Prediction of changes in the clinical pharmacokinetics of basic drugs on the basis of octanol-water partition coefficients.
A physiologically based pharmacokinetic model for basic drugs has been established on the basis of octanol-water partition coefficients of the non-ionized, unbound drugs (Poct). The parameters for the physiological model in man were estimated from a regression equation obtained for the relationships between the Poct and the tissue-plasma partition coefficient, the hepatic intrinsic clearance (CLint,h) and the blood-to-plasma concentration ratio in rabbits. The plasma concentrations observed after intravenous administration of ten basic drugs (3.2 mg kg-1) to rabbits agreed with the levels predicted using the physiological model (r = 0.710-0.980). In man, the predicted plasma concentrations of basic drugs were in good agreement with reported values (r = 0.729-0.973), except for diazepam and pentazocine. Variations in plasma and brain-concentration profiles of clomipramine and nitrazepam in various disease states were simulated using the model. We assumed that the changes in unbound fraction of drug in serum (fp), CLint,h and the hepatic blood flow rate were from 0.25- to 4-fold that of the control and that fat volume changed by 0.2- to 5-fold. With regard to changes in fp, we predicted that the brain-plasma concentration ratio of clomipramine was 1.5- to 25-fold that of the control 24 h after intravenous administration, although the variations in the plasma concentration-time profiles were less marked. Plasma concentrations predicted for several basic drugs were in good agreement with reported values and this physiological model could be useful for predicting drug-disposition kinetics in man.


Addition of amines to the triple bond in alpha,alpha,alpha-trichloromethylpropargyl mesylate: synthesis of alpha,alpha-dichloromethylenaminones and preparation of 2-phenyl-4-dichloromethylquinolines.
[reaction: see text] Addition of amines to the triple bond in alpha,alpha,alpha-trichloromethylpropargyl mesylate to give alpha,alpha-dichloromethylenaminones and its use in the preparation of 2-phenyl-4-dichloromethylquinolines in good yields are reported.


Integrating local indigenous knowledge to enhance risk reduction and adaptation strategies to drought and climate variability: The plight of smallholder farmers in Chirumhanzu district, Zimbabwe.
This article focuses on drought risk reduction and climate change adaptation strategies adopted by rural households to sustain their livelihood activities. The overall objective was to understand the local household's responses to the changing climate especially drought. The study was carried out in Chirumhanzu district in Zimbabwe and used a mixed methods approach combining 217 household surveys, targeted focus group discussions, participatory learning actions methods, key informant interviews and a document review. Household data were analysed using Statistical Package for Social Sciences and thematic content analysis was used for the qualitative data. We found that the majority of households showed awareness of several risk reduction and adaptation strategies to implement during and/or when drought was predicted, with 56% of the respondents stating stocking of grain as initial strategy. Other strategies adopted at household level included early planting (at first rains), conservation farming, planting small grains and dry planting. Indigenous and traditional knowledge systems and practices, including local people's holistic view of the community and environment, were a major resource for adapting to climate change and drought risks. However, these indigenous knowledge systems and practices had not been consistently used in the existing adaptation and risk-reduction efforts. Indigenous knowledge was not sufficiently acknowledged and integrated into formal risk reduction and adaptation strategies, which resulted in limited success for external interventions. There is need for integration of local and indigenous knowledge systems and external interventions to build household livelihoods that are resilient to climate risks.


Expression of the protooncogenes c-myc, c-fos, and c-fms in acute myelocytic leukemia at diagnosis and in remission.
RNA transcript levels of the protooncogenes c-myc, c-fos, and c-fms were measured in bone marrow cells obtained from patients with acute myelocytic leukemia at diagnosis or in complete remission. As controls, normal bone marrow cells were studied. The c-myc RNA levels are significantly higher in acute myelocytic leukemia cells at diagnosis than in remission or in normal marrow cells. In most instances the high c-myc RNA levels are a reflection of the high proportion of immature cells present in leukemic marrows. The bone marrow cells of several patients contain extremely high levels of c-myc RNA, levels which cannot be accounted for by the proportion of immature cells present in the bone marrow. The leukemic cells of patients with morphologically indistinguishable leukemias manifest different patterns of c-myc, c-fos, and c-fms expression. This observation is consistent with differences in behavior of leukemic cells even among patients with the same French-American-British type of leukemia. The normal-appearing bone marrow cells of some acute myelocytic leukemia patients in complete remission differ from normal bone marrow cells in having slightly higher c-myc RNA levels, as well as in the pattern of expression of c-fos and c-fms. The possible use of protooncogene expression patterns to subdivide the French-American-British categories of acute myelocytic leukemia into subtypes with greater prognostic significance is discussed.


Glutathione peroxidase in early and advanced Parkinson's disease.
A defective antioxidant scavenging system plays a major role in one of the theories of the pathogenesis of Parkinson's disease. The aim of this study was to investigate whether there is a general difference in antioxidant activity between early and advanced cases of Parkinson's disease. Twenty five recently diagnosed patients, without any clinical fluctuations (group A), and 25 patients in a late phase of the disease with severe fluctuations in response to levodopa therapy (group B) were included in the study. Erythrocyte glutathione peroxidase was determined as a measure of antioxidant activity and significantly lower values were found in group B than in group A. Regression analyses in groups A and B showed significant correlation between glutathione peroxidase and duration of disease, but not between glutathione peroxidase and age of patients.


Review on plants with CNS-effects used in traditional South African medicine against mental diseases.
The majority of the population in South Africa use traditional health care to treat various mental conditions. In this review, we present ethnobotanical information on plants used by the traditional healers in South Africa to treat mental illnesses, specifically epilepsy, depression, age-related dementia and debilitative mental disorders. Details of the recent scientific studies conducted on some of these plants are reviewed. Extracts of Searsia chirindensis, Cotelydon orbiculata and Leonotis leonurus have shown in vivo anticonvulsant activity. Extracts from Searsia dentata and Searsia pyroides showed spontaneous epileptiform discharge in mouse cortical slices, and acted as NMDA-receptor antagonists. Apigenin, amentoflavone and agathisflavone with affinity to the benzodiazepine site on the GABA(A)-receptor were isolated from Searsia pyroides. Naringenin with affinity to the GABA(A)-benzodiazepine receptor was isolated from Mentha aquatica. Agapanthus campanulatus, Boophone disticha, Mondia whitei and Xysmalobium undulatum exhibited antidepressant-like activity in three in vivo models for depression. Amaryllidaceae alkaloids with activity to the serotonin transporter were isolated from Boophone disticha. The alkaloid mesembrine, which act as a serotonin reuptake inhibitor, was isolated from Sceletium tortuosum. Investigations of plants used to treat age-related dementia and debilitative mental disorders lead to the isolation of a number of Amaryllidaceae alkaloids with acetylcholinesterase inhibitory activity from Boophone disticha and Crinum species. Extracts of Mentha aquatica, Gasteria croucheri, Ruta graveolens and Scotia brachypetala inhibited MAO-B. Naringenin was isolated from Mentha aquatica as a MAO inhibitor. Only a small number of the more than 300 southern African plant species reported to treat or affect the CNS have been scientifically evaluated. Very few of the active compounds have been isolated and identified.


Phenotypic difference between Bcg(r) and Bcg(s) macrophages is related to differences in protein-kinase-C-dependent signalling.
Mice of diverse genetic backgrounds may be classified as being either resistant or susceptible to infection with Mycobacteria. These phenotypes appear to be determined by a single gene on chromosome 1, the Bcg gene, and are expressed at the level of the macrophage in vitro. When compared to macrophages from mice of the susceptible phenotype (Bcg[s]), macrophages from mice of the resistant phenotype (Bcg[r]) show enhanced functional properties including increased expression of MHC class II molecules, increased nitric oxide production, and greater capacity to inhibit the growth of several intracellular pathogens. The bacteriostatic activity of B10R and B10S macrophages correlated with the amount of nitric oxide produced by the macrophages. Since protein kinase C (PKC) has been shown to be involved in the induction of a range of macrophage functional activities, experiments were conducted to examine the possibility that phenotypic differences between Bcg(r) and Bcg(s) macrophages may be related to differences in PKC-dependent signalling. Macrophage cell lines were derived from mice congenic at the Bcg locus that are either resistant (B10R) or susceptible (B10S) to infection with Mycobacteria. In the basal state, PKC-specific activity was significantly increased in the cytosolic fractions of B10R cells when compared to B10S cells. Following phorbol myristate acetate (PMA) treatment and following the stimulation with Mycobacteria bovis BCG, PKC-specific activity increased significantly in membrane fractions of both B10R and B10S cells, but the absolute level was significantly greater in particulate fractions from B10R macrophages. Furthermore, B10R cells had a superior ability to phosphorylate endogenous substrates compared to B10S macrophages. Scatchard analysis of phorbol ester receptors revealed no differences between B10R and B10S cells. In contrast, the sensitivity of partially purified PKC from B10S cells to activation in vitro by diacylglycerol was decreased by approximately 50% when compared to enzyme from B10R cells. Western-blotting analysis using antibodies specific for PKC isoforms (alpha, beta, delta, epsilon, zeta and eta) showed similar levels of PKC isoforms present in B10R and B10S cells. To examine whether differences in PKC activity of B10R and B10S cells had functional consequences, the induction of c-fos gene expression was compared in the two cell lines. In response either to infection with M. bovis BCG or to stimulation with PMA, c-fos mRNA levels in B10R macrophages were increased 2-4-fold in comparison to B10S macrophages. Since we have previously found that the bacteriostatic activity of B10R and B10S macrophages correlated with the amount of nitric oxide produced by the macrophages, we have tested if the enhancement of PKC activity in these macrophages affects their ability to produce nitric oxide. We have found that interferon-gamma-(IFNgamma)-induced secretion of nitric oxide by B10R macrophages could be augmented a few fold by the activation of PKC whereas, in B10S macrophages stimulated with IFNgamma, nitric oxide release could be augmented by only about 10-20%. These results indicate that the differences in PKC activity between B10R and B10S macrophages may contribute to altered responsiveness to IFNgamma that results in different production of effector molecules crucial for bacteriostatic activity against M. bovis BCG.


Hybrid incompatibility between Drosophila virilis and D. lummei is stronger in the presence of transposable elements.
Mismatches between parental genomes in selfish elements are frequently hypothesized to underlie hybrid dysfunction and drive speciation. However, because the genetic basis of most hybrid incompatibilities is unknown, testing the contribution of selfish elements to reproductive isolation is difficult. Here, we evaluated the role of transposable elements (TEs) in hybrid incompatibilities between Drosophila virilis and D. lummei by experimentally comparing hybrid incompatibility in a cross where active TEs are present in D. virilis (TE+) and absent in D. lummei, to a cross where these TEs are absent from both D. virilis (TE-) and D. lummei genotypes. Using genomic data, we confirmed copy number differences in TEs between the D. virilis (TE+) strain and both the D. virilis (TE-) strain and D. lummei. We observed F1 postzygotic reproductive isolation exclusively in the interspecific cross involving TE+ D. virilis but not in crosses involving TE- D. virilis. This mirrors intraspecies dysgenesis where atrophied testes only occur when TE+ D. virilis is the paternal parent. A series of backcross experiments, that accounted for alternative models of hybrid incompatibility, showed that both F1 hybrid incompatibility and intrastrain dysgenesis are consistent with the action of TEs rather than genic interactions. Thus, our data suggest that this TE mechanism manifests as two different incompatibility phenotypes. A further Y-autosome interaction contributes to additional, sex-specific, inviability in one direction of this cross-combination. These experiments demonstrate that TEs that cause intraspecies dysgenesis can increase reproductive isolation between closely related lineages, thereby adding to the processes that consolidate speciation.


Large energy storage efficiency of the dielectric layer of graphene nanocapacitors.
Electric capacitors are commonly used in electronic circuits for the short-term storage of small amounts of energy. It is desirable however to use capacitors to store much larger energy amounts to replace rechargeable batteries. Unfortunately existing capacitors cannot store sufficient energy to be able to replace common electrochemical energy storage systems. Here we examine the energy storage capabilities of graphene nanocapacitors, which are tri-layer devices involving an Al film, Al2O3 dielectric layer, and a single layer of carbon atoms, i.e., graphene. This is a purely electronic capacitor and therefore it can function in a wide temperature interval. The capacitor shows a high dielectric breakdown electric field strength, of the order of 1000 kV mm-1 (i.e., 1 GV m-1), which is much larger than the table value of the Al2O3 dielectric strength. The corresponding energy density is 10-100 times larger than the energy density of a common electrolytic capacitor. Moreover, we discover that the amount of charge stored in the dielectric layer can be equal or can even exceed the amount of charge stored on the capacitor plates. The dielectric discharge current follows a power-law time dependence. We suggest a model to explain this behavior.


Long period fiber grating nano-optrode for cancer biomarker detection.
We report an innovative fiber optic nano-optrode based on Long Period Gratings (LPGs) working in reflection mode for the detection of human Thyroglobulin (TG), a protein marker of differentiated thyroid cancer. The reflection-type LPG (RT-LPG) biosensor, coated with a single layer of atactic polystyrene (aPS) onto which a specific, high affinity anti-Tg antibody was adsorbed, allowed the label-free detection of Tg in the needle washouts of fine-needle aspiration biopsies, at concentrations useful for pre- and post-operative assessment of the biomarker levels. Analyte recognition and capture were confirmed with a parallel on fiber ELISA-like assay using, in pilot tests, the biotinylated protein and HRP-labeled streptavidin for its detection. Dose-dependent experiments showed that the detection is linearly dependent on concentration within the range between 0 and 4 ng/mL, while antibody saturation occurs for higher protein levels. The system is characterized by a very high sensitivity and specificity allowing the ex-vivo detection of sub ng/ml concentrations of human Tg from needle washouts of fine-needle aspiration biopsies of thyroid nodule from different patients.


The role of the somatotropic system in cognition and other cerebral functions.
Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) receptors can be found in several areas of the brain. GH receptors are mainly found in the choroid plexus, thalamus, hypothalamus, pituitary, putamen, and hippocampus, whereas IGF-1 receptors are mainly concentrated in the hippocampus and parahippocampal areas. In early life, GH and IGF-1 have an important role in the development and differentiation of the central nervous system. In the more developed central nervous system, GH and IGF-1 are thought to have a variety of functions such as a neuroprotective function, an appetite increasing function, various cognitive functions, and perhaps a blood flow-regulating function. In GH-deficient children and adults, improvement of cognitive functions was observed after the administration of GH. Furthermore, specific cognitive functions in healthy older subjects may improve after increasing GH or IGF-1 levels.


The effects of 11 weeks whole body vibration training on jump height, contractile properties and activation of human knee extensors.
The purpose of the present study was to investigate whether 11 weeks of whole body vibration (WBV) training applied in a way that is commonly seen in practice, i.e. without additional loads, would improve muscle activation and/or contractile properties of the knee extensor muscles and counter movement jump height in healthy subjects. Ten subjects belonging to the experimental group trained three times a week and stood bare-foot with a 110 degrees knee angle on a vibration platform (30 Hz, 8 mm amplitude). They underwent five to eight sets of 1-min vibration with 1 min rest in between. Ten control subjects followed the same training programme but stood (110 degrees knee angle) beside the platform. Before, during and following the training period the subjects were tested. Values [mean (SEM)] obtained in the last test were expressed as percentages of the baseline value and presented for control and experimental groups. Quadriceps femoris isometric muscle force [105.4 (6.2)%, 99.9 (2.0)%; P=0.69], voluntary activation [107.1 (6.0)%, 101.1 (2.3)%; P=0.55] and maximal rate of voluntary force rise [95.4 (6.0)%, 103.3 (7.7)%; P=0.57] did not improve. The maximal rate of force rise during electrical stimulation was increased [102.3 (4.5)%, 123.6 (7.5)%; P=0.02]. Counter movement jump height was not affected by WBV [103.7 (1.8)%, 103.0 (2.8)%; P=0.71]. In conclusion, 11 weeks of standard two-legged WBV training without additional training loads did not improve functional knee extensor muscle strength in healthy young subjects.


Role of prostaglandin-mediated mechanisms during experimentally induced endotoxin fever in the lactating goat.
The effects of endotoxin (LPS) on the cortisol, glucose, NEFA (non-esterified fatty acids), STH (somatotropin) and oxytocin levels in plasma of goats are described. The changes in plasma cortisol, STH and NEFA, as well as in RT (rectal temperature) were compared after i.v. and i.mam. administration of endotoxin. The other parameters, glucose and oxytocin, were followed only after i.v. endotoxin administration. The observed metabolic and hormonal alterations in plasma were also studied after pretreating the goats with the non-steroidal anti-inflammatory and antipyretic drug flurbiprofen in order to evaluate the possible involvement of prostaglandin in these phenomena. After i.v. administration of LPS a biphasic temperature curve for the highest dose of LPS with peak maxima at 1h and 4h after LPS challenge, was observed. Intramammary administration of endotoxin induces a monophasic fever response, with a latency time of approximately 3h, and peak values after 6h. The onset of the fever response in the i.v. experiments coincided with the oxytocin maximum and with early hyperglycemia. Intravenous endotoxin in goats also induces an increase in plasma NEFA, cortisol and STH. The early increase in NEFA, with a maximum after 2h and occurring before the fever peak, is followed by a significant rise in cortisol with peak effects after 3 h. The increase in plasma STH coincided with the decrease in plasma NEFA returning to control levels again. Peak concentrations in plasma STH occurred after 4 h. All the changes observed after the i.v. administration of endotoxin are dose-dependent. Pretreating goats with flurbiprofen completely abolished fever response, as well as the early hyperglycemia and the oxytocin release to i.v. LPS, indicating that these changes were prostaglandin-mediated and might be a reflexion of an activation of the sympathetic adrenomedullary system. The LPS-induced changes in plasma cortisol, NEFA and STH are only partly depressed and delayed by flurbiprofen. The residual hormonal responses to high doses of endotoxin suggest that an additional direct action of circulating endotoxins on the hypothalamus cannot be excluded. Intramammary LPS administration in goats only induced a very weak increase in plasma cortisol. The complex interplay of hormones and metabolic substances in the homeostasis of the inflammation reaction is discussed.


Structural analysis of the inactive state of the Escherichia coli DNA polymerase clamp-loader complex.
Clamp-loader complexes are heteropentameric AAA+ ATPases that load sliding clamps onto DNA. The structure of the nucleotide-free Escherichia coli clamp loader had been determined previously and led to the proposal that the clamp-loader cycles between an inactive state, in which the ATPase domains form a closed ring, and an active state that opens up to form a "C" shape. The crystal structure was interpreted as being closer to the active state than the inactive state. The crystal structure of a nucleotide-bound eukaryotic clamp loader [replication factor C (RFC)] revealed a different and more tightly packed spiral organization of the ATPase domains, raising questions about the significance of the conformation seen earlier for the bacterial clamp loader. We describe crystal structures of the E. coli clamp-loader complex bound to the ATP analog ATPgammaS (at a resolution of 3.5 A) and ADP (at a resolution of 4.1 A). These structures are similar to that of the nucleotide-free clamp-loader complex. Only two of the three functional ATP-binding sites are occupied by ATPgammaS or ADP in these structures, and the bound nucleotides make no interfacial contacts in the complex. These results, along with data from isothermal titration calorimetry, molecular dynamics simulations, and comparison with the RFC structure, suggest that the more open form of the E. coli clamp loader described earlier and in the present work corresponds to a stable inactive state of the clamp loader in which the ATPase domains are prevented from engaging the clamp in the highly cooperative manner seen in the fully ATP-loaded RFC-clamp structure.


Validation of a heat-inducible Ixodes scapularis HSP70 promoter and developing a tick-specific 3xP3 promoter sequence in ISE6 cells.
Ixodes scapularis is an important vector of many pathogens, including the causative agent of Lyme disease, tick-borne encephalitis, and anaplasmosis. The study of gene function in I. scapularis and other ticks has been hampered by the lack of genetic tools, such as an inducible promoter to permit temporal control over transgenes encoding protein or double-stranded RNA expression. Studies of vector-pathogen relationships would also benefit from the capability to activate anti-pathogen genes at different times during pathogen infection and dissemination. We have characterized an intergenic sequence upstream of the heat shock protein 70 (HSP70) gene that can drive Renilla luciferase expression and mCherry fluorescence in the I. scapularis cell line ISE6. In another construct, we replaced the Drosophila melanogaster minimal HSP70 promoter in the synthetic 3xP3 promoter with a minimal portion of the I. scapularis HSP70 promoter and generated an I. scapularis specific 3xP3 (Is3xP3) promoter. Both promoter constructs, IsHSP70 and Is3xP3, allow for heat-inducible expression of mCherry fluorescence in ISE6 cells with an approximately 10-fold increase in the percentage of fluorescent positive cells upon exposure to a 2 h heat shock. These promoters described here will be valuable tools for gene function studies and temporal control of gene expression, including anti-pathogen genes.


Changes within the "normal" cerebral white matter of multiple sclerosis patients during acute attacks and during high-dose cortisone therapy assessed by means of quantitative MRI.
Changes in the apparently unaffected cerebral white matter of multiple sclerosis (MS) patients were studied during acute attacks as well as during high-dose prednisolone therapy. Serial MR scans of patients with a clinically definite diagnosis were performed on four defined occasions: before an episode, within three days after its onset, after 10 days of therapy as well as four weeks later. Thirteen patients agreed to cooperate in forming a MRI data base and to be rescanned immediately after the onset of an acute relapse. Within one year, six patients had such episodes, one of them had a second bout. Both T1 and T2 relaxation times within the apparently normal white matter were significantly prolonged in all cerebral lobes compared to a control group of healthy volunteers. During the acute attacks as well as during therapy the T1 values remained as before. The T2 values were elevated only in two out of six cases during the episode. After therapy a considerable clinical improvement was seen in all cases, but a significant T2 decrease as a possible effect of cortisone was noted in only one case. We conclude that the prolonged relaxation times T1 and T2 within the apparently normal cerebral white matter of MS patients are the result of a number of molecular events differing considerably among individual patients and that serial measurements of these relaxation times do not consistently change during an acute relapse and do not reflect clinical improvement after high dose prednisolone therapy.


Novel algorithm for coexpression detection in time-varying microarray data sets.
When analyzing the results of microarray experiments, biologists generally use unsupervised categorization tools. However, such tools regard each time point as an independent dimension and utilize the Euclidean distance to compute the similarities between expressions. Furthermore, some of these methods require the number of clusters to be determined in advance, which is clearly impossible in the case of a new dataset. Therefore, this study proposes a novel scheme, designated as the Variation-based Coexpression Detection (VCD) algorithm, to analyze the trends of expressions based on their variation over time. The proposed algorithm has two advantages. First, it is unnecessary to determine the number of clusters in advance since the algorithm automatically detects those genes whose profiles are grouped together and creates patterns for these groups. Second, the algorithm features a new measurement criterion for calculating the degree of change of the expressions between adjacent time points and evaluating their trend similarities. Three real-world microarray datasets are employed to evaluate the performance of the proposed algorithm.


Zipper and layer-by-layer assemblies of artificial photosystems analyzed by combining optical and piezoelectric surface techniques.
Quartz crystal microbalance (QCM) and surface plasmon resonance (SPR) were used to study zipper and layer-by-layer multilayer assemblies of artificial photosystems based on naphthalenediimides (NDIs) attached to an oligophenylethynyl (OPE-NDI) or p-oligophenyl (POP-NDI) backbone in dry and wet state. For the most interesting OPE-NDI zipper, one obtains for the dry film a monolayer thickness of 1.85 nm and a density of 1.58 g/cm(3), while the wet film has a larger monolayer thickness of 3.6 nm with a water content of 36%. The dry thickness of a monolayer in OPE-NDI zippers corresponds to about one-half of the length of the OPE scaffold in agreement with the proposed structure of the zipper. The low water content of the OPE-NDI films confirms their compact structure. The dry monolayer thickness of the POP-NDI films of 1.45 nm is smaller than that for the OPE-NDI films, which is probably related to a tilt of the POP scaffolds within the adsorbed layer. The POP-NDI films swell in water much more substantially, suggesting a much more open structure. These features are in excellent agreement with the better photophysical performance of the OPE-NDI assemblies when compared to the POP-NDI films.


Dual modes of antitumor action of an amphiphilic peptide A(9)K.
Following our recent report of attractive antibacterial properties of a designed amphiphilic peptide, A(9)K, we have investigated its antitumor activities by examining the modes of its action against different mammalian cell types. The peptide strongly inhibited the growth of cancerous HeLa cells and human promyelocytic leukemia HL60 cells whilst remaining benign to the host cells, including Cos 7 cells, mouse fibroblast NIH3T3 cells and human red blood cells. Images from SEM and fluorescence microscopy showed that A(9)K penetrated HeLa cell membranes and disrupted membrane structures, a feature broadly similar to that observed from its bactericidal actions. Further interactions of A(9)K with inner cellular membranes caused mitochondrial dysfunction associated with the F-actin reorganization and the decreased transcription of bcl-2 and c-myc genes, resulting in HeLa cell apoptosis in a mitochondria-induced apoptosis pathway. Thus A(9)K has high selectivity against cancerous cells and kills them by dual modes of action: membrane disruption and cell apoptosis. In addition, the peptide does not induce non-specific immunological effects and is not degraded by proteases. These features are crucial for developing their applications in future research.


Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy.
IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.


Pathological and parasitological aspects of the first autochthonous case of human paragonimiasis in Venezuela.
A worm found in histopathologic sections of a lung piece of a young Venezuelan male was identified as a Paragonimus sp. Definitive identification of the species was not possible since only a deteriorated segment of the worm was recovered, nevertheless comparison with other known species is discussed. This is the first report of an indigenous case of human paragonimiasis in Venezuela.


Personality and personality disorders in urban and rural Africa: results from a field trial in burkina faso.
When conducting research in different cultural settings, assessing measurement equivalence is of prime importance to determine if constructs and scores can be compared across groups. Structural equivalence implies that constructs have the same meaning across groups, metric equivalence implies that the metric of the scales remains stable across groups, and full scale or scalar equivalence implies that the origin of the scales is the same across groups. Several studies have observed that the structure underlying both normal personality and personality disorders (PDs) is stable across cultures. Most of this cross-cultural research was conducted in Western and Asian cultures. In Africa, the few studies were conducted with well-educated participants using French or English instruments. No research was conducted in Africa with less privileged or preliterate samples. The aim of this research was to study the structure and expression of normal and abnormal personality in an urban and a rural sample in Burkina Faso. The sample included 1,750 participants, with a sub-sample from the urban area of Ouagadougou (n = 1,249) and another sub-sample from a rural village, Soumiaga (n = 501). Most participants answered an interview consisting of a Mooré language adaptation of the Revised NEO Personality Inventory and of the International Personality Disorders Examination. Mooré is the language of the Mossi ethnic group, and the most frequently spoken local language in Burkina Faso. A sub-sample completed the same self-report instruments in French. Demographic variables only had a small impact on normal and abnormal personality traits mean levels. The structure underlying normal personality was unstable across regions and languages, illustrating that translating a complex psychological inventory into a native African language is a very difficult task. The structure underlying abnormal personality and the metric of PDs scales were stable across regions. As scalar equivalence was not reached, mean differences cannot be interpreted. Nevertheless, these differences could be due to an exaggerated expression of abnormal traits valued in the two cultural settings. Our results suggest that studies using a different methodology should be conducted to understand what is considered, in different cultures, as deviating from the expectations of the individual's culture, and as a significant impairment in self and interpersonal functioning, as defined by the DSM-5.


Optimizing Antihypertensive Medication Classification in Electronic Health Record-Based Data: Classification System Development and Methodological Comparison.
Computable phenotypes have the ability to utilize data within the electronic health record (EHR) to identify patients with certain characteristics. Many computable phenotypes rely on multiple types of data within the EHR including prescription drug information. Hypertension (HTN)-related computable phenotypes are particularly dependent on the correct classification of antihypertensive prescription drug information, as well as corresponding diagnoses and blood pressure information. This study aimed to create an antihypertensive drug classification system to be utilized with EHR-based data as part of HTN-related computable phenotypes. We compared 4 different antihypertensive drug classification systems based off of 4 different methodologies and terminologies, including 3 RxNorm Concept Unique Identifier (RxCUI)-based classifications and 1 medication name-based classification. The RxCUI-based classifications utilized data from (1) the Drug Ontology, (2) the new Medication Reference Terminology, and (3) the Anatomical Therapeutic Chemical Classification System and DrugBank, whereas the medication name-based classification relied on antihypertensive drug names. Each classification system was applied to EHR-based prescription drug data from hypertensive patients in the OneFlorida Data Trust. There were 13,627 unique RxCUIs and 8025 unique medication names from the 13,879,046 prescriptions. We observed a broad overlap between the 4 methods, with 84.1% (691/822) to 95.3% (695/729) of terms overlapping pairwise between the different classification methods. Key differences arose from drug products with multiple dosage forms, drug products with an indication of benign prostatic hyperplasia, drug products that contain more than 1 ingredient (combination products), and terms within the classification systems corresponding to retired or obsolete RxCUIs. In total, 2 antihypertensive drug classifications were constructed, one based on RxCUIs and one based on medication name, that can be used in future computable phenotypes that require antihypertensive drug classifications.


Epithelialization of the anterior chamber after transcorneal (McCannel) suture.
A 35-year-old woman developed epithelialization of the anterior chamber with secondary glaucoma, following the use of a transcorneal (McCannel-type) suture to repair a traumatic iridodialysis. Clinical photographs and histologic documentation illustrate the potential for this serious complication from this surgical technique.


Assessing analytical variability of measurement of vitamin A in corn-soy blend.
Two multilaboratory investigations were conducted by SUSTAIN to assess variability in the measurement of vitamin A, the marker used to verify levels of vitamin premix addition to enriched/fortified food aid products, including the widely distributed corn-soy blend (CSB). CSB specifications identify AACC Approved Method 86-06 or equivalent methods for vitamin A analysis, however there is no requirement to demonstrate equivalency. CSB samples with known and blinded levels of vitamin A and a reference standard were analyzed by 16 laboratories using their respective methods. Calculated coefficients of variation across all laboratories and methods for unknown samples and reference standard were 35 and 7.1%, respectively, suggesting the largest source of variation is the vitamin extraction procedure. Laboratories generally overestimated low levels and underestimated high levels of vitamin A within the range of 6000 and 16 000 IU/lb. Only two laboratories demonstrated excellent internal precision (+/- 300 IU vitamin A/lb) and reported values within 95% confidence interval for all blinded samples. Results of this study have implications both for quality control in food aid products (due to the use of vitamin A as a marker) and for regulatory oversight of vitamin A content in commercial food products.


Controlling the activity of the Tec kinase Itk by mutation of the phenylalanine gatekeeper residue.
The regulatory spine is a set of conserved residues that are assembled and disassembled upon activation and inactivation of kinases. We recently identified the regulatory spine within the immunologically important Tec family kinases and have shown that in addition to the core spine residues within the kinase domain itself, contributions from the SH2-kinase linker region result in an extended spine structure for this kinase family. Disruption of the regulatory spine, either by mutation or by removal of the amino-terminal SH2-kinase linker region or by mutation of core spine residues, leads to inactivation of the Tec kinases. With a focus on the Tec family members, Itk and Btk, we now show that the gatekeeper residue is also critical for the assembly of the regulatory spine. Mutation of the bulky Itk F434 gatekeeper residue to alanine or glycine inactivates Itk. The activity of the Itk F434A mutant can be recovered by a secondary site mutation within the N-terminal lobe, specifically L432I. The Itk L432I mutation likely rescues the activity of the gatekeeper F434A mutation by promoting the assembly of the regulatory spine. We also show that mutation of the Itk and Btk gatekeeper residues to methionine is sufficient to activate the isolated kinase domains of Tec kinases in the absence of the amino-terminal SH2-kinase linker. Thus, shifting the conformational equilibrium between the assembled and disassembled states of the regulatory spine by changing the nature of the gatekeeper residue is key to regulating the activity of Tec kinases.


Effects of entomopathogenic nematodes on evolution of pink bollworm resistance to Bacillus thuringiensis toxin Cry1Ac.
The evolution of resistance by pests can reduce the efficacy of transgenic crops that produce insecticidal toxins from Bacillus thuringiensis (Bt). However, fitness costs may act to delay pest resistance to Bt toxins. Meta-analysis of results from four previous studies revealed that the entomopathogenic nematode Steinernema riobrave (Rhabditida: Steinernematidae) imposed a 20% fitness cost for larvae of pink bollworm, Pectinophora gossypiella (Saunders) (Lepidoptera: Gelechiidae), that were homozygous for resistance to Bt toxin Cry1Ac, but no significant fitness cost was detected for heterozygotes. We conducted greenhouse and laboratory selection experiments to determine whether S. riobrave would delay the evolution of pink bollworm resistance to Cry1Ac. We mimicked the high dose/refuge scenario in the greenhouse with Bt cotton (Gossypium hirsutum L.) plants and refuges of non-Bt cotton plants, and in the laboratory with diet containing Cry1Ac and refuges of untreated diet. In both experiments, half of the replicates were exposed to S. riobrave and half were not. In the greenhouse, S. riobrave did not delay resistance. In the laboratory, S. riobrave delayed resistance after two generations but not after four generations. Simulation modeling showed that an initial resistance allele frequency > 0.015 and population bottlenecks can diminish or eliminate the resistance-delaying effects of fitness costs. We hypothesize that these factors may have reduced the resistance-delaying effects of S. riobrave in the selection experiments. The experimental and modeling results suggest that entomopathogenic nematodes could slow the evolution of pest resistance to Bt crops, but only under some conditions.


Differential expression of IL-1 and TNF receptors in inflammatory arthritis and osteoarthritis.
Pathological joint events in both inflammatory arthritis and degenerative arthritis are perpetuated by complex cytokine interactions. Two cytokines, IL-1 and TNF alpha, appear to be the major culprits in the pathogenesis of synovitis and in cartilage damage in these joint diseases. To analyze the expression of IL-1 and TNF alpha and their receptors on synovial and cartilage tissue, we performed an immunohistochemical study on knee biopsies from patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and osteoarthritis (OA). Results identified a prevalent positivity to cytokines and their receptors of synovial cells from RA and PsA with respect to OA patients. In cartilage specimens, most RA and PsA patients showed no expression of the studied receptors, whereas the majority of OA biopsies were positive for all types of examined receptors except IL-1R2. Our study suggests that the cartilage is the main target of these cytokines in OA, while in IA IL-1 and TNF alpha exert their action in synovial tissue. In all the studied pathologies (RA, PsA, OA) the synovial tissue and the cartilage were differentially involved, indicating the importance of investigating both structures in joint disease studies.


Hematopoietic Npc1 mutation shifts gut microbiota composition in Ldlr-/- mice on a high-fat, high-cholesterol diet.
While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the contribution of host genetics is rather unexplored. As several findings suggested a role for the lysosomal lipid transporter Niemann-Pick type C1 (NPC1) in macrophages during MetS, we here explored whether a hematopoietic Npc1 mutation, induced via bone marrow transplantation, influences gut microbiota composition in low-density lipoprotein receptor knockout (Ldlr-/-) mice fed a high-fat, high-cholesterol (HFC) diet for 12 weeks. Ldlr-/- mice fed a HFC diet mimic a human plasma lipoprotein profile and show features of MetS, providing a model to explore the role of host genetics on gut microbiota under MetS conditions. Fecal samples were used to profile the microbial composition by 16 s ribosomal RNA gene sequencing. The hematopoietic Npc1 mutation shifted the gut microbiota composition and increased microbial richness and diversity. Variations in plasma lipid levels correlated with microbial diversity and richness as well as with several bacterial genera. This study suggests that host genetic influences on lipid metabolism affect the gut microbiome under MetS conditions. Future research investigating the role of host genetics on gut microbiota might therefore lead to identification of diagnostic and therapeutic targets for MetS.


The forkhead transcription factor FOXK2 promotes AP-1-mediated transcriptional regulation.
The transcriptional control circuitry in eukaryotic cells is complex and is orchestrated by combinatorially acting transcription factors. Forkhead transcription factors often function in concert with heterotypic transcription factors to specify distinct transcriptional programs. Here, we demonstrate that FOXK2 participates in combinatorial transcriptional control with the AP-1 transcription factor. FOXK2 binding regions are widespread throughout the genome and are often coassociated with AP-1 binding motifs. FOXK2 acts to promote AP-1-dependent gene expression changes in response to activation of the AP-1 pathway. In this context, FOXK2 is required for the efficient recruitment of AP-1 to chromatin. Thus, we have uncovered an important new molecular mechanism that controls AP-1-dependent gene expression.


[Reintegration of victimized children and adolescents in their parents' view].
This study aims at learning, from some aggressor families' point of view, the way reintegration of child and adolescent victims into their own families happen, in the city of Ribeirão Preto-SP in 2002. The methodology used is descriptive and qualitative; data were collected through interviews and observation of participants. Nine families whose children were institutionalized were surveyed. Results showed that the institutionalization of children is a way for some families to rethink the kind of education parents are providing their childrenwith/their own education. For the other ones, it was perceived as a support for behavioral problems. As noticed, some parents stressed a negative influence falling upon their children, which made them more disobedient on their return home, and causing disciplinary procedures harder to be established. The conclusion is that reintegration of the target children/adolescents is harnessed by violence happening inside families.


[Operative treatment of severe forms of congenital elevation of the scapula in children].
The article presents results of operative treatment of 36 children with severe forms of congenital high scapula. An original and used by us method of operative treatment of children with a severe form of Sprengel deformity is described. Distinctive features of the method are: mobilization of the suprascapular vascular-nervous bundle, correction of scapula deformities followed by a recovery of congruency of the sliding surfaces of the scapula and chest, physiological fixation of the scapula in the new place, separating off the paravertebral muscles and their sewing on to the medial edge of the scapula that allows a recovery of the function of lost trapezoid and rhomboid muscles and in some cases a shortening osteotomy of the clavicle is performed preventing the descending of the scapula. An analysis of the external view of the shoulder made after the operation has shown that the result was good in 57.5% of children, satisfactory in 42.5%. The functional indices characterizing the increased amplitude of movements in the shoulder joint were good in 47.5%, and satisfactory in 52.5%. The cosmetic and functional results of the treatment allow the developed technique to be recommended for treatment of severe forms of the Sprengel disease in children.


Patient reminder and patient recall systems to improve immunization rates.
Immunization rates for children and adults are rising, but coverage levels have not reached optimal goals. As a result of low immunization rates, vaccine-preventable diseases still occur. In an era of increasing complexity of immunization schedules, rising expectations about the performance of primary care and large demands on primary care physicians, it is important to understand and promote interventions that work in primary care settings to increase immunization coverage. A common theme across immunization programs in all nations involves the challenge of determining the denominator of eligible recipients (e.g. all children who should receive the measles vaccine) and identifying the best strategy to ensure high vaccination rates. Strategies have focused on patient-oriented interventions (e.g., patient reminders), provider interventions and system interventions. One intervention strategy involves patient reminder and recall systems. To assess the effectiveness of patient reminder and recall systems in improving immunization rates and compare the effects of various types of reminders in different settings or patient populations. A systematic search was performed for the initial review using MEDLINE (1966-1998) and four other bibliographic databases: EMBASE, PsychINFO, Sociological Abstracts, and CAB Abstracts. Authors also performed a search of The Effective Practice and Organisation of Care (EPOC) register in April 2001 to update the review. Two authors reviewed the lists of titles and abstracts and used the inclusion criteria to mark potentially relevant articles for full review. The reference lists of all relevant articles and reviews were back searched for additional studies. Publications of abstracts, proceedings from scientific meetings and files of study collaborators were also searched for references. In December 2004 the EPOC register was searched to identify relevant articles to update the review. Randomized controlled trials (RCT), controlled before and after studies (CBA) and interrupted time series (ITS) studies written in English. Health care personnel who deliver immunizations and children (birth to 18 years) or adults (18 years and up) who receive immunizations in any setting. Any intervention that falls within the EPOC scope (See Group Details) and that includes patient reminder or recall systems, or both, in at least one arm of the study. Immunization rates or the proportion of the target population up-to-date on recommended immunizations. Outcomes were acceptable for either individual vaccinations (e.g. influenza vaccination) or standard combinations of recommended vaccinations (e.g. all recommended vaccinations by a specific date or age). Each study was read independently by two reviewers. Disagreements between reviewers were resolved by a formal reconciliation process to achieve consensus. Results are presented for individual studies as relative rates for randomized controlled trials and as absolute changes in percentage points for controlled before and after studies. Pooled results for RCTs only were presented using the random effects model. Five new studies were added for this update. Increases in immunization rates due to reminders were in the range of 1 to 20 percentage points. Reminders were effective for childhood vaccinations (OR = 1.45, 95% CI =1.28, 1.66), childhood influenza vaccinations (OR = 2.87, 95% CI = 1.65, 4.98), adult pneumococcus, tetanus, and Hepatitis B (OR = 2.19, 95% CI = 1.21, 3.99), and adult influenza vaccinations (OR = 1.66, 95% CI = 1.31, 2.09). All types of reminders were effective (postcards, letters, telephone or autodialer calls), with telephone being the most effective but most costly. Patient reminder and recall systems in primary care settings are effective in improving immunization rates within developed countries.


Selective downregulation of ubiquitin conjugation cascade mRNA occurs in the senescent rat soleus muscle.
Aging-related alterations of the ubiquitin proteasome pathway (UPP) have been reported in locomotor skeletal muscle. Specifically, declines in proteasome activity have been observed in the soleus of senescent animals compared to the soleus of young controls. However, the influence of aging on the mRNA levels of key components within the ubiquitin conjugation cascade (UCC) remains unknown. We hypothesized that aged soleus muscle would exhibit downregulated expression of select UCC mRNA and decreased levels of ubiquitin-protein conjugates. To test this postulate, we harvested soleus muscles from 6 and 24-26 month old Fisher 344 rats. Aging resulted in a decline in mRNA expression of two key UCC components in soleus muscle; ubiquitin conjugating enzyme E2(14k) (E2(14k)) and muscle ring finger-1 (MuRF1). Surprisingly, no age-related differences existed in the total content of endogenous ubiquitin-protein conjugates in the soleus muscle. Nonetheless, a selective decrease in the level of ubiquitin-protein conjugates ( approximately 30kDa) was detected in the soleus of senescent animals. These results indicate that the soleus muscle displays a differential mRNA response of select UCC components to aging. Furthermore, the decline in E2(14k) and MuRF1 mRNA levels may contribute to altered substrate degradation by the UCC in the soleus muscle of senescent rats.


Lamin A/C deficiency enables increased myosin-II bipolar filament ensembles that promote divergent actomyosin network anomalies through self-organization.
Nuclear envelope proteins influence cell cytoarchitecure by poorly understood mechanisms. Here we show that small interfering RNA-mediated silencing of lamin A/C (LMNA) promotes contrasting stress fiber assembly and disassembly in individual cells and within cell populations. We show that LMNA-deficient cells have elevated myosin-II bipolar filament accumulations, irregular formation of actin comet tails and podosome-like adhesions, increased steady state nuclear localization of the mechanosensitive transcription factors MKL1 and YAP, and induced expression of some MKL1/serum response factor-regulated genes such as that encoding myosin-IIA (MYH9). Our studies utilizing live cell imaging and pharmacological inhibition of myosin-II support a mechanism of deregulated myosin-II self-organizing activity at the nexus of divergent actin cytoskeletal aberrations resulting from LMNA loss. In light of our results, we propose a model of how the nucleus, via linkage to the cytoplasmic actomyosin network, may act to control myosin-II contractile behavior through both mechanical and transcriptional feedback mechanisms.


Glaucoma in Ectropion Uveae Syndrome: A Case Report and Literature Review.
To report a case of advanced childhood glaucoma secondary to congenital ectropion uveae (CEU). The patient was a seven-year-old boy with unilateral glaucoma secondary to CEU and facial asymmetry, mild unilateral ptosis, and proptosis in the left eye. The intraocular pressure (IOP) was 28 mmHg and cup-to-disc ratio was 0.8 in the left eye. After starting glaucoma medication, IOP decreased to 21 mmHg. In view of the uncontrolled IOP with medication and high cup-to-disc ratio and increased axial length of the left eye, mitomycin-C (MMC)-augmented trabeculectomy was planned. Despite sub-tenon MMC injection and bleb needling, the bleb failed after six months, and we had to perform a shunt procedure to control the IOP. Although CEU is rare, ophthalmologists should be familiar with this syndrome because of the high frequency of glaucoma and its challenging management during childhood.


Cost-effectiveness of thrombolysis within 4.5 hours of acute ischemic stroke: experience from Australian stroke center.
Previous economic studies outside Australia have demonstrated that patients treated with tissue-type plasminogen activator (tPA) within 4.5 hours of stroke onset have lower healthcare costs than those not. We aim to perform cost-effectiveness analysis of intravenous tPA in an Australian setting. Data on clinical outcomes and costs were derived for 378 patients who received intravenous tPA within 4.5 hours of stroke onset at Royal Melbourne Hospital (Australia) between January 2003 and December 2011. To simulate clinical outcomes and costs for a hypothetical control group assumed not to have received tPA, we applied efficacy data from a meta-analysis of randomized trials to outcomes observed in the tPA group. During a 1-year time-horizon, net costs, years of life lived, and quality-adjusted life-years were compared and incremental cost-effectiveness ratios derived for tPA versus no tPA. In the study population, mean (SD) age was 68.2 (13.5) years and 206 (54.5%) were men. Median National Institutes of Health Stroke Scale score (interquartile range) at presentation was 12.5 (8-18). Compared with no tPA, we estimated that tPA would result in 0.02 life-years and 0.04 quality-adjusted life-years saved per person>1 year. The net cost of tPA was AUD $55.61 per patient. The incremental cost-effectiveness ratios were AUD $2377 per life-year saved and AUD $1478 per quality-adjusted life-years saved. Because the costs of tPA are incurred only once, the incremental cost-effectiveness ratios would decrease with increasing time-horizon. Uncertainty analyses indicated the results to be robust. Intravenous tPA within 4.5 hours represents a cost-effective intervention for acute ischemic stroke.


Follow up after breast cancer -- views of Australian women.
Survivorship care after breast cancer treatment is increasingly complex as it aims to manage the long term effects of cancer and its treatment, including psychosocial needs. While survivorship care is traditionally delivered by surgeons and specialist oncologists in Australia, general practitioners are ideally placed to manage these issues. This study explored the attitudes of 20 breast cancer survivors to GP involvement in follow up care through semi-structured telephone interviews, which were analysed using qualitative methods. Women were reluctant to change from specialist based care but identified many potential benefits of GP involvement in long term cancer care. They expressed an interest in shared care programs between specialists and GPs. Some participants thought that additional training may be required if GPs were to deliver this care. This study shows cautious interest from breast cancer survivors for increasing GP involvement in follow up care. These views should be considered as alternative models of care are developed.


A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study.
After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. Patients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided. Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (< 30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥ 6 months. Noteworthy, tumor density reduction and [(18)F]2-fluoro-2-deoxy-d-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.


Accuracy of plasma neutrophil gelatinase-associated lipocalin in the early diagnosis of contrast-induced acute kidney injury in critical illness.
Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for acute kidney injury (AKI). We evaluated the diagnostic and prognostic accuracies of plasma NGAL (pNGAL) for contrast-induced AKI (CI-AKI) in critically ill patients. In a prospective observational study in two adult intensive care units in a university hospital, 100 consecutive critically ill patients with stable serum creatinine concentrations up to 48 h before contrast medium (CM) injection were enrolled. Serial blood sampling for pNGAL analysis was performed at enrolment, 2, 6, and 24 h after CM injection. The primary outcome was CI-AKI, defined by AKIN criteria, within the first 72 h following CM injection. Secondary outcomes were the need for renal replacement therapy (RRT) and mortality. Of the 98 patients analyzed, 30 developed CI-AKI. The pNGAL levels did not differ in patients with or without CI-AKI, and were higher in septic patients compared to nonseptic patients, and in patients with AKI preceding CM injection. The discriminative value of pNGAL to predict CI-AKI and mortality was poor; although, it did predict the need for RRT requirement after CM injection (area under receiver-operating characteristic curve, 0.85, 0.80, 0.83 and 0.86 at H0, H2, H6 and H24, respectively). CI-AKI was common in critically ill patients. pNGAL levels were higher in patients with sepsis or previous AKI, but did not help to diagnose CI-AKI any earlier than serum creatinine after CM injection. However, pNGAL could be of interest to detect patients at risk of subsequent RRT requirement.


Navigating power dynamics in engaging communities in end-of-life issues - Lessons learned from developing community-based intergenerational arts initiatives about death and loss.
Lack of community engagement in end-of-life issues and age-segregation in Swedish society motivated us to develop Studio DöBra, a community-based intergenerational arts initiative to support community engagement in end-of-life issues and develop intergenerational meeting places. Representatives from several community organizations formed a project group with first author MK, to develop Studio DöBra. Based on analysis of exploratory interviews with professionals involved in other, similar initiatives and data from Studio DöBra development, we discuss challenges related to power dynamics in developing initiatives to engage communities in end-of-life issues, and how these can inform the development of similar initiatives.


A proposed model for an optimal mentoring environment for medical residents: a literature review.
To develop a model of the optimal mentoring environment for medical residents. The authors propose that such an environment is a function of a relationship that rests upon a set of interactional foundations that allow a protégé to capitalize on the strengths of the mentor, and it facilitates behaviors that will enable the protégé to develop and internalize the requisite knowledge, skills, and attitudes (KSAs) as fully as possible. The authors searched the literature using Web of Science and Google Scholar in 2007-2008 to identify articles addressing the mentoring process and the context in which it occurs (mentoring environment), and the effect both have on KSA development. The authors distilled the attributes of a good mentor that were consistent across the 20 papers that met inclusion criteria and described good mentoring of residents or curricula for training mentors or residents. The authors identified six interactional foundations that underlie the optimal mentoring relationship: emotional safety, support, protégé-centeredness, informality, responsiveness, and respect. These foundations enable protégés to engage in four key developmental behaviors: exercising independence, reflecting, extrapolating, and synthesizing. This model identifies mentoring practices that empower protégés to engage in developmental behaviors that will help them become the best physicians possible. Educators may use this model to develop training tools to teach attendings how to create an optimal mentoring environment. Researchers can use the model to help guide their future investigations of mentoring in medicine.


Cysteine residues in the human cannabinoid receptor: only C257 and C264 are required for a functional receptor, and steric bulk at C386 impairs antagonist SR141716A binding.
The human neuronal cannabinoid receptor (CB1) is a G-protein-coupled receptor (GPCR) triggered by the psychoactive ingredients in marijuana, as well as endogenous cannabinoids produced in the brain. As with most GPCRs, the mechanism of CB1 activation is poorly understood. In this work, we have assessed the role of cysteine residues in CB1 ligand binding and activation, and demonstrate a method for mapping key determinants in CB1 structure and function. Through mutational analysis, we find that only two cysteines, C257 and C264, are required for high-level expression and receptor function. In addition, through cysteine reactivity studies, we find that a cysteine in transmembrane helix seven, C386 (C7.42), is reactive toward methanethiosulfonate (MTS) sulfhydryl labeling agents, and is thus solvent accessible. Interestingly, steric bulk introduced at this site, either through MTS labeling or by mutation, inhibits binding of the antagonist drug SR141716A (also known as Rimonabant or Accomplia), but does not affect the binding of the agonist CP55940. Our subsequent modeling studies suggest this effect is caused by steric clash of the modified C386 residue with the piperidine ring of SR141716A and/or disruption of an aromatic microdomain in the binding pocket. On the basis of these results, we hypothesize that bound SR141716A inhibits the ability of transmembrane helix 6 to move during formation of the functionally active receptor state.


The growing complexity of platelet aggregation.
Platelet aggregation, the process by which platelets adhere to each other at sites of vascular injury, has long been recognized as critical for hemostatic plug formation and thrombosis. Until relatively recently, platelet aggregation was considered a straightforward process involving the noncovalent bridging of integrin alpha(IIb)beta(3) receptors on the platelet surface by the dimeric adhesive protein fibrinogen. However, with recent technical advances enabling real-time analysis of platelet aggregation in vivo, it has become apparent that this process is much more complex and dynamic than previously anticipated. Over the last decade, it has become clear that platelet aggregation represents a multistep adhesion process involving distinct receptors and adhesive ligands, with the contribution of individual receptor-ligand interactions to the aggregation process dependent on the prevailing blood flow conditions. It now appears that at least 3 distinct mechanisms can initiate platelet aggregation, with each of these mechanisms operating over a specific shear range in vivo. The identification of shear-dependent mechanisms of platelet aggregation has raised the possibility that vascular-bed-specific inhibitors of platelet aggregation may be developed in the future that are safer and more effective than existing antiplatelet agents.


The Effect of Tutoring With Nonstandard Equations for Students With Mathematics Difficulty.
Students often misinterpret the equal sign (=) as operational instead of relational. Research indicates misinterpretation of the equal sign occurs because students receive relatively little exposure to equations that promote relational understanding of the equal sign. No study, however, has examined effects of nonstandard equations on the equation solving and equal-sign understanding of students with mathematics difficulty (MD). In the present study, second-grade students with MD (n = 51) were randomly assigned to standard equations tutoring, combined tutoring (standard and nonstandard equations), and no-tutoring control. Combined tutoring students demonstrated greater gains on equation-solving assessments and equal-sign tasks compared to the other two conditions. Standard tutoring students demonstrated improved skill on equation solving over control students, but combined tutoring students' performance gains were significantly larger. Results indicate that exposure to and practice with nonstandard equations positively influence student understanding of the equal sign.


The primary enamel knot determines the position of the first buccal cusp in developing mice molars.
The enamel knot (EK), which is located in the center of bud and cap stage tooth germs, is a transitory cluster of non-dividing epithelial cells. The EK acts as a signaling center that provides positional information for tooth morphogenesis and regulates the growth of tooth cusps by inducing secondary EKs. The morphological, cellular, and molecular events leading to the relationship between the primary and secondary EKs have not been described clearly. This study investigated the relationship between the primary and secondary EKs in the maxillary and mandibular first molars of mice. The location of the primary EK and secondary EKs was investigated by chasing Fgf4 expression patterns in tooth germ at some intervals of in vitro culture, and the relationship between the primary EK and secondary EK was examined by tracing the primary EK cells in the E13.5 tooth germs which were frontally half sliced to expose the primary EK. After 48 hr, the primary EK cells in the sliced tooth germs were located on the buccal secondary EKs, which correspond to the future paracone in maxilla and protoconid in mandible. The Bmp4 expression in buccal part of the dental mesenchyme might be related with the lower growth in buccal epithelium than in lingual epithelium, and the Msx2 expressing area in epithelium was overlapped with the enamel cord (or septum) and cell dense area. The enamel cord might connect the primary EK with enamel navel to fix the location of the primary EK in the buccal side during the cap to bell stages. Overall, these results suggest that primary EK cells strictly contribute to form the paracone or protoconid, which are the main cusps of the tooth in the maxilla or mandible.


Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study.
Next-generation sequencing (NGS) has transitioned from research to clinical routine, yet the comparability of different technologies for mutation profiling remains an open question. We performed a European multicenter (n=6) evaluation of three amplicon-based NGS assays targeting 11 genes recurrently mutated in chronic lymphocytic leukemia. Each assay was assessed by two centers using 48 pre-characterized chronic lymphocytic leukemia samples; libraries were sequenced on the Illumina MiSeq instrument and bioinformatics analyses were centralized. Across all centers the median percentage of target reads ≥100x ranged from 94.2- 99.8%. In order to rule out assay-specific technical variability, we first assessed variant calling at the individual assay level i.e., pairwise analysis of variants detected amongst partner centers. After filtering for variants present in the paired normal sample and removal of PCR/sequencing artefacts, the panels achieved 96.2% (Multiplicom), 97.7% (TruSeq) and 90% (HaloPlex) concordance at a variant allele frequency (VAF) >0.5%. Reproducibility was assessed by looking at the inter-laboratory variation in detecting mutations and 107 of 115 (93% concordance) mutations were detected by all six centers, while the remaining eight variants (7%) were undetected by a single center. Notably, 6 of 8 of these variants concerned minor subclonal mutations (VAF <5%). We sought to investigate low-frequency mutations further by using a high-sensitivity assay containing unique molecular identifiers, which confirmed the presence of several minor subclonal mutations. Thus, while amplicon-based approaches can be adopted for somatic mutation detection with VAF >5%, after rigorous validation, the use of unique molecular identifiers may be necessary to reach a higher sensitivity and ensure consistent and accurate detection of low-frequency variants.


Improving access to medicines for non-communicable diseases in rural India: a mixed methods study protocol using quasi-experimental design.
India has the distinction of financing its healthcare mainly through out-of-pocket expenses by individual families contributing to catastrophic health expenditure and impoverishment. Nearly 70 % of the expenditure is on medicines purchased at private pharmacies. Patients with chronic ailments are especially affected, as they often need lifelong medicines. Over the past years in India, there have been several efforts to improve drug availability at government primary health centres. In this study, we aim to understand health system factors that affect utilisation and access to generic medicines for people with non-communicable diseases. This study aims to understand if (and how) a package of interventions targeting primary health centres and community participation platforms affect utilisation and access to generic medicines for people with non-communicable diseases in the current district context in India. This study will employ a quasi-experimental design and a qualitative theory-driven approach. PHCs will be randomly assigned to one of three arms of the intervention. In one arm, PHCs will receive inputs to optimise service delivery for non-communicable diseases, while the second arm will receive an additional package of interventions to strengthen community participation platforms for improving non-communicable disease care. The third arm will be the control. We will conduct household and facility surveys, before and after the intervention and will estimate the effect of the intervention by difference-in-difference analysis. Sample size for measuring effects was calculated based on obtaining at least 30 households for each primary health centre spread across three distance-based clusters. Primary outcomes include availability and utilisation of medicines at primary health centres and out-of-pocket expenditure for medicines by non-communicable disease households. Focus group discussions with patients and in-depth interviews with health workers will also be conducted. Qualitative and process documentation data will be used to explain how the intervention could have worked. By taking into consideration several health system building blocks and trying to understand how they interact, our study aims to generate evidence for health planners on how to optimise health services to improve access to medicines. Protocol registered on Clinical Trials Registry of India with registration identifier number CTRI/2015/03/005640 on 17(th) March 2015.


Arterial pulsatility as an index of cerebral microangiopathy in diabetes.
This study was designed to evaluate cerebral hemodynamic changes related to diabetes mellitus (DM) with transcranial Doppler ultrasonography (TCD). We measured the flow velocities and the Gosling pulsatility index (PI) of the middle cerebral artery (MCA), extracranial internal carotid artery (ICA), and basilar artery (BA) in 56 stroke-free, normotensive patients with type 2 DM and 70 age- and gender-matched healthy volunteers. Patients were divided into 2 groups according to the presence of microvascular complications such as retinopathy, nephropathy, and neuropathy. Patients showed slightly lower hematocrit and higher serum fibrinogen levels than control subjects, but other clinical profiles, including stroke risk factors except for diabetes, were comparable between patients and controls. The flow velocity of the ICA but not the MCA and BA in patients regardless of the complication was significantly higher than that in controls. The PIs of the MCA and ICA were significantly higher in patients with complication than those without complication, as well as in controls. The PI of the BA was also significantly higher, even in patients without complication, than in controls. The PIs of the MCA and ICA but not the BA were closely correlated with the duration of DM (r(2)=0.46 and 0.34, respectively). This study defines TCD findings of diabetes-related cerebral hemodynamic changes and suggests that the PI reflects microangiopathic changes of cerebral vessels.


Effects of Sigma-1 Receptor Ligands on Peripheral Nerve Regeneration.
Peripheral nerve injuries lead to the loss of motor, sensory and autonomic functions in the territories supplied by the injured nerve. Currently, nerve injuries are managed by surgical repair procedures, and there are no effective drugs in the clinic for improving the capacity of axonal regeneration. Sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperon protein involved in many functions, including neuroprotection and neuroplasticity. A few previous studies using Sig-1R ligands reported results that suggest this receptor as a putative target to enhance regeneration. The aim of this study was to evaluate the possible effects of Sig-1R ligands on axonal regeneration in a sciatic nerve section and repair model in mice. To this end, mice were treated either with the Sig-1R agonist PRE-084 or the antagonist BD1063, and a Sig-1R knock-out (KO) mice group was also studied. The electrophysiological and histological data showed that treatment with Sig-1R ligands, or the lack of this protein, did not markedly modify the process of axonal regeneration and target reinnervation after sciatic nerve injury. Nevertheless, the nociceptive tests provided results indicating a role of Sig-1R in sensory perception after nerve injury, and immunohistochemical labeling indicated a regulatory role in inflammatory cell infiltration in the injured nerve.


Microfilaments and the hydrosmotic action of vasopressin in toad urinary bladder.
The role of cytoskeletal elements in the antidiuretic hormone (ADH)-induced hydrosmotic response of the toad bladder has been investigated with the microfilament and microtubule disrupting agents, cytochalasin B and colchicine. In the presence of a transmural osmotic gradient, addition of ADH resulted in a measured osmotic permeability coefficient (Pf) of 190 +/- 12 micrometers/s; preincubation with cytochalasin B (2 x 10(-5) M) reduced this value to 138 +/- 6. However, ADH-induced diffusional permeability to tritiated water (PD) was enhanced by 17% with cytochalasin B. The toxin caused a pronounced vacuolation in granular cells only when both ADH and an osmotic gradient were present. This led to experiments with brief glutaraldehyde fixation after hormonal stimulation but before osmotic gradient imposition. Subsequent osmotic flow measurements yielded Pf values of 180 +/- 18 and 210 +/- 7 micrometers/s for ADH and ADH + cytochalasin B, respectively. With gradient imposition only after tissue fixation, no structural alterations were found. We conclude that cytochalasin B inhibition is through disruption of the intracellular portion of the pathway for osmotic flows. Comparable experimentation with colchicine indicated that its interference is primarily with ADH action on the mucosal membrane itself. These results may bear on the significance of particle aggregation in the mucosal membrane, which has been thought to indicate ADH-induced water channels but which is reported to be precluded by cytochalasin B treatment.


Accuracy of stop-cursor method for determining systolic and pulse pressure variation.
Functional hemodynamic indicators (systolic pressure variation [SPV and SPV%] and pulse pressure variation [PPV%]) are sensitive and specific indicators of fluid responsiveness. It was unknown if these indicators could be accurately measured directly from the bedside monitor. Determine the accuracy of SPV, SPV%, and PPV% measurements by using a stop-cursor method compared with a digitized analog strip (gold standard). A prospective observational study using a convenience sample of 30 adult patients in a medical-surgical intensive care unit who were receiving mechanical ventilation and had no spontaneous breaths during 3 sequential ventilator breaths and had an optimized arterial catheter. The peak and nadir arterial pressure values for a ventilator cycle were simultaneously obtained by using the stop-cursor method on the bedside monitor and a hardcopy strip. The indicators were averaged over 3 breaths, and the difference between methods was calculated. Data were analyzed from 29 patients (1 patient excluded) on assist control ventilation (mean [SD] for tidal volume, 7.5 [2] mL/kg; positive end-expiratory pressure, 7 [4] cm H2O). For SPV, the mean bias was 0.4 (SD, 0.9) mm Hg (95% limits of agreement [LOA], -1.4 to 2.2 mm Hg); for SPV%, 0.3 (SD, 0.9; 95% LOA, -1.5% to 2.1%); for PPV%, 1.0 (SD, 3.3; 95% LOA, -5.5% to 7.5%). In only 1 case (PPV%) was there disagreement on fluid response characterization. Statistically significant small differences in SPV and SPV% were detected. The differences in SPV, SPV%, and PPV% were not clinically significant, suggesting that functional hemodynamic indicators can be obtained accurately with the stop-cursor method.


Underutilization of Statins When Indicated in HIV-Seropositive and Seronegative Women.
Increased life expectancy of persons living with HIV infection receiving antiretroviral therapy heightens the importance of preventing and treating chronic comorbidities such as cardiovascular disease. While guidelines have increasingly advocated more aggressive use of statins for low-density lipoprotein (LDL) cholesterol reduction, it is unclear whether people with HIV, especially women, are receiving statins when indicated, and whether their HIV disease is a factor in access. We assessed the cumulative incidence of statin use after an indication in the Women's Interagency HIV Study (WIHS), from 2000 to 2014. Additionally, we used weighted proportional hazards regression to estimate the effect of HIV serostatus on the time to initiation of a statin after an indication. Cumulative incidence of statin use 5 years after an indication was low: 38% in HIV-seropositive women and 30% in HIV-seronegative women. Compared to HIV-seronegative women, the weighted hazard ratio for initiation of a statin for HIV-seropositive women over 5 years was 0.94 [95% confidence interval (CI) 0.62, 1.43]. Applying the American College of Cardiology and the American Heart Association (ACC/AHA) guidelines increased the proportion of HIV-seropositive women with a statin indication from 16% to 45%. Clinicians treating HIV-seropositive women should consider more aggressive management of the dyslipidemia often found in this population.


Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease.
Dating back nearly 35 years ago to the Witschi hypothesis, epithelial cell dysfunction and abnormal wound healing have reemerged as central concepts in the pathophysiology of idiopathic pulmonary fibrosis (IPF) in adults and in interstitial lung disease in children. Alveolar type 2 (AT2) cells represent a metabolically active compartment in the distal air spaces responsible for pulmonary surfactant biosynthesis and function as a progenitor population required for maintenance of alveolar integrity. Rare mutations in surfactant system components have provided new clues to understanding broader questions regarding the role of AT2 cell dysfunction in the pathophysiology of fibrotic lung diseases. Drawing on data generated from a variety of model systems expressing disease-related surfactant component mutations [surfactant proteins A and C (SP-A and SP-C); the lipid transporter ABCA3], this review will examine the concept of epithelial dysfunction in fibrotic lung disease, provide an update on AT2 cell and surfactant biology, summarize cellular responses to mutant surfactant components [including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and intrinsic apoptosis], and examine quality control pathways (unfolded protein response, the ubiquitin-proteasome system, macroautophagy) that can be utilized to restore AT2 homeostasis. This integrated response and its derangement will be placed in the context of cell stress and quality control signatures found in patients with familial or sporadic IPF as well as non-surfactant-related AT2 cell dysfunction syndromes associated with a fibrotic lung phenotype. Finally, the need for targeted therapeutic strategies for pulmonary fibrosis that address epithelial ER stress, its downstream signaling, and cell quality control are discussed.


State-to-state resolved differential cross sections for rotationally inelastic scattering of ND3 with He.
State-to-state differential cross sections are reported for rotationally inelastic scattering of fully state-selected ND3 (j(k)(±) = 1(1)(-)) with He. Experimental measurements are compared with full close-coupling quantum-mechanical scattering calculations that used an ab initio potential energy surface. Results are presented for final states up to j'(k')(±) = 7(7)(-) at a mean collision energy of 430 cm(-1). For selected final quantum states, the effect of collision energy on the differential cross sections is also explored in the range 230-720 cm(-1). For the experimental studies, a hexapole electrostatic lens was used for the j(k)(±) state-selection of ND3 molecules in their electronic and vibrational ground states in a molecular beam. This state-selected molecular beam was then crossed with a beam of He atoms. The velocities of inelastically scattered ND3 molecules in single j'(k')(±) states were obtained by velocity map imaging, and converted to differential cross sections in the centre-of-mass frame by density-to-flux transformation. The close-coupling calculations reproduce well the measured angular distributions. For small changes in the rotational angular momentum quantum number (j), the ND3 is predominantly forward scattered, but the scattering shifts to the sideways and backward directions as Δj increases. For scattering into a given j'(k')(±) state, cross-sections for collisions that conserve the ± symmetry associated with the ND3 inversion vibration are larger and generally more forward scattered than the corresponding symmetry-changing processes.


Preventing and treating posttraumatic seizures: the human experience.
Posttraumatic epilepsy presents an ideal target for prevention efforts. Traumatic brain injury (TBI) is common, characteristics that put people at high risk such as penetrating injury or subdural hematoma or provoked seizures are easily identified, and the latency between the injury and the onset of epileptic seizures is frequently short. Several drugs have been tested for their ability to prevent provoked seizures and epilepsy after TBI. We describe the design of those studies and their results. Phenytoin and carbamazepine significantly reduce the incidence of provoked seizures. Phenobarbital and the combination of phenobarbital and phenytoin also look promising for reducing provoked seizures, but small sample sizes in the studies evaluating these drugs do not allow definitive conclusions. None of the drugs studied (phenytoin, phenobarbital, their combination, carbamazepine, valproate, or magnesium) have shown reliable evidence that they prevent, or even suppress, epileptic seizures after TBI. For most of the regimens tested (the phenytoin/phenobarbital combination being the exception), the best estimate of effect is under a 25% reduction in posttraumatic seizures, well less than the 50% reduction most studies were designed to detect. The evaluation of the tested drugs has serious limitations, however, and antiepileptic drugs (AEDs) developed since 1980 and other compounds have barely been tested at all. Better understanding the process of epileptogenesis, testing treatments that demonstrate antiepileptogenic effects in the laboratory, and performing thorough preclinical and phase II evaluations before attempting definitive trials should greatly improve the chance of identifying ways to prevent posttraumatic epilepsy, providing the ultimate cure for this condition.


[Prevention of atherosclerosis. The positional specificity of blood triglycerides and lipases, the particular milk lipids, and the modification of the fatty acids of vegetable oils and animal fats].
Milk is a biological medium that bears no resemblance to any of the biological fluids and tissues in primates and mammals in the positional composition of fatty acids (FA) in triglycerides. This is determined by the fact that at the very early phylogenesis of mammals, milk is to ensure a high postnatal bioavailability (absorption) of saturated palmitic FA, a substrate for neonatal energy supply despite all obstacles that are formed in the baby's intestine in vivo. Milk is destined for infant nutrition in the biology-destined period (not more than a year); assimilation of triglycerides that are so structurally unusual requires a) high isomerization activity in the enterocytes and b) the ability of blood lipases to hydrolyze palmitate-oleate-palmitate triglycerides as a component of oleic very-low-density lipoproteins. After the period permitted by nature, there is virtually no possibility to physiologically consume milk that contains structurally unusual triglycerides. The use of whole milk and its products by adults impairs the active, receptor cell absorption of FAs as ligand lipoproteins via apoE/B-100-endocytosis and enhances the generation of small, dense low-density lipoproteins as biological debris. The impaired biological function of endoecology and the debris accumulation of the intercellular medium lead to the activation of atheromatosis, atherothrombosis, and coronary sclerosis. Nature has given no sanction for turning the mammals that are not on milk to those on milk for whole life. Up to one year of age, the baby has in vivo conditions for the absorption and hydrolysis of triglycerides with palmitic FA at the sn-2 position. After one year of age, the expression of these lipases and coenzymes is over; re-expression occurs only with the activation of the biological function of locomotion - long-term strenuous physical activity. High physical activity expresses other genes, enzymes, coenzymes, and carrier proteins, which activate the hydrolysis of triglycerides high in palmitic FA. These mechanisms are similar to those activated in vivo during the early postnatal period.


Enable, Reconnect and Augment: A New ERA of Virtual Nature Research and Application.
Being exposed to natural environments is associated with improved health and well-being, as these environments are believed to promote feelings of "being away" from everyday struggles, positive emotional reactions and stress reduction. Despite these positive effects, humanity is becoming increasingly more distanced from nature due to societal changes, such as increased urbanization and the reduced accessibility of natural environments. Technology is also partly to blame, as research suggests that people replace nature contact with increased screen time. In this cross-section between nature and technology, we find technological nature which is progressing towards a point where we may be capable of simulating exposure to real nature. Concerns have been raised regarding this technology, as it is feared it will replace real nature. However, research suggests that virtual nature may have a more positive impact on society than a mere replacement of real nature, and this review propose several areas where virtual nature may be a beneficial addition to actual nature (Enable), help people reconnect with the real natural world (Reconnect) and "boost" human-nature interactions (Augment). Based on the current research and theoretical framework, this review proposes guidelines for future research within these areas, with the aim of advancing the field by producing high quality research.


Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
The goal of this study was to characterize a Swedish family with members affected by spinocerebellar ataxia 27 (SCA27), a rare autosomal dominant disease caused by mutations in fibroblast growth factor 14 (FGF14). Despite normal structural neuroimaging, psychiatric manifestations and intellectual disability are part of the SCA27 phenotype raising the need for functional neuroimaging. Here, we used clinical assessments, structural and functional neuroimaging to characterize these new SCA27 patients. Since one patient presents with a psychotic disorder, an exploratory study of markers of schizophrenia associated with GABAergic neurotransmission was performed in fgf14-/- mice, a preclinical model that replicates motor and learning deficits of SCA27. A comprehensive characterization that included clinical assessments, cognitive tests, structural neuroimaging studies, brain metabolism with 18 F-fluorodeoxyglucose PET ([18F] FDG PET) and genetic analyses was performed. Brains of fgf14-/- mice were studied with immunohistochemistry. Nine patients had ataxia, and all affected patients harboured an interstitial deletion of chromosome 13q33.1 encompassing the entire FGF14 and integrin subunit beta like 1 (ITGBL1) genes. New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients. Hypometabolism in the PFC was far more pronounced in a SCA27 patient with psychosis. Reduced expression of VGAT was found in the mPFC of fgf14-/- mice. This is the second largest SCA27 family identified to date. We provide new clinical and preclinical evidence for a significant psychiatric component in SCA27, strengthening the hypothesis of FGF14 as an important modulator of psychiatric disease.


[Beta-blockers and migraine. Efficacy of time-release propranolol versus placebo].
The efficacy and safety of long-acting propranolol (LA.P) 160 mg once-daily in the prophylactic treatment of migraine were tested against placebo in a multicentric, double-blind, randomized study comparing the two groups in a parallel manner over a treatment period of 12 weeks, and following a 4 week-placebo run-in period. Fifty-five out of the 74 patients who entered the trial included at the end of the run-in period. Forty-one patients completed the study. Out of the 14 patients who withdrew from the study, none discontinued because of side-effects. The statistical analysis was done according to the "intention to treat" principle. LA.P was significantly more efficient than placebo in reducing the frequency of migraine attacks (p = 0.01 by variance analysis). LA.P reduced the average number of monthly crises by 48% on day 84. There was a slight but significant reduction of the systolic blood pressure and heart rate in the erect position. There was no significant difference between LA.P and placebo regarding either the number of complaints or the number of side-effects elicited out of an 17 item questionnaire. None of the observed side effects led to a withdrawal of treatment.


Point-of-care ultrasound educational interventions in the neonatal intensive care unit: A systematic review.
The benefits of point-of-care ultrasound (POCUS) in the neonatal intensive care unit (NICU) have been widely recognized, but education on this area of practice remains variable. We reviewed published educational interventions regarding POCUS use in the NICU and whether they have led to sustainable increases in POCUS use. A systematic search of 6 databases was performed for publications from January 2000 to March 2021. Studies with quantitative data related to POCUS educational interventions in the NICU were included. Data on number of participants and roles, educational intervention, curriculum description, and project outcome measures (including sustainability) was extracted. The search resulted in 686 articles, of which nine studies met the inclusion criteria. Educational interventions included didactic sessions, simulation practice, animal practice, and practice in real patients. The most common assessment was based on the quality and accuracy of the images. At the participant level, the average time to reach proficiency ranged from eight hours and thirty-six minutes to five months, and none of the studies evaluated sustainability of POCUS use after the intervention. There is a lack of standardized training modules and assessments for POCUS use in the NICU. Given that none of the studies addressed sustainability or standardized training, we recommend that a standardized training protocol and assessment tool is developed and studied longitudinally; and that barriers to sustainable POCUS use in the NICU (such as billing issues and a lack of POCUS machines and instructors) be systematically addressed as part of this work.