In vitro characterization studies of self-microemulsified bosentan systems.
Bosentan is a poorly soluble drug and pose challenges in designing of drug delivery systems. The objective of this study is to enhance the solubility, dissolution and shelf-life of bosentan by formulating it as S-SMEDDS capsules. Solubility of bosentan was tested in various liquid vehicles such as oils (rice bran and sunflower), surfactants (span 20 and tween 80) and co-surfactants (PEG 400 and propylene glycol) and microemulsions were developed. Bosentan was incorporated into appropriate microemulsion systems which were previously identified from pseudo ternary phase diagrams. Bosentan-loaded SMEDDS were evaluated for drug content, drug release, zeta potential, and droplet size. The selected liquid SMEDDS were converted into solid SMEDDS by employing adsorption and melt granulation. Solid SMEDDS were characterized for micromeritics and evaluated for drug content, drug release, and shelf-life. Isotropic systems R5, R13, S5, and S13 with submicron droplet size had exhibited 85.45, 94.12, 81.67, and 96.64% drug release, respectively. Solid SMEDDS of MR13 and AS13 formulations with rapid reconstitution ability, exhibited 84.85 and 86.74% of on par drug release. The formulations were physicochemically intact for 1.02 and 1.56 years. Liquid SMEDDS composed with PEG400 had displayed optimal characters. Solid SMEDDS had high-dissolution profiles than bosentan due to modification in the crystalline structure of drug upon microemulsification. Thus, solid SMEDDS addressed the solubility, dissolution, and stability issues of bosentan and becomes an alternate for clinical convenience.


Root-zone hypoxia reduces growth of the tropical forage grass Urochloa humidicola in high-nutrient but not low-nutrient conditions.
The perennial C4 grass Urochloa humidicola is widely planted on infertile acidic and waterlogging-prone soils of tropical America. Waterlogging results in soil anoxia, and O2 deficiency can reduce nutrient uptake by roots. Interestingly, both nutrient deficiencies and soil waterlogging can enhance root cortical cell senescence, and the increased gas-filled porosity facilitates internal aeration of roots. We tested the influence of nutrient supply and root-zone O2 on root traits, leaf nutrient concentrations and growth of U. humidicola. Plants were grown in pots in a completely randomized design under aerated or stagnant deoxygenated hydroponic conditions and six nutrient regimes, with low to high concentrations of all essential elements, for 28 d in a controlled-temperature greenhouse. The standard acid solution (SAS) used was previously designed based on infertile acidic soils of the tropical America savannas, and step increases in the concentration of SAS were used in aerated or deoxygenated 0.1 % agar solution, which mimics changes in gas composition in waterlogged soils. Measurements included shoot and root growth, root porosity, root anatomy, radial O2 loss, and leaf tissue nutrient concentrations. Shoot dry mass was reduced for plants in stagnant compared with aerated conditions at high, but not at low, levels of mineral nutrition. In low-nutrition stagnant solution, roots were shorter, of greater porosity and had smaller radial thickness of the stele. Suberized lamellae and lignified sclerenchyma, as well as a strong barrier to radial O2 loss, were documented for roots from all treatments. Leaf nutrient concentrations of K, Mg and Ca (but not N, P and S) were higher in aerated than in stagnant conditions. Under low-nutrient conditions, plant growth in stagnant solution was equal to that in aerated solution, whereas under higher-nutrient regimes growth increased but dry mass in stagnant solution was less than in aerated solution. Slow growth in low-nutrient conditions limited any further response to the low O2 treatment, and greater porosity and smaller stele size in roots would enhance internal O2 movement within roots in the nutrient-limited stagnant conditions. A constitutive barrier to radial O2 loss and aerenchyma facilitates O2 movement to the tips of roots, which presumably contributes to maintaining nutrient uptake and the tolerance of U. humidicola to low O2 in the root-zone.


Memristive synapses connect brain and silicon spiking neurons.
Brain function relies on circuits of spiking neurons with synapses playing the key role of merging transmission with memory storage and processing. Electronics has made important advances to emulate neurons and synapses and brain-computer interfacing concepts that interlink brain and brain-inspired devices are beginning to materialise. We report on memristive links between brain and silicon spiking neurons that emulate transmission and plasticity properties of real synapses. A memristor paired with a metal-thin film titanium oxide microelectrode connects a silicon neuron to a neuron of the rat hippocampus. Memristive plasticity accounts for modulation of connection strength, while transmission is mediated by weighted stimuli through the thin film oxide leading to responses that resemble excitatory postsynaptic potentials. The reverse brain-to-silicon link is established through a microelectrode-memristor pair. On these bases, we demonstrate a three-neuron brain-silicon network where memristive synapses undergo long-term potentiation or depression driven by neuronal firing rates.


Nanoleakage Evaluation of Posterior Teeth Restored with Low Shrinkable Resin Composite- An invitro Study.
The effect of nanoleakage on the integrity of resin-dentin bond has been in interest for long-term adhesion. This study evaluated the nanoleakage in premolar teeth restored with low shrinkable resin composite. A total of 40 human premolars were used for nanoleakage evaluation in this study. Each group was divided into four equal groups; Group A: using silorane with its adhesive system. Group B: using silorane with G-bond. Group C: using Filtek supreme composite with G-bond. Group D: using Filtek supreme composite with AdheSE adhesive. Nanoleakage analysed using Scaning Electron Microscope (SEM) and Energy Dispersive X-Ray Spectrometery (EDX). The amount of silver present in hybrid layer depend on the adhesive used; this indicated different nanoleakage expressions in different adhesive systems. Filtek Z350 composite with G-bond showed clear silver uptake in both the adhesive and hybrid layer. Low shrinkable resin composite (silorane) with its adhesive system showed less silver penetration and slight silver peak on the elemental energy spectroscopy of energy dispersive X-Ray spectrometry (EDS) as compared to other samples. Adhesives used between different groups, influence the location and degree of nanoleakage. There is difference in nanoleakage patterns between two-step and one-step adhesives and also among the one-step adhesives themselves.


[Morphogenesis in planarians Dugesia tigrina].
We carried out computer morphometry in regenerates of planarians Dugesia tigrina. The blastema growth was analyzed in fragments of planarians after their fission and after transverse transection at different body levels. The blastema was growing at a higher rate on tail fragments than on the head fragments and the growth rate was the higher, the closer the transection was to the head end. After fission, the blastema was growing at a slower rate than after transection in the fission zone. The growth of adjacent blastemas formed on both sides after fission or transection proceeded at different rates as a function of new body polarity.


Concomitant tubercular and fungal cerebellar abscess in an immunocompromised girl.
Concomitant tubercular and fungal cerebellar abscess is rare and we report the first concomitant recurrent multi-lobulated tubercular and fungal cerebellar abscess in an immunocompromised girl with Histiocytosis-X. She presented with cerebellar abscess history diagnosed during the ongoing treatment for tuberculous meningitis. The abscess was drained. Upon the detection of cerebellar abscess recurrence and pulmonary infection, she was referred to our clinic five weeks after the first surgical intervention. Patient was conscious, co-operating but confused. She had severe cachexia, stiff neck and fever. Fundus examination showed bilateral papilledema. Cranial MR images revealed multiple lobulated lesions. Suboccipital craniectomy was performed and abscess was evacuated in toto. Lesion was multi-lobulated. Thick, yellow-gray purulent material was drained. Histopathological examinations yielded Langhans giant cells,budding and branching fungal structures. Fungal infection was identified. We emphasize that posterior decompression and total resection should be considered first in the management of lesions with mass effect in the posterior fossa. Also the presence of concomitant fatal fungal abscess highlights that although the clinic and former diagnoses of the patient may direct the clinician to a certain pathogen, unusual resistant organisms should not be.


[Functional state of the sympathoadrenal system in patients with the tuberculosis associated with HIV infection].
The results of study of adrenaline and noradrenaline concentration in urine in patients with pulmonary tuberculosis associated with HIV-infection are represented in the article. In patients with the tuberculosis/HIV by comparison to HIV-negative patients there is more high activity of the sympathoadrenal system. Revealed dependency of the functional condition of the sympathoadrenal system from volume pulmonary process. Such is a functional condition of the system can aggravate metabolic breaches and promote development to reduction of the mass of the body in patients with pulmonary tuberculosis associated with HIV-infection.


Diagnostic accuracy of midtrimester antenatal ultrasound for multicystic dysplastic kidneys.
To establish the diagnostic accuracy of obstetric ultrasound at a tertiary fetal medicine center in the prenatal detection of unilateral and bilateral multicystic dysplastic kidney (MCDK) in fetuses in which this condition was suspected, and to undertake a systematic review of the relevant literature. This was a retrospective observational study of all cases referred to a regional tertiary fetal medicine unit due to suspicion of either unilateral or bilateral MCDK between 1997 and 2015. Diagnosis was confirmed by postnatal ultrasound reports or postmortem examination. The accuracy of prenatal ultrasound in the diagnosis of MCDK was calculated. Using a systematic search strategy we also performed a review of the literature regarding the prenatal diagnosis and diagnostic accuracy of MCDK. We included 144 women in our analysis; 37 (25.7%) opted for pregnancy termination (TOP) (due to unilateral MCDK with additional abnormalities, suspected bilateral MCDK or severe obstructive uropathy). Complete pre- and postnatal data were available in 126 pregnancies, including 104 livebirths, 19 TOPs with postmortem findings available and three intrauterine fetal deaths. Two infants died shortly after birth (due to known bilateral MCDK or known cranial vault defect). The overall number of cases of MCDK confirmed postnatally was 100; of these, 98 were diagnosed prenatally (true positive), while two were thought to be hydronephrosis prenatally (false negative) and the diagnosis of MCDK was made after birth. In nine cases, the initial antenatal diagnosis of suspected MCDK was revised, either later in pregnancy (n = 2) or postnatally (n = 7) (false positive). Overall, the diagnostic accuracy in our population for the use of antenatal ultrasound to detect MCDK was 91.3%, while that reported in the existing literature was found to range from 53.3% to 100%. MCDK was isolated in the majority (71%) of cases, while in 29% of cases it was found to be associated with other renal and extrarenal fetal abnormalities. Antenatal ultrasound had a diagnostic accuracy of about 91% in the prediction of postnatal MCDK and can therefore be used to guide antenatal counseling. However, prenatal or postnatal revision of the diagnosis occurred in about 7% of cases and parents should be counseled appropriately. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Expression Status of UBE2Q2 in Colorectal Primary Tumors and Cell Lines.
Activation of the ubiquitin-proteasome pathway in various malignancies, including colorectal cancer, is established. This pathway mediates the degradation of damaged proteins and regulates growth and stress response. The novel human gene, UBE2Q2, with a putative ubiquitin-conjugating enzyme activity, is reported to be overexpressed in some malignancies. We sought to investigate the expression levels of the UBE2Q2 gene in colorectal cell lines as well as in cancerous and normal tissues from patients with colorectal cancer. Levels of UBE2Q2 mRNA in cell lines were assessed by Real-Time PCR. Western blotting was employed to investigate the levels of the UBE2Q2 protein in 8 colorectal cell lines and 43 colorectal tumor samples. Expression of UBE2Q2 was observed at the level of both mRNA and protein in colorectal cell lines, HT29/219, LS180, SW742, Caco2, HTC116, SW48, SW480, and SW1116. Increased levels of UBE2Q2 immunoreactivity was observed in the 65.11% (28 out of 43) of the colorectal carcinoma tissues when compared with their corresponding normal tissues. Difference between the mean intensities of UBE2Q2 bands from cancerous and normal tissues was statistically significant at P<0.001 (paired t test). We showed the expression pattern of the novel human gene, UBE2Q2, in 8 colorectal cell lines. Overexpression of UBE2Q2 in the majority of the colorectal carcinoma samples denotes that it may have implications for the pathogenesis of colorectal cancer.


AIDS: current implications and impact on nursing.
The pandemic proportions of human immunodeficiency virus (HIV) have already begun impacting health care in the United States. It is safe to say that in the near future nursing will have to formulate an aggressive response to this situation. This article addresses the origins of HIV and the resulting acquired immunodeficiency syndrome (AIDS) and discusses the impact on nursing. It also suggests ways in which nursing as a profession can respond to the epidemic of HIV and the fear which surrounds it.


Anoikis, extracellular matrix, and apoptosis factors in isolated cell transplantation.
Isolated cell transplantation (ICT) of pancreatic islets (PI), nerve tissue, hepatocytes, and other cells is an exciting new concept of transplantation. PI transplantation can be successful in reversing diabetes but, unlike whole pancreas, grafts have a unique and unexplained high failure rate, with over 60% loss by 3 to 6 months. We established that PI of rhesus monkeys have a high rate of death within 48 hours of isolation as a result of apoptosis, as measured with the Annexin V assay (Pharmingen, San Diego, Calif). In contrast, PI incompletely separated from the extracellular matrix (ECM) remained viable for prolonged periods in culture and performed superiorly in perifusion assays (insulin secretion of 4.6 +/- 0.8 times basal secretion). We studied the ability of the anti-AP Bcl-2 molecule, known to block anoikis (a mechanism of AP due to cell-ECM separation), to prevent apoptosis of isolated PI. PI transduced with an adenovirus-Bcl-2 gene complex showed a high viability and a low AP rate in culture versus control rhesus PI. In summary, PI protected from AP by a surrounding ECM mantle or by Adenovirol Vector (AdV) transduction of the Bcl-2 gene showed superior viability without AP in vitro and in vivo evidence of a preserved insulin secretion response to glucose.


[Economic impact of chronic, acute and global malnutrition in Peru].
To estimate the economic impact of chronic, acute and global malnutrition in Peru. This study, through an econometric model, estimated the economic impact of child malnutrition in two time horizons (incidental retrospective and prospective) during 2011, considering malnutrition-associated costs of health, education and productivity for the Peruvian economy. Information collected is a combination of data coming from the Demographic Survey of Family Health, the National Survey of Homes, the 2007 Census of Population and Housing, and public budget information, as well as estimates of risks a child is exposed to due to malnutrition during their first years of life. Nationwide it was found that in the perspective retrospective, the cost of child malnutrition in 2011 was 10,999 million soles, which was equal to 2.2% of GDP for that same year. Prospective costs nationwide, of those who by 2011 were 0 to 59 months, reached 4,505 million soles and represented 0.9% of GDP in 2011. Most cases stem from losses of productivity in both cases. Moreover, malnutrition affects much more both the Andes and jungle regions. The economic impact of child malnutrition represents a significant percentage of GDP, reason for which it is necessary to continue investing equitably in its prevention through participation with proven efficiency.


Differentiation between alpha promoter and regulator regions of herpes simplex virus 1: the functional domains and sequence of a movable alpha regulator.
The herpes simplex virus genome consists of at least three groups of genes--alpha, beta, and gamma--whose expression is coordinately regulated and sequentially ordered in a cascade fashion. We have established that the elements involved in regulation of alpha genes are a sequence that promotes gene expression and a sequence that confers alpha regulation on the gene by responding to trans-acting regulatory signals. The domains of these sequences were mapped by determining the regulation of thymidine kinase (TK) in L cells converted to TK+ phenotype by chimeric TK indicator genes. The chimeric genes were constructed from appropriate portions of the TK gene fused to donor sequences derived from the 5' nontranscribed and nontranslated leader portions of the viral alpha gene 4. The results were as follows. (i) The natural beta TK indicator extending 5' up to -80 and the chimeric alpha TK extending 5' up to -110 both converted cells to TK+ phenotype but were not regulated. (ii) A segment of the regulator region of the alpha gene 4, extending 5' from position -110, confers inducible alpha-type regulation when fused to the nonregulated but expressible beta TK indicator described above. (iii) The extent of gene induction appears to hinge on the size of the regulatory region inserted into the chimeric gene and correlates with the presence of repeated consensus sequences and G+C-rich inverted repeats in the regulatory region of the alpha gene 4 and other alpha genes.


Role of splice variants in the metastatic progression of prostate cancer.
AS (alternative splicing) and its role in disease, especially cancer, has come to forefront in research over the last few years. Alterations in the ratio of splice variants have been widely observed in cancer. Splice variants of cancer-associated genes have functions that can alter cellular phenotype, ultimately altering metastatic potential. As metastases are the cause of approximately 90% of all human cancer deaths, it is crucial to understand how AS is dysregulated in metastatic disease. We highlight some recent studies into the relationship between altered AS of key genes and the initiation of prostate cancer metastasis.


Hemorrhagic Transformations after Thrombectomy: Risk Factors and Clinical Relevance.
Hemorrhagic transformation (HT) is a major complication of acute ischemic stroke, potentially associated with clinical deterioration. We attempted to identify risk factors and evaluated clinical relevance of minor and major HTs following endovascular thrombectomy (ET) in isolated middle cerebral artery (MCA) occlusions. This is a retrospective single-center analysis of 409 patients with isolated MCA occlusion treated with ET. Patients' and procedural characteristics, severity of HT according to the European Cooperative Acute Stroke Study criteria, and clinical outcomes were analyzed. Multivariate logistic regression models with standard retention criteria (p < 0.1) were used to determine risk factors and clinical relevance of HT. Results are shown as adjusted OR (aOR) and respective 95% CIs. Good neurologic short-term outcome was defined as National Institutes of Health Stroke Scale (NIHSS) score <5 at the day of discharge. Of 299 patients included, hemorrhagic infarction (HI) was detected in 87 patients, while 13 patients developed parenchymal hematoma (PH). Higher age (aOR 0.970, 95% CI 0.947-0.993, p = 0.012), eligibility for intravenous recombinant tissue plasminogen activator (IV rtPA; aOR 0.512, 95% CI 0.267-0.982, p = 0.044), and complete recanalization (TICI 3, aOR 0.408, 95% CI 0.210-0.789, p = 0.008) were associated with a lower risk of HI. Risk factors for HI included higher admission NIHSS score (aOR 1.080, 95% CI 1.010-1.153, p = 0.024) and higher admission glucose levels (aOR 1.493, 95% CI 1.170-1.904, p = 0.001). Further, female sex tended to be associated with a lower risk of HI (aOR 0.601, 95% CI 0.316-1.143, p = 0.121), while a statistical trend was observable for proximal MCA occlusion (aOR 1.856, 95% CI 0.945-3.646, p = 0.073) and a history of hypertension (aOR 2.176, 95% CI 0.932-5.080, p = 0.072) to increase risk of HI. Longer intervals from symptom onset to first digital subtraction angiography runs (aOR 1.013, 95% CI 1.003-1.022, p = 0.009), lower preinterventional Alberta Stroke Program Early CT score (aOR 0.536, 95% CI 0.307-0.936, p = 0.028) and wake-up stroke (aOR 18.540, 95% CI 1.352-254.276, p = 0.029) were associated with PH. Both, PH and HI were independently associated with lower rates of good neurologic outcome (aOR 0.086, 95% CI 0.008-0.902, p = 0.041 and aOR 0.282, 95% CI 0.131-0.606, p = 0.001). Risk of HI following MCA occlusion and subsequent ET is mainly determined by factors influencing infarct severity. Good recanalization results seem to be protective against subsequent HI. Our results support the notion that occurrence of PH after ET is time dependent and risk increases with more extensive early ischemic damage. Both, HI and PH do not seem to be facilitated by bridging therapy with IV rtPA or the use of oral anticoagulants, but were independently associated with more severe neurologic disability. These results support the notion that HI is not a "benign" imaging sign.


Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo.
Studies in continuously cultured cells have established that familial Alzheimer's disease (FAD) mutant presenilin 1 (PS1) delays exit of the amyloid precursor protein (APP) from the trans-Golgi network (TGN). Here we report the first description of PS1-regulated APP trafficking in cerebral neurons in culture and in vivo. Using neurons from transgenic mice or a cell-free APP transport vesicle biogenesis system derived from the TGN of those neurons, we demonstrated that knocking-in an FAD-associated mutant PS1 transgene was associated with delayed kinetics of APP arrival at the cell surface. Apparently, this delay was at least partially attributable to impaired exit of APP from the TGN, which was documented in the cell-free APP transport vesicle biogenesis assay. To extend the study to APP and carboxyl terminal fragment (CTF) trafficking to cerebral neurons in vivo, we performed subcellular fractionation of brains from APP transgenic mice, some of which carried a second transgene encoding an FAD-associated mutant form of PS1. The presence of the FAD mutant PS1 was associated with a slight shift in the subcellular localization of both holoAPP and APP CTFs toward iodixanol density gradient fractions that were enriched in a marker for the TGN. In a parallel set of experiments, we used an APP : furin chimeric protein strategy to test the effect of artificially forcing TGN concentration of an APP : furin chimera that could be a substrate for beta- and gamma-cleavage. This chimeric substrate generated excess Abeta42 when compared with wildtype APP. These data indicate that the presence of an FAD-associated mutant human PS1 transgene is associated with redistribution of the APP and APP CTFs in brain neurons toward TGN-enriched fractions. The chimera experiment suggests that TGN-enrichment of a beta-/gamma-secretase substrate may play an integral role in the action of mutant PS1 to elevate brain levels of Abeta42.


Intranuclear localization of herpes simplex virus immediate-early and delayed-early proteins: evidence that ICP 4 is associated with progeny virus DNA.
The localization of ICP 4, ICP 8, DNA polymerase and alkaline exonuclease within herpes simplex virus type 1 (HSV)-infected cells has been examined by immunofluorescence using specific antibodies to these proteins. Cells were simultaneously counterstained with the DNA-binding fluorochrome 4,6-diamidino-2-phenylindole (DAPI) to reveal the intranuclear distribution of DNA. These studies showed that in the absence of virus DNA replication ICP 4, ICP 8 and DNA polymerase were diffusely distributed throughout the nucleus but during virus DNA replication these proteins accumulated at specific foci within the nucleus. Initially these foci were near the nuclear membrane but with continuing virus DNA replication they increased in size until the whole of the nucleus became affected. The increase in size of these foci was coincident with a redistribution of nuclear DNA and margination of chromatin at the nuclear membrane, as revealed by DAPI staining. The number of foci initially present in an infected cell was dependent on the multiplicity of infection. The distribution of ICP 4, ICP 8 and DNA polymerase within the nucleus was altered by treating the cells with DNase. The majority of alkaline exonuclease was diffusely distributed throughout the nucleus during virus DNA replication and did not localize at specific foci within the nucleus. Autoradiographic examination of the incorporation of [3H]thymidine in cells infected with HSV showed that viral DNA replication occurred in restricted areas within the nucleus that were similar, in terms of number, location and size, to the foci where ICP 4, ICP 8 and DNA polymerase accumulated. Furthermore, in cells blocked in mitosis following infection with HSV, ICP 4, ICP 8 and DNA polymerase, but not alkaline exonuclease, localized in areas outside the condensed chromatin structures. DAPI staining revealed the presence of DNA in these areas and, as such structures were never seen when uninfected cells had entered mitosis, it is suggested that this extrachromosomal DNA is of viral origin. These studies therefore suggest that ICP 4 is associated with progeny virus DNA and that while its intranuclear localization is initially at non-viral sites, as DNA replication proceeds so ICP 4 is recruited into areas of virus DNA transcription and replication.


Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases.
The X protein of hepatitis B virus (HBV-X) can act as a transactivator of transcription but its mechanism of action remains obscure. We have analyzed HBV-X transactivation in several cell types using 13 unrelated viral and cellular promoters and found that transactivation is more or less apparent in most cell types and is promiscuous and unrelated to specific sequence motifs within the target promoters. In general, though, HBV-X appears to act on enhancer elements since HBV-X had no effect on a minimal promoter, whereas HBV-X was able to transactivate after insertion of an AP-1 minienhancer. Several lines of evidence exclude the possibility that HBV-X interacts directly with the AP-1 enhancer or its binding proteins and suggest that the proximal target of HBV-X is peripheral to the transcription complex. This hypothesis is supported by the observation that inhibition of serine/threonine kinases, which regulate AP-1 activity (phorbol ester down-regulation or staurosporine inhibition of protein kinase C and a dominant negative mutant of Raf-1), blocked the ability of HBV-X to transactivate without affecting basal promoter activity. Furthermore, basal transcription from the AP-1-dependent promoter was increased by overexpression of protein kinase C and Raf-1 but HBV-X was unable to further stimulate, indicating that these kinases act subsequently to HBV-X. These data suggest that transactivation by HBV-X is an indirect result of the activation of cellular serine/threonine kinases including protein kinase C and Raf-1. This mode of action implies that HBV-X may affect other cellular processes, besides transcription, that are regulated by these kinases.


Assembly intracellular targeting and cell surface expression of the human N-methyl-D-aspartate receptor subunits NR1a and NR2A in transfected cells.
The intracellular trafficking, assembly, and cell surface targeting of the human N-methyl-D-aspartate receptor subunits NR1a and NR2A has been studied using both transiently and permanently transfected mammalian cell lines. The expression of either NR1a or NR2A alone does not result in significant cell surface expression of either subunit as determined by cell surface biotinylation and immunofluorescence staining. When NR1a is expressed alone large intracellular accumulations of the subunit are formed which do not co-localize with the golgi apparatus markers protein p58 and wheat germ agglutinin, but do co-localize with the endoplasmic reticulum marker calreticulin. Co-expression of NR1a and NR2A results in a reduction of these intracellular accumulations and the appearance of both subunits on the cell surface. Immunoprecipitation of NR1a from in vitro translated subunit proteins showed that NR2A could only be immunoprecipitated with NR1a when both subunits were co-synthesized in the presence of microsomes. When cells expressing NR1a and NR2A were incubated with [35S]methionine in the presence of Brefeldin-A, a drug which prevents protein transport from the endoplasmic reticulum, NR2A could be immunoprecipitated by an antiserum specific for NR1a. Together these results suggest that the NMDA receptor subunits are assembled in the endoplasmic reticulum and that co-synthesis of the subunits is necessary for their association and their successful cell surface targeting.


Inch-Scale Grain Boundary Free Organic Crystals Developed by Nucleation Seed-Controlled Shearing Method.
Crystals of organic semiconductors are excellent candidates for flexible and array-based electronics. Large-scale synthesis of organic crystals in a controllable way while maintaining homogeneous single-crystal property has been a great challenge. The existence of grain boundaries and small crystal domains, however, restrict the device performance and limit the access to commercially viable organic electronics in the industry. Herein, we report the inch-scale synthesis of highly oriented 2,7-dioctyl[1]benzothieno[3,2- b][1]benzothiophene (C8-BTBT) organic single crystal by nucleation seed-controlled shearing method. The organic field-effect transistors developed from such single crystal have excellent carrier mobility as high as 14.9 cm2 V-1 s-1 and uniformity (standard deviation is 1.3 cm2 V-1 s-1) of 225 devices. We also found that the rotation of the principal axis in the crystal is governed by the orientations of seeds and the possible mechanism behind this phenomenon is proposed based on the density functional theory calculations. We anticipate that this proposed approach will have great potential to be developed as a platform for the growth of organic crystals with high crystallinity on a large scale.


Relationship between pain and vertebral motion in chronic low-back pain subjects.
To investigate the relationship between intervertebral motion, intravertebral deformation and pain in chronic low-back pain patients. This study measured vertebral motion of the lumbar spine and associated pain in a select group of chronic low-back pain patients as they performed a standard battery of motions in all planes. Numerous studies have demonstrated that individuals with low-back pain have impaired spinal motion, yet few studies have examined the specific relationship between pain and motion parameters. Although it is accepted that the pain in mechanical low-back patients is due to specific spinal motions, no studies have related specific motions to pain measures. Percutaneous intra-pedicle screws were placed into the right and left L4 (or L5) and S1 segments of nine chronic low-back pain patients. The external fixator frame was removed following the clinical external fixation test. The 3D locations of the pedicle screws and the level of pain were recorded as the subjects performed a battery of motions. The relationship between the pain and motion parameters was assessed using linear discriminant analysis and neural network models. The neural network model showed a strong relationship between observed and predicted pain (R(2)=0.997). The discriminant analysis showed a weak relationship (R(2)=0.5). Vertebral motion parameters are strongly predictive of pain in this select group of chronic low-back pain patients. The nature of the relationship is nonlinear and involves interactions; neural networks are able to effectively describe these relationships. Specific patterns of intervertebral motion and intravertebral deformation result in pain in chronic low-back pain patients. This substantiates the mechanical back pain aetiology.


[Massive edema of the ovary: apropos of a case].
A case of massive ovarian oedema is reported with a review of the literature. We would like to point out the value of thinking about the diagnosis of massive ovarian oedema when confronted with an ovary that seems to contain a tumour and to ask for frozen-section examination. By doing this the diagnosis can be made and the ovary preserved after the torsion has been dealt with in a young girl who is usually nulligravida.


Comparative trial of Dexon (polyglycolic acid), collagen, and silk sutures in ophthalmic surgery.
The tissue reaction, absorption, and handling properties of Dexon synthetic absorbable sutures, which are made from polymerized hydroxyacetic acid, were compared with those of silk and collagen in 51 eye operations, consisting mainly of cataract extractions and squint corrections. There was no significant difference between the sutures as regards degree of tissue reaction. The Dexon sutures were very strong and the knots held well. The sizes used in this series were found to be a little too thick and stiff for use in micro-surgery; smaller sizes would be easier to use and still remain strong enough. The Dexon was reliably absorbed in 5 weeks on average. No serious adverse reactions were seen with any of the sutures. Dexon was as well tolerated as the control sutures but had the advantage over silk of being absorbed and over collagen of containing no foreign protein.


Effects of the Backbone and Chemical Linker on the Molecular Conductance of Nucleic Acid Duplexes.
Scanning tunneling microscope break junction measurements are used to examine how the molecular conductance of nucleic acids depends on the composition of their backbone and the linker group to the electrodes. Molecular conductances of 10 base pair long homoduplexes of DNA, aeg-PNA, γ-PNA, and a heteroduplex of DNA/aeg-PNA with identical nucleobase sequence were measured. The molecular conductance was found to vary by 12 to 13 times with the change in backbone. Computational studies show that the molecular conductance differences between nucleic acids of different backbones correlate with differences in backbone structural flexibility. The molecular conductance was also measured for duplexes connected to the electrode through two different linkers, one directly to the backbone and one directly to the nucleobase stack. While the linker causes an order-of-magnitude increase in the overall conductance for a particular duplex, the differences in the electrical conductance with backbone composition are preserved. The highest molecular conductance value, 0.06G0, was measured for aeg-PNA duplexes with a base stack linker. These findings reveal an important new strategy for creating longer and more complex electroactive, nucleic acid assemblies.


A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages.
C-type lectins serve multiple functions through recognizing carbohydrate chains. Here we report a novel C-type lectin, macrophage-inducible C-type lectin (Mincle), as a downstream target of NF-IL6 in macrophages. NF-IL6 belongs to the CCAAT/enhancer binding protein (C/EBP) of transcription factors and plays a crucial role in activated macrophages. However, what particular genes are regulated by NF-IL6 has been poorly defined in macrophages. Identification of downstream targets is required to elucidate the function of NF-IL6 in more detail. To identify downstream genes of NF-IL6, we screened a subtraction library constructed from wild-type and NF-IL6-deficient peritoneal macrophages and isolated Mincle that exhibits the highest homology to the members of group II C-type lectins. Mincle mRNA expression was strongly induced in response to several inflammatory stimuli, such as LPS, TNF-alpha, IL-6, and IFN-gamma in wild-type macrophages. In contrast, NF-IL6-deficient macrophages displayed a much lower level of Mincle mRNA induction following treatment with these inflammatory reagents. The mouse Mincle proximal promoter region contains an indispensable NF-IL6 binding element, demonstrating that Mincle is a direct target of NF-IL6. The Mincle gene locus was mapped at 0.6 centiMorgans proximal to CD4 on mouse chromosome 6.


Increased susceptibility to ventricular arrhythmias is associated with changes in Ca2+ regulatory proteins in paraplegic rats.
Paraplegia may increase susceptibility to ventricular arrhythmias by altering the autonomic control of the heart. Altered cardiac autonomic control has been documented to change the expression of genes that encode cardiac Ca2+ regulatory proteins. Therefore, we tested the hypothesis that paraplegia alters cardiac electrophysiology with concomitant changes in Ca2+ regulatory proteins in a manner that increases the susceptibility to ventricular arrhythmias. To test this hypothesis, intact (n = 10) and paraplegic (n = 6) male Wistar rats were chronically instrumented to measure atrioventricular (AV) interval, sinus cycle length, sinus node recovery time (SNRT), SNRT corrected for spontaneous sinus cycle (cSNRT), Wenckebach cycle length (WCL), and the electrical stimulation threshold to induce ventricular arrhythmias. In addition, relative protein abundance and mRNA expression for sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA), phospholamban, and the Na/Ca exchanger were determined in intact (n = 8) and paraplegic (n = 8) rats. Paraplegia significantly (P < 0.05) reduced AV interval (-25%), sinus cycle length (-24%), SNRT (-28%), cSNRT (-53%), WCL (-19%), and the electrical stimulation threshold to induce ventricular arrhythmia (-48%). Paraplegia significantly increased the relative protein abundances of SERCA (45%) and the Na/Ca exchanger (40%) and decreased phospholamban levels (-28%). In contrast, only the relative mRNA expression of the Na/Ca exchanger was increased (25%) in paraplegic rats. These data demonstrate that paraplegia enhances cardiac electrophysiological properties and alters Ca2+ regulatory proteins in a manner that increases susceptibility to ventricular arrhythmias.


Brassicaceae-specific Gretchen Hagen 3 acyl acid amido synthetases conjugate amino acids to chorismate, a precursor of aromatic amino acids and salicylic acid.
To modulate responses to developmental or environmental cues, plants use Gretchen Hagen 3 (GH3) acyl acid amido synthetases to conjugate an amino acid to a plant hormone, a reaction that regulates free hormone concentration and downstream responses. The model plant Arabidopsis thaliana has 19 GH3 proteins, of which 8 have confirmed biochemical functions. One Brassicaceae-specific clade of GH3 proteins was predicted to use benzoate as a substrate and includes AtGH3.7 and AtGH3.12/PBS3. Previously identified as a 4-hydroxybenzoic acid-glutamate synthetase, AtGH3.12/PBS3 influences pathogen defense responses through salicylic acid. Recent work has shown that AtGH3.12/PBS3 uses isochorismate as a substrate, forming an isochorismate-glutamate conjugate that converts into salicylic acid. Here, we show that AtGH3.7 and AtGH3.12/PBS3 can also conjugate chorismate to cysteine and glutamate, which act as precursors to aromatic amino acids and salicylic acid, respectively. The X-ray crystal structure of AtGH3.12/PBS3 in complex with AMP and chorismate at 1.94 Å resolution, along with site-directed mutagenesis, revealed how the active site potentially accommodates this substrate. Examination of Arabidopsis knockout lines indicated that the gh3.7 mutants do not alter growth and showed no increased susceptibility to the pathogen Pseudomonas syringae, unlike gh3.12 mutants, which were more susceptible than WT plants, as was the gh3.7/gh3.12 double mutant. The findings of our study suggest that GH3 proteins can use metabolic precursors of aromatic amino acids as substrates.


Angiotensin II, cell proliferation and angiogenesis regulator: biologic and therapeutic implications in cancer.
Angiotensin II (ANG II) is the main effector peptide in the renin-angiotensin system. It is generated by the activation of Angiotensin I through the Angiotensin II Converter Enzyme (ACE II). ANG II has multiple physiologic effects that regulate vascular tone, hormone secretion, tissue growth and neural activity. It has systemic (endocrine) and local (paracrine and autocrine) effects, favoring cell growth and differentiation through four types of receptors from which types 1 and 2 (AT(1) and AT(2)) are the most important. Stimulation of AT(1) leads to the activation of intracellular pathways that finally lead to vasoconstriction, inflammation and proliferation. The AT(2) receptor is mainly expressed in fetal tissue and scantly in the cardiovascular system under different circumstances. Its effects are opposite to those of the AT(1). The stimulation of AT(1) activates second messengers that lead to a rapid production of diacylglycerol and 1-4-5-inositol triphosphate, as well as to the activation of C protein. Several reports indicate that ANG II can induce neovascularization in experimental systems due to the expression of different growth factors such as angiopoietin 2, vascular endothelial factor, and its receptor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta and epidermal growth factor. Other mechanisms associated with ANG II induced angiogenesis are nitric oxide synthase and metalloproteinase expression, as well as inflammation induction. Angiogenesis is a fundamental process to tissue repair and development, and it participates in several pathologic processes. In addition, the AT(1) receptor is expressed in many malignant neoplasms and its blockade through ECA II inhibitors and ANG II antagonists has shown antineoplastic activity as well as angiogenesis inhibition in tumoral experimental models. This review discusses the mechanisms by which ANG II participates in neoplastic and non-neoplastic tissue angiogenesis and its possible therapeutic implications.


[Stability of serum immunoglobulin conformation in various tumors].
As shown by means of temperature-perturbation differential spectrophotometry blood serum immunoglobulins G from patients with gastric cancer and with some other tumors were more resistant to 2 M urea as compared with the immunoglobulins from healthy volunteers and patients with gastric ulcerous disease. The resistance of IgG conformation was altered in the course of gastric cancer treatment.


Alignment and political will: upscaling an Australian respectful relationships program.
Many small scale efficacious programs and interventions need to be 'scaled-up' in order to reach a larger population. Although it has been argued that interventions deemed suitable for upscaling need to have demonstrated effectiveness, be able to be implemented cost-effectively and be accepted by intended recipients, these factors alone are insufficient in explaining which programs are adopted more broadly. Upscaling research often identifies political will as a key factor in explaining whether programs are supported and up-scaled, but this research lacks any depth into how political will is formed and has not applied policy theories to understanding the upscaling process. This article uses a political science lens to examine the key factors in the upscaling process of a Respectful Relationships in Schools Program. Focus groups and interviews were conducted with project staff, managers and community organizations involved in the program. The results reveal how a key focusing event related to a highly profiled personal tragedy propelled family violence into the national spotlight. At the same time, the organization leading the respectful relationships program leveraged their networks to position the program within the education department which enabled the government to quickly respond to the issue. The study highlights that political will is not a stand-alone factor as depicted by up-scaling models, but rather is the end point of a complex process that involves many elements including the establishment of networks and aligned programs that can capitalize when opportunities arise.


Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice.
X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and is one of the most common causes of macular degeneration in young men. Our therapeutic approach for XLRS is based on the administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the intravitreal (IVT) route. Two Good Laboratory Practice studies, a 9-month study in New Zealand White rabbits (n = 124) injected with AAV8-scRS/IRBPhRS at doses of 2E9, 2E10, 2E11, and 1.5E12 vector genomes/eye (vg/eye), and a 6-month study in Rs1-KO mice (n = 162) dosed with 2E9 and 2E10 vg/eye of the same vector were conducted to assess ocular and systemic safety. A self-resolving, dose-dependent vitreal inflammation was the main ocular finding, and except for a single rabbit dosed with 1.5E12 vg/eye, which showed a retinal detachment, no other ocular adverse event was reported. Systemic toxicity was not identified in either species. Biodistribution analysis in Rs1-KO mice detected spread of vector genome in extraocular tissues, but no evidence of organ or tissues damage was found. These studies indicate that IVT administration of AAV8-scRS/IRBPhRS is safe and well tolerated and support its advancement into a phase 1/2a clinical trial for XLRS.


Isolation of an early T-cell precursor (CFU-TL) from human bone marrow.
CD2-CD3-CD4-CD8- human bone marrow (BM) cells were previously shown to generate T-cell clones in vitro. This capacity was abolished after treatment of this population with anti-CD7 monoclonal antibody and complement. In this study, using rosetting with sheep erythrocytes, complement-dependent cytotoxicity, and specific immunoadherence method, we isolated a minor BM subset that contained more than 80% CD7+CD2-CD3-CD4-CD8- cells with small lymphoid cell morphology. They comprised most early T-cell precursors (CFU-TL) as they displayed high capacity to generate T-cell clones when cultured in limiting dilutions. CFU-TL nature of these cells was also confirmed by the sequential expression of mature T-cell specific markers on their surface after in vitro induction. This BM subset also contained 2% to 3% CFU-GM precursors. Together, these results pointed to the existence of BM CD7+CD2- precursors with high differentiation potential and showed the commitment of most of them to T-cell lineage.


Advances in asymmetric visible-light photocatalysis, 2015-2019.
Asymmetric visible-light photocatalysis has recently drawn considerable attention of the scientific community owing to its unique activation modes and significance for the enantioselective green synthesis. In this review, the recent advances in the visible-light-triggered enantioselective synthesis, classified by different catalytic strategies, are summarized. The progress achieved in this area inspires us to develop new strategies, including the combination of photocatalysis with other catalytic modes and the design and synthesis of multifunctional chiral photocatalysts, in an attempt to incorporate chirality into the photo-mediated chemical transformations.


Pigmented villonodular synovitis/giant cell tumor in the knee.
Pigmented villonodular synovitis (PVNS) is a rare diagnosis in pediatric patients and commonly presents with symptoms of swelling and pain. Early diagnosis is important to prevent secondary degeneration into the subchondral bone. This review will analyze the etiology, clinical signs/symptoms, diagnosis, treatment, and recent literature on PVNS in the pediatric population. Many theories of PVNS etiology have been described in the literature; however, an inflammatory response has been most widely accepted. PVNS can occur in any joint, but most commonly in the knee. The most common treatment for PVNS is synovectomy, and long-term follow-up is necessary to detect disease persistence or recurrence. Although uncommon, PVNS does occur in the pediatric population and this diagnosis should be included in the differential of atraumatic joint swelling and pain.


A small-scale survey identifies selective and quantitative nucleo-cytoplasmic shuttling of a subset of CREM transcription factors.
Elucidating dynamic aspects of intracellular localization of proteins is essential to decipher their functional interaction networks. Although transcription factors lacking a detectable cytoplasmic fraction have been generally considered compartmentalized in the nucleus, some were found to shuttle into the cytoplasm, suggesting functional interactions therein. To further investigate how common, specific and quantitative is this traffic, we have employed the heterokaryon assay for a small-scale survey of nuclear factors not previously tested for their nucleo-cytoplasmic motion. We show that a subset of cAMP response element (CRE) binding proteins of the CREM type shuttles within a biologically meaningful time frame, revealing a continuous flow into the cytoplasm that persists during signaling. Their dynamic behavior, not involving the classical Exportin-1 pathway, could be ascribed to C-terminal sequences, containing, in addition to the bZIP domain and the NLS, a nuclear export activity and an inhibitory activity at an adjacent site. Other proteins examined in this study either did not shuttle significantly or, like CREB and distinct CREM isoforms, shuttled with markedly delayed kinetics, denoting considerable selectivity of this traffic. These findings raise the possibility that events associated with bi-directional transport and periodic transit through the cytoplasm may modulate activities of select nuclear transcription factors.


Use of oral anticoagulants and risk of prostate cancer: a population-based case-control study in Montreal, Canada.
A few recent epidemiological observations suggest that anticoagulant medications may protect against prostate cancer development. Most studies have been small or subjected to methodological issues, including potential confounding. We provide here new evidence on this association in the context of a population-based case-control study of prostate cancer conducted in Montreal, Canada. Cases were 1,588 men with incident prostate cancer, aged ≤75 years, diagnosed across French hospitals in the Montreal area between 2005 and 2009. Concurrently, 1,618 population controls from the same residential area and age distribution (±5 years) were randomly selected from the electoral list of French-speaking men. In-person interviews elicited information on socio-demographic, lifestyle and environmental factors, along with a detailed medical history. Unconditional logistic regression was used to assess the association between lifetime use of anticoagulants and prostate cancer risk. 102 subjects (2.6 % of cases and 3.7 % of controls) reported a history of oral anticoagulant therapy. After controlling for age, ancestry, education, family history of prostate cancer, prostate cancer screening frequency, diabetes, body mass index and statin use, ever use of oral anticoagulants showed a weak inverse, non-statistically significant association with prostate cancer (odds ratio 0.76, 95% confidence interval 0.50-1.16). Similar results were observed in analyses considering duration of use or indication for use, restricted to subjects recently screened or stratified by cancer aggressiveness. Our findings provide weak support for a protective effect of oral anticoagulant therapy against prostate cancer. Further confirmation is required, especially in light of potential bleeding complications associated with anticoagulants.


Long-term outcome and quality of life after transoral stapling for Zenker diverticulum.
To investigate long-term results and quality of life after transoral stapling of Zenker diverticulum. The data of all patients admitted to our institution for the surgical treatment of Zenker diverticulum were entered into a prospective database. Demographics, symptoms, intraoperative and postoperative data, morbidity, time to oral feeding, and length of hospital stay were recorded. All patients underwent upper gastrointestinal endoscopy and a barium swallow study to measure the length of the diverticulum from the apex of the septum to the bottom of the pouch. Transoral stapling was performed using a Weerda diverticuloscope under general anesthesia. Over time, the technique was modified by applying traction sutures to ease engagement of the common septum inside the stapler jaws. Perioperative variables, symptoms, long-term outcome, and quality of life were analyzed. The operation was considered successful if the patient reported complete remission (grade 1) or marked improvement (grade 2) of dysphagia, regurgitation, and respiratory symptoms. Statistical analysis was performed using Statistical Package for Social Science (SPSS, Version 15, SPSS, Inc., Chicago, IL). Between 2001 and 2013, the transoral approach was successfully completed in 100 patients with a median age of 75 years. Patients with a larger (≥3 cm) diverticulum were older than those with a smaller pouch (P<0.038). Complications occurred in 4% of the patients but there was no mortality. A statistically significant improvement of dysphagia and regurgitation scores (P<0.001) was recorded over a median follow-up of 63 mo. Similarly, a significant decrease in the median number of pneumonia episodes per year (P<0.001) was recorded after surgery. The overall long-term success rate of the procedure was 76%. The success rate of the operation was greater in patients of 70 years of age or older compared to younger individuals (P=0.038). Use of traction sutures on the septum was associated with an improved success rate compared with the standard procedure (P=0.04). All items of the health related quality of life questionnaire were significantly higher compared to baseline (P<0.05). Transoral stapling is safe and effective. The operation significantly improves patients' quality of life. It appears that elderly patients with large diverticula significantly benefit from the procedure and that the modified surgical technique including traction sutures can further improve the success rate.


Membrane penetration of Sendai virus glycoproteins during the early stages of fusion with liposomes as determined by hydrophobic photoaffinity labeling.
The hydrophobic photoaffinity label 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine was used to label Sendai virus proteins during fusion with cardiolipin and phosphatidylserine liposomes. Preferential labeling of the viral fusion protein during the initial stages of fusion demonstrated that this protein interacts with the hydrophobic core of the target membrane as an initiating event of virus-liposome fusion. Labeling showed time, temperature, and pH dependence consistent with earlier fluorescent measurements of fusion kinetics. The present method provides conclusive evidence supporting the hypothesis that hydrophobic interaction of the fusion protein with the target bilayer is an initial event in the fusion mechanism of viral membranes.


Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer.
The estrogen receptor (ER) is the target of tamoxifen, but endocrine therapies do not benefit all patients with ER positive tumors. We therefore hypothesized that copy number changes in the ESR1 gene, encoding ER, confer resistance. Within a consecutive series of ER positive, postmenopausal patients allocated to 5 years tamoxifen, we identified 61 patients with recurrence less than 4 years and 48 patients without recurrence at least 7 years after initiation of adjuvant tamoxifen. Archival tissue containing primary tumor was collected from 97 patients (89%). Tumor samples were analyzed for ESR1 copy number changes using FISH with a probe covering the ESR1 gene at 6q25 and a reference probe covering the centromere of chromosome 6. The assay was validated in a material of 120 normal breast samples. FISH analysis for ESR1 was successful in 91 patients (94%). Amplification (ratio ESR1/CEN-6 ≥ 2.0) was observed in 11 of 50 (22%) patients with early recurrence, compared to two of 41 (5%) patients without recurrence. The difference is statistically significant (P = 0.033). In both groups, two patients with ESR1 deletion (ratio ESR1/CEN-6 < 0.8) were identified. ESR1 amplification was significantly associated with poor disease-free survival (P = 0.0054) and overall survival (P = 0.0004). This pilot study supports our hypothesis that ESR1 amplification is associated with a poorer outcome following adjuvant treatment with tamoxifen in ER positive early breast cancer. This study also revealed the existence of ESR1 deletions. The prognostic and predictive impact of ESR1 copy number changes needs further exploration in clinical trials.


Clinical outcome in male patients with detrusor overactivity with impaired contractility.
To review the clinical outcomes of patients with voiding dysfunction who have detrusor overactivity with impaired contractility (DOIC) diagnosed with urodynamic studies. Urodynamic reports from 2005 to 2009 were reviewed, and 54 male patients had findings consistent with DOIC. Patients with acontractile or neuropathic bladders were excluded. Clinical outcomes were obtained from patient records. Of 54 men, 8 presented with voiding symptoms, 17 had storage symptoms, and 29 had mixed symptoms. Twenty-two had a previous transurethral resection of the prostate. The median follow-up was 12 months. Four patients received no intervention. Two patients were taught intermittent self-catheterization. Five patients underwent surgery to reduce outlet resistance and all reported improvement. Forty-three patients were started on pharmacotherapy; symptomatic improvement was reported by 9 of 16 patients commenced on anticholinergics alone, 6 of 16 on alpha-blockers alone, and 4 of 5 treated with a combination of alpha-blockers and anticholinergics. Eleven patients experienced no difference on pharmacotherapy and 2 reported deterioration. One patient developed acute urinary retention (18 months after commencing treatment with alpha-blockers). No patient had urosepsis. Anticholinergics and alpha-blockers appear to be safe in patients with DOIC. The risk of urinary retention and sepsis is low. The majority of patients report symptomatic benefit from either drugs or surgical treatment.


A review of community dental service provision for children attending special day schools.
To review current practices used to screen children attending special day and mainstream schools by the Community Dental Service (CDS) nationally and document the provision of care to children attending special day schools. The investigation used postal questionnaires requesting information relating to two types of special day schools. All CDS managers within the United Kingdom. Special day schools continue to remain priority schools for the CDS as two thirds of districts reported screening these schools more frequently than their mainstream schools. The majority of districts provide dental care to children at special day schools from fixed clinic locations with a minority using mobile dental units to provide dental care (40%). CONCLUSIONS; The continued integration of children with special needs into mainstream schools rather than their segregation into special schools will make the identification of this priority group more difficult for the CDS. The service should explore new methods of identifying these children rather than continuing to rely on the traditional methods of targeting establishments.


A Social-Marketing Intervention and Concussion-Reporting Beliefs.
Concussion-symptom education remains the primary approach used by athletic trainers to address underreporting of possible sport-related concussions. Social marketing represents an untapped approach to promote concussion reporting by communicating the benefits or consequences of reporting or not reporting, respectively. To apply expectancy value theory and identify how marketing the possible consequences of concealing concussion symptoms influenced young adults' concussion-reporting beliefs to increase the likelihood of reporting. Randomized controlled clinical trial. Laboratory. A total of 468 competitive collegiate club sport athletes at a large US university who engaged in 1 of 46 sports with various levels of concussion risk. Participants were randomly assigned by team to 1 of 3 conditions. The treatment condition was a social-marketing program focused on the possible consequences of the reporting decision. The control condition was traditional concussion-symptom education based on the National Collegiate Athletic Association's publication, "Concussion: A Fact Sheet for Student-Athletes." An additional condition mirrored the traditional symptom education but included a less clinical delivery. Positive and negative beliefs regarding concussion reporting were assessed. We applied expectancy value theory, which posits that changing beliefs in the short term will produce greater reporting intentions in the long term. Club sport athletes exposed to consequence-based social marketing showed higher levels of positive reporting beliefs and lower levels of negative reporting beliefs than athletes exposed to traditional or revised symptom education. We observed no differences between the traditional and revised symptom-education programs. Exposure to consequence-based marketing decreased negative beliefs about reporting (B = -0.165, P = .01) and increased positive beliefs about reporting (B = 0.165, P = .01). Social marketing offers athletic trainers another strategic tool for motivating athletes to report concussion symptoms by translating scientific findings into marketable statements and then communicating the benefits of reporting or the negative consequences of concealing concussion symptoms.


The role of centralised pain in osteoarthritis.
The mechanisms underlying chronic pain states, including osteoarthritis, differ from those underlying acute pain. In chronic pain states, central nervous system (CNS) factors often play a particularly prominent role. In many individuals with chronic pain, pain can occur with minimal or no evidence of ongoing nociceptive input. Medical subspecialties have applied a wide-range of labels to these pain conditions including fibromyalgia, irritable bowel syndrome and interstitial cystitis to name just a few. These same CNS processes can augment or magnify pain when there is ongoing nociceptive input, as in conditions such as osteoarthritis or autoimmune disorders. The hallmark of these 'centrally driven' pain conditions is a diffuse hyperalgesic state identifiable though the use of experimental sensory testing, that has been corroborated by functional neuroimaging. Characteristic symptoms of these central pain conditions include multifocal pain, fatigue, poor sleep, memory complaints and frequent co-morbid mood and anxiety disorders. In contrast to acute and peripheral pain states that are responsive to non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, central pain conditions respond best to CNS neuromodulating agents, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants. While osteoarthritis is generally considered a peripherally mediated pain state, a subset of these patients also manifests centrally driven pain characteristics. Thus, osteoarthritis can also be thought of as a "mixed" pain state and this requires a more tailored approach to treatment.


Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability.
Endothelial hyperperme ability leading to vascular leak is an important consequence of sepsis and sepsis-induced lung injury. We previously reported that heat shock protein (hsp) 90 inhibitor pretreatment improved pulmonary barrier dysfunction in a murine model of sepsis-induced lung injury. We now examine the effects of hsp90 inhibitors on LPS-mediated endothelial hyperpermeability, as reflected in changes in transendothelial electrical resistance (TER) of bovine pulmonary arterial endothelial cells (BPAEC). Vehicle-pretreated cells exposed to endotoxin exhibited a concentration-dependent decrease in TER, activation of pp60(Src), phosphorylation of the focal adhesion protein paxillin, and reduced expression of the adherens junction proteins, vascular endothelial (VE)-cadherin and beta-catenin. Pretreatment with the hsp90 inhibitor, radicicol, prevented the decrease in TER, maintained VE-cadherin and beta-catenin expression, and inhibited activation of pp60(Src) and phosphorylation of paxillin. Similarly, when BPAEC hyperpermeability was induced by endotoxin-activated neutrophils, pretreatment of neutrophils and/or endothelial cells with radicicol protected against the activated neutrophil-induced decrease in TER. Increased paxillin phosphorylation and decreased expression of beta-catenin and VE-cadherin were also observed in mouse lungs 12 h after intraperitoneal endotoxin and attenuated in mice pretreated with radicicol. These results suggest that hsp90 plays an important role in sepsis-associated endothelial barrier dysfunction.


Student perceived impact of a physical, kinetic and interactive model.
Current instructional tools for anatomy education are insufficient scaffolds for learning abstract visual concepts such as basic biomechanics. Diagrams, illustrations and even computer-generated models may be adequate for identification purposes, but are typically not effective when it comes to demonstrating dynamic functions. Evidence from educational concepts, such as the active learning principle in constructivism, indicate that current tools are ineffective due to a lack of opportunity for hands-on or interactive, learning. To address this, our interdisciplinary team designed an instructional model of the canine thoracic limb which is physical, kinetic and interactive. We hypothesised that the unique combination of these three crucial elements would enhance the student learning experience. In order to test this hypothesis, we asked 126 undergraduate students in a biomedical anatomy course to interact with the model. Students were then invited to complete a survey evaluating their experience using the thoracic limb model. Results from completed surveys showed that students perceived the model as easy to use and helpful with understanding basic biomechanical concepts. These results indicate that there is potential for the model to positively impact the students' learning. Future studies will include quantitative evaluation of student performance and cognitive impact in the biomedical anatomy course.


The metabotropic glutamate receptor system protects against ischemic free radical programmed cell death in rat brain endothelial cells.
As one of the key determinants of ischemic injury, cerebrovascular endothelial cell (EC) degeneration may be dependent upon the generation of the free radical nitric oxide (NO) and the subsequent induction of programmed cell death (PCD). Although the mechanisms that can prevent EC injury are most likely multifactorial in origin, the metabotropic glutamate receptor (mGluR) system may represent a novel therapeutic approach for ECs given the ability of the mGluR system to reverse neuronal cell injury. This study examined the modulation of individual subtypes of mGluRs during anoxia and NO toxicity in primary rat cerebrovascular ECs. Cell injury was determined through trypan blue dye exclusion, intracellular lactate dehydrogenase release, DNA fragmentation, membrane phosphatidylserine (PS) exposure, and cysteine protease activity. Anoxia, through the generation of NO, and exposure to exogenous NO were directly toxic to ECs. Exposure to NO rapidly decreased EC viability from 98% +/- 2% to 40% +/- 9%, increased DNA fragmentation from 2% +/- 2% to 61% +/- 9%, and increased membrane PS exposure from 3% +/- 3% to 66% +/- 6% over a 24-hour period. Activation of the mGluR system significantly increased EC survival through the prevention of NO-induced DNA fragmentation and cellular membrane PS residue exposure. In contrast, antagonism of the mGluR system failed to prevent PCD. Cytoprotection by the mGluR system was dependent, at least in part, upon the direct inhibition of NO-generated caspase 1- and caspase 3-like activities. Further investigation into the ability of the mGluR system to prevent PCD in ECs may open new therapeutic avenues for the treatment of cerebrovascular injury.


Asymptomatic novel coronavirus pneumonia patient outside Wuhan: The value of CT images in the course of the disease.
The purpose of this case report is to describe the imaging and associated clinical features of an asymptomatic novel coronavirus pneumonia (COVID-19) patient outside Wuhan, China. The principle findings are that in this patient with laboratory-confirmed COVID-19, CT findings preceded symptoms and included bilateral pleural effusions, previously not reported in association with COVID-19. The role of this case report is promotion of potential recognition amongst radiologists of this new disease, which has been declared a global health emergency by the World Health Organization (WHO).


[Analysis of incident reports in an anesthesiology unit of a university hospital].
Incident reporting is an effective strategy used to enhance patient safety. An incident is an event that could eventually result in harm to a patient. To classify and analyze incidents reported by an Anesthesiology division at a University hospital in Chile. A retrospective analysis of the reported incidents registered in our institutional database from January 2008 to January 2014. They were classified according to three variables proposed by the World Health Organization system to determine the type of incident and patients' potential harm. There were 297 reports registered. Etiologic classification according to the WHO system showed that 29% (n = 85) were related with management, 20% (59) with drugs, 20% (59) with medical devices, 16% (48) with procedures and 15% (46) with human factors. Seventy two percent (58) of incidents caused low or moderate harm and 28% (22) resulted in a severe adverse event or death. Our analysis highlights that a high rate of incidents are associated with management, the leading cause of reports in our center. Due to the low incident report rate in our country, it is difficult to perform appropriate comparisons with other centers. In the future, local incident reporting systems should be improved.


A comparison of 99mTc-MIBI myocardial SPET with electron beam computed tomography in the assessment of coronary artery disease.
We compared technetium-99m methoxyisobutylisonitrile (MIBI) myocardial perfusion single-photon emission tomography (SPET) (MPS) and electron beam computed tomography (EBCT) in order to assess their respective value in the detection of coronary artery disease (CAD). 99mTc-MIBI SPET (stress-resting) and EBCT studies were performed in 51 patients with suspected CAD who underwent coronary angiography (CAG). CAG showed that of the 51 patients, 36 had coronary stenosis >/=50% while 15 had normal results. A moderate positive rank correlation was found between coronary calcification detected by EBCT and MPS score (rs=0.5283, P<0.01). The concordance between EBCT and MPS for the evaluation of CAD was 72.5% (37/51). The sensitivity of EBCT in detecting CAD in 51 patients was comparable to that of MPS (81% vs 94%, NS). However, the accuracy of EBCT was lower than that of MPS (78% vs 94%, P<0.025). As regards the detection of individual coronary artery disease, there was no significant difference in sensitivity between EBCT and MPS (65% vs 75%, NS); however, the specificity and accuracy of EBCT were lower than those of MPS (specificity: 77% vs 95%, P<0.005; accuracy 71% vs 85%, P<0.005). The sensitivity, specificity and accuracy of MPS in detecting single-vessel disease were higher than those of EBCT (sensitivity: 86% vs 42%, P<0.025; specificity: 96% vs 70%, P<0.025; accuracy: 93% vs 61%, P<0.005). However, no significant differences in the sensitivity, specificity and accuracy of MPS and EBCT were found in respect of multivessel disease. 99mTc-MIBI myocardial perfusion SPET and EBCT provide different information in the assessment of CAD. The sensitivity of EBCT for the detection of CAD is comparable with that of MPS; however, the specificity and accuracy of EBCT are lower than those of MPS. More reliable results will be obtained if both myocardial perfusion SPET and EBCT are performed.


Nanowire arrays in multicrystalline silicon thin films on glass: a promising material for research and applications in nanotechnology.
Silicon nanowires (SiNW) were formed on large grained, electron-beam crystallized silicon (Si) thin films of only ∼6 μm thickness on glass using nanosphere lithography (NSL) in combination with reactive ion etching (RIE). Electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) studies revealed outstanding structural properties of this nanomaterial. It could be shown that SiNWs with entirely predetermined shapes including lengths, diameters and spacings and straight side walls form independently of their crystalline orientation and arrange in ordered arrays on glass. Furthermore, for the first time grain boundaries could be observed in individual, straightly etched SiNWs. After heat treatment an electronic grade surface quality of the SiNWs could be shown by X-ray photoelectron spectroscopy (XPS). Integrating sphere measurements show that SiNW patterning of the multicrystalline Si (mc-Si) starting thin film on glass substantially increases absorption and reduces reflection, as being desired for an application in thin film photovoltaics (PV). The multicrystalline SiNWs directly mark a starting point for research not only in PV but also in other areas like nanoelectronics, surface functionalization, and nanomechanics.


Challenges in using electronic health record data for CER: experience of 4 learning organizations and solutions applied.
To document the strengths and challenges of using electronic health records (EHRs) for comparative effectiveness research (CER). A replicated case study of comparative effectiveness in hypertension treatment was conducted across 4 health systems, with instructions to extract data and document problems encountered using a specified list of required data elements. Researchers at each health system documented successes and challenges, and suggested solutions for addressing challenges. Data challenges fell into 5 categories: missing data, erroneous data, uninterpretable data, inconsistencies among providers and over time, and data stored in noncoded text notes. Suggested strategies to address these issues include data validation steps, use of surrogate markers, natural language processing, and statistical techniques. A number of EHR issues can hamper the extraction of valid data for cross-health system comparative effectiveness studies. Our case example cautions against a blind reliance on EHR data as a single definitive data source. Nevertheless, EHR data are superior to administrative or claims data alone, and are cheaper and timelier than clinical trials or manual chart reviews. All 4 participating health systems are pursuing pathways to more effectively use EHR data for CER.A partnership between clinicians, researchers, and information technology specialists is encouraged as a way to capitalize on the wealth of information contained in the EHR. Future developments in both technology and care delivery hold promise for improvement in the ability to use EHR data for CER.


Physical activity as a protective factor against depressive symptoms in older Chinese veterans in the community: result from a national cross-sectional study.
Physical activity is generally considered to be effective in reducing the prevalence of depression and promoting remission of its symptoms. However, large-scale epidemiological research on this issue is lacking in older Chinese adults. We performed a nationwide epidemiological survey to determine the relationship between physical activity and depressive symptoms in older Chinese veterans in the community, with adjustment for potential confounders. A cross-sectional study was conducted in a representative sample of 9,676 community-dwelling older Chinese veterans. Depressive symptoms were identified using the Center for Epidemiological Studies Depression Scale. Physical activity was self-reported using a one-year physical activity questionnaire. Information about covariates was obtained by questionnaire-based interview. Relationships between study variables and symptoms of depression were estimated using unadjusted and adjusted analyses. The median age was 82.29 (interquartile range 80.25-84.60) years. In total, 81.84% of the study participants engaged in physical activity that was predominantly light in intensity. In unadjusted analyses, physical activity was associated with a significantly decreased likelihood of depressive symptoms (5.43% versus 18.83%, P<0.0001). Multivariate logistic regression with adjustment and controlling for confounders, physical activity was still inversely associated with depressive symptoms and was the only independent protective factor (odds ratio 0.57, 95% confidence interval 0.44-0.72, P<0.0001) among the associated factors in this study. In a univariate general linear model, there was a significant difference in Center for Epidemiological Studies Depression Scale score between subjects participating in active physical activity and those who did not (F=59.07, P<0.0001). This study found an inverse relationship between physical activity and symptoms of depression in older Chinese veterans in the community. It was also indicated that the antidepressant effect of physical activity probably extended to the oldest-old, and the light-intensity physical activity was probably available for the same protective effect. This information could be used to devise further interventions to prevent or ameliorate symptoms of depression.


Effectiveness of stent-graft placement for salvage of dysfunctional arteriovenous hemodialysis fistulas.
To determine the clinical effectiveness of stent-graft placement in dysfunctional autogenous hemodialysis fistulas. Between September 2006 and June 2008, 24 Fluency Plus stent-grafts were inserted in 17 patients with failing autogenous hemodialysis fistulas (two radiocephalic, 12 brachiocephalic, and three brachiobasilic). Six fistulas were thrombosed at presentation. Indications for stent-graft insertion included 10 residual stenoses, six pseudoaneurysms, and one fistuloplasty-induced rupture. Fistula function before and after intervention was assessed with ultrasound dilution technique. The technical success rate was 100%, as were the anatomic and clinical success rates. Via Kaplan-Meier method, the primary access patency rates were 94.1% at 3 months (95% CI, 0.461-0.995) and 88.2% at 6 and 12 months (95% CI, 0.468-0.980). The primary lesion patency rate was 94.1% (95% CI, 0.650-0.992) at 3, 6, and 12 months. The secondary access patency rate had a point estimate of 100% at 3 months, and was 93.8% (95% CI, 0.632-0.991) at 6 and 12 months. Univariate analysis suggested that male sex and left-sided accesses were associated with a longer primary access patency rate (P = .02). The binary restenosis rate at 6 months was 5.9%. Mean transonic flow rates were 667.5 mL/min before intervention and 2,076.0 mL/min after intervention (P = .03, Wilcoxon signed-rank test). No patients were lost to follow-up. Stent-graft placement in dysfunctional autogenous hemodialysis fistulas is technically feasible and effective in preserving function and preventing access abandonment, with patency rates that exceed historical patency rates with angioplasty and/or uncovered stents.


[Comparison of the effectiveness and cost of treatment with humid environment as compared to traditional cure. Clinical trial on primary care patients with venous leg ulcers and pressure ulcers].
The discovery of moist environment dressings as alternatives to the traditional treatments based on exposing wounds to air, opened new expectations for the care and treatment of chronic wounds. Over the years, these expectations have led to the availability of new moist environment dressings which have made it possible to improve the care provided to patients suffering this kind of wounds, as well as providing important reasons to weigh in terms of cost-benefit-effectiveness at the time of selecting which type of treatment should be employed. The lack of comparative analysis among traditional treatments and moist environment treatments for chronic wounds among patients receiving primary health care led the authors to perform an analysis comparing these aforementioned options of treatment on patients suffering venous leg ulcers or pressure ulcers. The authors designed a Randomized Clinical Trial involving patients receiving ambulatory care in order to compare the effectiveness and cost-benefit of traditional versus moist environment dressing during the treatment of patients suffering stage II or III pressure ulcers or venous leg ulcers. In this trial, variables related to effectiveness of both treatments, as well as their costs were analyzed. 70 wounds were included in this Randomized Clinical Trial, 41 were venous leg ulcers of which 21 received a moist environment treatment while 20 received traditional cure, the other 29 wounds were pressure ulcers of which 15 received moist environment dressings treatment and 14 received traditional dressings. No statistically significant differences were found among the defining variables for these lesions in either group under treatment. In the venous leg ulcer study group, the authors conclusions were an average of 18.13 days, 16.33 treatment sessions and a cost of 10,616 pesetas to heal one square centimeter of the initial surface area of a wound on patients treated with traditional treatment compared to an average of 18.22 days, 4.54 treatment sessions and a cost of 2409 pesetas to heal one square centimeter of the initial surface area of a wound on patients treated with moist environment dressings. In the pressure ulcers study group, the authors conclusions were an average of 12.18 days, 12.1 treatment sessions and a cost of 15,490 pesetas to heal one square centimeter of the initial surface area of a wound on patients treated with traditional treatment compared to an average of 7.12 days, 1.86 treatment sessions and a cost of 2610 pesetas to heal one square centimeter of the initial surface area of a wound on patients treated with moist environment dressings. The results of this randomized clinical trial demosntrated that the moist environment treatment group was more effective and had a better cost-benefit ratio than the traditional treatment group in the treatment of pressure ulcers and venous leg ulcers on patients cared for by nursing personnel in primary health care centers all of which agrees with publications consulted by authors.


Glycerol metabolism and its implication in virulence in Mycoplasma.
Glycerol and glycerol-containing compounds such as lipids belong to the most abundant organic compounds that may serve as nutrient for many bacteria. For the cell wall-less bacteria of the genus Mycoplasma, glycerol derived from phospholipids of their human or animal hosts is the major source of carbon and energy. The lipids are first degraded by lipases, and the resulting glycerophosphodiesters are transported into the cell and cleaved to release glycerol-3-phosphate. Alternatively, free glycerol can be transported, and then become phosphorylated. The oxidation of glycerol-3-phosphate in Mycoplasma spp. as well as in related firmicutes involves a hydrogen peroxide-generating glycerol-3-phosphate oxidase. This enzyme is a key player in the virulence of Mycoplasma spp. as the produced hydrogen peroxide is one of the major virulence factors of these bacteria. In this review, the different components involved in the utilization of lipids and glycerol in Mycoplasma pneumoniae and related bacteria are discussed.


Empirical validation of QUEST+ in PSE and JND estimations in visual discrimination tasks.
One of the most precise methods to establish psychometric functions and estimate threshold and slope parameters is the constant stimuli procedure. The large distribution of predetermined stimulus values presented to observers enables the psychometric functions to be fully developed, but makes this procedure time-consuming. Adaptive procedures enable reliable threshold estimation while reducing the number of trials by concentrating stimulus presentations around observers' supposed threshold. Here, the stimulus value for the next trial depends on observer's responses to the previous trials. One recent improvement of these procedures is to also estimate the slope (related to discrimination sensitivity). The Bayesian QUEST+ procedure (Watson Journal of Vision, 17(3), 10, 2017), a generalization and extension of the QUEST procedure, includes this refinement. Surprisingly, this procedure is barely used. Our goal was to empirically assess its precision to evaluate size, orientation, or temporal perception, in three yes/no discrimination tasks that increase in demands. In 72 adult participants in total, we compared points of subjective equivalence (PSEs) or simultaneity (PSSs) as well as discrimination sensitivity obtained with the QUEST+, constant stimuli, and simple up-down staircase procedures. While PSEs did not differ between procedures, sensitivity estimates obtained with the 64-trials QUEST+ procedure were overestimated (i.e., just-noticeable differences, or JNDs, were underestimated). Overall, agreement between procedures was good, and was at its best for the easiest tasks. This study empirically confirmed that the QUEST+ procedure can be considered as a method of choice to accelerate PSE estimation, while keeping in mind that sensitivity estimation should be handled with caution.


[Renal parenchyma resection--development, technique, problems (author's transl)].
Organ preservation by renal surgery is the principal and most pressing task of urology, according to Bischoff. In clinical practice at the present time, resection of the renal parenchyma is the principal aim and is to a large extent achieved. Sacrificing a localised diseased portion of the parenchyma (organ amputation) contributes to the survival of the rest of the organ (preservation of the organ). The additional inevitable loss of functional tissue must be kept as small as possible (sparing the organ). Decisive syndromes are nephrolithiasis, renal tumors and to a decreasing extent, tuberculosis of the urinary system. The operation, which usually takes the form of resection of the pole of the kidney, but which must sometimes be extended to heminephrectomy and even more, repeatedly underlies attempts at improvement both in animal experiments and in the clinical sphere.


Changes in rabbit cerebrum and cerebellum gangliosides during postnatal life. A study especially referring to alkali labile gangliosides.
The present study deals with the developmental behaviour of cytosolic and membrane-bound gangliosides, especially the alkali labile species, in rabbit cerebrum and cerebellum from birth to 6 months of life. At all ages the amount of cytosolic gangliosides was less than 0.5% of total gangliosides. The proportion of alkali labile gangliosides on the total membrane-bound ganglioside content and the profile of the individual alkali labile gangliosides during postnatal life were different in cerebellum and cerebrum. In cerebellum the proportion of alkali labile gangliosides progressively increased from 4.6% at birth to 16.7% at 6 months; in cerebrum the proportion decreased from 8.9% at birth to a minimum of 5.5% at 10 days, then slowly increased up to 8.1% at 6 months. All the major alkali labile gangliosides in cerebellum, especially O-Ac-GT1b and O-Ac-GQ1b, tended to accumulate during postnatal life. In cerebrum only two alkali labile gangliosides, namely O-Ac-GT1b and a species not yet identified, increased starting from the 10th day of life, while the other ones progressively diminished after birth.


Acquired factor VIII inhibitors.
Acquired hemophilia A is a rare bleeding diathesis caused by autoantibodies directed against clotting factor VIII and associated with an increased morbidity and mortality. This autoimmune disorder most commonly occurs in the elderly. Although it may be associated with several underlying pathologies, up to 50% of reported cases remain idiopathic. In contrast with congenital hemophilia, which is commonly characterized by hemarthroses, hemorrhages in patients with acquired hemophilia involve most frequently soft tissues. The 2 treatment priorities are to arrest the acute bleeding and to eradicate the factor VIII autoantibody. Acute bleeding episodes in patients with low-titer inhibitors can be treated using human factor VIII concentrates, whereas factor VIII bypassing agents, such as activated prothrombin complex concentrates or recombinant activated factor VII, are effective for the treatment of those with high-titer inhibitors. An analysis of the literature shows that the most effective first-line treatment for the eradication of factor VIII autoantibodies is the combination of steroids and cyclophosphamide. However, there is increasing evidence on the effectiveness of other treatment approaches, such as immune tolerance regimens and rituximab. If confirmed by large controlled studies, these innovative therapies might become a valid option for long-term eradication of factor VIII inhibitors.


Epigenetics of personality traits: an illustrative study of identical twins discordant for risk-taking behavior.
DNA methylation differences between identical twins could account for phenotypic twin discordance of behavioral traits and diseases. High throughput epigenomic microarray profiling can be a strategy of choice for identification of epigenetic differences in phenotypically different monozygotic (MZ) twins. Epigenomic profiling of a pair of MZ twins with quantified measures of psychometric discordance identified several DNA methylation differences, some of which may have developmental and behavioral implications and are consistent with the contrasting psychometric profiles of the twins. In particular, differential methylation of CpG islands proximal to the homeobox DLX1 gene could modulate stress responses and risk taking behavior, and deserve further attention as a potential marker of aversion to danger. The epigenetic difference detected at DLX1 of approximately 1.2 fold change was used to evaluate experimental design issues such as the required numbers of technical replicates. It also enabled us to estimate the power this technique would have to detect a functionally relevant epigenetic difference given a range of 1 to 50 twin pairs. We found that use of epigenomic microarray profiling in a relatively small number (15-25) of phenotypically discordant twin pairs has sufficient power to detect 1.2 fold epigenetic changes.


Bortezomib-enhanced radiosensitization through the suppression of radiation-induced nuclear factor-κB activity in human oral cancer cells.
Oral cancer cells have a significantly augmented nuclear factor-κB (NF-κB) activity and the inhibition of this activity suppresses tumor growth. Bortezomib is a proteasome inhibitor and a drug used for molecular-targeted therapy (targets NF-κB). In this study, we investigated whether bortezomib would be effective as an inhibitor of proliferation and a radiosensitizer for the treatment of oral cancer. We demonstrate that bortezomib inhibits NF-κB activity and cell proliferation. The combined treatment with bortezomib and radiation (RT) suppressed NF-κB activity and cell growth in vitro and in vivo compared with RT treatment alone. To investigate the mechanisms by which bortezomib suppresses tumor growth, the expression of signaling molecules downstream of NF-κB were examined by ELISA. The combined treatment significantly inhibited the radiation-induced production of angiogenic factors and decreased the number of blood vessels in the tumor tissues. Although the expression of anti-apoptotic proteins was upregulated by RT, bortezomib downregulated the RT-induced expression of these proteins. Moreover, the expression of cleaved poly(ADP-ribose) polymerase in vitro and in vivo was enhanced by bortezomib, indicating that bortezomib inhibits tumor growth by inducing apoptosis. This study clearly demonstrates that bortezomib significantly inhibits tumor growth and that the combined treatment with bortezomib and RT results in a significant inhibition of tumor growth. The mechanisms underlying the inhibition of tumor growth by bortezomib include the suppression of angiogenesis and the induction of apoptosis. A novel molecular targeting therapy including bortezomib may be effective in the treatment of oral cancer by suppressing NF-κB activity.


L-arginine metabolism in early-onset and late-onset pre-eclamptic pregnancies.
The present case-control study was undertaken to investigate l-arginine metabolism in pregnant women with early-onset and late-onset pre-eclampsia. Attempts were made to differentiate these two distinct diseases entities by using measured and derived parameters of l-arginine metabolism. Thirty-six patients with early-onset, 17 patients with late-onset pre-eclampsia and 15 healthy pregnant women at term were studied. Patients were categorized according to the weeks of gestation (< 34 vs. ≥ 34) at the appearance of clinical symptoms (hypertension + proteinuria). Venous samples were taken at gestational age of 29.8 ± 2.5, 36.1 ± 2.2 and 39.2 ± 1.2 weeks, respectively. L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), monomethylarginine (MMA) and l-ornithine were measured by LC-MS/MS method. L-arginine/ADMA, l-ornithine/l-arginine, ADMA/SDMA ratios and the arginine methylation index (arg-MI) were calculated. Plasma levels of ADMA and MMA were significantly higher (p < 0.002) in pre-eclamptic patients than in healthy women. No significant differences could be detected between patients with early-onset and late-onset pre-eclampsia in either parameter studied. L-ornithine correlated positively with ADMA (r = 0.526, p < 0.001) and MMA (r = 0.533, p < 0.001) in the whole study population, and inversely with l-arginine (r = - 0.277, p < 0.044) in the pre-eclamptic group. When compared with maternal plasma in venous cord blood l-arginine was markedly reduced (p < 0.05) and there was a significant elevation in ADMA, SDMA, MMA and l-ornithine (p < 0.001, for each) without discernible differences between the study groups. Parameters of l-arginine metabolism do not discriminate the early-onset from late-onset pre-eclampsia. Our study provided indirect evidences for the redirection of l-arginine-NOS to the l-arginine-arginase pathway.


[Treatment of young transsexuals in the Netherlands].
For more than ten years transsexual adolescents have been diagnosed and treated psychologically at the department of Child and Adolescent Psychiatry, University Medical Centre in Utrecht, the Netherlands. The medical part of the treatment takes place at the Academic Hospital of the Free University of Amsterdam. Diagnosis is done in two phases: the first diagnostic phase and the 'real life test'. In this second phase the ability to live in the opposite gender role is tested. Gender dysphoric non-transsexual adolescents are offered psychological or psychiatric interventions. For transsexual adolescents with the express wish to undergo a sex change two types of hormones are prescribed. First, hormones which halt the own pubertal development, then cross-sex hormones with irreversible effects. Surgery for adolescents is not different from surgery for adults. Although the cause of transsexuality is probably impaired sexual differentiation at cerebral level, it appears that the risk of unjustified treatment is higher when the treatment is administered at an early age than in adults; justified treatment, however, has better results when it is administered at an early age.