Erythrocyte sodium-lithium countertransport and proliferative diabetic retinopathy.
To investigate whether elevated erythrocyte Na+/Li+ countertransport (Na+/Li+ CT) activity is present in patients with proliferative diabetic retinopathy (PDR). The rate of Na+/Li+ CT activity assayed in 21 patients with type 1 diabetes mellitus (DM) presenting PDR was compared with 10 patients with nonproliferative retinopathy (NPDR) and with 11 patients with normal fundi. Twelve normal volunteers with no family history of hypertension were used as a control group. The albumin excretion rate was determined by nephelometry, and the glomerular filtration rate was measured by the plasma clearance of eidetic acid labeled with chromium-51. Patients with PDR showed higher diastolic blood pressure levels (mean +/- SD) compared with those with NPDR or normal fundi (95 +/- 13 versus 90 +/- 09 and 82 +/- 19 mm Hg, P = 0.02, respectively). The albumin excretion rate was higher [geometric mean (range)], and the glomerular filtration rate was lower (mean +/- SD) in patients with PDR than in those with NPDR or normal fundi [333 (2 to 5140) versus 32 (5.9 to 2200) and 6 (1.5 to 306) microg/min, P = 0.01, and 63 +/- 33 versus 99 +/- 37 and 93 +/- 43 ml/min, P = 0.02, respectively]. The mean Na+/Li+ CT in patients with PDR was significantly higher than in patients with NPDR or normal fundi and control group (0.46 +/-0.20 versus 0.32 +/- 0.12, 0.32 +/- 11, and 0.21 +/- 0.07 mM/L red blood cells (RBC)/h, respectively, P = 0.0001). In a multiple logistic regression analysis, with PDR as the dependent variable, Na+/Li+ CT (odds ratio [OR]: 4.7, confidence interval [CI]: 1.2-17.6, P = 0.02), diastolic blood pressure (OR, 3.4; CI, 1.3 to 9.6; P = 0.018), and glomerular filtration rate (OR, 5.1; CI, 1.6-17.7; P = 0.007) were the only variables that were maintained in the equation, indicating that they were the main determinants of PDR. Patients with type 1 DM and proliferative retinopathy have elevated erythrocyte Na+/Li+ CT.


Hierarchical and homotopic correlations of spontaneous neural activity within the visual cortex of the sighted and blind.
Spontaneous neural activity within visual cortex is synchronized by both monosynaptic, hierarchical connections between visual areas and indirect, network-level activity. We examined the interplay of hierarchical and network connectivity in human visual cortex by measuring the organization of spontaneous neural signals within the visual cortex in total darkness using functional magnetic resonance imaging (fMRI). Twenty-five blind (14 congenital and 11 postnatal) participants with equally severe vision loss and 22 sighted subjects were studied. An anatomical template based on cortical surface topology was used for all subjects to identify the quarter-field components of visual areas V1-V3, and assign retinotopic organization. Cortical visual areas that represent the same quadrant of the visual field were considered to have a hierarchical relationship, while the spatially separated quarters of the same visual area were considered homotopic. Blindness was found to enhance correlations between hierarchical cortical areas as compared to indirect, homotopic areas at both the level of visual areas (p = 0.000031) and fine, retinotopic scale (p = 0.0024). A specific effect of congenital, but not postnatal, blindness was to further broaden the cortico-cortico connections between hierarchical visual areas (p = 0.0029). This finding is consistent with animal studies that observe a broadening of axonal terminal arborization when the visual cortex is deprived of early input. We therefore find separable roles for vision in developing and maintaining the intrinsic neural activity of visual cortex.


Mechanism of repair of acrolein- and malondialdehyde-derived exocyclic guanine adducts by the α-ketoglutarate/Fe(II) dioxygenase AlkB.
The structurally related exocyclic guanine adducts α-hydroxypropano-dG (α-OH-PdG), γ-hydroxypropano-dG (γ-OH-PdG), and M1dG are formed when DNA is exposed to the reactive aldehydes acrolein and malondialdehyde (MDA). These lesions are believed to form the basis for the observed cytotoxicity and mutagenicity of acrolein and MDA. In an effort to understand the enzymatic pathways and chemical mechanisms that are involved in the repair of acrolein- and MDA-induced DNA damage, we investigated the ability of the DNA repair enzyme AlkB, an α-ketoglutarate/Fe(II) dependent dioxygenase, to process α-OH-PdG, γ-OH-PdG, and M1dG in both single- and double-stranded DNA contexts. By monitoring the repair reactions using quadrupole time-of-flight (Q-TOF) mass spectrometry, it was established that AlkB can oxidatively dealkylate γ-OH-PdG most efficiently, followed by M1dG and α-OH-PdG. The AlkB repair mechanism involved multiple intermediates and complex, overlapping repair pathways. For example, the three exocyclic guanine adducts were shown to be in equilibrium with open-ring aldehydic forms, which were trapped using (pentafluorobenzyl)hydroxylamine (PFBHA) or NaBH4. AlkB repaired the trapped open-ring form of γ-OH-PdG but not the trapped open-ring of α-OH-PdG. Taken together, this study provides a detailed mechanism by which three-carbon bridge exocyclic guanine adducts can be processed by AlkB and suggests an important role for the AlkB family of dioxygenases in protecting against the deleterious biological consequences of acrolein and MDA.


Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib.
Bruton's tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development.


Intracranial vertebral artery dissection resulting in fatal subarachnoid hemorrhage: clinical and histopathological investigations from a medicolegal perspective.
Subarachnoid hemorrhage (SAH) due to a ruptured intracranial vertebral artery (VA) dissection sometimes results in a sudden fatal outcome. The authors analyzed the relationship between clinical features and histopathological characteristics among fatal cases to establish valuable information for clinical diagnostics and prophylaxis. This study included 58 medicolegal autopsy cases of ruptured intracranial VA dissection among 553 fatal nontraumatic cases of SAH that occurred between January 2000 and December 2007. Their clinical features were obtained from autopsy records. Histopathological investigations were performed on cross-sections obtained from all 4-mm segments of whole bilateral intracranial VAs and prepared with H & E and elastica van Gieson staining. The autopsy cases included 47 males and 11 females, showing a marked predilection for males. The mean age was 46.8 +/- 7.7 years, with 78% of the patients in their 40s or 50s. Hypertension was the most frequently encountered history; it was found in 36% of cases from clinical history and in 55% of cases based on autopsy findings. Prodromal symptoms related to intracranial VA dissections were detected in 43% of patients. Headache or neck pain lasting hours to weeks was a frequent complaint. Of patients with prodromal symptoms, 44% had consulted doctors; however, in none of these was SAH or intracranial VA dissection diagnosed at a preventable stage. Autopsy revealed fusiform aneurysms with medial dissecting hematomas. Apart from ruptured intracranial VA dissection, previous intracranial VA dissection was detected in 25 cases (43%); among them, 10 showed previous dissection of the bilateral intracranial VAs. The incidence of prodromal symptoms (60%) among the patients with previous intracranial VA dissection was significantly higher than that (30%) among cases without previous dissection (chi-square test; p = 0.023). Most previous intracranial VA dissections formed a single lumen resembling nonspecific atherosclerotic lesions, with the exception of 3 cases (12%) with a double lumen. Intracranial VA dissection resulting in fatal SAH frequently affects middle-aged men with untreated hypertension. Related to the high frequency of prodromal symptoms, latent previous intracranial VA dissection was histopathologically detected. Furthermore, intracranial VA dissection tends to induce multiple lesions affecting both intracranial VAs recurrently. This suggests the importance of an awareness of sustained whole intracranial VA vulnerability for the prevention of recurrence. The incidence of prodromal symptoms was significantly higher among patients with previous intracranial VA dissections. Thus, earlier diagnosis of intracranial VA dissections at the unruptured stage is desirable for prophylaxis against fatal SAH.


Events in Early Life are Associated with Female Reproductive Ageing: A UK Biobank Study.
The available oocyte pool is determined before birth, with the majority of oocytes lost before puberty. We hypothesised that events occurring before birth, in childhood or in adolescence ('early-life risk factors') could influence the size of the oocyte pool and thus the timing of menopause. We included cross-sectional data from 273,474 women from the UK Biobank, recruited in 2006-2010 from across the UK. We analysed the association of early menopause with events occurring before adulthood in 11,781 cases (menopause aged under 45) and 173,641 controls (menopause/pre-menopausal at ≥ 45 years), in models controlling for potential confounding variables. Being part of a multiple birth was strongly associated with early menopause (odds ratio = 1.42, confidence interval: 1.11, 1.82, P = 8.0 × 10(-9), fully-adjusted model). Earlier age at menarche (odds ratio = 1.03, confidence interval: 1.01, 1.06, P = 2.5 × 10(-6)) and earlier year of birth were also associated with EM (odds ratio = 1.02, confidence interval: 1.00, 1.04, P = 8.0 × 10(-6)). We also confirmed previously reported associations with smoking, drinking alcohol, educational level and number of births. We identified an association between multiple births and early menopause, which connects events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life.


[Stratification of risk factors of progressing of acute respiratory infection in children].
The work purpose is the complex estimation of endogenous intoxication (change of optical density of plasma and erythrocytes), depressions of tissue hypoxia and functions of protective system, clinical and laboratory stratification of the risks-factors promoting progressing of disease and complication of pneumonia. There was carried cross-section study. The study included 36 patients from 1 to 7 years with an acute respiratory infection. The control group was made up of 19 healthy children. The comparative analysis of results of the specified factors and laboratory research set as the purpose to reveal the predictable negative risk factors. Evaluation of the quantitative findings of risks-factors was carried out in 95 % taking into account the confidence interval (CI). For the acute respiratory infection complicated with pneumonia, was determined strongly marked toxemia, and also high activity of antioxidant systems (SOD and catalase) and lysosomal enzymes (catepsin, RNA) was noted. The prognosis of the authentic risks-factors of acute respiratory disease was defined with following indicators: age of the child - before three years; hereditary background with a respiratory system pathology; the tobacco use in a family; low level of knowledge of parents; incomplete treatment; change of optical density of plasma and erythrocytes; fall (reduction) of redox-potential of the system of energy maintenance. We developed predictable model on probability of expected complications of respiratory system and groups of low, average and high risk were allocated.


Metal-rich chalcogenides. Synthesis, structure, and bonding of the layered Lu11Te4. Comparison with the similar Sc8Te3 and Ti11Se4.
The high-yield synthesis of Lu11Te4 by reaction of the components and annealing at 1200 degrees C is described. The structure determined by single-crystal diffraction means is monoclinic C2/m, Z = 6, a = 30.412(3) A, b = 3.9504(4) A, c = 21.073(2) A, beta = 102.96 degrees and consists of two independent condensed puckered sheets of Lu separated by individual Te atoms. Notwithstanding, the geometric structure is closely related to but distinctly different from those of both Sc8Te3 and Ti11Se4 (also C2/m), principally through displacements of pairs of atoms (the structure of the last was determined by electron diffraction). Further, close electronic similarities among the three structures are demonstrated by EHTB results in terms of both effective atom charge and bond overlap population trends between equivalent positions or functions.


In vitro studies of biomedical magnesium alloys in a simulated physiological environment: a review.
In spite of the immense potential of biodegradable magnesium alloys, the fast degradation rates of Mg-based biomedical implants in the physiological environment impose severe limitations in many clinical applications. Consequently, extensive in vitro studies have been carried out to investigate the materials' performance and fathom the associated mechanisms. Here, an up-to-date review of the in vitro studies on biomedical magnesium alloys in a simulated physiological environment is provided. This review focuses on four topics: (1) materials selection and in vitro biocompatibility of biomedical magnesium alloys; (2) in vitro degradation of biomedical magnesium alloys in simulated physiological environments, specifically discussing corrosion types, degradation rates, corrosion products and impact of the constituents in body fluids on materials degradation; (3) selection of suitable test media for in vitro assessment; and (4) future research trends.


Neonatal outcome following methadone exposure in utero.
To examine the relationship between maternal methadone exposure and neonatal head circumference and abstinence syndrome, we examined the records of 172 opiate-addicted gravidas enrolled in a methadone maintenance program in an urban hospital over a 2-year period. Higher doses of methadone in the third trimester were associated with increased head circumference reflecting both increased gestational duration and improved overall growth. Neonatal withdrawal was positively correlated with gestational age at delivery and race, with nonblack infants exhibiting higher neonatal abstinence scores than blacks following adjustment for maternal dose and gestational age at delivery. Selection of optimal methadone dosage is a complex problem in which the favorable neurobehavioral outcome associated with increased growth and gestational age must be weighed against the risks associated with more severe neonatal withdrawal. Our findings of improved overall fetal growth and gestational duration associated with higher methadone doses suggest that more liberal methadone dosing in pregnancy may improve long-term neonatal outcome.


Understanding the limitations of "quasi-mandatory" approaches to enrolment in community-based health insurance: Empirical evidence from Tanzania.
In recent decades, a growing number of low-income countries (LICs) have experimented with voluntary community-based health insurance (CBHI), as an instrument to extend social health protection to the rural poor and the informal sector. While modest successes have been achieved, important challenges remain with regard to the recruitment and retention of members, and the regular collection of membership fees. In this context, there is a growing consensus among policymakers that there is a need to experiment with mandatory approaches towards CBHI. In some localities in Tanzania, local actors in charge of community health funds (CHFs) are now relying on what is best described as quasi-mandatory enrolment strategies, such as increasing user fees for non-members, automatically enrolling beneficiaries of cash transfer programmes and enrolling the exempted groups (people who are entitled to free healthcare). We find that, while these quasi-mandatory enrolment strategies may temporarily increase enrolment rates, dropout and the non-payment of contributions remain important problems. These problems are at least partly related to supply side issues, notably to inadequate benefit packages. Overall, these findings indicate the limitations of any strategy to increase enrolment into CBHI, which is not coupled to clear improvements in the supply and quality of healthcare.


Suitable parameter choice on quantitative morphology of A549 cell in epithelial-mesenchymal transition.
Evaluation of morphological changes in cells is an integral part of study on epithelial to mesenchymal transition (EMT), however, only a few papers reported the changes in quantitative parameters and no article compared different parameters for demanding better parameters. In the study, the purpose was to investigate suitable parameters for quantitative evaluation of EMT morphological changes. A549 human lung adenocarcinoma cell line was selected for the study. Some cells were stimulated by transforming growth factor-β1 (TGF-β1) for EMT, and other cells were as control without TGF-β1 stimulation. Subsequently, cells were placed in phase contrast microscope and three arbitrary fields were captured and saved with a personal computer. Using the tools of Photoshop software, some cells in an image were selected, segmented out and exchanged into unique hue, and other part in the image was shifted into another unique hue. The cells were calculated with 29 morphological parameters by Image Pro Plus software. A parameter between cells with or without TGF-β1 stimulation was compared statistically and nine parameters were significantly different between them. Receiver operating characteristic curve (ROC curve) of a parameter was described with SPSS software and F-test was used to compare two areas under the curves (AUCs) in Excel. Among them, roundness and radius ratio were the most AUCs and were significant higher than the other parameters. The results provided a new method with quantitative assessment of cell morphology during EMT, and found out two parameters, roundness and radius ratio, as suitable for quantification.


Morphological, microbiological and ultrastructural aspects of sepsis by Aeromonas hydrophila in Piaractus mesopotamicus.
Aeromonas bacteria can cause an infection characterized by septicemia and is one of the most common pathogens in tropical fish. This disease is responsible for high morbidity and mortality rates, causing considerable losses in aquaculture. Thus, the understanding of its pathophysiology is crucial to develop control strategies of this bacterial infection in farmed fish. This study aimed to characterize early pathological aspects of acute sepsis in pacu (Piaractus mesopotamicus) experimentally infected with Aeromonas hydrophila. A total of 160 juvenile pacus were inoculated intraperitoneally with A. hydrophila (1.78 x 109 CFU/mL) and at 0 (control), 1, 3, 6, and 9 hours post-inoculation (hpi), animals were anesthetized and samples were collected for microbiological, light microscopy and transmission electron microscopy (TEM) analyzes. The results showed the occurrence of hemodynamic alterations, such as hemorrhage and congestion, which were observed mainly after 6 and 9 hpi. It was possible to re-isolate Aeromonas at all sampling times except in control group. However, just after 9 hpi it was possible to find the bacteria in all fish and tissues. Light microscopy analyses revealed a degenerative process, necrosis and vascular damage mainly at 6 and 9 hpi. According to the ultrastructural examination, areas of cellular death were identified in all examined tissues, especially at 6 and 9 hpi. However, the most severe, related to necrosis, were observed after 6 and 9 hpi. The findings suggested that this bacterium spreads in the first hpi through the fish organs, mainly affecting spleen, liver and kidney, causing irreversible lesions at the molecular level.


Determinants of early dilated cardiomyopathy in neonates with congenital complete atrioventricular block.
Dilated cardiomyopathy (DCM) can occur in infants with congenital complete atrioventricular block (CCAVB) treated by permanent pacemaker (PM), even without other congenital heart defects. The objective is to find the risk factors of this complication. Retrospective analysis of a single-centre experience. Since 1992, 25 patients, aged 25 (1-355) days [median (range)], with normal ejection fraction (EF), underwent PM implantation (13 DDD, 12 VVIR) with an RV-pacing site. Follow-up was 4 (0.3-16) years. DCM occurred after 4 (3-23) months in eight patients (32%). Univariate analysis identified the following risk factors: younger age at implantation [5 (1-85) days vs. 90 (1-355) P = 0.007], a broad QRS (50 vs. 18% P = 0.03), prolonged QTc at implantation (63 vs. 0%, P = 0.001), and greater duration of heart rate >160 bpm during the first month after implantation (18 vs. 2%, P = 0.03). By multivariate analysis prolonged QTc was the only significant risk factor for DCM (hazard ratio: 23, P < 0.001, 95% confidence interval: 4-128). One patient died of heart failure, one was lost to follow up, and two were compensated on anticongestive therapy. EF normalized in four patients after resynchronization therapy (two patients), normalization of AV conduction or changing pacing mode to allow predominant narrow QRS junctional rhythm (one patient each). Neonates with CCAVB without other congenital heart defects and prolonged QTc are at high risk for DCM possibly due to electromechanical dyssynchrony induced by high-rate RV pacing. In patients in whom RV pacing was discontinued, EF became normal.


Association between platelet parameters and mortality in coronavirus disease 2019: Retrospective cohort study.
Thrombocytopenia has been implicated in patients infected with severe acute respiratory syndrome coronavirus 2, while the association of platelet count and changes with subsequent mortality remains unclear. The clinical and laboratory data of 383 patients with the definite outcome by March 1, 2020 in the Central Hospital of Wuhan were reviewed. The association between platelet parameters and mortality risk was estimated by utilizing Cox proportional hazard regression models. Among the 383 patients, 334 (87.2%) were discharged and survived, and 49 (12.8%) died. Thrombocytopenia at admission was associated with mortality of almost three times as high as that for those without thrombocytopenia (P < 0.05). Cox regression analyses revealed that platelet count was an independent risk factor associated with in-hospital mortality in a dose-dependent manner. An increment of per 50 × 109/L in platelets was associated with a 40% decrease in mortality (hazard ratio: 0.60, 95%CI: 0.43, 0.84). Dynamic changes of platelets were also closely related to death during hospitalization. Baseline platelet levels and changes were associated with subsequent mortality. Monitoring platelets during hospitalization may be important in the prognosis of patients with coronavirus disease in 2019.


Diet, diabetes and schizophrenia: review and hypothesis.
Diabetes is more common in people with schizophrenia than in the general population. To explore the possible reasons for the association between diabetes and schizophrenia. Diet and other lifestyle factors in patients with schizophrenia were reviewed as risk factors for diabetes. People with schizophrenia show features of the metabolic syndrome at the onset of illness, before treatment. They also eat a poor diet, take little exercise and have high rates of smoking. Food intake may be increased further by antipsychotic medication. Nutritional factors appear to have a key role in the development of diabetes in patients with schizophrenia and may also affect the outcome and severity of schizophrenia. A common pathway through which diet might contribute to the development of both diabetes and schizophrenia is proposed. Lifestyle factors may influence outcomes in both diabetes and schizophrenia. Lifestyle interventions are the key to improving the long-term health of people with schizophrenia.


Crystal structure and function of human nucleoplasmin (npm2): a histone chaperone in oocytes and embryos.
Human Npm2 is an ortholog of Xenopus nucleoplasmin (Np), a chaperone that binds histones. We have determined the crystal structure of a truncated Npm2-core at 1.9 Å resolution and show that the N-terminal domains of Npm2 and Np form similar pentamers. This allowed us to model an Npm2 decamer which may be formed by hydrogen bonds between quasi-conserved residues in the interface between two pentamers. Interestingly, the Npm2 pentamer lacks a prototypical A1-acidic tract in each of its subunits. This feature may be responsible for the inability of Npm2-core to bind histones. However, Npm2 with a large acidic tract in its C-terminal tail (Npm2-A2) is able to bind histones and form large complexes. Fluorescence resonance energy transfer experiments and biochemical analysis of loop mutations support the premise that nucleoplasmins form decamers when they bind H2A-H2B dimers and H3-H4 tetramers simultaneously. In the absence of histone tetramers, these chaperones bind H2A-H2B dimers with a single pentamer forming the central hub. When taken together, our data provide insights into the mechanism of histone binding by nucleoplasmins.


Modifying rheological properties of psyllium by gamma irradiation enables development of low glycaemic index food with a predicted gastrointestinal tolerance.
Gel forming dietary fibre like psyllium (PS) is effective in slowing down rate of digestion as well as absorption of glucose thereby reducing the postprandial glucose level and hence is used to develop functional foods for diabetic patients. The fortification level is however limited which otherwise elicit unwanted rheological response and poor sensorial quality in final product. In the present study this limitation was overcome by improving the functionality of the fibre by gamma radiation processing of the polysaccharides. We assessed the changes in rheological properties of radiation processed PS (RPPS) at different doses which enabled us to optimise the irradiation dose and levels of fortification of the RPPS in wheat flour for preparation of Indian unleavened bread (chapati). We observed that PS processed at a dose of 25 kGy could be incorporated to a level as high as 14 % in wheat flour yielding a sensorially better product compared to unfortified wheat flour. Further, the most striking effect observed for RPPS fortified chapati was reduction in the release of glucose upon subjecting to simulated gastrointestinal digestion. Finally, clinical and in vitro fermentation studies also confirmed a low GI value and high gastrointestinal tolerance of RPPS fortified chapati.


Activity of vestibular nuclei neurons during vestibular and optokinetic stimulation in the alert mouse.
As a result of the availability of genetic mutant strains and development of noninvasive eye movements recording techniques, the mouse stands as a very interesting model for bridging the gap among behavioral responses, neuronal response dynamics studied in vivo, and cellular mechanisms investigated in vitro. Here we characterized the responses of individual neurons in the mouse vestibular nuclei during vestibular (horizontal whole body rotations) and full field visual stimulation. The majority of neurons ( approximately 2/3) were sensitive to vestibular stimulation but not to eye movements. During the vestibular-ocular reflex (VOR), these neurons discharged in a manner comparable to the "vestibular only" (VO) neurons that have been previously described in primates. The remaining neurons [eye-movement-sensitive (ES) neurons] encoded both head-velocity and eye-position information during the VOR. When vestibular and visual stimulation were applied so that there was sensory conflict, the behavioral gain of the VOR was reduced. In turn, the modulation of sensitivity of VO neurons remained unaffected, whereas that of ES neurons was reduced. ES neurons were also modulated in response to full field visual stimulation that evoked the optokinetic reflex (OKR). Mouse VO neurons, however, unlike their primate counterpart, were not modulated during OKR. Taken together, our results show that the integration of visual and vestibular information in the mouse vestibular nucleus is limited to a subpopulation of neurons which likely supports gaze stabilization for both VOR and OKR.


Outcomes of patients with acute leukaemia who relapsed after reduced-intensity stem cell transplantation from HLA-identical or one antigen-mismatched related donors.
The characteristics of relapse following reduced-intensity stem-cell transplantation (RIST) remain to be clarified. We reviewed the medical records of 19 patients with acute leukaemia [acute myeloid leukaemia (AML), 16; acute lymphoblastic leukaemia (ALL), 3] who relapsed after RIST from related donors using purine-analogue-based regimens. Their median age was 55 years (range, 29-65 years). Median interval between RIST and relapse was 4.9 months (range, 1.8-24.9 months). Three chose not to receive interventions. The remaining 16 patients received withdrawal of immunosuppression (n = 3), chemotherapy (n = 2), donor lymphocyte infusion (n = 10) and second transplantation (n = 7), alone (n = 9) or in combination (n = 7). Four are alive with a median follow-up of 27.6 months (range, 16.0-28.9 months); three in remission and one in relapse. The 2-year overall survival after relapse was 28.9%. Causes of death in 15 patients included progressive disease (n = 7), graft-versus-host disease (n = 5) and infections (n = 3). Cumulative incidences of relapse-related and non-relapse-related deaths at 2 years after relapse were 37% and 32% respectively. Two prognostic factors were identified on univariate analysis: age [P = 0.017; hazard ratio (HR), 1.16; 95% confidence interval (CI), 1.03-1.32], and ALL as underlying disease (P = 0.011; HR, 10.4; 95% CI, 1.73-62.4). Some AML patients who relapse after RIST achieve durable remission with allogeneic immunotherapy-based interventions; however they carry a significant risk of non-relapse mortality.


Steroid receptor coactivator 1 links the steroid and interferon gamma response pathways.
We show here that steroid receptor coactivator 1 (SRC-1) is a coactivator of MHC class II genes that stimulates their interferon gamma (IFNgamma) and class II transactivator (CIITA)-mediated expression. SRC-1 interacts physically with the N-terminal activation domain of CIITA through two regions: one central [extending from amino acids (aa) 360-839] that contains the nuclear receptors binding region and one C-terminal (aa 1138-1441) that contains the activation domain 2. Using chromatin immunoprecipitation assays we show that SRC-1 recruitment on the class II promoter is enhanced upon IFNgamma stimulation. Most importantly, SRC-1 relieves the inhibitory action of estrogens on the IFNgamma-mediated induction of class II genes in transient transfection assays. We provide evidence that inhibition by estradiol is due to multiple events such as slightly reduced recruitment of CIITA and SRC-1 and severely inhibited assembly of the preinitiation complex.


[Use of percutaneous transluminal coronary angioplasty in treating acute myocardial infarct patients].
Transcutaneous transluminal coronary angioplastics was performed in 8 patients with acute myocardial infarction. In five patients dilatation of the coronary artery was carried out after intracoronary thrombolytic therapy and in the 3 others without the preliminary infusion of streptokinase. The method proved effective in 6 out of the 8 patients: the diameter of stenosis of the coronary artery decreased on the average from 70.4 +/- 3.9 to 23.5 +/- 12.9%, the area of stenosis reduced from 91.1 +/- 2.3 to 40.8 +/- 12.9%. Control angiography conducted in 4-5 weeks showed that in all five patients examined, the effect of the dilatation persisted. An improvement of the contractile function of the left ventricle was also observed.


Pheromone components affect motivation and induce persistent modulation of associative learning and memory in honey bees.
Since their discovery in insects, pheromones are considered as ubiquitous and stereotyped chemical messengers acting in intraspecific animal communication. Here we studied the effect of pheromones in a different context as we investigated their capacity to induce persistent modulations of associative learning and memory. We used honey bees, Apis mellifera, and combined olfactory conditioning and pheromone preexposure with disruption of neural activity and two-photon imaging of olfactory brain circuits, to characterize the effect of pheromones on olfactory learning and memory. Geraniol, an attractive pheromone component, and 2-heptanone, an aversive pheromone, improved and impaired, respectively, olfactory learning and memory via a durable modulation of appetitive motivation, which left odor processing unaffected. Consistently, interfering with aminergic circuits mediating appetitive motivation rescued or diminished the cognitive effects induced by pheromone components. We thus show that these chemical messengers act as important modulators of motivational processes and influence thereby animal cognition.


Unilateral massive hemothorax in Dengue hemorrhagic fever: a unique presentation.
Dengue hemorrhagic fever is a more serious form of disease characterised by plasma leakage syndrome, thrombocytopenia and disseminated intravascular coagulation. We present a 51 year old male who presented with fever, petechiae and acute onset of breathlessness. Emergency chest rhoentogram showed a massive right sided pleural effusion. On insertion of intercostal drain, there was a sudden gush of blood tinged fluid suggestive of hemothorax. There was no history of trauma or bleeding tendencies. Laboratory investigations revealed a raised hematocrit and severe thrombocytopenia. Dengue IgM was surprisingly positive. After aggressive supportive management the patient gradually improved and was discharged. While bilateral pleural effusion is a known occurrence in dengue hemorrhagic fever, massive hemothorax is unheard of. We report the first case in literature of dengue hemorrhagic fever presenting as unilateral massive hemothorax. A suspicion of dengue must also be borne in mind in cases of non-traumatic hemothorax especially in endemic areas.


Repairing TALEN-mediated double-strand break by microhomology-mediated recombination in tobacco plastids generates abundant subgenomic DNA.
Transcription activator-like effector nuclease (TALEN) technology has been widely used to edit nuclear genomes in plants but rarely for editing organellar genomes. In addition, ciprofloxacin, commonly used to cause the double-strand break of organellar DNA for studying the repair mechanism in plants, confers no organellar selectivity and site-specificity. To demonstrate the feasibility of TALEN-mediated chloroplast DNA editing and to use it for studying the repair mechanism in plastids, we developed a TALEN-mediated editing technology fused with chloroplast transit peptide (cpTALEN) to site-specifically edit the rpoB gene via Agrobacteria-mediated transformation of tobacco leaf. Transgenic plants showed various degrees of chlorotic phenotype. Repairing damaged plastid DNA resulted in point mutation, large deletion and small inversion surrounding the rpoB gene by homologous recombination and/or microhomology-mediated recombination. In an albino line, microhomology-mediated recombination via a pair of 12-bp direct repeats between rpoC2 and ycf2 genes generated the chimeric ycf2-rpoC2 subgenome, with the level about 3- to 5-fold higher for subgenomic DNA than ycf2. Additionally, the expression of chimeric ycf2-rpoC2 transcripts versus ycf2 mRNA agreed well with the level of corresponding DNA. The ycf2-rpoC2 subgenomic DNA might independently and preferentially replicate in plastids.


[The dynamics of the spatial organization of communities of small mammals (exemplified by rodents of the trans-Altai Gobi of Mongolia)].
Between-year variation of rodent population densities was studied in the central part of trans-Altai Gobi, Mongolia, in summers of a nine year period. Variation in spatial structure of the desert rodent community in 1982-84 and in 1992 was examined by the use of discriminant function analysis. Although population densities, breadth and positions of niches of many species tended to vary independently, the positive conjunct variation was found for the most ecologically distinctive species. This can be explained by limitations of the climate. Although a guild structure of the community was pronounced each year, there were significant between year shifts in niche breadth and niche centres along certain axes of ecological space. Within year nearest neighbours in niche overlap (high seasonal overlap) differed in between year variation in abundance. It is supposed that interspecific competition could contribute to development of community structure.


Anti-tumor Efficacy Assessment of the Sigma Receptor Pan Modulator RC-106. A Promising Therapeutic Tool for Pancreatic Cancer.
Introduction: Pancreatic cancer (PC) is one of the most lethal tumor worldwide, with no prognosis improvement over the past 20-years. The silent progressive nature of this neoplasia hampers the early diagnosis, and the surgical resection of the tumor, thus chemotherapy remains the only available therapeutic option. Sigma receptors (SRs) are a class of receptors proposed as new cancer therapeutic targets due to their over-expression in tumor cells and their involvement in cancer biology. The main localization of these receptors strongly suggests their potential role in ER unfolded protein response (ER-UPR), a condition frequently occurring in several pathological settings, including cancer. Our group has recently identified RC-106, a novel pan-SR modulator with good in vitro antiproliferative activities toward a panel of different cancer cell lines. In the present study, we investigated the in vitro properties and pharmacological profile of RC-106 in PC cell lines with the aim to identify a potential lead candidate for the treatment of this tumor. Methods: Pancreatic cancer cell lines Panc-1, Capan-1, and Capan-2 have been used in all experiments. S1R and TMEM97/S2R expression in PC cell lines was quantified by Real-Time qRT-PCR and Western Blot experiments. MTS assay was used to assess the antiproliferative effect of RC-106. The apoptotic properties of RC-106 was evaluated by TUNEL and caspase activation assays. GRP78/BiP, ATF4, and CHOP was quantified to evaluate ER-UPR. Proteasome activity was investigated by a specific fluorescent-based assay. Scratch wound healing assay was used to asses RC-106 effect on cell migration. In addition, we delineated the in vivo pharmacokinetic profile and pancreas distribution of RC-106 in male CD-1 mice. Results: Panc-1, Capan-1, and Capan-2 express both SRs. RC-106 exerts an antiproliferative and pro-apoptotic effect in all examined cell lines. Cells exposure to RC-106 induces the increase of the expression of ER-UPR related proteins, and the inhibition of proteasome activity. Moreover, RC-106 is able to decrease PC cell lines motility. The in vivo results show that RC-106 is more concentrated in pancreas than plasma. Conclusion: Overall, our data evidenced that the pan-SR modulator RC-106 is an optimal candidate for in vivo studies in animal models of PC.


Flunarizine enhances survival and regeneration of sensory and motor neurons after peripheral nerve injury.
The diphenylpiperazine, flunarizine, partially prevents apoptosis after trophic factor deprivation in neural crest-derived neurons. Flunarizine protects dorsal root ganglion neurons (DRG) after nerve growth factor (NGF) withdrawal in vitro and after peripheral nerve injury in newborn rats in vivo. We have further studied the mechanisms of neuronal protection by flunarizine. Oligosomal DNA fragmentation, a hallmark of apoptosis, was significantly decreased by treatment of DRG neurons with flunarizine after NGF deprivation. We examined the effect on survival of the timing of administration of flunarizine to DRG neurons both in vitro and in vivo. Flunarizine effectively rescued dissociated DRG neurons if administered up to six hours after NGF withdrawal. In vivo, flunarizine prevented DRG neuronal death after sciatic axotomy in newborn rats if given soon after injury. Long-term experiments were done to test the ability of flunarizine to protect neurons and enhance regeneration after sciatic nerve injury. Newborn rats were subjected to peripheral nerve injury and administered flunarizine for four weeks; no further treatment was given for an additional 12 weeks. The group treated with flunarizine demonstrated a significantly increased number of DRG and spinal motor neurons that had regenerated axons into the distal sciatic nerve as determined by retrograde labeling with HRR Myelinated axons in the sural nerve in the group treated with flunarizine increased by nearly two-fold compared to control animals. Thus, flunarizine was able to enhance survival and promote long-term regeneration of sensory and motor spinal neurons after peripheral nerve injury.


Provider-based research networks demonstrate greater hospice use for minority patients with lung cancer.
The Community Clinical Oncology Program (CCOP) and Minority-Based Community Clinical Oncology Program (MBCCOP) are provider-based research networks (PBRN) that improve minority enrollment in cancer-focused clinical trials. We hypothesized that affiliation with a PBRN may also mitigate racial differences in hospice enrollment for patients with lung cancer. We used the SEER-Medicare data, linked to the National Cancer Institute's CCOP program data, to identify all patients (≥ age 65 years) with lung cancer, diagnosed from 2001 to 2007. We defined clinical treatment settings as CCOP, MBCCOP, academic, or community-affiliated and used multivariable logistic regression analysis to determine factors associated with hospice enrollment. Forty-one thousand eight hundred eighty-five (55.1%) patients with lung cancer enrolled in hospice before death. Approximately 55% of CCOP, 57% of MBCCOP, 57% of academic, and 52% of community patients enrolled. Patients who were more likely to enroll were female (odds ratio [OR], 1.36; 95% CI, 1.31 to 1.40); ≥ age 79 years (OR, 1.11; 95%CI, 1.06 to 1.16); white; lived in more educated areas; had minimal comorbidities; and had distant disease. Asian and black patients in academic (41.1% and 50.4%, respectively) and community practices (35.2% and 43.4%, respectively) were less likely to enroll in hospice compared with white patients (academic, 58.8%; community, 53.1%). However, hospice enrollment was equivalent for black and white patients in MBCCOP (59.5% v 57.2%) and CCOP (52.2% v 56.3%) practices. Minority patients with lung cancer receiving treatment in cancer-focused PBRN- affiliated practices have greater hospice enrollment than those treated in academic and community practices.


Website discussion forums: results of an Australian project to promote telecommunication in dermatology.
Discussion forums on the Internet allow doctors to discuss issues of interest in a rapid, convenient and educational manner. In March 2002, the department of dermatology at the St George Hospital in Sydney launched a national Website with an online discussion forum for dermatologists. Features of the Website forum include the ability to moderate the discussion boards, a choice of public or private discussions and receipt of automatic email notifications. Over three months, three dermatologists posted a total of 13 messages on three different topics. The low rate of participation by dermatologists may have been due to lack of time or familiarity with the technology. Increased promotion to and education of dermatologists who are most likely to use the discussion forum may improve utilization of this means of communication.


Progress and prospect of nanotechnology for cardiac fibrosis treatment.
Cardiac fibrosis is the excessive accumulation of extracellular matrix components in the heart, leading to reduced cardiac functionality and heart failure. This review provides an overview of the therapeutic applications of nanotechnology for the treatment of cardiac fibrosis. We first delve into the fundamental pathophysiology of cardiac fibrosis, highlighting the key molecular players, including Matrix Metalloproteinases, Transforming Growth Factor-beta, and several growth factors, cytokines, and signaling molecules. Each target presents a unique opportunity to develop targeted nano-therapies. We then focus on recent advancements in nanotechnology and how nanoparticles can be engineered to deliver drugs or therapeutic genes. These advanced delivery approaches have shown significant potential to inhibit fibrosis-promoting factors, thereby mitigating the fibrotic response and potentially reversing disease progression. In addition, we discuss the challenges associated with developing and translating nanotechnology-based drug delivery systems, including ensuring biocompatibility, safety, and regulatory compliance. This review highlights how nanotechnology can bridge the gap between lab research and clinical practice for treating cardiac fibrosis.


Identifying public water facilities with low spatial variability of disinfection by-products for epidemiological investigations.
Epidemiological studies of disinfection by-products (DBPs) and reproductive outcomes have been hampered by misclassification of exposure. In most epidemiological studies conducted to date, all persons living within the boundaries of a water distribution system have been assigned a common exposure value based on facility-wide averages of trihalomethane (THM) concentrations. Since THMs do not develop uniformly throughout a distribution system, assignment of facility-wide averages may be inappropriate. One approach to mitigate this potential for misclassification is to select communities for epidemiological investigations that are served by distribution systems with consistently low spatial variability of THMs. A feasibility study was conducted to develop methods for community selection using the Information Collection Rule (ICR) database, assembled by the US Environmental Protection Agency. The ICR database contains quarterly DBP concentrations collected between 1997 and 1998 from the distribution systems of 198 public water facilities with minimum service populations of 100,000 persons. Facilities with low spatial variation of THMs were identified using two methods; 33 facilities were found with low spatial variability based on one or both methods. Because brominated THMs may be important predictors of risk for adverse reproductive outcomes, sites were categorised into three exposure profiles according to proportion of brominated THM species and average TTHM concentration. The correlation between THMs and haloacetic acids (HAAs) in these facilities was evaluated to see whether selection by total trihalomethanes (TTHMs) corresponds to low spatial variability for HAAs. TTHMs were only moderately correlated with HAAs (r = 0.623). Results provide a simple method for a priori selection of sites with low spatial variability from state or national public water facility datasets as a means to reduce exposure misclassification in epidemiological studies of DBPs.


Diagnostic potential of sefA DNA probes to Salmonella enteritidis and certain other O-serogroup D1 Salmonella serovars.
Salmonella enteritidis thin fimbriae, SEF14, were found to be restricted to S. dublin and the predominantly poultry-associated members of the Salmonella O-serogroup D1, S. enteritidis, S. berta, S. gallinarum and S. pullorum, when tested by Western and ELISA analysis from among 90 Salmonella isolates of 42 serovars, as well as from members of several related genera of the Enterobacteriaceae. These five serovars and a single isolate of S. typhi (D1) were also detected by hybridization of genomic DNA from 732 Salmonella isolates of 117 serogroups to gene probes derived from the S. enteritidis sefA (fimbrin gene), sefB (chaperone) or sefC (outer membrane protein) genes encoding proteins involved in SEF14 biosynthesis. None of 250 Enterobacteriaceae or 27 other eubacterial isolates tested hybridized to the sef probes. The sefA, sefB and sefC genes were amplified from these six Salmonella serovars by PCR using primer pairs designed from sefA, sefB or sefC of S. enteritidis. DNA sequencing of sefA genes from these five serovars indicated limited sequence variability among sefA genes and recognition of individual base pairs which could potentially differentiate certain strains of S. enteritidis, S. dublin and S. gallinarum.


Histological Study of The Healing of Traumatic Tympanic Membrane Perforation After Vivosorb and Epifilm Application.
Untreated traumatic tympanic membrane perforations (TMPs) may lead to permanent perforations and hearing loss. There are many materials that have been previously used for repairing the TMPs. The purpose of this study is to evaluate the clinical and histological effects of Vivosorb (Vv) and Epifilm on healing of TMPs in a rat model. The posterior-inferior quadrant of the tympanic membranes (TMs) in right ears of 14 rats was perforated using a 20-g needle and then the animals were randomly divided into 2 equal groups (n = 7). The perforated right TMs were treated with either Vv (Vv group) or Epifilm (Ep group). The left TMs of 7 rats were perforated in same way and allowed to close spontaneously without any topical material applications (spontaneous closure group as sham control, SC). The left tympanic membranes of the other 7 rats were not perforated and used as normal controls (NC group). On postoperative 15th day, tympanic bullas were extracted from killed rats and examined morphometrically and histopathologically. Perforation closure rate was 85.7% (6/7) in both Vv and SC groups. Perforations of Ep group closed in 7/7 (100%) ears. The thicknesses of the perforated membranes were increased in SC and especially Vv groups. Also, connective tissue fibrosis, blood clots, and epithelial degenerations were detected in SC and Vv groups. The mean fibroblastic reaction scores of Vv, Ep, and SC groups were 2.14(+), 0.57(+), and 1.71(+) respectively, on comparison with NC group. The mean neovascularization score was 1.42(+) in Vv group, 0.14(+) in Ep group, and 0.57(+) in SC group. Vivosorb and especially Epifilm can improve the healing process in traumatic TMPs and additionally, Epifilm might be more preferred for the treatment of TMPs because of causing lesser fibrosis.


Lung impedance measurements to monitor alveolar ventilation.
Electrical impedance tomography (EIT) is an attractive method of monitoring patients during mechanical ventilation because it can provide a noninvasive continuous image of pulmonary impedance, which indicates the distribution of ventilation. This article will discuss ongoing research on EIT, with a focus on methodological aspects and limitations and novel approaches in terms of pathophysiology, diagnosis and therapeutic advancements. EIT enables the detection of regional distribution of alveolar ventilation and, thus, the quantification of local inhomogeneities in lung mechanics. By detecting recruitment and derecruitment, a positive end-expiratory pressure level at which tidal ventilation is relatively homogeneous in all lung regions can be defined. Additionally, different approaches to characterize the temporal local behaviour of lung tissue during ventilation have been proposed, which adds important information. There is growing evidence that supports EIT usage as a bedside measure to individually optimize ventilator settings in critically ill patients in order to prevent ventilator-induced lung injury. A standardization of current approaches to analyse and interpret EIT data is required in order to facilitate the clinical implementation.


Effects of dystrophin isoforms on signal transduction through neural retina: genotype-phenotype analysis of duchenne muscular dystrophy mouse mutants.
Duchenne and Becker muscular dystrophy patients have mutations in the dystrophin gene. Most show reduced b-wave amplitudes in the dark-adapted electroretinogram (ERG). We studied normal C57BL/6J mice and five X-linked muscular dystrophy strains with different dystrophin mutations to determine whether the location of the mutation within the gene affects the mouse ERG and to correlate such effects with dystrophin isoform expression. Amplitudes and implicit times were measured for a-waves, b-waves, and digitally filtered oscillatory potentials. mdx and mdxCv5 mice, with mutations near the amino terminus and lacking expression of Dp427, had ERGs similar to those of C57BL/6J mice. mdxCv2 and mdxCv4 mice, with mutations in the center of dystrophin and who do not express isoforms Dp427, Dp260, or Dp140 (mdxCv4), had increased b-wave and oscillatory potential implicit times. mdxCv3 mice, with a mutation near the carboxy terminus resulting in deficiency of all dystrophin isoforms, had increased b-wave and oscillatory potential implicit times and reduced scotopic b-wave amplitudes. Fitting the a-wave data to a transduction activation phase mathematical model showed normal responses for all phenotypes, suggesting that the b-wave delays are due to defects beyond the rod outer segment, most likely at the rod to on-bipolar cell synapse. The variation in the ERG phenotype with the position of the dystrophin gene mutation suggests that there are different contributions by each isoform to retinal electrophysiology. Although Dp427 and Dp140 isoforms do not appear to be important contributors to the ERG, lack of Dp260 and possibly Dp71 isoforms is associated with an abnormal ERG.


Essential Oil from Melaleuca leucadendra: Antimicrobial, Antikinetoplastid, Antiproliferative and Cytotoxic Assessment.
Essential oils (EOs) are known for their use in cosmetics, food industries, and traditional medicine. This study presents the chemical composition and therapeutic properties against kinetoplastid and eukaryotic cells of the EO from Melaleucaleucadendra (L.) L. (Myrtaceae). Forty-five compounds were identified in the oil by GC-MS, containing a major component the 1,8-cineole (61%). The EO inhibits the growth of Leishmania amazonensis and Trypanosoma brucei at IC50 values <10 μg/mL. However, 1,8 cineole was not the main compound responsible for the activity. Against malignant (22Rv1, MCF-7, EFO-21, including resistant sublines MCF-7/Rap and MCF-7/4OHTAMO) and non-malignant (MCF-10A, J774A.1 and peritoneal macrophage) cells, IC50 values from 55 to 98 μg/mL and from 94 to 144 μg/mL were obtained, respectively. However, no activity was observed on Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger, Candida parapsilosis, Microsporum canis, or Trypanosoma cruzi. The EO was able to control the lesion size and parasite burden in the model of cutaneous leishmaniasis in BALB/c mice caused by L. amazonensis compared to untreated animals (p < 0.05) and similar with those treated with Glucantime® (p > 0.05). This work constitutes the first evidence of antiproliferative potentialities of EO from M. leucadendra growing in Cuba and could promote further preclinical investigations to confirm the medical value of this plant, in particular for leishmaniasis treatment.


Single-Cell Transcriptomics Analysis of Human Small Antral Follicles.
Human ovarian folliculogenesis is a highly regulated and complex process. Characterization of follicular cell signatures during this dynamic process is important to understand follicle fate (to grow, become dominant, or undergo atresia). The transcriptional signature of human oocytes and granulosa cells (GCs) in early-growing and ovulatory follicles have been previously described; however, that of oocytes with surrounding GCs in small antral follicles have not been studied yet. Here, we have generated a unique dataset of single-cell transcriptomics (SmartSeq2) consisting of the oocyte with surrounding GCs from several individual (non-dominant) small antral follicles isolated from adult human ovaries. We have identified two main types of (healthy) follicles, with a distinct oocyte and GC signature. Using the CellphoneDB algorithm, we then investigated the bi-directional ligand-receptor interactions regarding the transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP), wingless-type (MMTV)-integration site (WNT), NOTCH, and receptor tyrosine kinases (RTK) signaling pathways between oocyte and GCs within each antral follicle type. Our work not only revealed the diversity of small antral follicles, but also contributes to fill the gap in mapping the molecular landscape of human folliculogenesis and oogenesis.


delta(13)C and delta(2)H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane.
Previous work in these laboratories and by Butzenlechner et al. and Culp et al. has demonstrated that the delta(2)H isotope value of industrial benzaldehyde produced by the catalytic oxidation of toluene is profoundly positive, usually in the range +300 per thousand to +500 per thousand. Synthetic routes leading to amphetamine, methylamphetamine or their precursors and commencing with such benzaldehyde may be expected to exhibit unusually positive delta(2)H values. Results are presented for delta(13)C and delta(2)H isotope values of 1-phenyl-2-nitropropene synthesized from an industrial source of benzaldehyde, having a positive delta(2)H isotope value, by a Knoevenagel condensation with nitroethane. Results are also presented for delta(13)C and delta(2)H isotope values for amphetamine prepared from the resulting 1-phenyl-2-nitropropene. The values obtained were compared with delta(13)C and delta(2)H isotope values obtained for an amphetamine sample prepared using a synthetic route that did not involve benzaldehyde. Finally, results are presented for samples of benzaldehyde, 1-phenyl-2-nitropropene and amphetamine that had been seized at a clandestine amphetamine laboratory.


Serum leptin in short children born small for gestational age: relationship with the growth response to growth hormone treatment. The Swedish Study Group for Growth Hormone Treatment.
The product of the obese (ob) gene, leptin, is an adipocyte-derived hormone that is involved in the regulation of appetite and body weight. This study was undertaken in order to describe the basal serum levels of leptin in prepubertal short children born small for gestational age (SGA) and their relationship with growth parameters, before and during growth hormone (GH) treatment. Eighty-nine prepubertal short children (66 boys, 23 girls; height standard deviation score (SDS), -5.4 to -2.0; age, 2.0 to 12.8 years) born SGA, 12 of whom (9 boys, 3 girls) had signs of Silver-Russell syndrome, were included in the study. Serum leptin concentrations were measured by radioimmunoassay. Leptin levels in the children born SGA were compared with those in a reference group of 109 prepubertal healthy children born at an appropriate size for gestational age (AGA). The mean (S.D.) change in height SDS was 0.11 (0.22) during the year before the start of GH therapy (0.1 IU/kg/day) and increased to 0.82 (0.44) during the first year (P < 0.001) and to 1.28 (0.59) during the 2-year period of GH therapy (P < 0.001). The children born SGA were significantly leaner than the reference group. An inverse correlation was found between leptin and chronological age in the SGA group (r = -0.31, P < 0.01). The mean serum level of leptin in the children born SGA who were older than 5.5 years of age was 2.8 micrograms/l which was significantly lower than the mean value of 3.7 micrograms/l found in the children born AGA of the same age range. The difference remained after adjustment of leptin levels for sex, age, body mass index (BMI) and weight-for-height SDS (WHSDSSDS). Leptin correlated with WHSDSSDS (r = 0.32, P < 0.001) and BMI (r = 0.36, P < 0.01) in the reference population, but not in the SGA group. No correlation was found between leptin and spontaneous 24-h GH secretion, insulin-like growth factor (IGF)-I or IGF-binding protein-3 levels, or with fasting insulin or cortisol levels. Leptin levels at the start of GH treatment were correlated with the growth response over both 1 year (r = 0.46, P < 0.001) and 2 years (r = 0.51, P < 0.001) of GH therapy. Using multiple regression analysis, models including leptin levels at the start of GH therapy could explain 51% of the variance in the growth response after 1 year and 44% after 2 years of GH treatment. In conclusion, serum leptin levels are reduced in short children born SGA and are inversely correlated with chronological age. Leptin concentrations correlate with the growth response to GH treatment and might be used as a marker for predicting the growth response to GH treatment.


Multidetector-row computed tomography for the preoperative evaluation of axillary nodal status in patients with breast cancer.
We evaluated the effectiveness of multidetector-row computed tomography (MD-CT) for detecting axillary lymph nodal status (ALNS) in patients with breast cancer. We reviewed 42 patients with breast cancer. A metastatic lymph node on MD-CT was defined as oval or round, with more than 5 mm on the short axis. We evaluated ALNS preoperatively by both palpation and MD-CT findings and performed sentinel lymph node biopsy (SLNB) and complete axillary lymph node dissection (ALND). For establishing the ALNS, MD-CT showed a sensitivity of 76.9%, a specificity of 96.6%, and an accuracy of 90.5%. On the basis of the MD-CT findings, misdiagnosis was made in 4 of the 42 patients, only one of which was false positive. On the other hand, one patient with a histologically negative sentinel lymph node (SLN) result had metastasis only in a non-SLN. Preoperative MD-CT showed a positive node in this patient. Multidetector-row computed tomography assists in identifying women who require ALND without SLNB, with sufficient positive predictive value. False-negative detection by SLNB could be avoided with careful interpretation of the axillary lymph nodes shown by MD-CT.


Cell-killing by paclitaxel in a metastatic murine melanoma cell line is mediated by extensive telomere erosion with no decrease in telomerase activity.
The purpose of this study was to investigate and compare the effects of paclitaxel and its water-soluble conjugates (sodium-pentetic acid-paclitaxel; polyethylene glycol-paclitaxel, and poly[L-glutamic acid]-paclitaxel) on chromosome morphology and induction of apoptosis in a metastatic murine melanoma cell line (K1735 clone X-21). For this, murine melanoma cells were treated continuously for 72 h with three concentrations (1.2 microM, 2.4 microM, and 4.8 microM) of each of paclitaxel, and conjugates. Another set of cells were pulse-treated at 2.4 microM, 4.8 microM and 9.6 microM concentrations of each of these drugs for 4 h and the recovered cells were examined after 72 h. Control cultures received only the solvents (dimethyl sulfoxide or water). Our results showed a significant increase in the frequencies of telomeric associations, chromosome aberrations, polyploidization, distorted and disintegrated chromosome morphology, and reduced telomeric signal intensity by fluorescence in situ hybridization, in treated cultures as compared to the controls. However, we detected no change in telomerase activity. In addition, the majority of interphase nuclei in treated cells showed apoptotic bodies, with chromatin condensation. These in vitro results suggest that cell death induced by paclitaxel and its water-soluble conjugates is due to the loss of telomeric repeats, as shown by reduced signal flourescence and increased telomeric associations.


Relationship between distance from major larval habitats and abundance of adult mosquitoes in semiarid plains landscapes in Colorado.
We examined the relationship between distance from major larval habitats and abundance of adult mosquitoes in the semiarid plains landscape characteristic of eastern Colorado. Mosquito collection was conducted from late June to early August 2007 and included trap locations at distances ranging from <10 m up to 20-150 m and 160-373 m from three major larval habitats: one area along a river corridor and two small reservoirs. The study yielded 65,140 mosquitoes of 14 species, and five species were sufficiently abundant to be included in statistical analyses: Aedes vexans (Meigen), Culex tarsalis Coquillett, Ochlerotatus dorsalis (Meigen) (=Ae. dorsalis), Ochlerotatus melanimon (Dyar) (=Ae. melanimon), and Culex pipiens L. Distance to nearest major larval habitat was not strongly related to Culex abundance within the approximately = 400-m range from larval habitats examined in this study. Abundance of Ae. vexans declined significantly with distance from the larval habitat, whereas abundance was significantly higher in the 20-150- and 160-373-m classes compared with areas within 10 m of the larval habitat for both Ochlerotatus species. Except for Ae. vexans, however, we did not find monotonic increasing or decreasing abundance trends associated with distance from larval habitats for the 400-m range examined. This, combined with a finding that fine-scale habitat heterogeneity influenced abundance for most of the mosquitoes examined, underscores the importance of considering not only distance from larval habitat but also fine-scale habitat heterogeneity to understand how important nuisance-biters and West Nile virus (family Flaviviridae, genus Flavivirus, WNV) vectors use the landscape. We also discuss how these results relate to previous studies from western North America and explore their relevance to operational implementation of adulticides to suppress mosquito vectors during WNV disease outbreaks in the Great Plains.


Sarcoid myositis: a rare presentation.
A 50-year-old lady with a background of Perthes disease and multiple bilateral hip revisions presented with symptoms of right hip pain. She was unable to raise and weight bear on the right leg. Hip examination revealed limited flexion and extension to 15-20 ° due to pain. Her blood tests and x-rays showed no obvious acute problems. She was treated with mobilisation and analgesia, and had a bone scan that revealed no acute issues. Further examination revealed she had generalised weakness in her upper arm. A creatine kinase marker showed a level of over 2000. Therefore, an MRI and a muscle biopsy were done. A diagnosis of sarcoid myositis was made and the patient was put on steroids. She was able to make a full recovery. This case highlights the consideration of rare diseases in more highly complex cases.


Post-adenoidectomy quality of life in children with refractory chronic rhinosinusitis.
This study aimed to evaluate post-adenoidectomy quality of life in children with refractory chronic rhinosinusitis. A prospective interventional study of children aged 4-12 years with chronic refractory rhinosinusitis was conducted. A total of 60 children completed follow up. Nasal endoscopy and non-contrast computed tomography of the paranasal sinuses were performed, and both symptoms and their effects on patient quality of life pre- and post-adenoidectomy were evaluated. The most frequent symptoms were nasal obstruction, cough, fever and fatigue, which were experienced by 100 per cent, 90 per cent, 85 per cent and 81.7 per cent of children, respectively. Nasal endoscopy showed oedema and discharge were present in all children. A statistically significant post-operative improvement in sinus and nasal quality of life was seen in 53 children (88.3 per cent). Adenoidectomy is a simple, first-line surgical procedure for managing paediatric chronic rhinosinusitis refractory to maximal medical therapy and leads to an improved quality of life.


Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold.
The effects of hepatic portal infusions of isotonic glucose on glucose intake (3.2%) were evaluated with use of the intraoral intake test, which, unlike traditional tests, permits delivery of portal infusions in explicit temporal relationship to intake onset in nondeprived rats. Continuous or discontinuous portal infusions (0.1 ml/min) of isotonic glucose or saline were initiated 0, 30, 60, or 120 min before meal onset. Jugular infusions of isotonic saline or glucose and portal infusions of isotonic saline were without effect. For all effective portal glucose infusions, intake was suppressed by approximately 30% of baseline values. Because the duration (and quantity) of effective portal glucose infusions varied by a factor of 10, we conclude that intraoral intake suppression under these conditions is all or none in nature. Whether an intake suppression was obtained depended more on when the infusion was delivered than on how much was infused. Thus 1.5 ml of isotonic glucose infused between 60 and 45 min before the intake test was effective, whereas 3.0 ml infused for the 30 min before intake was without effect. These results suggest that the liver participates in the control of future intake but not in the termination of an ongoing meal. The temporal requirement for intake suppression should be considered in analyses of the metabolic, hormonal, and/or neural mechanisms that underlie the liver's contribution to intake control.


Prediction of optoelectronic properties of Cu2O using neural network potential.
Neural network potentials (NNPs) trained against density functional theory (DFT) are capable of reproducing the potential energy surface at a fraction of the computational cost. However, most NNP implementations focus on energy and forces. In this work, we modified the NNP model introduced by Behler and Parrinello to predict Fermi energy, band edges, and partial density of states of Cu2O. Our NNP can reproduce the DFT potential energy surface and properties at a fraction of the computational cost. We used our NNP to perform molecular dynamics (MD) simulations and validated the predicted properties against DFT calculations. Our model achieved a root mean squared error of 16 meV for the energy prediction. Furthermore, we show that the standard deviation of the energies predicted by the ensemble of training snapshots can be used to estimate the uncertainty in the predictions. This allows us to switch from the NNP to DFT on-the-fly during the MD simulation to evaluate the forces when the uncertainty is high.


Pre- and postjunctional effects of a thromboxane mimetic in canine bronchi.
Thromboxane A2 is believed to participate in causation of hyperreactivity of airway smooth muscle (ASM). We therefore investigated the effects of a thromboxane mimetic (U-46619) on isolated ring segments of canine bronchial ASM (3rd to 5th order). U-46619 (10(-9)-10(-5) M) was found to elicit tonic contraction, membrane depolarization, and oscillations in membrane potential. These effects were sensitive to blockade of thromboxane receptors (using 10(-8) M L 670, 596); the mechanical response was insensitive to 3 x 10(-8) M atropine, 10(-7) M nitrendipine, or exposure to Ca(2+)-free media [(containing 0.5 mM ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)]. U-46619 also potentiated electrical field stimulation-elicited contractions and excitatory junction potentials without altering the sensitivity to carbachol. This potentiation was also sensitive to L 670,596 but not to blockade of adrenoceptors (using phentolamine plus propranolol). We conclude that canine bronchial ASM possesses both prejunctional and postjunctional thromboxane receptors. The former potentiate cholinergic neurotransmission through a mechanism not involving adrenoceptors. The latter excite the ASM through a mechanism not involving muscarinic receptors and that utilizes intracellular Ca2+ (rather than extracellular Ca2+). Excitation-contraction coupling was found to be pharmacomechanical in nature (rather than electromechanical).


Precision of digital vision systems.
The precision of geometric features such as the centroid, area, perimeter, and orientation measured by a 2-D digital vision system is analyzed and tested experimentally. The digitizing error of various geometric features can be expressed in terms of the dimensionless perimeter of the object. As a result of this work, the sampling process can be simplified or eliminated. The analysis is also expanded to cover the 3-D digital vision systems.


Effects of serotonin reuptake inhibitors on aggressive behavior in psychiatrically hospitalized adolescents: results of an open trial.
Low concentrations of the neurotransmitter serotonin and its 5-hydroxyindoleacetic acid metabolite in the central nervous system have been associated with increased aggressive behavior in animals and humans. Controlled clinical trials of serotonin agonists in depressed adults have suggested that aggressive behavior is less likely during treatment with these medications than with placebo, but there have been no previous studies of selective serotonin reuptake inhibitors (SSRIs) and aggression in children. We prospectively followed the course of aggressive behavior in 19 psychiatrically hospitalized adolescents (not selected for aggressiveness) who received open clinical trials of fluoxetine, paroxetine, or sertraline. The patients received standard doses (equivalent to fluoxetine 10-40 mg daily) for a minimum of 5 weeks. The starting dose was 15 +/- 5 mg, and dosages were raised at a mean rate of 5 mg every 4 days up to a mean dose of 25 +/- 10 mg daily. Results from trials of the three SSRIs were clustered because the sample sizes were not sufficient for separate analyses. Overall, there were no statistically meaningful improvements in the level of aggressive behavior, as measured on a modified version of the Overt Aggression Scale, over the course of these patients' SSRI trials. Symptoms of physical aggression toward others or self were manifest in 12 of the 19 patients while on SSRIs. Of the 19 patients, 13 were assessed both on and off SSRIs: verbal aggression (p = 0.04), physical aggression toward objects (p = 0.05), and physical aggression toward self (p < 0.02) occurred significantly more frequently on SSRIs than off; no increase was observed in physical aggression toward others. Patients with the highest baseline aggressivity scores did not show greater improvement during SSRI treatment. Further research is warranted, particularly to explore whether SSRIs may have therapeutic effects on aggression at higher (or lower) doses than were administered in this open trial.


Mcm1 promotes replication initiation by binding specific elements at replication origins.
Minichromosome maintenance protein 1 (Mcm1) is required for efficient replication of autonomously replicating sequence (ARS)-containing plasmids in yeast cells. Reduced DNA binding activity in the Mcm1-1 mutant protein (P97L) results in selective initiation of a subset of replication origins and causes instability of ARS-containing plasmids. This plasmid instability in the mcm1-1 mutant can be overcome for a subset of ARSs by the inclusion of flanking sequences. Previous work showed that Mcm1 binds sequences flanking the minimal functional domains of ARSs. Here, we dissected two conserved telomeric X ARSs, ARS120 (XARS6L) and ARS131a (XARS7R), that replicate with different efficiencies in the mcm1-1 mutant. We found that additional Mcm1 binding sites in the C domain of ARS120 that are missing in ARS131a are responsible for efficient replication of ARS120 in the mcm1-1 mutant. Mutating a conserved Mcm1 binding site in the C domain diminished replication efficiency in ARS120 in wild-type cells, and increasing the number of Mcm1 binding sites stimulated replication efficiency. Our results suggest that threshold occupancy of Mcm1 in the C domain of telomeric ARSs is required for efficient initiation. We propose that origin usage in Saccharomyces cerevisiae may be regulated by the occupancy of Mcm1 at replication origins.


Mechanisms of long non-coding RNA function in colorectal cancer tumorigenesis.
Colorectal cancer (CRC) is one of the most common cancers globally. Although a variety of CRC screening methods have been developed, many patients are diagnosed at advanced stages of CRC with tumor invasion and distance metastasis. Several studies have suggested the long noncoding RNAs (lncRNAs) as one of the main contributors in CRC tumorigenesis, although the exact underlying mechanism of lncRNAs in CRC is still unknown. Numerous studies have indicated aberrant expression of lncRNAs in CRC through different modes of action such as cell proliferation, apoptosis, cell cycle, DNA repair response, drug-resistance, migration, and metastasis. Furthermore, lncRNA polymorphisms can influence the risk of CRC development. Accordingly, lncRNAs can be served as promising diagnostic or prognostic biomarkers and also desired therapeutic targets affecting the outcome of patients with CRC. In this review, we summarized the updated and novel evidence that identifies different roles of lncRNAs in the tumorigenesis of CRC.


Ex vivo culture of CD34+/Lin-/DR- cells in stroma-derived soluble factors, interleukin-3, and macrophage inflammatory protein-1alpha maintains not only myeloid but also lymphoid progenitors in a novel switch culture assay.
We have demonstrated that long-term culture initiating cells (LTC-IC) are maintained in a stroma noncontact (SNC) culture where progenitors are separated from stroma by a microporous membrane and LTC-IC can proliferate if the culture is supplemented with interleukin-3 (IL-3) and macrophage inflammatory protein-1alpha (MIP-1alpha). We hypothesize that the same conditions, which result in LTC-IC proliferation, may also maintain lymphoid progenitors. Natural killer (NK) cells are of lymphoid lineage and a stromal-based culture can induce CD34+/Lin-/DR- cells to differentiate along the NK cell lineage. We developed a three-step switch culture assay that was required to demonstrate the persistence of NK progenitors in CD34+/Lin-/DR- cells assayed in SNC cultures supplemented with IL-3 and MIP-1alpha. When CD34+/Lin-/DR- progeny from the SNC culture were plated sequentially into "NK cell progenitor switch" conditions (contact with stromal ligands, hydrocortisone-containing long-term culture medium, IL-2, IL-7, and stem cell factor [SCF]) followed by "NK cell differentiation" conditions (contact with stromal ligands, human serum, no hydrocortisone, and IL-2), significant numbers of CD56+/CD3- NK resulted, which exhibited cytotoxic activity against K562 targets. All steps are required because a switch from SNC cultures with IL-3 and MIP-1alpha directly to "NK cell differentiation" conditions failed to yield NK cells suggesting that critical step(s) in lymphoid commitment were missing. Additional experiments showed that CD34+/CD33- cells present after SNC cultures with IL-3 and MIP-1alpha, which contained up to 30% LTC-IC, are capable of NK outgrowth using the three-step switch culture. Limiting dilution analysis from these experiments showed a cloning frequency within the cultured CD34+/CD33- population similar to fresh sorted CD34+/Lin-/DR- cells. However, after addition of FLT-3 ligand, the frequency of primitive progenitors able to develop along the NK lineage increased 10-fold. In conclusion, culture of primitive adult marrow progenitors ex vivo in stroma-derived soluble factors, MIP-1alpha, and IL-3 maintains both very primitive myeloid (LTC-IC) and lymphoid (NK) progenitors and suggests that these conditions may support expansion of human hematopoietic stem cells. Addition of FLT-3 ligand to IL-2, IL-7 SCF, and stromal factors are important in early stages of NK development.


Back to school readiness scale for children with oncological problems: 7-18 years of age.
Childhood cancers are one of the important health problems in both developed and underdeveloped countries. The cancer treatment process is a difficult period that can last for months or years, interrupt school activities for a while, or even cause them to leave completely, and require long-term hospitalization. This study was carried out to develop the Back to School Readiness Scale for Children with Oncological Problems: 7-18 years of age, and to establish its validity and reliability. The research is a methodological study and the validity and reliability study of a developed scale was conducted. Kaiser-Meyer-Olkin (KMO) value was determined as 0.951. As a result of Bartlett's test analysis, Chi-Square value is 6261.566, degree of freedom is 703 and the value found is significant (p = 0.00, p < 0.05). While the loadings of the items on the first factor vary between 0.79 and 0.46, the loads on the second factor vary between 0.76 and.47. The item-total-test correlation value is 0.63. Total Croncabh alpha (α) value of the scale is 0.97. Back to School Readiness Scale for Children with Oncological Problems: 7-18 years of age is a valid and reliable measurement tool. Returning to school is a difficult process for children living with cancer due to long-term hospitalization. This scale can be used by both pediatric nurses and school nurses to evaluate children's return to school. Additionally, children and families can get an idea about preparing for returning to school by applying this scale.


Safety and Efficacy of a Novel Shunt Surgery Combined with Foam Sclerotherapy of Varices for Prehepatic Portal Hypertension: A Pilot Study.
This pilot study investigated the safety and efficacy of a novel shunt surgery combined with foam sclerotherapy of varices in patients with prehepatic portal hypertension. Twenty-seven patients who were diagnosed with prehepatic portal hypertension and underwent shunt surgeries were divided into three groups by surgery type: shunt surgery alone (Group A), shunt surgery and devascularization (Group B), and shunt surgery combined with foam sclerotherapy (Group C). Between-group differences in operation time, intraoperative blood loss, portal pressure decrease, postoperative complications, rebleeding rates, encephalopathy, mortality rates and remission of gastroesophageal varices were compared. Groups A, B and C had similar operation times, intraoperative bleeding, and portal pressure decrease. The remission rates of varices differed significantly (p<0.001): one patient in Group A and 6 patients in Group B had partial response, and all 9 patients in Group C had remission (2 complete, 7 partial). Two Group A patients and one Group B patient developed recurrent gastrointestinal bleeding postoperatively within 12 months. No postoperative recurrence or bleeding was observed in Group C, and no sclerotherapy-related complications were observed. Shunt surgery combined with foam sclerotherapy obliterates varices more effectively than shunt surgery alone does, decreasing the risk of postoperative rebleeding from residual gastroesophageal varices. This novel surgery is safe and effective with good short-term outcomes.


Hyperplasia and hypertrophy of chicken cardiac myocytes during posthatching development.
For characterization of the growth pattern of cardiac myocytes during posthatching development, cardiac myocytes were enzymatically isolated from the ventricles of 1-, 15-, 29-, and 42-day-old chickens for measurement of myocyte nucleation, length, width, volume, and number, and for immunolabeling of cytoskeletal proteins. Ventricular myocyte number increased 156% from day 1 to day 42. Average cell volume increased more than 400%, and myocytes lengthened 125%, but cell width only increased 53% during this period. All myocytes were mononucleated at day 1. At day 15, 18% of myocytes became binucleated with < 1% of myocytes containing more than two nuclei. Interestingly, binucleated myocytes were able to divide with two nuclei going through mitosis at the same time. As demonstrated by staining with tubulin and alpha-actinin antibodies, two mitotic spindles and two cleavage furrows were formed in dividing binucleated myocytes. At day 42, binucleated myocytes increased to 44% with 11% of myocytes containing more than two nuclei. Sarcomeric alpha-actinin was partially disassembled in prometaphase and was reorganized into regular Z lines of sarcomeres in telophase. Desmin was disassembled in prophase and was reassembled during late telophase. These results suggest that chicken myocytes undergo hypertrophy and continue to proliferate during posthatching maturation, although it is currently believed that myocytes of all vertebrates withdraw from the cell cycle shortly after birth. We provide direct evidence for the first time of in vivo myocyte division in 6-wk-old chicken hearts.


Effects of saponins, quercetin, eugenol, and cinnamaldehyde on fatty acid biohydrogenation of forage polyunsaturated fatty acids in dual-flow continuous culture fermenters.
Four different plant secondary metabolites were screened for their effect on rumen biohydrogenation of forage long-chain fatty acids, using dual-flow continuous culture fermenters. Treatments were as follows: control (no additive), positive control (12 mg/L of monensin), and plant extracts (500 and 1,000 mg/L of triterpene saponin; 250 and 500 mg/L of quercetin; 250 mg/L of eugenol; 500 mg/L of cinnamaldehyde). Monensin increased propionate, decreased acetate and butyrate proportions, and inhibited the complete biohydrogenation of fatty acids resulting in the accumulation of intermediates of the biohydrogenation process (C18:2 trans-11, cis-15 rather than C18:1 trans-11). Cinnamaldehyde decreased total VFA concentration and proportions of odd and branched-chain fatty acids in total fat effluent. Apparent biohydrogenation of C18:2n-6 and C18:3n-3 was also less, and a shift from the major known biohydrogenation pathway to a secondary pathway of C18:2n-6 was observed, as evidenced by an accumulation of C18:1 trans-10 and trans-10, cis-12 CLA. Quercetin (500 mg/L) increased total VFA concentration, but no shifts in the pathways or extent of biohydrogenation were observed. Eugenol resulted in the accumulation of C18:1 trans-15 and C18:1 cis-15, end products of an alternative biohydrogenation pathway of C18:3n-3. Triterpene saponins did not affect the fermentation pattern, the biohydrogenation pathways, or the extent of biohydrogenation. At the doses tested in this study, we could only show a direct relation between changes in the rumen fatty acid metabolism and the presence of cinnamaldehyde but not for eugenol, quercetin, or triterpene saponins.


The dynamic nature of food reward processing in the brain.
The dominant view in the literature is that increased neural reactivity to high-caloric palatable foods in the mesocorticolimbic system is a stable-specific characteristic of obese people. In this review, we argue that this viewpoint may not be justified, and we propose that the neural response to food stimuli is dynamic, and in synchrony with the current motivational and cognitive state of an individual. We will further motivate why a clear mental task in the scanner is a necessity for drawing conclusions from neural activity, and why multivariate approaches to functional MRI (fMRI) data-analysis may carry the field forward. From the reviewed literature we draw the conclusions that: neural food-cue reactivity depends strongly on cognitive factors such as the use of cognitive regulation strategies, task demands, and focus of attention; neural activity in the mesocorticolimbic system is not proportionate to the hedonic value of presented food stimuli; and multivariate approaches to fMRI data-analysis have shown that hedonic value can be decoded from multivoxel patterns of neural activity. Future research should take the dynamic nature of food-reward processing into account and take advantage from state-of-the-art multivariate approaches to fMRI data-analysis.


Midregional pro-atrial natriuretic peptide for the diagnosis of cardiac-related dyspnea according to renal function in the emergency department: a comparison with B-type natriuretic peptide (BNP) and N-terminal proBNP.
Although renal dysfunction influences the threshold values of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in diagnosis of cardiac-related dyspnea (CRD), its effects on midregional pro-atrial natriuretic peptide (MR-proANP) threshold values are unknown. We evaluated the impact of renal function on MR-proANP concentrations and compared our results to those of BNP and NT-proBNP. MR-proANP, BNP, and NT-proBNP concentrations were measured in blood samples collected routinely from dyspneic patients admitted to the emergency department. Patients were subdivided into tertiles based on their estimated glomerular filtration rate [eGFR, in mL · min(-1) · (1.73 m(2))(-1)]: tertiles 1 (<44.3), 2 (44.3-58.5), and 3 (≥58.6). Of 378 patients studied, 69% (n = 260) had impaired renal function [<60 mL · min(-1) · (1.73 m(2))(-1)] and 30% (n = 114) had CRD. MR-proANP, BNP, and NT-proBNP concentrations were significantly increased in patients with impaired renal function. In each tertile, all peptides remained significantly increased in CRD patients by comparison with non-CRD patients. By ROC analysis, MR-proANP, BNP, and NT-proBNP threshold values for the diagnosis of CRD increased as eGFR decreased from tertile 3 to tertile 1. Areas under the ROC curve for all peptides were significantly lower in tertile 1. Using adapted thresholds, MR-proANP, BNP, and NT-proBNP remained independently predictive of CRD, even in tertile 1 patients. Renal function influences optimum cutoff points of MR-proANP for the diagnosis of CRD. With use of an optimum threshold value adapted to the eGFR category, MR-proANP remains as effective as BNP and NT-proBNP in independently predicting a diagnosis of CRD in the emergency department.


4-(1H-Tetra-zol-5-yl)-1H-indole.
There are two mol-ecules with similar configurations in the asymmetric unit of the title compound, C(9)H(7)N(5), which are linked by inter-molecular N-H⋯N hydrogen bonds into chains with graph-set motif C(2) (2)(8) along the b axis. The indole core has the expected planar geometry in the two mol-ecules, with a maximum deviation of 0.008 (8) Å from the least-squares plane defined by the nine constituent atoms, and the dihedral angles between the indole and tetra-zole rings are similar [42.4 (2) and 42.7 (2)°].


Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention.
Vascular pathologies constitute a major cause of graft rejection after organ transplantation. Recent studies have documented an improvement in transplant outcome when organs are preserved through pulsatile perfusion; however, the underlying mechanisms of these observations are poorly characterized. We hypothesized that the temporary absence of flow occurring in the context of organ cold storage conditions disrupts endothelial vasoprotective programs, and that this consequence of stasis may be a target for pharmacological modulation. The expression of the transcription factor Kruppel-like factor 2 (KLF2) and its vasoprotective target genes were assessed during cold storage conditions in cultured human endothelial cells and murine aortic segments. In addition, we evaluated the effect of simvastatin used as a supplement in a cold preservation solution on the expression of vasoprotective genes, and on endothelial activation and apoptosis. The expression of endothelial KLF2 and its vasoprotective transcriptional targets were rapidly lost during cold preservation in vitro and ex vivo. Importantly, simvastatin treatment blocked the decay of KLF2, sustaining a vasoprotective phenotype, and preventing endothelial activation and apoptosis. Flow stasis leads to acute endothelial dysfunction and apoptosis in the context of cold storage conditions. Supplementation of organ preservation solutions with pharmacologic agents that restore endothelial vasoprotective programs, by upregulating KLF2, may represent a significant advancement of current organ preservation techniques.


[Multiple myeloma with monoclonal IgE gammopathy (author's transl)].
In a 48-year-old female patient with monoclonal gammopathy and histologically proven plasmocytoma IgE could be demonstrated in bone marrow plasma cells by means of direct immunofluorescence. Immunoelectrophoresis showed a light-chain type chi. Radiographically diffuse osteolytic skeletal lesions were found. Bence-Jones proteinuria and plasma cell leukaemia were absent. This patient represents the fourth recognized case of IgE myeloma. The chi/lambda ratio in IgE myeloma is 1:1 according to present knowledge.


Microsurgical treatment of unruptured middle cerebral artery aneurysms: a large, contemporary experience.
OBJECTIVEAdvances in endovascular therapy for the treatment of middle cerebral artery (MCA) aneurysms have led to scrutiny of its benefits compared with microsurgical repair. To provide information regarding complication rates and outcomes, the authors reviewed the results of a large series of unruptured MCA aneurysms treated with open microsurgery.METHODSThe authors included all patients who underwent surgical repair of an unruptured MCA aneurysm between 1997 and 2015. All surgical procedures, including clipping, wrapping, bypass, and parent artery occlusion, were performed by a single neurosurgeon. Aneurysm occlusion was assessed using intraoperative digital subtraction angiography (DSA) or DSA and indocyanine green videoangiography in all cases. Postoperatively, all patients were monitored in a neurointensive care unit overnight. Clinical follow-up was scheduled for 2-4 weeks after surgery, and angiographic follow-up was performed in those patients with subtotally occluded aneurysms at 1, 2, and 5 years postoperation.RESULTSThe authors treated 750 unruptured MCA aneurysms in 716 patients: 649 (86.5%) aneurysms were small, 75 (10.0%) were large, and 26 (3.5%) were giant. Most aneurysms (n = 677, 90%) were treated by primary clip reconstruction. The surgical morbidity rate was 2.8%, and the mortality rate was 0%. Complete angiographic aneurysm occlusion was achieved in 92.0% of aneurysms. At final follow-up, 713 patients had a modified Rankin Scale (mRS) score of 0, 2 patients had an mRS score of 2 or 3, and 1 had an mRS score of 4.CONCLUSIONSIn high-volume centers, microsurgical management of MCA aneurysms can be performed with very low morbidity rates. Currently, microsurgical repair appears to be a highly effective method of treating MCA aneurysms.


English-based Pediatric Emergency Medicine Software Improves Physician Test Performance on Common Pediatric Emergencies: A Multicenter Study in Vietnam.
Global health agencies and the Vietnam Ministry of Health have identified pediatric emergency care and health information technology as high priority goals. Clinical decision support (CDS) software provides physicians with access to current literature to answer clinical queries, but there is limited impact data in developing countries. We hypothesized that Vietnamese physicians will demonstrate improved test performance on common pediatric emergencies using CDS technologies despite being in English. This multicenter, prospective, pretest-posttest study was conducted in 11 Vietnamese hospitals enrolled a convenience sample of physicians who attended an 80-minute software training on a pediatric CDS software (PEMSoft). Two multiple-choice exams (A, B) were administered before and after the session. Participants, who received Test A as a pretest, received Test B as a posttest, and vice versa. Participants used the CDS software for the posttest. The primary outcome measure was the mean percentage difference in physician scores between the pretest and posttest, as calculated by a paired, two-tailed t-test. For the 203 participants, the mean pretest, posttest, and improvement scores were 37% (95% CI: 35-38%), 70% (95% CI: 68-72%), and 33% (95% CI: 30-36%), respectively, with p<0.0001. This represents an 89% improvement over baseline. Subgroup analysis of practice setting, clinical experience, and comfort level with written English and computers showed that all subgroups equivalently improved their test scores. After brief training, Vietnamese physicians can effectively use an English-based CDS software based on improved performance on a written clinical exam. Given this rapid improvement, CDS technologies may serve as a transformative tool in resource-poor environments.


Rapid method for determining serum bactericidal activity.
To screen large numbers of sera, a method was devised which utilizes the Steers-Foltz replicator which is usually used to determine minimal inhibitory concentration for antibiotics. Each of the wells (9 by 15 mm) of the replicator is filled with 0.06 ml of serum, 0.02 ml of a 10(5) suspension of organisms, and 0.02 ml of diluent (tris(hydroxymethyl)aminomethane-hydrochloride buffer, pH 8.4). The mixtures are incubated for 3 h, and samples are taken at 0, 1, 2, and 3 h by stamping duplicate nutrient agar plates (approximately 0.04 ml from each well). Plates are incubated overnight, and bactericidal activity is estimated by visual inspection of bacterial growth at each site for each sampling time. Results obtained with 28 serum-organism pairs paralleled standard pipetting-pour plate methods. The replicator method for determining bactericidal activity allows for the testing of a large number of samples and requires negligible amounts of serum.