[Sodium valproate--still a current antiepileptic agent?].
In Switzerland valproate is in use as an anticonvulsant drug since 25 years. On this occasion we present a synopsis of the state of knowledge about its mechanism of action, pharmacokinetics, clinical efficacy, side effects, drug interactions, and administration with respect to special clinical situations.


[Vitamin D deficiency during pregnancy : what's the local situation ?]
Vitamin D deficiency is a worldwide health problem, also during pregnancy. Inadequate maternal vitamin D status in pregnancy is associated with poor fetal growth, impaired bone development and rickets in infants after birth. Furthermore, higher rates of preeclampsia and gestational diabetes are associated with low maternal vitamin D status during pregnancy. Toxicity of vitamin D is rare. Most countries recommend vitamin D supplementation during pregnancy but guidelines are controversial and inadequate compared to real mother's and child's needs. Wath's the best strategy to follow and supplement mother during pregnancy? In a study carried out at the maternity clinic Notre-Dame des Bruyères (CHU Liège), we studied for a year the vitamin D concentrations of young women at start of pregnancy and of others after delivery to evaluate the local situation and management of vitamin D status during pregnancy. We did not collect the cord blood samples in this study. However, this is a project we would like to achieve soon. This would allow us to compare the vitamin D results of the mother at the time of delivery, to those of the cord blood of their respective child.


Improved Metrological Traceability of Particle Size Values Measured with Line-Start Incremental Centrifugal Liquid Sedimentation.
Line-start incremental centrifugal liquid sedimentation (disc-CLS) is a powerful method to determine particle size based on the principles of Stokes' law. Because several of the input quantities of the Stokes equation cannot be easily determined for this case of a rotating disc, the disc-CLS approach relies on calibrating the sedimentation time scale with reference particles. To use these calibrant particles for establishing metrological traceability, they must fulfill the same requirements as those imposed on a certified reference material, i.e., their certified Stokes diameter and density value must come with a realistic measurement uncertainty and with a traceability statement. As is the case for several other techniques, the calibrants do not always come with uncertainties for the assigned modal diameter and effective particle density. The lack of such information and the absence of a traceability statement make it difficult for the end-user to estimate the uncertainty of the measurement results and to compare them with results obtained by others. We present the results of a collaborative study that aimed at demonstrating the traceability of particle size results obtained with disc-CLS. For this purpose, the particle size and effective particle density of polyvinyl chloride calibrants were measured using different validated methods, and measurement uncertainties were estimated according to the Guide to the Expression of Uncertainty in Measurement. The results indicate that the modal Stokes diameter and effective particle density that are assigned to the calibrants are accurate within 5% and 3.5%, respectively, and that they can be used to establish traceability of particle size results obtained with disc-CLS. This conclusion has a great impact on the traceability statement of certified particle size reference materials, for which the traceability is limited to the size and density values of the calibrant particles.


[Imaging of rectal cancer--key to treatment decisions].
The current guidelines (EURECCA consensus statement 2013) for preoperative imaging of rectal cancer recommend MRI for local staging and CT of the chest, abdomen and pelvis for detection of distant metastases. High resolution MR enables preoperative identification of poor prognostic features. These poor prognostic features are correlated with an increased risk of local recurrence and/or metastatic disease. MRI enables the preoperative multidisciplinary team to decide whether a patient benefits from adjuvant therapy and which surgical technique should be used. A radiological structured report helps clinicians get the most out of the report and increases the number of optimal reports.


Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer.
BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.


Technical note: A system for continuous recording of ruminal pH in cattle.
Continuous recording of ruminal pH in cannulated cattle has been practiced to study rumen metabolism. However, most systems reported did not permit animal mobility during pH recording. Therefore, the objective of this study was to develop a continuous rumen pH data acquisition system that permitted animal mobility during data acquisition. A further objective was to compare the pH readings obtained using the continuous recording system to readings obtained at the same time using spot sampling. The continuous recording system was composed of a heavy-duty electrode and a data logger. The electrode was attached to a 0.5-kg weight to help maintain the electrode in the ventral sac of the rumen. The electrode was connected via a 0.5-m cable to a lightweight data logger that was mounted on the animal's back using a belt wrapped around the girth. The data logger was battery powered and could hold over 13,000 pH data values. A personal digital assistant was used to configure and download data from the data logger during the experiment. Ruminal pH was continuously recorded (every 10 s) using a dry Holstein cow fed alfalfa hay ad libitum in a 3-d experiment to compare the performance of the continuous system to spot samples taken from the ventral sac of the rumen, the same location as the continuous electrode. The spot samples were collected 3 times per d for 3 d. At every sampling time, 3 replicate samples were collected, pH was determined immediately using a handheld pH meter, and readings were averaged (n = 3) and compared with the average of the 3 pH readings recorded using the continuous system at the same time. The pH recorded by spot sampling (6.63 +/- 0.04) was greater (P = 0.009) than that of the continuous system (6.56 +/- 0.03), with a correlation of r = 0.88 (P = 0.002). The continuous recording system has the potential to facilitate measurement of ruminal pH in free-roaming cattle.


On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.
Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next-generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.


The rpoE gene encoding the sigma E (sigma 24) heat shock sigma factor of Escherichia coli.
Previous work has established that the transcription factor sigma E (sigma 24) is necessary for maintaining the induction of the heat shock response of Escherichia coli at high temperatures. We have identified the gene encoding sigma E using a genetic screen designed to isolate trans-acting mutations that abolish expression from either htrA or rpoHP3, two promoters recognized uniquely by sigma E-containing RNA polymerase. Such a screen was achieved by transducing strains carrying a single copy of either phtrA-lacZ or rpoHP3-lacZ fusions with mutagenized bacteriophage P1 lysates and screening for Lac- mutant colonies at 22 degrees C. Lac- mutants were subsequently tested for inability to grow at 43 degrees C (Ts- phenotype). Only those Lac- Ts- mutants that were unable to accumulate heat shock proteins at 50 degrees C were retained for further characterization. In a complementary approach, those genes which when cloned on a multicopy plasmid led to higher constitutive expression of the sigma E regulon were characterized and mapped. Both approaches identified the same gene, rpoE, mapping at 55.5 min on the E.coli genetic map and encoding a polypeptide of 191 amino acid residues. The wild-type and a mutant rpoE gene products were over-expressed and purified. It was found that the purified wild-type sigma E protein, when used in in vitro run-off transcription assays in combination with core RNA polymerase, was able to direct transcription from the htrA and rpoHP3 promoters, but not from known sigma 70-dependent promoters. In vivo and in vitro analyses of rpoE transcriptional regulation showed that the rpoE gene is transcribed from two major promoters, one of which is positively regulated by sigma E itself.


[Evaluation of irregular hepatectomy for primary liver carcinoma].
From 1964 to 1985, 120 patients with primary liver carcinoma were treated by operation in our hospital. Regular hepatectomy was done in 7 patients, palliative irregular hepatectomy in 28 and radical irregular in 85. The operation mortality was 4.2% in irregular hepatectomy group (113 cases) but 14.3% in regular hepatectomy group (7 cases) (P greater than 0.05). The 1, 3 and 5 year survival rates were 68.8%, 48.1% and 20.0% in radical irregular hepatectomy group but 83.3%, 33.3% and 16.7% in regular hepatectomy group. 10 of 28 patients treated by palliative hepatectomy were added with radiation. Majority of these patients died in 1 year after operation but 2 patients survived for more than 2 years and 1 for more than 7 years. The data show that in Asia, the incidence of primary liver carcinoma concurrent with liver cirrhosis is high and irregular hepatectomy is a suitable treatment. There is no difference between irregular and regular hepatectomy groups in the prognosis. But the former could reduce the operative time, mortality and the possibility of bleeding and complications.


The development of peripheral visual acuity in human infants. A preliminary study.
In 74 infants, we tested the resolution of gratings centered at 10 degrees in the peripheral visual field. The estimation of acuity was based on the direction of the first saccade from a fixation stimulus toward a peripheral grating stimulus. We also tested the development of the infants' "best acuity", using a method of forced-choice preferential looking (68 infants). Peripheral acuity developed dramatically in the first months of life and reached a plateau at about 4 months. By contrast, "best acuity" continued to increase significantly during the second half of the first year of age. At all ages, peripheral acuity was lower than the resolution evaluated with the same stimuli under free-viewing conditions. We conclude that, in spite of the known immaturity of the fovea in newborns (Abramov et al. 1982), even the youngest infants we tested (2 months old) showed a functional superiority of the central over the peripheral visual field.


High-performance voltammetric sensor for dichlorophenol based on β-cyclodextrin functionalized boron-doped graphene composite aerogels.
2, 2-methylenebis (4-chlorophenol) (dichlorophenol, Dcp) is a priority pollutant that poses a serious health threat to the public. Thus, the sensitive analysis of Dcp is of great significance. Heteroatom-doped carbon nanomaterials modified electrodes have been proven to be good electrocatalysts for electrochemical sensing application. β-cyclodextrin (β-CD) as a signal amplifier has also been utilized in biosensors. Inspired by these, in this study, a new composite of β-CD and three-dimensional (3D) boron-doped graphene aerogels (BGAs/β-CD) has been designed as a high-performance electrochemical sensing platform for Dcp determination. Graphene aerogels possess high specific surface area, large pore volume and good conductivity, which ensure rapid mass transfer and accelerated electron transfer. Besides, boron doping causes uneven charge distribution on the graphene lattice surface, producing a large amount of flowing π electrons, which provide abundant active sites for the catalytic oxidation reaction of Dcp. In addition, Dcp molecules could be captured into β-CD through host-guest recognition, which can effectively amplify the detection signal. Combining the merits of BGAs and β-CD, the BGAs/β-CD based sensor achieved sensitive detection of Dcp. Under optimized experimental conditions, the oxidation currents and the concentration of Dcp had a good linear relationship within 1.0 nM ∼ 21 μM. The detection limit was estimated as 0.33 nM (S/N = 3). This study might provide a new basis for the fabrication of 3D BG-based aerogel architectural material and its application in Dcp detection.


Novel 3D-Printed Biocarriers from Aluminosilicate Materials.
The addition of biocarriers can improve biological processes in bioreactors, since their surface allows for the immobilization, attachment, protection, and growth of microorganisms. In addition, the development of a biofilm layer allows for the colonization of microorganisms in the biocarriers. The structure, composition, and roughness of the biocarriers' surface are crucial factors that affect the development of the biofilm. In the current work, the aluminosilicate zeolites 13X and ZSM-5 were examined as the main building components of the biocarrier scaffolds, using bentonite, montmorillonite, and halloysite nanotubes as inorganic binders in various combinations. We utilized 3D printing to form pastes into monoliths that underwent heat treatment. The 3D-printed biocarriers were subjected to a mechanical analysis, including density, compression, and nanoindentation tests. Furthermore, the 3D-printed biocarriers were morphologically and structurally characterized using nitrogen adsorption at 77 K (LN2), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The stress-strain response of the materials was obtained through nanoindentation tests combined with the finite element analysis (FEA). These tests were also utilized to simulate the lattice geometries under compression loading conditions to investigate their deformation and stress distribution in relation to experimental compression testing. The results indicated that the 3D-printed biocarrier of 13X/halloysite nanotubes was endowed with a high specific surface area of 711 m2/g and extended mesoporous structure. Due to these assets, its bulk density of 1.67 g/cm3 was one of the lowest observed amongst the biocarriers derived from the various combinations of materials. The biocarriers based on the 13X zeolite exhibited the highest mechanical stability and appropriate morphological features. The 13X/halloysite nanotubes scaffold exhibited a hardness value of 45.64 MPa, which is moderate compared to the rest, while it presented the highest value of modulus of elasticity. In conclusion, aluminosilicate zeolites and their combinations with clays and inorganic nanotubes provide 3D-printed biocarriers with various textural and structural properties, which can be utilized to improve biological processes, while the most favorable characteristics are observed when utilizing the combination of 13X/halloysite nanotubes.


Structural Basis for Copper-Oxygen Mediated C-H Bond Activation by the Formylglycine-Generating Enzyme.
The formylglycine-generating enzyme (FGE) is a unique copper protein that catalyzes oxygen-dependent C-H activation. We describe 1.66 Å- and 1.28 Å-resolution crystal structures of FGE from Thermomonospora curvata in complex with either AgI or CdII providing definitive evidence for a high-affinity metal-binding site in this enzyme. The structures reveal a bis-cysteine linear coordination of the monovalent metal, and tetrahedral coordination of the bivalent metal. Similar coordination changes may occur in the active enzyme as a result of CuI/II redox cycling. Complexation of copper atoms by two cysteine residues is common among copper-trafficking proteins, but is unprecedented for redox-active copper enzymes or synthetic copper catalysts.


Deviations From Best Practice: Findings From a Certified Patient Safety Organization Remote-Verification Observational Study of Intravenous Compounding of Chemotherapeutic and Ancillary Drugs.
Background: Chemotherapeutic and immunomodulatory medications can pose a serious risk to patient and healthcare provider safety because of complex processes, cytotoxicity, and prevalent medication use. Objective: To evaluate chemotherapeutic and ancillary medication compounding in hospital pharmacies using a remote verification system, focusing on pharmaceutical deviations from best practice, compounding time, medication waste, and cost. Methods: This retrospective, blinded observational study used a remote intravenous (IV) workflow verification system to examine IV chemotherapeutic compounding errors in large hospital systems. A Patient Safety Organization securely obtained >5000 compounding records and photos from the IV workflow system. Blinded pharmacists evaluated IV chemotherapy preparations using picture slide viewers to assess any deviations from best practice. Time variables, medication waste, STAT vs non-STAT orders, and cost were also evaluated. Results: The most frequently reported deviations from best practice included medications exceeding the >10% additive volume guideline (35.9%) and inaccurate dose labels (28.3%). Time flow analyses demonstrated a substantial increase in total compounding time per vial for 1 vs 2 vials. Most medications in this analysis had an average waste ranging from 0-.36 vials. STAT orders, accounting for 38.4% of all orders, wasted more medication than non-STAT orders. Gemcitabine cost analyses showed an association for number of vials and compounding time with overall cost per dose. Conclusion: Substantial inconsistencies between workflow stations were observed-highlighting the lack of standardization across chemotherapeutics, volume of medication waste during preparation, and the need to establish improved quality controls to safeguard patient and health care provider safety.


Inference of kinase-signaling networks in human myeloid cell line models by Phosphoproteomics using kinase activity enrichment analysis (KAEA).
Despite the introduction of targeted therapies, most patients with myeloid malignancies will not be cured and progress. Genomics is useful to elucidate the mutational landscape but remains limited in the prediction of therapeutic outcome and identification of targets for resistance. Dysregulation of phosphorylation-based signaling pathways is a hallmark of cancer, and therefore, kinase-inhibitors are playing an increasingly important role as targeted treatments. Untargeted phosphoproteomics analysis pipelines have been published but show limitations in inferring kinase-activities and identifying potential biomarkers of response and resistance. We developed a phosphoproteomics workflow based on titanium dioxide phosphopeptide enrichment with subsequent analysis by liquid chromatography tandem mass spectrometry (LC-MS). We applied a novel Kinase-Activity Enrichment Analysis (KAEA) pipeline on differential phosphoproteomics profiles, which is based on the recently published SetRank enrichment algorithm with reduced false positive rates. Kinase activities were inferred by this algorithm using an extensive reference database comprising five experimentally validated kinase-substrate meta-databases complemented with the NetworKIN in-silico prediction tool. For the proof of concept, we used human myeloid cell lines (K562, NB4, THP1, OCI-AML3, MOLM13 and MV4-11) with known oncogenic drivers and exposed them to clinically established kinase-inhibitors. Biologically meaningful over- and under-active kinases were identified by KAEA in the unperturbed human myeloid cell lines (K562, NB4, THP1, OCI-AML3 and MOLM13). To increase the inhibition signal of the driving oncogenic kinases, we exposed the K562 (BCR-ABL1) and MOLM13/MV4-11 (FLT3-ITD) cell lines to either Nilotinib or Midostaurin kinase inhibitors, respectively. We observed correct detection of expected direct (ABL, KIT, SRC) and indirect (MAPK) targets of Nilotinib in K562 as well as indirect (PRKC, MAPK, AKT, RPS6K) targets of Midostaurin in MOLM13/MV4-11, respectively. Moreover, our pipeline was able to characterize unexplored kinase-activities within the corresponding signaling networks. We developed and validated a novel KAEA pipeline for the analysis of differential phosphoproteomics MS profiling data. We provide translational researchers with an improved instrument to characterize the biological behavior of kinases in response or resistance to targeted treatment. Further investigations are warranted to determine the utility of KAEA to characterize mechanisms of disease progression and treatment failure using primary patient samples.


Essential food hygiene certificate examination: examination papers reviewed.
One thousand papers for the Essential Food Hygiene examination, chosen consecutively from those being processed in RSH House on 6-7 April 1994, were reviewed. The purpose of the review was to assess the impact of the redesigned course and the new examination papers which were introduced from 1 January 1994. The pass rate for the sample was 96.7% which was somewhat lower than the pass rate of 99.2% for the whole of 1993 when the previous examination papers were in use. Out of 1000 papers 33 were failures. Eighteen candidates had obtained the 70% pass mark yet still failed because one of the two questions on temperature control had been answered incorrectly. The requirement to answer both those questions correctly in order to obtain a certificate was introduced with the new examination papers and marked a major change. The conclusion from this snapshot study was that the majority of Tutors and the candidates from their courses had achieved a high degree of examination success. In particular, Tutors had secured a major objective by ensuring that trainees had a clear understanding of the concepts of temperature control. Only a minority were having difficulty. Of the 33 individuals who failed, 18 came from just four of the 108 courses.


miR-214 is Stretch-Sensitive in Aortic Valve and Inhibits Aortic Valve Calcification.
miR-214 has been recently found to be significantly downregulated in calcified human aortic valves (AVs). ER stress, especially the ATF4-mediated pathway, has also been shown to be significantly upregulated in calcific AV disease. Since elevated cyclic stretch is one of the major mechanical stimuli for AV calcification and ATF4 is a validated target of miR-214, we investigated the effect of cyclic stretch on miR-214 expression as well as those of ATF4 and two downstream genes (CHOP and BCL2L1). Porcine aortic valve (PAV) leaflets were cyclically stretched at 15% for 48 h in regular medium and for 1 week in osteogenic medium to simulate the early remodeling and late calcification stages of stretch-induced AV disease, respectively. For both stages, 10% cyclic stretch served as the physiological counterpart. RT-qPCR revealed that miR-214 expression was significantly downregulated during the late calcification stage, whereas the mRNA expression of ATF4 and BCL2L1 was upregulated and downregulated, respectively, during both early remodeling and late calcification stages. When PAV leaflets were statically transfected with miR-214 mimic in osteogenic medium for 2 weeks, calcification was significantly reduced compared to the control mimic case. This implies that miR-214 may have a protective role in stretch-induced calcific AV disease.


Higher expression of SATB2 in hepatocellular carcinoma of African Americans determines more aggressive phenotypes than those of Caucasian Americans.
In the United States, Hepatocellular Carcinoma (HCC) incidence has tripled over the past two decades. The disease has disproportionately affected minority and disadvantaged populations. The purpose of this study was to examine the expression of SATB2 gene in HCC cells derived from African Americans (AA) and Caucasian Americans (CA) and assess its oncogenic potential by measuring cell viability, spheroid formation, epithelial-mesenchymal transition (EMT), stem cell markers and pluripotency maintaining factors in cancer stem cells (CSCs). We compared the expression of SATB2 in human primary hepatocytes, HCC cells derived from AA and CA, and HCC CSCs. Hepatocellular carcinoma cells derived from AA expressed the higher level of SATB2 than those from CA. By comparison, normal human hepatocytes did not express SATB2. Higher expression of SATB2 in HCC cells from AA was associated with greater growth rate, cell viability, colony formation and EMT characteristics than those from CA. Knockout of SATB2 in CSCs by Crispr/Cas9 technique significantly inhibited the expression of SATB2 gene, stem cell markers (CD24, CD44 and CD133), pluripotency maintaining factors (c-Myc, KLF4, SOX2 and OCT4), and EMT compared with non-targeting control group. The expression of SATB2 was negatively correlated with miR34a. SATB2 rescued the miR-34a-mediated inhibition of CSC's viability. These data suggest that SATB2 is an oncogenic factor, and its higher expression may explain the disparity in HCC outcomes among AA.


18F-Fluoromisonidazole positron emission tomography (FMISO-PET) may reflect hypoxia and cell proliferation activity in oral squamous cell carcinoma.
Hypoxia is a common feature and prognostic factor in cancer. 18F-fluoromisonidazole (FMISO) positron emission tomography (PET) can detect tumor hypoxia noninvasively. The aim of this study was to assess the correlations between FMISO-PET and 18 F-fluorodexyglucose (FDG)-PET parameters with cell proliferation and hypoxia in patients with oral squamous cell carcinoma (OSCC). Twenty-three preoperative patients with OSCC were included. The tumor/muscle ratio (TMR) of FMISO-PET, the maximum standardized uptake values (SUVmax) of FDG-PET, metabolic tumor volume, and total lesion glycolysis were measured. Ki-67 and hypoxia-inducible factor-1α (HIF-1α) expression was immunohistochemically evaluated. FMISO TMR (P = .003) and FDG SUVmax (P = .04) were significantly higher in patients with high expression of Ki-67 compared with those with low expression of Ki-67. FMISO TMR (P = .006) and FDG SUVmax (P = .01) were also significantly higher in patients with HIF-1α expression than in those without HIF-1α expression. Metabolic tumor volume was not significantly related to either Ki-67 or HIF-1α expression. Multivariate analysis showed that FMISO TMR was independently predictive of Ki-67 (P = .002; odds ratio 31.1) and HIF-1α (P = .049; odds ratio 10.5) expression. FMISO-PET showed significant relationships with Ki-67 and HIF-1α expression, which are key features of cell proliferation and hypoxia in OSCC.


A review of functional neuroimaging studies of vagus nerve stimulation (VNS).
Vagus nerve stimulation (VNS) is a new method for preventing and treating seizures, and shows promise as a potential new antidepressant. The mechanisms of action of VNS are still unknown, although the afferent direct and secondary connections of the vagus nerve are well established and are the most likely route of VNS brain effects. Over the past several years, many groups have used functional brain imaging to better understand VNS effects on the brain. Since these studies differ somewhat in their methodologies, findings and conclusions, at first glance, this literature may appear inconsistent. Although disagreement exists regarding the specific locations and the direction of brain activation, the differences across studies are largely due to different methods, and the results are not entirely inconsistent. We provide an overview of these functional imaging studies of VNS. PET (positron emission tomography) and SPECT (single photon emission computed tomography) studies have implicated several brain areas affected by VNS, without being able to define the key structures consistently and immediately activated by VNS. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging), with its relatively high spatio-temporal resolution, performed during VNS, can reveal the location and level of the brain's immediate response to VNS. As a whole, these studies demonstrate that VNS causes immediate and longer-term changes in brain regions with vagus innervations and which have been implicated in neuropsychiatric disorders. These include the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla. Functional neuroimaging studies have the potential to provide greater insight into the brain circuitry behind the activity of VNS.


[Wisconsin Card Sorting Test in psychological examination of patients with psychiatric disorders].
Wisconsin Card Sorting Test is a psychological test designed to examine the working memory and the executive functions. The low scores in WCST point at disturbances in abstract reasoning, lack of flexibility in thinking and difficulties in changing reactions in response to the new stimulation from the surrounding. WCST is especially sensitive to the damages in the frontal lobe. WCST can be used in the individual examination of healthy adults, youths and children, and who people suffer from psychiatric disorders. The aim of the study is the analysis of using the WCST in psychological diagnosis of psychiatric and neurological patients who suffer from: schizophrenia, affective disorders and brain damage.


Nails and nail disorders in children and adults.
Abnormalities of the nails can provide both subtle and obvious clues to common medical problems or severe systemic diseases. Heredity, minor injuries and a variety of infections account for many changes in the appearance of nails. Several dermatologic disorders, such as psoriasis and alopecia areata, and other multisystem disorders may present with nail changes; abnormalities of the nails may be the single most prominent feature. Common habits and the use of various cosmetics also may result in nail changes. Awareness of normal nail variants and well-defined abnormalities and their disease associations will be beneficial to most clinicians. Specific management and therapy for most nail problems are usually simple and appropriate for primary care physicians.


Chondroitin Sulfate/Dermatan Sulfate-Protein Interactions and Their Biological Functions in Human Diseases: Implications and Analytical Tools.
Chondroitin sulfate (CS) and dermatan sulfate (DS) are linear anionic polysaccharides that are widely present on the cell surface and in the cell matrix and connective tissue. CS and DS chains are usually attached to core proteins and are present in the form of proteoglycans (PGs). They not only are important structural substances but also bind to a variety of cytokines, growth factors, cell surface receptors, adhesion molecules, enzymes and fibrillary glycoproteins to execute series of important biological functions. CS and DS exhibit variable sulfation patterns and different sequence arrangements, and their molecular weights also vary within a large range, increasing the structural complexity and diversity of CS/DS. The structure-function relationship of CS/DS PGs directly and indirectly involves them in a variety of physiological and pathological processes. Accumulating evidence suggests that CS/DS serves as an important cofactor for many cell behaviors. Understanding the molecular basis of these interactions helps to elucidate the occurrence and development of various diseases and the development of new therapeutic approaches. The present article reviews the physiological and pathological processes in which CS and DS participate through their interactions with different proteins. Moreover, classic and emerging glycosaminoglycan (GAG)-protein interaction analysis tools and their applications in CS/DS-protein characterization are also discussed.


Review of ICU nutrition support practices: implementing the nurse-led enteral feeding algorithm.
Many intensive care units (ICUs) have standard feeding protocols which promote safe early initiation of enteral feeding. The use of these protocols has been shown to increase the incidence of enteral feeding and achieve greater adequacy of nutrition support. A multidisciplinary working party developed and implemented a nurse-led enteral feeding algorithm which enabled senior nursing staff to set safe and nutritionally adequate target feed volumes based upon patient body weight. The algorithm incorporated best practice-based referral criteria so that patients at nutritional risk were referred for tailored dietetic assessment. The aims were to determine compliance with the ICU nurse-led enteral feeding algorithm and to ascertain its safety and efficacy. A 3-month prospective audit was conducted by specialist ICU dietitians. Data were obtained from electronic patient records and through observing feeding practices. Data collected included prescribed feed type and infusion rate versus volume received, frequency of gastric aspiration and prokinetic usage. In all, 90% (n = 43) of referrals received by the dietitian met the referral criteria. Absolute compliance with patients receiving correct type and volumes of feed, with a correct feed prescription and an accurate documented weight was just 2% (n = 1). Despite this finding, 60% of patients were actually receiving the correct feed regimen. If the nurse-led enteral feeding algorithm is wholly adhered to, the ICU dietitian need not formally assess every ICU patient. Nursing staff require further support in assessing patient body weight alongside an ongoing intensive educational programme for the multidisciplinary team and regular reaudit.


Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma.
Hypoxia stimulates hepatocellular carcinoma (HCC) cell growth via hexokinase (HK) II induction, and alternatively, HK II inhibition induces apoptosis by activating mitochondrial signaling. This study was to investigate whether the induction of HK II by hypoxia is associated with enhanced mitochondrial stability and to confirm the apoptosis-inducing efficacy of HK II inhibitor in an in vivo model of HCC. Mitochondrial stability was examined by treating isolated mitochondria with deoxycholate, a permeability-enhancing agent. Alteration of permeability transition pore complex composition was analyzed by immunoprecipitation and immunoblotting. An in vivo model of HCC was established in C3H mice i.d. implanted with MH134 cells. The antitumor efficacy of i.p. given 3-bromopyruvate (3-BrPA), a HK II inhibitor, was evaluated by measuring tumor volumes and quantifying apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining and (99m)Tc-hydrazinonicotinamide-Annexin V scans. Hypoxia enhanced mitochondrial stability, and this was inhibited by 3-BrPA treatment. In particular, HK II levels in permeability transition pore complex immunoprecipitates were reduced after 3-BrPA treatment. In mice treated with 3-BrPA, mean tumor volumes and tumor volume growth were found to be significantly reduced. Moreover, percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly increased in 3-BrPA-treated mice, and this apoptosis-inducing efficacy was reflected in vivo by (99m)Tc-hydrazinonicotinamide-Annexin V imaging. Our results show that hypoxia enhances mitochondrial stability via HK II induction and that HK II inhibitor treatment exhibits an in vivo antitumor effect by inducing apoptosis. Therefore, HK II inhibitors may be therapeutically useful for the treatment of advanced infiltrative hypovascular HCCs, which are growing in a hypoxic environment.


Spondylodiscitis complicated by the ingestion of a button battery: a case report.
A one-and-a-half year old boy who presented with a cough, irritability, and refusal of food was found to have an impacted foreign body in his upper esophagus. We present the radiologic findings of the foreign body (a button battery) impacted in the upper esophagus and its complications; namely, mediastinitis and spondylodiscitis after endoscopic removal. Further, plain radiograph and MR imaging findings are discussed along with literature review.


Urinary biomarkers for the early diagnosis of kidney cancer.
To test the hypothesis that increased tumor expression of proteins such as aquaporin-1 (AQP1) and adipophilin (ADFP) in patients with renal cancer would result in increased urine AQP1 and ADFP excretion. Prenephrectomy and postnephrectomy (pseudocontrol) urine samples were collected from 42 patients with an incidental radiographically discovered renal mass and presurgical presumptive diagnosis of kidney cancer from July 8, 2008, through March 10, 2009. Also enrolled were 15 control patients who underwent nonrenal surgery and 19 healthy volunteers. Urine AQP1 and ADFP concentrations normalized to urine creatinine were determined by sensitive and specific Western blot assays. Mean +/- SD preexcision urine AQP1 and ADFP concentrations (76+/-29 and 117+/-74 arbitrary units, respectively) in patients with a pathologic diagnosis of clear cell (n=22) or papillary (n=10) cancer were significantly greater than in patients with renal cancer of nonproximal tubule origin, control surgical patients, and healthy volunteers (combined values of 0.1+/-0.1 and 1.0+/-1.6 arbitrary units, respectively; n=44; P<.001). The AQP1 and ADFP concentrations decreased 88% to 97% in the 25 patients with clear cell or papillary cancer who provided postnephrectomy follow-up urine samples. In patients with clear cell and papillary carcinoma, a linear correlation (Spearman) was found between tumor size and preexcision urine AQP1 or ADFP concentration (r=0.82 and 0.76, respectively; P<.001 for each). Urine AQP1 and ADFP concentrations appear to be sensitive and specific biomarkers of kidney cancers of proximal tubule origin. These biomarkers may be useful to diagnose an imaged renal mass and screen for kidney cancer at an early stage. clinicaltrials.gov Identifier: NCT00851994.


No Association of Polymorphisms in Nav1.7 or Nerve Growth Factor Receptor Genes with Trigeminal Neuralgia.
Trigeminal neuralgia is defined as a sudden severe shock-like pain within the distribution of the trigeminal nerve. Pain is a subjective experience that is influenced by gender, culture, environment, psychological traits, and genes. Sodium channels and nerve growth factor play important roles in the transmission of nociceptive signals and pain. The aim of this study was to investigate the occurrence of Nav1.7 sodium channel and nerve growth factor receptor TrkA gene polymorphisms (SCN9A/rs6746030 and NTRK1/rs633, respectively) in trigeminal neuralgia patients. Ninety-six subjects from pain specialty centers in the southeastern region of Brazil were divided into 2 groups: 48 with classical trigeminal neuralgia diagnosis and 48 controls. Pain was evaluated using the visual analog scale and multidimensional McGill Pain Questionnaire. Genomic DNA was obtained from oral swabs in all individuals and was analyzed by real-time polymerase chain reaction. No association was observed between evaluated polymorphisms and trigeminal neuralgia. For allele analyses, patients and controls had similar frequencies for both genes. Genotype distribution or allele frequencies of polymorphisms analyzed here did not correlate to pain scores. Although no association of evaluated polymorphisms and trigeminal neuralgia diagnosis or pain severity was observed, our data do not exclude the possibility that other genotypes affecting the expression of Nav1.7 or TrkA are associated with the disease. Further studies should investigate distinct genetic polymorphisms and epigenetic factors that may be important in expression of these molecules.


DNA polymorphism in B-domain of the estrogen receptor-alpha among Japanese women.
A silent mutation in B-domain of the estrogen receptor-alpha (ER B) change codon 87 (from GCG to GCC) is clinically correlated with frequent spontaneous abortion and familial history of breast cancer among Caucasian patients. However, none of the 167 Japanese female patients and 46 Japanese female healthy volunteers showed ER B variant. Therefore, this DNA polymorphism might involve a genetic racial difference, and appears not to be correlated with frequent spontaneous abortion or familial history of breast cancer at least among Japanese women.


Delayed onset of peroneal neuropathy after minor ankle torsion in a 9-year-old boy.
Ankle sprain is only rarely reported as the cause of peroneal nerve palsy and occurs predominantly in adults. Peroneal nerve palsy following an ankle sprain is extremely rare in children. Furthermore, peroneal nerve palsy most commonly results from a severe ankle sprain with considerable pain and edema. Peroneal nerve palsy after minor ankle torsion without major clinical symptoms of ankle sprain is uncommon. Here, we report the case of a 9-year-old boy who developed right peroneal neuropathy, leading to foot drop, following minor ankle plantar flexion/inversion torsion. Electrophysiological findings confirmed a focal neuropathy around the fibular head. The neurologic symptoms resolved completely 4 months after the injury. This case emphasizes that peroneal neuropathy can occur after minor ankle torsion without evident ankle sprain symptoms. Moreover, electrophysiological evaluation is very helpful to confirm the diagnosis and is important for prognostic evaluation.


[Cerebrolysin Treatment Reduces the Risk of Mild Cognitive Decline to Dementia in 1st-Degree Relatives of Alzheimer's Patients: A Prospective Comparative Study].
To evaluate the long-term effects of annual course therapy with Cerebrolysin on cognitive functioning and the risk of transition to dementia in relatives of patients with Alzheimer's disease (AD) with amnestic-type mild cognitive decline syndrome (aMCI) in comparison with the same group untreated relatives. The cohort included 88 first-degree relatives of BA patients with aMCI syndrome aged 50 to 82 years (mean age 65.0±9.9 years) of which 46 people received course therapy with Cerebrolysin and 42 people were not treated. Clinical, neuropsychological, statistical methods were used. Conducted annual course therapy with Cerebrolysin (a total of 3 courses of infusion therapy: for a course of 20 intravenous infusions of 20 ml of Cerebrolysin in 100 ml of isotonic saline) followed by a follow-up study after 3 months after the end of the therapeutic period. The dynamics of cognitive functioning in the therapeutic group was compared with the corresponding dynamics in the comparison group over the same period. The assessment was carried out on day 0, by the end of 1, 14, 27 and 30 months research. In the therapeutic group, according to the CGI-I scale, by the end of the 3rd course of therapy, in 95.7% of cases, a pronounced or moderate improvement was achieved after each of the courses on all scales and tests. In this group, by the end of the therapeutic period, a significant improvement in the initial mean group scores was established. According to the all scales and tests, a significant improvement of the initial average group scores was found after each course of therapy (p<0.05). In the comparison group there was a significant deterioration (p<0.05) of the average group scores of most of the cognitive scales and test by the end of the observation. The annual conversion from aMCI to dementia due to probable AD was 9.5% only in the comparison group. The average group indicators of all scales and tests significantly worsened starting from the 14th month of observation in the comparison group. The absence of cases of aMCI conversion to dementia in the treated patients for 2.5 years of observation can serve as confirmation of a disease-modifying effect in Cerebrolysin. These results indicate the need for more extensive clinical studies of the preventive effects of Cerebrolysin and to explore the possibility of including such therapy in drug prevention programs for AD in people at high risk for this disease.


Molecular-like hierarchical self-assembly of monolayers of mixtures of particles.
We present a technique that uses an externally applied electric field to self-assemble monolayers of mixtures of particles into molecular-like hierarchical arrangements on fluid-liquid interfaces. The arrangements consist of composite particles (analogous to molecules) which are arranged in a pattern. The structure of a composite particle depends on factors such as the relative sizes of the particles and their polarizabilities, and the electric field intensity. If the particles sizes differ by a factor of two or more, the composite particle has a larger particle at its core and several smaller particles form a ring around it. The number of particles in the ring and the spacing between the composite particles depend on their polarizabilities and the electric field intensity. Approximately same sized particles form chains (analogous to polymeric molecules) in which positively and negatively polarized particles alternate.


[Progress of effect and mechanisms of Tripterygium wilfordii on immune system].
Traditional Chinese medicine Tripterygium wilfordii Hook.f( TWHF) is a natural botanical drug in China. It has complex chemical compositions and has been used for a long history. TWHF was used as an insecticide to protect crops at early stage,and it was later found to have significant effects in the treatment of rheumatoid arthritis,attaining great concerns. With further researches,it was found that TWHF can treat various diseases in the medical field due to a variety of pharmacological activities such as anti-cancer,neuroprotection,anti-inflammatory and immune-suppressing,particularly. Multiple extracts of TWHF have unique immunosuppressive function,playing an immune role through multi-target and multi-channel,with significant effect in the treatment of autoimmune diseases. As an immune-suppressing drug,TWHF is worthy of in-depth research due to its broad application prospects. While achieving good clinical efficacy,reports about its toxic effects to multiple systems of the body are also increasing,greatly hindering its clinical application. In order to fully understand the immune-suppressing function of TWHF and reduce or avoid the occurrence of toxic and side effects,we summarized recent progress of TWHF on the immune organs,cells and factors in recent years,as well as the pharmacology and toxic effects,hoping to provide a scientific and reasonable reference for its wider use in clinical treatment.


Attach-Pull-Release Calculations of Ligand Binding and Conformational Changes on the First BRD4 Bromodomain.
Bromodomains, protein domains involved in epigenetic regulation, are able to bind small molecules with high affinity. In the present study, we report free energy calculations for the binding of seven ligands to the first BRD4 bromodomain, using the attach-pull-release (APR) method to compute the reversible work of removing the ligands from the binding site and then allowing the protein to relax conformationally. We test three different water models, TIP3P, TIP4PEw, and SPC/E, as well as the GAFF and GAFF2 parameter sets for the ligands. Our simulations show that the apo crystal structure of BRD4 is only metastable, with a structural transition happening in the absence of the ligand typically after 20 ns of simulation. We compute the free energy change for this transition with a separate APR calculation on the free protein and include its contribution to the ligand binding free energies, which generally causes an underestimation of the affinities. By testing different water models and ligand parameters, we are also able to assess their influence in our results and determine which one produces the best agreement with the experimental data. Both free energies associated with the conformational change and ligand binding are affected by the choice of water model, with the two sets of ligand parameters affecting their binding free energies to a lesser degree. Across all six combinations of water model and ligand potential function, the Pearson correlation coefficients between calculated and experimental binding free energies range from 0.55 to 0.83, and the root-mean-square errors range from 1.4-3.2 kcal/mol. The current protocol also yields encouraging preliminary results when used to assess the relative stability of ligand poses generated by docking or other methods, as illustrated for two different ligands. Our method takes advantage of the high performance provided by graphics processing units and can readily be applied to other ligands as well as other protein systems.


The effect of range overlap on ecological niche divergence depends on spatial scale in monkeyflowers.
Patterns of niche divergence and geographical range overlap of closely related species provide insights into the evolutionary dynamics of ecological niches. When ranges overlap, shared selective pressures may preserve niche similarity along coarse-scale macrohabitat axes (e.g., bioclimates). Alternatively, competitive interactions may drive greater divergence along local-scale microhabitat axes (e.g., micro-topographical features). We tested these hypotheses in 16 species pairs of western North American monkeyflowers (Erythranthe and Diplacus, formerly Mimulus) with estimations of species' niches, geographic ranges, and a robust phylogeny. We found that macrohabitat niche divergence decreased with increasing range overlap, consistent with convergent selection operating at a coarse scale. No significant relationship was detected for microhabitat niches. Additionally, niche divergence was greater for recently diverged pairs along all macrohabitat niche axes, but greater for distantly diverged pairs along one microhabitat axis related to vegetation cover. For species pairs with partially overlapping ranges, greater microhabitat divergence was detected in sympatry than in allopatry for at least one niche axis for three of four pairs, consistent with character displacement in sympatry. Thus, coarse- and local-scale niche divergence show dissimilar patterns in relation to range overlap and divergence time, perhaps because the relative importance of convergent versus divergent selection depends on spatial scale.


Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia.
Aggressive natural killer-cell leukemia (ANKL) is a rare, lethal disease with pathologic features that are underdescribed in the literature, particularly in Western nations. In addition, although data on the molecular pathogenesis of ANKL has been reported, evaluation of such data in a clinicopathologic context remains limited. Patients diagnosed with ANKL were identified retrospectively. Detailed demographic and clinicopathologic data were analyzed. We assessed novel markers by immunohistochemistry and performed targeted next-generation sequencing analysis. The study group included 9 men and 3 women with a median age at diagnosis of 47.5 years (range, 20 to 75 y). Two distinct patterns of bone marrow involvement were identified: interstitial and sinusoidal. The neoplastic cells were positive for CD56 and CD94, and negative for surface CD3, CD5, and CD57 in all cases assessed. They were also positive for CD2 (10/12), c-MYC (6/8), BCL2 (6/8), CD16 (5/7), EBER (9/12), CD7 (6/11), pSTAT3 (3/8), CD8 (2/6), PD-L1 (2/8), CD4 (2/11), CD8 (2/6), and CD158 (1/5). Aberrant p53 expression was identified in most (7/8) cases; p53 was strongly expressed in 4 cases. Conventional cytogenetic analysis showed clonal abnormalities in 5 of 12 cases. TP53 mutations were detected in 3 of 6 cases, whereas ASXL1 and TET2 mutations were each detected in 2 of 6 cases. Patients had very poor outcomes despite intensive chemotherapy, with a median survival of 2 months. ANKL exhibits 2 distinct patterns of tissue involvement. Neoplastic cells in ANKL are commonly positive for c-MYC and EBER, and they have a high frequency of p53 overexpression, frequently with corresponding TP53 mutations.


Cell cycle progression of murine sarcoma cells after x irradiation or heat shock.
DNA histograms of exponentially growing EMT-6 cells in vitro were obtained at regular time intervals after exposure at 300 rads of x rays or one hour of heat shock at 43 degrees C. After either treatment, about 70% of the cells retained clonogenicity. Irradiation induced the expected block in the G2 + M phase, resulting in an increase of cells in that phase during the first 5 hours after exposure. Heat shock caused a block in both the S and G2 +M phases.


Free Gingival Graft to Increase Keratinized Mucosa after Placing of Mandibular Fixed Implant-Supported Prosthesis.
Insufficiently keratinized tissue can be increased surgically by free gingival grafting. The presence or reconstruction of keratinized mucosa around the implant can facilitate restorative procedure and allow the maintenance of an oral hygiene routine without irritation or discomfort to the patient. The aim of this clinical case report is to describe an oral rehabilitation procedure of an edentulous patient with absence of keratinized mucosa in the interforaminal area, using a free gingival graft associated with a mandibular fixed implant-supported prosthesis. The treatment included the manufacturing of a maxillary complete denture and a mandibular fixed implant-supported prosthesis followed by a free gingival graft to increase the width of the mandibular keratinized mucosa. Free gingival graft was obtained from the palate and grafted on the buccal side of interforaminal area. The follow-up of 02 and 12 months after mucogingival surgery showed that the free gingival graft promoted peri-implant health, hygiene, and patient comfort. Clinical Significance. The free gingival graft is an effective treatment in increasing the width of mandibular keratinized mucosa on the buccal side of the interforaminal area and provided an improvement in maintaining the health of peri-implant tissues which allows for better oral hygiene.


Cystic fibrosis alpha 2-macroglobulin protease interaction in vitro.
alpha 2-Macroglobulin was purified from plasma of five cystic fibrosis patients and five normal controls. SDS gel electrophoresis of native alpha 2-macroglobulin from cystic fibrosis patients and normal donors showed identical subunit molecular weights, as did trypsin cleavage products. Cystic fibrosis and control alpha 2-macroglobulins were indistinguishable by isoelectric focusing and exhibited appropriate shifts in isoelectric point following binding of trypsin. The trypsin-binding capacities of control and cystic fibrosis alpha 2-macroglobulins did not differ, nor did the esterolytic activity of the trypsin-alpha 2-macroglobulin complexes.


Astrocyte function from information processing to cognition and cognitive impairment.
Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer's disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities.


The effect of galanin on baseline and GHRH-induced growth hormone secretion in obese children.
We have evaluated the effect of the administration of galanin (Gal), a newly identified hypothalamic peptide, on baseline and GHRH-induced GH rise in five obese children and in seven controls. The GH response to GHRH (hpGRF(1-29), 1 microgram/kg i.v.), and to Gal (15 micrograms/kg/h for 1 h), evaluated both as the maximum GH peak and as integrated area under the curve (AUC), was significantly lower in the obese children than in the controls. Simultaneous administration of Gal plus GHRH significantly increased the GH response to GHRH in all the obese subjects, so that their mean peak GH levels and AUC after Gal plus GHRH were similar to those of the control children after GHRH. Also, in control children Gal caused a significant augmentation of the GH response to GHRH. Mean peak GH levels and mean AUC after Gal plus GHRH were significantly higher in the controls than in the obese children given the same treatment. Our data indicate that obese children have a blunted GH response to Gal, which, however, is able to enhance the GH response to GHRH. This observation strengthens the view that the mechanism of action of Gal involves modulation of endogenous somatostatin (SRIH) release. In addition, similarity between the effects of Gal and pyridostigmine on baseline and GHRH-stimulated GH release in obese children may indicate the existence of a cholinergic link in the action of Gal.


Extending the boundaries of occupational health psychology: state-of-the-art reviews. II.
The nature of work changes over the life course for both men and women, yet the substance and meaning of both paid and unpaid activities varies considerably by gender. The articles in this special section extend the study of work and health by applying an ecology of the life course perspective to retirement, by extending the definition of work to include unpaid activity outside formal employment, and by examining the elements of causal analysis in longitudinal studies.


The effect of parachlorophenylalanine and active immunization against vasoactive intestinal peptide on reproductive activities of broiler breeder hens photostimulated with green light.
Photostimulation of retinal photoreceptors appears to inhibit reproductive activity in birds. In the present study, the involvement of serotonin and vasoactive intestinal peptide was investigated in relation to reproductive failure associated with retinal photostimulation. Hens at 23 wk of age were divided into six rooms equipped with individual cages. At 24 wk of age, three rooms were photostimulated (14L:10D) with white light (control). Three rooms had two parallel lighting systems, red (660 nm) and green (560 nm), which were both on during 6 h of the 14-h light period. Upon photostimulation, the red light was turned off after 6 h, and the green light was left on for a total of 14 h (Green). Five hens from each room served as controls, five hens were immunized against vasoactive intestinal peptide, and five hens received parachlorophenylalanine, an inhibitor of serotonin biosynthesis. Parachlorophenylalanine treatment increased reproductive performance and mRNA expression of GnRH-I, LH-beta and FSH-beta (P < 0.05) in the Green group to levels which did not differ from those of the White (control) group. Immunization against vasoactive intestinal peptide reduced plasma concentration and pituitary mRNA expression of prolactin but did not affect expression of gonadal axis genes. Collectively, the results suggest that retinal photostimulation inhibits the reproductive axis through serotonin and not through vasoactive intestinal peptide.


Who will benefit more from maintenance therapy of metastatic colorectal cancer?
Whether there is a difference in the efficacy of maintenance treatment for metastatic colorectal cancer (mCRC) between patients who achieve complete response (CR)/partial response (PR) and those with stable disease (SD) after induction treatment is controversial. PubMed, Cochrane Systematic Reviews, the Cochrane Collaboration Central Register of Controlled Clinical Trials, ClinicalTrials.gov, and databases of conferences were queried to identify randomized controlled trials evaluating the efficacy of maintenance treatment for mCRC patients. The search included articles dated from the inception of these resources until June 20, 2017. We estimated hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Network meta-analysis was performed to compare the efficacy of four regimens as maintenance treatment. Three randomized controlled trials comprising 1,301 patients were included in this network meta-analysis. Patients who achieved CR/PR after induction therapy benefited more from maintenance treatment than patients who achieved SD (PFS: HR [CR/PR] 1.50, 95% CI 1.09-2.08, vs. HR [SD] 1.35, 95% CI 1.04-1.74; OS: HR [CR/PR] 1.04, 95% CI 0.94-1.15, vs. HR [SD] 1.03, 95% CI 0.99-1.07). The results of network meta-analysis suggested that chemotherapy alone and observation were inferior to chemotherapy plus bevacizumab as maintenance treatment. Patients with mCRC who achieve CR/PR after induction therapy might benefit more from maintenance treatment than those with SD. Chemotherapy plus bevacizumab was the most appropriate regimen for maintenance treatment.


Influence of the facet joint angle on facet joint degeneration following pedicle screw fixation without fusion in thoracolumbar fractures.
Posterior approach pedicle screw fixation without fusion is widely used in the treatment of neurologically intact type A3 thoracolumbar fractures. To analyze the influence of the facet joint (FJ) angle on FJ degeneration following posterior approach pedicle screw fixation without fusion in neurologically intact type A3 thoracolumbar fractures. Fifty-eight patients who underwent pedicle screw fixation via the traditional posterior approach (n= 28) or the Wiltse approach (n= 30) were enrolled. A CT scan was performed before fixation and before fixation removal (Within 1.5 to 2 years after fixation) to evaluate the FJs parameters, including FJ inclination (FJI), FJ tropism (FJT), FJ violation, and FJ degeneration grade (FJDG), of three fixed segments and the adjacent segment below the fixed segments. There was no significant difference in FJ violation rate, FJDG deterioration, or FJ angle between the two groups (P> 0.05). FJDG deterioration showed a weak positive correlation with FJI and FJT before fixation, and the angular change in FJI (P< 0.05); and FJT before fixation and the angular change in FJI were risk factors for FJDG deterioration (P< 0.01). The Wiltse approach did not increase the rate of FJDG deterioration and FJs angle changes. However, the FJT before fixation and the angular change in FJI were risk factors for FJDG deterioration.


Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation.
Aberrant expression of proteins often underlies many diseases, including cancer. A recently developed approach in drug development is small molecule-mediated, selective degradation of dysregulated proteins. We have devised a protein-knockdown system that utilizes chimeric molecules termed specific and nongenetic IAP-dependent protein erasers (SNIPERs) to induce ubiquitylation and proteasomal degradation of various target proteins. SNIPER(ER)-87 consists of an inhibitor of apoptosis protein (IAP) ligand LCL161 derivative that is conjugated to the estrogen receptor α (ERα) ligand 4-hydroxytamoxifen by a PEG linker, and we have previously reported that this SNIPER efficiently degrades the ERα protein. Here, we report that derivatization of the IAP ligand module yields SNIPER(ER)s with superior protein-knockdown activity. These improved SNIPER(ER)s exhibited higher binding affinities to IAPs and induced more potent degradation of ERα than does SNIPER(ER)-87. Further, they induced simultaneous degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and delayed degradation of X-linked IAP (XIAP). Notably, these reengineered SNIPER(ER)s efficiently induced apoptosis in MCF-7 human breast cancer cells that require IAPs for continued cellular survival. We found that one of these molecules, SNIPER(ER)-110, inhibits the growth of MCF-7 tumor xenografts in mice more potently than the previously characterized SNIPER(ER)-87. Mechanistic analysis revealed that our novel SNIPER(ER)s preferentially recruit XIAP, rather than cIAP1, to degrade ERα. Our results suggest that derivatized IAP ligands could facilitate further development of SNIPERs with potent protein-knockdown and cytocidal activities against cancer cells requiring IAPs for survival.


[Iron deficiency : a new target in treating chronic heart failure ?]
Iron deficiency is now recognized as an independent predictor of poor outcome in patients with chronic heart failure and reduced left ventricular ejection fraction. In randomized controlled trials, treatment with ferric carboxymaltose results in improvement in functional capacity, symptoms and quality of life, and might reduce hospitalizations. Thus, the recent European Society of Cardiology guidelines on heart failure recommend treating these patients with intravenous ferric carboxymaltose, whether or not anemic.


Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system.
During recent years, novel insights in basic immunology and advances in biotechnology have contributed to an increased understanding of the pathogenetic mechanisms of immune-mediated disorders of the peripheral nervous system. This increased knowledge has an impact on the management of patients with this class of disorders. Current advances are outlined and their implication for therapeutic approaches addressed. As a prototypic immune-mediated neuropathy, special emphasis is placed on the pathogenesis and treatment of the Guillain-Barré syndrome and its variants. Moreover, neuropathies of the chronic inflammatory demyelinating, multifocal motor, and nonsystemic vasculitic types are discussed. This review summarizes recent progress with currently available therapies and--on the basis of present immunopathogenetic concepts--outlines future treatment strategies.


Influenza a virus polymerase is an integral component of the CPSF30-NS1A protein complex in infected cells.
The NS1A protein of influenza A virus binds the cellular CPSF30 protein, thereby inhibiting the 3'-end processing of all cellular pre-mRNAs, including beta interferon pre-mRNA. X-ray crystallography identified the CPSF30-binding pocket on the influenza virus A/Udorn/72 (Ud) NS1A protein and the critical role of two hydrophobic NS1A amino acids outside the pocket, F103 and M106, in stabilizing the CPSF30-NS1A complex. Although the NS1A protein of the 1997 H5N1 influenza A/Hong Kong/483/97 (HK97) virus contains L (not F) at position 103 and I (not M) at position 106, it binds CPSF30 in vivo to a significant extent because cognate (HK97) internal proteins stabilize the CPSF30-NS1A complex in infected cells. Here we show that the cognate HK97 polymerase complex, containing the viral polymerase proteins (PB1, PB2, and PA) and the nucleocapsid protein (NP), is responsible for this stabilization. The noncognate Ud polymerase complex cannot carry out this stabilization, but it can stabilize CPSF30 binding to a mutated (F103L M106I) cognate Ud NS1A protein. These results suggested that the viral polymerase complex is an integral component of the CPSF30-NS1A protein complex in infected cells even when the cognate NS1A protein contains F103 and M106, and we show that this is indeed the case. Finally, we show that cognate PA protein and NP, but not cognate PB1 and PB2 proteins, are required for stabilizing the CPSF30-NS1A complex, indicating that the NS1A protein interacts primarily with its cognate PA protein and NP in a complex that includes the cellular CPSF30 protein.


Action of rat prolactin on plasma somatomedin levels in the rat and on somatomedin release from perfused rat liver.
Rat prolactin at a concentration of 50 ng/ml perfusion medium stimulated the production of somatomedin-like activity (SLA) from the perfused liver of normal rats. The effect was demonstrable in perfusions performed at 11.00 h in which rat prolactin caused a mean (+/- S.E.M.) increase in the uptake of [35S]sulphate into rat costal cartilage in vitro of 64 +/- 14% in comparison with controls, but at 15.00 h no effect was observed. No effect or rat prolactin on hypophysectomized rat liver was detectable at 11.00 h. Hypophysectomized and sham-operated rats were given five intravenous injections of 50 microgram rat prolactin or a similar volume of hormone solvent at 12 h intervals. Plasma somatomedin activity (SMA) and cartilage metabolism, measured by the uptake of radioactive sulphate and thymidine by costal cartilage in vitro, were similar in hypophysectomized animals given rat prolactin or hormone solvent. Sham-operated rats given rat prolactin showed a significant increase of plasma SMA and cartilage metabolism compared with control animals. The production of SLA by rat liver in response to rat prolactin may be related to the density of specific hepatic lactogenic receptors, since these are absent or present only in low numbers in hypophysectomized animals.


β-Cell protection and antidiabetic activities of Crassocephalum crepidioides (Asteraceae) Benth. S. Moore extract against alloxan-induced oxidative stress via regulation of apoptosis and reactive oxygen species (ROS).
Medicinal plants are becoming more popular in the treatment of various diseases because of the adverse effects of the current therapy, especially antioxidant plant components such as phenols and flavonoids have a protective role against oxidative stress-induced degenerative diseases like diabetes. Thus, the purpose of this study was to investigate β-cell protection and antidiabetic activities of Crassocephalum crepidioides (Asteraceae) Benth. S. Moore. The in-vitro study was conducted by the pancreatic β-cell culture and α-amylase inhibition technique which includes two methods, namely starch-iodine method and 3,5-dinitrosalicylic acid (DNSA) method. On the other hand, the in-vivo study was performed by oral glucose tolerance test (OGTT) method and alloxan-induced diabetes method by using Wistar albino rat. At the end pancreatic specimens were removed and processed for histopathological study. The plant extract showed significant (*p < 0.05, **p < 0.01) effect on hyperglycemia as compared to standard (Gliclazide) in OGTT. The plant extract showed efficient protection activity of pancreatic β-cell from cell death in INS-1 cell line by significantly reduced (*p < 0.05, **p < 0.01) the levels alloxan-induced apoptosis and intracellular reactive oxygen species (ROS) accumulation. In addition, the plant extract showed a significant (*p < 0.05, **p < 0.01) effect on hyperglycemia by increases in percent of β-cells present in each islet (45% - 60%) compared to the diabetic group. The result showed that C. crepidioides had β-cell protection and antidiabetic activities in pancreatic β-cell culture and Wistar albino rat.


Morphological changes of human teeth with Er:YAG laser irradiation.
The purpose of this study was to investigate morphological changes in human enamel and dentin structures irradiated with the use of an Er:YAG laser. Despite the high number of research projects concerned with digital applications of lasers, few studies have targeted the effects of Er:YAG laser irradiation on human enamel or dentin structures. Enamel and dentin surfaces of 40 extracted human teeth were irradiated for 5 seconds with a 2.94 microns wavelength, at an output of 300 mJ. Histological and scanning electron microscope studies were then performed to determine the morphological changes in the enamel and dentin structures of those teeth. The Er:YAG laser beam produced defects without signs of serious thermal damage to enamel or dentin. Undesirable thermal effects such as surface cracking or carbonization were not observed. Histological examinations revealed the presence of a thin basophilic line at the bottom and along the walls of defects in the dentin. These morphological changes were evidence of minimal thermal damage to surrounding tissue. These findings suggest that it is possible to remove the enamel and dentin using Er:YAG laser irradiation with minimal thermal changes. However, the mechanism involved in the ablation of enamel and dentin by Er:YAG laser irradiation has not been clarified in this study. Therefore, more research is necessary before the Er:YAG laser can be used clinically in the future.


Risk factors for conversion to conventional laparoscopic cholecystectomy in single incision laparoscopic cholecystectomy.
The aim of this study was to investigate the risk factors for conversion to conventional laparoscopic cholecystectomy (CLC) in single incision laparoscopic cholecystectomy (SILC) along with the proposal for procedure selection guidelines in treating patients with benign gallbladder (GB) diseases. SILC was performed in 697 cases between April 2010 and July 2014. Seventeen cases (2.4%) underwent conversion to conventional LC. We compared these 2 groups and analyzed the risk factors for conversion to CLC. In univariate analysis, American Society of Anesthesiologist score > 3, preoperative percutaneous transhepatic GB drainage status and pathology (acute cholecystitis or GB empyema) were significant risk factors for conversion (P = 0.010, P = 0.019 and P < 0.001). In multivariate analysis, pathology (acute cholecystitis or GB empyema) was significant risk factors for conversion to CLC in SILC (P < 0.001). Although SILC is a feasible method for most patients with benign GB disease, CLC has to be considered in patients with acute cholecystitis or GB empyema because it is likely to result in inadequate visualization of the Calot's triangle and greater bleeding risk.


First-line treatment for osteoarthritis. Part 1: Pathophysiology, assessment, and pharmacologic interventions.
While surgical interventions often relieve severe pain for those with osteoarthritis (OA), there are thousands of patients with this common and disabling condition who do not receive surgery. Pharmacologic and nonpharmacologic interventions may offer a reduction in pain and improvement in physical functioning. To help patients with OA, nurses should conduct thorough assessments based on pathophysiology, and plan appropriate care with the patient. In this first article of a two-part series, the pathophysiology and classification of OA are presented. Assessment factors are discussed, and pharmacologic interventions are presented. Part 2 of this series, to run in the November/December issue, will focus on nonpharmacologic interventions and evaluation.


Long-term results of surgical treatment for pulmonary valve stenosis.
109 children who survived surgical treatment for isolated pulmonary valve stenosis were followed for up to 17 years. In all the postoperative status was assessed as satisfactory. Cardiac catheterization repeated in 43 gave a resting valve gradient below 40 mmHg. The 22 children whose pulmonary valves had been excised were as healthy as the 87 who had undergone pulmonary valvotomy. Consideration was given to the desirable length of postoperative review. Except for the few children with symptoms before operation, a postoperative increase in exercise tolerance was not a feature.


Sexual predators who target elders: findings from the first national study of sexual abuse in care facilities.
This article reports research findings concerning 119 alleged sexual perpetrators who were reported to state authorities for abusing elderly individuals residing in care facilities. The largest group of accused was employees of the facilities, followed by facility residents. Family members of the alleged victims and visitors to the facilities also were among those reported as sexually abusive. Investigation of the allegations by Adult Protective Services and regulatory staff resulted in 32 of these individuals being confirmed as sexual perpetrators against vulnerable elders. Male and female alleged and confirmed sexual perpetrators were identified as well as both male and female elderly sexual abuse victims. Perpetrator characteristics, victim vulnerabilities, abuse acts, locations of assaults, and available case outcomes are presented. Implications of the findings are discussed.


Inhibition of antibody formation in intrauterine varicella virus infection.
Serological and clinical follow-up of 35 pregnancies complicated with varicella-zoster virus (VZV) infection showed insufficient antibody response in 2 children with undetectable IgG levels in ELISA and indirect haemagglutination (IHA) test. Secondary infection with VZV at the age of 4 1/2 years of the first child and inapparent infection at the age of 4 years and 3 months in the second child born with congenital varicella lead to seroconversion against VZV. None of the children in question developed acquired varicella primoinfection. We believe that a temporary specific inhibition of antibody formation was caused by transplacentar transmission of maternal antibodies into foetal circulation.


In depth characterization of midbrain organoids derived from wild type iPSC lines.
The ability to model human neurological tissues in vitro has been a major hurdle to effective drug development for neurological disorders. iPSC-derived brain organoids have emerged as a compelling solution to this problem as they have the potential to relevantly model the protein expression pattern and physiology of specific brain regions. Although many protocols now exist for the production of brain organoids, few attempts have been made to do an in-depth kinetic evaluation of expression of mature regiospecific markers of brain organoids. To address this, we differentiated midbrain-specific brain organoids from iPSC-lines derived from three apparently healthy individuals using a matrix-free, bioreactor method. We monitored the expression of midbrain-specific neuronal markers from 7 to 90-days using immunofluorescence and immunohistology. The organoids were further characterized using electron microscopy and RNA-seq. In addition to serving as a potential benchmark for the future evaluation of other differentiation protocols, the markers observed in this study can be useful as control parameters to identify and evaluate the disease phenotypes in midbrain organoid derived from patient iPSC-lines with genetic neurological disorders.


Blood pressure measurement in hemodialysis patients.
Measurement of blood pressure (BP) poses some unique challenges in hemodialysis patients. Timing of BP measurement in relation to dialysis, changes in interdialytic weight gain, and inconsistent BP measurement technique in dialysis units contribute to the variability of BP readings in this population. This may contribute to the equivocal relationship between hypertension and cardiovascular outcomes documented in several epidemiologic studies in this population. Home BP readings are promising, but need to be validated as a measure of the burden of hypertension in this population. It is important to standardize BP measurement in all hemodialysis units according to published guidelines to improve the management of hypertension. Future research studies should carefully validate the technique used to measure BP.


The balance between apoptosis and autophagy regulates testis regression and recrudescence in the seasonal-breeding South American plains vizcacha, Lagostomus maximus.
Mammalian testis undergoes deep changes in their architecture and function during photoregression conditions in seasonal breeders. Particularly, the testicular mechanisms that regulate the transition between the active (functional) and inactive (regression) stage vary between species. The aim of the present study was to analyze the incidence of proliferation, apoptosis and autophagy in the testicular seminiferous ephitelium of a seasonal breeder, Lagostomus maximus, during the annual reproductive cycle. We observed that proliferating spermatogonia increased from the active testis until reaching the maximum peak in the activating testis. During the annual reproductive cycle, the quantity of apoptotic-TUNEL positive spermatogonia and meiotic germ cells was constant and this might be regulated by the members of the BCL2 family. Only in the activating testis, apoptosis of germ cells was almost undetectable. The analysis of the autophagic-related proteins BECN1 and LC3 showed their localization in Leydig cells and the germ cells in the active and activating testis. In the inactive testis, BECN1 and LC3 ceased to be immunolocalized within the seminiferous tubules and the mRNA expression of both regulators decreased. Moreover, the expression of BECN1 and LC3 and also the apoptotic index were up regulated in testicular cultures subjected to nutritional stress. These results suggest a possible interaction between apoptosis and autophagy in the active and activating testis (characterized by high metabolic requirement and nutrient), where autophagy could promote survival over cell death. In the inactive testis, the absence of autophagic-related proteins might explain the massive loss of germ cells, suggesting that autophagy plays new and key role in the alterations of the seminiferous epithelium during photoregression.


Predicting aberrant CpG island methylation.
Epigenetic silencing associated with aberrant methylation of promoter region CpG islands is one mechanism leading to loss of tumor suppressor function in human cancer. Profiling of CpG island methylation indicates that some genes are more frequently methylated than others, and that each tumor type is associated with a unique set of methylated genes. However, little is known about why certain genes succumb to this aberrant event. To address this question, we used Restriction Landmark Genome Scanning to analyze the susceptibility of 1,749 unselected CpG islands to de novo methylation driven by overexpression of DNA cytosine-5-methyltransferase 1 (DNMT1). We found that although the overall incidence of CpG island methylation was increased in cells overexpressing DNMT1, not all loci were equally affected. The majority of CpG islands (69.9%) were resistant to de novo methylation, regardless of DNMT1 overexpression. In contrast, we identified a subset of methylation-prone CpG islands (3.8%) that were consistently hypermethylated in multiple DNMT1 overexpressing clones. Methylation-prone and methylation-resistant CpG islands were not significantly different with respect to size, C+G content, CpG frequency, chromosomal location, or promoter association. We used DNA pattern recognition and supervised learning techniques to derive a classification function based on the frequency of seven novel sequence patterns that was capable of discriminating methylation-prone from methylation-resistant CpG islands with 82% accuracy. The data indicate that CpG islands differ in their intrinsic susceptibility to de novo methylation, and suggest that the propensity for a CpG island to become aberrantly methylated can be predicted based on its sequence context.


Prepared to Respond? Exploring Personal Disaster Preparedness and Nursing Staff Response to Disasters.
This pilot study explored personal disaster preparedness of nursing staff and their ability and willingness to respond following a disaster. All nurses from a single hospital were invited to participate; 91 completed an online survey asking them to rate their ability and willingness to report to work following the disaster scenarios and to indicate whether they had pursued various preparedness activities. Data were analyzed by descriptive and inferential statistics using Minitab 17 Statistical Software. Participants reflected a cross-section of major acute care units and nursing specialties. The majority of participants indicated being able and willing to report to work following the disaster scenarios. Personal disaster preparedness varied, with few activities pursued by the majority. Few scenarios produced a relationship between preparedness activities and ability or willingness to report to work. Despite the majority of participants indicating they would be able and willing to report to work during a disaster, they acknowledged barriers affecting them. Most disaster scenarios showed no statistically significant relationship with preparedness activities. Nurses should consider barriers that affect their own availability for work following a disaster and identify potential solutions. Future research related to mitigation of possible barriers to surge capacity would be useful.


Predominant expression of circulating CD3+ lymphocytes bearing gamma T cell receptor in a prolonged immunodeficiency after allogeneic bone marrow transplantation.
The cell surface expression of alpha:beta heterodimer was studied using WT31 monoclonal antibody, in peripheral blood lymphocytes (PBL) from a patient who developed a prolonged immunodeficiency after allogeneic bone marrow transplantation. This patient, grafted for chronic myelogenous leukemia, received T cell depleted bone marrow from her HLA, A, B, D matched sibling. The late occurrence of opportunistic infection, led us to analyze the phenotype of patient PBL. 70% of PBL were CD3+ and 29% WT31+, indicating that the majority of CD3+ PBL did not express the alpha:beta heterodimer. Transcription of the genes encoding the alpha, beta, and gamma chains was assessed in cell lines derived from PBL, by Northern blot analysis. We showed that the CD3+ WT31- subset expressed a truncated, beta mRNA (1.0 kb) and also truncated alpha transcript (1.4 kb). To determine the CD3-associated structure on CD3+ WT31- cell line, immunoprecipitation assays were performed using monoclonal anti-CD3 and an hetero antiserum against gamma peptides. These CD3+ WT31- cells expressed a disulfide linked dimer, composed of products of gamma gene (37 kD, 40 kD) and of undefined delta chain (45 kD). Functional analyses were performed in PBL before and after sorting with WT31 and anti-CD3 antibody. These circulating CD3+ WT31- cells were unable to proliferate when triggered with anti-T3 beads and they seemed to mediate a suppressor activity on CD3+ WT31+ cells.


Transient expression of [D-Ala2] deltorphin I-like immunoreactivity in prenatal rat small intestine.
We studied the distribution of immunoreactive elements for [D-Ala2] deltorphin I (DADTI), a delta-opioid receptor ligand, in fetal and postnatal rat small intestine. DADTI-like immunoreactive cells were detected transiently on embryonic Days 20 and 21. Electron microscopic examination revealed that positive staining occurred in mucous epithelial cells, either mature goblet cells or undifferentiated cells containing only a few mucous granules. Positive immunoreaction products in mature goblet cells were confined in their apical cytoplasm to the luminal parts of mucous granule aggregates. The result suggests that a DADTI-like molecule(s) is synthesized in rat intestinal goblet cells and is secreted in a diacrine fashion into the intestinal lumen at a late fetal period. The molecule(s) thus secreted may be important for the intestine of rats just before birth, because DADTI-like immunopositive goblet cells are no longer seen at any postnatal period.


Losartan ointment relieves hypertrophic scars and keloid: A pilot study.
Keloid and hypertrophic scars are two types of fibrosis caused by extracellular matrix overexpression, and angiotensin II via AT1 receptor is known to play a key role in stimulation of fibrosis. A pilot placebo controlled single blind study was carried out on patients with hypertrophic scars and keloids. A total of 37 adult volunteers were randomly assigned into losartan 5% or placebo treatment groups. The treatment was performed twice a day for three months and a 6-month follow-up. The treatment was evaluated using Vancouver scar scale method. Totally, 30 participants were analyzed (Losartan ointment n = 20; placebo ointment n = 10; seven placebo volunteers left the study because they thought the treatment was not effective for them). In the losartan group, VSS scores dropped significantly (p < 0.01) both in keloid and hypertrophic scar patients. Vascularity and pliability were significantly reduced by losartan treatment (p < 0.05). It can be concluded that losartan potassium ointment (5%) can alleviate the keloid and hypertrophic scar.


[Damage control surgery: a review].
To present a monographic review of the damage control surgery. Consult and literature review (131 references). We analyzed these relevant articles in relation to damage control surgery. From each reference we obtain concepts, data and techniques derivates of damage control surgery. Damage control surgery is a surgical technique that attempts to avoid the triad of coagulopathy,hypothermia and acidosis through application of three phases in patients with multiple lesions. These phases are: Initial laparotomy, stabilization in ICU and definitive surgery. During initial laparotomy efforts are made to controlling the surgical and non surgical bleeding (through packing) and avoid peritoneal contamination. During the stabilization phase the hypothermia, acidosis and coagulopathy are corrected in ICU. In definitive surgery, packing is removed and makes the definitive repair of lesions. For the trauma surgeon is important the knowledge about the concepts related to damage control surgery. This is applicable to multiple trauma patients, and disaster situations like terrorism acts and natural disasters.


Immune System and Regeneration.
The review article is devoted to a role of pluripotent stem cells and immune system in renewal of tissues (regeneration). Cell-precursors (progenitor cells) and differentiated cells can be divided a limited number of times and aren't capable of ensuring regeneration of tissues during the whole process of ontogenesis. The renewal of tissues during the whole long period is impossible without the participation of a specialized system which is responsible for regeneration. The given system is made up of pluripotent stem cells which are capable of differentiating themselves into all types of somatic cells, and into a line of genital cells. These stem cells are also capable of reproducing themselves over the whole lifespan of the organism. The participation of pluripotent stem cells and the possible mediation of antigen-presenting cells and T-helpers/T-suppressors in the complex with molecules of the MHC I class/II class make it possible to consider that exactly this immune system is responsible for regeneration of tissues in the organism. The participation in the regeneration process is the most important (and perhaps the leading) function of the immune system. With age the quantity of pluripotent stem cells gradually decreases. It leads to violation of renewal of tissues at people over 35-40 years old. Transfusion of mononuclear fraction of peripheral blood procured from young donors 18-23 years old with the same blood groups and sex as the recipient (RF patent number 2350340), allows people over 40-50 years old to reestablish the pool of pluripotent stem cells and the process of tissue renewal.


Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor.
Supplemental androgen therapy has enhanced virilization in only a few patients with partial androgen insensitivity (PAIS). We herein report on virilization in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor. At the age of 19 yr, the patient sought medical attention because of undervirilization. Endocrine findings were typical for androgen insensitivity, but 5alpha-reductase activity and androgen binding characteristics in fibroblasts cultured from genital skin were normal. In an attempt to improve virilization, high dose testosterone enanthate treatment (250 mg by i.m. injection once a week) was begun. After 3.5 yr of this treatment, marked promotion of virilization was achieved, i.e. lowering of voice, male pattern secondary hair distribution, marked growth of beard and coarse body hair, increase in phallic size, increase in bone mineral density, and decrease in mammary gland size. In addition, serum lipid levels were not affected. To our knowledge this is the first documentation of successful treatment in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor.


Antioxidant and anti-ageing activities of mycelia zinc polysaccharide from Pholiota nameko SW-03.
Edible fungi polysaccharides usually exhibit antioxidant activity, and zinc has been shown to have antioxidant properties. In the present work, Pholiota nameko SW-03 was used as a vector of zinc biotransformation in order to obtain mycelia zinc polysaccharide (MZPS), and the structural characterization and anti-ageing activity of MZPS were investigated. Pholiota nameko SW-03 could accumulate zinc in the form of zinc-enriched polysaccharide, and the zinc content in MZPS was 16.39 ± 0.72 mg g(-1) . Three fractions (MZPS-1, MZPS-2 and MZPS-3) were successfully isolated. The main fraction (MZPS-2) with the highest antioxidant activity in vitro was composed of glucose, mannose, glucuronic acid, galactose, galacturonic acid and arabinose in a molar ratio of 172.59:5.29:4.61:4.20:1.01:1.00, with a weight-average molecular weight of 13.63 kDa. The anti-ageing capability was measured in d-galactose-induced ageing mice, and the results showed that MZPS could improve antioxidant status (superoxide dismutase, total antioxidant capability, malondialdehyde and lipid peroxide), indicating that MZPS had strong anti-ageing capability in vivo. This study suggested that organification of zinc through edible fungi liquid fermentation provided a novel method to produce MZPS, which might be used as a natural antioxidant to slow the progression of ageing.


Draft Genome Sequences of Mycobacterium kansasii Clinical Strains.
Mycobacterium kansasii is a nontuberculous mycobacterial (NTM) pathogen, frequently isolated from clinical samples and responsible for a large part of NTM infections in the human population. Here, we report the draft genome sequences of 12 M. kansasii strains isolated from clinical and host-associated sources from the Netherlands, Germany, and Poland.


Conversion of a Bi nanowire array to an array of Bi-Bi2O3 core-shell nanowires and Bi2O3 nanotubes.
A template-based heat-treatment method has been developed to convert metal nanowire arrays into arrays of metal-metal oxide core-shell nanowires and single-crystalline metal oxide nanotubes. This process is demonstrated by kinetically controlling the conversion of single-crystalline Bi nanowires to Bi-Bi(2)O(3) core-shell nanowires via a multistep, slow oxidation method, and then controlling their further conversion to a single-crystalline Bi(2)O(3) nanotube array via fast oxidation. This process can conveniently be extended to fabricate a free-standing, easily oxidized metal-metal oxide nanowire and metal oxide nanotube array, which may have future applications in nanoscale optics, electronics, and magnetics.


Molecular diagnostics for Chagas disease: up to date and novel methodologies.
Chagas disease is caused by the parasite Trypanosoma cruzi. It affects 7 million people, mainly in Latin America. Diagnosis is usually made serologically, but at some clinical scenarios serology cannot be used. Then, molecular detection is required for early detection of congenital transmission, treatment response follow up, and diagnosis of immune-suppression reactivation. However, present tests are technically demanding and require well-equipped laboratories which make them unfeasible in low-resources endemic regions. Areas covered: Available molecular tools for detection of T. cruzi DNA, paying particular attention to quantitative PCR protocols, and to the latest developments of user-friendly molecular diagnostic methodologies. Expert commentary: In the absence of appropriate biomarkers, molecular diagnosis is the only option for the assessment of treatment response. Besides, it is very useful for the early detection of acute infections, like congenital cases. Since current Chagas disease molecular tests are restricted to referential labs, research efforts must focus in the implementation of easy-to-use diagnostic tools in order to overcome the access to diagnosis gap.