.


Estimation of the bio-accessibility of methylmercury from aquatic foods using a PBTK model with an approximate Bayesian computation method in Chinese pregnant women.
Fish are the primary source of protein and docosahexaenoic acid (DHA) for pregnant women and children, but methylmercury (MeHg) pollution is the potential hazard of fish consumption. In risk assessments, the bio-accessibility of MeHg is usually assumed to be 100%, which could lead to overestimation of dietary exposure. An existing PBTK model was adapted to estimate parameters of the bio-accessibility based on MeHg exposure data from a cohort of 397 Chinese pregnant women. The posterior distributions of parameters were determined by using the ABC - MCMC. RMSEP and Spearman's rank correlation coefficients (Rho) were calculated to determine the goodness of model fitting. The Monte Carlo analysis was performed for the parameter distributions to estimate the model variability. The median of daily MeHg intake and maternal MeHg levels were 0.018 μg/kg bw and 3.01 μg/kg in the early and middle terms of pregnancy. The estimated bio-accessibility of freshwater fish, marine fish and others were 46.1, 17.3 and 58.2%, separately. The RMSEP improved from 11.18 to 2.54 and the Rho improved from 0.19 to 0.22 after bio-accessibility optimization. The model variability was estimated to be 2.6. The bio-accessibility estimated in this study was comparable to that determined in previous in vitro studies. The optimized model could improve the prediction performance on the MeHg body burden by dietary exposure.


Assessment of potential causes of falsely positive Mycobacterium tuberculosis breath test.
A suite of volatiles have previously been identified as specific markers of Mycobacterium tuberculosis metabolism in vitro. These markers - methyl phenylacetate, methyl p-anisate, methyl nicotinate, o-phenylanisole with the addition of methyl salicylate, may also be derived from other sources and confound development of a breath test for tuberculosis. To identify potential sources of these potential biomarkers food products, cosmetics, TB medication, environmental air and cigarette smoke were analysed for these markers using solid phase microextraction coupled with Gas Chromatography/Mass Spectrometry. Breath from healthy subjects, including smokers was also tested. Methyl salicylate was commonly detected, making this unsuitable as a specific marker for M. tuberculosis. Methyl nicotinate was detected repeatedly in cigarettes. Methyl phenylacetate was detected in 1.7% of healthy subjects and o-phenylanisole in just 1% of healthy breath indicating these may be more suitable for inclusion in the tuberculosis breath test due to their low "background" level. These results justify further clinical studies to further explore these markers as specific indicators of M. tuberculosis infection.


Deconstructing the concept of the healthy eater self-schematic: relations to dietary intake, weight and eating cognitions.
This study investigated differences in dietary intake, weight status, food preoccupation, and attributions about healthy eating lapses between individuals classified as healthy eater self-schematics and nonschematics. The study also assessed whether the separate dimensions of the self-schema construct (self-description as a healthy eater and perceived importance of being a healthy eater to self-image) are related to these health outcomes. College students (N=125; 82% female) completed questionnaires assessing healthy eater self-schema status, dietary intake, weight status, food preoccupation, and lapse attributions. Results revealed that females who were classified as healthy eater self-schematics ate more fruits and vegetables, ate less junk food and had lower BMIs than nonschematics. Healthy eater self-schematics also engaged in more positive thoughts and fewer negative thoughts about food, made less stable attributions about lapses in healthy eating and endorsed more personal control over lapses. When the two dimensions of the self-schema were examined separately, self-description appeared to be more related to these outcomes than perceived importance.


Enhancing gray-to-white matter contrast in 3T T1 spin-echo brain scans by optimizing flip angle.
Compared with MR imaging at 1.5T T1-weighted spin-echo imaging at 3T shows up with reduced gray-to-white matter contrast. The purpose of the present study was to show the effects of alterations of different flip angles as an easily accessible parameter to increase gray-to-white matter contrast. Spin-echo T1 sequences of 6 healthy volunteers were acquired in a 3T head scanner with 5 different flip angles. Observer-independent contrast-to-noise ratios for gray versus white matter from different flip angles, as well as subjective ratings of image quality from 2 blinded neuroradiologists, were compared statistically. Gray-to-white matter contrast increased significantly with decreasing flip angle. No artifacts were introduced by decreasing flip angles, and T1 contrast characteristics were robust and stable at lowered flip angles. Also, specific absorption ratios significantly decreased with decreasing flip angles. Using a flip angle of 50 degrees significantly increases gray-to-white matter contrast in T1 spin-echo brain scans at 3T B0 field strength.


Going beyond a First Reader: A Machine Learning Methodology for Optimizing Cost and Performance in Breast Ultrasound Diagnosis.
The goal of this study was to devise a machine learning methodology as a viable low-cost alternative to a second reader to help augment physicians' interpretations of breast ultrasound images in differentiating benign and malignant masses. Two independent feature sets consisting of visual features based on a radiologist's interpretation of images and computer-extracted features when used as first and second readers and combined by adaptive boosting (AdaBoost) and a pruning classifier resulted in a very high level of diagnostic performance (area under the receiver operating characteristic curve = 0.98) at a cost of pruning a fraction (20%) of the cases for further evaluation by independent methods. AdaBoost also improved the diagnostic performance of the individual human observers and increased the agreement between their analyses. Pairing AdaBoost with selective pruning is a principled methodology for achieving high diagnostic performance without the added cost of an additional reader for differentiating solid breast masses by ultrasound.


Impact of rock materials and biofertilizations on P and K availability for maize (Zea Maize) under calcareous soil conditions.
The present work evaluated the synergistic effects of soil fertilization with rock P and K materials and co-inoculation with P and K-dissolving bacteria [PDB (Bacillus megaterium var. phosphaticum) and KDB (Bacillus mucilaginosus and B. subtilis)] on the improvement of P and K uptake, P and K availability and growth of maize plant grown under limited P and K soil conditions (calcareous soil). The experiment was establishment with eight treatments: without rock P and K materials or bacteria inoculation (control), rock P (RP), rock K (RK), RP + PDB, RK + KDB and R(P + K)+(P + K)DB. Under the same conditions of this study, co-inoculation of PDB and KDB in conjunction with direct application of rock P and K materials (R(P + K)) into the soil increased P and K availability and uptake, and the plant growth (shoot and root growth) of maize plants grown on P and K limited soils.


Diagnosis of Barrett's esophagus and esophageal varices using a magnetically assisted capsule endoscopy system.
Magnetically assisted capsule endoscopy (MACE) potentially offers a comfortable, patient friendly, and community-based alternative to gastroscopy (EGD). This pilot study aims to explore whether this approach can be used to accurately diagnose Barrett's esophagus (BE) and esophageal varices. The MiroCam Navi capsule system was used to examine the upper GI tract in patients due to undergo a clinically indicated EGD. A total of 50 participants were enrolled: 34 had known pathology (17 BE, 17 esophageal varices [EV]) and 16 controls. Patients underwent the MACE procedure with the operator blinded to the indication and any previous endoscopic diagnoses. The subsequent EGD was performed by an endoscopist blinded to the MACE findings. Diagnostic yield, comfort, and patient preference between the 2 modalities were compared. The mean age of the participants was 61 years, the male/female ratio was 2.1:1, the mean body mass index was 29.5 kg/m2, and the average chest measurement was 105.3 cm. Forty-seven patients underwent both procedures; 3 patients were unable to swallow the capsule. With the use of the magnet, it was possible to hold the capsule within the esophagus for a mean duration of 190 seconds and up to a maximum of 634 seconds. A correct real-time MACE diagnosis was made in 11 of 15 patients with EV (sensitivity 73.3% [95% confidence interval (CI), 44.9%-92.2%] and specificity 100% [95% CI, 89.1%-100%]) and 15 of 16 patients with BE (sensitivity 93.8% [95% CI, 69.8%-99.8%] and specificity of 100% [95% CI, 88.8%-100%]). MACE was considered more comfortable than conventional endoscopy (P < .0001); the mean score was 9.2 for MACE compared with 6.7 for EGD when assessed on a 10-point scale. No MACE- or EGD-related adverse events occurred. This pilot study demonstrates that MACE is both safe and well tolerated by patients. Accuracy for the diagnosis of BE was high, and therefore MACE may have a role in screening for this condition. (Clinical trial registration number: NCT02852161.).


Acute coronary syndromes in diabetes: Biomarkers of endothelial injury improve risk stratification and help identify predictors of risk.
Patients with diabetes mellitus (DM) are at an increased risk of acute coronary syndrome (ACS); however, the factors predicting those at highest risk are not well understood. We identified risk factors in those with DM that best predict high ACS risk based on a multiple endothelial injury biomarker algorithm. We studied adults with DM from a clinical registry with measures of a coronary artery disease prediction algorithm (CADPA) score identifying 5-year ACS risk from nine markers. Stepwise logistic regression provided odds ratios for the relationship of age, gender, and individual risk factors not part of the CADPA algorithm with the likelihood of a high risk CADPA score. We studied 1,613 adults with DM (women: 47.3%, ages 22 to 100, mean age 63.2 years). Of these, 6.1% had a low, 13.2% intermediate, and 80.7% high risk CADPA score. From stepwise logistic regression, women were less likely to have a high risk CADPA score (odds ratio [OR] 0.21, 95% confidence intervals [CI] 0.15-0.29, p<.0001), while age (per standard deviation [SD]) (OR 5.04, [4.12-6.17], p<.0001), body mass index (BMI per SD) (OR 1.34, [1.14-1.58], p = 0.004), hypertension (OR 1.60, [1.15-2.24], p = 0.006), current smoking (OR 2.55, [1.56-4.16], p = 0.0002), hsCRP (per SD) (OR 1.24, [1.01-1.53], p = 0.04), and triglycerides (per SD) (OR 1.26, [1.04-1.54], p = 0.02) were more likely to have a high risk CADPA score. Age, men, hypertension, BMI, current smoking, hsCRP, and triglycerides are key factors in those with DM associated with higher ACS risk.


The Contribution of Human Herpes Viruses to γδ T Cell Mobilisation in Co-Infections.
γδ T cells are activated in viral, bacterial and parasitic infections. Among viruses that promote γδ T cell mobilisation in humans, herpes viruses (HHVs) occupy a particular place since they infect the majority of the human population and persist indefinitely in the organism in a latent state. Thus, other infections should, in most instances, be considered co-infections, and the reactivation of HHV is a serious confounding factor in attributing γδ T cell alterations to a particular pathogen in human diseases. We review here the literature data on γδ T cell mobilisation in HHV infections and co-infections, and discuss the possible contribution of HHVs to γδ alterations observed in various infectious settings. As multiple infections seemingly mobilise overlapping γδ subsets, we also address the concept of possible cross-protection.


Resource and manpower calculations for the provision of hepatobiliary surgical services in the UK.
The provision of specialist non-transplant hepatobiliary services in the UK is fragmented and there is little consensus on the manpower and resource requirements to meet the needs of defined populations. We report our experience with a hepatobiliary service established 5 years ago in Sheffield to provide a tertiary referral service to the population of the North Trent health area and attempt to provide estimates of resource requirements based on patterns of current use. A total of 615 patients with hepatobiliary conditions requiring specialist treatment were referred to the service during 1997-2002. The majority of patients (69%) were referred for consideration of liver resection for colorectal liver metastases. In all, 251 resections were performed in 240 (39% of all referred) patients. The current operation rates for colorectal metastases are about 4 per 100,000 population per year and for other complex hepatobiliary procedures are also 4 per 100,000 population per year giving a total "need" of 8 procedures per 100,000 population per year. For the current population in England and Wales, this would mean 25 specialist hepatobiliary centres performing in total approximately 2000 hepatic resections for colorectal cancer metastases and 2000 other tertiary hepatobiliary procedures each year. Our experience supports the model of centralisation of non-transplant hepatobiliary surgical services and indicates the extent of hitherto unmet demand in our geographical area. We estimate that a minimum of two full-time specialist hepatobiliary surgeons with appropriate ancillary support are required for a typical population of 2 million people in the UK.


Increased Vitamin B12 levels are associated with mortality in critically ill medical patients.
We describe an observational study in critically ill medical patients showing the association between serum Vitamin B12 levels measured on or near admission and the outcome in these patients. We used the database of patients admitted to the Medical Intensive Care Unit (MICU) at the Hadassah-Hebrew University Medical Center in Jerusalem, Israel, to analyze associations between patient demographics, background, diagnoses and serum Vitamin B12 levels with hospital and 90 day outcomes. Higher mean Vitamin B12 levels were found in patients who did not survive their hospital stay (1719 pg/ml vs 1003 pg/ml, p < 0.01). Those who had died by 90 days after admission to the MICU also had higher Vitamin B12 levels than survivors (1593 pg/ml vs 990 pg/ml). Regression analysis showed that elevated Vitamin B12 levels were associated with increased 90 day mortality, even after controlling for other variables. Survival analysis also showed an increased mortality rate in patients with Vitamin B12 levels over 900 pg/ml (p < 0.0002). Our data show that high serum Vitamin B12 levels are associated with increased mortality in critically ill medical patients. We suggest that Vitamin B12 levels should be included in the work-up of all medical intensive care patients, particularly those with a chronic health history and increased severity of illness.


Demonstration in children of oligoclonal IgG bands in unconcentrated CSF using agarose isoelectric focusing and immunolabeling.
Agarose isoelectric focusing, followed by protein transfer to cellulose nitrate membrane and double-antibody avidin-biotin peroxidase staining (avidin-biotin agarose isoelectric focusing), was used to demonstrate oligoclonal IgG bands in unconcentrated cerebrospinal fluid (CSF) and serum; 161 consecutive pediatric patients, ages 6 months to 16 years with a variety of mainly neurologic disorders, were studied. The procedure was standardized for agarose isoelectric focusing (AIF) using 5 microliter specimens containing 125 ng of IgG. Oligoclonal bands were found in the CSF of 12% of the patients; bands were found simultaneously in the CSF and serum of 10% of the patients, mostly those with nervous system infections, but also those with central nervous system tumors, seizures, or migraine. In about 50% of positive cases, oligoclonal bands constituted the only CSF abnormality, reflecting an abnormal humoral immune response within the CSF-central nervous system compartment. Avidin-biotin AIF can be recommended as an integrated part of routine CSF examinations in children.


Three-loop technique for A2 pulley reconstruction.
A three-loop technique of secondary A2 pulley reconstruction has been developed by the authors. This method was applied to six fingers of six patients. The average follow-up period was 21 months and ranged from a minimum of 9 months to a maximum of 3 years. Total active motion of metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints improved by 30 degrees on the average from the preoperative 175 degrees to the postoperative 205 degrees. Similarly, tip palm distance showed an improvement of 10 mm on the average from the preoperative 32 mm to the postoperative 22 mm. Satisfactory grip functions were restored for all patients after the secondary pulley reconstruction.


Comprehensive proteomic profiles of mouse AApoAII amyloid fibrils provide insights into the involvement of lipoproteins in the pathology of amyloidosis.
Amyloidosis is a disorder characterized by extracellular fibrillar deposits of misfolded proteins. The amyloid deposits commonly contain several non-fibrillar proteins as amyloid-associated proteins, but their roles in amyloidosis pathology are still unknown. In mouse senile amyloidosis, apolipoprotein A-II (ApoA-II) forms extracellular amyloid fibril (AApoAII) deposits with other proteins (AApoAII-associated proteins) in many organs. We previously reported that R1.P1-Apoa2c mice provide a reproducible model of AApoAII amyloidosis. In order to investigate the sequential alterations of AApoAII-associated protein, we performed a proteomic analysis of amyloid fibrils extracted from mouse liver tissues that contained different levels of AApoAII deposition. We identified 6 AApoAII-associated proteins that constituted 20 of the top-ranked proteins in mice with severe AApoAII deposition. Although the amount of AApoAII-associated proteins increased with the progression of amyloidosis, the relative abundance of AApoAII-associated proteins changed little throughout the progression of amyloidosis. On the other hand, plasma levels of these proteins showed dramatic changes during the progression of amyloidosis. In addition, we confirmed that AApoAII-associated proteins were significantly associated with lipid metabolism based on functional enrichment analysis, and lipids were co-deposited with AApoAII fibrils from early stages of development of amyloidosis. Thus, these results demonstrate that lipoproteins are involved in AApoAII amyloidosis pathology. This study presented proteomic profiles of AApoAII amyloidosis during disease progression and it revealed co-deposition of lipids with AApoAII deposits based on functional analyses. The relative abundance of AApoAII-associated proteins in the amyloid fibril fractions did not change over the course of development of AApoAII amyloidosis pathology. However, their concentrations in plasma changed dramatically with progression of the disease. Interestingly, several AApoAII-associated proteins have been found as constituents of lipid-rich lesions of other degenerative diseases, such as atherosclerosis and age-related macular degeneration. The common protein components among these diseases with lipid-rich deposits could be accounted for by a lipoprotein retention model.


Fluoresceinated estrone binding by cells from human breast cancers obtained by needle aspiration.
Despite widespread use there are disadvantages associated with biochemical methods for ER determination. Since there is increasing emphasis on earlier detection of primary breast cancers there is clearly a need for a method which requires only small numbers of tumor cells. A variety of other clinical situations exist in which the availability of a technic that could supply information regarding tumor ER from a small cell population would be helpful. This report presents our experience with 17-fluoresceinated estrone (17-FE) binding for detecting the proportion of estrone binding cells in samples obtained by fine-needle aspiration of tumors prior to their removal. The findings from the aspirated cells employing 17-FE were compared with results obtained from aliquots of the same tumors following their removal using both cytochemical (17-FE) and biochemical (3H-estradiol binding) methods for ER determination. When biochemically determined ER values (fmol/mg cytosol protein) were compared to the proportion of fluorescent cells observed either in cells from needle aspirates prior to tumor removal or in cells from the removed tumor there was no direct quantitative relationship. That lack of correlation is to be expected and does not indicate that one or the other method is inappropriate. It was found, however, that 100% of tumors having ER levels greater than or equal to 10 fmol had greater than or equal to 10% marker positive cells. Fifty-four percent of tumors with a negative or borderline (less than 10 fmol) ER level had less than 10% marker positive cells. The less satisfactory correlation in biochemically ER negative tumors may be related to false negative biochemical determinations. The better correlation between results from the biochemical method and those with 17-FE binding using needle aspirates than between the former and the latter when cells from fragments of removed tumor were used for cytochemical analysis, and the lack of concordance in 17-FE binding by the two cell suspensions (from needle aspirates and from parts of the removed tumor) may be related to the heterogeneity of the cellular composition of a tumor as regards ER content and consequently to the methods of sampling. The authors' experience in this and previous studies using 17-FE for determination of the proportion of putatively ER positive cells indicate that the method is worthy of further evaluation and consideration for experimental and clinical use.


The impact of the COVID-19 pandemic on inequalities in lifestyle behaviours and mental health and wellbeing of elementary school children in northern Canada.
The COVID-19 pandemic has negatively affected children's lifestyle behaviours and mental health and wellbeing, and concerns have been raised that COVID-19 has also increased health inequalities. No study to date has quantified the impact of COVID-19 on health inequalities among children. We compared pre-pandemic vs. post-lockdown inequalities in lifestyle behaviours and mental health and wellbeing among children living in rural and remote northern communities. We surveyed 473 grade 4-6 students (9-12 years of age) from 11 schools in rural and remote communities in northern Canada in 2018 (pre-pandemic), and 443 grade 4-6 students from the same schools in 2020 (post-lockdown). The surveys included questions on sedentary behaviours, physical activity, dietary intake, and mental health and wellbeing. We measured inequality in these behaviors using the Gini coefficient, a unitless measure ranging from 0 to 1 with a higher value indicating greater inequality. We used temporal changes (2020 vs. 2018) in Gini coefficients to assess the impact of COVID-19 on inequalities in lifestyle behaviours and mental health and wellbeing separately among girls and boys. Inequalities in all examined lifestyle behaviours increased between 2018 and 2020. Inequalities in watching TV, playing video games, and using a cell phone increased among girls, while inequalities in playing video games, using computers and tablets, and consumption of sugar, salt, saturated fat and total fat increased among boys. Changes in inequalities in mental health and wellbeing were small and not statistically significant. The findings suggest that the COVID-19 pandemic has exacerbated inequalities in lifestyle behaviours among children living in rural and remote northern communities. If not addressed, these differences may translate into exacerbated inequalities in future health. The findings further suggest that school health programs can help mitigate the negative impact of the pandemic on lifestyle behaviours and mental health and wellbeing.


Neonatal pyogenic liver abscess following omphalitis: A case report.
Liver abscesses in neonates are rare. Omphalitis is a very rare cause. We report a case of a voluminous neonatal pyogenic liver abscess following omphalitis, successfully managed in our institution. A 21-day-old full-term female newborn was brought to our institution for progressive febrile swelling of the right hypochondrium. The parents reported umbilical suppuration. Clinical examination confirmed the presence of a mass extending from the epigastric region to the right hypochondrium in a febrile baby with no other abnormalities. Laboratory investigations revealed an elevated C-reactive protein level (64 mg/dl) and hyperleukocytosis (20,800/mm3) with neutrophil predominance and normochromic microcytic anemia (hemoglobin 8.2 g/dl). Her first abdominal ultrasound was interpreted as a cyst of the common bile duct. Triple antibiotic therapy with cephalosporin, ampicillin and gentamycin was started, but unsuccessful. Abdominal ultrasound was repeated, revealing a hepatic abscess in segment 8, with a volume of approximately 17 ml. Percutaneous echo-guided drainage was performed and antibiotic therapy was readjusted after identification of the germ (Staphylococcus aureus) with good outcome. The baby was discharged two weeks later. At one month follow-up, the baby was completely asymptomatic. As neonatal liver abscesses are unusual, they can lead to misdiagnosis. Omphalitis is a very rare cause. Treatment by percutaneous echo-guided drainage is simple and effective.


Preventive effect of beta-blockers in the development of aortic dilation in giant cell arteritis-related aortitis.
To analyze whether beta-blockers (BBs), in addition to conventional care, can decrease the risk of aortic dilation in giant-cell arteritis (GCA)-related aortitis. We conducted in a single medical center retrospective study including 65 consecutive patients with GCA-related aortitis who all underwent aortic morphology control during follow-up. The impact of previous cardiovascular (CV) risk factors and/or events on BB prescription and on the risk for new aortic dilation was analyzed using a weighted (8-point maximum) score between 0 (i.e., 0/8 CV risk factors and events) and 1 (i.e., 8/8). Among the 65 patients with GCA-related aortitis, 15 (23%) were taking BBs before GCA diagnosis and continued them thereafter. The vascular score was significantly higher in patients who received BBs (0.25 [0.125-0.625] vs. 0.125 [0-0.625] in patients without BBs, p < 0.0001). The median follow-up was 91 [25-163] months in GCA patients taking BBs and 61 [14-248] months in patients not taking BBs (p = 0.13). None of the patients taking BBs developed a new aortic dilation, whereas 15 (15/50; 30%) patients not taking BBs did (p = 0.01), as detected at a median time of 38 [6-120] months after the first imaging. Rates of other CV events during follow-up did not differ between the groups (p = 1). This study is the first to suggest that BBs in addition to conventional care in patients with GCA-related aortitis may help to prevent the risk of aortic dilation during follow-up. Larger-sized studies are required to confirm these results.


Biochemical characterization of the human RAD51 protein. II. Adenosine nucleotide binding and competition.
RecA mediated homologous recombination requires cooperative ATP binding and hydrolysis to assume and maintain an active, extended DNA-protein (nucleoprotein) filament. Human RAD51 protein (hRAD51) lacks the magnitude of ATP-induced cooperativity and catalytic efficiency displayed by RecA. Here, we examined hRAD51 binding and ATPase inhibition pattern by ADP and ATP/adenosine 5'-O-(thiotriphosphate) (ATPgammaS). hRAD51 fully saturates with ATP/ATPgammaS regardless of DNA cofactor (K(D) approximately 5 microm; 1 ATP/1 hRAD51). The binding of ADP to hRAD51 appeared bimodal. The first mode was identical to ATP/ATPgammaS binding (K(app1) approximately 3 microm; 1 ADP/1 hRAD51), while a second mode occurred at elevated ADP concentrations (K(app2) > or = 125 microm; >1 ADP/1 hRAD51). We could detect ADP --> ATP exchange in the high affinity ADP binding mode (K(app1)) but not the low affinity binding mode (K(app2)). At low ATP concentrations (<0.3 mm), ADP and ATPgammaS competitively inhibit the hRAD51 ATPase (K(m)((app)) > K(m)). However, at high ATP (>0.3 mm), the hRAD51 ATPase was stimulated by concentrations of ATPgammaS that were 20-fold above the K(D). Ammonium sulfate plus spermidine decreased the affinity of hRAD51 for ADP substantially ( approximately 10-fold) and ATP modestly ( approximately 3-fold). Our results suggest that ATP binding is not rate-limiting but that the inability to sustain an active nucleoprotein filament probably restricts the hRAD51 ATPase.


A chemically inducible IL-2 receptor signaling complex allows for effective in vitro and in vivo selection of engineered CD4+ T cells.
Engineered T cells represent an emerging therapeutic modality. However, complex engineering strategies can present a challenge for enriching and expanding therapeutic cells at clinical scale. In addition, lack of in vivo cytokine support can lead to poor engraftment of transferred T cells, including regulatory T cells (Treg). Here, we establish a cell-intrinsic selection system that leverages the dependency of primary T cells on IL-2 signaling. FRB-IL2RB and FKBP-IL2RG fusion proteins were identified permitting selective expansion of primary CD4+ T cells in rapamycin supplemented medium. This chemically inducible signaling complex (CISC) was subsequently incorporated into HDR donor templates designed to drive expression of the Treg master regulator FOXP3. Following editing of CD4+ T cells, CISC+ engineered Treg (CISC EngTreg) were selectively expanded using rapamycin and maintained Treg activity. Following transfer into immunodeficient mice treated with rapamycin, CISC EngTreg exhibited sustained engraftment in the absence of IL-2. Furthermore, in vivo CISC engagement increased the therapeutic activity of CISC EngTreg. Finally, an editing strategy targeting the TRAC locus permitted generation and selective enrichment of CISC+ functional CD19-CAR-T cells. Together, CISC provides a robust platform to achieve both in vitro enrichment and in vivo engraftment and activation, features likely beneficial across multiple gene-edited T cell applications.


Travelling wave solutions in a negative nonlinear diffusion-reaction model.
We use a geometric approach to prove the existence of smooth travelling wave solutions of a nonlinear diffusion-reaction equation with logistic kinetics and a convex nonlinear diffusivity function which changes sign twice in our domain of interest. We determine the minimum wave speed, [Formula: see text], and investigate its relation to the spectral stability of a desingularised linear operator associated with the travelling wave solutions.


Barriers and Solutions to Smart Water Grid Development.
This limited review of smart water grid (SWG) development, challenges, and solutions provides an initial assessment of early attempts at operating SWGs. Though the cost and adoption issues are critical, potential benefits of SWGs such as efficient water conservation and distribution sustain the development of SWGs around the world. The review finds that the keys to success are the new regulations concerning data access and ownership to solve problems of security and privacy; consumer literacy to accept and use SWGs; active private sector involvement to coordinate SWG development; government-funded pilot projects and trial centers; and integration with sustainable water management.


Liquid chromatography-quadrupole time of flight tandem mass spectrometry-based targeted metabolomic study for varietal discrimination of grapes according to plant sterols content.
Grapevine and derived products are rich in a wide range of compounds and its quality mainly depends on its metabolites, as a result of viticulture practices. Plant sterols, also called phytosterols (PS), are secondary metabolites regarded as bioactive substance present in grape berries and other plant-based food. The present study deals with a metabolomic approach focusing on phytosterols family in six varieties of Rioja grapes (Cabernet Sauvignon, Tempranillo, Graciano, Garnacha, White Garnacha and Viura), in order to find significant differences among them. Liquid chromatography- mass spectrometry with a quadrupole-time of flight mass analyzer (LC-QTOF) was used to find as many metabolites as possible in the different grape berry fractions, and using statistics to help finding significant clustering of the metabolic profile of pulp, peel and seeds in relation to the variety. The best chromatographic and detection conditions were achieved by gas phase ionization via atmospheric pressure chemical ionization (APCI) in positive mode. Furthermore, analysis with electrospray (ESI) is also needed for phytosterol derivatives confirmation. Putative compounds of interest in the analyzed samples were found by an automated compound extraction algorithm (Molecular Feature Extraction, MFE) and an initial differential expression from the data was created with the aid of commercial software. Once the data were collected, the results were filtered, aligned and normalized, and evaluating applying one-way analysis of variance (ANOVA) with a 95% significance level. For sample class prediction, partial least square-discriminant analysis (PLS-DA) is used as a supervised pattern recognition method and excellent separation among the grape varieties is shown. An overall accuracy of 93.3% (pulp samples), 100.0% (peel) or 96.7% (seeds) in discriminating between grape varieties was achieved when comparing the different fractions. In general, 7 PS derivatives were identified with ID scores higher than 84%.


Comparative analysis of key immune protection factors in H9N2 avian influenza viruses infected and immunized specific pathogen-free chicken.
H9N2 avian influenza viruses (AIV) continue to circulate in vaccinated chicken flocks in China, which prompted us to investigate the differential immune protection factors induced by H9N2 AIV infection and immunization for analyzing the reason of protection deficiency of H9N2 AIV inactivated vaccine. In this study, we firstly explored virus-induced optimal immune responses in chicken after H9N2 AIV infection. And, we found that H9N2 hemagglutination inhibition (HI) antibody level, antiviral interferon-stimulated genes including 2',5'-oligoadenylate synthetase-like and myxovirus resistance 1, CD8+ T cell response in peripheral blood lymphocytes (PBL) accompanied by the cytotoxicity-associated genes, including poly (ADP-ribose) polymerase and IFN-r play important roles in defending against H9N2 infection. Besides, we observed that vaccine immunization triggered the similar H9N2 HI antibody level as viral infection, the increase of CD4+ T cell percentage instead of CD8+ T cell percentage in PBL. Moreover, we further made a comparative analysis of immune-related gene expression profile in PBL and lung after H9N2 AIV infection and immunization, respectively. The results showed that vaccine immunization contributed to the up-regulation of Th2 cytokine. But the deficiency of cytotoxicity-associated genes induced by H9N2 AIV inactivated vaccine may be the potential key reason of protection deficiency. These findings provide evidence and direction for developing effective H9N2 AIV vaccines.


Chorionicity and neurodevelopmental outcomes in twin pregnancy: a systematic review and meta-analysis.
Through a systematic review and meta-analyses, we aimed to analyze the impact of chorionicity on neurodevelopment outcomes. We conducted a comprehensive search strategy through Medline, Embase, Web of Science, and reference lists of the retrieved studies until August 2022. Studies that examined the association between chorionicity and children's neurodevelopment outcomes were included. Twelve studies were included. Monochorionic (MC) twins increased the odds of neurodevelopment impairment, cerebral palsy compared to dichorionic (DC) twins. The differences in neurodevelopmental impairment and cerebral palsy between the two groups disappeared after excluding infants with twin-twin transfusion (TTTS). After fetoscopic laser surgery (FLS) for MC twins, there were no differences too. Compared to DC twins, MC twins were associated with an increased risk of neurodevelopment impairment. MC twins complicated by TTTS were at high risk of neurologic disability, and FLS was an acceptable treatment modality for them.


Transdiaphragmatic duodenal duplication in a premature infant.
A case of transdiaphragmatic duodenal duplication in a premature infant is presented. Vertebral abnormalities, which have invariably accompanied this disorder in reported cases so far, were characteristically absent. Therefore, the initial tentative diagnosis was right-sided diaphragmatic hernia. Barium examination was helpful in preoperative diagnosis.


Beyond the reaction progress variable: the meaning and significance of isotopic incorporation data.
Ecologists conduct isotopic incorporation experiments to determine the residence time of various stable isotopes in animal tissues. These experiments permit determining the time window through which isotopic ecologists perceive the course of diet changes, and therefore the scale of the inferences that we can make from isotopic data. Until recently, the results of these experiments were analyzed using first-order, one-compartment models. Cerling et al. (Oecologia 151:175-189, 2007) proposed an approach they named the reaction progress variable to: (1) determine how many compartments are needed to describe a pattern of istopic incorporation, and (2) to estimate the size and rate constant of each pool. We elaborate on the approach described by Cerling et al. (Oecologia 151:175-189, 2007) by providing a way to estimate average retention times for an isotope in a tissue (and its associate error) for multi-compartment models. We also qualify the interpretation of the parameters in multi-compartment models by showing that many possible mechanisms yield models with the same functional form. Multi-compartment models are phenomenological, rather than mechanistic descriptions, of incorporation data. Finally, we propose the use of information theoretic criteria to assess the number of compartments that must be included in models of isotopic incorporation.


Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR.
Epidermal growth factor receptor (EGFR)-mediated cell signaling is critical for mammary epithelial cell growth and survival; however, targeting EGFR has shown no or only minimal therapeutic benefit in patients with breast cancer. Here, we report a novel regulatory mechanism of EGFR signaling that may explain the low response rates. We found that breast tumor kinase (Brk)/protein-tyrosine kinase 6 (PTK6), a nonreceptor protein-tyrosine kinase highly expressed in most human breast tumors, interacted with EGFR and sustained ligand-induced EGFR signaling. We demonstrate that Brk inhibits ligand-induced EGFR degradation through uncoupling activated EGFR from casitas B-lineage lymphoma-mediated EGFR ubiquitination. In addition, upon activation by EGFR, Brk directly phosphorylated Y845 in the EGFR kinase domain, thereby further potentiating EGFR kinase activity. Experimental elevation of Brk conferred resistance of breast cancer cells to cetuximab (an EGFR-blocking antibody)-induced inhibition of cell signaling and proliferation, whereas knockdown of Brk sensitized the cells to cetuximab by inducing apoptosis. Our findings reveal a previously unknown role of Brk in EGFR-targeted therapy.


A case of lupus nephritis coexisting with podocytic infolding associated with Takayasu's arteritis.
A 61-year-old Japanese woman with both Takayasu's arteritis (TA) and systemic lupus erythematosus (SLE) presented with proteinuria due to glomerulopathy associated with podocytic infolding. She presented with unequal pulses in the upper extremities at 38 years old. TA was diagnosed on the basis of angiographic identification of stenosis in the left subclavian artery. Eight years after onset of TA, SLE was diagnosed on the basis of clinical and laboratory findings, including proteinuria, hematological and immunological abnormalities, high titer of antinuclear antibody, and a positive lupus band test on the skin. A renal biopsy showed lupus nephritis coexisting with podocytic infolding associated with TA, which has rarely been reported. After low-dose prednisolone therapy and immunosuppressive therapy by cyclosporine for 14 years, proteinuria has persisted without deterioration of serum creatinine levels.


Eliciting relative preferences for the attributes of health insurance schemes among rural consumers in India.
There is a limited understanding of the preferences of rural consumers in India for health insurance schemes. In this article, we investigate the preferences of the rural population for the attributes of a health insurance scheme by implementing a discrete choice experiment (DCE). We identified six attributes through qualitative and quantitative study: enrollment, management, benefit package, coverage, transportation facility, and monthly premium. A D-efficient design of 18 choices has been constructed, each comprising two health insurance choices. We collected the representative sample from 675 household heads of the rural population through personal interviews. The preferences for the attributes and attribute levels were estimated using the multinomial logit (MNL) and random-parameter logit (RPL) models. The analysis shows that all attribute levels significantly affect the choice behavior (P < 0.05). The relative order of preferences for attributes are; enrollment, benefit package, monthly premium, management, coverage, and transportation.


Mandibular reconstructions using computer-aided design/computer-aided manufacturing: A systematic review of a defect-based reconstructive algorithm.
Modern planning techniques, including computer-aided design/computer-aided manufacturing (CAD-CAM) can be used to plan reconstructive surgery, optimising aesthetic outcomes and functional rehabilitation. However, although many such applications are available, no systematic protocol yet describes the entire reconstructive procedure, which must include virtual planning, custom manufacture, and a reconstructive algorithm. We reviewed current practices in this novel field, analysed case series described in the literature, and developed a new, defect-based reconstructive algorithm. We also evaluated methods of mandibular reconstruction featuring virtual planning, the use of surgical guides, and laser printing of custom titanium bony plates to support composite free flaps, and evaluated their utility.


Habit-reversal treatment for children's stuttering: assessment in three settings.
Two boys (9 and 14 years old) participated in an evaluation of treatment for stuttering. Habit reversal procedures (awareness training, regulated breathing, and social support) were combined with teaching positive attitudes to parents. During treatment, stuttering frequencies decreased, speech rates increased, and speech naturalness ratings increased. These changes occurred in the clinic, the child's home, and the child's school. After treatment, stuttering remained low in the clinic and at home, but increased stuttering was found at school.


Retinal aneurysms in adult cytomegalovirus retinitis.
We observed aneurysms of the retinal arteries, capillaries, and venules occurring in a patient with cytomegalovirus retinitis. These aneurysms were caused by involvement of the retinal vascular endothelium resulting in focal weaknesses in the vascular walls. The clinical appearance of this retinitis superficially resembled retinal branch vein occlusion.


Tranexamic acid usage in hip fracture surgery: a meta-analysis and meta-regression analysis of current practice.
The use of tranexamic acid (TXA) in hip fracture surgery remains inconclusive. The aim of the present meta-analysis was to assess the role of TXA use in hip fracture surgery, and attempt to disclose possible factors which might influence TXA efficacy and safety. A systematic computerized literature search was conducted to retrieve all randomized controlled trials (RCTs) and cohort studies regarding TXA use in hip fracture surgery. Overall efficacy and safety were evaluated. Then, subgroup and meta-regression analyses were conducted to disclose the influence of geographic area, fracture type, administration route, frequency and dosage of TXA, blood transfusion threshold, and follow-up duration on the overall effect. Thirty-four RCTs and 11 cohort studies were included. Patients receiving TXA had a significant decrease in the need for blood transfusion, reduced total, intra-operative and post-operative blood loss, a decrease in pre- and postoperative hemoglobin difference, without increasing thromboembolic events risk. Subgroup analysis showed that topical TXA had a lower transfusion rate compared with controls, yet the result did not reach statistical significance. Also, TXA had similar efficacy and safety profiles in patients with different frequency and dosage of TXA. Current evidence indicated that intravenous administration of TXA could significantly reduce blood transfusion and blood loss without increasing risk of thromboembolic events. The frequency and dosage of TXA might not alter the beneficial effect. The application of topical TXA should be cautious.


Preparing the nursing student for internship in a pre-registration nursing program: developing a problem based approach with the use of high fidelity simulation equipment.
This paper aims to explore the development and evaluation results of a simulated skills package designed using a problem based learning approach with general nursing students. Internationally, the use of high fidelity simulated learning environments has escalated. This has occurred as a result of growing concerns relating to patient safety, patient litigation, lack of clinical opportunities for student nurses to gain experience and integration of new teaching methods into nursing curricula. There are however both proponents and opponents to the value of simulation and high fidelity simulation within nursing education. This study was conducted in an Irish school of nursing. A simulated learning support package was developed by nurse educators and piloted with 134 third year nursing students. This was evaluated using a questionnaire in which 87 students responded. Students generally found the simulation sessions realistic and useful in developing clinical skills, knowledge and confidence for clinical practice. However student issues regarding support with preparation for the session were highlighted. Also, the need for a more formalised structure for debriefing following the simulation sessions were identified. It is hoped that this paper will provide nurse educators with some guidance to aid future development of innovative and interactive teaching and learning strategies.


Effects of rosuvastatin on endothelial function in patients with familial combined hyperlipidaemia (FCH).
Although several studies have reported a positive effect of statins on endothelial vasoreactivity, most studies performed in subjects with type 2 diabetes mellitus report no effect at all. This lack of effect may be related to the existence of insulin resistance, or to insufficient lowering of atherogenic (apo)lipoproteins. Therefore, we tested in this study whether treatment of insulin resistant familial combined hyperlipidaemia (FCH) patients with a high dose (40 mg/day) of the potent rosuvastatin was able to improve endothelial function, without necessarily improving insulin sensitivity. In a double-blind randomised crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean [standard deviation] age 54 [7] years) underwent a 4-week run-in period after which they were randomised to treatment with placebo once daily for 12 weeks, followed by rosuvastatin 40 mg/day for 12 weeks or vice versa. Endothelial function was determined after 8 and 12 weeks of both treatment periods, respectively, by measurement of flow-mediated vasodilation (FMD) using high-resolution ultrasound and by measurement of vasodilator response to intrabrachial acetylcholine (Ach) by venous occlusion plethysmography (forearm blood flow [FBF]). Plasma levels of lipids, (apo)lipoproteins and high-sensitivity C-reactive protein (hsCRP) improved significantly after rosuvastatin therapy compared to placebo. However, rosuvastatin had no effect on homeostasis model assessment (HOMA)-indices or on vasodilator responses to intra-brachial acetylcholine-infusion (FBF-ratio increased from a mean of 1.28 [SD: 0.46] to 5.82 [3.44] after rosuvastatin and from 1.33 [0.67] to 5.99 [3.89] after placebo, p = 0.35). Endothelium-dependent FMD was also unchanged (1.6% [3.1%] vs. 3.2% [3.5]%, p = 0.56 rosuvastatin vs. placebo, respectively). In patients with FCH, a 12-week treatment of rosuvastatin 40 mg/day did not improve endothelial function (either in large conduit vessels or in resistance vessels), despite significant improvements in plasma lipids, (apo)lipoproteins. and low-grade inflammation.


Data on the movement behaviour of four species of grassland butterfly.
This Data in Brief article describes data on the movement behaviour of four species of grassland butterflies collected over three years and at four sites in southern England. The datasets consist of the movement tracks of Maniola jurtina, Aricia agestis, Pyronia tithonus, and Melanargia galathea, recorded using standard methods and presented as steps distances and turning angles. Sites consisted of nectar-rich field margins, meadows, and mown short turf grasslands with minimal flowers. In total, 783 unique movement tracks were collected. The data were used for analysing the movement behaviour of the species and for parameterising individual-based movement models.


Epigenetic modifications and chromosome conformations of the beta globin locus throughout development.
Human embryonic stem cells provide an alternative to using human embryos for studying developmentally regulated gene expression. The co-expression of high levels of embryonic ε and fetal γ globin by the hESC-derived erythroblasts allows the interrogation of ε globin regulation at the transcriptional and epigenetic level which could only be attained previously by studying cell lines or transgenic mice. In this study, we compared the histone modifications across the β globin locus of the undifferentiated hESCs and hESC-, FL-, and mobilized PB CD34(+) cells-derived erythroblasts, which have distinct globin expression patterns corresponding to their developmental stages. We demonstrated that the histone codes employed by the β globin locus are conserved throughout development. Furthermore, in spite of the close proximity of the ε globin promoter, as compared to the β or γ globin promoter, with the LCR, a chromatin loop was also formed between the LCR and the active ε globin promoter, similar to the loop that forms between the β or γ globin promoters and the LCR, in contrary to the previously proposed tracking mechanism.


Growth factor regulation of enterocyte nutrient transport during intestinal adaptation.
Intestinal adaptation occurs in response to injury or alteration in nutrient availability. It is both morphologic and physiologic in nature and can be mediated by growth factors and nutrients. Pathologic conditions such as short-bowel syndrome and inflammatory bowel disease lead to derangements in nutrient absorption that may exceed the body's regenerative and adaptive capacity. Failure to fully adapt often results in long-term dependence on parenteral nutrition, leading to decreased quality of life and excessive medical expenses. The therapeutic use of appropriate growth factors may increase the adaptive capabilities of the gut. Medline and current literature review. The major known nutrient transporters present in the gut and the mechanisms by which growth factors alter transport activity during intestinal adaptation are summarized. Growth factors have the potential to improve nutrient absorption in some bowel diseases.


Effects of prazosin on forearm resistance and capacitance vessels.
The effects of oral prazosin on the peripheral circulation were evaluated in 10 subjects, including 7 patients with chronic congestive failure due to coronary heart disease. To achieve this purpose the actions of 30 to 50 micrograms/kg body weight prazosin were assessed on both the forearm arteriolar and venous beds simultaneously with the use of the limb plethysmographic technique. Prazosin produced marked decline of forearm venous tone (FVT) from 44.5 +/- 12.3 to 14.3 +/- 3.1 mm Hg/ml (p less than 0.01) concomitant with marked decrease in forearm vascular resistance (FVR) from 70.2 +/- 11.4 to 48.4 +/- 4.9 mm Hg/ml/100 gm/min (p less than 0.05) which persisted for at least 60 mins without change in heart rate. These findings, demonstrating that prazosin induces systemic venodilation and peripheral arteriolodilation, indicate potential benefits of the oral drug for relief of pulmonary congestion and elevations of cardiac output in patients with chronic congestive heart failure.