De novo 3q/7q translocation and associated interstitial 7q35 deletion.
In the present report we describe a severely mentally retarded and dysmorphic female child with a de novo 3q/7q reciprocal translocation and loss of band 7q35. This finding supports the hypothesis that the occurrence of mental retardation and/or congenital malformations in de novo autosomal reciprocal translocation may be due to the loss of a small amount of chromatin material during this chromosomal rearrangement.


Endothelial ETS1 inhibition exacerbate blood-brain barrier dysfunction in multiple sclerosis through inducing endothelial-to-mesenchymal transition.
Blood-brain barrier (BBB) dysfunction has been recognized as an early pathological feature and contributing factor in multiple sclerosis. Endothelial-to-mesenchymal transition is a process associated with endothelial dysfunction leading to the disruption of vessel stability and barrier function, yet its functional consequence in multiple sclerosis remains unclear. Here, we demonstrated that endothelial-to-mesenchymal transition accompanied the blood-brain barrier dysfunction in several neurological disorders, especially in multiple sclerosis. The activity of transcription factor ETS1, which is highly expressed in endothelial cells (ECs) and responded to an inflammatory condition, is suppressed in the central nervous system (CNS) ECs in MS and its animal model experimental autoimmune encephalomyelitis. We identify ETS1 as a central regulator of endothelial-to-mesenchymal transition (EndMT) associated with the compromise of barrier integrity. These phenotypical and functional alterations can further induce high permeability, immune infiltration, and organ fibrosis in multiple sclerosis, thus promoting disease progression. Together, these results demonstrate a functional role of EndMT in blood-brain barrier dysfunction and propose ETS1 as a potential transcriptional switch of EndMT to target the development of multiple sclerosis.


Dual balloon technique for valvuloplasty of aortic stenosis in adults.
A dual balloon technique was studied in 16 patients with aortic stenosis in whom results with a single balloon (up to 20 mm, 5.5 cm or 25 mm, 3.0 cm in diameter and length, respectively) were judged to be suboptimal. Dual balloon valvuloplasty was performed using 2 balloons advanced and inflated simultaneously across the stenotic aortic valve orifice. For the group as a whole, the average peak transvalvular gradient was reduced from 79 +/- 8 to 57 +/- 7 mm Hg (mean +/- standard error) using a single balloon (p less than 0.0005), and reduced further to 36 +/- 4 mm Hg using dual balloons (p less than 0.0005 compared with single balloon results). Similarly, calculated aortic valve orifice area was increased from 0.45 +/- 0.04 to 0.57 +/- 0.05 cm2 using a single balloon (p less than 0.0005), and further increased to 0.77 +/- 0.06 cm2 using dual balloons (p less than 0.0005). Dual balloon dilation caused no complications directly attributable to the use of 2 balloons, including no exacerbation of aortic regurgitation. These results suggest that dual balloon valvuloplasty is safe and efficacious in selected patients with aortic stenosis.


Optimal surgical performance attenuates physiologic risk in high-acuity operations.
The interplay between baseline physiology, operative performance, and postoperative recovery is poorly defined. We describe the beneficial effect of a successful operation on outcomes across the full spectrum of physiologic risk for an elective high-acuity procedure. Four hundred twelve consecutive pancreatic resections, performed between 2001 and 2008, were analyzed according to the Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity. Baseline physiology was classified according to the Physiologic Severity Score: minor (< or = 16); intermediate (17 to 23); vulnerable (> or = 24). Surgical performance was assigned by the Operative Severity Score: class I (< or = 14); class II (15 to 17); class III (> or = 18). Physiologic and operative predictions were independently correlated with actual clinical and economic outcomes and then merged to measure the influence of surgical performance beyond baseline physiology. As baseline physiology declines, patients suffer more complications and require more therapeutic and invasive interventions. Within each physiologic risk grade, class I operations (optimal surgical performances) were associated with lower rates of morbidity, shorter hospital stays, and improved cost efficiency. Deeper analysis reveals that intraoperative blood loss is the most variable and influential factor affecting physiologic risk. Each additional unit (375 mL) of blood loss increases the odds of morbidity by 45%, prolongs hospital stay by 1 day, and costs an additional $4,000 per patient. Predictive risk assessment accurately demonstrates that escalating physiologic risk worsens postoperative morbidity, prolongs hospital duration, and increases costs after such high-acuity operations. These effects are attenuated by improved operative performance.


Prevention of ischemia/reperfusion injury in the rat liver by atrial natriuretic peptide.
Atrial natriuretic peptide (ANP) protects against hypoxia/reoxygenation-induced damage of cultured hepatocytes, thus suggesting a therapeutic potential in the liver. Therefore, the effects of ANP on hepatic ischemia/reperfusion injury after warm ischemia were studied. Livers of male Sprague-Dawley rats subjected to 60 minutes of warm ischemia at 37 degrees C were perfused in the presence or absence of 200 and 20 nmol/L ANP. Sinusoidal lactate dehydrogenase efflux increased to 2000 +/- 264 and 126 +/- 50 mU.min-1.g liver-1 after 1 minute and 60 minutes of reperfusion, but it only increased to 1240 +/- 160 and 22 +/- 16 mU.min-1.g liver-1 in the presence of 200 nmol/L ANP during the preischemic and postischemic perfusion period. The postischemic bile flow (0.67 +/- 0.18 microL.min-1.g liver-1) was significantly improved with 200 nmol/L ANP (0.92 +/- 0.05) and showed a linear correlation to biliary glutathione excretion. In contrast, 20 nmol/L ANP had no protective effects. Administration of 200 nmol/L ANP during the preischemic perfusion period alone (but not after starting reperfusion) markedly preserved postischemic liver function. Continuous ANP administration or ANP pretreatment alone prevents hepatic ischemia/reperfusion injury, possibly because of influences on intracellular signal transduction processes. The correlation between bile flow and biliary glutathione excretion supports the hypothesis that biliary glutathione transport is one of the osmotic driving forces in postischemic bile formation.


Context Effects in Western Herbal Medicine: Fundamental to Effectiveness?
Western herbal medicine (WHM) is a complex healthcare system that uses traditional plant-based medicines in patient care. Typical preparations are individualized polyherbal formulae that, unlike herbal pills, retain the odor and taste of whole herbs. Qualitative studies in WHM show patient-practitioner relationships to be collaborative. Health narratives are co-constructed, leading to assessments, and treatments with personal significance for participants. It is hypothesized that the distinct characteristics of traditional herbal preparations and patient-herbalist interactions, in conjunction with the WHM physical healthcare environment, evoke context (placebo) effects that are fundamental to the overall effectiveness of herbal treatment. These context effects may need to be minimized to demonstrate pharmacological efficacy of herbal formulae in randomized, placebo-controlled trials, optimized to demonstrate effectiveness of WHM in pragmatic trials, and consciously harnessed to enhance outcomes in clinical practice.


Age-related cognitive decline in spatial learning and memory of C57BL/6J mice.
During the last decades, most of the preclinical neurodegenerative research was performed in mouse models of amyloidosis, tauopathies or α-synucleinopathies preferentially maintained on a C57BL/6J background. However, comprehensive neurobehavioural data from C57BL/6J mice outlining the critical point of spontaneous cognitive decline are incomplete. In this study, we aimed for the neurobehavioural phenotyping of hippocampus-dependent spatial learning and memory of aging C57BL/6J mice. Neurobehavioural phenotyping was performed by means of a Morris Water Maze (MWM) and a Novel Object Recognition (NOR) test. MWM measurements revealed signs of age-related memory loss in C57BL/6J animals from the age of 6 months onward. The NOR assessment strengthened latter finding by decreasing discrimination indexes (DI) and recognition indexes (RI) starting from the age of 6 months. Taken together, these findings contribute to the current knowledge of spontaneous cognitive behaviours of this perhaps most widely used mouse strain and serve as a benchmark for dementia mouse models to distinguish spontaneous from pathological neurodegenerative behaviour.


Assessment of myopic rebound effect after discontinuation of treatment with 0.01% atropine eye drops in Japanese school-age children.
Having previously demonstrated the efficacy of 0.01% atropine eye drops for inhibiting progression of childhood myopia, we conducted additional analyses to assess post-treatment changes in myopia progression. Analysis of follow-up data from a previously reported randomized controlled trial METHODS: A mixed-effects model was used to compare intergroup changes in spherical equivalent (SE) and axial length (AL) at 1 month and 12 months after discontinuation of 2-year treatment with atropine or placebo in 167 school-age children. Follow-up measurements were available for 149 participants at 1 month after discontinuation of treatment and for 51 participants at 12 months after discontinuation. At 1 month post-treatment, differences between the atropine and placebo groups in least squares (LS) mean changes in SE and AL, respectively, from 24 months were -0.06 diopters (D) (95% CI: -0.21, 0.08; P = .39) and 0.02 mm (95% CI: -0.05, 0.08; P = .60). At 12 months post-treatment, intergroup differences (atropine vs placebo) in LS mean changes in SE and AL, respectively, were -0.13 D (95% CI: -0.35, 0.10; P = .26) and -0.02 mm (95% CI: -0.12, 0.09; P = .75). LS mean changes in SE and AL from treatment discontinuation did not differ between the groups at 1 or 12 months post-treatment. Axial elongation was significantly less in the atropine group than in the placebo group. The suppression effect obtained at 2 years was maintained after 12 months. The absence of intergroup differences in myopia progression since treatment cessation suggests that myopic rebound did not occur.


A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation.
Type 3 long-QT syndrome (LQT-3) is caused by gain-of-function mutations in the SCN5A encoding the cardiac sodium channel. Familial atrial fibrillation (AF), previously considered a potassium channelopathy, has recently been related to sodium genetic variants, both in isolated forms and in patients with underlying heart disease. The purpose of this study was to describe the first family associating LQT-3 and AF due to a gain-of-function mutation in SCN5A and assess the usefulness of the sodium blocker flecainide in individuals with both phenotypes. Complete family screening was performed after identifying a proband showing paroxysmal AF and a long QT interval suggestive of LQT-3. Secondary causes of AF were ruled out in all individuals. Flecainide was used in two patients for LQT-3 diagnosis and therapeutic treatment of AF. Genetic screening was performed by direct sequencing of the exons and exon-intron boundaries of SCN5A. We identified a three-generation family (eight members), all of them showing long QT intervals. Paroxysmal AF initiated between 20 and 35 years of age in all three adults. The flecainide test led to shortening of the QTc interval. Flecainide was also effective in acutely restoring sinus rhythm. A Y1795C mutation was identified in all members. This is the first report showing an association of familial AF and LQT-3 due to a mutation in SCN5A. This finding provides further evidence of the role of SCN5A in AF. We also confirm the usefulness of flecainide in this particular complex phenotype, both as a diagnostic tool for LQT-3 and as an acute treatment for AF.


Depressive symptomatology in first-degree family caregivers of Alzheimer disease patients: a cross-ethnic comparison.
This study investigated the prevalence of depressive symptoms among White Hispanic (WH) and White non-Hispanic (WNH) first-degree family caregivers. We screened 653 primary caregivers of family members with possible or probable Alzheimer disease who presented at our outpatient memory disorders clinic. Caregiver depression was assessed utilizing the Center for Epidemiologic Studies-Depression (CES-D) Scale. Overall, depression (CES-D scores > or = 16) was more common among WH (45%) than among WNH (36%) caregivers (p < 0.05). Elevated CES-D scores among the entire caregiving sample were also linked with being a female spouse (p=0.002), increased level of patient cognitive impairment (p=0.002), and patient psychosis (p=0.002). Risk factors for caregiver depression were identified and compared when the sample was stratified by ethnicity (WH and WNH) and generation (spouses and children). Patient cognitive impairment was a predictor of caregiver depression only among WH spouses and children, whereas patient psychosis was a predictor only among WNH spouses. Female caregiver gender was the most robust risk factor for caregiver depression, being a predictor in all groups except WH children. Implications of this study include the need for increased clinical sensitivity to depression in ethnic minority caregivers, treatment of psychiatric morbidity in dementia caregivers, and respite care for caregivers with high risk for depression.


Study on the interaction of sulforaphane with human and bovine serum albumins.
Sulforaphane; [1-isothiocyanato-4-(methylsulfinyl) butane], (SFN) is an isothiocyanate derived from glucoraphanin present in cruciferous vegetables and has a variety of potential chemopreventive actions. This study was designed to examine the interaction of sulforaphane with HSA and BSA. FTIR, UV-Vis spectroscopic methods as well as molecular modeling were used to determine the drug binding mode, binding constant and the effect of drug complexation on serum albumins stability and conformation. Structural analysis showed that SFN bind HSA and BSA via polypeptide polar groups with overall binding constants of KSFN-HSA=6.54×10(4) and KSFN-BSA=8.55×10(4) M(-1). HSA and BSA conformations were altered by a major reduction of α-helix upon SFN interaction. These results suggest that serum albumins might act as carrier proteins for SFN in delivering them to target tissues.


The impact of COVID-19 on air quality levels in Portugal: A way to assess traffic contribution.
The pandemic caused by coronavirus COVID-19 is having a worldwide impact that affects health, the economy and indirectly affects the air pollution in cities. In Portugal, the number of cases increased continually (32700 confirmed cases as of May 31, 2020), which has affected the health system and caused movement restrictions which in turn affects the air pollution in the country. This article analyses the indirect effect produced by this pandemic on air pollution in Portugal, by comparison of data from a period of movement restriction of the citizens by the government - COVID lockdown period (March-May 2020) with data from baseline conditions (mean of the mirrored periods from the five previous years (March-May from 2015 to 2019)). Air quality data - in particular NO2 and PM10 hourly concentration - from more than 20 monitoring stations spread over mainland Portugal was used to perform this evaluation. The mean reduction observed on pollutant concentrations was higher for NO2 (41%) than for PM10 (18%). For NO2, mean reductions were more significant in traffic (reaching values higher than 60% in some monitoring stations) and background urban sites than in rural stations. The reduction of NO2 concentration observed in traffic sites were compared to the estimation of traffic contribution by the incremental method, suggesting that this latter approach is not consistent (lower in same sites and higher in others) and alerting to the careful use of this approach in future works.


Data in support of a central role of plasminogen activator inhibitor-2 polymorphism in recurrent cardiovascular disease risk in the setting of high HDL cholesterol and C-reactive protein using Bayesian network modeling.
Data is presented that was utilized as the basis for Bayesian network modeling of influence pathways focusing on the central role of a polymorphism of plasminogen activator inhibitor-2 (PAI-2) on recurrent cardiovascular disease risk in patients with high levels of HDL cholesterol and C-reactive protein (CRP) as a marker of inflammation, "Influences on Plasminogen Activator Inhibitor-2 Polymorphism-Associated Recurrent Cardiovascular Disease Risk in Patients with High HDL Cholesterol and Inflammation" (Corsetti et al., 2016; [1]). The data consist of occurrence of recurrent coronary events in 166 post myocardial infarction patients along with 1. clinical data on gender, race, age, and body mass index; 2. blood level data on 17 biomarkers; and 3. genotype data on 53 presumptive CVD-related single nucleotide polymorphisms. Additionally, a flow diagram of the Bayesian modeling procedure is presented along with Bayesian network subgraphs (root nodes to outcome events) utilized as the data from which PAI-2 associated influence pathways were derived (Corsetti et al., 2016; [1]).


Targeting the Tumor Microenvironment in Brain Metastasis.
Dynamic interplay between cancer cells and the surrounding microenvironment is a feature of the metastatic process. Successful metastatic brain colonization requires complex mechanisms that ultimately allow tumor cells to adapt to the unique microenvironment of the central nervous system, evade immune destruction, survive, and grow. Accumulating evidence suggests that components of the brain tumor microenvironment (TME) play a vital role in the metastatic cascade. In this review, the authors summarize the contribution of the TME to the development and progression of brain metastasis. They also highlight opportunities for TME-directed targeted therapy.


Kynurenic acid antagonizes the excitatory postsynaptic potential elicited in neostriatal neurons in the in vitro slice of the rat.
Stimulation of corpus callosum in rat brain slices evoked an excitatory postsynaptic potential (EPSP) in neostriatal neurons. This EPSP is greatly reduced by exposing the slice to kynurenic acid (KY). The action of KY is reversed when the preparation is bathed in normal Ringer's solution. KY reduces the EPSP amplitude in a dose-dependent fashion, with 1 mM KY attenuating the potential by 86%. The effect is not due to a conductance change, since KY treatment does not alter the neuron's input resistance.


The synpolydactyly homolog (spdh) mutation in the mouse -- a defect in patterning and growth of limb cartilage elements.
We have investigated the recessive mouse mutant synpolydactyly homolog (spdh) as a model for human synpolydactyly (SPD). As in human SPD, the spdh phenotype consists of central polydactyly, syndactyly and brachydactyly and is caused by the expansion of a polyalanine encoding repeat in the 5' region of the Hoxd13 gene. We performed a detailed phenotypic and functional analysis of spdh/spdh embryos using skeletal preparations, histology, in situ hybridization, BrdU labeling of proliferating cells, and in vitro expression studies. The absence of normal phalangeal joints and the misexpression of genes involved in joint formation demonstrate a role for Hox-genes in joint patterning. The spdh mutation results in abnormal limb pattering, defective chondrocyte differentiation, and in a drastic reduction in proliferation. Abnormal chondrocyte differentiation and proliferation persisted after birth and correlated with the expression of the mutant Hoxd13 and other Hox-genes during late-embryonic and postnatal growth.


Comparison of the use of rRNA probes and conventional methods in identifying strains of Lactobacillus sake and L. curvatus isolated from meat.
Published 23S rRNA directed probes for the species Lactobacillus sake and L. curvatus were used for rapid identification of lactic acid bacteria (LAB) isolated from meat. Of 96 strains of LAB from pork loin, 23 hybridised with the probe for L. sake and 16 with the probe for L. curvatus. Of 20 LAB strains from bologna, 19 strains hybridised with L. sake. By comparison with conventional biochemical tests, the probes provided a reliable identification.


Absence of lecithin from the stromata of the red cells of certain animals (ruminants), and its relation to venom hemolysis.
Lipide extracts of the red cells of several animal species have been analyzed chromatographically. Genetically determined differences in phospholipide composition were found. Lecithin is absent from the cells of ox, sheep, and goat. Cells containing lecithin are susceptible to the direct hemolysin of cobra venom while cells not containing lecithin are resistant. The facts indicate that the direct hemolysin is a lecithinase.


Preferential costimulation by CD80 results in IL-10-dependent TGF-beta1(+) -adaptive regulatory T cell generation.
Costimulatory ligands CD80 and CD86 have different binding preferences and affinities to their receptors, CD28 and CTLA-4. Earlier, we demonstrated that CD80 binds to CTLA-4 with higher affinity and has a role in suppressing T cell response. The current study demonstrates that not only did blockade of CD86 upon Ag presentation by bone marrow-derived dendritic cells (DC) to OVA-specific T cells result in induction of hyporesponsive T cells but also that these T cells could suppress the proliferative response of effector T cells. These T cells showed TGF-beta1 on their surface and secreted TGF-beta1 and IL-10 upon restimulation. Although blockade of CTLA-4 and neutralization of IL-10 profoundly inhibited the induction of these TGF-beta1(+) T cells, their ability to suppress the effector T cell proliferation was abrogated by neutralization of TGF-beta1 alone. Induction of TGF-beta1(+) and IL-10(+) T cells was found to be independent of natural CD4(+)CD25(+) regulatory T cells, demonstrating that preferential ligation of CTLA-4 by CD80 induced IL-10 production by effector T cells, which in turn promoted the secretion of TGF-beta1. Treatment of prediabetic NOD mice with islet beta cell Ag-pulsed CD86(-/-) DCs, but not CD80(-/-) DCs, resulted in the induction of TGF-beta1- and IL-10-producing cells, significant suppression of insulitis, and delay of the onset of hyperglycemia. These observations demonstrate not only that CD80 preferentially binds to CTLA-4 but also that interaction during Ag presentation can result in IL-10-dependent TGF-beta1(+) regulatory T cell induction, reinstating the potential of approaches to preferentially engage CTLA-4 through CD80 during self-Ag presentation in suppressing autoimmunity.


Partial characterization of two serologically related DNA-binding proteins specified by the cottontail rabbit herpesvirus CTHV.
We have previously described two serologically related DNA-binding phosphoproteins of different apparent molecular mass (75 kDa and 35 kDa) produced in cottontail rabbit herpesvirus (CTHV)-infected cells. The 75 kDa protein appeared before the 35 kDa protein in the infectious cycle. Here, we extend the characterization of these proteins. Protease V8 fingerprints of methionine-labelled 35 kDa protein showed four major peptide products, three of which co-migrated with major peptides from digests of the 75 kDa protein. The fourth peptide, with an estimated mass of 10 kDa, reacted with an antiserum recognizing both proteins. In vitro translation of total or poly A-containing RNA isolated from infected cells at 24 h to 72 h post-infection produced only the 75 kDa protein as measured by immunoprecipitation with anti-75/35 kDa serum, suggesting that the 35 kDa protein is derived from the 75 kDa protein by proteolytic cleavage. Virus-specific RNA obtained by prehybridization to CTHV DNA also produced the 75 kDA protein, confirming its viral origin. The putative gene for the 75 kDa protein was localized to a region on the CTHV DNA restricted by PvuII.


Prognostic implications of neutrophil-lymphocyte ratio in COVID-19.
The clinical presentation of COVID-19 ranges from a mild, self-limiting disease, to multiple organ failure and death. Most severe COVID-19 cases present low lymphocytes counts and high leukocytes counts, and accumulated evidence suggests that in a subgroup of patients presenting severe COVID-19, there may be a hyperinflammatory response driving a severe hypercytokinaemia which may be, at least in part, signalling the presence of an underlying endothelial dysfunction. In this context, available data suggest a prognostic role of neutrophil-lymphocyte ratio (NLR) in various inflammatory diseases and oncological processes. Following this rationale, we hypothesized that NLR, as a marker of endothelial dysfunction, may be useful in identifying patients with a poor prognosis in hospitalized COVID-19 cases. A retrospective observational study performed at Hospital Universitario HM Puerta del Sur, Madrid, Spain, which included 119 patients with COVID-19 from 1 March to 31 March 2020. Patients were categorized according to WHO R&D Expert Group. Forty-five (12.1%) patients experienced severe acute respiratory failure requiring respiratory support. Forty-seven (12.6%) patients died. Those with worse outcomes were older (P = .002) and presented significantly higher NLR at admission (P = .001), greater increase in Peak NLR (P < .001) and higher increasing speed of NLR (P = .003) compared with follow-up patients. In a multivariable logistic regression, age, cardiovascular disease and C-reactive protein at admission and Peak NLR were significantly associated with death. NLR is an easily measurable, available, cost-effective and reliable parameter, which continuous monitoring could be useful for the diagnosis and treatment of COVID-19.


A promising genomic transfectant into Xeroderma pigmentosum group A with highly amplified mouse DNA and intermediate UV resistance turns revertant.
Following transfection of genomic mouse DNA into an SV40 transformed fibroblast cell line from a patient with Xeroderma pigmentosum (complementation group A, XPA), a single UV resistant cell clone was isolated out of a total of 10(4) independent transfectants. The recipient XPA cell line has as yet not produced spontaneous revertants among 2.2 x 10(8) cells. The isolated cell clone contains 50-70 kb of mouse sequences which are heavily amplified (500-fold), and has acquired both intermediate resistance to UV killing and intermediate unscheduled DNA synthesis (UDS) capacity. By continued passage without selective pressure, cells were generated, which had lost both the dominant marker gene and repetitive mouse sequences. Single colonies of these cells were still intermediately resistant to UV suggesting that either undetected unique mouse DNA had segregated from the bulk of repetitive DNA, or, more likely, that the initially isolated transfectant was a spontaneous revertant. This documents that a persuasive clone isolated can still be a false positive (spontaneous revertant) and that an extremely laborious approach may lead into a dead end.


Physical health among the Finnish spinal cord injury population according to the Patient Reported Outcome Measurement Information System (PROMIS®).
The aim of this study is to assess the physical health in the Finnish Spinal cord injury (SCI) population using the Patient Reported Outcome Measurement Information System (PROMIS®) and make a comparison to the general United States (US) population. Furthermore, the aim is to explore the associations between pain interference, pain intensity, sleep disturbance, and fatigue and physical function. Cross-sectional study. This study is part of the Finnish Spinal Cord Injury (FinSCI) community survey study. Community, Finland. 884 persons with SCI. Not applicable. Physical health was measured with custom Patient Reported Outcome Measure System (PROMIS®) short forms. Higher age and lesion level indicated more severe physical function impairments. Persons ≥46 years exhibited more pain interference symptoms compared to younger participants. On average, the Finnish SCI population had 1.3 SD lower physical function and 0.9 SD higher pain interference T-scores compared to the US general population (P < 0.001). The most significant association was observed between pain interference and physical function (r = -0.364, P < 0.001). The present study provides a description of the state of physical health in the Finnish spinal cord injury population, as well as the associations between the physical health areas. The results highlight the substantiality of pain management in terms of improving physical function. NCT04649814.


Synthesis of chalcone-amidobenzothiazole conjugates as antimitotic and apoptotic inducing agents.
A series of chalcone-amidobenzothiazole conjugates (9a-k and 10a,b) have been synthesized and evaluated for their anticancer activity. All these compounds exhibited potent activity and the IC(50) of two potential compounds (9a and 9f) against different cancer cell lines are in the range of 0.85-3.3 μM. Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phase in A549 cell line leading to caspase-3 dependent apoptotic cell death. The tubulin polymerization assay (IC(50) of 9a is 3.5 μM and 9f is 5.2 μM) and immuofluorescence analysis showed that these compounds effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Further, Annexin staining also suggested that these compounds induced cell death by apoptosis. Moreover, docking experiments have shown that they interact and bind efficiently with tubulin protein. Overall, the current study demonstrates that the synthesis of chalcone-amidobenzothiazole conjugates as promising anticancer agents with potent G2/M arrest and apoptotic-inducing activities via targeting tubulin.


Derivation and validation of a prediction score for acute kidney injury in patients hospitalized with acute heart failure in a Chinese cohort.
Acute kidney injury (AKI) is a common complication among patients hospitalized for acute heart failure (AHF), and is associated with increased mortality. The goal of this study was to derive and validate a prediction score for AKI in AHF patients. The hospital medical records of 1709 patients with AHF were reviewed. AKI was defined as an increase in serum creatinine (SCr) of ≥26.4 μmol/L or ≥50% within 48 h. A multivariate logistic regression analysis was undertaken to develop a new prediction score. The area under the receiver operating characteristic (ROC) curve and the Hosmer-Lemeshow goodness-of-fit statistic test were calculated to assess the discrimination and calibration of the prediction score, respectively. Acute kidney injury developed in 32.2% of patients with AHF. Factors independently associated with the risk of AKI included: ≥70 years of age, ≥3 previous hospital admissions for AHF, systolic blood pressure <90 mmHg, serum sodium <130 mmol/L, heart functional class IV, proteinuria, SCr ≥104 μmol/L and intravenous furosemide dose ≥80 mg/day. A prediction score for AKI was derived based on the β coefficients of each risk factor. Patients with ≥8 points would be considered at high risk for development of AKI (55.1% incidence vs 18% in those with <8 points, P < 0.001). Both the derived and validated datasets showed adequate discrimination (area under ROC curve was 0.76 in both datasets) and calibration (Hosmer-Lemeshow statistic test, P = 0.98 and 0.13, respectively). The newly derived and validated clinical prediction score may effectively predict AKI in the patients hospitalized with AHF.


Coordinated induction of drug transporters and phase I and II metabolism in human liver slices.
Although regulation of phase I drug metabolism in human liver is relatively well studied, the regulation of phase II enzymes and of drug transporters is incompletely characterized. Therefore, we used human liver slices to investigate the PXR, CAR and AhR-mediated induction of drug transporters and phase I and II metabolic enzymes. Precision-cut human liver slices were incubated for 5 or 24h with prototypical inducers: phenobarbital (PB) (50 microM) for CAR, beta-naphthoflavone (BNF) (25 microM) for AhR, and rifampicin (RIF) (10 microM) for PXR, and gene expression of the phase I enzymes CYP1A1, 1A2, 3A4, 3A5, 2B6, 2A6, the phase II enzymes UGT1A1 and 1A6, and the transporters MRP2, MDR1, BSEP, NTCP and OATP8 was measured. BNF induced CYP1A1, UGT1A1 and UGT1A6 and MRP2, NTCP and MDR1. RIF induced CYP3A4, 3A5, 2B6, 2A6, UGT1A1, UGT1A6 and BSEP, MRP2 and MDR1 and slightly downregulated OATP8. PB induced CYP3A4, 3A5, 2B6 and 2A6, UGT1A1 and all transporters. Large interindividual differences were found with respect to the level of induction. Enzyme activity of CYP3A4, measured by testosterone metabolism, was increased after 24h by RIF. 7-Ethoxycoumarin O-deethylation activity, mediated predominantly by CYP 1A1/1A2 but also by other CYPs, was increased after 24h with PB. We have shown that regulation of all phases of the (in)activation of a drug via the CAR, AhR and the PXR pathways can be studied in human liver slices. The concomitant induction of metabolic enzymes and transporters shows that also in the human liver transporters and metabolic enzymes are regulated coordinately.


A new negative control gene for amino acid biosynthesis in Saccharomyces cerevisiae.
Enzyme levels in multiple amino acid biosynthetic pathways in yeast are coregulated. This control is effected largely at the transcriptional level by a number of regulatory genes. We report the isolation and characterization of a new negative regulatory gene, GCD4, for this general control system. GCD4 mutations are recessive and define a single Medelian gene on chromosome III. A gcd4 mutation results in resistance to different amino acid analogs and elevated, but fully inducible, mRNA levels of genes under general control. Epistasis analysis indicates that GCD4 acts more directly than the positive regulators GCN1, GCN2, GCN3 and GCN5, but less directly than GCN4, on the transcription of the amino acid biosynthetic genes. These data imply that GCD4 is a negative regulator of the positive effector, GCN4. Although GCD4 occupies the same position relative to the GCN genes as other GCD genes, it produces a unique phenotype. These results illustrate the diversity of function of negative regulators in general control.


Decomposing interaction and mediating effects of race/ethnicity and circulating blood levels of cystatin C on cognitive status in the United States health and retirement study.
Elevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia. In a pooled cross-sectional sample of the Health and Retirement Study (n = 9,923), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24 vs. ≤1.24 mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, other biomarkers, and chronic conditions. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity. Overall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.2; 95% CI: 1.0, 1.5). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 0.7 (95% CI: -0.1, 2.4), the attributable proportion was 0.1 (95% CI: -0.2, 0.4), and the synergy index was 1.1 (95% CI: 0.8, 1.8) in a fully adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: -0, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 8% (95% CI: -5, 22%). Analyses for Hispanic relative to non-white participants suggested moderation by race/ethnicity, but not mediation. Elevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White.


A family-oriented intervention programme to curtail obesity from five years of age had no effect over no intervention.
To examine the effect of a family-oriented multidisciplinary intervention programme to curtail weight increase in young children with obesity. Children who weighed more than one kilogram above the 97th percentile for height at the preschool assessment in Oppland County, Norway, were identified. Parents residing in one part of the county were invited to participate in a group-based three-year intervention programme while the rest had no interventions. Body mass index (BMI) and family characteristics at entry and measurements at birth were explanatory variables, and change in BMI standard deviation score (SDS) the outcome measure. For the intervention group, outcome was also related to skinfold thicknesses, waist-to-height ratio and physical ability. The programme was completed by 31 families in the intervention and 33 in the control group. At entry, the respective median (interquartile) age was 5.83 (0.36) and 5.74 (0.66) years, and the BMI SDS 2.35 (1.06) and 1.95 (0.49), P = .012. The median decrease in BMI SDS was 0.19 in both groups. The decline increased with increasing BMI SDS at entry, but irrespective of group. Social or behavioural factor or other anthropometric measures were not associated with outcome. The intervention programme had no effect on BMI SDS.


The study of the influence of DDT on the antirachitic activity of vitamin D in rats.
Rachitic Wistar strain rats were administered with a therapeutic dose of vitamin D3 or vitamin D3 with DDT or cod-liver oil containing the same and tenfold larger amount of DDT. No alterations in the activity of vitamin D were found.


Long-lasting rescue of schizophrenia-relevant cognitive impairments via risperidone-loaded microPlates.
Schizophrenia is a disorder characterized by cognitive impairment and psychotic symptoms that fluctuate over time and can only be mitigated with the chronic administration of antipsychotics. Here, we propose biodegradable microPlates made of PLGA for the sustained release of risperidone over several weeks. Two microPlate configurations - short: 20 × 20 × 10 μm; tall: 20 × 20 × 20 μm - are engineered and compared to conventional ~ 10 μm PLGA microspheres in terms of risperidone loading and release. Tall microPlates realize the slowest release documenting a 35% risperidone delivery at 100 days with a residual rate of 30 ng/ml. Short microPlates and microspheres present similar release profiles with over 50% of the loaded risperidone delivered within the first 40 days. Then, the therapeutic efficacy of one single intraperitoneal injection of risperidone microPlates is compared to the daily administration of free risperidone in heterozygous knockout mice for dysbindin-1, a clinically relevant mouse model of cognitive and psychiatric liability. In temporal order object recognition tasks, mice treated with risperidone microPlates outperform those receiving free risperidone up to 2, 4, 8, and 12 weeks of observation. This suggests that the sustained release of antipsychotics from one-time microPlate deposition can rescue cognitive impairment in dysbindin mice for up to several weeks. Overall, these results demonstrate that risperidone-loaded microPlates are a promising platform for improving cognitive symptoms associated to schizophrenia. Moreover, the long-term efficacy with one single administration could be of clinical relevance in terms of patient's compliance and adherence to the treatment regimen. Single injection of long-acting risperidone-loaded µPL ameliorates the dysbindin-induced deficit in a clinically relevant mouse model of cognitive and psychiatric liability for up to 12 weeks.


Multidimensional voice analysis of reflux laryngitis patients.
The aim of the study was to analyze and quantify the voice characteristics of reflux laryngitis (RL) patients and to determine the most important voice tests and voice-quality parameters in the functional diagnostics of RL. The voices of 83 RL patients and 31 persons in the control group were evaluated. Vocal function was assessed using a multidimensional set of video laryngostroboscopic, perceptual, acoustic, aerodynamic and subjective measurements according to the protocol elaborated by the Committee on Phoniatrics of the European Laryngological Society. The mean values of the hoarseness visual analogue scale assessment and voice handicap index were significantly higher (P<0.05) in the group of RL patients as compared to the controls. Objective voice assessment revealed a significant increase in mean values of jitter, shimmer and normalized noise energy (NNE), along with a significant decrease in pitch range, maximum frequency, phonetogram area (S) and maximum phonation time (MPT) in RL patients, both in the male and female subgroups. According to the results of discriminant analysis, the NNE, MPT, S and intensity range were determined as an optimum set for functional diagnostics of RL. The derived function (equation) makes it possible to assign the person to the group of RL patients with an accuracy of 86.7%. The sensitivity and specificity of eight voice parameters were found to be higher than 50%. The results of the present study demonstrate a reduction of phonation capabilities and voice quality in RL patients. Multidimensional voice evaluation makes it possible to detect significant differences in mean values of perceptual, subjective and objective voice quality parameters between RL patients and controls groups. Therefore, multidimensional voice analysis is an important tool in the functional diagnostics of RL.


Early surgical repair of iatrogenic ureterovaginal fistula secondary to gynecologic surgery.
To describe the early surgical repair of iatrogenic ureterovaginal fistula (UVF) secondary to gynecologic surgery, and evaluate the efficacy and feasibility of early surgical intervention. Data were retrospectively reviewed for 52 patients with iatrogenic UVF who underwent early surgical repair between January 1996 and January 2011 at the Sir Run Run Shaw Hospital, Hangzhou, China. Preoperative patient characteristics and postoperative endpoints, including type of index procedure, repair technique, operative time, perioperative complications, and postoperative follow-up data were assessed. All early surgical repairs were uneventful. The mean time from diagnosis to surgery was 15.7days (range, 14-21days). The mean operative time was 73.4min (range, 51-110min) for ureteroneocystostomy, and 104min (range, 91.5-153min) for Boari flap procedure. The mean estimated blood loss was 57.8mL (range, 35-80mL). No major intraoperative complications occurred, although 5 patients had postoperative surgical site infections. Forty-three patients were followed for a mean of 18.4months (range, 10.5-24.0months). Ureteral stricture with asymptomatic hydronephrosis occurred in 2 (4.7%) patients. Ipsilateral renal function was preserved in all patients. Early surgical repair of UVF secondary to gynecologic surgery was safe and effective, and preserved ipsilateral renal function.


Fructan:fructan 1-fructosyltransferase, a key enzyme for biosynthesis of graminan oligomers in hardened wheat.
Fructans play important roles not only as a carbon source for survival under persistent snow cover but also as agents that protect against various stresses in overwintering plants. Complex fructans having both beta-(2,1)- and beta-(2,6)-linked fructosyl units accumulate in wheat (Triticum aestivum L.) during cold hardening. We detected fructan: fructan 1-fructosyltransferase (1-FFT; EC 188.8.131.52) activity for catalyzing the formation and extension of beta-(2,1)-linked fructans in hardened wheat tissues, cloned cDNAs (wft3 and wft4) of 1-FFT, and analyzed the enzymatic properties of a wft3 recombinant protein (Wft3m) produced by yeast. Wft3m transferred beta-(2,1)-linked fructosyl units to phlein, an extension of sucrose through beta-(2,6)-linked fructosyl units, as well as to inulin, an extension of sucrose through beta-(2,1)-linked fructosyl units, but could not efficiently synthesize long inulin oligomers. Incubation of a mixture of Wft3m and another recombinant protein of wheat, sucrose:fructan 6-fructosyltransferase (6-SFT), with sucrose and 1-kestotriose produced fructans similar to those that accumulated in hardened wheat tissues. The results demonstrate that 1-FFT produces branches of beta-(2,1)-linked fructosyl units to phlein and graminan oligomers synthesized by 6-SFT and contributes to accumulation of fructans containing beta-(2,1)- and beta-(2,6)-linked fructosyl units. In combination with sucrose:sucrose 1-fructosyltransferase (1-SST; EC 184.108.40.206) and 6-SFT, 1-FFT is necessary for fructan synthesis in hardened wheat.


Dynamic signatures of the Eureka effect: an EEG study.
The Eureka effect refers to the common experience of suddenly solving a problem. Here, we study this effect in a pattern recognition paradigm that requires the segmentation of complex scenes and recognition of objects on the basis of Gestalt rules and prior knowledge. In the experiments, both sensory evidence and prior knowledge were manipulated in order to obtain trials that do or do not converge toward a perceptual solution. Subjects had to detect objects in blurred scenes and indicate recognition with manual responses. Neural dynamics were assessed with high-density Electroencephalography (EEG) recordings. The results show significant changes of neural dynamics with respect to spectral distribution, coherence, phase locking, and fractal dimensionality. The Eureka effect was associated with increased coherence of oscillations in the alpha and theta bands over widely distributed regions of the cortical mantle predominantly in the right hemisphere. This increase in coherence was associated with decreased beta power over parietal and central regions and with decreased alpha power over frontal and occipital areas. In addition, there was a right hemisphere-lateralized reduction of fractal dimensionality. We propose that the Eureka effect requires cooperation of cortical regions involved in working memory, creative thinking, and the control of attention.


Hemolytic uremic syndrome due to an altered factor H triggered by neonatal pertussis.
We report on a previously healthy newborn suffering from severe Bordetella pertussis infection who developed hemolytic uremic syndrome (HUS) a few weeks after the onset of whooping cough, with a fatal outcome. A factor H protein with abnormal mobility was found in the serum of the patient as analyzed by Western blotting, indicating that B. pertussis infection might have triggered HUS in a genetically predisposed patient.


Congenital heart disease in the era of COVID-19 pandemic.
The pandemic of COVID-19 presents an unprecedented challenge to identify effective prevention and treatment. Scientific literature has exploded with many news concerning the different experiences and the first studies in the world. To date May 5 2020, if we carry out a search in pubmed with the keyword "COVID-19", more than 9000 papers appear. While if we carry out a search with the keywords "congenital heart disease and COVID-19", we find only 4 results. This is a viewpoint in which we summarize the most important problems that emerged with the most recent data in the literature.


[Modifications of the technic of endolaryngeal extirpation. The author's own functional technic of laryngectomy].
A brief summary of the original technique will be made incorporating the following modifications and additions: glottis substituted by neoglottis muscles, sternohyoid or external perichondrium. Supraglottis substituted by remaining tissues of the epiglottis or neoepiglottis. Hypopharynx, section medium line of the pharynx constrictor. Suturing of cartilage with homologous donor cartilage. An evaluation will be made of the functional results.


An improved method for murine laser-induced choroidal neovascularization lesion quantification from optical coherence tomography images.
Laser-induced choroidal neovascularization (L-CNV) in murine models is a standard method for assessing therapies, genetics, and mechanisms relevant to the blinding eye disease neovascular or "wet" age-related macular degeneration. The ex vivo evaluation of these lesions involves confocal microscopy analysis. In vivo evaluation via optical coherence tomography (OCT) has previously been established and allows longitudinal assessment of lesion development. However, to produce robust data, evaluation of many lesions may be required, which can be a slow, arduous process. A prior, manual method for quantifying these lesions as ellipsoids from orthogonal OCT images was effective but time consuming. We therefore developed an OCT lesion quantification that is simplified, streamlined, and less time-consuming.


The HBV HBX gene expressed in E. coli is recognised by sera from hepatitis patients.
We have cloned the X gene (HBx) and the HBc antigen (HBc Ag) gene of human hepatitis B virus (HBV) in Escherichia coli as fusion products with beta-galactosidase. Both HBV genes are expressed in E. coli strain CSR 603. Expression is detected by u.v. irradiation of the bacteria, metabolic labelling and electrophoresis of the labelled extracts on SDS-polyacrylamide gels. The HBc Ag protein produced in bacteria can be recognised by anti-HBc sera and peptides derived from the protein are also recognised by anti-HBe sera. The HBx protein is recognised by some, but not all, sera which are anti-HBe positive. HBx Ag is also recognised by a woodchuck antibody similar to anti-HBe (anti-WHe). These results constitute the first proof that the open reading frame X is a true viral gene and is expressed during HBV (and WHV) infection and that an HBx/anti-HBx system, which may have important biological implications, can exist in parallel with the classic HBe/anti-HBe system.


Validation of an equation for predicting energy cost of arm ergometry in women.
Few studies have examined the validity of metabolic equations for the prediction of energy cost (VO(2)) of arm ergometry in women. Therefore, the purpose of this study was (a) to compare directly measured and predicted VO(2) values using the American College of Sports Medicine (ACSM) equation and (b) to develop and validate a prediction equation for women. A sample of 60 female subjects with mean (+/-SD) age, weight and height 26.5 +/- 14.4 years, 61.5 +/- 7.6 kg, 163.3 +/- 6.0 cm, respectively, was randomly assigned to an equation group (N = 40) and a cross validation group (N = 20). All subjects performed an incremental arm ergometry test (10 W increases every 2 min), until termination criteria were met. Repeated measures ANOVA indicated significant differences between the measured VO(2) and ACSM predicted VO(2) during all the incremental test work rate. Multiple linear regression analysis was used to develop the following upper body exercise VO(2) prediction equation: VO(2)(ml . kg(-1) . min(-1) = 23.461 - (0.272 x Body Weight) + (0.403 x watts) [R(2) = 0.82, SEE = 2.79] Cross validation indicated lower variability using the current prediction equation. An additional independent sample of 13 subjects performed a 30-min steady-state test at 40% of their pre-determined maximal work rate. VO(2) measured during the 30 min steady-state test (was significantly different P < 0.05) from the ACSM prediction at all time intervals. There were no significant differences using the above equation following the 5 min time interval. Therefore, a new equation is proposed as a means of providing a gender-specific energy cost prediction equation.


Evaluation of platelet concentrates stored for 5 days with reduced plasma volume.
Currently, platelet concentrates (PCs) are stored in a suspending plasma volume of 45 to 65 mL. Previous studies using second-generation containers indicated that PCs stored for 5 days at volumes less than 30 mL have reduced in vivo percentage recoveries as compared to PCs stored at volumes of 50 mL or more. This study has evaluated the effect of PC plasma volume on the maintenance of in vivo and in vitro platelet properties following 5 days of storage, with the purpose of establishing the minimum plasma volume in the range of 30 to 50 mL. Twenty paired studies were performed in which identical populations of platelets from the same donor (obtained by double manual apheresis) were stored in a normal volume (55-60 mL, control) and reduced volume (30-50 mL, test) of plasma. Comparison of in vivo viability between test and control PCs was performed after random radiolabeling of 1 unit with 51Cr and of the other with 111In, with simultaneous transfusion and with calculation of percentage recovery and the area below the survival curve (integral) as measures of viability. When test unit volumes were > or = 35 mL, essentially identical platelet survival curves and in vitro results were obtained for test and control. The integral and the percentage recovery for the test units were (mean, 95% confidence interval) 98.7 (96.3-101.0) and 99.0 percent (94.7-103.3) of those values in the control units, respectively. Test units with volume < or = 34 mL demonstrated reduced in vivo viability with integral and percentage recovery of 81.1 (68.9-93.3) and 80.4 (69.3-91.5), respectively, as compared to the control units. This loss was associated with increased metabolic activity (lactate production), which may suggest platelet activation due to the increased surface-to-PC volume ratio. These results show that the storage volume of PCs may be reduced from 50 to 60 mL to 35 to 40 mL without any significant decrease in in vivo or in vitro platelet quality.


A systematic-analysis of predicted miR-21 targets identifies a signature for lung cancer.
The well-known oncomiR-miR-21 was previously reported oncogenic activity in lung cancer. We sought to determine the expression of all predicted target genes of miR-21 and their potential function, pathways and networks, which are involved in the biological behavior of lung cancer. After a systematic review of English language studies of lung cancer-related molecules were pooled; genes were classified in three functional groups by gene ontology (GO) analysis. The key molecules were indentified by establishing lung cancer related networks and pathways. MiR-21 targets were predicted by computational method, followed by screening for matched gene symbols in NCBI human sequences and GO, pathway and network analysis. MiR-21 targets and their network, which are involved in the malignant mechanisms of lung cancer, were obtained by the final integrative analysis. We indentified the potential functions, pathways and networks of lung cancer relating molecules and miR-21 targets respectively in the initial analysis. In the final integrative analysis of lung cancer related miR-21-targets analysis, 24 hub genes were identified by overlap calculation, suggesting that miR-21 may play an important role in the development and progression of lung cancer through JAK/STAT signal pathway, MAPK signaling pathway, Wnt signaling pathway, cell cycle, PPAR signaling pathway, apoptosis pathway and other pathways. Our data may help researchers to predict the molecular mechanisms of miR-21 in the development and progression of lung cancer comprehensively. Moreover, the present data indicate that miR-21-targets may be a series of promising candidates as biomarkers for lung cancer.


Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenström's macroglobulinemia.
Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Whether resveratrol could inhibit proliferation or induce cytotoxicity in Waldenström's macroglobulinemia (WM) was investigated. We studied resveratrol-induced inhibition of proliferation and induction of cytotoxicity in WM cell lines, WM primary tumor cells, IgM-secreting cells, and peripheral blood mononuclear cells. The mechanisms of action and different signaling pathways involved were studied using Western blot and gene expression profile analysis. Resveratrol activity was also evaluated in the bone marrow microenvironment. We finally investigated whether or not resveratrol could have any synergistic effect if used in combination with other drugs widely used in the treatment of WM. A schematic image illustrating the location and expression of the aurora kinases A, B, and C during mitosis. Resveratrol inhibited proliferation and induced cytotoxicity against WM cells, IgM-secreting cells, as well as primary WM cells, without affecting peripheral blood mononuclear cells; down-regulated Akt, extracellular signal-regulated kinase mitogen-activated protein kinases, and Wnt signaling pathways, as well as Akt activity; induced cell cycle arrest and apoptosis; and triggered c-Jun-NH(2)-terminal-kinase activation, followed by the activation of intrinsic and extrinsic caspase pathways. Lastly, adherence to bone marrow stromal cells did not confer protection to WM cells against resveratrol-induced cytotoxicity. Furthermore, resveratrol showed synergistic cytotoxicity when combined with dexamethasone, fludarabine, and bortezomib. Our data show that resveratrol has significant antitumor activity in WM, providing the framework for clinical trials in this disease.


World Workshop on Oral Medicine VII: Non-opioid pain management of head and neck chemo/radiation-induced mucositis: A systematic review.
To evaluate the current evidence regarding the effectiveness of non-opioid interventions for the therapeutic management of pain in head and neck cancer patients with oral mucositis resulting from radiotherapy only or chemoradiotherapy. A literature search was conducted which included randomised controlled trials that assessed patient-related outcome of pain in patients with oral mucositis associated with radiation therapy only or chemoradiotherapy. Literature searches were conducted in MEDLINE via Pubmed, Embase, Scopus and CINAHL. The electronic searches identified 846 articles. Screening revealed that six articles met all eligibility inclusion criteria. Interventions showing statistically significant benefits to reduce oral mucositis associated pain compared to placebo included doxepin (p < 0.001, 95% CI -6.7 to -2.1), amitriptyline (p = 0.04), diclofenac (p < 0.01) and benzydamine (p = 0.014). Non-opioid interventions, including topical doxepin, amitriptyline, diclofenac and benzydamine, were found to provide relief of pain due to mucositis, and when effective may allow for reduction in the use of opioids in pain management.


"AV nodal" reentry: Part II: AV nodal, AV junctional, or atrionodal reentry?
The classical model of "atrioventricular (AV) nodal" reentrant tachycardia suggests that the reentrant circuit is entirely within the compact AV node and that AV nodal tissue is present proximal and distal to the circuit. Recent evidence from mapping studies and from examination of the effects of curative procedures, however, suggests that the upper end of the circuit uses perinodal atrial or transitional tissue. Moreover, the anatomical substrate of dual "AV nodal" pathways is likely to be the multiple connections between compact AV node and atrium rather than discrete intranodal pathways. The antegrade slow pathway appears to be situated at the posteroinferior approaches to the AV node in the region between the coronary sinus orifice and the tricuspid annulus. The retrograde fast pathway appears to be situated in the anterior atrionodal connections at the apex of Koch's triangle, close to the His bundle. The lower turnaround point of the circuit is likely to be within the AV node.


Avascular necrosis of common bones seen in the ED.
Missed diagnosis of avascular necrosis (AVN) may result in substantial morbidity. Early diagnosis is crucial for appropriate intervention and, ultimately, improved outcome. Emerging physicians need to recognize AVN to avoid unsatisfactory clinical results for their patients. Avascular necrosis (AVN) of the bone can occur when the blood supply to the bone is disrupted and is usually found in areas with terminal circulation. Commonly involved bones include the femoral head, talus, and scaphoid.


Silenced Myeloblastosis Protein Suppresses Oral Tongue Squamous Cell Carcinoma via the microRNA-130a/Cylindromatosis Axis [Retraction].
[This retracts the article DOI: 10.2147/CMAR.S252340.].


Effects of radiotherapy fractionation on breast stromal activity.
We study the dynamics of tumor cell progression as growth factors and ionizing radiation (IR) combine to modify cellular microenvironments. Breast tumor growth depends on the behavior of cancer cells in their microenvironment, and both components are affected by IR fractionation parameters. TGF-β1 promotes differentiation of fibroblasts to myofibroblasts, which stiffens the extracellular matrix (ECM) and promotes malignant cell phenotypes. IR generates reactive oxygen species (ROS) that damages and inactivates cells thus controlling proliferation. The effects of TGF-β1 and IR at various fraction sizes on ECM stiffness and fibroblast differenation are studied using MRC-5 fibroblasts in 3-D collagen cultures.


Successful treatment of Erdheim-Chester disease by interleukin-1 receptor antagonist protein.
Erdheim-Chester disease is a rare non-langerhans systemic histiocytosis of unknown origin, associated with bone diseases and severe visceral complications. Therapies have been disappointing. A recombinant form of interleukin-1 receptor antagonist (anakinra) has been used in a few cases when usual treatment fails. We report a new case of successfully interleukin-1 receptor antagonist treatment in Erdheim-Chester disease.


A rapid radioimmunoassay, using a nylon support, for amatoxins from Amanita mushrooms.
A fetuin derivative of alpha-amanitin was prepared and used as an antigen in rabbits. The antigen was superior to previous bovine serum albumin derivatives of beta-amanitin by its lower toxicity and high immunogenicity. On the other hand, the antibodies raised with the alpha-amanitin derivative did not show full crossreactivity with the other amatoxins, as did the immunoglobulins induced by protein derivatives of beta-amanitin. The procedure for activating nylon surfaces and coupling proteins onto them was improved with respect to surface charge and homogeneity. A partially purified IgG-fraction derived from the sera of rabbits immunized against amatoxins was covalently attached to the activated nylon surfaces. The covalently coupled immunoglobulins were complexed with a tritiated amatoxin. Then small pieces of the nylon sheet were punched out and incubated with the amatoxin solution to be analyzed. This procedure represents a method for dosing, in one step and without pipetting, the immunoglobulins and the labelled hapten. Determination of amatoxin concentrations was achieved by counting the radioactivity in the incubation fluid. The limit of detection was about 3 ng of amatoxins per ml. The radioimmunoassay was used to measure amatoxin concentrations in serum, urine, duodenal fluid, and gastric juice of patients with Amanita poisoning. Since such assays can be performed in 2-3 hr, the results can be used to determine the therapeutic protocol. The assay was likewise used to determine the concentration of amatoxins in mushroom tissue. For Amanita phalloides, for example, we found that the amatoxin concentration (mg/g dry weight) is 4.5 times higher in the gills than in the bulb.


Detection and Quantification of Protein Spots by Pinnacle.
Accurate spot detection and quantification is a challenging task that must be performed effectively in order to properly extract the proteomic information from two-dimensional (2-D) gel electrophoresis images. In Morris et al., Bioinformatics 24:529-536, 2008, we introduced Pinnacle, an automatic, fast, effective noncommercial package for spot detection and quantification for 2-D gel images, and subsequently we have developed a freely available gui-based interface for applying the method to a set of gels. In this chapter, we overview Pinnacle, and in a step-by-step manner we describe how to use the software to obtain spot lists and quantifications, to be used for comparative proteomic analysis.


Histological features of uteroplacental vessels in normal and hypertensive patients in relation to birthweight.
Placental bed biopsies were obtained during caesarean section from normal, pre-eclamptic and hypertensive pregnancies. Of the 14 biopsies from normal pregnancies 13 showed normal vascular physiological changes in the decidua and in the myometrium. Biopsies from 24 pregnancies complicated by pre-eclampsia showed acute atherosis in 18 and physiological changes limited to the decidua in six; none had normal physiological changes. Biopsies from five hypertensive patients showed all three types of histological changes. The mean birthweight centile was lower in the group with atherosis than in the group with limited and the group with normal physiological changes.


The influence of acculturation on the risk of preterm birth and low birthweight in migrant women residing in Western Australia.
The risk of preterm birth (PTB) and low birthweight (LBW) may change over time the longer that immigrants reside in their adopted countries. We aimed to study the influence of acculturation on the risk of these outcomes in Australia. A retrospective cohort study using linked health data for all non-Indigenous births from 2005-2013 in Western Australia was undertaken. Acculturation was assessed through age on arrival, length of residence, interpreter use and having an Australian-born partner. Adjusted odds ratios (aOR) for term-LBW and PTB (all, spontaneous, medically-indicated) were calculated using multivariable logistic regression in migrants from six ethnicities (white, Asian, Indian, African, Māori, and 'other') for different levels of acculturation, compared to the Australian-born population as the reference. The least acculturated migrant women, those from non-white non-Māori ethnic backgrounds who immigrated at age ≥18 years, had an overseas-born partner, lived in Australia for < 5 years and used a paid interpreter, had 58% (aOR 1.58, 95% CI 1.15-2.18) higher the risk of term-LBW and 40% (aOR 0.60, 95% CI 0.45-0.80) lower risk of spontaneous PTB compared to the Australian-born women. The most acculturated migrant women, those from non-white non-Māori ethnic backgrounds who immigrated at age <18 years, had an Australian-born partner, lived in Australia for > 10 years and did not use an interpreter, had similar risk of term-LBW but 43% (aOR 1.43, 95% CI 1.14-1.78) higher risk of spontaneous PTB than the Australian-born women. Acculturation is an important factor to consider when providing antenatal care to prevent PTB and LBW in migrants. Acculturation may reduce the risk of term-LBW but, conversely, may increase the risk of spontaneous PTB in migrant women residing in Western Australia. However, the effect may vary by ethnicity and warrants further investigation to fully understand the processes involved.


Long-term outcomes of single paediatric vs. ideal adult renal allograft transplants in adult recipients.
To compare the outcomes of single paediatric vs. adult kidneys transplanted into adult recipients. A retrospective single-centre review of 38 single cadaver kidney transplants from donors less than five yr of age to wait-listed patients of low body mass index (BMI). Survival of grafts and quality of renal function were compared with 121 similarly low BMI recipients of grafts from donors 18-45 yr of age that were transplanted during the same period. Immunosuppression consisted of sirolimus, minimal-dose cyclosporine and prednisone. The mean age of the paediatric vs. adult donors was 2.8+/-1.0 and 31.1+/-9.2 yr, respectively (p<0.01) and of the recipients, 42.0+/-12.4 and 45.7+/-14.8 yr, respectively (p=NS). The mean BMI of paediatric vs. adult donor kidney recipients was 21.8+/-2.9 and 22.4+/-2.0 kg/m2 (p=NS). Sixty-six per cent of paediatric donor recipients were women compared with 44% of adult donor recipients (p=0.03). Death censored actuarial graft survivals at one and five yr for recipients of paediatric vs. adult donor grafts were 93 and 84% compared with 93 and 85% (p=NS). There were no graft losses because of technical complications in the paediatric kidney donor group. At one and five yr post-transplantation, the mean estimated creatinine clearances of the paediatric donor graft recipients were 52.9+/-19.6 and 54.0+/-17.8 mL/min, respectively, compared with 56.4+/-19.8 and 49.1+/-21.7 mL/min for recipients of adult donor grafts at the same times (p=NS). Transplantation of single paediatric donor kidneys into low BMI adult recipients provided equivalent outcomes to those of grafts from adult donors between the ages of 18 and 45 yr.


Treatment of dementia with Lewy bodies and Parkinson's disease dementia.
Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) account for 10-15% of late onset dementias. Key treatment targets include cognitive and functional impairments, neuropsychiatric symptoms including intense and persistent visual hallucinations, and parkinsonism. Six-month, placebo-controlled randomized controlled trials (RCTs) of the cholinesterase inhibitor rivastigmine have indicated modest but significant benefits in cognition, function, global outcome and neuropsychiatric symptoms in both PDD and DLB. The evidence base for other cholinesterase inhibitors from RCTs is inconclusive. More recent RCTs with memantine in PDD/DLB patients indicate a benefit with regard to global outcome, with some suggestion of a specific benefit with respect to sleep disturbance. Given the risk of severe antipsychotic sensitivity reactions, antipsychotics should be avoided. A significant proportion of PDD/DLB patients are responsive to levodopa, but care needs to be taken with anti-parkinsonian treatments because of their potential propensity to exacerbate neuropsychiatric symptoms, particularly hallucinations.


Evaluation of efficacy of novel optically activated digital endoscope protection system against laser energy damage.
To evaluate the reliability and efficacy of a novel endoscope protection system (EPS) against direct laser energy damage. We performed in vitro evaluations of a novel EPS prototype that uses optical feedback from the digital sensor of the DUR-D ureteroscope to terminate the laser energy on retraction of the laser fiber into the ureteroscope. We evaluated various speeds of retraction (0.5, 2.0, and 5.0 cm/s) in normal saline and various concentrations of indigo carmine and human blood. We also evaluated the protrusion distance at which shutdown occurred with the laser fiber cladding cleaved at 0, 3, and 5 mm from the end of the fiber. Twenty trials of each condition were performed. In normal saline and blood dilutions of up to 10 g/L, the EPS worked with 100% efficiency for all trials. For blood dilutions of 10 g/L or greater and indigo carmine concentrations of 0.16 g/L or greater, the reliability of the EPS deteriorated. Lasers stripped of 0, 3, and 5 mm of cladding initiated shutdown at 2.9 +/- 0.13, 5.1 +/- 0.09, and 8.2 +/- 0.15 mm from the ureteroscope distal end, respectively (P <0.01). A single DUR-D ureteroscope was used for all trials and remained completely intact through 120 retractions of the active laser fiber into the channel. In this evaluation, the novel EPS was highly effective and reliable. When using indigo carmine or high-density blood concentrations, the efficacy of the EPS was compromised. The EPS should be used to complement standard safe laser technique rather than to replace it.


Ribavirin priming improves the virological response to antiviral treatment in transplanted patients with recurrent hepatitis C: a pilot study.
Patients with hepatitis C recurrence after liver transplantation represent a clinical challenge. Antiviral treatment in transplant patients has usually poor tolerability and limited efficacy, with a mean sustained virological response (SVR) of 30%. Our pilot study was aimed at evaluating whether 8-week ribavirin pre-treatment could increase either adherence or antiviral effect of a 48-week combination therapy. Ribavirin pre-treatment (8 weeks) was started with 600 mg daily and increased to 10.4 mg/kg/day. After pre-treatment, 1.5 μg/kg/week pegylated interferon-α2b was added for 48 additional weeks of combination therapy. Blood count, liver function tests and plasma HCV-RNA were examined monthly. Ribavirin plasma concentrations were determined by HPLC. Thirteen patients (mean age 53±2 years, 11 males) were treated: eight were HCV genotype 1/4; five were genotype 2/3. The median baseline HCV RNA level was 6.5 log(10) (range 5.84-7.42 log(10)). During ribavirin pre-treatment the median HCV RNA levels decreased significantly (5.7 log(10) ; P=0.023). During combination therapy 6/13 (46%) patients exhibited a rapid virological response (RVR) and 10/13 (77%) patients a complete early virological response, two were non-responders. A decline of 0.5 log(10) HCV RNA during pre-treatment predicted RVR. SVR occurred in six patients (46%): four were genotype 2/3. Stable ribavirin dose reduction was required in only two patients (15%) in whom transient interferon reduction was also required. This proof-of-concept study indicates that ribavirin pre-treatment increased the tolerability of the antiviral treatment, and improved its efficacy in liver transplant patients. Moreover, the degree of HCV RNA decline during pre-treatment allowed one to predict on-treatment response.


t(8;21;14)(q22;q22;q24) is a novel variant of t(8;21) with chimeric transcripts of AML1-ETO in acute myelogenous leukemia.
We report a male patient with acute myelogenous leukemia (AML; French-American-British M2) associated with AML1-ETO. Cytogenetic studies showed a complex karyotype including a novel translocation (8;21;14)(q22;q22;q24) in all analyzed cells. This three-way translocation was confirmed with spectral karyotyping. Reverse transcription-polymerase chain reaction analysis for AML1-ETO chimeric transcripts showed the presence of the fusion product with the expected size. Translocation (8;21;14)(q22;q22;q24) is a novel variant of t(8;21)(q22;q22), possibly having a common molecular pathogenetic mechanism.


Somatostatinoma of the Ampulla: An Incidental Postoperative Finding Following Colorectal Cancer Resection.
Somatostatinoma of the gastrointestinal tract is a rare finding, especially arising from the ampulla of Vater. We present a man recently diagnosed with rectal adenocarcinoma who was found on imaging to have an ampullary mass. Histology and immunohistochemical staining of the biopsied tissue were consistent with a nonfunctioning somatostatinoma. The patient had neurofibromatosis, which have been reported in patients with ampullary somatostatinomas. Our case highlights the importance of gastrointestinal findings in those with underlying genetic conditions.


The Magellanic Corona as the key to the formation of the Magellanic Stream.
The dominant gaseous structure in the Galactic halo is the Magellanic Stream. This extended network of neutral and ionized filaments surrounds the Large Magellanic Cloud (LMC) and the Small Magellanic Cloud (SMC), the two most massive satellite galaxies of the Milky Way1-4. Recent observations indicate that the LMC and SMC are on their first passage around the Galaxy5, that the Magellanic Stream is made up of gas stripped from both clouds2,6,7 and that the majority of this gas is ionized8,9. Although it has long been suspected that tidal forces10,11 and ram-pressure stripping12,13 contributed to the formation of the Magellanic Stream, models have not been able to provide a full understanding of its origins3. Several recent developments-including the discovery of dwarf galaxies associated with the Magellanic group14-16, determination of the high mass of the LMC17, detection of highly ionized gas near stars in the LMC18,19 and predictions of cosmological simulations20,21-support the existence of a halo of warm (roughly 500,000 kelvin) ionized gas around the LMC (the 'Magellanic Corona'). Here we report that, by including this Magellanic Corona in hydrodynamic simulations of the Magellanic Clouds falling onto the Milky Way, we can reproduce the Magellanic Stream and its leading arm. Our simulations explain the filamentary structure, spatial extent, radial-velocity gradient and total ionized-gas mass of the Magellanic Stream. We predict that the Magellanic Corona will be unambiguously observable via high-ionization absorption lines in the ultraviolet spectra of background quasars lying near the LMC.


Long-term follow up of cervical cancer patients with unexplained squamous cell carcinoma antigen elevation after post-therapy surveillance using positron emission tomography.
We aimed to define the long-term follow-up results in cervical cancer patients with unexplained squamous cell carcinoma antigen (SCC-Ag) elevation (negative conventional imaging studies, computed tomography or magnetic resonance imaging) after definitive treatment using positron emission tomography (PET). Of the 27 women with unexplained SCC-Ag elevation, 13 died or were alive with disease (12 PET true-positive, one PET false-negative) in our previous report. In this study, we reported long-term follow-up results for all the 14 patients remaining cancer-free at cut-off of our previous analysis (seven with true-negative PET and two with false-positive PET, and five with true-positive PET having received successful curative salvage therapy). The seven patients with true-negative PET studies remained recurrence-free (median follow up, 70 months; range, 11-84). Two patients had pelvic inflammatory disease; their SCC-Ag levels returned to the normal range after eradication of infection. Two other patients had recurrent cystitis, and their SCC-Ag levels normalized at 5 and 36 months, respectively. The two patients with false-positive PET/computed tomography were disease-free 73.5 and 70 months from original PET studies, respectively. In contrast, of the five patients with successful salvage, two are alive without disease (at 80 and 86.7 months), one died of radiation cystitis at 54 months, and two died of their cancer subsequent to previous analysis. Cystitis or pelvic inflammatory disease may cause unexplained elevation of SCC-Ag after definitive treatment. A negative PET study usually indicates absence of disease. PET is a useful tool to identify curable recurrences, especially when SCC-Ag < 4 ng/mL.


The apoprotein precursor of the major light-harvesting complex of photosystem II (LHCIIb) is inserted primarily into stromal lamellae and subsequently migrates to the grana.
The formation of the lateral distribution of the major antenna complex of photosystem II (LHCIIb) between the granal and stromal lamellae was studied. Specifically, the localization of the insertion and the assembly of the precursor of the apoprotein of LHCIIb (pLHCP) were studied with isolated thylakoids. After insertion of pLHCP into isolated thylakoids, fractionation of the latter into granal and stromal lamellar was performed. At 25 degrees C most of the precursor was located in the granal lamellae, although both highly purified granal and stromal lamellar fractions demonstrated a similar capability to insert pLHCP. When the insertion reaction to the thylakoids was performed at 10 degrees C, followed by their separation into stromal and granal lamellae, the labelled pLHCP was localized in the stromal ones. To examine whether pLHCP inserts into both granal and stromal lamellae, or preferentially into stromal lamellae and subsequently migrating to granal lamellae, a chase experiment was performed. Insertion of pLHCP at 10 degrees C was followed by chase of the radioactive precursor with excess of non-radioactive pLHCP at 25 degrees C. From the results presented it is evident that the level of pLHCP in stromal lamellae was gradually reduced, while it gradually accumulated in the granal lamellae. Furthermore, the pLHCP in the stromal lamellae was found to be in a 'free' form, while after migrating to the granal lamellae it assembled into the pigmented LHCIIb.


Genetic determinants of efficiency of magnetic laser therapy of essential hypertension.
The efficiency of magnetic laser therapy was evaluated in patients with essential hypertension (stages I and II). The role of angiotensinogen, angiotensin-converting enzyme, type II bradykinin receptor, and endothelial nitrogen oxide synthetase gene polymorphism in the realization of hypotensive effect of magnetic laser therapy was evaluated. The hypotensive effect of magnetic laser therapy depends on the polymorphism of the studied genes and is maximum in patients with MM polymorphism of angiotensinogen gene and DD polymorphism of angiotensin-converting enzyme gene. Additive interaction between angiotensin-converting enzyme and angiotensinogen genes in the formation of hemodynamic effects of magnetic laser therapy was detected.


Eating disorders and body image of undergraduate men.
Eating disorders and body dissatisfaction among undergraduate men are less documented and researched than are eating disorders and body dissatisfaction among undergraduate women. In this study, the authors examined these issues in undergraduate men to identify similarities and differences between this population and undergraduate women. In a random sample of undergraduates, the authors categorized respondents by gender and by presence or absence of an eating disorder. The authors compared undergraduate men with an eating disorder with (1) undergraduate women with an eating disorder and (2) undergraduate men without an eating disorder. The patterns of responses suggest that undergraduate men with an eating disorder are preoccupied with body shape and tone but not necessarily with losing weight. The authors discuss implications for future prevention as well as clinical and research efforts based on male symptoms within the diagnostic category of bulimia nervosa and eating disorder, not otherwise specified.


The efficacy of induction chemotherapy in the treatment of stage II nasopharyngeal carcinoma in intensity modulated radiotherapy era.
To evaluate the efficacy of induction chemotherapy in the treatment of stage II nasopharyngeal carcinoma (NPC) in era of intensity modulated radiotherapy (IMRT). A total of 173 patients with American Joint Committee on Cancer (AJCC) 7th stage II NPC from two institutions were included. All patients were divided into two groups: induction chemotherapy + concurrent chemoradiotherapy group (ICRT) group and concurrent chemoradiotherapy group (CCRT). Induction chemotherapy was consisted of one to three cycles of cisplatin plus fluorouracil (PF) or paclitaxel plus cisplatin (TP). Concurrent chemotherapy included one to three cycles of cisplatin. We retrospectively assessed overall survival (OS), progression-free survival (PFS), locoregional failure free survival (LRFFS) and distant metastasis free survival (DMFS) in patients of both groups. T-test, Chi-square test, Kaplan-Meier methodology and Cox proportional hazards model were used to analyze. With a median follow up of 64.7 months, no significant difference was found in grade 3-4 hematologic toxicity, liver dysfunction and renal impairment between ICRT and CCRT group. Univariable analyses shown adding induction chemotherapy to CCRT significantly decreased 5-year OS (87.9% vs 95.5%, P = 0.033), 5-year PFS (74.0% vs 86.1%, P = 0.035), 5-year LRFFS (80.0% vs 91.2%, P = 0.016), but there was no statistically significant difference in 5-year DMFS (87.1% vs 94.7%, P = 0.095). In multivariable analyses, we found the consistent results that induction chemotherapy was a negative factor associated with OS (HR of death = 3.768, 95% CI = 1.117-12.709; P = 0.032), PFS (HR of progression = 2.156, 95% CI = 1.060-4.386; P = 0.034), LRFFS (HR of locoregional relapse = 2.435, 95% CI = 1.009-5.874; P = 0.048) and also DMFS (HR of metastasis = 2.873, 95% CI = 1.005-8.211; P = 0.049), in stage II NPC patients. In present study, we found that induction chemotherapy caused deleterious effect on stage II NPC patients. However, this is a retrospective study and the adverse effects of induction chemotherapy has not been previously reported. It warrants further investigation.


Combination of all-trans retinoic acid and interferon-gamma upregulated p27(kip1) and down regulated CDK2 to cause cell cycle arrest leading to differentiation and apoptosis in human glioblastoma LN18 (PTEN-proficient) and U87MG (PTEN-deficient) cells.
Deletion or mutation of phosphatase and tensin homolog located on chromosome ten (PTEN) occurs in as high as 80% glioblastoma. All-trans retinoic acid (ATRA) induces differentiation in cancer cells. Interferon-gamma (IFN-gamma) induces apoptosis in many cancers including glioblastoma. We used the combination of ATRA and IFN-gamma to control growth of human glioblastoma LN18 (PTEN-proficient) and U87MG (PTEN-deficient) cells and explored any advantage of having PTEN in the cells. LN18 and U87MG cells were treated with ATRA (1 microM) for 7 days and then IFN-gamma (5 ng/ml) for 1 day. Methylene blue staining indicated astrocytic differentiation. Wright staining and ApopTag assay showed characteristic features of apoptosis. Western blotting demonstrated the levels of specific proteins. ATRA and IFN-gamma alone and in combination could induce apoptosis in LN18 cells; while ATRA alone induced differentiation only, IFN-gamma alone induced apoptosis, and ATRA plus IFN-gamma increased apoptosis in U87MG cells. The variation in induction of apoptosis by ATRA alone might be attributed to difference in PTEN expression in the two cell lines. Compared with control cells, IFN-gamma alone and ATRA plus IFN-gamma increased PTEN expression in LN18 cells while there was no PTEN expression or induction in U87MG cells after treatments with ATRA alone and ATRA plus IFN-gamma. Apoptosis in both cell lines was associated with increases in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c into the cytosol, and calpain and caspase-3 activities. Treatments elevated p27(kip1) and decreased CDK2 levels in both cell lines, indicating cell cycle arrest at G(1)/S phase. The combination of ATRA and IFN-gamma could control the growth of both PTEN-proficient and PTEN-deficient glioblastoma cells by arresting cell division and inducing differentiation and apoptosis. Thus, our study indicated that the growth of both PTEN-proficient and PTEN-deficient glioblastoma cells could effectively be controlled by treatment with the combination of ATRA and IFN-gamma.


Comparison of primary and secondary 26S rRNA structures in two Tetrahymena species: evidence for a strong evolutionary and structural constraint in expansion segments.
We have determined the nucleotide sequence of the 26S large subunit (LSU) rRNA genes for two Tetrahymena species, T. thermophila and T. pyriformis. The inferred rRNA sequences are presented in their most probable secondary structures based on compensatory mutations, energy, and conservation criteria. The majority of the nucleotide changes between the two Tetrahymena LSU rRNAs and the positions of a relatively large deletion and of the processing cleavage sites resulting in the generation of the hidden break are all located within the so-called divergent domains or expansion segments. These are regions within the common core of secondary structure where expansions have taken place during the evolution of the rRNA of higher eukaryotes. The dispensable nature of some of the expansion segments has been taken as evidence of their non-functionality. However, our data show that a considerable selective constraint has operated to preserve the secondary structure of these segments. Especially in the case of the D2 and D8 segments, the presence of a considerable number of compensatory base changes suggests that the secondary structure of these regions is of functional importance. Alternatively, these expansion segments may have maintained characteristic folding patterns because only such structures are being tolerated within otherwise functionally important regions.


Four-level evaluation of health promotion intervention for preventing early childhood caries: a randomized controlled trial.
Early childhood caries (ECC) is the most common dental disease among children, which can affect children's primary teeth during their teething. This study evaluates an intervention for preventing early childhood caries in a pediatric population in Ahvaz, Iran. The population of this study (IRCT2017070210804N10) consists of 104 women with 12 to 36 months of age without dental caries referred to a health care center in Ahvaz, Iran. The children were randomly assigned to either an experimental or control group in equal numbers. First, the demographic information of participants was collected through a questionnaire containing components of perceived threat, health literacy, and oral health behaviors using a valid and reliable questionnaire. The ECC status of the children was established by a dentist. Control group received "standard well baby care". The experimental group received standard well baby care in addition to educational interventions, including lecture and group discussion. After 6 months, the participant completed the questionnaire for the second time, and the children's teeth were reexamined. Data were analyzed using SPSS version 15 at a significance level of p < 0.05. The mean ages of women and children were 31 ± 6.68 years and 18 ± 7.21 months, respectively. Before the intervention, no significant difference was documented between the groups for the study variables, p > 0.05. However, after the intervention, a significant difference was observed between the perceived threats (41.15 ± 4.46 in the experimental group and 38.26 ± 4.21 in the control group, p = 0.001), health literacy (20.98 ± 2.15 in the experimental group and 19.76 ± 2.70 in the control group, p = 0.01), oral health behaviors (7.75 ± 2.30 in the experimental group and 6.15 ± 2.65 in the control group, p = 0.01), and the incidence of ECC (13% in the experimental group and 35% in the control group, p = 0.001). This intervention had positive effects on the perceived threat, health literacy, and health behaviors; and the intervention could reduce the incidence of ECC. The finding of this study provided a suggestion for evidence-based decision-making processes regarding ECCs prevention programs. IRCT2017070210804N10 (retrospectively registered).


Enzymolysis of chitosan by papain and its kinetics.
Low molecular weight chitosan (LMWC) was obtained by the enzymolysis of chitosan by papain. Enzymolysis conditions (initial chitosan concentration, temperature, pH and ratio of papain to chitosan) were optimized by conducting experiments at three different levels using the response surface methodology (RSM) to obtain high soluble reducing sugars (SRSs) concentrations. Meanwhile, the influence of chitosan substrate concentration on the activity of papain was assessed in the experiments. The enzymolysis process was analyzed using pseudo-first-order and pseudo-second-order kinetic models and the experiment data were found to be more consistent with the pseudo-second-order kinetic model. In addition, the kinetic behavior of the enzymolysis was also investigated by using Haldane model, and chitosan exhibited substrate inhibition. It was clear that the Haldane kinetic model adequately described the dynamic behavior of the chitosan enzymolysis by papain. When the initial chitosan concentration was above 8.0g/L, the papain was overloaded and exhibited significant inhibition.


Closure of the complicated patent ductus arteriosus.
A technique for closure of the complicated ductus arteriosus is described which has proved both simple and safe. The technique embodies the use of profound hypothermia, low flow, and direct suture of the pulmonary end of the ductus arteriosus through a pulmonary arteriotomy. No operative deaths have occurred among 4 patients so treated, and no complications from air embolism or hemorrhage have been encountered.


Improving antenatal prediction of small-for-gestational-age neonates by using customized versus population-based reference standards.
The purpose of this study was to evaluate whether the use of customized fetal reference standards improves the prenatal detection of intrauterine growth restriction. We conducted a retrospective cohort study. Singleton pregnancies with a diagnosis of a small-for-gestational-age (SGA) fetus based on the in utero reference standard of Hadlock et al (Am J Obstet Gynecol 1985; 151:333-337; Radiology 1991; 181:129-133) were identified from our ultrasound database, and customized percentiles were calculated by adjusting for maternal height, weight, ethnicity, parity, and sex. A total of 300 pregnancies were identified as SGA by both the Hadlock and customized standards, and 60 were identified as SGA by the Hadlock standard only. Small-for-gestational age pregnancies identified by the Hadlock standard only were significantly less likely to have any abnormal sonographic findings, including an elevated head to abdominal circumference ratio (8.3% versus 21.7%; P = .019), oligohydramnios (3.3% versus 13%; P = .027), abnormal umbilical artery Doppler findings (3.4% versus 14.7%; P = .017), maternal hypertensive disease (3.3% versus 12.7%; P = .041), and preterm delivery (6.7% versus 27.7%; P < .001). There was no difference in neonatal intensive care unit admission rates; however, neonates identified as SGA by the Hadlock standard only were less likely to have a postnatal diagnosis of SGA (9.1% versus 78.3%; P < .001) and had a shorter neonatal intensive care unit stay (median, 2 versus 8 days; P < .001). Using a customized standard, we have identified a population of pregnancies with low rates of antenatal complications and sonographic findings associated with pathologic growth. Adoption of customized standards to improve our antenatal detection rate of intrauterine growth restriction may decrease the need for intervention in healthy but constitutionally small fetuses.


A case of lymphoma occurring in an ovarian teratoma.
We describe the discovery, by pathology, of a totally unexpected diagnosis involving an ovarian teratoma. A middle-aged woman underwent routine total abdominal hysterectomy and bilateral salpingoophrectomy for ultrasonically diagnosed uterine fibroids and a coexistent benign right ovarian cyst. The operative findings were of fibroid uterus and right ovarian teratoma. However, pathology revealed a malignant lymphoma occurring in, and arising from, the teratoma. The routine removal of a presumed ovarian teratoma may yield unexpected results. Ovarian teratomas are indeed cellular chimeras.


Resiliency of on-demand multimodal transit systems during a pandemic.
During the COVID-19 pandemic, the collapse of the public transit ridership led to significant budget deficits due to dramatic decreases in fare revenues. Additionally, public transit agencies are facing challenges of reduced vehicle capacity due to social distancing requirements, additional costs of cleaning and protective equipment, and increased downtime for vehicle cleaning. Due to these constraints on resources and budgets, many transit agencies have adopted essential service plans with reduced service hours, number of routes, or frequencies. This paper studies the resiliency during a pandemic of On-Demand Multimodal Transit Systems (ODMTS), a new generation of transit systems that combine a network of high-frequency trains and buses with on-demand shuttles to serve the first and last miles and act as feeders to the fixed network. It presents a case study for the city of Atlanta and evaluates ODMTS for multiple scenarios of depressed demand and social distancing representing various stages of the pandemic. The case study relies on an optimization pipeline that provides an end-to-end ODMTS solution by bringing together methods for demand estimation, network design, fleet sizing, and real-time dispatching. These methods are adapted to work in a multimodal setting and to satisfy practical constraints. In particular, a limit is imposed on the number of passenger transfers, and a new network design model is introduced to avoid the computational burden stemming from this constraint. Real data from the Metropolitan Atlanta Rapid Transit Authority (MARTA) is used to conduct the case study, and the results are evaluated with a high-fidelity simulation. The case study demonstrates how ODMTS provide a resilient solution in terms of cost, convenience, and accessibility for this wide range of scenarios.