Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids.
Reciprocal regulation of metabolism and signaling allows cells to modulate their activity in accordance with their metabolic resources. Thus, amino acids could activate signal transduction pathways that control cell metabolism. To test this hypothesis, we analyzed the effect of amino acids on fructose-2,6-bisphosphate (Fru-2,6-P2) metabolism. We demonstrate that amino acids increase Fru-2,6-P2 concentration in HeLa and in MCF7 human cells. In conjunction with this, 6-phosphofructo-2-kinase activity, glucose uptake, and lactate concentration were increased. These data correlate with the specific phosphorylation of heart 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2) isoenzyme at Ser-483. This activation was mediated by the PI3K and p38 signaling pathways. Furthermore, Akt inactivation blocked PFKFB2 phosphorylation and Fru-2,6-P2 production, thereby suggesting that the above signaling pathways converge at Akt kinase. In accordance with these results, kinase assays showed that amino acid-activated Akt phosphorylated PFKFB2 at Ser-483 and that knockdown experiments confirmed that the increase in Fru-2,6-P2 concentration induced by amino acids was due to PFKFB2. In addition, similar effects on Fru-2,6-P2 metabolism were observed in freshly isolated rat cardiomyocytes treated with amino acids, which indicates that these effects are not restricted to human cancer cells. In these cardiomyocytes, the glucose consumption and the production of lactate and ATP suggest an increase of glycolytic flux. Taken together, these results demonstrate that amino acids stimulate Fru-2,6-P2 synthesis by Akt-dependent PFKFB2 phosphorylation and activation and show how signaling and metabolism are inextricably linked.


Sequencing of ALK Inhibitors in ALK+ Non-Small Cell Lung Cancer.
Major therapeutic advances have occurred over the last several years in the management of advanced ALK+ NSCLC patients. Crizotinib was the first agent approved for the management of ALK+ NSCLC patients after it demonstrated significantly greater clinical benefit compared to chemotherapy. Several next generation ALK inhibitors have demonstrated clinical benefit in patients with crizotinib refractory NSCLC patients including in the CNS. Based on available data, therapy with a next generation ALK inhibitor can be initiated following therapy with crizotinib without any assessment of the molecular mechanisms of resistance. The appropriate therapy for patients with progressive disease following two ALK inhibitors is not well defined. In patients with an ALK-resistant mutation in their tumor, an ALK inhibitor with activity against the mutation would be the most appropriate therapy. In others, chemotherapy and PD-1 directed agents can be considered. Clinical data suggests that ALK+ patients are less likely to benefit from PD-1 directed agents and therefore chemotherapy should be considered prior to these agents for the management of ALK+ NSCLC patients.


Investigating the Model of Community-Based Case Management in the New South Wales Brain Injury Rehabilitation Program: A Prospective Multicenter Study.
To investigate a model of community-based case management (CM). New South Wales (NSW) Brain Injury Rehabilitation Program (BIRP). All clinicians (N = 72) providing CM within 14 BIRP community rehabilitation teams. A prospective, multicenter study. A purpose-designed survey. Participants from the 12 adult and 2 pediatric services (8 located in metropolitan areas, 6 in rural areas) completed a 3-part survey investigating their organizational context, clinical approach, and CM interventions. Between-groups analyses explored differences among individual services, as well as differences based on age (adult vs pediatric) and location (metropolitan vs rural). All services provided a direct service model of CM. The underlying principles were uniform across services (more direct than indirect service provision; with more client-related than administrative-related tasks; more holistic than service-led in defining client needs; with decision making equally directed by staff and clients; and undertaking a more comprehensive than minimalist range of tasks). CM interventions included the provision of individual support, family support, advocacy, and community development alongside assessment, monitoring, referral, and liaison tasks. There were little differences in practice based on age or location. The NSW BIRP has drawn upon the results to produce a model of service for CM.


[Use of external photoprotective agents in children living in the area of Prague].
Development of skin melanoma is related to the higher exposition to ultraviolet light, namely to the repeated sun burning of children. Because no valid information on the use of photoprotection in children can be found, an extensive search on the use of such measures, their galenic form and protective features was undertaken in order to evaluate the situation and to suggest necessary improvements. A group of 140 children aged 3 to 15 years, part of the group living in Prague, another part living outside the city was examined whether they use some local photoprotection during longer exposition to sun. If the answer was positive, it was followed in which season the photoprotection is used and whether it was used repeatedly. We also questioned on the forms of the local photoprotectives and the value of solar protective factor. Beside the description of sun tanning characteristics of children, we were informed by their parents that 59% of children use the photoprotection regularly, 41% only occasionally. The age of the first use of protection was 3.75 years. Photoprotection was used once a day in 28% of children, repeated use (during bathing, seashore stay, tourism) was reported in 72% of cases. The galenic form of photoprotective was most frequently a sun tanning creme (42%), a sun tanning milk (30%), both forms alternatively (8%), an oil (8%) or some other form (14%). The value of photoprotective factor was reported by 108 out of 131 parents and it was less than 10 in 9 children, 11 to 22 in 60 children, 21 to 40 in 36 children and over 40 in 3 children.


Does Self-Licensing Benefit Self-Regulation Over Time? An Ecological Momentary Assessment Study of Food Temptations.
Self-licensing, employing reasons to justify indulgence, may help resolve the conflict between immediate temptations and long-term goals in favor of the former. It was hypothesized that this conflict-resolving potential of self-licensing may benefit self-regulation over time. With a momentary assessment design, we examined how self-licensing affects self-regulatory ability and the capacity to deal with subsequent self-regulatory conflicts. One hundred thirty-six female participants filled out surveys eight times per day for one week. Food temptation strength, conflict, resistance, and enactment were assessed, as well as license opportunity and perceived self-regulatory ability. When self-licensing opportunity was high (vs. low), a weaker association between temptation strength and conflict was observed. High license opportunity was associated with higher perceived self-regulatory ability for instances of low degrees of temptation enactment and predicted better handling of subsequent conflict after high degrees of prior temptation enactment. These results suggest that self-licensing can support self-regulation after initial failure.


[A method for systematic internal quality assurance in surgery].
Between April 1993 and December 1996, the data of 3183 patients were recorded and analyzed in a program for internal quality assurance at the Department of General and Abdominal Surgery of the University of Mainz. The measuring of perioperative risk, the finding of intraoperative influences and the objective rating of quality of treatment were achieved by means of eight different operation-specific documentation sheets and the data records of the operation theater. With our system it is possible to measure differences between several surgeons and also differences in comparison to national and international results. By means of prospective collection of patient data and the built-in control mechanisms we obtain a lot of exact and nearly complete data. The information gained not only reflects the performance of a department, but can also be used as an instrument for the planning of work and deduction. Through optimized therapy the program can lead to an improvement of quality.


Correlation between lifetime heterogeneity and kinetics heterogeneity during chlorophyll fluorescence induction in leaves: 1. Mono-frequency phase and modulation analysis reveals a conformational change of a PSII pigment complex during the IP thermal phase.
The relationship between the fluorescence lifetime (tau) and yield (Phi) obtained in phase and modulation fluorometry at 54 MHz during the chlorophyll fluorescence induction in dark-adapted leaves under low actinic light has been investigated. Three typical phases have been identified: (i) linear during the OI photochemical rise, (ii) convex curvature during the subsequent IP thermal rise, and (iii) linear during the PS slow decay. A similar relationship has been obtained in the fluorescence induction for the fluorescence yield measured at 685 nm plotted versus the fluorescence yield measured at 735 nm. A spectrally resolved analysis shows that the curvature of the tau-Phi relationship is not due to chlorophyll fluorescence reabsorption effects. Several other hypotheses are discussed and we conclude that the curvature of the tau-Phi relationship is due to a variable and transitory nonphotochemical quenching. We tentatively propose that this quenching results from a conformational change of a pigment-protein complex of Photosystem II core antenna during the IP phase and could explain both spectral and temporal transitory changes of the fluorescence. A variable blue shift of the 685 nm peak of the fluorescence spectrum during the IP phase has been observed, supporting this hypothesis.


Colon cancer in rats and diet in the Sonoran desert region of Mexico.
The role of dietary fiber in colon cancer is still not clear. Epidemiological studies suggest a protective role for high fiber intake. However the data suggest that the effects of fiber must be considered in the context of the total diet and its interactions with other dietary components. The typical Sonora diet is high in dietary fiber (7.8%) and the majority of this fiber (71%) is insoluble. Comparing the incidence of colon cancer in Sonora with its neighboring state of Arizona, in 1991, Sonora reported 40 cases of colon cancer, a population of 1,823,606, compared to 1432 for Arizona (3,763,322 inhabitants). The typical regional diet was evaluated for its protective effect in the development of colon cancer in rats injected with azoxymethane, AOM. The regional diet showed a tendency to protect against colon cancer, an incidence of 45% compared to 66% for the control diet, although this effect was not significant (p = 0.15). Further studies are needed to fully evaluate the diet and certain interactive dietary factors such as fat, quantity as well as type, protein, calcium and antioxidant nutrients.


Acute Aortic Regurgitation in the Current Era of Percutaneous Treatment: Pathophysiology and Hemodynamics.
Aortic regurgitation (AR) is characterized by the backflow of blood from the aorta to the left ventricle. Acute AR typically causes severe pulmonary edema and hypotension, and is a surgical emergency. In chronic AR, however, compensatory mechanisms can clinically compensate for years, with normal left ventricular function and no symptoms. While the hemodynamic mechanisms of chronic AR on the left ventricle are well described, the hemodynamic mechanisms of acute AR are not clear. Most of the literature on acute AR includes either small series or case reports. During the past decade the number of transcatheter aortic valve replacements (TAVRs) performed has increased dramatically, and TAVR is now an accepted treatment option for patients with severe aortic stenosis who are not surgical candidates or are at high risk for surgery. However, potential acute mild to severe AR occurring after TAVR seems a new and common cause of AR. Since more than mild AR increases the risk of mortality, the quantification of AR severity is a major challenge after TAVR. More accurate, reproducible and quantitative criteria need to be developed to assess and highlight the unknowns of acute AR. Information relating to the pathophysiology and hemodynamics of acute AR and TAVR-related acute AR, respectively, are collated in this review.


Information-theoretic CAD system in mammography: entropy-based indexing for computational efficiency and robust performance.
We have previously presented a knowledge-based computer-assisted detection (KB-CADe) system for the detection of mammographic masses. The system is designed to compare a query mammographic region with mammographic templates of known ground truth. The templates are stored in an adaptive knowledge database. Image similarity is assessed with information theoretic measures (e.g., mutual information) derived directly from the image histograms. A previous study suggested that the diagnostic performance of the system steadily improves as the knowledge database is initially enriched with more templates. However, as the database increases in size, an exhaustive comparison of the query case with each stored template becomes computationally burdensome. Furthermore, blind storing of new templates may result in redundancies that do not necessarily improve diagnostic performance. To address these concerns we investigated an entropy-based indexing scheme for improving the speed of analysis and for satisfying database storage restrictions without compromising the overall diagnostic performance of our KB-CADe system. The indexing scheme was evaluated on two different datasets as (i) a search mechanism to sort through the knowledge database, and (ii) a selection mechanism to build a smaller, concise knowledge database that is easier to maintain but still effective. There were two important findings in the study. First, entropy-based indexing is an effective strategy to identify fast a subset of templates that are most relevant to a given query. Only this subset could be analyzed in more detail using mutual information for optimized decision making regarding the query. Second, a selective entropy-based deposit strategy may be preferable where only high entropy cases are maintained in the knowledge database. Overall, the proposed entropy-based indexing scheme was shown to reduce the computational cost of our KB-CADe system by 55% to 80% while maintaining the system's diagnostic performance.


Quality-by-Design (QbD): An integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and process design space development.
The aim of this work was to develop an integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and design space development. A dynamic co-precipitation process by gradually introducing water to the ternary system of naproxen-Eudragit L100-alcohol was monitored at real-time in situ via Lasentec FBRM and PVM. 3D map of count-time-chord length revealed three distinguishable process stages: incubation, transition, and steady-state. The effects of high risk process variables (slurry temperature, stirring rate, and water addition rate) on both derived co-precipitation process rates and final chord-length-distribution were evaluated systematically using a 3(3) full factorial design. Critical process variables were identified via ANOVA for both transition and steady state. General linear models (GLM) were then used for parameter estimation for each critical variable. Clear trends about effects of each critical variable during transition and steady state were found by GLM and were interpreted using fundamental process principles and Nyvlt's transfer model. Neural network models were able to link process variables with response variables at transition and steady state with R(2) of 0.88-0.98. PVM images evidenced nucleation and crystal growth. Contour plots illustrated design space via critical process variables' ranges. It demonstrated the utility of integrated PAT approach for QbD development.


Homocysteine and cardiovascular diseases.
Elevated homocysteine blood concentrations have been identified as an independent risk factor for the development of atherosclerotic lesions. The metabolism of the amino acid homocysteine in the human body involves the vitamins folic acid, B-12 and B-6 as essential cofactors and coenzymes, respectively. There is an inverse relationship between the status of the relevant B-vitamins and the homocysteine blood concentration. Supplementation of these vitamins results in a significant reduction of the homocysteine level. However, nutritive amounts seems to be sufficient to obtain this reduction, even in the case of elevated homocysteine levels.


Multi-omics reveal differentiation and maintenance of dimorphic flowers in an alpine plant on the Qinghai-Tibet Plateau.
Dimorphic flowers growing on a single individual plant play a critical role in extreme adaption and reproductive assurance in plants and have high ecological and evolutionary significance. However, the omics bases underlying such a differentiation and maintenance remain largely unknown. We aimed to investigate this through genomic, transcriptome and metabolomic analyses of dimorphic flowers in an alpine biennial, Sinoswertia tetraptera (Gentianaceae). A high-quality chromosome-level genome sequence (903 Mb) was first assembled for S. tetraptera with 31,359 protein-coding genes annotated. Two rounds of recent independent whole-genome duplication (WGD) were revealed. Numerous genes from the recent species-specific WGD were found to be differentially expressed in the two types of flowers, and this may have helped contribute to the origin of this innovative trait. The genes with contrasting expressions between flowers were related to biosynthesis of hormones, floral pigments (carotenoids and flavonoids) and iridoid compounds, which are involved in both flower development and colour. Metabolomic analyses similarly suggested differential concentrations of these chemicals in the two types of flowers. The expression interactions between multiple genes may together lead to contrasting morphology and chemical concentration and open versus closed pollination of the dimorphic flowers in this species for reproductive assurance.


Advances in the Diagnosis of Obstructive Sleep Apnea: Drug-Induced Sleep Endoscopy.
Drug-induced sleep endoscopy was introduced in 1991 and has recently evolved into a pivotal instrument for patients in whom obstructive sleep apnea surgery is considered. Here, we discuss the indications, contraindications, technique, anesthesia, scoring systems, validity, and insights of the literature.


A Clinical Efficacy of PRRT in Patients with Advanced, Nonresectable, Paraganglioma-Pheochromocytoma, Related to SDHx Gene Mutation.
Paragangliomas and pheochromytomas (PPGLs) exhibit variable malignancy, advanced/hormonally active/progressive need therapy. PRRT (Peptide Receptor Radionuclide Therapy) could be an option for these patients. To evaluate the effectiveness of PRRT (90Y DOTATATE), based on overall survival (OS) and progression-free survival (PFS), in patients with PPGLs, related to SDHx gene mutation, we conducted a prospective open-label, single-center, phase II study. Thirteen patients were observed, eight PGL1 and five PGL4, all with advanced, non-resectable tumors, and eight had metastases. All were treated with 90Y DOTATATE. Efficacy was based on OS and PFS, and radiological response was based on RECIST. Hormonal activity was evaluated using serum-fractionated free catecholamines. Eight subjects had a clinical response, three were stable, and two exhibited disease progression. Among four patients with hormonally-active PPGLs, three showed a reduction and one showed normalization. OS for all was 68.0 months; PFS was 35.0 months. OS in PGL4 = 25.0 vs. N.R. (not reached) in PGL1. PFS in PGL4 = 12.0 vs. N.R. in PGL1. A difference was seen in the OS and PFS in patients who did not respond clinically, compared to those who did, OS = 22.0 vs. N.R. PFS = 7.0 vs. N.R. A difference in the OS and PFS was noted in patients with liver and bone involvement compared to those without. PRRT is an effective therapy in selected population of patients with SDHx, in those with locally-advanced, non-resectable tumors. Furthermore, it is effective regardless of the secretory status.


The prevalence and management of heart failure in Dutch nursing homes; design of a multi-centre cross-sectional study.
Heart failure is likely to be particularly prevalent in the nursing home population, but reliable data about the prevalence of heart failure in nursing homes are lacking. Therefore the aims of this study are to investigate (a) the prevalence and management of heart failure in nursing home residents and (b) the relation between heart failure and care dependency as well as heart failure and quality of life in nursing home residents. Nursing home residents in the southern part of the Netherlands, aged over 65 years and receiving long-term somatic or psychogeriatric care will be included in the study. A panel of two cardiologists and a geriatrician will diagnose heart failure based on data collected from actual clinical examinations (including history, physical examination, ECG, cardiac markers and echocardiography), patient records and questionnaires. Care dependency will be measured using the Care Dependency Scale. To measure the quality of life of the participating residents, the Qualidem will be used for psychogeriatric residents and the SF-12 and VAS for somatic residents. The study will provide an insight into the actual prevalence and management of heart failure in nursing home residents as well as their quality of life and care dependency. Dutch trial register NTR2663.


Multidrug-resistant bacteria in lung transplantation.
The review of infections in lung transplantation is beyond the scope of this article as it is a comprehensive topic, however we aim to focus on infections with multidrug-resistant (MDR) microorganisms in this patient population. New emerging clinical studies have provided data regarding outcomes in lung transplant recipients with MDR bacterial infections. Isolation of MDR bacteria from lung donors preoperatively has not been associated with worse outcomes in recipients. Patients with cystic fibrosis colonized with MDR bacteria do not have increased 1 year mortality rates compared to those without MDR bacteria.


Cutaneous manifestations, viral load, and prognosis among hospitalised patients with COVID-19: a cohort study.
Various cutaneous manifestations have been reported as symptoms of coronavirus disease 2019 (COVID-19), which may facilitate early clinical diagnosis and management. This study explored the incidence of cutaneous manifestations among hospitalised patients with COVID-19 and investigated its relationships with viral load, co-morbidities, and outcomes. This retrospective study included adult patients admitted to a tertiary hospital for COVID-19 from July to September 2020. Clinical information, co-morbidities, viral load (cycle threshold [Ct] value), and outcomes were analysed. In total, 219 patients with confirmed COVID-19 were included. Twenty patients presented with new onset of rash. The incidence of new rash was 9.1% (95% confidence interval=6.25%-14.4%). The most common manifestations were maculopapular exanthem (n=6, 42.9%, median Ct value: 24.8), followed by livedo reticularis (n=4, 28.6%, median Ct value: 21.3), varicella-like lesions (n=2, 14.3%, median Ct value: 19.3), urticaria (n=1, 7.1%, median Ct value: 14.4), and acral chilblain and petechiae (n=1, 7.1%, median Ct value: 33.1). The median Ct values for patients with and without rash were 22.9 and 24.1, respectively (P=0.58). There were no significant differences in mortality or hospital stay between patients with and without rash. Patients with rash were more likely to display fever on admission (P<0.01). Regardless of cutaneous manifestations, patients with older age, hypertension, and chronic kidney disease stage ≥3 had significantly higher viral load and mortality (P<0.05). This study revealed no associations between cutaneous manifestation and viral load or clinical outcomes. Older patients with multiple co-morbidities have risks of high viral load and mortality; they should be closely monitored.


Structure-function relationship of the macular visual field sensitivity and the ganglion cell complex thickness in glaucoma.
We attempted to understand better the relationship between the macular visual field (VF) mean sensitivity (MS) assessed by standard automated perimetry (SAP) and the ganglion cell complex thickness (GCCT), and macular peripapillary retinal nerve fiber layer thickness (mpRNFLT) assessed by spectral domain optical coherence tomography (SD-OCT, RTVue-100) in open-angle glaucoma (OAG) patients. We enrolled in the study 217 OAG patients with baseline intraocular pressure (IOP) in the statistically normal range. GCCT and mpRNFLT measurements, using the ganglion cell complex (GCC) and the optic nerve head (ONH) modes of RTVue-100 OCT, were obtained for analysis. Macular VF sensitivity was recorded in the dB and 1/L scales. The relationship of the function (MS) and structure (GCCT, mpRNFLT) was sought globally and in two VF sectors (superior and inferior). The relationship of the macular VF sensitivity (dB) to the GCC, and mpRNFL global (R(2) = 0.111, 0.127) and sectoral (superior R(2) = 0.358, 0.171; inferior R(2) = 0.227, 0.263) thicknesses were statistically significant (all P < 0.05). The relationship of the macular VF sensitivity to the GCCT differed significantly from that of the macular VF sensitivity to the mpRNFL in the superior VF sector (R(2) = 0.358 vs. 0.171, P < 0.05). GCCT determined by SD-OCT (RTVue-100) showed a statistically significant structure-function association with macular VF, and the strength of the association was greater than that of the mpRNFL with macular VF in the superior central VF area.


Photoluminescence properties of Ca2 Al2 O5 :RE3+ (RE = Eu, Dy and Tb) phosphors for solid state lighting.
Ca2 Al2 O5 :Eu3+ , Ca2 Al2 O5 :Dy3+ and Ca2 Al2 O5 :Tb3+ phosphors were synthesized using a combustion synthesis method. The prepared phosphors were characterized by X-ray powder diffraction for phase purity, by scanning electron microscopy for morphology, and by photoluminescence for emission and excitation measurements. The Ca2 Al2 O5 :Eu3+ phosphors could be efficiently excited at 396 nm and showed red emission at 594 nm and 616 nm due to 5 D0 → 7 F1 and 5 D0 → 7 F2 transitions. Dy3+ -doped phosphors showed blue emission at 482 nm and yellow emission at 573 nm. Ca2 Al2 O5 :Tb3+ phosphors showed emission at 545 nm when excited at 352 nm. Concentration quenching occurred in both Eu3+ and Dy3+ phosphors at 0.5 mol%. Photoluminescence results suggested that the aluminate-based phosphor could be a potential candidate for application in environmentally friendly based lighting technologies.


Electric-acoustic interactions in the hearing cochlea: single fiber recordings.
The present study investigates interactions of simultaneous electric and acoustic stimulation in single auditory nerve fibers in normal hearing cats. First, the auditory nerve was accessed with a microelectrode and response areas of single nerve fibers were determined for acoustic stimulation. Second, response thresholds to extracochlear sinusoidal electric stimulation using ball electrodes positioned at the round window were measured. Third, interactions that occurred with combined electric-acoustic stimulation were investigated in two areas: (1) the spectral domain (frequency response areas) and (2) the temporal domain (phase-locking to each stimulus) at moderate stimulus intensities (electric: 6 dB re threshold, acoustic: 20-40 dB re threshold at the characteristic frequency, CF). For fibers responding to both modalities responses to both electric and acoustic stimulation could be clearly identified. CFs, thresholds, and bandwidth (Q10dB) of acoustic responses were not significantly affected by simultaneous electric stimulation. Phase-locking of electric responses decreased in the presence of acoustic stimulation. Indication for electric stimulation of inner hair cells with 125 and 250 Hz were observed. However, these did not disturb the acoustic receptive fields of auditory nerve fibers. There was a trade-off between these responses when the intensities of the stimulation were varied: Relatively more intense stimulation dominated less intense stimulation. The scarcity of interaction between the different stimulus modalities demonstrates the ability of electric-acoustic stimulation to transfer useful information through both stimulation channels at the same time despite cochlear electrophonic effects. Application of 30 Hz electric stimulation resulted in a strong suppression of acoustic activity in the anodic phase of the stimulus. An electric stimulation like this might thus be used to control acoustic responses. This article is part of a Special Issue entitled <Lasker Award>.


Variant of the Triple A syndrome.
The Triple A syndrome is a rare condition comprising achalasia, alacrima and adrenocorticotrophic hormone (ACTH) insensitivity. A 12 year old Chinese girl with a variant of this syndrome (achalasia and alacrima), presenting with failure to thrive, is reported. Typical appearances of achalasia on barium swallow subsequently led to the correct diagnosis. The radiologist may be the first to recognize this syndrome and hence help anticipate its potentially life-threatening sequelae.


Drug resistance molecules: lessons from oncology.
Tumour cell insensitivity to anticancer drugs frequently appears as multidrug resistance (MDR), associated with overexpression of one or more of a set of at least 10 different molecules, causing reduced drug levels at the intracellular target sites. They include transmembrane transporter proteins such as P glycoprotein, MRP1-9 and BCRP. In addition, the lung-resistance protein, recently identified as the major vault protein, has been associated with MDR. We have generated monoclonal antibodies that specifically recognize most of these proteins, which we are using to try to identify their roles in clinical drug resistance, and also to explore their occurrence in normal human tissues and physiology. Both types of studies will also provide further insights into the molecular features of drugs associated with distinct MDR transporters.


Comparison of the predicted impact of a screwworm fly outbreak in Australia using a growth index model and a life-cycle model.
The spatial population dynamics of an Old World screwworm fly, Chrysomya bezziana Villeneuve (OWS), outbreak in Australia have been modelled in two ways. The first model uses weekly growth indices derived from climatic data to predict the adult female population. The second is a detailed cohort life-cycle model. Due to technical and time constraints, the growth index model is preferred as the biological component of a much larger bioeconomic model because of its smaller program size and faster execution. In deciding whether adoption of the growth index model would be at the expense of scientific accuracy, the life-cycle model was developed as a yardstick. We showed that the growth index model was a practical and adequate substitution for the OWS life-cycle model and a novel spatial/temporal modelling approach with generic qualities. We elaborate on the previously reported growth index model, describe the life-cycle model and compare the results of both models. In the event of an OWS incursion in northern or eastern Australia, given average climatic conditions, both models predict that most of the suitable range (some 2.3M km2) will be colonized within 4-5 years if an eradication campaign is not attempted. Much of its permanent range would be in tropical and subtropical extensive grazing regions. Where computer or funding resources are restrictive, models incorporating growth indices may prove adequate for spatial population studies of some species.


Nutritional and biochemical factors influencing the biological effects of cyanide.
Investigation of the dietary interaction between cyanide and selenium in the chick, whereby cyanide alleviates selenium toxicity, suggests that cyanide alters metabolic reductive potential. Cyanide enhances the elimination of selenium as dimethyl selenide, the formation of which requires both reducing equivalents and methyl groups. Even when the methionine supply is adequate, meeting the need for the methyl groups, the interaction can be lost if there is a deficiency of certain micronutrients or an excess of vitamin K. Cyanide reduces liver glycogen, implying greater emphasis on anaerobic metabolism through inhibition of cytochrome oxidase. This may increase reductive potential but may also result in increased free radical production, processes that can be modified by levels of micronutrients. There is no evidence that an excess of sulphur amino acids can markedly enhance cyanide detoxification, although, for reasons that are not yet clear, cystine may be beneficial. However, the balance of dietary amino acids may be more critical than had been realized, because an excess of alanine appears to exacerbate cyanide toxicity.


Ubiquitin-protein conjugates in different structures of the central nervous system of the rat.
The capacity to form ubiquitin (Ub)-protein conjugates was investigated in the cytosol of different structures of the rat central nervous system (CNS) in order to confirm the presence of this extralysosomal, adenosine triphosphate (ATP)-dependent, protein degradation system as well as its structural localization. Using 125I-Ub, we found that in the presence of ATP, the cytosol obtained from whole brains was able to form high molecular weight Ub-protein conjugates. These conjugates could be detected after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and radioautography. The formation of these conjugates was much higher in the cerebral cortex than in the brain stem, which is mainly constituted by white matter, being intermediate in the cytosol isolated from whole brain total homogenates. These results suggested to us that under normal conditions the capacity to form Ub-protein conjugates was mainly located in structures containing neuronal cell bodies. Strong support for this contention was obtained when the cytosol isolated from rat optic nerves or from oligodendroglial cells isolated from whole brain was found to be totally unable to form Ub-protein conjugates. The inability of certain CNS structures to form conjugates with Ub could be attributed, among other reasons, to the lack of enzymes catalyzing the various steps of the Ub degradation system, to the absence of short half-life (target) proteins in those structures, or to the lack of activity of the enzymes catalyzing the reaction due to regulatory control mechanisms operating under normal conditions.


Simple and efficient way of speeding up transmission calculations with k-point sampling.
The transmissions as functions of energy are central for electron or phonon transport in the Landauer transport picture. We suggest a simple and computationally "cheap" post-processing scheme to interpolate transmission functions over k-points to get smooth well-converged average transmission functions. This is relevant for data obtained using typical "expensive" first principles calculations where the leads/electrodes are described by periodic boundary conditions. We show examples of transport in graphene structures where a speed-up of an order of magnitude is easily obtained.


From cereus to anthrax and back again: Assessment of the temperature-dependent phenotypic switching in the "cross-over" strain Bacillus cereus G9241.
Bacillus cereus G9241 was isolated from a Louisiana welder suffering from an anthrax-like infection. The organism carries two transcriptional regulators that have previously been proposed to be incompatible with each other in Bacillus anthracis: the pleiotropic transcriptional regulator PlcR found in most members of the Bacillus cereus group but truncated in all B. anthracis isolates, and the anthrax toxin regulator AtxA found in all B. anthracis strains and a few B. cereus sensu stricto strains. Here we report cytotoxic and hemolytic activity of cell free B. cereus G9241 culture supernatants cultured at 25°C to various eukaryotic cells. However, this is not observed at the mammalian infection relevant temperature 37°C, behaving much like the supernatants generated by B. anthracis. Using a combination of genetic and proteomic approaches to understand this unique phenotype, we identified several PlcR-regulated toxins to be secreted highly at 25°C compared to 37°C. Furthermore, results suggest that differential expression of the protease involved in processing the PlcR quorum sensing activator molecule PapR appears to be the limiting step for the production of PlcR-regulated toxins at 37°C, giving rise to the temperature-dependent hemolytic and cytotoxic activity of the culture supernatants. This study provides an insight on how B. cereus G9241 is able to "switch" between B. cereus and B. anthracis-like phenotypes in a temperature-dependent manner, potentially accommodating the activities of both PlcR and AtxA.


Voltammetric sizing of a sphere.
The size of a glass sphere positioned in the center of a microdisk electrode is determined by using a simple electrochemical procedure and is confirmed, additionally, by a microscopical measurement of the sphere at the time of the electrochemical measurement. The cyclic voltammetric response of the naked electrode and of the electrode with the sphere positioned in its center is recorded over a wide range of scan rates (0.002-1.5 V s(-1)). The size of the sphere is then determined by comparison of the experimental voltammogram with simulations for each individual scan rate.


Exercise effects on erythrocyte deformability in exercise-induced arterial hypoxemia.
Exercise-induced arterial hypoxemia (EIAH) is often found in endurance-trained subjects at high exercise intensity. The role of erythrocyte deformability (ED) in EIAH has been scarcely explored. We aimed to explore the role of erythrocyte properties and lactate accumulation in the response of ED in EIAH. ED was determined in 10 sedentary and in 16 trained subjects, both before and after a maximal incremental test, and after recovery, along with mean corpuscular volume (MCV) and red blood cell lactate concentrations. EIAH was found in 6 trained subjects (∆SaO2=-8.25±4.03%). Sedentary and non-EIAH trained subjects showed reduced ED after exercise, while no effect on ED was found in EIAH trained subjects. After exercise, lactate concentrations rose and MCV increased equally in all groups. ED is strongly driven by cell volume, but the different ED response to exercise in EIAH shows that other cellular mechanisms may be implicated. Interactions between membrane and cytoskeleton, which have been found to be O2-regulated, play a role in ED. The drop in SaO2 in EIAH subjects can improve ED response to exercise. This can be an adaptive mechanism that enhances muscular and pulmonary perfusion, and allows the achievement of high exercise intensity in EIAH despite lower O2 arterial transport.


The passing of the night watch: night nursing reform in the London teaching hospitals, 1856-90.
At the beginning of the nineteenth century a separate team of women called the "night watch" was responsible for the night nursing in the London teaching hospitals. Rough, uneducated, and frequently the "scrubbers," or charwomen, who cleaned the halls and stairways in the hospitals in the daytime, the night watchers came to be closely identified with Dickens's Sarah Gamp. As the century progressed, the expanding capabilities of the new academic medicine forced an improvement in the standard of nursing. The difficulty in finding clinically experienced nurses who were willing to work nights at an affordable price, however, made it possible for the night watchers to remain in the new professionally organized hospital long after such unskilled and undisciplined workers had been phased out of other areas of the late Victorian workforce. By the end of the century when hospitals began rotating partially trained probationer, or student, nurses onto nights, the night watchers finally disappeared from the teaching hospitals.


Phage display as a tool to discover blood-brain barrier (BBB)-shuttle peptides: panning against a human BBB cellular model.
Most potential drugs for the treatment of central nervous system disorders do not cross the blood-brain barrier (BBB). Much research effort has been devoted to the discovery of new BBB-shuttle peptides-most of which have been identified by phage display. Here we report for the first time on the use of phage display against a human BBB cellular model which mimics the characteristics of the BBB. From the panning experiment of a 12-mer library, the SGVYKVAYDWQH (SGV) peptide sequence was selected and its permeability validated in the aforementioned model. Furthermore, internalization studies suggested that SGV internalizes through a clathrin-mediated mechanism and that it increases the uptake of a cargo in endothelial cells. These results highlight the usefulness of in vitro BBB models for the discovery of BBB-shuttle peptides through phage display libraries.


Electrical conductivity imaging by magnetic resonance electrical impedance tomography (MREIT).
Magnetic resonance electrical impedance tomography (MREIT) is a recently developed imaging technique that combines MRI and electrical impedance tomography (EIT). In MREIT, cross-sectional electrical conductivity images are reconstructed from the internal magnetic field density data produced inside an electrically conducting subject when an electrical current is injected into the subject. In this work the results of an electrical conductivity imaging experiment are presented, along with some practical considerations regarding MREIT. The MREIT experiment was performed with a 0.3 Tesla MRI system on a phantom made of two compartments with different electrical conductivities. The current density inside the phantom was measured by the MR current density imaging (MRCDI) technique. The measured current density was then used for conductivity image reconstruction by the J-substitution algorithm. The conductivity phantom images obtained with an injection current of 28mA showed conductivity errors of about 25.5%.


Tailored Metabolic Workup for Urolithiasis - The Debate Continues.
Urolithiasis is one of the commonest afflictions of the urinary tract. Stones are of various chemical compositions, some share some common etiology; but most are specific to the structure and composition of stone. In view of highly recurrent nature of this condition, it is logical to have strategies for prevention. However, due to multiple factors most patients receive no or fragmented information on prevention. The current controversy is to the extent of metabolic workup in adult first time stone former. This requires longitudinal studies to show benefit in prevention strategies. Patients at high risk can have recurrence in weeks to years, depending upon the composition and attending risk factor. They should be targeted with concentric and tailored prevention protocols. The major urological guidelines (EAU and AUA) recommend basic stone workup for all patients. However, indication for detailed workup are less well documented, so one potential solution is to tailor metaphylaxis strategies for individual patient.


Structure and Function of the Stressosome Signalling Hub.
The stressosome is a multi-protein signal integration and transduction hub found in a wide range of bacterial species. The role that the stressosome plays in regulating the transcription of genes involved in the general stress response has been studied most extensively in the Gram-positive model organism Bacillus subtilis. The stressosome receives and relays the signal(s) that initiate a complex phosphorylation-dependent partner switching cascade, resulting in the activation of the alternative sigma factor σB. This sigma factor controls transcription of more than 150 genes involved in the general stress response. X-ray crystal structures of individual components of the stressosome and single-particle cryo-EM reconstructions of stressosome complexes, coupled with biochemical and single cell analyses, have permitted a detailed understanding of the dynamic signalling behaviour that arises from this multi-protein complex. Furthermore, bioinformatics analyses indicate that genetic modules encoding key stressosome proteins are found in a wide range of bacterial species, indicating an evolutionary advantage afforded by stressosome complexes. Interestingly, the genetic modules are associated with a variety of signalling modules encoding secondary messenger regulation systems, as well as classical two-component signal transduction systems, suggesting a diversification in function. In this chapter we review the current research into stressosome systems and discuss the functional implications of the unique structure of these signalling complexes.


Distance measurements to quadrupolar nuclei: Evolution of the rotational echo double resonance technique.
Molecular structure determination is the basis for understanding chemical processes and the property of materials. The direct dependence of the magnetic dipolar interaction on the distance makes solid-state nuclear magnetic resonance (NMR) an excellent tool to study molecular structure when X-ray crystallography fails to provide atomic-resolution data. Although techniques to measure distances between pairs of isolated nuclear spin-1/2 pairs are routine and easy to implement using the rotational echo double resonance (REDOR) experiment (Gullion & Schaefer, 1989), the existence of a nucleus with a spin > 1/2, appearing in approximately 75% of the elements in the periodic table, poses a challenge due to difficulties stemming from the large nuclear quadrupolar coupling constant (QCC). This mini-review presents the existing solid-state magic-angle spinning NMR techniques aimed toward the efficient and accurate determination of internuclear distances between a spin-1/2 and a "quadrupolar" nucleus having a spin larger than one half. Analytical expressions are provided for the various recoupling curves stemming from different techniques, and a coherent nomenclature for these various techniques is suggested. Treatment of some special cases such as multiple spin effects and spins with close Larmor frequencies is also discussed. The most advanced methods can recouple spins with quadrupolar frequencies up to tens of megahertz and beyond, expanding the distance measurement capabilities of solid-state NMR to an increasingly growing number of applications and nuclear spin systems.


Anatomy and morphometry of the distal gracilis muscle tendon in adults and foetuses.
Ten human gracilis muscles obtained from adults and ten gracilis muscles collected from human foetuses between the 15th and 21st week of gestation were examined. The results of this preparatory study show that the gracilis muscle in adults is narrow and long - 482 mm on average. The distal tendon of gracilis muscle is long, 294 mm on average. It can be divided into two sections - external part, outside the muscle belly, and internal, intramuscular, part. The latter one is partially covered by muscle fibres and some of it is completely hidden inside the muscle belly, which is on average 76 mm long. Presence of an intramuscular part of the distal tendon was also demonstrated in the foetal material. Moreover, very strong correlations between particular muscle lengths were noted in foetuses. (Folia Morphol 2018; 77, 1: 138-143).


miR-455-5p promotes cell growth and invasion by targeting SOCO3 in non-small cell lung cancer.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. miR-455-5p has increased expression and the ability to promote tumorigenesis in certain cancers. However, the role of miR-455-5p in NSCLC has not been sufficiently investigated. SOCS3 (suppressor of cytokine signaling 3), an important tumor suppressor, is often aberrantly inactivated in various tumors, but it is currently unclear whether SOCO3 is a target of miR-455-5p. In the present study, we investigated the role of miR-455-5p in NSCLC. We found that the expression of miR-455-5p was up-regulated in NSCLC tumor tissues compared to corresponding noncancerous tissues, and its expression was correlated with metastasis and tumor node metastasis in NSCLC tissue. We then showed that miR-455-5p promoted migration, invasion and proliferation in NSCLC cell lines. Additionally, we also found that SOCS3 was the direct target gene of miR-455-5p. Consistently, the expression of SOCS3 was negatively correlated with the expression of miR-455-5p in NSCLC tissues. We further show that aberrant miR-455-5p expression is partially controlled by activated ERK signaling in NSCLC. Therefore, miR-455-5p could enhance the growth and metastasis of NSCLC by inhibiting SOCS3, thus providing a potential molecular therapeutic target for the treatment of NSCLC patients.


Many-body exchange-overlap interactions in rare gases and water.
Generalized-gradient approximations (GGAs) of density-functional theory can suffer from substantial many-body errors in molecular systems interacting through weak non-covalent forces. Here, the errors of a range of GGAs for the 3-body energies of trimers of rare gases and water are investigated. The patterns of 3-body errors are similar for all the systems, and are related to the form of the exchange-enhancement factor FX(x) at large reduced gradient x, which also governs 2-body exchange-overlap errors. However, it is shown that the 3-body and 2-body errors depend in opposite ways on FX(x), so that they tend to cancel in molecular aggregates. Embedding arguments are used to achieve a partial separation of contributions to 3-body error from polarization, non-local correlation, and exchange, and it emerges that exchange is a major contributor. The practical importance of beyond-2-body errors is illustrated by the energetics of the water hexamer. An analysis of exchange-energy distributions is used to elucidate why 2-body and 3-body errors of GGAs depend in opposite ways on FX(x). The relevance of the present analysis to a range of other molecular systems is noted.


Descriptive study of measles vaccination second dose reporting and barriers to improving coverage in six districts in Malawi.
Malawi's National Immunization Program introduced a second routine dose of measles containing vaccine (MCV2) in 2015 but found coverage lagging. We assessed data quality and gaps in service delivery. Investigators used a modified data quality audit in 6 low performing districts accompanied by questionnaires for health facilities (HF) and households with children with >1 vaccination. MCV2 doses administered according to source were: 733 in registers, 2364 in reports, 1655 in district reports, 2761 in the electronic database. There was 77% agreement regarding status for MCV2 between the register and the home-based record (HBR). Drop-out differences were found between HF according to the practice of waiting for a minimum number of children to open an MCV vial, canceling sessions due to stock-out and requesting payment for a home-based record. Eighty one percent (81%) of children whose caregivers knew 2 doses were needed had received MCV2 vs fifty eight (58%) of children whose caregivers didn't know. Sixty two (62%) of children who were charged for HBR received MCV2 vs 78% reporting no charge. The drop-out between the first and second doses of MCV was high and inconsistent with elimination goals. The quality of administrative data in these 6 districts was found to be poor. This investigation found that session cancelation, charging for HBR and lack of caregiver knowledge affected completion of the vaccination series. The authors recommend program improvements in these areas to increase uptake of MCV2 and improved reporting practices at all levels of the system.


Membrane protein phosphorylation in the intact erythrocytes of genetically dystrophic hamsters.
Membrane protein phosphorylation has been measured in both normal and dystrophic (BIO 53.58) hamsters. After radiolabeling intact erythrocytes with exogenous 32Pi, band 3 polypeptides from dystrophic hamsters had increased incorporation of 32P, compared to age-matched controls. This was verified by membrane protein fractionation. The use of intact cell phosphorylation avoids many of the sources of experimental variability noted in experiments with isolated membranes. This work, using an animal model for the disease, supports the hypothesis of a generalized membrane defect in the muscular dystrophies.


Nucleic acid-based diagnostics for infectious diseases in public health affairs.
Infectious diseases, mostly caused by bacteria and viruses but also a result of fungal and parasitic infection, have been one of the most important public health concerns throughout human history. The first step in combating these pathogens is to get a timely and accurate diagnosis at an affordable cost. Many kinds of diagnostics have been developed, such as pathogen culture, biochemical tests and serological tests, to help detect and fight against the causative agents of diseases. However, these diagnostic tests are generally unsatisfactory because they are not particularly sensitive and specific and are unable to deliver speedy results. Nucleic acid-based diagnostics, detecting pathogens through the identification of their genomic sequences, have shown promise to overcome the above limitations and become more widely adopted in clinical tests. Here we review some of the most popular nucleic acid-based diagnostics and focus on their adaptability and applicability to routine clinical usage. We also compare and contrast the characteristics of different types of nucleic acid-based diagnostics.


Rotating cantilever-based low-frequency double-fiber grating acceleration sensor.
Acceleration sensors play an important role in bridges, dams, seismic monitoring, geological exploration, and more. Aiming at the problem that it is still difficult to accurately measure low-frequency vibration signals with low-frequency acceleration sensors, a high-sensitivity, wide-low-band fiber Bragg grating (FBG) acceleration sensor incorporating a rotating cantilever and springs was proposed. A sensor mechanics model was built, and its key parameters were analyzed theoretically and optimized in size. ANSYS Workbench was used for simulation analysis, and the physical sensor was developed while a low-frequency test platform was established for performance tests. The experimental results suggested that the natural frequency of the sensor was 78 Hz, the operating frequency band was 1-55 Hz, the sensitivity was 1127.2 pm/g, the transverse interference immunity was less than 5.45%, and the dynamic range was 86.45 dB. With high sensitivity, wide low frequency band, and excellent temperature compensation characteristics, the designed sensor could provide a reference for the design of like FBG acceleration sensors.


Possible role for calmodulin in insulin release. Studies with trifluoperazine in rat pancreatic islets.
The role of calmodulin in insulin secretion from rat pancreatic islets has been examined by the use of trifluoperazine, an inhibitor of calmodulin-Ca++-directed functions. It was found that 30 microM trifluoperazine caused 50% inhibition, and 100 microM, up to 73% inhibition of 16.7 mM glucose-stimulated insulin release. 100 microM trifluoperazine caused a similar inhibition of 10 mM glyceraldehyde-stimulated release. Therefore, the site of action of trifluoperazine in glucose stimulus-secretion coupling appears to be after the trioses. As trifluoperazine had no effect upon insulin release stimulated by 1 mM 3-isobutyl-1-methylxanthine, the inhibitory effect of trifluoperazine appears to be rather specific. Further, the process of exocytosis per se is not affected. It was also found that although trifluoperazine inhibited the effect of glucose to stimulate insulin release, it did not affect the synergism between glucose and 3-isobutyl-1-methylxanthine to potentiate insulin release. It may be concluded that trifluoperazine selectively inhibits one part of the mechanism by which glucose stimulates insulin release. Calmodulin plays a role in the stimulation of insulin release by glucose at a site between metabolism of trioses and elevation of cytosol Ca++, but is not involved in the final process of exocytosis.


Gas within hemophiliac pelvic pseudotumors: CT demonstration.
Three hemophiliac patients are presented who had gas within their pelvic pseudotumors demonstrated by computed tomography. Etiologies of the gas included iatrogenically introduced gas from infection, failed tube drainage of the pseudotumor, and a communication between the pseudotumor and the bladder containing a Foley catheter.


Fiber-laser frequency combs with subhertz relative linewidths.
We investigate the comb linewidths of self-referenced, fiber-laser-based frequency combs by measuring the heterodyne beat signal between two independent frequency combs that are phase locked to a common cw optical reference. We demonstrate that the optical comb lines can exhibit instrument-limited, subhertz relative linewidths across the comb spectra from 1200 to 1720 nm with a residual integrated optical phase jitter of approximately 1 rad in a 60 mHz to 500 kHz bandwidth. The projected relative pulse timing jitter is approximately 1 fs. This performance approaches that of Ti:sapphire frequency combs.


Surfactant-Enhanced Solubilization of Chlorinated Organic Compounds Contained in DNAPL from Lindane Waste: Effect of Surfactant Type and pH.
Application of surfactants in the remediation of polluted sites with dense nonaqueous phase liquid (DNAPL) still requires knowledge of partitioning between surfactants and pollutants in the organic and aqueous phases and the time necessary to reach this balance. Two real DNAPLs, generated as wastes in the lindane production and taken from the polluted sites from Sabiñanigo (Spain), were used for investigating the solubilization of 28 chlorinated organic compounds (COCs) applying aqueous surfactant solutions of three nonionic surfactants (E-Mulse® 3 (E3), Tween®80 (T80), and a mixture of Tween®80-Span®80 (TS80)) and an anionic surfactant (sodium dodecyl sulfate (SDS)). The initial concentrations of surfactants were tested within the range of 3-17 g·L-1. The pH was also modified from 7 to >12. The uptake of nonionic surfactants into the organic phase was higher than the anionic surfactants. Solubilization of COCs with the nonionic surfactants showed similar molar solubilization ratios (MSR = 4.33 mmolCOCs·g-1surf), higher than SDS (MSR = 0.70 mmolCOCs·g-1SDS). Furthermore, under strong alkaline conditions, the MSR value of the nonionic surfactants was unchanged, and the MSR of SDS value increased (MSR = 1.32 mmolCOCs·g-1SDS). The nonionic surfactants did not produce preferential solubilization of COCs; meanwhile, SDS preferentially dissolved the more polar compounds in DNAPL. The time required to reach phase equilibrium was between 24 and 48 h, and this contact time should be assured to optimize the effect of the surfactant injected on COC solubilization.


Equivalence of fusion rates after rigid internal fixation of the occiput to C-2 with or without C-1 instrumentation.
The object of this study was to assess a multiinstitutional experience with pediatric occipitocervical constructs to determine whether a difference exists between the fusion and complication rates of constructs with or without direct C-1 instrumentation. Seventy-seven cases of occiput-C2 instrumentation and fusion, performed at 9 children's hospitals, were retrospectively analyzed. Entry criteria included atlantooccipital instability with or without atlantoaxial instability. Any case involving subaxial instability was excluded. Constructs were divided into 3 groups based on the characteristics of the anchoring spinal instrumentation: Group 1, C-2 instrumentation; Group 2, C-1 and C-2 instrumentation without transarticular screw (TAS) placement; and Group 3, any TAS placement. Groups were compared based on rates of fusion and perioperative complications. Group 1 consisted of 16 patients (20.8%) and had a 100% rate of radiographically demonstrated fusion. Group 2 included 22 patients (28.6%), and a 100% fusion rate was achieved, although 2 cases were lost to follow-up before documented fusion. Group 3 included 39 patients (50.6%) and demonstrated a 100% radiographic fusion rate. Complication rates were 12.5, 13.7, and 5.1%, respectively. There were 3 vertebral artery injuries, 1 (4.5%) in Group 2 and 2 (5.1%) in Group 3. High fusion rates and low complication rates were achieved with each configuration examined. There was no difference in fusion rates between the group without (Group 1) and those with (Groups 2 and 3) C-1 instrumentation. These findings indicated that in the pediatric population, excellent occipitocervical fusion rates can be accomplished without directly instrumenting C-1.


Analysis of integration in nursing science and practice.
To clarify the definition of integration and to identify universal aspects of the experience of integration related to healing, health, and nursing care. An integrative review concept analysis method was used. Relevant reports were identified by a computer-assisted search using the keyword integration in CINAHL from 1966 to 2004 and by reviewing the reference lists of retrieved reports. The final sample included 56 reports; 36 were empirical and 20 were theoretical. Data were extracted from primary sources on the definition of integration, aspects of the process, antecedents, consequences, and facilitators. Data display matrices were used and were iteratively compared to derive a process model of integration related to health. A wide range of primary sources indicated that integration is an important aspect of healing or recovery from illness. Integration is defined as a complex person-environment interaction whereby new life experiences (i.e., illness) are assimilated into the self and activities of daily living, thereby contributing to overall life balance. Results of this analysis indicate the importance of the concept of integration to the science and practice of nursing. The process of integration appears to be a significant phase that occurs between a diagnosis of illness and subsequent physical and emotional healing.


Successful treatment of bleeding gastro-intestinal angiodysplasia in hereditary haemorrhagic telangiectasia with thalidomide.
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by epistaxis, cutaneous telangiectasia and visceral arterio-venous malformations (AVMs). It affects approximately one in 5000 people. Control of sustained and repeated haemorrhages from telangiectasias in the nose and gut in patients who may be transfusion dependent is clinically challenging. After repeated endoscopic coagulations, multiple lesions often recur at other sites of gastro-intestinal tract, where endoscopic therapy or surgical resection is not possible. Hormonal therapy has been employed for more than 50 years but has recently been shown to be ineffective. Thalidomide, with its antiangiogenic mechanism of action, seems to be promising drug as a treatment option where other modalities have been unsuccessful. In this article, the authors discuss a novel treatment of bleeding gastro-intestinal angiodysplasia.


Affinity chromatography as a means to study multienzyme complexes involved in murein synthesis.
The interaction of murein hydrolases and synthases was studied by affinity chromatography. The lytic transglycosylases Slt70 and MltB of E. coli were purified and covalently linked to CNBr-activated Sepharose. Membrane extracts were analyzed for proteins that interact with the immobilized murein hydrolases. Slt70-Sepharose was found to retain the PBPs 1b, 1c, 2, and 3. Likewise MltB-Sepharose enriched PBP 1b, 1c, and 3. Thus both lytic transglycosylases have an affinity for a transpeptidase, PBP2 and/or 3, as well as for the bifunctional transpeptidase/transglycosylase 1b. Interestingly, in addition, the poorly characterized PBP 1c interacts strongly with both Slt70 and MltB. It is speculated that the lytic transglycosylases assemble a multienzyme complex consisting of hydrolases and synthases, which is involved in growth of the stress-bearing murein sacculus.


Arbitrary function resonance tuner of the optical microcavity with sub-MHz resolution.
Tuning the resonance frequency of an optical whispering gallery mode microcavity is extremely important in its various applications. Here we report the design and implementation of a function resonance tuner of an optical microcavity with a resolution of about 650 kHz (7 pm at 1450 nm band). A piezoelectric nano-positioner is used to mechanically compress the microsphere in its axial direction. Furthermore, the resonance can be periodically tuned as an arbitrary function, such as the sine and sigmoid functions, with over 99% fitting accuracy. This Letter greatly expands the application of ultrahigh quality factor microresonators in a multi-mode coupling system or time-floquet system.


Differential subcellular distribution of mortalin in mortal and immortal mouse and human fibroblasts.
Mortalin, p66mot-1, from the cytosolic fractions of mouse embryonic fibroblasts (MEF) has been identified. We have cloned and characterized it as a novel member of mouse hsp70 family [R. Wadhwa, S. C. Kaul, Y. Ikawa, and Y. Sugimoto (1993) J. Biol. Chem. 268, 6615-6621]. We report that immortal clones from MEF such as NIH 3T3, RS4, and Balb/c 3T3 harbor the same or a very similar protein but in the perinuclear locale. Biochemical analysis revealed that the proteins from mortal (MEF) and immortal (NIH 3T3) fibroblasts do not show gross differences. However, the phenomenon of differential distribution of p66 protein in mortal and immortal fibroblasts is conserved in three different strains of mouse and, interestingly, in human fibroblasts, too. The data suggest that at least one common step is involved in immortalization of mouse and human fibroblasts and also point to the practical implication(s) of such easily detectable differences.


Vitamin C intake and risk of ischemic heart disease in a population with a high prevalence of smoking.
Epidemiological data on the relationship between vitamin C intake and ischemic heart disease (IHD) risk are limited in the Asian population, with a high prevalence of smoking. This study aims to investigate the association between vitamin C intake and the incidence of non-fatal IHD in Korean men. The case group consisted of 108 patients with electrocardiogram-confirmed myocardial infarction or angiographically confirmed (>or=50% stenosis) coronary artery disease (CAD) who were admitted to a university teaching hospital in Seoul, Korea. The controls were 142 age-matched patients admitted to the departments of ophthalmology and orthopedic surgery at the same hospital. Vitamin C intake was assessed by a nutritionist using a semi-quantitative food frequency method, and body mass index (BMI), tobacco use and past history of cardiovascular disease were determined by examination and interview. After controlling for cardiovascular risk factors, including BMI, smoking, past history of hypertension, past history of hyperlipidemia, dietary intakes of energy, total fat (or subtype of fat), cholesterol, beta-carotene, and vitamin E, the odds ratio (OR) of non-fatal IHD was 0.34 (95% confidence interval (CI) 0.13-0.90) in the highest tertile of vitamin C intake compared with those in the lowest tertile. In a subgroup analysis, which compared nonsmokers in the highest tertile of vitamin C intake to current smokers in the lowest tertile of vitamin C intake, the odds ratio of developing non-fatal IHD was 0.12 (95% CI 0.02-0.77). This study suggests that higher intake of vitamin C is associated with the decreased risk of non-fatal IHD in a population with a high prevalence of smoking.


Age and antiaging technique influence reactions to age concealment.
Despite the rapid expansion of the antiaging cosmetic industry in recent years, little is known about the current social judgment consequences of concealing one's age. In two studies, we examined perceivers' evaluations and mental representations of individuals who engage in age concealment. In Study 1, we assessed young and older adults' reactions toward a middle-aged or older adult target who engaged in mild or major forms of age concealment. In Study 2, we examined the social consequences of age concealment in greater detail by including younger middle-aged targets and expanding the range of concealment procedures used. Targets received less favorable evaluations (a) to the extent that they engaged in invasive procedures, (b) when they were viewed by young adults rather than by older adults, and to some degree, (c) if they were middle-aged adults rather than older adults. Participants held different expectations concerning aging and age concealment depending on the age of the target and the antiaging technique used. These findings suggest that reactions to age concealment vary according to the concealment technique used, the age of the perceiver, and to some extent, the age of the target.


Transverse verses midline incisions for abdominal surgery.
The choice of surgical incision in the abdomen is determined by access for surgery. It has been suggested that utilising a transverse or oblique rather than a midline incision may influence other parameters such as recovery and complication rates. However, there is little consensus in the literature as to whether a particular incision confers any advantage. To determine whether a midline incision or a transverse incision (including oblique incision) confers any recovery advantage to the patient. Search terms included randomised trials containing combinations of the following: 'abdominal', 'incisions', 'horizontal', 'transverse', 'vertical', 'midline', and 'laparotomy'. All prospective randomised trials comparing midline with transverse incisions for abdominal surgery were included. Caesarian sections were excluded. Two review authors assessed the methodological quality of potentially eligible trials and independently extracted data from the included trials. A wide range of outcome measures was considered. Due to differences in the method of assessment, the variability of data and the heterogeneity of the participant groups it was difficult to pool some of the outcome data. Despite these limitations, and potentially significant biases related to methodological quality, there was evidence to suggest that a transverse or oblique incision may be less painful and have less impact on pulmonary function than a midline incision, particularly in the early postoperative period. However, there was no difference seen in early or late postoperative complications between a transverse or oblique and a midline incision and recovery times were similar. Both analgesia use and pulmonary compromise may be reduced with a transverse or oblique incision but this does not seem to be significant clinically as complication rates and recovery times are the same as with midline incision. The methodological and clinical diversity and the potential for bias in the included studies also mean that the results in favour of a transverse or oblique incision, particularly with regard to analgesic use, should be treated with caution. The optimal incision for abdominal surgery still remains the preference of the surgeon.


Dissociation of beta-hydroxy-beta-methylglutaryl-CoA reductase activity from the overall rate of cholesterol synthesis in the liver following the intravenous administration of lipid.
After the intravenous administration to the intact rat of triglyceride carried in either intestinal lipoproteins or in an artificial fat emulsion, the enzymatic activities of microsomal beta-hydroxy-beta-methylglutaryl-CoA reductase activity in the liver assayed in vitro became markedly elevated. This elevation of enzyme activity was not associated with a corresponding change in the overall rate of cholesterol synthesis in the rat liver slice as measured by the incorporation of either [3H]water or [1-14C]octanoate into nonsaponifiable lipids or into digitonin-precipitable sterols. The degree of dissociation of hydroxymethylglutaryl-CoA reductase activity from the overall rate of cholesterol synthesis correlated closely with the amount of lipid administered to the animal, the level of circulating lipids, and the level of ketone synthesis manifest in the liver cell suggesting that this phenomenon might be the consequence of a detergent effect of elevated cellular levels of fatty acids. In any event, under these experimental circumstances hydroxymethylglutaryl-CoA redutase activity no longer reflects the rate at which the liver cell is synthesizing cholesterol.


[Ultrasound diagnosis of hand and finger joints. Changes in arthritis].
Arthritis of the hand and finger joints is seen with unspecific and specific signs, as known from the hip and knee joints. The examination has to be done with special applicators (small sized with 7-13 MHz). Especially signs such as erosions and surrounding synovitis ensure the diagnosis of rheumatoid arthritis.


Experimental demonstration of simultaneous mode and polarization-division multiplexing based on silicon densely packed waveguide array.
A silicon mode and polarization-division multiplexing scheme based on a densely packed waveguide array structured as a bus waveguide is introduced. A short adiabatic taper is adopted for (de)multiplexing. Such a structure shows theoretical insertion losses that are <0.05 dB and crosstalk that is <-20 dB over a wide wavelength band for all five supported modes. The structures for (de)multiplexing are fabricated and characterized experimentally. A device, which consists of a multiplexer, a 50-μm-long straight-bus waveguide, and a demultiplexer, exhibits insertion losses that are <0.6 dB and crosstalk that is <-15 dB over an 80 nm wavelength band. The demonstrated (de)multiplexer has a total length of 60 μm, and the bus waveguide has an effective width of 1.58 μm.


The effect of body mass and physical activity on the development of guinea pig osteoarthrosis.
We quantitatively evaluated the morphological and biochemical effects of body mass and physical activity on spontaneously developing guinea pig osteoarthrosis (OA). 6-month-old male guinea pigs were allocated to 3 groups: controls (C) living under standard laboratory conditions with food ad libitum; mobilized animals (M) allowed unrestricted motion in large rooms with food ad libitum; and a diet group (D) weight-matched with the M-group. At 9- and 12-months of age they were killed and the left proximal tibia was processed for quantitative histology and the right tibial articular cartilage for analyses of glycosaminoglycan (GAG). OA mostly occurred on the medial condyle's central part not covered by the meniscus. The thinnest cartilage was found in 12-month-old M-animals (M12), which had 60% of the central cartilage surface affected by lesions that extended down to the mineralized cartilage. C12 had 25% exposed mineralized cartilage and D12, 2%. Subchondral bone density followed the loading patterns--the highest in M12 and lowest in D12. M12 had the lowest cartilage GAG concentrations. Load appears to be a key external factor in guinea pig OA. An increase in physical activity may be chondroprotective in the early phase, but harmful when fibrillations eventually have developed. This is underscored by the extensive OA changes in M12, although these animals weighed about the same as D12 (which had the least extensive OA). Therefore, a reduction in body mass seems to retard the progression of OA in animals, which are mainly subjected to a static load (C12 and D12), but not sufficiently in animals with a more dynamic load (M12). Changes in morphological patterns are paralleled by changes in GAG concentration, which probably reflect the metabolic capacity of the cartilage.


Systematic review of colorectal cancer screening guidelines for average-risk adults: Summarizing the current global recommendations.
To summarize and compare worldwide colorectal cancer (CRC) screening recommendations in order to identify similarities and disparities. A systematic literature search was performed using MEDLINE, EMBASE, Scopus, CENTRAL and ISI Web of knowledge identifying all average-risk CRC screening guideline publications within the last ten years and/or position statements published in the last 2 years. In addition, a hand-search of the webpages of National Gastroenterology Society websites, the National Guideline Clearinghouse, the BMJ Clinical Evidence website, Google and Google Scholar was performed. Fifteen guidelines were identified. Six guidelines were published in North America, four in Europe, four in Asia and one from the World Gastroenterology Organization. The majority of guidelines recommend screening average-risk individuals between ages 50 and 75 using colonoscopy (every 10 years), or flexible sigmoidoscopy (FS, every 5 years) or fecal occult blood test (FOBT, mainly the Fecal Immunochemical Test, annually or biennially). Disparities throughout the different guidelines are found relating to the use of colonoscopy, rank order between test, screening intervals and optimal age ranges for screening. Average risk individuals between 50 and 75 years should undergo CRC screening. Recommendations for optimal surveillance intervals, preferred tests/test cascade as well as the optimal timing when to start and stop screening differ regionally and should be considered for clinical decision making. Furthermore, local resource availability and patient preferences are important to increase CRC screening uptake, as any screening is better than none.


Space occupying lesion of brain: An unusual site for a common infection.
Filariasis is a public health menace and is a cause for concern due to its endemicity in tropical and subtropical countries of Africa, Asia, and Western Pacific. Even in endemic areas, it is rare to find filariasis in fluid specimens especially cerebrospinal fluid. Herein, we report a case of unsuspected filarial parasitic infection in an adult male admitted as a case of space occupying lesion in brain with suspicion of lymphoma/granulomatous disease on the basis of clinicoradiological details. To the best of our knowledge, such an extensive brain involvement by filariasis has not been reported before.


Application of UHPLC-MS/MS method to monitor the occurrence of sulfonamides and their transformation products in soil in Silesia, Poland.
Sulfonamides circulating in the environment lead to disturbances in food chains and local ecosystems, but most importantly contribute to development of resistance genes, which generate problems with multidrug-resistant bacterial infections treatment. In urban areas, sources of sulfonamide distribution in soils have received comparatively less attention in contrast to rural regions, where animal-derived manure, used as a natural fertilizer, is considered the main source. The aim of this study was to determine eight sulfonamides (sulfadiazine, sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, sulfapyridine, sulfathiazole, and sulfisoxazole) in environmental soil samples collected from urbanized regions in Silesian Voivodeship with increased animal activity. These soils were grouped according to the organic carbon content. It was necessary to develop versatile and efficient extraction and determination method to analyze selected sulfonamides in various soil types. The developed LC-MS/MS method for sulfonamides analyzing was validated. The obtained recoveries exceeded 45% for soil with medium organic carbon content and 88% for sample with a very low organic carbon content (arenaceous quartz). The obtained results show the high impact of organic matter on analytes adsorption in soil, which influences recovery. All eight sulfa drugs were determined in environmental samples in the concentration range 1.5-10.5 ng g-1. The transformation products of the analytes were also identified, and 29 transformation products were detected in 24 out of 27 extracts from soil samples.


The Frequency of Malnutrition in Patients with Type 2 Diabetes.
Obesity is one of the most common comorbidities of diabetes mellitus (DM) whose frequency is rapidly increasing nowadays. Although obesity caused by excessive and unbalanced nutrition often accompanies diabetes; malnutrition is another complication of diabetes. This study was conducted to investigate the frequency of malnutrition in individuals with diabetes. This study is a cross-sectional study. The patients with type 2 diabetes followed up in the diabetes outpatient clinic of a university hospital between February and March 2018 were included in the study. Anthropometric measurements of the patients and "Nutritional Risk Screening-2002" (NRS-2002) scores were recorded. A total of 222 (F:132 59.4%) patients were included in the study. When two groups with higher NRS (≥3) and lower NRS (<3) scores less than 3 were compared, any significant difference was not detected between two groups in terms of age, waist circumference and HbA1c values. Only BMI was found to be lower in the group with malnutrition risk (p:0.030). When the patients were evaluated in terms of diabetes treatments and risk of malnutrition, any significant intergroup difference was not found (p:0.847). It was found that there is a risk of malnutrition in one of every seven diabetics with a high body mass index who were being followed up in the diabetes outpatient clinic.


Cardiac calcified amorphous tumour associated with multiple myeloma.
We report an 86-year-old woman who was diagnosed with multiple myeloma (MM) and was receiving chemotherapy since the age of 82. A high echoic mass attached to the mitral valve was observed on transthoracic echocardiography 4 years after the treatment. The possibility of malignancy could not be ruled out, and hence, the mass was excised surgically. Pathologically, most of the mass consisted of calcified lesion without tumour tissue, and these findings were not inconsistent with calcified amorphous tumour (CAT). This case suggests that CAT may be associated with MM and has been reported after a thorough literature review.


Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1 beta in 3T3-L1 adipocytes.
The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1 beta on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1 beta. Thus, IL-1 beta induced TIMP-1 secretion in a dose-dependent manner with maximal 3.5-fold upregulation seen at 0.67 ng/ml IL-1 beta relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1 beta in a dose-dependent fashion with 2.5-fold induction seen at IL-1 beta concentrations as low as 0.02 ng/ml and maximal 8.1-fold upregulation found at 20 ng/ml effector. Induction of TIMP-1 mRNA was also time dependent with maximal 9.6-fold upregulation detectable after 8 h of IL-1 beta treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1 beta-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1 beta, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.


Electro-Magnetic Nano-Particle Bound Beclin1 siRNA Crosses the Blood-Brain Barrier to Attenuate the Inflammatory Effects of HIV-1 Infection in Vitro.
The purpose of this study was to evaluate a novel drug delivery system comprised of ferric-cobalt electro-magnetic nano-material (CoFe2O4@ BaTiO3; MENP) bound to siRNA targeting Beclin1 (MENP-siBeclin1) to cross the blood-brain barrier (BBB) and attenuate the neurotoxic effects of HIV-1 infection in the central nervous system following on-demand release of siRNA using an in vitro primary human BBB model. Beclin1 is a key protein in the regulation of the autophagy pathway and we have recently demonstrated the importance of Beclin1 in regulating viral replication and viral-induced inflammation in HIV-1-infected microglia. The MENP-siBeclin1 nano-formulation did not compromise the physiological function or integrity of the BBB model. Furthermore, the in vitro BBB data revealed that MENP-siBeclin1 could efficiently attenuate viral replication and viral-induced inflammation, likely due to STAT1/ NF-κB signaling pathways. MENP-siBeclin1 also silenced Beclin1 protein expression in HIV-1-infected microglial cells within the model system. In addition, the cytotoxic effects of direct treatment with siBeclin1 and MENP alone or in nano-formulation on primary human neuronal cells showed a minimal amount of cell death. Overall, the data shows that the nano-formulation can silence the BECN1 gene as an effective mechanism to attenuate HIV-1 replication and viral-induced inflammation in the context of the BBB.


Safer, silencing-resistant lentiviral vectors: optimization of the ubiquitous chromatin-opening element through elimination of aberrant splicing.
Gammaretroviral and lentiviral vectors have been used successfully in several clinical gene therapy trials, although powerful enhancer elements have caused insertional mutagenesis and clonal dysregulation. Self-inactivating vectors with internal heterologous regulatory elements have been developed as potentially safer and more effective alternatives. Lentiviral vectors containing a ubiquitous chromatin opening element from the human HNRPA2B1-CBX3 locus (A2UCOE), which allows position-independent, long-term transgene expression, are particularly promising. In a recently described assay, aberrantly spliced mRNA transcripts initiated in the vector A2UCOE sequence were found to lead to upregulation of growth hormone receptor gene (Ghr) expression in transduced murine Bcl-15 cells. Aberrant hybrid mRNA species formed between A2UCOE and a number of other cellular genes were also detected in transduced human PLB-985 myelomonocytic cells. Modification of the A2UCOE by mutation or deletion of recognized and potential cryptic splice donor sites was able to abrogate these splicing events and hybrid mRNA formation in Bcl-15 cells. This modification did not compromise A2UCOE regulatory activity in terms of resistance to CpG methylation and gene silencing in murine P19 embryonic carcinoma cells. These refined A2UCOE regulatory elements are likely to improve intrinsic biosafety and may be particularly useful for a number of clinical applications where robust gene expression is desirable.


Estimation of fetal and effective dose for CT examinations.
Doses from CT examinations are difficult to estimate. However, they are requested more frequently due to the increase in CT examinations. In particular, fetal dose estimations are frequently required for patients who have discovered, subsequent to the examination, that they were pregnant when the examination was conducted. A computer model has been developed to facilitate such dose calculations. This model combines empirical beam data with anatomical information. The model has been verified using thermoluminescent dosemeter (TLD) readings of internal and surface dose from both phantoms and patients, including intrauterine doses for patients undergoing afterloading gynaecological intracavitary treatment. Although only limited experimental data were available, the results indicate that the model accurately predicts uterine doses within acceptable errors. This approach has been validated for fetal dose estimation. The model was also used in a comparison with the nationally available CT dose data from the National Radiological Protection Board (NRPB). The two models were found to be in agreement for fetal dose estimations.


Effects of recreational soccer on physical fitness and health indices in sedentary healthy and unhealthy subjects.
Recreational soccer (RS) is becoming a popular alternative to the classical continuous exercise mode used for the improvement of cardiovascular and metabolic fitness in untrained people. The objective of this paper was to conduct a detailed systematic review of the literature, identifying the physiological responses to RS and the training effects of RS on aerobic fitness and health in untrained healthy individuals and clinical patients. PubMed, Google Scholar and ScienceDirect databases were searched using terms related to recreational soccer. Inclusion criteria were randomized controlled trials (RCT) that assessed acute physiological responses to RS or the training effects of RS on physical fitness and health in sedentary, untrained subjects of any age or health status. All studies were assessed for methodological quality using the PEDro scale. Thirty-five articles met the inclusion criteria; seven examined the acute response to RS, and 28 assessed training effects. Clear evidence was found that RS had positive effects on many health-related indices and variables, including VO2max (gains of 7-16%), blood pressure (reductions of 6-13 mmHg), body composition (decreased fat mass and improved indices of bone health), and metabolic and cardiac function. These positive effects were observed in both healthy individuals and clinical patients, irrespective of age or sex. Although this review provides clear evidence of the positive effects of RS on health, most studies had limitations of methodology (an average PEDro score < 6). Furthermore, many of the training studies were from a small number of research groups. Future studies should be extended to other countries and institutions to ensure generality of the results. Regular RS training leads to significant cardiovascular and muscular adaptations and gains of health both in sedentary individuals and clinical patients at all ages, suggesting that RS is a potentially highly motivational method to enhance population health.


Image-guided intensity-modulated radiotherapy for refractory bilateral breast cancer in a patient with extensive cutaneous metastasis in the chest and abdominal walls.
Treatment for bilateral breast cancer with chest wall and abdominal skin invasion normally involves conventional radiotherapy (RT); however, conventional RT provides inadequate target volume coverage and excessive treatment of large volumes of normal tissue. Helical tomotherapy (HT) has the ability to deliver continuous craniocaudal irradiation that suppresses junction problems and provides good conformity of dose distribution. A 47-year-old female with stage IV bilateral breast cancer with chest wall and pectoralis major muscle invasion, lymphadenopathy, bilateral pleural effusion, and multiple bone metastases received chemotherapy and target therapy beginning in January 2014; 4 months after the initiation of chemotherapy, computed tomography revealed progression of chest and abdominal wall invasion. A total dose of 70.2 Gy was delivered to both breasts, the chest wall, the abdominal wall, and the bilateral supraclavicular nodal areas in 39 fractions via HT. The total planning target volume was 4,533.29 cm(3). The percent of lung volume receiving at least 20 Gy (V20) was 28%, 22%, and 25% for the right lung, left lung, and whole lung, respectively. The mean dose to the heart was 8.6 Gy. Follow-up computed tomography revealed complete response after the RT course. Grade 1 dysphagia, weight loss, grade 2 neutropenia, and grade 3 dermatitis were noted during the RT course. Pain score decreased from 6 to 1. No cardiac, pulmonary, liver, or intestinal toxicity developed during treatment or follow-up. Concurrent HT with or without systemic treatment could be a safe salvage therapy for chemorefractory locally advanced breast cancer patients with extensive cutaneous metastasis.


Feasibility of Targeted Next-Generation DNA Sequencing for Expanding Population Newborn Screening.
Newborn screening (NBS) is an effective public health intervention that reduces death and disability from treatable genetic diseases, but many conditions are not screened due to a lack of a suitable assay. Whole genome and whole exome sequencing can potentially expand NBS but there remain many technical challenges preventing their use in population NBS. We investigated if targeted gene sequencing (TGS) is a feasible methodology for expanding NBS. We constructed a TGS panel of 164 genes which screens for a broad range of inherited conditions. We designed a high-volume, low-turnaround laboratory and bioinformatics workflow that avoids the technical and data interpretation challenges associated with whole genome and whole exome sequencing. A methods-based analytical validation of the assay was completed and test performance in 2552 newborns examined. We calculated annual birth estimates for each condition to assess cost-effectiveness. Assay analytical sensitivity was >99% and specificity was 100%. Of the newborns screened, 1.3% tested positive for a condition. On average, each individual had 225 variants to interpret and 1.8% were variants of uncertain significance (VUS). The turnaround time was 7 to 10 days. Maximum batch size was 1536 samples. We demonstrate that a TGS assay could be incorporated into an NBS program soon to increase the number of conditions screened. Additionally, we conclude that NBS using TGS may be cost-effective.


Stress induced right ventricular dysfunction: an indication of reversible right ventricular ischaemia.
Stress induced changes in left ventricular ejection fraction are widely used in the detection and assessment of coronary artery disease. This study demonstrates that right ventricular dysfunction may also occur, and assesses its significance in terms of coronary artery anatomy. This study involved 14 normal subjects and 26 with coronary artery disease investigated by equilibrium radionuclide ventriculography, at rest and during maximal dynamic exercise. Mean normal resting right ventricular ejection fraction (RVEF) was 0.40 (SD 0.118), and all normal subjects increased RVEF with stress (mean delta RVEF + 0.13 SD 0.099). Mean delta RVEF in the subjects with coronary artery disease was significantly lower at 0.00 (SD 0.080), but there was overlap between the two groups. The largest falls in RVEF were seen if the right coronary artery was occluded without retrograde filling. In this subgroup with the most severely compromised right ventricular perfusion (nine subjects), RVEF always fell with stress, and mean delta RVEF was -0.08 (SD 0.050). There was no significant correlation between delta LVEF and delta RVEF, implying that the right ventricular dysfunction was due to right ventricular ischaemia, rather than secondary to left ventricular dysfunction. Stress induced right ventricular ischaemia can therefore be detected readily by radionuclide ventriculography.


Emotion regulation difficulties in traumatized youth: a meta-analysis and conceptual review.
This article provides a quantitative and conceptual review of emotion regulation difficulties in trauma-exposed young people, and informs future directions in the field. Despite long-standing interest in the influence of emotion regulation difficulties on different internalizing and externalizing psychiatric disorders in childhood, several questions remain unresolved with respect to children and adolescents with PTSD (post-traumatic stress disorder). Meta-analytic data from adult victims suggest that emotion regulation problems are associated with PTSD, but this has never been studied in children and young people. We therefore provide a conceptual review of features related to the phenomenology, assessment, severity and treatment of emotion regulation difficulties in trauma-exposed children and young people. We combine this with a meta-analysis of published literature. We searched studies in Medline, PsychINFO, and Embase databases based on pre-selected criteria. Eight hundred and eighty-six papers were identified and 41 were included. We found that children and adolescents with a diagnosis of PTSD reported more emotion regulation difficulties than those who did not develop PTSD, and that the overall association between the two symptom dimensions was moderately strong. We identify a number of research priorities: the development of instruments to assess emotion regulation difficulties in children, the design of studies that describe its prevalence in young epidemiological traumatized samples, its predictive role in the onset, severity and persistence of post-traumatic symptoms, and its relevance as a moderator, outcome or treatment target for young survivors.


Zinc-dependent Deacetylase (HDAC) Inhibitors with Different Zinc Binding Groups.
The state of histone acetylation plays a very crucial role in carcinogenesis and its development by chromatin remodeling and thus altering transcription of oncogenes and tumor suppressor genes. Such epigenetic regulation was controlled by zinc-dependent histone deacetylases (HDACs), one of the major regulators. Due to the therapeutic potential of HDACs as one of the promising drug targets in cancer, HDAC inhibitors have been intensively investigated over the last few decades. Notably, there are five HDAC inhibitors already approved to the market. Vorinostat (SAHA), Belinostat (PXD-101) and Romidepsin (FK228) have been approved by Food and Drug Administration (FDA) in USA for treating cutaneous T-cell lymphoma (CTCL) or peripheral T cell lymphoma (PTCL) while Panbinostat (LBH-589) has also been approved by the FDA for the treatment of multiple myeloma. Recently, Chidamide was approved by China Food and Drug Administration (CFDA) for the treatment of PTCL. The structural feature of almost all HDAC inhibitors consists of Cap group, linker, and zinc-binding group (ZBG). The binding of ZBG groups to zinc ion plays a decisive role in the inhibition of HDAC. Therefore, we will summarize the developed HDAC inhibitors according to different ZBG groups and discuss their binding mode with zinc ion.