A Rare Case of Allergic Bronchopulmonary Aspergillosis Progressing to Cardiac Tamponade in the Al Qassim Region of Saudi Arabia.
Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by an exaggerated response of the immune system (a hypersensitivity response) to the fungus Aspergillus. Aspergillus-associated pericarditis leading to pericardial tamponade is rare. In our case, we presented a case of a 22-year-old female asthmatic patient with no other medical conditions who presented to the emergency department (ED) complaining of severe chest tightness and shortness of breath. Echocardiography revealed significant pleural and pericardial effusion consistent with cardiac tamponade. Both pleural and pericardial fluids were hemorrhagic. Four months later, she presented to the ED with chief complaints of shortness of breath and a cough lasting two days. She was admitted as a case of asthma exacerbation. In the following months, when the patient visited the pulmonology outpatient clinic, the doctors recommended for specific IgE test. Allergen-specific IgE testing was positive for A. fumigatus to confirm the presence of ABPA. As we rolled out other causes of cardiac tamponade, we link the development of cardiac tamponade secondary to an underlying Aspergillus infection. We report this case with the aim of improving clinical knowledge regarding probable causes of cardiac tamponade in patients with asthma, which may facilitate the establishment of early diagnosis and treatment protocols.


Docosahexaenoic acid induces increases in [Ca2+]i via inositol 1,4,5-triphosphate production and activates protein kinase C gamma and -delta via phosphatidylserine binding site: implication in apoptosis in U937 cells.
We investigated, in monocytic leukemia U937 cells, the effects of docosahexaenoic acid (DHA; 22:6 n-3) on calcium signaling and determined the implication of phospholipase C (PLC) and protein kinase C (PKC) in this pathway. DHA induced dose-dependent increases in [Ca2+]i, which were contributed by intracellular pool, via the production of inositol-1,4,5-triphosphate (IP3) and store-operated Ca2+ (SOC) influx, via opening of Ca2+ release-activated Ca2+ (CRAC) channels. Chemical inhibition of PLC, PKCgamma, and PKCdelta, but not of PKCbeta I/II, PKCalpha, or PKCbetaI, significantly diminished DHA-induced increases in [Ca2+]i. In vitro PKC assays revealed that DHA induced a approximately 2-fold increase in PKCgamma and -delta activities, which were temporally correlated with the DHA-induced increases in [Ca2+]i. In cell-free assays, DHA, but not other structural analogs of fatty acids, activated these PKC isoforms. Competition experiments revealed that DHA-induced activation of both the PKCs was dose-dependently inhibited by phosphatidylserine (PS). Furthermore, DHA induced apoptosis via reactive oxygen species (ROS) production, followed by caspase-3 activation. Chemical inhibition of PKCgamma/delta and of SOC/CRAC channels significantly attenuated both DHA-stimulated ROS production and caspase-3 activity. Our study suggests that DHA-induced activation of PLC/IP3 pathway and activation of PKCgamma/delta, via its action on PS binding site, may be involved in apoptosis in U937 cells.


Asymmetric total synthesis of (-)-leuconoxine via chiral phosphoric acid catalyzed desymmetrization of a prochiral diester.
The asymmetric total synthesis of (-)-leuconoxine has been achieved. The desymmetrization of a prochiral diester using a chiral phosphoric acid catalyst produced a highly enantioenriched lactam with excellent yield. The ring construction featuring an intramolecular N-acyliminium cyclization and the one-step pyrrolidone formation using Bestmann's ylide was successfully accomplished.


Electrocardiographic changes in therapeutic hypothermia.
During therapeutic hypothermia (TH), electrocardiographic (ECG) abnormalities such as Osborn waves and/or ST-segment elevation have been described. However, the incidence and prognostic value of these ECG changes are uncertain given the small-scale studies that have been carried out to date. The aim of this study is to further evaluate the electrocardiographic changes during TH. During a period of 3 years, 81 patients (age 63 ± 14 years) were included retrospectively. All patients underwent TH after being resuscitated. ECG registrations before, during and after TH were collected and analyzed. Patients were divided into two groups based on the presence or absence of transmural ischemia ST elevation on the first representative ECG upon arrival at the hospital (ST-segment elevation myocardial infarction (STEMI) and non-STEMI). A total of 243 ECGs were analyzed. During TH 24 patients (30%) had Osborn waves, which disappeared in 22 patients (92%) after regaining normal body temperature. The presence of Osborn waves was not associated with age, gender, average pH, electrolytes, or lactate levels and was not associated with excess in-hospital mortality. In 10 patients (12%, six non-STEMI patients) new STEMI was observed during TH, which disappeared after TH discontinuation. The STEMI group (44 patients) had significantly more Osborn waves during TH than the non-STEMI group (38.6% vs. 15.2%, odds ratio = 3.508; 95% confidence interval = 1.281 to 9.610). Hypothermia-induced Osborn waves are relatively common and are not associated with an unfavorable short-term outcome. TH is associated with ECG changes that may mimic STEMI.


Microsomal Ethanol-Oxidizing System: Success Over 50 Years and an Encouraging Future.
Fifty years ago, in 1968, the pioneering scientists Charles S. Lieber and Leonore M. DeCarli discovered the capacity for liver microsomes to oxidize ethanol (EtOH) and named it the microsomal ethanol-oxidizing system (MEOS), which revolutionized clinical and experimental alcohol research. The last 50 years of MEOS are now reviewed and highlighted. Since its discovery and as outlined in a plethora of studies, significant insight was gained regarding the fascinating nature of MEOS: (i) MEOS is distinct from alcohol dehydrogenase and catalase, representing a multienzyme complex with cytochrome P450 (CYP) and its preferred isoenzyme CYP 2E1, NADPH-cytochrome P450 reductase, and phospholipids; (ii) it plays a significant role in alcohol metabolism at high alcohol concentrations and after induction due to prolonged alcohol use; (iii) hydroxyl radicals and superoxide radicals promote microsomal EtOH oxidation, assisted by phospholipid peroxides; (iv) new aspects focus on microsomal oxidative stress through generation of reactive oxygen species (ROS), with intermediates such as hydroxyethyl radical, ethoxy radical, acetyl radical, singlet radical, hydroxyl radical, alkoxyl radical, and peroxyl radical; (v) triggered by CYP 2E1, ROS are involved in the initiation and perpetuation of alcoholic liver injury, consequently shifting the previous nutrition-based concept to a clear molecular-based disease; (vi) intestinal CYP 2E1 induction and ROS are involved in endotoxemia, leaky gut, and intestinal microbiome modifications, together with hepatic CYP 2E1 and liver injury; (vii) circulating blood CYP 2E1 exosomes may be of diagnostic value; (viii) circadian rhythms provide high MEOS activities associated with significant alcohol metabolism and potential toxicity risks as a largely neglected topic; and (ix) a variety of genetic animal models are useful and have been applied elucidating mechanistic aspects of MEOS. In essence, MEOS along with its CYP 2E1 component currently explains several mechanistic steps leading to alcoholic liver injury and has a promising future in alcohol research.


Engelhardt and children: the failure of libertarian bioethics in pediatric interactions.
In Engelhardt's secular bioethics, moral obligations derive from contracts and agreements between rational persons, and no infants or children and few adolescents meet Engelhardt's requirements for being a rational person. This is a problem, as one cannot have any direct secular moral obligations toward nonpersons such as infants and adolescents. The Engelhardtian concepts of ownership, indenture, and social personhood, which are meant to allow the theory to accommodate children and adolescents adequately, fail to give an Engelhardtian any actual means of determining the right action to take in difficult cases, even on his or her own terms. Thus, the theory is incapable of determining the morally correct action to take in cases involving children and therefore is unhelpful in dealing with moral questions involving children.


Hands-free continuous carotid Doppler ultrasound for detection of the pulse during cardiac arrest in a porcine model.
Pulse palpation is an unreliable method for diagnosing cardiac arrest. To address this limitation, continuous hemodynamic monitoring may be a viable solution. Therefore, we developed a novel, hands-free Doppler system, RescueDoppler, to detect the pulse continuously in the carotid artery. In twelve pigs, we evaluated RescueDoppleŕs potential to measure blood flow velocity in three situations where pulse palpation of the carotid artery was insufficient: (1) systolic blood pressure below 60 mmHg, (2) ventricular fibrillation (VF) and (3) pulseless electrical activity (PEA). (1) Low blood pressure was induced using a Fogarty balloon catheter to occlude the inferior vena cava. (2) An implantable cardioverter-defibrillator induced VF. (3) Myocardial infarction after microembolization of the left coronary artery caused True-PEA. Invasive blood pressure was measured in the contralateral carotid artery. Time-averaged blood flow velocity (TAV) in the carotid artery was related to mean arterial pressure (MAP) in a linear mixed model. RescueDoppler identified pulsatile blood flow in 41/41 events with systolic blood pressure below 60 mmHg, with lowest blood pressure of 19 mmHg. In addition the absence of spontaneous circulation was identified in 21/21 VF events and true PEA in 2/2 events. The intraclass correlation coefficient within animals for TAV and MAP was 0.94 (95% CI. 0.85-0.98). In a porcine model, RescueDoppler reliably identified pulsative blood flow with blood pressures below 60 mmHg. During VF and PEA, circulatory arrest was rapidly and accurately demonstrated. RescueDoppler could potentially replace unreliable pulse palpation during cardiac arrest and cardiopulmonary resuscitation.


The damage signals hypothesis of Alzheimer's disease pathogenesis.
Virtually none of the hypotheses on Alzheimer's disease (AD) pathogenesis address the earliest events that trigger the molecular alterations that precede cerebral degeneration and account for the diversity of risk factors that converge on a well-defined disease phenotype. We propose that long-term activation of the innate immune system by an individual array of risk factors constitutes a unifying mechanism leading to the triggering of an inflammatory cascade that converges in cytoskeletal alterations (tau aggregation, paired helical filament formation) as a previously hypothesized final common pathway in AD. The key pathogenic phenomena consist in the long-term, maladaptive activation of innate immunity-triggering receptors--such as the toll-like and advanced glycation end-products receptors, and others located in the microglial membrane--by seemingly heterogeneous risk factors such as hyperlipidemia, hyperglycemia, oxidative stress, head injury, amyloid oligomers, etc. Our hypothesis provides a unifying mechanism that explains both the diversity of risk factors acting over long periods of time and the individual response to such insults. This formulation is amenable to both empirical testing and implementation into therapeutic strategies that may lead to effective prevention of AD as well as other disorders in which impaired regulation of the innate immunity is the unifying cause of the condition.


Rare desmoplastic trichilemmoma associated with sebaceous nevus.
Nevus sebaceous of Jadassohn is a congenital hamartoma that usually affects the scalp and face. Several benign or malignant neoplasias may develop in the lesion and the most common are trichoblastoma, syringocystadenoma papilliferum, and basal cell carcinoma. Trichilemmoma is a benign solid tumor originating from external sheath cells of pilosebaceous follicles. When it is characterized by a central zone of desmoplasia, it is called desmoplastic trichilemmoma. We report a case of a 58-year-old patient who developed a tumor in a sebaceous nevus. We performed a total excision of the lesion. Histopathological diagnosis was compatible with desmoplastic trichilemmoma. Our literature review reveals that the occurrence of trichilemmoma desmoplastic is unusual. Moreover, it can mimic an invasive carcinoma on histological and clinical examinations. This fact confirms the importance of reporting the occurrence of this rare cancer in a nevus sebaceous of Jadassohn.


A fibronectin fragment stimulates intervertebral disc degeneration in vivo.
A radiographic, histologic, biochemical, and gene expression study was conducted in vivo in a rabbit model to determine the effect of injection of the N-terminal 30 kDa fibronectin fragment (Fn-f) into the intervertebral disc along with various control substances. To determine if the Fn-f is able to induce disc degeneration in vivo. Animal models of disc degeneration are crucial to defining the molecular events involved in disc degeneration. Although spontaneous and induced models of disc degeneration have been described, none is ideal for molecular studies. A better understanding of disc degeneration at the molecular level is necessary to promote rational design of therapies for degenerative disc disease. Thirty-one New Zealand white rabbits underwent injection of Fn-f and control substances into the central region of separate lumbar discs using a fine needle. Euthanasia was performed at the 2-, 4-, 8-, 12-, and 16-week time points and the discs were examined radiographically, histologically, biochemically, and with gene expression. Radiographs demonstrated anterior osteophyte formation at Fn-f-injected disc spaces by the 12-week time point. Histology demonstrated a progressive loss of the normal architecture of the nucleus pulposus and anulus fibrosus over the 16-week study period. A progressive loss of proteoglycans was documented using GAG assay but total collagen did not appear to change appreciably. Gene expression studies demonstrated a significant down-regulation of both aggrecan and type II collagen mRNA between the 8- and 16-week time points. Fn-f appears to induce a progressive degenerative process within the intervertebral disc after injection that resembles degenerative disc disease. This model has several significant advantages for the study of disc degeneration at the molecular level. Further studies are warranted to elucidate the mechanism and molecular events associated with Fn-f-mediated disc degeneration.


An update on the advancements in the treatment of agitation in Alzheimer's disease.
Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren't effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn't necessarily outweigh associated risks. Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation. Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.


Relating linear vibrational spectroscopy to condensed-phase hydrogen-bonded structures: Liquid-to-supercritical water.
The pressure and temperature-dependent linear absorption spectrum of partially deuterated water HOD dissolved in heavy water D(2)O was measured in the OH-stretching spectral region. The temperature was varied in the interval of 298 K</=T</=700 K while the density was changed within the range of 12 moll</=rho</=58 moll corresponding to the liquid and the supercritical phases of the fluid solution. The spectra were analyzed in terms of the temperature and density dependent frequency of maximal absorbance nu(max)(T,rho) and their full widths at half maximum Deltanu(T,rho). In parallel, molecular dynamics simulations of the fluid solution were carried out to obtain the average nearest neighbor O-O distance r(OO) ((1))(T,rho) and its dispersion Deltar(OO) ((1))(T,rho) at any state point (T,rho) for which an absorption spectrum was recorded. A correlation is presented between the experimental spectroscopic quantities nu(max)(T,rho) and Deltanu(T,rho) on the one hand and the local structural quantities r(OO) ((1))(T,rho) and Deltar(OO) ((1))(T,rho) on the other. This intuitive correlation can be used as a critical test for future perturbational simulations of the OH-stretching frequency shifts with hydrogen-bond geometry. Finally, a connection is made to the average hydrogen-bond connectivity in the fluid via the temperature and density dependent dielectric constant of water.


Influence of chloroquine and lidocaine on retention and cytotoxic effects of [131I]EGF: studies on cultured glioma cells.
Targeting of toxic substances to the epidermal growth factor, EGF, receptor might be an attractive therapeutic approach because of the increased receptor-expression in some human tumours such as, for example, malignant gliomas and squamous lung carcinomas. Radiation effects of [131I]EGF on human malignant glioma cells growing as monolayers were analysed in this study. The cells were, in all cases, incubated for 25 min with about 350 kBq/ml [131I]EGF, which gave a total binding of 3.2-3.5 kBq/10(5) cells. The rapid release of activity from the cells caused by the normal degradation of EGF was inhibited by incubation with 30 microM chloroquine or 5 mM lidocaine added to the cell culture medium. These substances are, at these concentrations, known to inhibit proteolytic processes in lysosomes. No effects of the inhibitors alone were observed on cell growth and clonogenic survival. Inhibition of EGF degradation by chloroquine or lidocaine resulted in a significantly prolonged association of 131I with the test cells. About 70% of the initially bound radioactivity remained in the cells giving, after 6 h, a binding of 2.1-2.5 kBq/10(5) cells. A 6 h exposure to the radiation from 131I decays, mediated mainly by specifically bound EGF, gave a survival value of about 50%. Such an effect corresponds to a treatment of 2.5 Gy 60Co gamma-radiation. This is promising considering that, when monolayers are applied, only a very small fraction of the released energy from the 131I decays is deposited in the cells. Effects from non-receptor bound [131I]EGF were analysed after presaturation of the receptors with non-radioactive EGF, and gave no or very small changes in survival.


Dietary quercetin, immune functions and colonic carcinogenesis in rats.
Rats fed 100 mg/kg quercetin (QUE) daily for 7 weeks had significantly enhanced natural killer cell activity compared to their vehicle (VEH)-fed control. In contrast, rats fed 100 mg/kg QUE and treated with the colon carcinogen, azoxymethane had significantly reduced natural killer cell activity compared to their VEH-fed azoxymethane-treated control. There was no significant difference in natural killer cell activity between the two control groups. Antibody production and delayed-type hypersensitivity were not altered by QUE feeding in any treatment group. In vitro exposure of splenic natural killer cells to 1mM QUE significantly decreased natural killer cell cytotoxicity. Lower QUE concentrations produced a non-significant reduction in natural killer cell activity that was restored to control values at 1 x 10(-13)M QUE. The distribution, multiplicity and total number of colonic preneoplastic lesions, aberrant crypt foci, was not significantly different in the QUE-fed azoxymethane-treated rats when compared to azoxymethane-treated vehicle-fed rats at the conclusion of 7 week feeding period. We found no correlation between immune function and development of preneoplastic colon lesions in this study.


Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo.
Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo. Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR.


Beyond bioethics: reckoning with the public health paradigm.
In the wake of scandal over troubling research abuses, the 1970s witnessed the birth of a new system of ethical oversight. The bioethics framework, with its emphasis on autonomy, assumed a commanding role in debates regarding how to weigh the needs of society against the rights of individuals. Yet the history of resistance to oversight underscores that some domains of science hewed to a different paradigm of accountability--one that elevated the common good over individual rights. Federal officials have now proposed to dramatically limit the reach of ethical oversight. The Institute of Medicine has called for a rollback of the federal privacy rule. The changing emphasis makes it imperative to grapple with the history of the public interest paradigm.


Importance of the putative furin recognition site 742RNRR745 for antiangiogenic Sema3C activity in vitro.
Angiogenesis is one of the key processes in the growth and development of tumors. Class-3 semaphorins (Sema3) are characterized as axon guidance factors involved in tumor angiogenesis by interacting with the vascular endothelial growth factor signaling pathway. Sema3 proteins convey their regulatory signals by binding to neuropilins and plexins receptors, which are located on the effector cell. These processes are regulated by furin endoproteinases that cleave RXRR motifs within the Sema, plexin-semaphorins-integrin, and C-terminal basic domains of Sema3 protein. Several studies have shown that the furin-mediated processing of the basic domain of Sema3F and Sema3A is critical for association with receptors. It is unclear, however, if this mechanism can also be applied to other Sema3 proteins, including the main subject of this study, Sema3C. To address this question, we generated a variant of the full-length human Sema3C carrying point mutation R745A at the basic domain at the hypothetical furin recognition site 742RNRR745, which would disable the processing of Sema3C at this specific location. The effects produced by this mutation were tested in an in vitro angiogenesis assay together with the wild-type Sema3C, Sema3A, and Sema3F proteins. Our results showed that the inhibitory effect of Sema3C on microcapillary formation by human umbilical vein endothelial cells could be abrogated upon mutation at the Sema3C basic domain within putative furin cleavage site 742RNRR745, indicating that this site was essential for the Sema3 biological activity.


Establishment of a Rapid Detection Method for Yeast-like Symbionts in Brown Planthopper Based on Droplet Digital PCR Technology.
The brown planthopper Nilaparvata lugens (Stål) (BPH) is a typical monophagous sucking rice pest. Over the course of their evolution, BPH and its symbionts have established an interdependent and mutually beneficial relationship, with the symbionts being important to the growth, development, reproduction, and variation in virulence of BPH. Yeast-like symbionts (YLS), harbored in the abdomen fat body cells of BPH, are vital to the growth and reproduction of the host. In recent research, the symbionts in BPH have mainly been detected using blood cell counting, PCR, real-time quantitative PCR, and other methods. These methods are vulnerable to external interference, cumbersome, time consuming and laborious. Droplet digital PCR (ddPCR) does not need a standard curve, can achieve absolute quantification, does not rely on Cq values, and is more useful for analyzing copy number variation, gene mutations, and relative gene expression. A rapid detection method for the YLS of BPH based on ddPCR was established and optimized in this study. The results showed that the method's limits of detection for the two species of YLS (Ascomycetes symbionts and Pichia guilliermondii) were 1.3 copies/μL and 1.2 copies/μL, respectively. The coefficient of variation of the sample repetition was less than 5%; therefore, the ddPCR method established in this study had good sensitivity, specificity, and repeatability. It can be used to detect the YLS of BPH rapidly and accurately.


Nonidentical twins: Comparison of frequentist and Bayesian lasso for Cox models.
One important task in translational cancer research is the search for new prognostic biomarkers to improve survival prognosis for patients. The use of high-throughput technologies allows simultaneous measurement of genome-wide gene expression or other genomic data for all patients in a clinical trial. Penalized likelihood methods such as lasso regression can be applied to such high-dimensional data, where the number of (genomic) covariables is usually much larger than the sample size. There is a connection between the lasso and the Bayesian regression model with independent Laplace priors on the regression parameters, and understanding this connection has been useful for understanding the properties of lasso estimates in linear models (e.g. Park and Casella, 2008). In this paper, we study the lasso in the frequentist and Bayesian frameworks in the context of Cox models. For the Bayesian lasso we extend the approach by Lee et al. (2011). In particular, we impose the lasso penalty only on the genome features, but not on relevant clinical covariates, to allow the mandatory inclusion of important established factors. We investigate the models in high- and low-dimensional simulation settings and in an application to chronic lymphocytic leukemia.


Bardoxolone treatment alleviates lipopolysaccharide (LPS)-induced acute lung injury through suppressing inflammation and oxidative stress regulated by Nrf2 signaling.
Nuclear factor-erythroid 2 related factor 2 (Nrf2) plays critical roles in attenuating various inflammation- and oxidative stress-induced diseases, including acute lung injury (ALI). Bardoxolone (Bard), a synthetic triterpenoid based on natural product oleanolic acid, is one of the most potent Nrf2 activator. However, if Bard could prevent lipopolysaccharide (LPS)-induced ALI by inducing Nrf2 activation and its down-streaming signals, is still poorly understood. In this study, we attempted to explore the protective effect of Bard on ALI and the underlying molecular mechanisms. The results indicated that Bard significantly attenuated ALI through reducing the lung wet/dry weight ratio and protein concentration, neutrophil infiltration, malondialdehyde (MDA) and myeloperoxidase (MPO) levels, and improving superoxide dismutase (SOD) and glutathione (GSH) activities. In addition, Bard effectively ameliorated histopathological alterations, reactive oxygen species (ROS) production, pro-inflammatory cytokines release, and the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX2) and high mobility group box 1 (HMGB1). Moreover, the inhibitory role of Bard in inflammation was also attributed to its suppression of nuclear factor-κB (NF-κB) signaling. Furthermore, the activation of mitogen-activated protein kinases (MAPKs) signaling, including p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), induced by LPS was substantially ameliorated by Bard. The beneficial effects of Bard on ALI were confirmed in LPS-incubated cells in vitro. Meanwhile, the in vitro studies also demonstrated that Bard-improved ALI was largely due to its role in inducing Nrf2 signaling through a dose-dependent manner. Importantly, we found that Bard-attenuated histological changes, inflammation, ROS production, NF-κB and MAPKs signaling in Nrf2+/+ mice were significantly abolished in mice with Nrf2 knockout. Therefore, our study for the first time provided evidence that Bard could effectively ameliorate LPS-induced ALI by reducing oxidative stress and inflammation mainly through the activation of Nrf2 signaling.


Estradiol regulates different genes in human breast tumor xenografts compared with the identical cells in culture.
In breast cancers, estrogen receptor (ER) levels are highly correlated with response to endocrine therapies. We sought to define mechanisms of estrogen (E) signaling in a solid breast tumor model using gene expression profiling. ER(+) T47D-Y human breast cancer cells were grown as xenografts in ovariectomized nude mice under four conditions: 1) 17beta-estradiol for 8 wk (E); 2) without E for 8 wk (control); 3) E for 7 wk followed by 1 wk of E withdrawal (Ewd); or 4) E for 8 wk plus tamoxifen for the last week. E-regulated genes were defined as those that differed significantly between control and E and/or between E and Ewd or control and Ewd. These protocols generated 188 in vivo E-regulated genes that showed two major patterns of regulation. Approximately 46% returned to basal states after Ewd (class I genes); 53% did not (class II genes). In addition, more than 70% of class II-regulated genes also failed to reverse in response to tamoxifen. These genes may be interesting for the study of hormone-resistance issues. A subset of in vivo E-regulated genes appears on lists of clinical ER discriminator genes. These may be useful therapeutic targets or markers of E activity. Comparison of in vivo E-regulated genes with those regulated in identical cells in vitro after 6 and 24 h of E treatment demonstrate only 11% overlap. This indicates the extent to which gene expression profiles are uniquely dependent on hormone-treatment times and the cellular microenvironment.


Separating lentiviral vector injection and induction of gene expression in time, does not prevent an immune response to rtTA in rats.
Lentiviral gene transfer can provide long-term expression of therapeutic genes such as erythropoietin. Because overexpression of erythropoietin can be toxic, regulated expression is needed. Doxycycline inducible vectors can regulate expression of therapeutic transgenes efficiently. However, because they express an immunogenic transactivator (rtTA), their utility for gene therapy is limited. In addition to immunogenic proteins that are expressed from inducible vectors, injection of the vector itself is likely to elicit an immune response because viral capsid proteins will induce "danger signals" that trigger an innate response and recruit inflammatory cells. We have developed an autoregulatory lentiviral vector in which basal expression of rtTA is very low. This enabled us to temporally separate the injection of virus and the expression of the therapeutic gene and rtTA. Wistar rats were injected with an autoregulatory rat erythropoietin expression vector. Two or six weeks after injection, erythropoietin expression was induced by doxycycline. This resulted in an increase of the hematocrit, irrespective of the timing of the induction. However, most rats only responded once to doxycycline administration. Antibodies against rtTA were detected in the early and late induction groups. Our results suggest that, even when viral vector capsid proteins have disappeared, expression of foreign proteins in muscle will lead to an immune response.


[Nature of breaks inducible in DNA at the early stages of interphase cell death].
Dynamics of changes in 3'-OH- and 5'-OH-ends of DNA was determined by "nick"-translation and direct polynucleotide kinase reaction, respectively, in animal thymocytes after irradiation and administration of hydrocortisone. Breaks bearing both 3'-OH- and 5'-OH-ends were found in DNA after irradiation. In 40 min repair of single-strand breaks was almost completed, and enzymatic breaks were accumulated with 3'-OH-ends only. 60 min after the administration of hydrocortisone, the number of nuclear DNA breaks containing 3'-OH-ends, but not 5'-OH-ends, sharply increased. Upon DNA autolysis in isolated nuclei acid nuclease produced 5'-OH-ends, and Ca2+/Mg2+-dependent nuclease, 3'-OH-ends. No activity of Mg2+-dependent nuclease was registered either in the nuclei of control thymocytes or in the nuclei isolated from thymocytes of exposed rats.


[Bronchiolitis obliterans organizing pneumonia with acute respiratory insufficiency].
A 22-year-old woman was hospitalized because of fever of 39 degrees C and increasing dyspnoea. The chest radiograph demonstrated coarse confluent opacities bilaterally. Despite antibiotic treatment the condition deteriorated acutely after 2 days. All efforts to find an infectious agent, including immunological tests, were unsuccessful. Artificial ventilation became necessary because of increasing respiratory failure with an arterial oxygen partial pressure of 56 mm Hg, CO2 of 41 mm Hg and a respiratory rate of 60/min. Histological examination of a transthoracic lung biopsy revealed bronchiolitis obliterans organizing pneumonia, which was treated with prednisolone. The initial dose was 500 mg/d, gradually reduced to 12.5 mg/d over 2 weeks. The clinical and radiological findings improved markedly after 2 days and the patient discharged herself after 3 weeks and there was no follow-up.


Liver transplantation for Echinococcus granulosus hydatid disease.
The authors report their experience with 6 patients requiring liver transplantation who suffered with liver infestation by Echinococcus granulosus. One patient presented with acute Budd-Chiari syndrome because obstruction of hepatic veins was produced during the first operation; the other 5 patients received liver transplants for terminal chronic liver disease (2 secondary sclerosing cholangitis, 2 secondary biliary cirrhosis, and 1 postnecrotic cirrhosis of the liver). All the patients had been operated previously on for hydatidosis and were at the end of liver functional disorder. Some of the patients had undergone many operations, making the transplantation procedure even more difficult. One patient required a second transplant for primary graft failure; he died 40 days later from cerebrovascular accident. Another patient died 7 months after transplant from pulmonary embolism. The other 4 patients are alive and in optimal condition 37-65 months after transplantation. Hepatic hydatidosis--in principle, a benign disease--can cause hepatic complications that eventually require liver transplantation. The transplantation procedure is more difficult than usual in these cases. Although postoperative complications are frequent, most patients achieve prolonged survival and a good quality of life.


[Immunotherapy using T cells for treating viral infections].
Recipients of hematopoietic stem cell transplantation suffering from severe immunosuppression and immune dysregulation because of GVHD or other causes are at higher risk of viral infection. Often, cytomegalovirus and EB virus are reactivated from their latent state in these patients ; viral infections thus remain a primary cause of severe morbidity and mortality. Since the 1990s, virus-specific T cells have been generated by different methods using immunogenic epitope peptides or EBV-LCL from transplant donors, and studies have demonstrated the efficacy of these methods. However, establishing such order-made, virus-specific T cells requires 8-10 weeks, which is not feasible for application in the frontline of clinics. Recent advances, such as direct donor T cell selection using peptide-HLA multimers or cytokine capture method and virus-specific T cells bank generated using third-party donors, facilitated the broadening of the applicability of this method. The clinical development of virus-specific T-cell therapy is considered as the prototype of future T-cell immunotherapy for various infections or malignant diseases.


Different powered toothbrushes for plaque control and gingival health.
Powered brushes were first introduced commercially in the 1960s. A recent systematic review suggested the superiority of certain modes of powered over manual toothbrushing for plaque and gingivitis reduction. That review did not allow for direct comparison between different modes of powered toothbrush. To compare different modes of powered toothbrushing against each other for plaque reduction and the health of the gingivae. Other factors to be assessed were calculus and stain removal, cost, dependability and adverse effects. The following databases were searched: Cochrane Oral Health Group's Trials Register (to 26 July 2010); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3); MEDLINE via OVID (1950 to 26 July 2010); EMBASE via OVID (1980 to 26 July 2010); CINAHL via EBSCO (1982 to 26 July 2010). There were no language restrictions. Trials were considered for inclusion with the following criteria: random allocation of participants; no compromised manual dexterity; unsupervised powered toothbrushing for at least 4 weeks. The primary outcomes were the plaque and gingivitis scores after powered toothbrush use during trial period. Data extraction was performed independently and in duplicate. The authors of trials were contacted to provide missing data where possible. The effect measure for each meta-analysis was the standardised mean difference (SMD) with 95% confidence intervals (CI) using the random-effects model. Potential sources of heterogeneity were assessed. The review included data from 15 trials with 1015 participants. Due to the dearth of trials assessing the same mode of action, no definitive conclusions can be stated regarding the superiority of one mode of powered toothbrush over any other. Only minor and transient side effects were reported. Cost, dependability were not reported. Further trials of good quality are required to establish if any mode of action has superiority over the other modes of action for powered toothbrushes.


[Study on critical quality attributes of Qingjin Huatan Decoction based on serum pharmacochemistry].
Qingjin Huatan Decoction is a classic prescription with the effects of clearing heat, moistening lung, resolving phlegm, and relieving cough. In order to explore the critical quality attributes of Qingjin Huatan Decoction, we identified the blood components of Qingjin Huatan Decoction by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS) under the following conditions, chromatographic column: Acquity UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 μm); mobile phase: 0.1% formic acid acetonitrile(A)-0.1% formic acid in water(B); gradient elution; flow rate: 0.2 mL·min~(-1); column temperature: 30 ℃; injection volume: 5 μL. The electrospray ionization(ESI) source was used to collect data in both positive and negative ion modes under the following conditions, capillary voltage: 3 kV for the positive ion mode and 2 kV for the negative ion mode; ion source temperature: 110 ℃; cone voltage: 30 V; cone gas flow rate: 50 L·h~(-1); nitrogen degassing temperature: 350 ℃; degassing volume flow rate: 800 L·h~(-1); scanning range: m/z 50-2 000. In this experiment, a total of 66 related components of Qingjin Huatan Decoction were identified, including 22 prototype components and 44 metabolites. The results of this study preliminarily revealed the pharmacodynamic material basis of Qingjin Huatan Decoction in vivo, which has provided an experimental basis for the determination of quality markers of Qingjin Huatan Decoction and the development of new drugs.


Profile of tuberculosis patients with delayed sputum smear conversion in the Pacific island of Vanuatu.
National tuberculosis control programme, Vanuatu. To assess tuberculosis (TB) trends, characterise sputum smear-positive patients with non-conversion at 2 months and assess their treatment outcomes. Evaluation of programme data over a 9-year period (2004-2012), comparing 2-month sputum non-converters (delayed converters) with sputum smear converters diagnosed in 2011 and 2012. Annual TB case numbers were similar over the study period, with an average TB notification rate of 58 per 100 000 population. Of 417 sputum smear-positive cases, 74 (18%) were delayed converters. Delayed converters were more likely than converters (88% vs. 79%) to have had high pre-treatment sputum smear grades (OR 2.5, 95%CI 0.97-6.45). Among delayed converters, treatment adherence was high (99% good adherence), outcomes were generally good (90% treatment success, 85% cure, 4% treatment failure) and no drug resistance was detected. Deaths were unexpectedly common among converters (11/80, 14%), with significantly more deaths in Tafea than in Shefa Province (7/58 vs. 2/80, OR 5.35, 95%CI 1.07-26.79). Tafea Province also had the greatest number of delayed converters (30/74, 40.5%) and the highest TB incidence rate. Delayed sputum conversion was relatively uncommon, and was not associated with adverse outcomes or drug resistance. Regional differences require further investigation to better understand local factors that may compromise patient management.


Clinical practice evaluation of combination of atosiban, ritodrine and ketoprofen for inhibiting preterm labor.
The aim of this study was to compare the efficacy and tolerability of atosiban vs ritodrine administered as single-drug or as combination therapy with the COX inhibitor ketoprofen in the treatment of preterm labor and to investigate how frequent is the need for combination therapy with ketoprofen. Ninety-one women with diagnosis of threatened preterm delivery at 24-33 weeks' gestation were enrolled in an observational case-control study. Forty-seven received IV atosiban (6.75 mg initial dose, 300 microg/min loading dose for 3 hours, 100 microg/min maintenance dose for 48-96 hours) and 44 IV ritodrine (0.05-0.3 mg/min). When response to the first drug in the first 2-4 hours was unsatisfactory, ketoprofen was added (100 mg loading dose IV and 100-150 mg maintenance dose every 12 hours) for a maximum of 48 hours. Ketoprofen was added in 51.1% of the atosiban group and 47.7% of the ritodrine group (P 0.75, not statistically significant). The percentages of women non delivered in the two groups were 85.1% vs 81.8% at 48 hours (P=0.44) and 59.6% vs 54.5% at 7 days (P=0.39). One woman treated with atosiban reported transient dyspnea at the administration of the bolus dose; 20.5% of women who received ritodrine developed tachycardia and 4.5% dyspnea (P=0.001). Neonatal mortality and morbidity were comparable in both groups and unrelated to ketoprofen exposure. Atosiban efficacy was comparable to ritodrine, but with a superior safety profile. A large proportion of women in both groups required second-line ketoprofen therapy, with comparable neonatal outcomes.


Variation in Pathologist Classification of Colorectal Adenomas and Serrated Polyps.
Endoscopist quality measures such as adenoma detection rate (ADR) and serrated polyp detection rates (SPDRs) depend on pathologist classification of histology. Although variation in pathologic interpretation is recognized, we add to the literature by quantifying the impact of pathologic variability on endoscopist performance. We used natural language processing to abstract relevant data from colonoscopy and related pathology reports performed over 2 years at four clinical sites. We quantified each pathologist's likelihood of classifying polyp specimens as adenomas or serrated polyps. We estimated the impact on endoscopists' ADR and SPDR of sending their specimens to pathologists with higher or lower classification rates. We observed 85,526 colonoscopies performed by 119 endoscopists; 50,453 had a polyp specimen, which were analyzed by 48 pathologists. There was greater variation across pathologists in classification of serrated polyps than in classification of adenomas. We estimate the endoscopist's average SPDR would be 0.5% if all their specimens were analyzed by the pathologist in our sample with the lowest classification rate and 12.0% if all their specimens were analyzed by the pathologist with the highest classification rate. In contrast, the endoscopist's average ADR would be 28.5% and 42.4% if their specimens were analyzed by the pathologist with lowest and highest classification rate, respectively. There is significant variation in pathologic interpretation, which more substantially affects endoscopist SPDR than ADR.


RP-HPLC enantioseparation of β-adrenolytics using micellar mobile phase without organic solvents.
Enantioseparation of a few commonly administered racemic β-adrenolytics (namely, carvedilol, betaxolol, salbutamol and bisoprolol) has been achieved using a water micellar mobile phase containing surfactants (sodium dodecyl sulphate and Brij-35) without organic solvents as a new approach in RP-HPLC. Two chiral derivatizing reagents based on enantiomerically pure (S)-(-)-levofloxacin were synthesized using N-hydroxysuccinimide and N-hydroxybenzotriazole as the activation auxiliaries. Diastereomeric derivatives of the chosen β-adrenolytics were synthesized under microwave irradiation in a very short reaction time. The (S)-(-)-levofloxacin moiety enhanced molar absorbance of the diastereomeric derivatives resulting in very low limit of detection (1.618 and 4.902 ng/mL, respectively, for diastereomeric derivatives of (RS)-betaxolol and better resolution with lower retention times (for all the analytes), in comparison to literature reports. There was 15-20 times less consumption of mobile phase because of lower retention time.


Percutaneous implantation of a second device in patients with residual right-to-left shunt after patent foramen ovale closure.
The management of patients with residual right-to-left shunt (rRLS) after percutaneous patent foramen ovale (PFO) closure is debated. The aim of this study was to define the incidence of moderate-to-large rRLS and to report the feasibility, safety and long-term clinical outcome of transcatheter closure of rRLS. From June 2000 to March 2013, 322 subjects underwent percutaneous PFO closure. In 39 patients (12.1%) with moderate-to-large rRLS on transcranial Doppler (TCD) and/or transesophageal echocardiogram a second cardiac catheterization was performed with the aim of completing the closure. A second closure device was implanted in 21 patients (53.8%). In the remaining 18 (46.2%), a second device was not delivered for the following reasons: in 13 (72.2%) no residual passage could be crossed, in 5 (27.8%) the residual shunt was deemed to be negligible. No complications occurred. After the second procedure, complete closure was proved by TCD in 16/21 (76.2%) subjects. One patient received a third device. During follow-up (41 ± 19 months), no cerebrovascular ischemic accidents occurred. A second percutaneous PFO occlusion device can be safely implanted in patients with significant rRLS. However, a moderate-to-large rRLS on TCD and/or TEE may not necessarily represent a significant risk of further paradoxical embolization.


Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.
Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.


Channelling free energy into work in biological processes.
The process by which free energy from ATP or an ion gradient is coupled to work--either osmotic work, by a membrane pump, or mechanical work, by a molecular motor--as well as the development of force by a molecular motor, can be explained by mechanisms dependent on substrate binding energy. Coupling involves a reaction sequence that combines the driving and driven reactions and that is controlled at switch points where the mobility of the coupling protein and its specificity in binding and catalysis can be abruptly altered; the altered state is an intermediate (or transition state) in the coupled reaction, the unaltered state an intermediate in the uncoupled reaction (slippage). The balance between these states, which is determined by the increase in substrate binding energy in the transformation, decides the relative importance of the coupled and uncoupled paths. On this basis a general expression for switching may be derived: the tightness of coupling is limited by a ratio of substrate dissociation constants before and after a controlling change in state: Rate(coupled)/Rate(uncoupled) < or = Kinitial state/Kfinal state. When binding energy is used in this way to distort the conformation of a protein, mechanical work is done; the work is internal but becomes external if the protein is connected to an external load. External work, force F multiplied by distance d, is then limited by a ratio of substrate dissociation constants before and after the conformational change: W = Fd < RT In(Kinitial state/Kfinal state). The ratios of dissociation constants, estimated from published values of the force exerted by molecular motors, are > 1 x 10(4) for myosin and > 2 x 10(4) for kinesin. From the tightness of coupling of the anion exchange carrier of red cells the ratio of constants for coupling is > or = 4 x 10(4). These increments can be accounted for by conversion of a surface complex to an enclosed complex, as in chelate formation. The work done by an ATP-driven motor is limited by the free energy of ATP hydrolysis, but the force developed is independent of the ATP reaction, and comes from binding energy with either the driving or driven substrate.


The influence mechanism of interlocking director network on corporate risk-taking from the perspective of network embeddedness: Evidence from China.
The interlocking director network can not only help achieve low-cost information sharing and exchange learning among enterprises, but also provide essential resource support for corporate risk-taking behavior. This study aims to empirically analyze the impact, mechanism of action, and boundary of influence of interlocking director network (NET) on corporate risk-taking (RISK) using data of Chinese A-share listed companies from 2007 to 2020.The results show: (1) There is a significant positive correlation between NET and RISK, and the above results are still established after a series of robustness tests. (2) Mechanistic tests show that the NET can promote RISK through two channels: alleviating financing constraints and increasing R&D investment. (3) Further analysis reveals the promotion of NET on RISK is more significant in non-state-owned enterprises and enterprises with higher industry competition intensity. These findings have positive implications for the construction of an inter-enterprise interlocking director network and the enhancement the of the risk-taking level.


[Prevalence of celiac disease markers in a French cohort of children and adolescents with type 1 diabete mellitus].
The aim of this study was to determine the prevalence of celiac disease (CD) markers in a French cohort of 84 children type 1 diabetics. Detection of antitransglutaminase (AtTG), antiendomysium (AEA) and antigliadin (AGA) antibodies was performed. Group 1 included 81 (96.4%) diabetic patients with negative antibodies. Group 2 included 3 patients (3.6%) with positive serological markers: 1 AGA-AEA-AtTG and 1 AEA-AtTG with proved histological diagnosis and 1 AGA positive with negative histology. No statistically significant difference was observed between the groups with regard to age, duration of diabetes, familial target stature, and ratios Height/Age and Weight/Height. Presence of CD serological markers was related to a lower level of HbA1c. Prevalence of CD serological markers is important in this French cohort but lower than other countries.


Primary Occipital Ewing's Sarcoma with Subsequent Spinal Seeding.
Ewing's sarcoma is a primary bone cancer that mainly affects the long bones. This malignancy is particularly common in pediatric patients. Primary cranial involvement accounts for 1% of cases, with occipital involvement considered extremely rare. In this case study, primary occipital Ewing's sarcoma with a posterior fossa mass and subsequent relapse resulting in spinal seeding is reported. A 3-year-old patient presented with a 1-year history of left-sided headaches, localized over the occipital bone with progressive torticollis. Computed tomography (CT) imaging showed a mass in the left posterior fossa compressing the brainstem. The patient then underwent surgical excision followed by adjuvant chemoradiation therapy. Two years later, the patient presented with severe lower back pain and urinary incontinence. Whole-spine magnetic resonance imaging (MRI) showed cerebrospinal fluid (CSF) seeding from the L5 to the S4 vertebrae. Primary cranial Ewing's sarcoma is considered in the differential diagnosis of children with extra-axial posterior fossa mass associated with destructive permeative bone lesions. Although primary cranial Ewing's sarcoma typically has good prognosis, our patient developed metastasis in the lower spine. Therefore, with CNS Ewing's sarcoma, screening of the entire neural axis should be taken into consideration for early detection of CSF seeding metastasis in order to decrease the associated morbidity and mortality.


Dofequidar fumarate (MS-209) in combination with cyclophosphamide, doxorubicin, and fluorouracil for patients with advanced or recurrent breast cancer.
To evaluate the efficacy and tolerability of dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance. In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m2) and fluorouracil (500 mg/m2) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable. ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin. Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.


Effects of random noise on a simple class of growing network models.
We investigate the effects of random noise on network systems. In particular, we consider a simple class of growing network models whose topological structure is determined by the preferred attachment A(k). We introduce a noise-induced attachment A(k) which includes fluctuations in the number of links of individual nodes due to a random noise. We carry out the numerical simulations to show that the topological structure of the networks is determined not only by A(k) but also by the strength of the noise. Analytic and numerical solutions are also presented to support this observation. In addition, we study the stability of networks against attacks under the noisy condition. Similarly, we introduce a noise-induced preferred deletion B(k), and show that noise is an essential feature to determine the stability of networks.


[Association of serotonin transporter linked polymorphic region 44 bp variable number of tandem repeat polymorphism with Tourette syndrome].
To assess the association between the serotonin transporter linked polymorphic region (5-HTTLPR) 44 bp variable number of tandem repeat (VNTR) polymorphism and Tourette syndrome (TS) in ethnic Han Chinese trios. A total of 252 TS trios (patients and their parents) were recruited. Genetic contribution of the 5-HTTLPR 44 bp VNTR polymorphism was evaluated by genotyping, haplotype relative risk (HRR) analysis and transmission disequilibrium test (TDT) statistics. To enhance the efficiency of the test, haplotype-based HRR (HHRR) was also performed. The TDT, HRR and HHRR analyses have revealed a significant association of the 5-HTTLPR 44 bp VNTR polymorphism with TS, and provided a strong evidence for an over-transmission of L allele from parents to the affected children (TDT: χ² = 6.680, df= 1, P= 0.012; HRR: χ² = 9.345, P= 0.002, OR= 1.739, 95% CI for 1.218-2.483). For 204 male and 48 female TS trios, TDT and HRR were analyzed separately. The results showed a significant association between 5-HTTLPR and male TS (for males. TDT: χ² = 4.643, df= 1, P= 0.038; for females, TDT: χ² = 2.189, df= 1, P= 0.188). 5-HTTLPR may be the susceptibility gene for male TS patients among the Chinese Han population. However, the results need to be replicated in datasets collected from different populations.


[Heterogeneity of acetylcholine receptor antibodies in patients with myasthenia gravis].
Antibodies against the nicotinic acetylcholine receptor in sera of 21 myasthenia gravis patients were checked for their ability to block or split binding of alpha-bungarotoxin to the human acetylcholine receptor. Affinity-purified acetylcholine receptors from human skeletal muscle were used in parallel in the common precipitation assay and an inhibition assay. Cross-reactivity of acetylcholine receptor antibodies was analyzed with receptor preparation from different species (calf, rat, Torpedo c. and Electrophorus e.), purified identically to high specific activity. An antibody pattern was set up for each patient and related to the clinical state of the disease. alpha-Bungarotoxin-inhibiting antibodies were demonstrable in 74% of myasthenia gravis patients, alpha-bgt displacing antibodies were found in 39% of the investigated sera. Broad cross-reactivity with acetylcholine receptors from other mammalian muscle was evident (calf 75%, rat 90%) only very few sera reacted with acetylcholine receptors from electric fish (Torpedo c. 14%, Electrophorus e. 38%). Antibody concentrations determined by using xenoantigens were much lower than those obtained by human acetylcholine receptor. The lack of a clear-cut correlation between the amount of serum antibodies and the clinical state of myasthenia gravis can be explained by the established antibody-heterogeneity, shown by a constant antibody pattern characteristic for each patient. However, between this specific antibody pattern and the state of the disease no correlation could be established either.


Reduced placental telomere length during pregnancies complicated by intrauterine growth restriction.
Recent studies have shown that telomere length was significantly reduced in placentas collected at delivery from pregnancies complicated by intrauterine growth restriction secondary to placental insufficiency. Placental telomere length measurement during ongoing pregnancies complicated by intrauterine growth restriction has never been reported. This was the main objective of our study. In our center, late chorionic villus samplings were performed between 18 and 37 weeks of amenorrhea in 24 subjects with severe intrauterine growth restriction (cases) and in 28 subjects with other indications for prenatal diagnosis (controls). Placental insufficiency was assessed by histo-pathological examination. Relative measurement of telomere length was carried out prospectively by quantitative Fluorescent In Situ Hybridization using fluorescent Peptide Nucleic Acid probes on interphase nuclei obtained from long-term cultured villi and with an automated epifluorescent microscope. A quantitative Polymerase Chain Reaction technique was performed to confirm the quantitative Fluorescent In Situ Hybridization results. The number of copies of gene loci encoding the RNA template (hTERC) and the catalytic subunit (hTERT) of the enzyme complex telomerase were also estimated in these placentas by Fluorescent In Situ Hybridization. Mean fluorescence intensity of telomere probes estimated by quantitative Fluorescent In Situ Hybridization was significantly less for cases compared to controls (p<0.001). This result indicated that mean telomere length was significantly reduced in placentas during pregnancies complicated by intrauterine growth restriction. Reduced telomere length was confirmed by the quantitative Polymerase Chain Reaction technique. No copy number variation of the hTERC and hTERT loci was noticed for cases, or for controls. This study clearly demonstrates a reduction of placental telomere length in ongoing pregnancies (from 18 to 37 weeks of amenorrhea) complicated by severe intrauterine growth restriction secondary to placental insufficiency.


A pilot epidemiologic study of diabetes mellitus in the Sudan.
Records of 523 consecutive diabetic patients attending a diabetic clinic in Wad Madeni, Central Region, Sudan, were reviewed to determine epidemiologic features and the relation between their diabetes and nutritional state. The male to female ratio was 0.97:1. The age at diagnosis ranged between 0-61 years with a mean age of 51.7 +/- 11.9 years for males and 49.4 +/- 11.4 for females. Obesity was a feature, in that 47.4% of females and 30% of males were determined to be in excess of normal body mass index (BMI) standards. A family history of diabetes was present in 67% of cases. Hypertension was present in 38% of cases; it was slightly more common among females than males (52% vs 48%), respectively. Insulin was employed for control of diabetes in 75% of cases, and oral hypoglycaemics in 20%. The remainder were on diet therapy alone. Thirty-four percent of the patients are rural dwellers that should be saved from disabling and even fatal complications of the disease in combination with malnutrition and infectious diseases that hasten death in rural areas. It is hoped that the interest of those concerned regarding public health implications of the findings in this study will be stimulated.


Differential gene expression analysis under salinity stress in the selected turmeric (Curcuma longa L.) cultivars for curcuminoid biosynthesis.
Curcuminoids are the phenolic compounds found exclusively in turmeric. Their presence is known to increase immunity and resistance against certain cancers and neurological disorders in humans also, protecting the plant itself against salinity stress. In this experiment, we studied the expression levels of MAPK1 and DCS genes, their curcuminoid biosynthesis under salinity stress conditions so that the impact of individual genes can be understood using semi- quantitative PCR. The expressions of the genes with respect to curcuminoid biosynthesis showed fluctuations in their band intensity values due to the production of curcuminoids, which is initiated first in the leaves followed by the rhizomes. Not all the genes responsible for the curcuminoid biosynthesis show positive regulation under salt stress conditions which is observed in response to the severity of the stress imposed on the cultivars. In our findings, both the genes MAPK1 and DCS were down-regulated for curcuminoid biosynthesis compared to their controls in both the cultivars Vallabh Sharad and Selection 1.


Oxygen transfer properties of a bioreactor for use within a nuclear magnetic resonance spectrometer.
Nuclear magnetic resonance (NMR) spectroscopic analysis of whole cells is an important emerging technique for noninvasive and nondestructive monitoring of cell physiology. However, this technique requires extremely high cell densities. Attempts to maintain densities above the carrying capacity of a maintenance system result in the demise of the entire culture. To define conditions for maintaining mammalian cells at high densities for NMR studies, we have designed a bioreactor to operate under defined, oxygen-limited conditions within an NMR spectrometer. The bioreactor utilizes hollow fibers to deliver nutrients and remove wastes from an agitated cell suspension. The mass transfer properties of the fibers with respect to oxygen were determined. Ehrlich Ascites Tumor (EAT) cells were supplied with glutamine as the respiratory carbon source. The maximum viable cell density supported by a given oxygen concentration in the fluid flowing through the fiber lumen was predicted and then confirmed experimentally on the bench and in the spectrometer.


Alkaline treatment effect on the properties of in-situ synthesised ZnO nanoparticles on cotton fabric.
In this study, an in-situ approach was used to synthesise zinc oxide nanoparticles on the surface of cotton fabric. The effect of alkaline pre- and after-treatment and Zn(2+) concentration was studied on the morphological, structural, thermal, photocatalytic, and antibacterial properties of loaded cotton fabrics. Scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffractometer, thermogravimetric analysis, and attenuated total reflection Fourier transform infrared spectrometer were used to characterise the properties of loaded cotton fabrics. Alkaline after-treatment of cotton fabric presented more dispersed zinc oxide nanoparticles, and an increase in Zn(2+) concentration led to form agglomerated nanoparticles on the surface of cotton fibres. The loaded cotton fabrics with zinc oxide nanoparticles presented an inhibition zone against Staphylococcus aureus and Escherichia coli. In addition, the stain of methylene blue on the surface of loaded samples was degraded after irradiated under visible light.


Response of pulmonary macrophages to unilateral instillation of carbon.
Production and delivery of macrophages to the alveoli are dependent upon chemotactic and mitogenic stimuli. To determine whether these mechanisms occur uniformly throughout the lungs or are localized to the areas of particulate deposition, the authors instilled 4 mg of carbon in one lung of a rat, the other lung serving as a control. Following split-lung lavage, little change was seen in the number of cells lavaged from nontreated lungs, whereas the yield of macrophages from the black lungs rose from 32 X 10(4) to 400 X 10(4) after 2 days; control values were not attained until 3 weeks. Labeling indices for cell nuclei in the white lungs were slightly elevated, whereas in the black lungs the value rose from 0.4 to 1.0-1.5% for 3 weeks before falling to normal. The increased labeling was limited to interstitial cells. The results provide further support for the dual origin of alveolar macrophages and indicate the importance of local generation of chemotactic and mitogenic factors in stimulating the cellular response and in directing these cells to the sites of maximal deposition of particles.


Bio-utilization of cheese manufacturing wastes (cheese whey powder) for bioethanol and specific product (galactonic acid) production via a two-step bioprocess.
Cheese whey, produced from coagulation of milk during cheese manufacture, is a major environmental pollutant. The most abundant component in cheese whey is lactose, which is a potential resource for various value-added chemicals. Here, a two-step bioprocess using Saccharomyces cerevisiae and Gluconobacter oxydans to bioconvert cheese whey into ethanol and galactonic acid was first proposed. First, the lactose in cheese whey powder was pretreated with β-galactosidase to obtain glucose and galactose. Subsequently, the glucose was selectively fermented to ethanol by S. cerevisiae to enable G. oxydans-mediated biooxidation of galactose to galactonic acid. Finally, approximately 110 g ethanol, 320 g galactonate, and 150 g mixed protein (residual cheese whey protein and cell protein) was produced from 1 kg CWP. These results are suggestive of alternative methods for management of cheese whey, which may reduce its impact on the environment and result in production of value-added biochemicals.


Li3VO4 anchored graphene nanosheets for long-life and high-rate lithium-ion batteries.
Li3VO4 nanoparticles embedded in graphene nanosheets (Li3VO4@GNS) were obtained using a sol-gel method. The composite presents excellent high-rate performance with a stable capacity of 133 mA h g(-1) at 50 C and long-life performance with a capacity retention rate of 63.1% after 5000 cycles at 5 C.


Creation of anastomoses between an extracardiac artery and the coronary circulation. Proof that myocardial angiogenesis occurs and can provide nutritional blood flow to the myocardium.
The purpose of this investigation was to determine whether blood vessels could develop de novo between an extracardiac artery and a collateral-dependent zone of the heart and to quantify the nutritive blood flow afforded by the new vessels. We also adapted the preparation so that angiogenically active agents could be chronically administered directly to the site of neovascularization in subsequent studies. To induce neovascularization between a systemic artery and the coronary circulation, the left internal mammary artery (IMA) was implanted in an intramyocardial tunnel in proximity to the left anterior descending coronary artery (LAD). A tube situated in the distal IMA connected to an implanted pump provided for continuous intra-arterial infusion at the site of angiogenesis. During the same procedure, an ameroid constrictor was placed on the proximal LAD, rendering its perfusion territory collateral dependent during a 2-3 week period. After 8 weeks, the functional capacity of the anastomoses established between the implanted IMA and the LAD territory was assessed by determining regional myocardial blood flow under basal conditions, during adenosine-induced vasodilatation, and during differential occlusions of the IMA and left circumflex coronary artery (LCCA). For all dogs, IMA occlusion decreased maximal LAD territory flow from 1.31 +/- 0.11 to 1.16 +/- 0.10 ml/min/g (p less than 0.005). Occlusion of the LCCA decreased LAD zone flow to 0.73 +/- 0.12 ml/min/g, whereas occlusion of the IMA in addition to the LCCA further decreased LAD zone flow to 0.42 +/- 0.11 ml/min/g (p less than 0.02). The IMA provided measurable nutritive blood flow in seven of 12 dogs, and in these dogs, the artery provided 30.0 +/- 2.5% of total LAD zone collateral conductance under conditions of maximal vasodilatation (range, 23-42%). We conclude that angiogenesis can occur between an implanted internal mammary artery and the native coronary circulation in dogs, providing modest nutritive blood flow to a collateral-dependent region. Further studies will be necessary to determine whether direct, local infusion of angiogenically active factors can enhance neovascularization and whether sufficient flow can be reliably supplied to make some variant of this approach clinically applicable.


Design and development of an expert system to assist diagnosis and treatment of chronic hepatitis using traditional Chinese medicine.
The treatment of chronic hepatitis with traditional Chinese medicine shows good therapeutic effectiveness in clinical practice. Since the process for the diagnosis in Chinese medicine is quite different from that of modern Western medicine, many physicians of modern medicine cannot practise it readily and effectively. We describe an expert system designed to support physicians who may not be familiar with the domain of traditional Chinese medicine, to treat chronic hepatitis by using Chinese medicine. This system was developed by logic programming language PROLOG, where the knowledge of Chinese medicine is represented in a semantic network structure and the reasoning strategy is based on the hypothesize-and-test approach. This system can guide the user to collect patient information easily, and based on those items of information this leads to the possible diagnosis and treatment for chronic hepatitis using Chinese medicine. The results of this system are compared with 40 patient case records and analysed by a specialist in Chinese medicine.


The relationship between disease severity, disability and psychological distress in patients undergoing PUVA treatment for psoriasis.
Patients suffering from severe psoriasis report high levels of personal distress and disability as a result of their disease. The purpose of this study was to examine the relationship between disease severity, personal distress and disability. Twenty-two patients provided a self-rating of disease severity and completed the Psoriasis Disability Index (PDI) and the General Health Questionnaire (GHQ). A dermatologist provided a clinical assessment from the case notes. Although the clinical assessment was not related to patient ratings, patient-rated severity scores, GHQ and PDI were correlated with each other. GHQ could only be predicted by disease severity when it was mediated by PDI scores. These results indicated that psoriasis affects psychological distress through its effects on the patients' everyday lives.


Geotrichum capitatum fungemia with skin lesions similar to varicella in a patient with acute lymphocytic leukemia.
Varicella-zoster virus (VZV) can cause increased morbidity and mortality in immunocompromised persons. Varicella lesions (macules, papules and vesicles) often appear first on the scalp, face or trunk. We report the case of a leukemic patient who developed multiple maculopapular rashes with central vesicles after chemotherapy. The skin lesions were first noted on the scalp, face and then trunk and extremities. These manifestations were similar to those caused by VZV. Both blood culture and skin vesicle fluid culture yielded Geotrichum capitatum, which is a thermotolerant, yeast-like fungus that forms on culture cream-colored wrinkled colonies. Serology study and throat swab culture for VZV were negative. This case raises the possibility that fungal infection can manifest chickenpox-like skin lesions in immunocompromised patients.


The role of phospholipase in mitochondrial dysfunction after coronary reperfusion in the canine myocardium.
The left anterior descending coronary artery of a dog was occluded for 15 min followed by a 5 min reperfusion in order to investigate the mechanism responsible for the paradoxical exacerbation of heart mitochondrial dysfunction caused by reperfusion. The mitochondrial function was assessed and the concentration of Ca++, phospholipids and free fatty acids (FFA) were determined. The relative importance of mitochondrial lysophospholipids was also investigated. Eleven dogs (30.6%) developed "reperfusion arrhythmia" (arrhythmia group) but 25 did not (control group). Although mitochondrial dysfunction was observed in the reperfused area even in the control group, a greater impairment of mitochondrial function was observed in the reperfused area in the arrhythmia group. There was no significant difference in the contents of FFA and phospholipids in the mitochondria from the normal area of both groups and from the reperfused area of the control group. However, a marked increase in eight FFA and a significant decrease in phospholipids were observed in the mitochondria from the reperfused area of the arrhythmia group. A significant increase in Ca++ content both in the myocardium and the mitochondria from the reperfused area was observed in the arrhythmia group but not in the control group. In separate experiments, the mitochondria prepared from dog left ventricle were incubated with either phospholipase C (PhC) or phospholipase A2 ( PhA2 ). Both phospholipases induced severe mitochondrial dysfunction. PhC induced a significant increase in FFA, quite analogous to the changes in mitochondrial FFA caused by reperfusion in vivo. PhA2 also induced a tremendous increase in FFA but only in the content of unsaturated FFA. Although PhC did not affect the lysophospholipid profiles, PhA2 induced lysophosphatidyl choline. These results indicate that mitochondrial damages characteristic of the early phase of coronary reperfusion may be caused by the action of PhC, activated by increased intracellular Ca++, which in turn induces degradation of the mitochondrial membrane.


Electrical, enzymatic graphene biosensing of 5-aminosalicylic acid.
We present an electrical biosensing of 5-aminosalicylic acid (5-ASA) based on a peroxidase-immobilized graphene sensor on a microfluidic paper. The sensor shows a sensitive detection range from 0.5 to 20 μM and a total measuring time of 2 min with a simple fabrication procedure.


Design and Evaluation of Passive Shoulder Joint Tracking Module for Upper-Limb Rehabilitation Robots.
As the number of people suffering from shoulder movement disabilities increases, there is a rising demand for shoulder rehabilitation. The natural motion of the shoulder joint [glenohumeral (GH) joint] includes not only three-degrees-of-freedom (DOF) rotation but also three-DOF translation of the joint center due to simultaneous motion of the shoulder girdle. If the motion of the shoulder girdle is restricted, then the arm cannot be raised above a certain posture. This paper presents a passive shoulder joint tracking device that allows three-DOF translation of the shoulder joint while compensating for gravity. The single-DOF vertical tracker with a constant-force spring compensates for the gross weight of the user's arm, the upper limb rehabilitation device, and the tracker itself while allowing vertical tracking motion. The two-DOF horizontal tracker consists of two linear guides arranged perpendicular to each other. The tracker freely follows the shoulder joint in the horizontal plane. The effect of using the passive shoulder joint tracking device was evaluated by means of experiments by combining two popular commercial upper limb rehabilitation apparatuses with the proposed tracker. Nineteen subjects (8 healthy persons and 11 patients with shoulder impairments) participated in the evaluation study. The movement of the GH joint and the interactive force between the subject and the commercial rehabilitation device were analyzed when subjects made the following shoulder movements: flexion/extension and abduction/adduction. The improved tracker allowed a greater range of motion and reduced interaction. The tracker can be combined with existing commercial rehabilitation devices for more natural shoulder movement during rehabilitation tasks.


Adult health screening and referral in the emergency department.
The United States Public Health Service (USPHS) recommends using all available patient encounters to provide preventive healthcare to patients. Many studies have demonstrated the importance of performing preventive care in the emergency department (ED). These studies have used the ED as a location for patient identification and treatment, rather than as a referral site. The primary objective of this study was to identify and refer patients with unmet healthcare needs seen in the Emergency Department. A secondary objective was to determine if the patient would accept health referrals and follow-up with a doctor or clinic. Age and gender-specific algorithms were developed from the USPHS Clinicians' Book of Preventative Health, Second Edition. A convenience sample of patients who presented to the emergency department was asked to participate in the study to obtain 50 subjects in each age and gender grouping. After one week the patients were followed up by telephone, and after one month the computer database was queried to confirm that an appointment had been made with a doctor or clinic as recommended. Three hundred and twelve patients in the Emergency Department were enrolled in the study. The demographic profile of the patients surveyed consisted of 152 (48.7%) African Americans, 81 (26.0%) Hispanics, and 12 (3.8%) Caucasians. Of those enrolled, 59.9% had a primary care physician, and 78.2% had insurance coverage. The study revealed that 28.8% of the subjects did not need a referral, 51.3% needed 1 to 3 referrals, and 19.9% needed 4 to 8 referrals. The most common needs were for tetanus immunizations (41.2%) and stool for occult blood (41.0%); the least common was for Pap smears (2.6%) and blood pressure (2.0%). Most patients accepted the referrals (88.3%), but only a fourth of those (22.6%) reported making a follow-up appointment. The appointment was confirmed in the computer system in 39.6% of the cases. The highest rate of follow-up was for prostate screening (41.4%); the least was for drug abuse (0.0%). Most of the patients in this study were found to have unmet healthcare needs. Many of the patients were given referrals and followed up with the clinic or physician for the healthcare problems identified. This study reinforces the value of the USPHS guideline to use all available patient encounters for preventive healthcare.


Physicochemical Parameters Affecting the Electrospray Ionization Efficiency of Amino Acids after Acylation.
Electrospray ionization (ESI) is widely used in liquid chromatography coupled to mass spectrometry (LC-MS) for the analysis of biomolecules. However, the ESI process is still not completely understood, and it is often a matter of trial and error to enhance ESI efficiency and, hence, the response of a given set of compounds. In this work we performed a systematic study of the ESI response of 14 amino acids that were acylated with organic acid anhydrides of increasing chain length and with poly(ethylene glycol) (PEG) changing certain physicochemical properties in a predictable manner. By comparing the ESI response of 70 derivatives, we found that there was a strong correlation between the calculated molecular volume and the ESI response, while correlation with hydrophobicity (log P values), pKa, and the inverse calculated surface tension was significantly lower although still present, especially for individual derivatized amino acids with increasing acyl chain lengths. Acylation with PEG containing five ethylene glycol units led to the largest gain in ESI response. This response was maximal independent of the calculated physicochemical properties or the type of amino acid. Since no actual physicochemical data is available for most derivatized compounds, the responses were also used as input for a quantitative structure-property relationship (QSPR) model to find the best physicochemical descriptors relating to the ESI response from molecular structures using the amino acids and their derivatives as a reference set. A topological descriptor related to molecular size (SPAN) was isolated next to a descriptor related to the atomic composition and structural groups (BIC0). The validity of the model was checked with a test set of 43 additional compounds that were unrelated to amino acids. While prediction was generally good (R2 > 0.9), compounds containing halogen atoms or nitro groups gave a lower predicted ESI response.


Two acyl-CoA dehydrogenases of Acinetobacter sp. strain M-1 that uses very long-chain n-alkanes.
Two genes encoding acyl-CoA dehydrogenases, acdA and acdB, arranged in tandem, were found in the chromosomal DNA of Acinetobacter sp. strain M-1. AcdA was purified from the parental strain and AcdB was purified from an Escherichia coli strain expressing the cloned gene. The substrate specificities of the two enzymes suggest that AcdA is a medium-chain acyl-CoA dehydrogenase and that AcdB is a long-chain acyl-CoA dehydrogenase. Characterization of n-alkane metabolism in Acinetobacter sp. strain M-1 has revealed parallel pathways as well as enzymes with overlapping specificities in a single pathway. The two acyl-CoA dehydrogenases described here provide another example of the physiological complexity underlying n-alkane utilization.


Separation of Four Phenylpropanoid Glycosides from a Chinese Herb by HSCCC.
Four phenylpropanoid glycosides (PPGs), such as echinacoside, wiedemannioside C, forsythoside B and verbascoside, were isolated and purified from the Tibetan medicinal herb Pedicularis longiflora Rudolph. var. tubiformis (Klotz) Tsoong by high-speed counter-current chromatography (HSCCC) combined with macroporous resin (MR) column separation for the first time. In the present study, the two-phase solvent system composed of ethyl acetate-n-butanol-water (10 : 6:15, v/v/v) was used for HSCCC separation. A total of 3.5 mg of echinacoside, 12.6 mg of wiedemannioside C, 22.7 mg of forsythoside B and 48.7 mg of verbascoside with the purity of 93.6, 97.9, 97.8 and 98.1%, respectively, were obtained from 120 mg of crude sample. The HSCCC fractions were analyzed by HPLC, and the chemical structures were identified by (1)H NMR and (13)C NMR. The results demonstrate that MR coupled with HSCCC is a powerful technique for separation of PPGs from natural products.


[Measurement of thallium content in human urine by atomic absorption spectrometry after acute poisoning].
The problem of poisoning with thallium-containing substances continues to be of current concern. According to the Bureau of Forensic Medical Examination, Moscow, specimens of biological materials from more than 20 victims of such poisoning were delivered for analysis in 2006. The total number of thallium poisoning episodes during the period since 1996 exceeded 50. Materials for thallium determination in biological fluids (human blood and urine) using flame atomic absorption spectrometry were prepared by dry mineralization of accurately weighed samples; acidic solutions of the products of mineralization were used for analysis. Due to peculiar kinetic features of thallium ion absorption in the gastro-intestinal tract, blood could not be used as a biological marker of poisoning. The level of thallium in urine samples was found to vary from 1.00 to 4,600 mcg/l (with the estimation of confidence intervals in each case). Results of chemical analysis correlated with pathological symptoms derived from the patients' discharge summaries and literature reports on dose-effect relationships. Based on these findings, practically all the examined cases were characterized as severe acute poisoning.


Nucleic Acid Architectonics for pH-Responsive DNA Systems and Devices.
Nucleic acid-based architectures have opened up numerous opportunities for basic and applied research in the field of DNA nanotechnology. The scheme of molecular architectonics of nucleic acids exploits conventional and unconventional base pairing interactions to integrate molecular partners in constructing functional molecular architectures and devices. The pH-responsive functional nucleic acid systems and devices have gained interest in diagnostics and therapeutics because of their biocompatibility and structural programmability. In this Mini-Review, we discuss recent advancements in the area of nucleic acid architectonics with a special emphasis on pH-driven molecular systems including molecular and nanoarchitectures, templated architectures and nanoclusters, nanomachines, hydrogels, targeted bioimaging, and drug delivery architectures. Finally, the Mini-Review is concluded by highlighting the challenges and opportunities for future developments.


Noninvasive Ultrasound Retinal Stimulation for Vision Restoration at High Spatiotemporal Resolution.
Objective. Retinal degeneration involving progressive deterioration and loss of function of photoreceptors is a major cause of permanent vision loss worldwide. Strategies to treat these incurable conditions incorporate retinal prostheses via electrically stimulating surviving retinal neurons with implanted devices in the eye, optogenetic therapy, and sonogenetic therapy. Existing challenges of these strategies include invasive manner, complex implantation surgeries, and risky gene therapy. Methods and Results. Here, we show that direct ultrasound stimulation on the retina can evoke neuron activities from the visual centers including the superior colliculus and the primary visual cortex (V1), in either normal-sighted or retinal degenerated blind rats in vivo. The neuron activities induced by the customized spherically focused 3.1 MHz ultrasound transducer have shown both good spatial resolution of 250 μm and temporal resolution of 5 Hz in the rat visual centers. An additional customized 4.4 MHz helical transducer was further implemented to generate a static stimulation pattern of letter forms. Conclusion. Our findings demonstrate that ultrasound stimulation of the retina in vivo is a safe and effective approach with high spatiotemporal resolution, indicating a promising future of ultrasound stimulation as a novel and noninvasive visual prosthesis for translational applications in blind patients.


Colloidal Quantum Dot Inks for Single-Step-Fabricated Field-Effect Transistors: The Importance of Postdeposition Ligand Removal.
Colloidal quantum dots are a class of solution-processed semiconductors with good prospects for photovoltaic and optoelectronic applications. Removal of the surfactant, so-called ligand exchange, is a crucial step in making the solid films conductive, but performing it in solid state introduces surface defects and cracks in the films. Hence, the formation of thick, device-grade films have only been possible through layer-by-layer processing, limiting the technological interest for quantum dot solids. Solution-phase ligand exchange before the deposition allows for the direct deposition of thick, homogeneous films suitable for device applications. In this work, fabrication of field-effect transistors in a single step is reported using blade-coating, an upscalable, industrially relevant technique. Most importantly, a postdeposition washing step results in device properties comparable to the best layer-by-layer processed devices, opening the way for large-scale fabrication and further interest from the research community.


The intestinal epithelial cell: immunological aspects.
IECs likely play an important role in immunological defense mechanism. Apart from being a passive barrier against luminal bacteria, IECs secrete protective and microbiocidal products such as ITF, complement components and cryptdins into the lumen. Moreover, IECs produce secretory component that is essential for the transport of IgA from the lamina propria into the lumen. IECs also have regulatory functions. They express adhesion molecules important in the homing of T cells and other leukocytes, and likely modulate T cell functions in a paracrine way. Furthermore, IECs secrete cytokines, either constitutively or after bacterial challenge, and they express cytokine receptors. Lastly, IECs may play an important role as non-professional antigen-presenting cells by expressing classical MHC class I and class II and nonclassical MHC class I molecules on the cell surface. This aspect is particularly intriguing in that IECs also express a FcR that may have a function in luminal antigen sampling.


Hepatocellular Adenoma in an Infant With Burn-McKeown Syndrome: Report of a Case.
Hepatocellular adenomas (HCA) in infants are exceedingly rare with only 5 cases reported to the best of our knowledge, all of them preceding the classification of HCA. Here we present an autopsy case of a 9-month-old girl with Burn-McKeown syndrome with an incidental liver nodule in the right lobe measuring 1.5 cm in greatest dimension. The lesion was composed of an unencapsulated proliferation of hepatocytes with multiple unaccompanied arteries without well-formed portal tracts, and an intact reticulin framework without thickened hepatic plates, findings consistent with an HCA. Glutamine synthetase (GS), lipid fatty acid-binding protein (LFABP), c-reactive protein (CRP), serum amyloid-a (SAA), beta-catenin and CD34 immunostains were performed. GS was diffusely and strongly positive in the lesion, CD34 showed heterogenous staining of sinusoids within the lesion without a well-formed rim from the background liver and beta-catenin was negative for nuclear staining. CRP and SAA were considered negative, and LFABP was retained. Molecular testing showed no CTNNB1 variants and found two tier 3 variants involving CHEK2 and PTEN genes. These findings are consistent with an unclassified HCA (U-HCA) per the 2019 WHO Classification of Tumors, representing the youngest patient reported. This raises the possibility that some HCAs are congenital or develop very early in life, remaining undiagnosed until later in life.


Meeting Code Blue Requirements Using a Team-Based Simulation.
Immediate high-quality cardiopulmonary resuscitation (CPR) and early defibrillation are essential to survival, yet CPR skills deteriorate without frequent repetition. Basic Life Support-focused Code Blue team-based simulation is needed in continuing education to bridge this gap. This article outlines a teaching plan for hospital orientation and subsequent scenarios to improve the resuscitation response. [J Contin Educ Nurs. 2020;51(5):205-208.].


Divalent cation induced re-entrant condensation behavior for lipopolysaccharides.
Lipopolysaccharides (LPSs) are negatively charged molecules covering the surface of Gram-negative bacteria (GNB). Adding divalent cations (DCs) is important to stabilize the LPS bilayer. Thus, DCs are always only considered as membrane stabilizing ions. Here, on the basis of a coarse-grained (CG) Martini force field, we conduct molecular dynamic (MD) simulations to study the divalent cation mediated LPS interaction and the stability of the LPS membrane in a wide range of DC concentrations. By measuring the LPS binding free energy and the LPS-LPS aggregate from the association course between two LPS molecules, we find that the initial addition of DCs may significantly facilitate the aggregation of LPSs into a compact structure, while sequentially adding more DCs only unpacks the LPS aggregate and drives the dissolution of LPSs. With an increasing concentration of DCs, we find a gradual replacement of DCs to monovalent cations as condensed counterions on the LPS, which follows a sign change from negative to positive in terms of the LPS effective charge and a switch of LPSs in solution from undergoing precipitation to resolubilization on adding DCs. This interaction change in the level of two LPSs accounts for the structure variation of the LPS assembly on a larger scale, where the LPS packing rigidity in the assembly bilayer is found with a similar nonmonotonic dependence with the DC concentration. Thus, our results demonstrate for the first time the presence of a re-entrant condensation behavior for LPS molecules, which can be exploited for developing novel membrane-perturbing agents based on multivalent ions as efficient GNB antibiotics.